Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor)

Found these articles intriguing.
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Dr. med. Heinrich Kremer (Barcelona 2004)
The secret of cancer: "short-circuit" in the photon switch
Change in the medical world-view of tumorology - The rational Cell Symbiosis Therapy concept

http://ummafrapp.de/krebs/Kremer/kremer_the_secret_of_cancer.html

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According to Wikipedia, dichloroacetate decreases lactate production by shifting the metabolism of pyruvate from glycolysis towards oxidation in the mitochondria. That is the reason the substance has been used to treat lactic acidosis. Its use in cancer has only recently been pioneered and the University of Alberta researchers caution that more trials are needed, before DCA can be recommended as an anti-tumor agent.

It is against this background that we should see the discovery of Heinrich Kremer, MD, a German medical doctor who is perhaps best known for his unconventional views on AIDS. Kremer says that the current view, according to which the mitochondria's normal energy production pathway is based on chemical oxidation does not go deep enough to allow an understanding of the underlying mechanisms of cancer.

Kremer's discovery is described in his book The Silent Revolution in Cancer and AIDS, which is available here in English: http://aliveandwellsf.org/kremer/book.html and here in Italian. (site is dead - Cr6)

The new view on cancer is explained in detail in an article titled The Secret of Cancer: Short-circuit in the Photon Switch, due for publication shortly. I will link it here as soon as it becomes available. Meanwhile, here is a sneak preview.

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Cancer and ATP: The Photon Energy Pathway

(for the full article, we must await publication in the July issue of Townsend Letter for Doctors)

Although the mutation theory of oncogenesis is generally accepted today, it does not explain how cancer cells seemingly are able to evade all the body's normal mechanisms that prevent and correct such mutations, and how they can invade and metastasize in different tissues from those that are primarily concerned.

Consequently, our standard therapies, which are based on the assumption that the deviated cells must be destroyed and which attempt to do so by a slash, burn and poison approach operated by the surgeon, the radiologist and the oncologist, are of little use in prolonging the patient's life or effecting real cures.


Evolution

To understand the new concept of oncogenesis, we must take a look at the evolution of cells and organisms. Cells as present in today's organisms are the result of a fusion, in prehistoric times, of two different types of unicellular life forms into a unique symbiotic combination. A type of cell of the archaea family and another type of the bacteria family entered into symbiosis and formed what is now known as a protist. The cells of mammals including humans today contain genes from both original families. The bacterial symbionts have evolved into the mitochondria which are delegated to take care of energy production.


ATP Energy Pathways

In cancer, the bacterial symbionts go on strike - they refuse to produce any more of the ATP energy molecules they are normally busy churning out all day. The cells thus have to revert to an alternate mode of energy production (glycolysis) which involves fermentation of sugars. This is very much more inefficient than the normal cellular energy mechanism.

But more importantly, and here comes Kremer's very interesting discovery, the normal mode of energy production is not a pure chemical energy pathway. ATP (adenosine triphosphate) is made up of three molecule groups. A base adenine ring that absorbs light quanta in the near ultraviolet band of 270 nanometer wavelength, one sugar molecule and a molecular string with three phosphate groups.

The currently accepted view is that energy production and storage in ATP is by means of chemical energy, stored in the phosphate bonds. The bond energy is then released by hydrolysis in the cytoplasm, where it is used to drive energetic and metabolic processes. Not so, says Kremer. Hydrolysis only yields heat energy, which is not sufficient to drive all the various cell processes. The secret lies in the adenine groups of ATP which absorb photons, but the role of adenine is not adequately explained in the prevailing hypothesis.

The essential components of mitochondrial cell respiration are light absorbing molecules that react to frequencies from the near ultraviolet band down to the yellow/orange spectral range of visible light. Yet, the source of energy for these cellular power plants is not sunlight, as one might easily be led to assume. The flow of para-magnetically aligned electrons in the respiratory organelles gives rise to a low frequency pulsating electromagnetic field which, enormously accelerated through catalytic processes activated by enzymes, in turn activates a spin-mediated information and energy transfer from the physical vacuum, the zero point field, to the biological entity. Consequently, the human organism isn't governed by heat transfer but by a light frequency modulated energy transformation from space background or physical vacuum to the living organism.

Cancer is a result of the disturbance of the enzyme mediated transformation of that energy. The affected cells lose their ability to communicate with other cells around them and they change not only their way of making energy but they become - for all practical purposes - separate unicellular entities that must divide and form a colony to survive. That colony is what we then see as the tumor, the visible manifestation of cancer.

The exact mechanism of that transformation and how the disturbance, once active, feeds back to cause these changes in the cancer cells, is explained - it is a rather technical subject - in Kremer's paper. We will have to wait for its publication to get the whole story.


Curcumin

In the meantime, however, we can say that curcumin, a natural substance in the family of polyphenols contained in turmeric root or curcuma longa and used as a natural coloring agent and a spice, has been found to be beneficial to cancer patients in research at the Anderson Cancer Research Center. See Can a Common Spice Be Used to Treat Cancer?.

Kremer explains that the anti-cancer properties of curcumin are a consequence of its ability to absorb photons in the violet spectral range of visible light at a wavelength of 415 nanometers. This particular property of the healthy spice is what enables it to bridge the broken pathway of photonic energy production and information transfer, thus bringing the affected cells back into the fold, to make them once more function as parts of the organism.

While, admittedly, more research is needed, the pioneering efforts of Kremer will go a long way to point us in the right direction. I hope I was able to stimulate some interest in that new discovery and that you, my readers, are as eagerly awaiting publication of Kremer's research article and book in English as I am.

Watch here for links as soon as they become available.


Meanwhile, there is news that microwaves - as used in mobile telephony - drastically increase the risk of certain cancers. See Cancer Risks from Microwaves Confirmed.

http://www.newmediaexplorer.org/sepp/2007/05/23/cancer_and_atp_the_photon_energy_pathway.htm

Also:
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https://medicalxpress.com/news/2007-06-alternative-theory-cancer.html


The metabolic advantage of tumor cells

Maurice Israël1Email author and Laurent Schwartz2

Molecular Cancer
201110:70

https://doi.org/10.1186/1476-4598-10-70

Israël and Schwartz; licensee BioMed Central Ltd. 2011
Received: 7 March 2011
Accepted: 7 June 2011
Published: 7 June 2011

Abstract

1-Oncogenes express proteins of "Tyrosine kinase receptor pathways", a receptor family including insulin or IGF-Growth Hormone receptors. Other oncogenes alter the PP2A phosphatase brake over these kinases.
2-Experiments on pancreatectomized animals; treated with pure insulin or total pancreatic extracts, showed that choline in the extract, preserved them from hepatomas.
Since choline is a methyle donor, and since methylation regulates PP2A, the choline protection may result from PP2A methylation, which then attenuates kinases.
3-Moreover, kinases activated by the boosted signaling pathway inactivate pyruvate kinase and pyruvate dehydrogenase. In addition, demethylated PP2A would no longer dephosphorylate these enzymes. A "bottleneck" between glycolysis and the oxidative-citrate cycle interrupts the glycolytic pyruvate supply now provided via proteolysis and alanine transamination. This pyruvate forms lactate (Warburg effect) and NAD+ for glycolysis. Lipolysis and fatty acids provide acetyl CoA; the citrate condensation increases, unusual oxaloacetate sources are available. ATP citrate lyase follows, supporting aberrant transaminations with glutaminolysis and tumor lipogenesis. Truncated urea cycles, increased polyamine synthesis, consume the methyl donor SAM favoring carcinogenesis.
4-The decrease of butyrate, a histone deacetylase inhibitor, elicits epigenic changes (PETEN, P53, IGFBP decrease; hexokinase, fetal-genes-M2, increase)
5-IGFBP stops binding the IGF - IGFR complex, it is perhaps no longer inherited by a single mitotic daughter cell; leading to two daughter cells with a mitotic capability.
6-An excess of IGF induces a decrease of the major histocompatibility complex MHC1, Natural killer lymphocytes should eliminate such cells that start the tumor, unless the fever prostaglandin PGE2 or inflammation, inhibit them...

https://molecular-cancer.biomedcentral.com/articles/10.1186/1476-4598-10-70


The Figure 1 shows how tumors bypass the PK and PDH bottlenecks and evidently, the increase of glucose influx above the bottleneck, favors the supply of substrates to the pentose shunt, as pentose is needed for synthesizing ribonucleotides, RNA and DNA. The Figure 1 represents the stop below the citrate condensation. Hence, citrate quits the mitochondria to give via ATP citrate lyase, acetyl CoA and OAA in the cytosol of tumor cells. Acetyl CoA supports the synthesis of fatty acids and the formation of triglycerides. The other product of the ATP citrate lyase reaction, OAA, drives the transaminase cascade (ALAT and GOT transaminases) in a direction that consumes GLU and glutamine and converts in fine alanine into pyruvate and lactate plus NAD+. This consumes protein body stores that provide amino acids and much alanine (like in starvation). The Figure 1 indicates that malate dehydrogenase is a source of NAD+ converting OAA into malate, which backs-up LDH. Part of the malate converts to pyruvate (malic enzyme) and processed by LDH. Moreover, malate enters in mitochondria via the shuttle and gives back OAA to feed the citrate condensation. Glutamine will also provide amino groups for the "de novo" synthesis of purine and pyrimidine bases particularly needed by tumor cells. The Figure 1 indicates that ASP shuttled out of the mitochondrial, joins the ASP formed by cytosolic transaminases, to feed the synthesis of pyrimidine bases via ASP transcarbamylase, a process also enhanced in tumor cells. In tumors, this silences the argininosuccinate synthetase step of the urea cycle [18–20]. This blockade also limits the supply of fumarate to the Krebs cycle. The latter, utilizes the α ketoglutarate provided by the transaminase reaction, since α ketoglutarate coming via aconitase slows down. Indeed, NO and peroxynitrite increase in tumors and probably block aconitase. The Figure 1 indicates the cleavage of arginine into urea and ornithine. In tumors, the ornithine production increases, following the polyamine pathway. Ornithine is decarboxylated into putrescine by ornithine decarboxylase, then it captures the backbone of S adenosyl methionine (SAM) to form polyamines spermine then spermidine, the enzyme controlling the process is SAM decarboxylase. The other reaction product, 5-methlthioribose is then decomposed into methylthioribose and adenine, providing purine bases to the tumor. We shall analyze below the role of SAM in the carcinogenic mechanism, its destruction aggravates the process.

http://media.springernature.com/lw785/springer-static/image/art%3A10.1186%2F1476-4598-10-70/MediaObjects/12943_2011_Article_890_Fig1_HTML.jpg

Figure 1

Cancer metabolism. Glycolysis is elevated in tumors, but a pyruvate kinase (PK) "bottleneck" interrupts phosphoenol pyruvate (PEP) to pyruvate conversion. Thus, alanine following muscle proteolysis transaminates to pyruvate, feeding lactate dehydrogenase, converting pyruvate to lactate, (Warburg effect) and NAD+ required for glycolysis. Cytosolic malate dehydrogenase also provides NAD+ (in OAA to MAL direction). Malate moves through the shuttle giving back OAA in the mitochondria. Below the PK-bottleneck, pyruvate dehydrogenase (PDH) is phosphorylated (second bottleneck). However, citrate condensation increases: acetyl-CoA, will thus come from fatty acids β-oxydation and lipolysis, while OAA sources are via PEP carboxy kinase, and malate dehydrogenase, (pyruvate carboxylase is inactive). Citrate quits the mitochondria, (note interrupted Krebs cycle). In the cytosol, ATPcitrate lyase cleaves citrate into acetyl CoA and OAA. Acetyl CoA will make fatty acids-triglycerides. Above all, OAA pushes transaminases in a direction usually associated to gluconeogenesis! This consumes protein stores, providing alanine (ALA); like glutamine, it is essential for tumors. The transaminases output is aspartate (ASP) it joins with ASP from the shuttle and feeds ASP transcarbamylase, starting pyrimidine synthesis. ASP in not processed by argininosuccinate synthetase, which is blocked, interrupting the urea cycle. Arginine gives ornithine via arginase, ornithine is decarboxylated into putrescine by ornithine decarboxylase. Putrescine and SAM form polyamines (spermine spermidine) via SAM decarboxylase. The other product 5-methylthioadenosine provides adenine. Arginine deprivation should affect tumors. The SAM destruction impairs methylations, particularly of PP2A, removing the "signaling kinase brake", PP2A also fails to dephosphorylate PK and PDH, forming the "bottlenecks". (Black arrows = interrupted pathways).

In summary, it is like if the mechanism switching from gluconeogenesis to glycolysis was jammed in tumors, PK and PDH are at rest, like for gluconeogenesis, but citrate synthase is on. Thus, citric acid condensation pulls the glucose flux in the glycolytic direction, which needs NAD+; it will come from the pyruvate to lactate conversion by lactate dehydrogenase (LDH) no longer in competition with a quiescent Pcarb. Since the citrate condensation consumes acetyl CoA, ketone bodies do not form; while citrate will support the synthesis of triglycerides via ATP citrate lyase and fatty acid synthesis... The cytosolic OAA drives the transaminases in a direction consuming amino acid. The result of these metabolic changes is that tumors burn glucose while consuming muscle protein and lipid stores of the organism. In a normal physiological situation, one mobilizes stores for making glucose or ketone bodies, but not while burning glucose! Tumor cell metabolism gives them a selective advantage over normal cells. However, one may attack some vulnerable points.

https://molecular-cancer.biomedcentral.com/articles/10.1186/1476-4598-10-70

He mentions of few things like "zero-point"... hmm. Mentions also a Photon Switch.
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Biochemistry and medical science have failed to this day to explain the function of the adenine groups of ATP as no biochemical reaction with this adenine ring molecule is shown. However, an understanding can be gained, within the framework of the cell symbiosis concept, from the biophysical attributes of light absorption of the adenine group. All essential components of mitochondrial cell respiration are light absorbing molecules with characteristic "frequency windows" of absorption maxima from nearly UV spectrum to the longer wave yellow/orange spectral range of visible light up to ca. 600nm. Yet the source of the electromagnetic energy is not sunlight. In fact a low frequency pulsating electromagnetic field is induced by the constant flow of uncoupled, paramagnetic aligned electrons in the respiratory organelles. The electromotive power generated by this process is catalytically enormously strengthened by the enzyme complexes of the respiratory chain (acceleration factor1017). .

This effects an interaction between the electrons and the protons likewise aligned parallel to the induced magnetic field dependent on the strength of the magnetic field between the antiparallel aligned electrons and protons. This process produces a quantum dynamic transfer of information via photon exchange energy. The source of photons is ultimately fluctuations of resonance frequencies of the physical vacuum (zero-point energy field). The transferred information is stored in the spin of the protons that proceed to the ATP synthesis complex via proton gradients. There the resonance information is transferred by a unique rotation system to the adenine group of ATP whose electrons can move freely in the alternating double bonds of the ring molecules. The ATP serves as an "antennae molecule" for the reception and relaying of resonance information from the "morphogenetic background field." Human symbiosis is consequently not a heat power machine but a light frequency modulated information transforming medium. All the time this cell symbiosis is resonance coupled with the lowest not yet materialized energy status (physical vacuum as inexhaustible "global information pool").

   In oncogenesis, for a diversity of reasons, there is a functional disturbance especially to the 4th enzyme complex of the respiratory chain. The task of this complex, according to conventional opinions, is to transfer the inflowing electrons to molecular oxygen at the end of the respiratory chain and thus reduce it to water. In the cell symbiosis concept, however, the crucial factor is that in reducing O² to water completed electron couplings induce an antimagnetic impulse, and the electromagnetic alternating field for resonance information transfer switches on and off at an extremely fast periodic time interval (in picoseconds). If the electron flows to O² , however, are permanently disturbed then a failure in the modulation of ATP occurs and increasing numbers of oxygen and other radicals form that can attack and damage the macromolecules (nucleic acids, proteins, lipids, carbohydrates). In order to prevent this danger the key enzyme hemoxygenase upregulates. This enzyme uses O²  as cofactor for the production of carbon monoxide (CO). In cases of long-term surplus production CO gas has crucial effects on cancer cell transformation:

-CO gas effects a characteristic phase shifting of the absorption of visible light from components of the respiratory chain and as a result "short-circuits" the photon switch for the modulation of the information transfer to the mitochondrial ATP

-CO gas activates in the cytoplasm certain regulator proteins for the stimulation of the cell division cycle also without external growth signals (see above: 1st "acquired capability")

-CO gas effects via enzymatic overactivation of the important secondary messenger substance cyclic guanosin monophosphate (cGMP) the inhibition or blockade of communication between neighboring cells (2nd "acquired capability" of cancer cells)

-CO gas blocks programmed cell death by bonding onto the bivalent iron in important key enzymes (3rd "acquired capability" of cancer cells)

The result is a polar program reversal: The transformed cancer cells remain trapped, dependent on the degree of malignancy, in a continuous cell division cycle and can not switch back to the differentiated cell performances of the respective cell types without biological compensatory aid. According to recent clinical knowledge the cancer cells become especially malign and disperse massive metastatic cells when the O² supply to tumor cells via capillary blood vessels is impeded. In these cases chemotherapy and radiation treatment are no longer effective as without the presence of molecular oxygen programmed cell death of the cancer cells can no longer be induced. In this situation cancer patients are considered incurable by oncologists using standard cancer therapy.

In 2003, American cancer researchers confirmed a functional disruption of cancer cells in the 4th complex of the respiratory chain despite simultaneously intact messenger RNA and intact mitochondrial DNA, without being able to explain this phenomenon. However, at the end of 2002 a cancer research group from Helsinki University, after many years of animal experiments and clinical studies, were able to exactly document for the first time - using electronmicroscopes and mass spectrometers – that the transformation to cancer cells is actually caused by the loss of control of the cell division cycle of the mitochondria. The clinical research team could demonstrate that the tumor cells after a relatively short time had re-programmed to intact, normal differentiated cells without signs of programmed cell death by using a particular experimentally mediated bioimmunological compensation therapy on various human cancer diseases. These patients under conventional tumor therapy had a survival status of on average less than 12 months. In 2003 researchers from the Anderson Cancer Research Center of the University of Texas in Houston published the first wide-ranging overview about the hundreds of animal experiments on the effects of curcumin, the active ingredient of turmeric (Curcuma Longa, from the ginger family, biochemically, curcumin I from the molecular family of polyphenols, also termed bioflavonoids, synthesized from plants) on cancer cells and metastases. The researchers were amazed to discover that curcumin effectively inhibited nearly all signal paths in tumor cells and metastases. The researchers were unable to provide an explanation to this wide-ranging effect. The actions of curcumin can, however, be explained if you know that curcumin in the violet spectral range of visible light absorbs with nearly the same wavelength - 415 nm - as the electron-transferring molecule cytochrome c that is more rapidly broken up by the protective enzyme hemoxygenase in cancer cells. In cancer cells curcumin, so to say, bridges the III and IV complex photon switch “short-circuit” of the respiratory chain in mitochondria and thus normalizes the information transfer for maintaining modulation of ATP. The quoted research data show that (in opposition to the prevailing cancer theories of supposedly irreparable gene defects in the nucleus) the demonstrated functional disruptions of the transfer of information in cell symbionts can be re-normalized by means of an adequate biological compensation therapy. The concept of cell symbiosis therapy (Kremer 2001) derived from knowledge gained from cell symbiosis research has in the meantime led to spectacular therapeutic successes (in individual cases even in cancer diseases that had been declared incurable). There is a broad spectrum of classes of substances responding to natural light available and the potential is by no means exhausted. What is desperately needed, however, is a comprehensive overhaul of the current state of research with the aim of developing optimized therapeutic formulations and to make them available for clinical and therapeutic practice. Admittedly, achieving this purpose through an interdisciplinary research group within the established health system is not to be expected in the foreseeable future, as conventional medical science has largely remained stuck in the one-sided thermodynamic energy concepts of the 19th Century.

http://ummafrapp.de/krebs/Kremer/kremer_the_secret_of_cancer.html

The flow of para-magnetically aligned electrons in the respiratory organelles gives rise to a low frequency pulsating electromagnetic field which, enormously accelerated through catalytic processes activated by enzymes, in turn activates a spin-mediated information and energy transfer from the physical vacuum, the zero point field, to the biological entity. Consequently, the human organism isn't governed by heat transfer but by a light frequency modulated energy transformation from space background or physical vacuum to the living organism.

There is no zero-point energy or borrowing from the vacuum. We can assume all charge input is based on Mathis's principles and theories, since he's the only one so far who's ever really proposed or outlined them. Even the cells themselves experience charge recycling.

Researchers develop new dichloroacetate formulation for cancer treatment
April 16, 2014 by Jessica Luton, University of Georgia

Shanta Dhar, right, and Sean Marrache

Health forums were abuzz in 2007 with news that a simple, inexpensive chemical may serve as a viable treatment to many forms of cancer. The drug dichloroacetate, or DCA, was touted as a cure-all, but after years of work, scientists are still searching for ways to make the unique treatment as effective as possible.

Now, researchers at the University of Georgia have discovered a new way to deliver this drug that may one day make it a viable treatment for numerous forms of cancer. They published their findings in the American Chemical Society's journal ACS Chemical Biology.

"DCA shows great promise as a potential cancer treatment, but the drug doesn't find and attack cancer cells very efficiently in the doses researchers are testing," said Shanta Dhar, an assistant professor of chemistry in the UGA Franklin College of Arts and Sciences. "We have developed a new compound based on DCA that is three orders of magnitude more potent than standard treatments."

Every cell in the body needs energy to divide and grow, and most of them do this by breaking down sugar. When cells misbehave, they are normally deprived of their food and die in a process called apoptosis.

Cancerous cells, however, find a way around the natural order by discovering other sources of energy. Dhar's technology, which she calls Mito-DCA, destroys the cancer by focusing on a part of the cell called mitochondria, commonly known as the powerhouse of cells because they generate most of the cell's chemical energy.

"By targeting the mitochondria, we can force cancerous cells to die just as regular malfunctioning cells would," said Dhar, who is part of the UGA Cancer Center. "But the drug we have developed affects only cancerous cells, leaving normal cells undisturbed."

In their experiments, Dhar and her research team exposed cancer cells to Mito-DCA. The results showed that the engineered chemical substance was able to switch the glycolysis-based metabolism of cancer cells to glucose oxidation, meaning that the cancer cells can once again die via apoptosis.

Mito-DCA also suppressed the production of lactic acid in cancerous cells, which allows them to avoid detection by the body's immune system. With this cloaking device damaged, the body's own T-cells are better able to recognize tumors and eliminate them.

https://medicalxpress.com/news/2014-04-dichloroacetate-cancer-treatment.html (more at link...)

https://therenodispatch.blogspot.com/2012/10/what-is-dca-real-story-behind-this.html

Overview of DCA:


Canadian Martin Winer on DCA with two Doctors and their research findings:

Don't mean to overpost on this topic but these are some related links with DCA and ATP/Glucose/Glycosis/Warburg Effect/mitochondria activity:
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http://www.theglobeandmail.com/life/health-and-fitness/fructose-can-trigger-cancer-cells-to-grow-faster-study-finds/article1316253/

In another study, the researchers explain that cancer cells initiate a "lactate shuttle" to move lactate -- the "food" -- from the connective tissue to the cancer cells. There's a transporter that is "spilling" lactate from the connective tissue and a transporter that then "gobbles" it up in the cancer cells."

The implication is that the fibroblasts in the connective tissue are feeding cancer cells directly via pumps, called MCT1 and MCT4, or mono-carboxylate transporters. The researchers see that lactate is like "candy" for cancer cells. And cancer cells are addicted to this supply of "candy."

"We've essentially shown for the first time that there is lactate shuttle in human tumors," said Dr. Lisanti. "It was first discovered nearly 100 years ago in muscles, 15 years ago in the brain, and now we've shown this shuttle also exists in human tumors."
It's all the same mechanism, where one cell type literally "feeds" the other. The cancer cells are the "Queen Bees," and the connective tissue cells are the "Worker Bees." In this analogy, the "Queen Bees" use aging and inflammation as the signal to tell the "Worker Bees" to make more food.
Researchers also identified MCT4 as a biomarker for oxidative stress in cancer-associated fibroblasts, and inhibiting it could be a powerful new anti-cancer therapy.
"If lethal cancer is a disease of "accelerated aging" in the tumor's connective tissue, then cancer patients may benefit from therapy with strong antioxidants and anti-inflammatory drugs," said Dr. Lisanti. "Antioxidant therapy will "cut off the fuel supply" for cancer cells." Antioxidants also have a natural anti-inflammatory action.
...
https://en.wikipedia.org/wiki/Starvation_response
General
The energetic requirements of a body are composed of the basal metabolic rate and the physical activity level. This caloric requirement can be met with protein, fat, carbohydrates, alcohol, or a mixture of those. Glucose is the general metabolic fuel, and can be metabolized by any cell. Fructose and some other nutrients can only be metabolized in the liver, where their metabolites transform into either glucose stored as glycogen in the liver and in muscles, or into fatty acids stored in adipose tissue.
...
Simple sugar, lactate, is like 'candy for cancer cells': Cancer cells accelerate aging and inflammation in the body to drive tumor growth
https://www.sciencedaily.com/releases/2011/05/110526152549.htm
https://www.cancer.gov/news-events/cancer-currents-blog/2016/cancer-metabolism-lactate

Related article with big claims from many years back.

Ancient remedy? An extract from the wormwood plant kills breast cancer cells in a test tube.
Wormwood Extract Kills Cancer Cells

By Deborah HillNov. 30, 2001 , 12:00 AM

Medieval as it sounds, scientists are testing a recipe of wormwood and iron on breast cancer cells, and so far the results are encouraging. In a new study, researchers report that artemesinin--a derivative of the wormwood plant--kills iron-enriched breast cancer cells but doesn't harm many healthy ones. Artemesinin's destructive properties are triggered by higher than normal levels of iron in cancer cells.

Many experiments have found that artemesinin turns deadly in the presence of iron. In Asia and Africa, artemesinin tablets are widely and, in many cases, successfully used to treat malaria, because the parasite has a high iron concentration. Cancer cells can also be rich in iron, as they often soak up the mineral to facilitate cell division. The cells bring in extra iron with the help of transferrin receptors, special receiving points that funnel the mineral into the cell. Although normal cells also have transferrin receptors, cancerous ones can have many more.
https://www.sciencemag.org/news/2001/11/wormwood-extract-kills-cancer-cells
...

Lactic Acidosis as a Result of Iron Deficiency
Clement A. Finch, Philip D. Gollnick, Michael P. Hlastala, Louise R. Miller, Erick Dillmann, and Bruce Mackler

First published July 1, 1979 - More info
It is concluded that iron deficiency by a depletion in the iron-containing mitochondrial enzyme, α-glycerophosphate oxidase, impairs glycolysis, resulting in excess lactate formation, which at high levels leads to cessation of physical activity.
https://www.jci.org/articles/view/109431
...


The Glycogen Shunt Maintains Glycolytic Homeostasis and the Warburg Effect in Cancer
Robert G. Shulman, Douglas L. Rothman'Correspondence information about the author Douglas L. Rothman

The Glycogen Shunt Maintains Glycolytic Homeostasis and the Warburg Effect in Cancer
DOI: https://doi.org/10.1016/j.trecan.2017.09.007 |


Under aerobic conditions cancer cells consume more glucose than they oxidize for energy, a phenomenon known as the Warburg effect.

There have been many proposed critical functions for the Warburg effect in cancer cells, but none have been definitively shown.

The glycogen shunt has been recently shown to be essential for cancer cell survival.

The critical role of the glycogen shunt in maintaining metabolic homeostasis, recently shown in yeast, provides a novel explanation and mechanism for its importance in cancer cells and the Warburg effect.

Despite many decades of study there is a lack of a quantitative explanation for the Warburg effect in cancer. We propose that the glycogen shunt, a pathway recently shown to be critical for cancer cell survival, may explain the excess lactate generation under aerobic conditions characteristic of the Warburg effect. The proposal is based on research on yeast and mammalian muscle and brain that demonstrates that the glycogen shunt functions to maintain homeostasis of glycolytic intermediates and ATP during large shifts in glucose supply or demand. Loss of the glycogen shunt leads to cell death under substrate stress. Similarities between the glycogen shunt in yeast and cancer cells lead us here to propose a parallel explanation of the lactate produced by cancer cells in the Warburg effect. The model also explains the need for the active tetramer and inactive dimer forms of pyruvate kinase (PKM2) in cancer cells, similar to the two forms of Pyk2p in yeast, as critical for regulating the glycogen shunt flux. The novel role proposed for the glycogen shunt implicates the high activities of glycogen synthase and fructose bisphosphatase in tumors as potential targets for therapy.

http://www.cell.com/trends/cancer/fulltext/S2405-8033(17)30193-0

To test artemesinin's effect on breast cancer cells, bioengineers Henry Lai and Narendra Singh of the University of Washington, Seattle, enriched segregated normal breast cells and radiation-resistant cancerous ones with holotransferrin, a compound normally found in the body that carries iron to the cells. Then the team dosed the cells with artemesinin. As the pair reports in the 16 November issue of Life Sciences, almost all the cancer cells exposed to holotransferrin and artemesinin died within 16 hours. The compounds killed only a few of the normal cells. Lai believes that because a breast cancer cell contains five to 15 more receptors than normal, it absorbs iron more readily and hence is more susceptible to artemesinin's attack.

"This looks very promising," says Gary Poser, an organic chemist at Johns Hopkins University in Baltimore, Maryland. Still, he adds, "other researchers need to replicate these results." The next step, says Poser, is to treat a mixture of normal and cancerous cells, instead of segregating the two. Lai and others are also interested in artemesinin's effect on other cancers.

https://www.sciencemag.org/news/2001/11/wormwood-extract-kills-cancer-cells

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Duke scientists show why cells starved of iron burn more glucose
Duke University Medical Center
https://www.eurekalert.org/pub_releases/2008-06/dumc-dss060808.php

The first response to iron deficiency is to shut down the energy hub of the cell, the mitochondria, which takes glucose and turns it efficiently into cell energy fuel, or ATP. The mitochondria depend greatly on iron. As a cell becomes more starved for iron, it "dials down" the mitochondrial processes by degrading the mRNAs encoding the proteins involved in such processes, and thus, some iron is freed up, Thiele said.

The second response is to shut down iron storage pathways and other, more dispensable biochemical reactions that depend on iron. "When you are low on iron, you don't want to save it and take it out of use," Thiele explained.

The third response is to increase glucose utilization pathways outside of the mitochondria, which is a much less efficient way to produce energy. Glucose molecules processed for energy outside of the mitochondria create about 18 times less energy, said co-author Sandra Vergara, a doctoral student in Thiele's lab.

"Cellular iron balance follows the rules of economics," Vergara said. "During scarcity, the cell prioritizes the utilization of iron, saving it for more essential processes. This prioritization comes at a cellular cost, which is reflected in the higher demand for glucose, so the cell can keep the correct amount of energy flowing."

If we run low on ATP, we become tired and lethargic, which are symptoms of iron deficiency, Thiele said. "Iron is hard for humans to get from plant sources, which form the basis for most of the world's diet." Iron is very abundant in nature, but cells have a hard time taking it up, because it can change its form inside the body.

J Clin Invest. 1987 Feb;79(2):588-94.
Dichloroacetate inhibits glycolysis and augments insulin-stimulated glycogen synthesis in rat muscle.
Clark AS, Mitch WE, Goodman MN, Fagan JM, Goheer MA, Curnow RT.

Abstract

The decrease in plasma lactate during dichloroacetate (DCA) treatment is attributed to stimulation of lactate oxidation. To determine whether DCA also inhibits lactate production, we measured glucose metabolism in muscles of fed and fasted rats incubated with DCA and insulin. DCA increased glucose-6-phosphate, an allosteric modifier of glycogen synthase, approximately 50% and increased muscle glycogen synthesis and glycogen content greater than 25%. Lactate release fell; inhibition of glycolysis accounted for greater than 80% of the decrease. This was associated with a decrease in intracellular AMP, but no change in citrate or ATP. When lactate oxidation was increased by raising extracellular lactate, glycolysis decreased (r = - 0.91), suggesting that lactate oxidation regulates glycolysis. When muscle lactate production was greatly stimulated by thermal injury, DCA increased glycogen synthesis, normalized glycogen content, and inhibited glycolysis, thereby reducing lactate release. The major effect of DCA on lactate metabolism in muscle is to inhibit glycolysis.

https://www.ncbi.nlm.nih.gov/pubmed/3543056

...

Dichloroacetate Stimulates Glycogen Accumulation in Primary Hepatocytes through an Insulin-Independent Mechanism

Melissa K. Lingohr Richard J. Bull Junko Kato-Weinstein Brian D. Thrall
Toxicological Sciences, Volume 68, Issue 2, 1 August 2002, Pages 508–515, https://doi.org/10.1093/toxsci/68.2.508
Published: 01 August 2002


Abstract

Dichloroacetate (DCA), a by-product of water chlorination, causes liver cancer in B6C3F1 mice. A hallmark response observed in mice exposed to carcinogenic doses of DCA is an accumulation of hepatic glycogen content. To distinguish whether the in vivo glycogenic effect of DCA was dependent on insulin and insulin signaling proteins, experiments were conducted in isolated hepatocytes where insulin concentrations could be controlled. In hepatocytes isolated from male B6C3F1 mice, DCA increased glycogen levels in a dose-related manner, independently of insulin. The accumulation of hepatocellular glycogen induced by DCA was not the result of decreased glycogenolysis, since DCA had no effect on the rate of glucagon-stimulated glycogen breakdown. Glycogen accumulation caused by DCA treatment was not hindered by inhibitors of extracellular-regulated protein kinase kinase (Erk1/2 kinase or MEK) or p70 kDa S6 protein kinase (p70S6K), but was completely blocked by the phosphatidylinositol 3-kinase (PI3K) inhibitors, LY294002 and wortmannin. Similarly, insulin-stimulated glycogen deposition was not influenced by the Erk1/2 kinase inhibitor, PD098509, or the p70S6K inhibitor, rapamycin. Unlike DCA-stimulated glycogen deposition, PI3K-inhibition only partially blocked the glycogenic effect of insulin. DCA did not cause phosphorylation of the downstream PI3K target protein, protein kinase B (PKB/Akt). The phosphorylation of PKB/Akt did not correlate to insulin-stimulated glycogenesis either. Similar to insulin, DCA in the medium decreased IR expression in isolated hepatocytes. The results indicate DCA increases hepatocellular glycogen accumulation through a PI3K-dependent mechanism that does not involve PKB/Akt and is, at least in part, different from the classical insulin-stimulated glycogenesis pathway. Somewhat surprisingly, insulin-stimulated glycogenesis also appears not to involve PKB/Akt in isolated murine hepatocytes.
dichloroacetate, glycogen, insulin, insulin receptor, PKB/Akt, PI3K, hepatocyte

Dichloroacetate (DCA) is a common by-product formed during drinking water chlorination and is hepatocarcinogenic in B6C3F1 mice and F344 rats (Bull et al., 1990; DeAngelo et al., 1991, 1996; Pereira, 1996; Stauber and Bull, 1997). A hallmark effect of DCA treatment in mice is a marked accumulation of hepatocellular glycogen (Bull et al., 1990; Kato-Weinstein et al., 1998). The dose-response relationship for glycogen accumulation in mice closely parallels the dose-response relationship for the carcinogenic effects of DCA (Bull et al., 1990; Kato-Weinstein et al., 1998; Stauber and Bull, 1997). It is not known whether the mechanisms by which DCA causes hepatocellular carcinoma and stimulates hepatocellular glycogen content are related. However, a link between altered glycogen metabolism and liver cancer risk is suggested by the fact that patients with glycogen storage disease have a significantly increased incidence of liver cancer (Alshak et al., 1994; Conti and Kemeny, 1992; Labrune et al., 1997).

Glycogen synthase is the rate-limiting enzyme of glycogen biosynthesis, and its activation is regulated by a reversible dephosphorylation mechanism in which several insulin-controlled phosphatases and kinases can be involved (Pugazenthi and Khandelwal, 1995). The principal signaling pathway by which insulin stimulates glycogen synthase is via activation of the insulin receptor (IR), leading to phosphatidylinositol-3′ kinase (PI3K)-dependent activation of protein kinase B (PKB/Akt), inactivation of glycogen synthase kinase-3 (GSK-3), and increased activity of glycogen synthase (GS) (Cohen, 1999; Cross et al., 1995, 1997; Lawrence and Roach, 1997; Park et al., 1999). PI3K-dependent activation of the p70 kDa S6 protein kinase (p70S6K) as well as activation of the Ras/Raf/MEK/Erk1/2 signaling pathway have also been linked with GSK-3 inactivation and increased glycogen synthesis (Azpiazu et al., 1996; Dent et al., 1990; Park et al., 1999; Shepherd et al., 1995; Sutherland and Cohen, 1994; Sutherland et al., 1993). In addition to their role in regulating metabolism, the activities of PI3K, PKB/Akt and Erk1/2 play important roles in regulating cell proliferation and apoptosis in hepatocytes (reviewed in Band et al., 1999; Galetic et al., 1999; Mounho and Thrall, 1999; Roberts et al., 2000).

https://academic.oup.com/toxsci/article/68/2/508/1660564

Sugars Increase Non-Heme Iron Bioavailability in Human Epithelial Intestinal and Liver Cells

Tatiana Christides ,Paul Sharp
Published: December 10, 2013
https://doi.org/10.1371/journal.pone.0083031

Abstract

Previous studies have suggested that sugars enhance iron bioavailability, possibly through either chelation or altering the oxidation state of the metal, however, results have been inconclusive. Sugar intake in the last 20 years has increased dramatically, and iron status disorders are significant public health problems worldwide; therefore understanding the nutritional implications of iron-sugar interactions is particularly relevant. In this study we measured the effects of sugars on non-heme iron bioavailability in human intestinal Caco-2 cells and HepG2 hepatoma cells using ferritin formation as a surrogate marker for iron uptake. The effect of sugars on iron oxidation state was examined by measuring ferrous iron formation in different sugar-iron solutions with a ferrozine-based assay. Fructose significantly increased iron-induced ferritin formation in both Caco-2 and HepG2 cells. In addition, high-fructose corn syrup (HFCS-55) increased Caco-2 cell iron-induced ferritin; these effects were negated by the addition of either tannic acid or phytic acid. Fructose combined with FeCl3 increased ferrozine-chelatable ferrous iron levels by approximately 300%. In conclusion, fructose increases iron bioavailability in human intestinal Caco-2 and HepG2 cells. Given the large amount of simple and rapidly digestible sugars in the modern diet their effects on iron bioavailability may have important patho-physiological consequences. Further studies are warranted to characterize these interactions.

Introduction

Evidence that simple sugars such as glucose and fructose affect iron bioavailability first arose in the 1960s from work showing that sugars were able to chelate inorganic iron and form stable, low molecular weight soluble complexes [1]. These sugar-iron complexes were readily absorbed across the intestinal mucosa of rodent models [2], [3]. Given that intake of fructose and sucrose has increased dramatically worldwide in the past 40 years, especially in the Western world, while at the same time iron deficiency and iron excess remain significant public health concerns [4]–[6], understanding the nutritional implications of iron-sugar interactions is particularly relevant.

Excess sugar is blamed for a myriad of modern health problems, but whether sugars might actually be protective against iron deficiency, or contribute to either total body or cellular iron overload is unknown. Insufficient body iron levels are associated with significant health consequences, and approximately 2 billion people suffer from iron deficiency. Furthermore, iron overload related to either primary (e.g. hereditary hemochromatosis) or secondary (e.g. beta-thalassemia) abnormalities in iron metabolism is prevalent in many populations [6], [7]. There is also interest in the role that disordered regulation of intracellular iron levels plays in the pathogenesis of several non-communicable diseases including non-alcoholic fatty liver disease (NAFLD) [8], [9].

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0083031

Citation: Christides T, Sharp P (2013) Sugars Increase Non-Heme Iron Bioavailability in Human Epithelial Intestinal and Liver Cells. PLoS ONE 8(12): e83031. https://doi.org/10.1371/journal.pone.0083031

Something like Biophoton's are probably in play as well with Cancer.  This is seen as a "pseudo-science" by some researchers. Though, there are Biophotons operating in the brain apparently.

https://en.wikipedia.org/wiki/Biophoton

....

https://www.technologyreview.com/s/608797/are-there-optical-communication-channels-in-our-brains/

Are There Optical Communication Channels in Our Brains?
Neuroscientists have long observed biophotons produced in brain tissue. Nobody knows what these photons are for, but researchers are beginning to explore the possibilities.

by Emerging Technology from the arXiv September 6, 2017

Here’s an interesting question: are there optical communication channels in the brain? This may be a radical suggestion but one for which there is more than a little evidence to think it is worth pursuing.

Many organisms produce light to communicate, to attract mates, and so on. Twenty years ago, biologists discovered that rat brains also produce photons in certain circumstances. The light is weak and hard to detect, but neuroscientists were surprised to find it at all.

Since then, the evidence has grown. So-called biophotons seem to be produced naturally in the brain and elsewhere by the decay of certain electronically excited molecular species. Mammalian brains produce biophotons with wavelength of between 200 and 1,300 nanometers—in other words, from near infrared to ultraviolet.


...
Biophoton Communication: Can Cells Talk Using Light?

(more at link)

A growing body of evidence suggests that the molecular machinery of life emits and absorb photons. Now one biologist has evidence that this light is a new form of cellular communication.

   May 22, 2012

One of the more curious backwaters of biology is the study of biophotons: optical or ultraviolet photons emitted by living cells in a way that is distinct from conventional bioluminescence.

Nobody is quite sure how cells produce biophotons but the latest thinking is that various molecular processes can emit photons and that these are transported to the cell surface by energy carying excitons. A similar process carries the energy from photons across giant protein matrices during photosynthesis.

Whatever the mechanism, a growing number of biologists are convinced that when you switch off the lights, cells are bathed in the pale fireworks of a biophoton display.

This is not a bright phenomena. Biophotons are usually produced at the rate of dozens per second per square centimetre of cell culture.

https://www.technologyreview.com/s/427982/biophoton-communication-can-cells-talk-using-light/

Ref: arxiv.org/abs/1205.4134: Photonic Communications and Information Encoding in Biological Systems
That’s not many. And it’s why the notion that biophoton activity is actually a form of cellular communication is somewhat controversial.    

Today, Sergey Mayburov at the Lebedev Institute of Physics in Moscow adds some extra evidence to the debate.

Mayburov has spent many hours in the dark watching fish eggs and recording the patterns of biophotons that these cells emit.

The question he aims to answer is whether the stream of photons has any discernible structure that would qualify it as a form of communication.

The answer is that is does, he says. Biophoton streams consist of short quasiperiodic bursts, which he says are remarkably similar to those used to send binary data over a noisy channel. That might help explain how cells can detect such low levels of radiation in a noisy environment.

If he’s right, then this could help to explain a number of interesting phenomenon that some biologists attribute to biophoton communication.

In several experiments, biophotons from a growing plant seem to increase the rate of cell division in other plants by 30 per cent. That’s a growth rate that is significantly higher than is possible with ordinary light that is several orders of magnitude more intense.

Other experiments have shown that the biophotons from growing eggs can encourage the growth of other eggs of a similar age. However, the biophotons from mature eggs can hinder and disrupt the growth of younger eggs at a different stage of development. In some cases, biophotons from older eggs seem to stop the growth of immature eggs entirely.

Mayburov’s work won’t end the controversy; not by any means. There are still many outstanding questions. One important problem is to better understand the cellular mechanisms at work–how the molecular machinery inside cells produces photons and how it might be influenced by them.

.....


Are There Optical Communication Channels in Our Brains?
Neuroscientists have long observed biophotons produced in brain tissue. Nobody knows what these photons are for, but researchers are beginning to explore the possibilities.

by Emerging Technology from the arXiv September 6, 2017

Here’s an interesting question: are there optical communication channels in the brain? This may be a radical suggestion but one for which there is more than a little evidence to think it is worth pursuing.

Related to "biophotons" and cancer...pretty interesting overall:
--------

Cancer Nanotechnol. 2013; 4(1-3): 21–26.
Published online 2013 March 28. doi:  10.1007/s12645-013-0034-7
PMCID: PMC4451865
Enhancement of biophoton emission of prostate cancer cells by Ag nanoparticles
Marius Hossu, Lun Ma, Xiaoju Zou, and Wei Chen corresponding author

Abstract

Ultraweak intrinsic bioluminescence of cancer cell is a noninvasive method of assessing bioenergetic status of the investigated cells. This weak biophoton emission generated by prostate cancer cells (PC3) was measured in the presence of Ag nanoparticles and its correlation with singlet oxygen production was investigated. The comparison between nanoparticles concentration, bioluminescence intensity, and cell survival showed that Ag nanoparticles do not significantly affect cell survival at used concentration but they increase cell bioluminescent processes. It was also confirmed that singlet oxygen contributes to biophoton emission, that Ag nanoparticles increase this contribution, and that there are secondary mechanisms independent of singlet oxygen by which Ag nanoparticles contribute to increased cellular bioluminescence, possibly through plasmon resonance enhancement of intrinsic fluorescence.

Keywords: Silver nanoparticle, Bioluminescence, Biophoton, PC3, Cancer, Singlet oxygen, Plasmon resonance

Introduction

Luminescence investigation is a fundamental tool in cellular biology and a useful method in understanding molecular mechanisms of medical therapies. One of these methods is the measurement of intrinsic bioluminescence of living tissue, process also called biophoton emission (BPE) (Popp et al. 1988; Cohen and Popp 1997; Kobayashi and Inaba 2000; Chang 2008). The advantage of using BPE is that it monitors intrinsic processes of the investigated biological system versus the interaction of the system with an external stimulus, be it light in fluorescence, magnetic field in MRI, X-ray in CT, etc. It was demonstrated that all cells emits light during normal metabolic processes ( Kobayashi and Inaba 2000; Chang 2008). However, due to its extremely low intensity and its sensitivity to interaction with ambient light, this intrinsic bioluminescence was rarely used as a monitoring tool for cells’ physiology or pathology. The typical light emission is in the order of tens of photons per second per square centimeter of tissue hence the term biophoton is used more often and only very sensitive and very low noise phototomultipliers are used to record it. One of the emission’s mechanisms was correlated with the generation of metastable excited states by high energetic metabolic processes (cellular respiration, phagocytosis, mitosis, neural activity) and by oxidative reactions (Cilento 1988; Villablanca and Cilento 1985; Devaraj et al. 1997; Van Wijk et al. 2008). Most common identified excited molecules are intrinsic fluorophores, singlet oxygen, or excited carbonil (Villablanca and Cilento 1985). Other suggested sources are excitons in macromolecules, particularly DNA and collagen ( Popp et al. 1984; Brizhik et al. 2001; Brizhik 2008). Since all these mechanisms are intimately related to each cell’s functions, BPE analysis was proposed as a noninvasive descriptor at deep quantum level of biological systems (Cohen and Popp 1997; Chang 2008; Popp et al. 1994; Hossu and Rupert 2006) and it was suggested to be a global indicator of viability, reactivity, and health of a living organism (Popp et al. 1994; Bajpai 2003; Hossu and Rupert 2006).

Since cancer is one of the major causes of death any new in vivo and in vitro study could potentially reflect into life-saving protocols. Understanding molecular events including luminescence in cancer could provide helpful insights on the action mechanism of various therapies, whereas monitoring cells behavior through luminescence could also help in identifying specific points of intervention into cellular functions. Few attempts were performed to measure the intrinsic BPE of cancer cells (Grasso et al. 1992; Amano et al. 1995; Kim et al. 2005a, b, 2006) indentifying mostly the differences between cancer and normal tissues. Based on these results BPE was also proposed as a possible noninvasive imaging method to identify cancer (Kim et al. 2006; Takeda et al. 2004; Popp 2009).

On the other hand silver nanoparticles (AgNP) were extensively evaluated for their interaction with biological systems, mostly for their antimicrobial and antiseptic properties (Lansdown 2006; Chen and Schluesener 2008; Rai et al. 2009). AgNP’s low toxicity for normal cells and their intrinsic antimicrobial characteristics might be of benefit if they will also be used in cancer therapy (Nowack 2010). However, recent data show that in higher concentrations, AgNP may be cytotoxic (El Badawy et al. 2011; Hackenberg et al. 2011; AshaRani et al. 2009), effect that may be detrimental for normal physiology but helpful in oncology. It was also shown that in a plant system AgNP intensify BPE (Hossu et al. 2010) without interfering with normal plant curing mechanisms; however, no data are available for correlation between intrinsic BPE of cancer cells and AgNP. Therefore this BPE study of cancer cells in the presence of AgNP will provide a window into direct effect of these NPs onto high energetic cellular processes, without the interferences from external intervention. Since one major therapeutic mechanism in cancer is based on reactive oxygen species (ROS) mainly singlet oxygen (1O2) and 1O2 is also involved in BPE we specifically tested the correlation between BPE and 1O2 generation in the presence of AgNP.

Materials and methods

Chemicals used were of analytical grade from Sigma Chemical Co. (St. Louis, MO) and used without further purification. 1O2 chemiluminescent sensor: trans-1-(2′-Methoxyvinyl)pyrene (MVP) was purchased from Invitrogen (Carlsbad, CA) and diluted to a concentration of 10 μM before use. Sodium azide (NaN3) solution was prepared in 10 μM concentration. AgNP were prepared according to previously described methods by standard wet chemical synthesis based on reduction reactions (Huang et al. 2007; Zhang et al. 2008; Hossu et al. 2010). The initial dimensions of AgNPs were estimated to be 6–20 nm, verified by dynamic light scattering and transmission electron microscopy as shown in Fig. 1. They were kept in a separate dark storage chamber at room temperature. The initial concentration was estimated at 10−8 M (6 × 109 NP/μL) based on chemistry ratios and confirmed using absorption spectrometry.

HR TEM of AgNP in low and high magnification (insert). Relative spherical shape of the particles is seen in low magnification and fringes of crystalline structure are seen in high magnification

A photon counting system (Hamamatsu Photonics K.K., Hamamatsu, Japan) was used to observe time-dependent photon emission intensity. The system is equipped with a H6180-1 photomultiplier tube (PMT) providing a maximum spectral response from 240 to 630 nm and a C8855 counting system, operating at room temperature. The gate time for collecting the photon signal from the PMT was set at 1 s. The measuring room was light proofed with dark materials and only a red radiological safe light was used during the manipulation of the chemicals and cells to minimize delayed luminescence. The PMT was placed inside a custom made dark chamber equipped with thermostat controlled heating pad and the dark count was measured at the beginning of each experiment to ensure that its value was at the level of the instrument noise, i.e., seven to nine counts per second (CPS). This insured that any signal recorded was from the sample and not due to transient changes of a residual light in the room or in the dark chamber. The distance between the PMT and the sample was 5 mm in all measurements. Each set of data consisting of up to 10,000 measurements was recorded using C8855’s operating software (Hamamatsu, Japan) and processed using Microsoft Office Excel 2007 and OriginPro 8.5.0.

............
Note this is a sales site so I can't speak to efficacy, according to the site on "About" section the device is FDA approved. I guess somebody needs to create an "Anti-photon" device to really get things balanced properly .... Cr6:

https://www.balesphotonics.com/features-2/  (Light for stimulating Biophotons)


The BioPhoton 100 Professional

More Stimulating Light

The BioPhoton 100 Professional has mixed-spectrum Blue Light and 850 and 940nm far infrared light. It has been shown that blue light stimulates lymph activity, promotes healing of cutaneous injuries (burns, cuts, and contusions) and even helps to combat MRSA. The benefits of 850nm and 940nm near Infrared light include increased ATP production, vasodilation in injured tissues of arteries, lymphatics, and veins, stimulation of stem cells, reduced inflammation, relief of pain, myofascial release, increased delivery of oxygen into the mitochondria, increased production of collagen, and boosts immunity.

https://www.balesphotonics.com/thescience/


How Does Photon Therapy Work?

Photon therapy emits packets of light called photons. Photons break the painful inflammatory cycle by dilating small blood and lymphatic vessels. This increase in circulation removes the irritating inflammatory products and results in accelerated healing and pain relief. The immune system and nervous system are also stimulated by photons, which increases activity and leads to faster repair of damaged tissues.

Numerous tests show that the increase in circulation and reduction in pain associated with the use of photons is the result of an increase in the release of nitric oxide directly under the neurotransmitter.

60 years ago, Furchgott (et al JPETT 113:22, 1955) demonstrated the ability of photo energy to induce vasorelaxation. Furchgott, Ignatto, and Murad were awarded the Nobel Prize in Medicine in 1998 for their work in identifying nitric oxide as the molecule responsible for regulating blood pressure.

The Science Behind It

Photon, or near-infrared light therapy works at the cellular level in a phenomenon known as Photobiomodulation. Photons stimulate cytochrome-c oxidase, an enzyme associated with the third part of the electron transport chain inside the mitochondria. Cytochrome-c oxidase in turn causes increased levels of ATP synthase, an enzyme associated with the fourth part of the electron transport chain. ATP synthase synthesizes ATP production which has a cascade of beneficial effects at the cellular level.


Here Are the Effects of the BioPhoton 100 After Just a Few Treatments

Infrared imaging, or thermography, is used to detect changes in blood circulation. A baseline infrared image may be taken before therapy and used to determine the proper course of treatment. This image is then stored on the computer system. After an initial course of 4-6 treatments, the scan is repeated. Changes in blood circulation are noted and used to assess the efficacy of treatment and determine prognosis.

Below are some examples of pre- and post-treatment infrared scans. Orange to red warmer colors in the pretreatment images indicate inflammation and pain. Patients experiencing numbness and poor circulation before treatment show warmer colors after treatment indicating increased blood circulation.

Pre

Post


https://www.balesphotonics.com/results-2/

Increased Level of Extracellular ATP at Tumor Sites: In Vivo Imaging with Plasma Membrane Luciferase

Patrizia Pellegatti ,
Lizzia Raffaghello ,
Giovanna Bianchi,
Federica Piccardi,
Vito Pistoia,
Francesco Di Virgilio

PLOS Published: July 9, 2008
https://doi.org/10.1371/journal.pone.0002599
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0002599

Abstract

Background

There is growing awareness that tumour cells build up a “self-advantageous” microenvironment that reduces effectiveness of anti-tumour immune response. While many different immunosuppressive mechanisms are likely to come into play, recent evidence suggests that extracellular adenosine acting at A2A receptors may have a major role in down-modulating the immune response as cancerous tissues contain elevated levels of adenosine and adenosine break-down products. While there is no doubt that all cells possess plasma membrane adenosine transporters that mediate adenosine uptake and may also allow its release, it is now clear that most of extracellularly-generated adenosine originates from the catabolism of extracellular ATP.
Methodology/Principal Findings

Measurement of extracellular ATP is generally performed in cell supernatants by HPLC or soluble luciferin-luciferase assay, thus it generally turns out to be laborious and inaccurate. We have engineered a chimeric plasma membrane-targeted luciferase that allows in vivo real-time imaging of extracellular ATP. With this novel probe we have measured the ATP concentration within the tumour microenvironment of several experimentally-induced tumours.
Conclusions/Significance

Our results show that ATP in the tumour interstitium is in the hundrends micromolar range, while it is basically undetectable in healthy tissues. Here we show that a chimeric plasma membrane-targeted luciferase allows in vivo detection of high extracellular ATP concentration at tumour sites. On the contrary, tumour-free tissues show undetectable extracellular ATP levels. Extracellular ATP may be crucial for the tumour not only as a stimulus for growth but also as a source of an immunosuppressive agent such as adenosine. Our approach offers a new tool for the investigation of the biochemical composition of tumour milieu and for development of novel therapies based on the modulation of extracellular purine-based signalling.

....

Discussion

There is growing awareness that the tumour microenvironment has a key role in supporting tumour growth and in dictating the rules of host-tumour interaction [12], [5]. The tumour may wield host response by inducing the formation of protected niches that allow survival of cancer stem cells and their differentiation into mature cancer cells [13]. The tumour microenvironment which includes infiltrating inflammatory cells as well as stromal cells, is responsible for creating conditions that hinder the effectiveness of the host immune response and lead to immunoevasion, or even to tumour progression [14]. The biochemical composition of the tumour microenvironment is poorly known, but it is understood that it may profoundly change depending on tumor type and the host immunocompetence [15].

Depending on the tight balance between tumour-induced or tumour-released immunosuppressive factors and host-derived immunoactivating factors the microenvironment creates favourable or unfavourable conditions for tumour growth. This generates a network of facilitating or inhibitory interactions the effect of which is extremely difficult to anticipate. In this context hypoxic conditions that characterize several tumours may be an important component of the mechanism of tumour protection. Hypoxia causes the activation of hypoxia-inducible factor 1 α (HIF-1α) and accumulation of extracellular adenosine. Both factors are in principle very important in supporting tumour growth as HIF-1α controls angiogenesis and adenosine exerts a profound immunosuppressive activity, thus protecting the tumour from inflammatory cells. Recent data show that solid tumours have a gradient of adenosine concentration from the centre to the periphery, higher than the surrounding healthy tissue [6]. In addition, many tumours over-express enzymes involved in the catabolism of extracellular nucleotides and in the generation of adenosine [16]. Furthemore, glioblastoma cells injected in vivo together with apyrase show a reduced ability to produce tumours [17]. Accumulation of adenosine into the tumour microenvironment does not only protect tumour cells from the immune response, but may also exert a trophic effect on the tumour itself by stimulating endothelial cell proliferation and angiogenesis [18], [19], [20].

Although cells express carriers that may mediate adenosine translocation into the extracellular milieu, most extracellular adenosine is generated at the expenses of extracellular ATP via extracellular nucleotidases (ecto-ATPases and 5′-nucleotidase) [21], [22]. However, ATP in the tumour microenvironment is important not only as a source of adenosine but also for its intrinsic activity. In fact ATP itself modulates inflammation by triggering IL-1 maturation and release, dendritic cell differentiation by inducing a Th2-skewing phenotype and cell proliferation or cell death, depending on the concentrations and the activation of individual P2 receptors [23]. In addition, its has been recently shown that ATP causes shedding of metalloproteases (MMP9) [24] and expression of indoleamine oxygenase [25]; both activities may be very relevant for tumour progression as MMP9 release facilitates tumour invasion while indoleamine oxygenase has immunosuppressive activity.

Bioluminescence imaging is increasingly recognized as a powerful tool to study in vivo transcriptional regulation, signal transduction, activation of cancer-specific genes. So far, luciferase has been almost exclusively used as an intracellular reporter, to monitor the activity of specific transcriptional activators such as for example the estrogen receptor [26] or NF-κB [27]. In this study we show that cells engineered with luciferase can be also used to probe the extracellular space and to analyze the biochemical composition of the tumour microenvironment. Furthermore, since an increased ATP concentration is a feature of inflammation, engineering inflammatory cells with pmeLUC will make possible in vivo imaging of inflammation. Finally, since appending proper target sequences to luciferase may allow targeting to specific regions of the plasma membrane, we anticipate that pmeLUC may even allow to probe changes in the extracellular ATP concentration at restricted sites of cell-to-cell interaction.

Cell Metab. 2016 Dec 13;24(6):795-806. doi: 10.1016/j.cmet.2016.09.013. Epub 2016 Oct 27.
Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice.
Mills KF1, Yoshida S2, Stein LR1, Grozio A1, Kubota S3, Sasaki Y4, Redpath P5, Migaud ME5, Apte RS6, Uchida K2, Yoshino J7, Imai SI8.
Author information

Abstract

NAD+ availability decreases with age and in certain disease conditions. Nicotinamide mononucleotide (NMN), a key NAD+ intermediate, has been shown to enhance NAD+ biosynthesis and ameliorate various pathologies in mouse disease models. In this study, we conducted a 12-month-long NMN administration to regular chow-fed wild-type C57BL/6N mice during their normal aging. Orally administered NMN was quickly utilized to synthesize NAD+ in tissues. Remarkably, NMN effectively mitigates age-associated physiological decline in mice. Without any obvious toxicity or deleterious effects, NMN suppressed age-associated body weight gain, enhanced energy metabolism, promoted physical activity, improved insulin sensitivity and plasma lipid profile, and ameliorated eye function and other pathophysiologies. Consistent with these phenotypes, NMN prevented age-associated gene expression changes in key metabolic organs and enhanced mitochondrial oxidative metabolism and mitonuclear protein imbalance in skeletal muscle. These effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective anti-aging interventions in humans.

https://www.ncbi.nlm.nih.gov/pubmed/28068222

Toxins (Basel). 2015 Nov 3;7(11):4507-18. doi: 10.3390/toxins7114507.
Cytotoxic indole alkaloids against human leukemia cell lines from the toxic plant Peganum harmala.
Wang C1, Zhang Z2, Wang Y3, He X4.
Author information

Abstract

Bioactivity-guided fractionation was used to determine the cytotoxic alkaloids from the toxic plant Peganum harmala. Two novel indole alkaloids, together with ten known ones, were isolated and identified. The novel alkaloids were elucidated to be 2-(indol-3-yl)ethyl-α-L-rhamnopyranosyl-(1 → 6)-β-D-glucopyranoside (2) and 3-hydroxy-3-(N-acetyl-2-aminoethyl)-6-methoxyindol-2-one (3). The cytotoxicity against human leukemia cells was assayed for the alkaloids and some of them showed potent activity. Harmalacidine (compound 8, HMC) exhibited the highest cytotoxicity against U-937 cells with IC50 value of 3.1 ± 0.2 μmol/L. The cytotoxic mechanism of HMC was targeting the mitochondrial and protein tyrosine kinase signaling pathways (PTKs-Ras/Raf/ERK). The results strongly demonstrated that the alkaloids from Peganum harmala could be a promising candidate for the therapy of leukemia.

https://www.ncbi.nlm.nih.gov/pubmed/26540074


Abstract Title:

Cytotoxicity of alkaloids isolated from Peganum harmala seeds.
Abstract Source:

Pak J Pharm Sci. 2013 Jul ;26(4):699-706. PMID: 23811445

Abstract Author(s):

Fatima Lamchouri, Mustapha Zemzami, Akino Jossang, Abdellatif Abdellatif, Zafar H Israili, Badiaa Lyoussi
Article Affiliation:

Fatima Lamchouri
Abstract:

Peganum harmala is used in traditional medicine to treat a number of diseases including cancer. Our preliminary studies show that the alkaloidal extract of PH seed is cytotoxic to several tumor cell lines in vitro and has antitumor effect in a tumor model in vivo. The present investigation was aimed at extending our previous studies in identifying the components in P. harmala seed-extract responsible for the cytotoxic effects, and study the cytotoxic and antiproliferative activity of isolated alkaloids and total alkaloidal fraction (TAF) in several tumor cell lines. Four alkaloids: harmalicidine, harmine, peganine (vasicine) and vasicinone were isolated from the P. harmala seed-extract and their activity and that of TAF were tested a) for their cytotoxic activity against four tumor cell lines [three developed by us by chemical-induction in Wistar rats: 1) Med-mek carcinoma ; 2) UCP-med carcinoma ; 3) UCP-med sarcoma] ; and 4) SP2/O-Ag14, and b) for antiproliferative effect on cells of Jurkat, E6-1 clone (inhibition of incorporation of {(3)H-thymidine} in cellular DNA). The alkaloids and TAF inhibited the growth of tumor cell lines to varying degrees; Sp2/O-Ag14 was the most sensitive, with IC50 values (concentration of the active substance that inhibited the growth of the tumor cells by 50%) ranging between 2.43μg/mL and 19.20 μg/mL, while UCP-med carcinoma was the least sensitive (range of IC50 = 13.83 μg/mL to 59.97 μg/mL). Of the substances evaluated, harmine was the most active compound (IC50 for the 4 tumor cell lines varying between 2.43 μg/mL and 18.39 μg/mL), followed by TAF (range of IC50 =7.32 μg/mL to 13.83 μg/mL); peganine was the least active (IC50 = 50 μg/mL to>100μg/mL). In terms of antiproliferative effect, vasicinone and TAF were more potent than other substances: the concentration of vasicinone, and TAF needed to inhibit the incorporation of {(3)H-TDR} in the DNA cells of Jurkat, E6-1 clone by 50% (IC50) were 8.60 ± 0.023 μg/mL and 8.94 ± 0.017 μg/mL, respectively, while peganine was the least active (IC50>100μg/mL). The IC50 values for harmalacidine (27.10 ± 0.011 μg/mL) and harmine (46.57 ± 0.011 μg/mL) were intermediate. The harmala alkaloids inhibited the growth of four tumor cell lines, and proliferation of Jurkat cells with varying potencies. Harmine was the most potent in inhibiting cell growth, and vasicinone was most active as antiproliferating substance. The TAF had significant cytotoxic as well as antiproliferating activity.
Article Published Date : Jun 30, 2013
Study Type : In Vitro Study
Additional Links
Substances : Syrian rue : CK(1) : AC(1)
Diseases : Cancers: All : CK(14773) : AC(4596)
Pharmacological Actions : Antiproliferative : CK(2546) : AC(1685)
http://www.greenmedinfo.com/article/alkaloids-isolated-peganum-harmala-seeds-have-cytotoxicity-against-cancer-line
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Effects of Syrian Rue as a MAOI inhibitor - Cox-2 source (anti-cancer) -- must listen show:

http://quantifiedbody.podbean.com/mf/web/vseakj/Quantified-Body-Podcast-Ep-2-Brain-Neurotransmitter-Optimization-with-Dr-William-J-Walsh.mp3


Episode 2 – William J. Walsh
Optimizing Your Brain via Biochemistry

Our performance and quality of life is largely dependent on a delicate balance of brain biochemistry. It defines our mental health, mood, our anxiety, our focus and attention, cognitive performance and ultimately even our personality.

Today’s guest estimates that 80 to 90% of the population have some kind of biochemistry abnormality that affects their brain. This is based on insights from a database of biochemistry he has collected over 35 years with over 3 million biochemistry test assays. So while many of us may not be included within the 26% of the population included in clinical diagnoses for mental disorders, most of us can improve our mental wellbeing or cognitive performance by addressing biochemistry imbalances.

Today’s guest is Dr. William J. Walsh, founder of the WalshInstitute.org. Over his 35 year career he has treated 30,000 patients with a wide range of brain related disorders, successfully treating them by addressing biochemical, methylation and epigenetic abnormalities. The treatments are nutrient based to realign biochemistry, and thus drug free.

William is also a frequent lecturer at conferences across the world including organizations such as the American Psychiatric Association, the U.S. Senate and the National Institutes of Mental Health. In short, he’s got a very in long and deep CV backed up by those 35 years of experience.
“In the areas of depression and behavior disorders and ADD and even schizophrenia… about 95%… have those conditions because of their abnormal biochemistry and by correcting and normalizing these brain chemicals, we were able to help most of them.”
– William J. Walsh PhD

This is a great interview that goes into a lot of depth in biochemistry, the labs, as well as looking at the emerging area of epigenetics and how work there will help us resolve more health issues and optimizing your brain via biochemistry.

....

Syrian Rue has carved its name into the chronicles of time. Michelangelo used Syrian Rue (known also by its Latin name – Peganum harmala). Leonardo da Vinci said Syrian Rue is “miracle smart nutrient”. In the Middle East it is known as Esfand where its use dates back to pre-Zoroastrian ancient times . Most references to Syrian Rue in Persian history involve the use of magick. Greeks refer to it as Persaia botane. Shakespeare referred to it in his writings, although his personal use of it is unknown. Traces have been found in the hair of Egyptian mummified bodies.

When whole seeds are placed on hot charcoals the seeds explode like popcorn, releasing a fragrant smoke. It it very likely that the ancient “Soma Plant” is Syrian Rue by another name for the somatic science that surrounds it. Pedanius Dioscorides documented that Syrian Rue not only antidotes snake poisons but all deadly poisons, including poison mushrooms, scorpions, spiders, and mistletoe. Syrian Rue is also recommended for fevers with rigors(chills). Serapio calls it ‘the ultimate medicine against the evil of poisons’. Syrian Rue was used by thieves who robbed the houses of plague victims under the protection of their aromatic repellent. It is also known as the “anti-plague” plant. After the assignation of his father by poison, Mithridates King of Pontus studied poisons and used Syrian Rue to protect himself.

In addition to all the ancient documentation about Syrian Rue, more recent scientific observations from research teams around the world (fully referenced below) prove that the fluorescent harmala beta-carboline alkaloid combined with all the other alkaloids in Syrian Rue is arguably magical or contains a synergy of alkaloids which is responsible for the unusual combination of it being antibacterial, antiviral, and antiparasitic, as well as antimutagenic and antigenotoxic.

In 2007 it was first proposed that Syrian Rue might help with diabetes, by 2015 independent studies are reporting success with Rue, in 2017 now we know Type 2 diabetics might be able to achieve a reversal of their condition and Type 1 diabetes patients are able to produce healthy new pancreatic beta cells. Researchers all around the world are finding , documenting, and sharing the details of their discovery surrounding the healing powers of Syrian Rue, therefore we are not forced to blindly trust ancient knowledge as we consider the following modern science:

Growth Inhibitory Impact of Peganum harmala L. on Two Breast Cancer Cell Lines

The P. harmala extract exposure against two cancer cell lines, MDA-MB-231 and Mcf-7. In conclusion, the results of the current research address the anti-cancer effect of P. harmala L. to its alkaloid components mainly hamine and harmaline. It is suggested to perform further studies to elucidate the mechanism of action of both harmine and harmaline on more human cancer cell lines and eventual use of these herbal active principle compounds in future anti-cancer pharmaceutical is considerable.

Article 2, Volume 12, Issue 1, Winter 2014, Page 8-14 XML PDF (655 K)
Document Type: Research Paper
DOI: 10.5812/ijb.18562
Sahar Seyed Hassan Tehrani; Somayeh Hashemi Sheikh Shabani; Sattar Tahmasebi Enferadi ; Zohreh Rabiei

Vaginitis still remains as a health issue in women. It is notable that Candida albicans producing biofilm is considered a microorganism responsible for vaginitis is hard to treat. Peganum harmala was applied as an anti fungal in treatment for many infections in Iran. Therefore, this study goal to investigate the role of P. harmala in inhibition of biofilm formation in C. albicans. Results demonstrated that P. harmala in concentration of 12 μg/ml easily inhibited strong biofilm formation.

Osong Public Health and Research Perspectives Volume 7, Issue 2, April 2016, P 116-118
Elham Aboualigalehdari, Nourkhoda Sadeghifard, Morovat Taherikalani, Zaynab Zargoush, Zahra Tahmasebi, Behzad Badakhsh, Arman Rostamzad, Sobhan Ghafourian, Iraj Pakzad

The cytotoxic effects of peganum harmala were evaluated on six malignant cancer cells. Total alkaloids of the different parts were cytotoxic towards practically all cancer cell lines with IC50 ranging 1–52 µg/mL after 72 h of treatment. These data indicate that P. harmala alkaloids extract may support the traditional claims regarding its anticancer uses which could be helpful in providing of new cytotoxic agents against chemo-resistant cancer cells.

European Journal of Integrative Medicine Volume 9, January 2017, Pages 91-96
Lamine Bournine, Sihem Bensalem, Sofiane Fatmi, Fatiha Bedjou, Véronique Mathieue, Mokrane Iguer-Ouada, Robert Kisse, Pierre Duez

Peganum harmala has been shown to have antibacterial and anti-protozoal activity (cures protozoan infections also), including antibacterial activity against drug-resistant bacteria.

J. Nat. Prod. 44 (6): 745. PMID 7334386. doi:10.1021/np50018a025
Al-Shamma A, Drake S, Flynn DL

P harmala seeds extract showed significant in vitro and in vivo antileishmanial activities. Cutaneous leishmaniasis (CL), an endemic disease in many tropical and subtropical areas, including central and southern parts of Iran, continues to present serious treatment problems. The disease, although usually self-limiting, can cause considerable morbidity and may result in severe disfigurement. P. harmala, vasicine (peganine), has been found to kill the protozoan parasite Leishmania donovani.

Journal of Research in Medical Sciences. 2011 Aug; 16(: 1032–1039.
Parvaneh Rahimi-Moghaddam, Soltan Ahmed Ebrahimi, Hourmazd Ourmazdi, Monawar Selseleh, Maryam Karjalian, Giti Haj-Hassani, Mohammad Hossein Alimohammadian, Massoud Mahmoudian, and Massoumeh Shafiei

P. harmala has appreciable efficacy in destroying intracellular parasites in the vesicular forms. Because of its appreciable efficacy in destroying intracellular parasites as well as non-hepatotoxic and non-nephrotoxic nature, harmine, in the vesicular forms, may be considered for clinical application in humans.

Journal of Drug Targeting,
2004 Apr;12(3):165-75.
Lala S, Pramanick S, Mukhopadhyay S, Bandyopadhyay S, Basu M

In this study, we investigated the protective effects of Peganum harmala seeds extract (CPH) against chronic ethanol treatment. Hepatotoxicity was induced in male Wistar rats by administrating ethanol 35% (4?g/kg/day) for 6 weeks. CPH was co-administered with ethanol, by intraperitonial (IP) injection, at a dose of 10?mg/kg bw/day. Control rats were injected by saline solution (NaCl 9‰). Chronic ethanol administration intensified lipid peroxidation monitored by an increase of TBARS level in liver. Ethanol treatment caused also a drastic alteration in antioxidant defence system; hepatic superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities. A co-administration of CPH during ethanol treatment inhibited lipid peroxidation and improved antioxidants activities. However, treatment with P. harmala extract protects efficiently the hepatic function of alcoholic rats by the considerable decrease of aminotransferase contents in serum of ethanol-treated rats.

Archives of Physiology and Biochemistry – The Journal of Metabolic Diseases
Volume 121, Issue 2 Published online: 14 May 2015
Ezzeddine Bourogaa, Raoudha Mezghani Jarraya, Mohamed Damak & Abdelfattah Elfeki
http://dx.doi.org/10.3109/13813455.2015.1016974

Mice? It was 1999 then – from mice to men that is evolution in the end.

Peganum harmala seed extracts also show effectiveness against various tumor cell lines, both in vitro and in vivo. Results obtained indicate that alkaloids of Peganum have a high cell toxicity in vitro. The active principle at a dose of 50 mg/kg given orally to mice for 40 days was found to have significant antitumoural activity. Peganum harmala alkaloids thus possess significant antitumour potential, which could prove useful as a novel anticancer therapy.

1999 Nov-Dec;54(6):753-8.
Lamchouri F, Settaf A, Cherrah Y

Plant derived agents may exert a new approach to the treatment of leukaemia. The present study was an evaluation of proliferation, cytotoxicity and differentiation of harmine and harmaline on HL60 cells, alone or in combination with ATRA and G-CSF. Counting of cells, viability, MTT assay, morphology, NBT reduction and flow cytometry analysis were performed using CD11b and CD 14 monoclonal antibodies. The data showed that harmine and harmaline reduced proliferation in dose and time dependent manner. This shows that the direction of differentiation is dominantly determined by ATRA. These preliminary data implies a new approach in treatment of leukemia.

Archives of Pharmacal Research July 2007, Volume 30, Issue 7, pp 844
Farhad Zaker, Arezo Oody, Alireza Arjmand

Twelve indole alkaloids, including two novels, were purified and identified from P. harmala. The chemical structures were determined by spectroscopic and chemical methods. The cytotoxicities against five human leukemia cell lines were assayed for the alkaloids. Some alkaloids showed potent cytotoxicity against human leukemia cells. Harmalacidine (HMC) showed the highest cytotoxicity against U-937, which could induce cell apoptosis. The results suggest that the alkaloids have perfect selectivity for human leukemia cells.

Toxins (Basel). 2017 May; 9(5): 150.
Published online 2017 Apr 28. doi: 10.3390/toxins9050150
Yuan Li, Yunli Zhao, Xia Zhou, Wei Ni, Zhi Dai,Dong Yang, Junjun Hao, Lin Luo, Yaping Liu,Xiaodong Luo, and Xudong Zhao

The beta-carboline alkaloids present in medicinal plants, such as Peganum harmala and Eurycoma longifolia, have recently drawn attention due to their antitumor activities. Further mechanistic studies indicate that beta-carboline derivatives inhibit DNA topoisomerases and interfere with DNA synthesis. Moreover, some beta-carboline compounds are specific inhibitors of cyclin dependent kinases (CDKs). In this study we used budding yeast as a model system to investigate the antitumor mechanism of beta-carboline drugs. We found that DH334, a beta-carboline derivative, inhibits the growth of budding yeast.

Cancer and Biological Therapy, 2007 Aug;6(:1193-9. Epub 2007 May 4.Li Y, Liang F, Jiang W, Yu F, Cao R, Ma Q, Dai X, Jiang J, Wang Y, Si S.

We report the in vivo antioxidative properties of the aromatic (harmane, harmine, harmol) and dihydro-beta-carbolines (harmaline and harmalol) studied by using Saccharomyces cerevisiae strains proficient and deficient in antioxidant defenses. Their antimutagenic activity was also assayed in S. cerevisiae and the antigenotoxicity was tested by the comet assay in V79 cell line, when both eukaryotic systems were exposed to H(2)O(2). We show that the alkaloids have a significant protective effect against H(2)O(2) and paraquat oxidative agents in yeast cells, and that their ability to scavenge hydroxyl radicals contributes to their antimutagenic and antigenotoxic effects.

Mutagenesis. 2007 Jul;22(4):293-302. Epub 2007 Jun 1.
Moura DJ, Richter MF, Boeira JM, Pêgas Henriques JA, Saffi J

Gamma-harmine exhibited relatively good radioprotective effect. Gamma-harmine is the first alkaloid isolated from a plant having protective effects against whole-body lethal irradiation in mice

Yao Xue Xue Bao. 1995;30(9):715-7..

A 2016 study investigated the antimicrobial activity of Harmal ( Peganum harmala) aqueous extracts against two fungi (Aspergillusniger and Peniciliumitalicum) and two Gram negative bacteria (Escerichia coli and Salmonellatyphi). The Harmal methanolic extracts were found to inhibit mycelial radial growth of both fungi. This effect was found to be significant at first day of the experiment as well as the last days. Mycelial fresh and dry weights of both fungi were also greatly reduced with harmal extracts. The higher concentration of Harmal gave the maximum effect which decreased with dilution. The effect on mycelial growth was more pronounced on P.italicum than on A.niger. The effect of Harmal leaves extract on the two bacteria (E.coli and S.typhi) was evaluated by the inhibition zone and dilution methods. A clear zone of inhibition was shown by the extracts against both bacteria, although the inhibition was less against E.coli. The results of the dilution plate method showed that the log number of colonies of both bacteria was highly decreased with Harmal extract; however, S.typhi was more susceptible and greatly affected by the extract.

Journal of Microbiology Research, p-ISSN: 2166-5885 e-ISSN: 2166-5931, 2016
Abdel Moneim E. Sulieman, Ahmed A. Alghamdi, Vajid N. Veettil, Nasir A. Ibrahim

According to test results, P. harmala seeds extract showed potent antioxidant activity with IC50 values ranging between 40-129 µg/ml. In case of antibacterial assay, P. harmala seeds showed better inhibitory activity than leaves against both strains i.e. Staphylococcus aureus and Pseudomonas aeruginosa with values ranging between 70 to 100% while in case of antifungal assay water-acetone extract of seeds showed significant antifungal effect against Aspergillus niger. In terms of cytotoxic assay, hexane extract of seeds of were more cytotoxic against shrimp larvae (LD50 = 57.07 µg/ml). Aqueous extract of leaves of and acetone extract of seeds showed < 80% mortality in antileishmanial assay. GC-MS analysis revealed that leaves and seeds contain some important biological metabolites. It is concluded that selected plants could be a potential source of antileishmanial, antibacterial, antifungal and anticancer lead compound. Hence it is indicated to further investigate this plant in vitro as well as in vivo for new drug discovery.

International Journal of Biosciences, 9(1), 45-58, July 2016.
DOI: http://dx.doi.org/10.12692/ijb/9.1.45-58
Zainab Gul Kanwal, Abdul Hafeez, Ihsan Ul Haq, Tofeeq-Ur-Rehman, Syed Aun Muhammad, Irum Shazadi, Nighat Fatima, Nisar Ur Rehman

Introduction: Benign prostatic hyperplasia (BPH) is considered as a major cause of lower urinary tract symptoms (LUTS) in older men and its most common sign is nocturia. Objectives: This study aimed to determine the effect of the seeds of Peganum harmala compared with tamsulosin on alleviating urinary symptoms in patients with BPH. Patients and Methods: In this single blind clinical trial study, 90 patients diagnosed with BPH and LUTS, based on international prostate standard survey (IPSS) were divided into three groups. The first group was received oral capsule of P. harmala, the second group was administered tamsulosin with oral P. harmala seed and the third group was received tamsulosin drug and they were evaluated after 4 weeks. Results: The results showed that the difference between mean scores of IPSS was significant after the intervention (P=0.001). Besides, the mean of IPSS in the three groups was significantly different (P=0.001) (the first group 41.9±5.3, the second group 21.0±4.4 ,the third group 16.5±3.7 respectively). However, after the intervention, patients in the second group had the lowest average on most indicators of IPSS but the difference was only significant about urinary frequency, nocturia and intermittency(P<0.05). Conclusion: Application of Peganum harmala seed can be useful in reducing urinary symptoms in patients with BPH.

Journal of Renal Injury Prevention 2017 ;6(2):127-131. PMID: 28497089
Majid Shirani-Boroujeni, Saeed Heidari-Soureshjani, Zahra Keivani Hafshejani

Syrian Rue exhibits antisecretory and cytoprotective properties and is successfully treating gastric ulcers.
Phytomedicine Volume 20, Issue 13, 15 October 2013, Pages 1180-1185
Biochem Biophys Res Commun. 2011 Jun 3; 409(2):260-5

Two different studies showed bone anabolic effects of harmine. These findings suggest that harmine, as the main alkaloid of P. harmala, may be useful for treatment of some bone diseases. Harmine promotes osteoblast differentiation through bone morphogenetic protein signaling.

Yonezawa T, Lee JW, Hibino A, Asai M, Hojo H, Cha BY, Teruya T, Nagai K, Chung UI, Yagasaki K, Woo JT
European Journal of Pharmacology 2011 Jan 15; 650(2-3):511-8.

Using X-ray crystallographic analysis, Ten new alkaloids (peganumine B-I and two enantiomers), containing five β-carbolines, three quinazolones were isolated from the ethanol extract of Peganum harmala seeds testing their measured potential cytotoxicity and cholinesterase inhibitory activities.

DOI: 10.1039/C6RA00086J (Paper) RSC Adv., 2016, 6, 15976-15987
Ya-di Yang, Xue-mei Cheng, Wei Liu, Zhu-zhen Han, Gui-xin Chou, Ying Wang, Du-xin Sun, Zheng-tao Wang and Chang-hong Wang

Rats? Diabetic humans has been done already….

In 2016, a study indicated that hydroalcoholic extract of Peganum harmala seeds possesses antidiabetic and hypolipidemic activities in streptozotocin-induced diabetic male rats.

Cholesterol, Volume 2016 (2016), Article ID 7389864, 6 pages
Gholamreza Komeili, Mohammad Hashemi, and Mohsen Bameri-Niafar

Rats again… I have never heard of a human Parkinson’s Disease study with Syrian Rue, I expect to see one in 2018 if not by the close of 2017…..

Another 2016 study finds Peganum Harmala L. Extract Reduces Oxidative Stress and Improves Symptoms in 6-Hydroxydopamine-Induced Parkinson’s Disease in Rats.

Iran J Pharm Res. 2016 Winter;15(1):275-81. PMID:27610168 PMCID:PMC4986102
Rezaei M, Nasri S, Roughani M, Niknami Z, Ziai SA.

A 2016 study found that Syrian Rue fights dental plaque. An ethanolic extract of P. harmala can inhibit the growth of S. mutans. Despite the higher inhibitory effect of 0.2% chlorhexidine compared to 50 mg/mL of this extract, other studies indicate that higher concentrations of P. harmala extract can have similar or greater inhibitory effect against microorganisms. However, high cell toxicity of this extract on cells limits the use of this plant as an antimicrobial agent (like mouthwash) in oral cavity. Even if limited to low concentrations, either lonely or in combined preparations, its application might be more useful for resistant bacteria compared to the routine available mouthwashes. Further antimicrobial and cytotoxicity studies on animals or human subjects are needed to obtain more accurate and applicable results.

Journal of dentistry (Shiraz), 2016 Sep; 17(3): 213–218. PMCID: PMC5006831
Mohammad Motamedifar, Hengameh Khosropanah, and Shima Dabiri

The extract of Peganum harmala was used topically to treat certain dermatoses of inflammatory nature. Results were encouraging and proved the antibacterial, antifungal, antipruritic and probably antiprotozoal effects of the extract.

International Journal of Dermatology, May 1980, DOI:10.1111/j.1365-4362.1980.tb00305.x
El-Saad El-Rifaie M

In very very extremely large doses, Syrian Rue is an abortifacient in humans.

In a study on cattle, the curative effect of P. harmala was better than that of diminazene aceturate and produced minimal side effects proven safe for pregnant animals. It was concluded that the total alkaloid of P. harmale showed a marked effect as a treatment for haemosporidican infections in cattle.

Trop Anim Health Prod. 1997 Nov;29(4 Suppl):72S-76S.
Hu T, Fan B, Liang J, Zhao S, Dang P, Gao F, Dong M

https://syrianrue.org/research/

More on P. harmala and anti-tumor effects...

...
Pharmacogn Rev. 2013 Jul-Dec; 7(14): 199–212.
doi:  10.4103/0973-7847.120524
PMCID: PMC3841998
Pharmacological and therapeutic effects of Peganum harmala and its main alkaloids
Milad Moloudizargari, Peyman Mikaili,1 Shahin Aghajanshakeri, Mohammad Hossein Asghari, and Jalal Shayegh2
Author information ► Article notes ► Copyright and License information ►
This article has been cited by other articles in PMC.
Abstract

Wild Syrian rue (Peganum harmala L. family Zygophyllaceae) is well-known in Iran and various parts of this plant including, its seeds, bark, and root have been used as folk medicine. Recent years of research has demonstrated different pharmacological and therapeutic effects of P. harmala and its active alkaloids, especially harmine and harmaline. Analytical studies on the chemical composition of the plant show that the most important constituents of this plant are beta-carboline alkaloids such as harmalol, harmaline, and harmine. Harmine is the most studied among these naturally occurring alkaloids. In addition to P. harmala (Syrian rue), these beta-carbolines are present in many other plants such as Banisteria caapi and are used for the treatment of different diseases. This article reviews the traditional uses and pharmacological effects of total extract and individual active alkaloids of P. harmala (Syrian rue).
Keywords: Harmine, harmaline, peganum harmala, pharmacological effects, wild syrian rue

INTRODUCTION

Harmal[1] (Peganum harmala L. family Zygophyllaceae) is a perennial, glabrous plant which grows spontaneously in semi-arid conditions, steppe areas and sandy soils, native to eastern Mediterranean region. It is a shrub, 0.3-0.8 m tall with short creeping roots, white flowers and round seed capsules carrying more than 50 seeds. The plant is well-known in Iran and is widely distributed and used as a medicinal plant in Central Asia, North Africa and Middle East.[2,3,4,5] It has also been introduced in America and Australia. Dried capsules – mixed with other ingredients – are burnt as a charm against “the evil eye” among Iranians.[2] This plant is known as “Espand” in Iran, “Harmel” in North Africa and “African rue,” “Mexican rue” or “Turkish rue” in the United States.[6] Various parts of P. harmala including its seeds, fruits, root, and bark, have been used as folk medicine for a long time in Iran and other countries [Table 1]. Many pharmacological surveys have shown different effects of P. harmala [Table 4] and/or its active alkaloids (particularly harmaline) [Table 5].
Table 1
Table 1
Traditional uses of Peganum harmala
Table 4
Table 4
Chemical compounds of P. harmala
Table 5
Table 5
Toxic doses of various alkaloids of Peganum harmala

Studies carried out on the chemical composition of the extracts show that beta-carboline and quinazoline alkaloids are important compounds of this plant [Figure 1]. In one study, the concentration of harmaline in different parts of the plant including seeds, fruits, and capsule walls was determined by Reverse phase high-performance liquid chromatography (RP-HPLC) as 56.0 mg/g, 4.55 mg/g and 0.54 mg/g, respectively.[7] Although, harmaline and harmine are the most important alkaloids that are generally responsible for their beneficial effects, numerous studies show that other alkaloids present in P. harmala also have some roles in the pharmacological effects of the plant.[8] Harmaline (C13H15ON2) was first isolated by Göbel from the seeds and roots of P. harmala and is the major alkaloid of this plant.[6] In addition to P. harmala (Harmal), beta-carboline alkaloids are present in many other plants such as Banisteriopsis caapi (Malpighiaceae). They are also constituents of Ayahuasca, a hallucinogenic beverage ingested in rituals by the Amazonian tribes.[7] This article completely reviews the pharmacological effects of P. harmala [Table 2] and its active ingredients [Table 3].[6,7]
Table 2
Table 2
Pharmacological effects of Peganum harmala
Table 3
Table 3
Pharmacological effects of alkaloids of Peganum harmala
Figure 1
Figure 1
Molecular structure of major alkaloids of peganum harmala

CARDIOVASCULAR EFFECTS

P. harmala is one of the most frequently used medicinal plants to treat hypertension and cardiac disease worldwide.[9,85] It has also been shown in various pharmacological studies that P. harmala extract or its main active alkaloids, harmine, harmaline, Harman and harmalol, have different cardiovascular effects such as bradycardia, decreasing systemic arterial blood pressure and total peripheral vascular resistance, increasing pulse pressure, peak aortic flow and cardiac contractile force,[10] Vasorelaxant[11,12] and angiogenic inhibitory effects.[13]
Vasorelaxant and antihypertensive effects

The aqueous (AqE) extract of the seeds of P. harmala have antispasmodic, anticholinergic, antihistaminic and antiadrenergic effects.[14] One study on the cardiovascular effects of harmine, harmaline and harmalol indicated that these three alkaloids have vasorelaxant effects with rank order of relaxation potency of harmine >harmaline >harmalol. In case of the first two alkaloids this vasorelaxant activity was not only attributed to their interaction with the alpha 1-adrenergic receptors in vascular smooth muscles but also more importantly to their increasing effect on notric oxide (NO) release from the endothelial cells, which was dependent on the presence of external Ca2+. Harmalol had no effect on the release of NO from the endothelial cells and it weakly interacted with the cardiac 1,4-dihydropyridine binding site of L-type Ca2+ channels (Ki value of 408 microM).[11] In the same study, the vasorelaxant activity of harman, another active alkaloid of P. harmala, was shown with a mechanism of interaction with the L-type Ca2+ channels and increasing NO release from the endothelial cells so dependent on the presence of external Ca2+. These effects of harman may be involved in its hypotensive activity.[15] Another study indicates that the action of harmaline on the prostacyclin pathway also plays a role in its vasoleraxant activity.[12] It has been also shown that harmaline, harmalol and harmine decrease systemic arterial blood pressure and total peripheral vascular resistance obviously not due to activation of cholinergic, beta-adrenergic and histamine (H1) receptors. The harmaline-evoked decreases were frequently followed by a secondary increase and these two effects of harmalol were inconsistent.[10] Astulla et al. also showed in an in vitro study the vasorelaxant activity of vasicinone, another alkaloid isolated from the seeds of P. harmala, against phenylephrine-induced contraction of isolated rat aorta.[16]

Effects on the heart

There have been a few studies conducted regarding the direct effects of P. harmala extract and its alkaloids on heart muscle. For example, in one study it was shown that three P. harmala isolated alkaloids (Harmine, Harmaline and Harmalol) have ionotropic effect and also decrease heart rate in normal anesthetized dogs. Since neither vagotomy nor atropinization affected the harmala-induced bradycardia it became evident that the decrease in heart rate was not due to a negative chronotropic effect of the alkaloids.[10]

In another in vivo study, harman dose-dependently produced transient hypotension and long-lasting bradycardia in anesthetized rats.[11] Harmaline inhibits both 45Ca2+ uptake and efflux in cardiac sarcolemal vesicles in a dose-dependent manner.[17]

Angiogenic inhibitory effect

It was revealed in a study that harmine is a potent angiogenic inhibitor. This substance can significantly decrease the proliferation of vascular endothelial cells and reduce expression of different pro-angiogenic factors such as vascular endothelial growth factor, NO and pro-inflammatory cytokines. Nuclear factor-κB and other transcription factors like cAMP response element-binding (CREB) and Activating transcription factor 2 (ATF-2) involved in angiogenesis were also inhibited by harmine. Moreover, harmine decreased production of other factors by tumor cells, which play a significant role in angiogenesis like cyclooxygenase (COX-2), inducible nitric oxide synthase, and matrix metalloproteases.[13]
Inhibitory effect on platelet aggregation

The alkaloids of P. harmala are also shown to have anti-platelet aggregation effects.[18] However, there is not so much evidence on this effect of the plant so far.

EFFECTS ON NERVOUS SYSTEM

In traditional medicine, P. harmala has been used among societies to treat some nervous system disorders such as Parkinson's disease,[19] in psychiatric conditions[7] such as nervosity,[20] and to relieve rigorous pain.[21] The alkaloid content of P. harmala is shown to be psychoactive[22] and various in vitro and in vivo studies indicate a wide range of effects produced by P. harmala and its active alkaloids on both central and peripheral nervous system including, analgesia,[22,23] hallucination, excitation,[24] and anti-depressant effect.[25,26]

Some of these alkaloids such as harmaline, harmine, and norharmane are also endogenous compounds present in the body and since they have been found in high plasma concentrations in alcoholics,[27] drug addicts,[28] smokers,[29] and patients with Parkinson's disease,[30] they are thought to be crucially involved in various central nervous system (CNS) problems.

It has been also proven that P. harmala-derived beta-carbolines interact with opioid,[21] dopamine,[24] GABA (Gamma-Aminobutyric acid),[31] 5-hydroxytryptamine, benzodiazepine, and imidazoline[32] receptors present in the nervous system and this way induce their many pharmacological effects. Moreover, these alkaloids are neuroprotective[31,33] and strong inhibitors of monoamine oxidase and this important feature makes them a preferable target in the treatment of some conditions like depression.[25]

Mono amine oxidase inhibition and anti-depressant effect

Beta-carbolines present in P. harmala strongly inhibit monoamine oxidase enzyme that is the main factor in degradation and reuptake of monoamines like serotonin and norepinephrine. It was pointed out in an in vitro study that seed and root extracts of P. harmala significantly inhibits MAO-A but has no effect on MAO-B. In case of the seed extract the inhibitory effect was reversible and competitive with an IC50 of 27 μg/l and it was mostly attributed to harmaline and harmine. The strong inhibitory effect of the root extract was only due to harmine and the IC50 was calculated as159 μg/l.[7] It could be concluded that this inhibitory effect has the potential to reverse the MAO-mediated monoamine reduction in depression. Harmine at high doses increased the BDNF (Brain-derived neurotrophic factor) protein level, which is decreased in depressive conditions, while imipramine, a common anti-depression drug, had no such effect.[25] Farzin et al. revealed in a study on the anti-depressant effects of harmane, norharmane, and harmine using the mouse force swim test that these alkaloids of P. harmala have a significant dose-dependent anti-depressive effect with a suggested mechanism of acting on benzodiazepine receptors. It was shown in another in vitro study that the extract of P. harmala has the ability to inhibit catechol-O-methyltransferase and thereby the methylation of catecholamines with a mixed type mechanism.[34] All of these effects represent an idea that P. harmala and its derivatives could be used for treatment of mood disorders and are potent alternatives for current anti-depression drugs.

Analgesic and antinociceptive effects

The analgesic effect of different forms of P. harmala extract (ethyl acetate [EAE], butanolic [BE], and AqE) have been investigated in various parallel studies. The methods used in these studies include formalin, hot plate, and writhing tests. The results showed that all forms of the extracts produced the analgesic effect. Among the extracts, BE showed the maximum effect with a percentage of 35.12% in the writhing test. In case of the AqE, the nociceptive effect was only observed in the second phase of the formalin test. Treatment with both EAE and BE produced a dose-dependent analgesia. Since treatment with naloxone prevented the nociceptive effect of the extracts, it is concluded that an opioid-modulated mechanism is involved. The results also indicated that the extracts act both centrally and peripherally.[21,23,35]

Relation with Parkinson's disease

The endogenous harmala alkaloids have been proven to be involved in Parkinson's disease.[31] One study on both endogenous and exogenous beta-carbolines showed that they all have general DAT-mediated (Dopamine active transporter-mediated) dopaminergic toxicity and therefore, are involved in the pathogenesis of Parkinson's disease.[36] Adversely, it was revealed in an in vitro study that two of these endogenous compounds, norharman and 9-methylnorharman, have good anti-parkinsonism effects via inhibition of MAO-B, an enzyme involved in the production of parkinsonism-related substances from the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. However, naturally occurring beta-carbolines had almost no such inhibitory effect.[33]

In contrast, several studies on the anti-parkinsonism effect of B. caapi revealed that its beta-carboline content (harmine and harmaline) has significant effect against this disease through the inhibition of MAO-B.[37,38] Although, these beta-carbolines with anti-parkinsonism effect are also present in P. harmala, there have been no studies conducted regarding the possible effect of P. harmala isolated alkaloids against Parkinson's disease, thus far.

Other neuropsychological effects

There have been reports of other effects produced by P. harmala in the nervous system.

In an in vitro study desoxypeganine, one of the P. harmala alkaloids, dose-dependently decreased ethanol consumption in female Alko alcohol rats with no effect on food and fluid consumption.[39] This may represent a safe way to decrease the consumption of alcohol in alcoholics. Harmane, another alkaloid isolated from P. harmala induced amnesia with a suggested mechanism of interaction with dopaminic (D1 and D2) receptors.[24] Harmaline and harmane have been shown to modulate voltage-activated calcium- ICa (V)-channels in vitro and in a reversible and use independent manner.[31]

ANTIMICROBIAL EFFECTS

Various studies have shown different antiparasidal,[16,40] antifungal,[41,42] antibacterial[41,43] and insecticidal[44,45] effects of the alkaloids derived from P. harmala seeds. It has also been used widely as an anti-fungal[42] and antiparasidal[46] agent in traditional medicine of some parts of the world. For instance, in Saudi Arabia it has been so common to use P. harmala against fungal infections.[42] In one study, the methanolic, AqE and chloroform extracts of P. harmala were shown to have respectively strong, moderate, and slight inhibitory effects on the growth of Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger and Candida albicans.[42]

Preparations of P. harmala were also used in folk medicine of South-Eastern Spain as anti-leishmanial remedies.[46] Moreover, its powdered seeds and various extracts have been used as a remedy against tapeworm infections in men and animals in the indigenous system of medicine.[40]

Antiprotozoal effect

Various studies have been carried out investigating in vitro and in vivo effects of different P. harmala extracts on forms of leishmania parasites. One study on the effect of P. harmala extract on Leishmania infantum revealed that harmine and harmaline have weak anti-leishmanial activity against both promastigote and amastigote form of the parasite. At the same time, harmaline showed strong toxicity against the amastigote forms inside the macrophages. The suggested mechanism for this property is the inhibitory effect of harmaline on protein kinase C (PKC) action of the parasites.[47] Another study compared the in vitro antileishmanial activity of antimonyl tartrate and P. harmala extract against L. major. During this study the extract showed the same potency as antimonyl tartrate that means it could be a good alternative for the antimonial drugs as the first-line antileishmanial treatments with lots of severe side effects.[48] The effectiveness of the extract is mostly attributed to its beta-carboline content. P. harmala extract also decreased the lesion size and number of the parasites in cutaneous form of the disease.[49] In addition to the beta-carbolines, peganine another alkaloid of P. harmala, was shown to have strong in vitro and in vivo toxicity against both amastigotes and promastigotes of Leishmania donovani. A dose of 100 mg/kg body weight of peganine was effective against visceral leishmaniasis in hamsters.[50]

There have been several studies indicating effectiveness of P. harmala extract against theileriosis.[51,52] Two studies were conducted in Iran on the effect of P. harmala extract with a dose of 5mg/kg body weight once daily for 5 days on cattle[52] and sheep[51] theileriosis that showed a significant recovery rate of respectively 78% and 65%.

Beta-carbolines from the seeds of P. harmala showed strong trypanosomicidal activity against nifurtimux-resistant LQ strain of Trypanosoma cruzi. Inhibition of respiratory chain appears to be the possible determinant of this action of beta-carbolines.[53]

Furthermore, there have been reports of antiplasmodial activity of different P. harmala alkaloids such as vasicinone, deoxyvasicinone, and beta-carbolines.

Antibacterial activity

One of other important features of P. harmala alkaloids is their bactericidal activity that is comparable with that of common antibiotics, which have many adverse effects. Different species of bacteria have been shown to be susceptible to these alkaloids. For example Proteus vulgaris and Bacillus subtilis appeared to be very sensitive to harmine.[41] The activity of these alkaloids depended on the microorganism and the application method. For instance, the methanolic extract showed higher antibacterial potency against all tested micro-organisms (Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and P. vulgaris) than other chloroform and petroleum extracts in one study.[43]

It is concluded that P. harmala and its alkaloids could probably be used for the control of antibiotic resistant isolates of bacteria.[54]

Insecticidal and antifungal activity

In vitro treatment with individual alkaloids of P. harmala or a mixture of them was so efficient against A. niger and C. albicans with a minimal inhibitory concentration of total (crude) alkaloids respectively 0.333 ± 0.007 MIC (Minimum inhibitory concentration) (mg/ml) and 0.333 ± 0.007 MIC (mg/ml).[41] A synergistic activity of different alkaloids present in the crude extract might be involved in its strong effect.

Furthermore, there have been some reports about insecticidal activity of P. harmala-derived beta-carbolines indicating their inhibitory effects on the development and growth of the larval stages of some insects. For example harmaline prevented the development of larvae of Plodia interpunctella, an insect pest of stored food, to the pupal and adult stages.[44] This inhibitory effect of harmaline was due to its severe toxicity on the epithelial cells of the midgut that finally leads to shedding of the cytoplasm contents into the midgut lumen.

Another study showed the insecticidal activity of methanolic P. harmala extract against Tribolium castaneum, the stored grain pest. Larvae growth was significantly inhibited with the incorporation of the extract into their diet. The adult form of the insect was also susceptible. It could be a good idea to use P. harmala as a tool to control the population of such harmful insects.[45]

Antineoplasm, antiproliferative and antioxidant effects

Since ancient times, P. harmala has been used by traditional healers to make various preparations in the treatment of cancers and tumors in some parts of the world.[13,55] For example, it has been so common in traditional medicine of Morocco to use powdered seeds of P. harmala to treat skin and subcutaneous tumors.[56] The seed extract of P. harmala is the main component of a very common ethnobotanical preparation used against different cancers and neoplasms in Iran, namely Spinal-Z.[57,58]

The antitumor activity of P. harmala and its active alkaloids (mainly beta-carbolines) have also drawn attentions of many researchers worldwide that has led to various pharmacological studies regarding this important effect of P. harmala.[23,56] Various authors have reported cytotoxicity of P. harmala on tumor cell lines in vitro and in vivo. In one study, the methanolic extract of P. harmala reduced significantly proliferation of three tested tumor cell lines (UCP-Med (a tumor cell line), Med-mek carcinoma, and UCP-Med sarcoma) in all concentrations. This anti-proliferative effect was produced by the alkaloid fraction of the extract in the first 24 h of the treatment. A cell lysis effect was observed in the next 24 h and thus, resulted in complete cell death within 48 to 72 h.[56] The same results were observed with the total extract of the plant in another study. The extract also showed cytotoxicity against artificially grafted subcutaneous Sp2/O cell-line in BALB-c (Albino) mice.[56] Administration of different beta-carboline alkaloids isolated from P. harmala showed inhibitory effect against Lewis Lung cancer sarcoma-180 or HepA tumor in mice at rates of 15.3-49.5%. Substitution of formate at R3 and aryl at R9 of the tricyclic skeleton respectively decreased neurotoxicity and increased the inhibitory effects of the alkaloids that made them ideal agents to be used as novel antitumor drugs with lesser side effects.[55] Several in vitro and in vivo studies have revealed that these cytotoxicity and antitumor effects of P. harmala are related to its interaction with RNA,[59] DNA and its synthesis,[56,60] and inhibition of human Topoisomerase.[58] In a study conducted in Iran, it was shown using the DNA relaxation assay that the extract of P. harmala inhibits human DNA Topoisomerase I. This effect was attributed to the beta-carboline content of the extract and potency of the alkaloids were determined as harmine >harmane >harmaline in a way that treatment with the total extract showed weaker inhibitory effect than treatment with every individual alkaloid.[58] Another study indicated that harmine and its derivatives have inhibitory effect on human Topoisomerase I activity but no effect on Topoisomerase II. Intercalation of several carbolines into eukaryotic DNA has also been reported by many authors.[58,61] This intraction of beta-carbolines cause significant structural changes in DNA and interfere with its synthesis.[56,61] The alkaloid-DNA binding affinity was ordered as harmine >harmalol >harmaline >harmane >tryptoline. There are also other suggested mechanisms for the anti-tumor activity of P. harmala alkaloids. In an in vitro study by Li et al., budding yeast was used as a model to investigate the anti-tumor activity of P. harmala. Results showed that DH334, a beta-carboline derivative and an anticancer drug, specifically inhibits cyclin dependent kinases (CDKs) and blocks the initiation of cell cycle at the G1 phase. It also inhibited the kinase activity of Cdk2/CyclinA (a member of the cyclin family) in vitro. This could be another possible mechanism for the antitumor activity of the drug.[56,93]

Many pharmacological studies suggest an antioxidant and free radical scavenging effect of P. harmala. This effect has been attributed to the increasing effect of P. harmala extract on E2 (17β-estradiol) level as an important antioxidant and reactive oxygen species (ROS) scavenger.[12,62,63] In another study, the effects of harmaline and harmalol were tested on Digoxin-induced cytochrome P450 1A1 (CYP1A1), a carcinogen-activating enzyme, in human hepatoma HepG2 cells. These alkaloids significantly inhibited the enzyme via both transcriptional and posttranslational mechanisms in a concentration-dependent manner.[3] Ethanol and chloroform extracts of P. harmala showed protective effects against thiourea-induced carcinogenicity by normalization of neuron-specific enolase and thyroglobulin levels in animal models.[64] Other effects of the plant extract such as anti-proliferative effect on Leukemic cell lines,[65] inhibitory action on the metastasis of melanoma cells, inducing apoptosis in melanoma cells,[66] tumor angiogenesis inhibition,[13] and binding to RNA[61] have also been reported by various authors. In some cases, P. harmala showed a higher selectivity towards malignant cells than common anticancer drugs like doxorubicin.[57] All of these data suggest that P. harmala and its alkaloids possess the potential to be used as novel antioxidant and anti-tumor agents in anti-cancer therapy.

INDUCING EMMENAGOGUE AND ABORTION

P. harmala has been used traditionally as an effective emmenagogue and abortificient agent in the Middle East, India, and North Africa.[6,56,67] It has also been shown that abortion happens frequently among animals that digest this plant in a dry year.[8,68] Quinazoline alkaloids (e.g., vasicine and vasicinone) within P. harmala have been attributed to the abortificient effect of this plant.[8]

GASTROINTESTINAL EFFECTS

P. harmala extract and powdered seeds have been used in folk medicine of different parts of the world to treat colic in man and animals.[40] The efficiency of this plant in treatment of colic is due to its antispasmodic effect[69] probably as a result of blocking different types of intestinal calcium channels[70] by the alkaloid content of the plant specially harmaline. P. harmala also possesses noticeable nauseant[71] and emetic[7,72] effects.

OSTEOGENIC ACTIVITY

Two different studies conducted by Yonezawa et al. showed bone anabolic effects of harmine, in vivo and in vitro.[73,74] It was revealed that administration of 10 mg/kg/day of harmine inhibits formation and differentiation of osteoclasts in mice via down-regulation of c-Fos (A cellular proto-oncogene) and NFATc1 (Nuclear factor of activated T-cells, cytoplasmic 1) and thus, prevents osteoclast-mediated resorption. Adversly, it enhances osteoblast differentiation probably via inducing the expression of BMPs and activation of bone morphogenetic protein (BMP) and Runx2 pathways. It was also found that carbon C3C4 double-bond and 7-methoxy group of harmine plays an important role in these processes. These findings suggest that harmine, as the main alkaloid of P. harmala, may be useful for treatment of some bone diseases.

IMMUNE SYSTEM EFFECTS

Beta-carboline alkaloids of P. harmala are shown to have immune-modulatory effects in several studies.[26,75] Extracts of this plant have significant anti-inflammatory effect via the inhibition of some inflammatory mediators including prostaglandin E2 (PGE2) (100 μg/mg) and tumor necrosis factor alpha (TNF-α) (10 μg/mg).[46]

ANTIDIABETIC EFFECTS

P. harmala has been traditionally used to treat diabetes in folk medicine of some parts of the world.[69,76] This effect of P. harmala has been pharmacologically confirmed in several studies one of which showed that the plant would lose its hypoglycemic activity at high doses instead of increasing it.[77] Harmine is the main alkaloid of P. harmala that is involved in its anti-diabetic effect.[25] One study shows that harmine regulates the expression of peroxisome proliferator-activated receptor gamma (PPARγ), the main regulator of adipogenesis and the molecular target of the thiazolidinedione antidiabetic drugs, through inhibition of the Wnt signaling pathway. Therefore, it mimics the effects of PPARg ligands on adipocyte gene expression and insulin sensitivity without showing the side-effects of thiazolidinedione drugs such as weight gain.[78]

TOXICITY

In addition to all therapeutic effects of P. harmala, there have been several reports of human[79] and animal[68] intoxications induced by this plant. There are also experimental studies indicating P. harmala toxicity.[6,7] In an in vitro study, intrapretoneal administration of three different extracts of P. harmala at a dose of 50 mg/kg body weight induced sympthoms such as: Abdominal writhing, body tremors and slight decrease in locomotor activity,[21] while oral administration of these extracts showed no toxicity. There have been also the same symptoms reported in different human cases[2,6,80] following ingestions of P. haramala seed extract or infusion including: Neuro-sensorial symptoms, visual hallucination, slight elevation of body temperature, cardio-vascular disorder such as bradycardia and low blood pressure, psychomotor agitation, diffuse tremors, ataxia and vomiting. Despite animal intoxications in almost all of human cases, P. harmala poisonings were relieved in a few hours.[6] P. harmala extract is toxic at high-doses[7,77,81,82] and can cause paralysis, liver degeneration, spongiform changes in the central nervous system,[83] euphoria, convulsions, digestive problems (nausea, vomiting), hypothermia and bradycardia.[2,6,68,80] However, therapeutic doses have been reported to be safe in a rodent model.[54]

MAO inhibition activity of P. harmala components are the main cause for the toxicological effects after ingestion of the plant.[7] Moreover, the intercalation of P. harmala alkaloids into DNA has led to its mutagenic property which causes genotoxic effects.[84] P. harmala methanolic extract has showed teratogenic effects in female rats.[68] The extract prolonged diestrus phase, reduced number of living pups, and decreased the number of resorption. It also dose-dependantly decreased litter size.[8] These data all together suggest that care should be taken while using P. harmala and its derivatives as therapeutic agents in order to prevent probable intoxications.

DRUG INTERACTION

P. harmala is shown to interact with drug metabolism due to its significant effects on the expression of cytochrome P450s (CYP), the most important superfamily of drug metabolizing enzymes. Seeds of this plant dose-dependently increase the expression of CYP1A2, 2C19, and 3A4 whereas decrease the expression of CYP2B6, 2D6 and 2E1. Harmine and harmaline are the main contents involved. These data all together suggest that care should be taken when P. harmala is co-administered with other drugs.[3]

CONCLUSION

Our aim in preparing this paper was to show the traditional usage and previously confirmed pharmacological effects of P. harmala as one of the most well-known medicinal plants in Iran and to illustrate it's potential to be used as a novel source for the development of new drugs based on the most recent associated studies. As it is evident from this study, P. harmala has a wide range of pharmacological effects including cardiovascular, nervous system, gastrointestinal, antimicrobial, antidiabetic, osteogenic, immunomodulatory, emmenagogue, and antitumor activity among many other effects. Beta-carboline alkaloids contained in P. harmala are the most important contents of the plant responsible for most of its pharmacological effects. Since there have been many reports of intoxications following ingestion of specific amounts of P. harmala seeds, care should be taken by scientists and clinicians regarding usage of this plant for therapeutic purposes until adequate studies confirm the safety and quality of the plant. Finally, based on this information, this review provides the evidence for other researchers to introduce P. harmala as a safe and effective therapeutic source in the future.

http://europepmc.org/articles/PMC3841998

https://drjockers.com/sugar-feeds-cancer-growth/


Advantages of Glycolysis For Cancer

While some people see glycolysis in cancer cells as a byproduct of damaged mitochondria, it is also possible that cancer cells have adapted to favor glycolysis for its growth promoting properties.Not only does glycolysis produce energy more rapidly that aerobic respiration, but it actually promotes an environment where cancer cells can rapidly divide.

Excess lactic acid produced by cancer cells actually shuts off the body’s anticancer immune response by deactivating anti-tumor immune cells (2). This essentially shields cancer from the immune system.

At the same time, rapid cell growth requires a lot of raw materials to make new cells. One of the primary atoms needed in abundance to form new cell structures is carbon. Carbon atoms are linked together to form backbones that cell structures are built off of.

After glucose is metabolized, it leaves a 6-carbon chain. While aerobic respiration excretes this carbon through the breath via carbon dioxide, glycolysis retains it. It is thought that this allows for a more rapid division of cells through a higher availability of raw materials.

10 Ways Cancer Impacts Cancer
How Sugar Feeds Cancer Growth

As has been covered so far, cancer cells have an impaired ability to produce energy. Due to damaged mitochondrial structures, they perform glycolysis rather than aerobic respiration. As a result, they must upregulate glucose intake in order to support rapid division and growth.

At the same time glycolysis favors cancer growth in several ways. This why a ketogenic diet has been heavily investigated for being able to limit cancer growth by cutting off its primary fuel supply. In addition to this, there are other mechanisms by which sugar feeds cancer growth.

Sugar Inhibits Immune System Function
White Blood Cells

White blood cells are the soldiers of our immune system. They are a powerful force against foreign invaders in our bodies including cancer cells. In order to operate at their full capacity, they require high amounts of Vitamin C. This was discovered by Nobel Prize winner, Linus Pauling, in the 1960’s.

Unlike other animals, humans are not able to produce Vitamin C endogenously. Instead we must receive it from our foods and transport it to our cells for use. We then have internal antioxidant systems that help us to retain and recycle Vitamin C to get the most use out of it. This is a function of glutathione (3).

In the 1970’s Dr. John Ely discovered what is referred to as the Glucose-Ascorbate-Antagonism (GAA) Theory. Both glucose and Vitamin C are similar in structure and rely upon insulin in order to enter the cells via the Glut-1 receptor on the cell membrane. Unfortunately, glucose has a higher affinity for this receptor which means it is absorbed more readily than vitamin C.

It is thought that having high levels of blood sugar actually inhibits Vitamin C from entering the white blood cells, which drastically reduces immunity and therefore the ability to fight off cancer. So, while sugar feeds cancer, it also inhibits the immune system for acting upon cancer cells.

Linus Pauling Deficiency
Phagocytic Index

In order for white blood cells to destroy foreign pathogens within the body, they do so by engulfing them and essentially breaking them down into benign byproducts. This process is called phagocytosis. The measure of how well a white blood cell is able to perform this function is called the phagocytic index.

Therefore, in order to provide the best chance for the immune system to target cancer cells, they need to have a high phagocytic index.

Because of the relationship explained above between glucose and vitamin C, high levels of sugar circulating in the blood is thought to lower the phagocytic index of white blood cells, impairing their ability to fight cancer.  In fact, it has been shown that a blood sugar level of 120 actually reduces phagocytic index by 75% (4).

Sugar Vitamin C
Sugar Feeds Cancer via Insulin HMP Shunt

In addition to Vitamin C’s importance for proper phagocytic functioning of white blood cells, it is also critical for stimulation of the hexose monophosphate (HMP) pathway (5).

The HMP pathway produces NADPH which is used by white blood cells to make superoxide and reactive oxygen species that are used to destroy pathogens.  This HMP shunt also produces ribose and deoxyribose which provide important raw materials for the formation of new white blood cell RNA/DNA (6).

When the immune system is under attack it needs to quickly produce new immune cells.  If blood sugar is high enough to turn off the HMP shunt it will reduce the quantity of RNA/DNA and the amount of new immune cells formed.

Sugar Feeds Cancer via AMP-K

AMP-K stands for Adenosine Monophosphate-activated protein kinase. When ATP (Adenosine Triphosphate) is broken down for energy within cells, phosphate groups are removed to form ADP and AMP (Adenosine Diphosphate and Adenosine Monophosphate, respectively).

When the ratio of AMP to ATP is increased, it is a sign that energy is getting low and AMP-K signals the upregulation of ATP production. In this manner, AMP-K is an energy regulating molecule.

It has also been shown that upregulation of AMP-K diverts glucose away from cancer cells and towards the body’s healthy tissues (7). In fact, it is suggested that activation of AMP-K helps to reverse the glycolytic preference of cancer cells, giving them an energetic disadvantage (.

Luckily, AMP-K activity can be upregulated by intense exercise, carbohydrate restriction, and intermittent fasting (9, 10).

There are a number of peripheral benefits of AMP-K activation that are centered around key physiological pathways that are also associated with cancer growth. These include mTOR, the p53 gene, and COX-2 enzymes.

COX-2 Inhibition Potentiates Antiangiogenic Cancer Therapy and Prevents Metastasis in Preclinical Models

Lihong Xu1, Janine Stevens1, Mary Beth Hilton1,2, Steven Seaman1, Thomas P. Conrads3,*, Timothy D. Veenstra3, Daniel Logsdon2, Holly Morris4, Deborah A. Swing4, Nimit L. Patel5, Joseph Kalen5, Diana C. Haines6, Enrique Zudaire1 and Brad St. Croix1,†

See all authors and affiliations
Science Translational Medicine 25 Jun 2014:
Vol. 6, Issue 242, pp. 242ra84
DOI: 10.1126/scitranslmed.3008455

Abstract

Antiangiogenic agents that block vascular endothelial growth factor (VEGF) signaling are important components of current cancer treatment modalities but are limited by alternative ill-defined angiogenesis mechanisms that allow persistent tumor vascularization in the face of continued VEGF pathway blockade. We identified prostaglandin E2 (PGE2) as a soluble tumor-derived angiogenic factor associated with VEGF-independent angiogenesis. PGE2 production in preclinical breast and colon cancer models was tightly controlled by cyclooxygenase-2 (COX-2) expression, and COX-2 inhibition augmented VEGF pathway blockade to suppress angiogenesis and tumor growth, prevent metastasis, and increase overall survival. These results demonstrate the importance of the COX-2/PGE2 pathway in mediating resistance to VEGF pathway blockade and could aid in the rapid development of more efficacious anticancer therapies.

http://stm.sciencemag.org/content/6/242/242ra84

ATP Mediates NADPH Oxidase/ROS Generation and COX-2/PGE2 Expression in A549 Cells: Role of P2 Receptor-Dependent STAT3 Activation

Shin-Ei Cheng,
I-Ta Lee,
Chih-Chung Lin,
Wan-Ling Wu,
Li-Der Hsiao,
Chuen-Mao Yang

PLOS

Published: January 11, 2013
https://doi.org/10.1371/journal.pone.0054125

Abstract

Background

Up-regulation of cyclooxygenase (COX)-2 and its metabolite prostaglandin E2 (PGE2) are frequently implicated in lung inflammation. Extracellular nucleotides, such as ATP have been shown to act via activation of P2 purinoceptors, leading to COX-2 expression in various inflammatory diseases, such as lung inflammation. However, the mechanisms underlying ATP-induced COX-2 expression and PGE2 release remain unclear.

Principal Findings

Here, we showed that ATPγS induced COX-2 expression in A549 cells revealed by western blot and real-time PCR. Pretreatment with the inhibitors of P2 receptor (PPADS and suramin), PKC (Gö6983, Gö6976, Ro318220, and Rottlerin), ROS (Edaravone), NADPH oxidase [diphenyleneiodonium chloride (DPI) and apocynin], Jak2 (AG490), and STAT3 [cucurbitacin E (CBE)] and transfection with siRNAs of PKCα, PKCι, PKCμ, p47phox, Jak2, STAT3, and cPLA2 markedly reduced ATPγS-induced COX-2 expression and PGE2 production. In addition, pretreatment with the inhibitors of P2 receptor attenuated PKCs translocation from the cytosol to the membrane in response to ATPγS. Moreover, ATPγS-induced ROS generation and p47phox translocation was also reduced by pretreatment with the inhibitors of P2 receptor, PKC, and NADPH oxidase. On the other hand, ATPγS stimulated Jak2 and STAT3 activation which were inhibited by pretreatment with PPADS, suramin, Gö6983, Gö6976, Ro318220, GF109203X, Rottlerin, Edaravone, DPI, and apocynin in A549 cells.

Significance

Taken together, these results showed that ATPγS induced COX-2 expression and PGE2 production via a P2 receptor/PKC/NADPH oxidase/ROS/Jak2/STAT3/cPLA2 signaling pathway in A549 cells. Increased understanding of signal transduction mechanisms underlying COX-2 gene regulation will create opportunities for the development of anti-inflammation therapeutic strategies.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0054125

Taxifolin Suppresses UV-Induced Skin Carcinogenesis by Targeting EGFR and PI3K
Naomi Oi, Hanyong Chen, Myoung Ok Kim, Ronald A. Lubet, Ann M. Bode and Zigang Dong
DOI: 10.1158/1940-6207.CAPR-11-0397 Published September 2012

ArticleFigures & DataInfo & Metrics
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Abstract

Skin cancer is one of the most commonly diagnosed cancers in the United States. Taxifolin reportedly exerts multiple biologic effects, but the molecular mechanisms and direct target(s) of taxifolin in skin cancer chemoprevention are still unknown. In silico computer screening and kinase profiling results suggest that the EGF receptor (EGFR), phosphoinositide 3-kinase (PI3K), and Src are potential targets for taxifolin. Pull-down assay results showed that EGFR, PI3K, and Src directly interacted with taxifolin in vitro, whereas taxifolin bound to EGFR and PI3K, but not to Src in cells. ATP competition and in vitro kinase assay data revealed that taxifolin interacted with EGFR and PI3K at the ATP-binding pocket and inhibited their kinase activities. Western blot analysis showed that taxifolin suppressed UVB-induced phosphorylation of EGFR and Akt, and subsequently suppressed their signaling pathways in JB6 P+ mouse skin epidermal cells. Expression levels and promoter activity of COX-2 and prostaglandin E2 (PGE2) generation induced by UVB were also attenuated by taxifolin. The effect of taxifolin on UVB-induced signaling pathways and PGE2 generation was reduced in EGFR knockout murine embryonic fibroblasts (MEF) compared with EGFR wild-type MEFs. Taxifolin also inhibited EGF-induced cell transformation. Importantly, topical treatment of taxifolin to the dorsal skin significantly suppressed tumor incidence, volume, and multiplicity in a solar UV (SUV)-induced skin carcinogenesis mouse model. Further analysis showed that the taxifolin-treated group had a substantial reduction in SUV-induced phosphorylation of EGFR and Akt in mouse skin. These results suggest that taxifolin exerts chemopreventive activity against UV-induced skin carcinogenesis by targeting EGFR and PI3K. Cancer Prev Res; 5(9); 1103–14. 2012 AACR.

Introduction

Skin cancer is one of the most common cancers in the United States. Each year, more than 1,000,000 new cases of skin cancers are reported in the United States, making up 40% of all diagnosed cancers (1). Chronic UV exposure is recognized as a major etiologic factor of skin carcinogenesis (2). The UV spectrum can be divided into 3 wavelengths, UVA (320–400 nm), UVB (280–320 nm), and UVC (200–280 nm; refs. 3, 4). Although UVC is filtered out by the ozone layer, UVA and UVB reach the surface of the earth. Of the UV irradiation that reaches the surface of the earth, 90% to 99% is composed of UVA and 1% to 10% is composed of UVB (4). UVA is carcinogenic and causes photoaging and wrinkling of the skin (5). UVB is mainly responsible for a variety of skin diseases including melanoma and nonmelanoma skin cancers because it is capable of triggering the initiation, promotion, and progression phases of skin cancer (6, 7). Therefore, targeting UV-induced signaling might be an effective strategy for preventing skin carcinogenesis.

The EGF receptor (EGFR) is activated by UV radiation (. EGFR is a member of the receptor tyrosine kinase, and is reported to be activated and/or overexpressed in a variety of human cancers including UV-induced skin cancer (9, 10). UV irradiation rapidly activates EGFR through the induction of EGFR ligands and the inactivation of cytoplasmic protein tyrosine phosphatases that maintains low basal levels of phosphorylated EGFR (11–13). UV-activated EGFR in turn activates a number of signaling cascades, including extracellular signal–regulated kinases (ERK), p38 kinase, and c-jun-NH2-kinase (JNK), which are known regulators of cell division (14–16). In response to UV irradiation, EGFR also activates phosphoinositide 3-kinase (PI3K), leading to Akt activation and suppression of apoptosis (17). Therefore, the EGFR and PI3K/Akt signaling pathways are logical molecular targets for chemoprevention of UV-induced skin cancer.

Taxifolin, also known as dihydroquercetin, is a flavonone commonly found in onions (18), milk thistle (19), French maritime bark (20), and Douglas fir bark (21) in an aglycone or glycoside form. Taxifolin has multiple biologic effects, including antioxidant and anti-inflammatory effects, and plays a role in preventing cardiovascular disease (22–24). Recently, several studies have focused on taxifolin as a potential cancer chemopreventive agent. One study showed that aglycone form of taxifolin exerts chemopreventive effects through an antioxidant response element (ARE)-dependent mechanism in colon cancer cells (25). The taxifolin aglycone form is also reported to induce apoptosis in prostate cancer cells (26). Although these reports provide evidence that taxifolin might exert chemopreventive effects against several cancers, the molecular mechanisms and direct targets of taxifolin are still unclear. Herein, we report that taxifolin suppresses UVB-induced activation of signal transduction by directly inhibiting EGFR and PI3K in JB6 P+ mouse skin epidermal cells. Moreover, taxifolin strongly suppresses tumor incidence in a solar UV (SUV)-induced skin carcinogenesis mouse model. Thus, taxifolin acts as an inhibitor of EGFR and PI3K and is expected to have beneficial effects in the prevention of UV-induced skin carcinogenesis.

http://cancerpreventionresearch.aacrjournals.org/content/5/9/1103

2008 by the Association of Clinical Scientists, Inc.

Cancer Morphogenesis: Role of Mitochondrial Failure

Egil Fosslien

Department of Pathology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois

Address correspondence to Egil Fosslien, M.D., 502 Fairview Avenue, Glen Ellyn, IL 60137, USA; tel 630 469 6824; e-mail efosslie{at}uic.edu.

Abstract

Adenosine triphosphate (ATP) required for normal cell metabolism is mainly supplied by mitochondrial oxidative phosphorylation (OXPHOS), which is limited by available oxygen and modulated by cell signaling pathways. Primary or secondary OXPHOS failure shifts cell metabolism towards ATP generation by glycolysis (Warburg effect). The objective of this paper is to clarify the role of mitochondrial dysfunction in cancer morphogenesis and to elucidate how faulty morphogen gradient signaling and inflammatory mediators that regulate OXPHOS can cause cancer-induced morphogenesis. Developmental morphogenesis and cancer morphogenesis are regulated by morphogenetic fields. The importance of morphogenetic fields is illustrated by transplantation of metastatic melanoma cells into the chick-embryo; the tumor cells adapt morphologies that resemble normal cells and function normally in the host. A morphogen gradient is a simple form of morphogenetic field. Morphogens such as those of the transforming growth factor (TGF)-β family inhibit and stimulate basic cell proliferation at high and low concentrations respectively. Along a signaling gradient of declining TGF-β concentration, with increasing distance from the gradient source, cell proliferation is first gradually less inhibited, and then gradually stimulated, thus generating a concave curved structure. In 3D cell cultures, TGF-β concentration determines the diameter of the tubules it induces. TGF-β1 can modulate mitochondrial OXPHOS via adenine nucleotide translocase (ANT) or uncoupling protein (UCP) via COX-2 and prostaglandin (PG) E2. Thus, gradients of TGF-β can regulate the radius of curvature of tissues by modulating mitochondrial ATP generation. Derailment of morphogen control of mitochondrial ATP synthesis can lead to abnormal spatial variation in ATP supply, abnormal spatial distribution of cell proliferation, and cancer morphogenesis. Involvement of COX-2 in morphogen signaling is a mechanism whereby inflammation can promote carcinogenesis. Restoration of OXPHOS can reverse cancer morphogenesis and restore normal tissue morphology. Avoiding exposure to environmental mitochondrial toxins and toxic food ingredients should reduce the risk of cancer.

http://www.annclinlabsci.org/content/38/4/307.abstract

There is evidence that genetic markers (RNA codes) change even within different sections of a tumor.

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Research provides better understanding of how some cancer cells resist treatment

Download PDF Copy

March 23, 2018

An international team of researchers led by Lucio Miele, MD, PhD, Professor and Chair of Genetics at LSU Health New Orleans School of Medicine, and Justin Stebbing, BM BCh MA, PhD, Professor of Cancer Medicine and Medical Oncology at Imperial College of Medicine in London, has found new genetic mutations that promote the survival of cancer cells. The research also provided a clearer understanding of how some cancer cells are able to resist treatment. The findings are published in PLOS ONE, available here.

"All cancers are caused by genetic damage, mutations to key genes that control the lives of cells," notes Dr. Miele, who also heads LSU Health New Orleans' Precision Medicine Program. "Mutant genes that cancers depend upon for survival are called 'driver' mutations."

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The researchers tested genes in 44 cancers that no longer responded to therapy. These are not often tested in clinical practice. The tumor types included breast, lung, colorectal, sarcomas, neuroendocrine, gastric and ovarian, among others. They found that these advanced cancers had selected many new possible "driver" mutations never described before, in addition to drivers already known -- the cancers had evolved new driver mutations to become resistant.

No two cancers were genetically identical, even cancers of the same organs that looked the same under a microscope. In some cases, the researchers found evidence that an individual cancer had evolved two or even three drivers in the same gene, a sign that multiple cancer cell clones had evolved in the same tumor that had found different ways of mutating a particularly important gene. Many of these new genetic mutations are in functional pathways that can be targeted with existing drugs.

"These findings imply that genomic testing should be performed as early as possible to optimize therapy, before cancers evolve new mutations, and that recurrent cancers should be tested again, because their driver mutation may be different from those that existed at diagnosis," says Miele.

With this information, therapy could be tailored to the evolving genomic picture of each individual cancer -- the hallmark of precision medicine.

"We are working toward a day when we won't have to give a patient the devastating news that a cancer has come back and isn't responding to chemotherapy," Miele concludes.
Source:

http://www.lsuhsc.edu/

Quantifying Cancer and Reexamining Which Cancers May be Inhibited by Fasts

https://thequantifiedbody.net/quantifying-cancer-gene-fine/
http://quantifiedbody.podbean.com/mf/web/6iuter/Quantified-Body-Podcast-Ep-36-quantifying-cancer-with-Gene-Fine.mp3?_=1
https://thequantifiedbody.net/water-fasts-as-a-potential-tactic-to-beat-cancer/
http://quantifiedbody.podbean.com/mf/web/2fnzuv/Quantified-Body-Podcast-Ep-16-Cancer-as-a-Mitochondrial-Disease-with-Dr-Thomas-Seyfried.mp3?_=1

Water fasting or ketogenic therapies may be effective with some cancers, and not with others. Learn about the PET scan and how it can provide insights into whether a cancer is likely to be responsive or not to the water fast tactic we’ve covered in previous episodes.

In this episode, we return to look at ketosis and water fasts as a tool to help treat cancer. This builds on the previous episodes looking at Ketosis with Jimmy Moore and the impact of water fasts on cancer with Dr. Thomas Seyfried.

In this episode, we dig deeper into the cancer topic looking at how ketogenic or low-carb diets may contribute via mechanisms related to insulin and ketones to inhibit cancer growth. We look at why only some types of cancers may benefit from these types of ketogenic treatments, and the data behind it. The data backing up this episode, is that of the PET scan — Positron Emission Tomography. PET Scans can be used to understand what type of cancer a person is dealing with and more importantly, whether it is likely to respond to ketogenic therapies or not.
“For cancers that are dependent on glutamine more than glucose… They can be aggressive… and they may not show up on a PET scan, and they also may not be responsive to a low carbohydrate diet.“
– Dr. Eugene Fine

Our guest is Dr. Eugene Fine. He’s currently a professor of Clinical Nuclear Medicine at the Albert Einstein College of Medicine. Most recently, in 2012, he published a study in the scientific journal of Nutrition on 10 cancer patients treated with a low-carb diet. He’s currently expanding his research by working on the use of low-carbohydrate diets combined with chemotherapy in animals.

This is all linked through his area of specialism, which is PET scans — positron emission tomography — where he has been identifying and monitoring cancers for the use of this type of scan. We’ll also touch on some of his studies looking at the impact of ketones, in vivo, on normal cells and malignant cells, and how that differs compared to glucose.

The episode highlights, biomarkers, and links to the apps, devices and labs and everything else mentioned are below. Enjoy the show and let me know what you think in the comments!


What You’ll Learn

   Reducing carbohydrates in diet and reducing insulin secretion in the body may inhibit cancer growth (4:06).
   How ketones inhibit cancer cells (10:06).
   Why are cancer cells over-expressing uncoupling protein 2 and reactive oxygen species (12:35)?
   Dr. Fine explains how he uses PET scans to identify many different types of cancerous cells and severity by using fluorodeoxyglucose, or FDG (17:32).
   If the cancer does not show up on the PET scan (as is the case with prostate cancer and glutamine dependent cancers) it may not respond to a low carbohydrate diet (23:57).
   Dr. Fine discusses quantitating the PET scans (30:50).
   Any inflamed area might also show up on the PET scan associated with the FDG (32:36).
   This research is in the beginning phase and needs to be studied on a larger scale as the next step (34:11).
   Dr. Fine describes his “recharge trial” where cancer patients were put on a low carbohydrate diet to observe the effects of the diet (35:00).
   During the trial the patient’s blood levels were measured to determine whether they were ketotic (37:42).
   Dr. Fine discusses the results of this recharge trial by identifying that inhibiting insulin may have effects on cancer progression/remission (40:31).
   Cancer may adapt to the environment where it “grew up”. So if you develop cancer already on an low carb diet, will not be affected by a low carb diet as an intervention (45:05).
   Damien and Dr. Fine discuss other ways to change ketone/insulin levels (49:44).
   High calorie versus low calorie diets are discussed (53:13).
   The biomarkers Gene Fine tracks on a routine basis to monitor and improve his health, longevity and performance (1:03:29).
   Gene Fine’s one biggest recommendation on using body data to improve your health, longevity and performance (1:09:14).

Eugene J. Fine, MD

   Dr. Fine: biography and publications.
   PubMed Results
   “Recharge” trial: Pilot study conducted by Dr. Fine. More information can be found here and on Dr. Fine’s website through Albert Einstein College of Medicine.

Tools & Tactics
Drugs & Supplements

   Metformin: A drug which is used to improve blood sugar regulation in diabetes. Researchers are looking at its wider applications with cancer treatment as it has been found to inhibit insulin secretion.
   Ketone esters and salts: A new range of supplements making ketone bodies directly available to the body and thus inducing ketosis. There are various forms including Beta Hydroxybutyrate Monoesters (BHB monoesters), and Beta Hydroxybutyrate mineral salts (BHB combined with Na+, K+, and Ca2+). One available for purchase is Ketosports KetoForce and Ketosports KetoCaNa.

Diet & Nutrition

   Low-carbohydrate diet: this programme limits carbohydrate consumption to increase ketosis. This was the main discussion point for this episode.
   Ketogenic diet: The ketogenic diet is a low carb diet which also raises the level of ketone bodies in the blood.

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Episode 16 – Dr. Thomas Seyfried "Water Fasts" as a Potential Tactic to Beat Cancer


Show Notes

How the idea that a change in mitochondrial function is behind cancer started in the 1920s (4:10).
The ancient energy mechanism through which cancer cells can bypass the mitochondria through fermentation instead of normal mitochondrial respiration (7:20).
The part of mitochondrial function that seems to be compromised in cancer – oxidative phosphorylation (8:15).
Different types of cancer cells and tumors have varying damage to their mitochondria. The worst and most aggressive cancers have the least mitochondrial function (9:00).
The oncogenic paradox (9:00).
Lipids such as Cardiolipins in the inner membrane of mitochondria are the part responsible for respiration (15:10).
How Dr. Seyfried pooled research from over 50 years together to develop his conclusions on cancer and the mitochondria (18:00).
Therapeutic ketosis and fasting can enhance mitochondria (23:00).
Ketone bodies produce cleaner energy, with less oxidative stress (ROS) than glucose molecules, when used for fuel in the mitochondria (27:00).
Nuclear genetic mutations prevent cancer cells from adapting to use ketone bodies as their energy source (29:30).
Which biomarkers could be indicative of cancer risk? (33:10).
Using therapeutic fasting of several days to improve your metabolism (36:00).
Using combined blood glucose – ketone meters to take readings and using Dr. Seyfried’s calculator to calculate Glucose – Ketone Indices (38:00).
It requires 3 to 4 days of fasting to get into the therapeutic glucose – ketone index zone (42:00).
“Autolytic cannibalism” to improve overall mitochondrial function – the mitochondria can either be rescued, enhanced or consumed (47:30).
The difficulties with directly measuring mitochondrial respiration vs. anaerobic fermentation and lactic acid to assess cancer status (49:50).
Weight loss can come in two types, pathological and therapeutic. The weight loss via fasting is therapeutic and healthy (52:00).
Cancer patients do better with chemotherapy, with less symptoms, when they are in a fasted state (52:00).
Cancer centers currently do not offer mitochondrial based therapies, only chemo or immuno therapies (57:40).

https://thequantifiedbody.net/water-fasts-as-a-potential-tactic-to-beat-cancer/

From an article posted earlier on Sirt1. UCP2 proteins are a conduit for normal energy creation in the mito-chondria:

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Sirt1 and obesity-associated metabolic diseases

Hepatic metabolic derangements are key components in the development of fatty liver, insulin resistance, and atherosclerosis. Sirt1 is an important regulator of energy homeostasis in response to nutrient availability. Scientists demonstrated that hepatic Sirt1 regulates lipid homeostasis by positively regulating peroxisome proliferators-activated receptor α (PPARα), a nuclear receptor that mediates the adaptive response to fasting and starvation. Hepatocyte-specific deletion of Sirt1 impairs PPARα signaling and decreases fatty acid β-oxidation, whereas overexpression of Sirt1 induces the expression of PPARα targets. Sirt1 interacts with PPARα and is required to activate PPARα coactivator PGC-1α. When challenged with a high-fat diet, liver-specific Sirt1 knockout (KO) mice develop hepatic steatosis, hepatic inflammation, and endoplasmic reticulum stress [5]. Present research data indicate that Sirt1 plays a vital role in the regulation of hepatic lipid homeostasis and that pharmacological activation of Sirt1 may be important for the prevention of obesity associated metabolic diseases [5]. Other research also shows that manipulation of Sirt1 levels in the liver affects the expression of a number of genes involved in glucose and lipid metabolism [6]. Additionally, recent studies demonstrated that modest overexpression of Sirt1 resulted in a protective effect against high fat induced hepatic steatosis and glucose intolerance [7, 8]. Sirt1 orthologs also play a critical role in controlling SREBP-dependent gene regulation governing lipid/cholesterol homeostasis in metazoans in response to fasting cues. These findings may have important biomedical implications for the treatment of metabolic disorders associated with aberrant lipid/cholesterol homeostasis, including metabolic syndrome and atherosclerosis [9]. Sirt1 regulates uncoupling protein 2 (UCP2) in beta cells to affect insulin secretion. Regulation of UCP2 by Sirt1 may also be an important axis that is dysregulated by excess fat to contribute to obesity induced diabetes [10].

Sirt1 is a positive regulator of liver X receptor (LXR) proteins [11, 12], nuclear receptors that function as cholesterol sensors and regulate whole-body cholesterol and lipid homeostasis. LXR acetylation is evident at a single conserved lysine (K432 in LXRα and K433 in LXRβ) adjacent to the ligand-regulated activation domain AF2 [2]. Sirt1 interacts with LXR and promotes deacetylation and subsequent ubiquitination. Mutations of K432 eliminate activation of LXRα by this sirtuin [11]. Loss of Sirt1 in vivo reduces expression of a variety of LXR targets involved in lipid metabolism, including ABCA1, an ATP-binding cassette (ABC) transporter that mediates an early step of HDL biogenesis [2, 11]. Altogether these findings suggest that deacetylation of LXRs by Sirt1 may be a mechanism that affects atherosclerosis and other aging-associated diseases [11].

Above information suggests that Sirt1 is involved in regulation of obesity-associated metabolic diseases through regulating PGC-1α, UCP2 and LXR proteins.



Cancer and Sirt1

It has been shown that Sirt1 is significantly elevated in human prostate cancer [13], acute myeloid leukemia [14], and primary colon cancer [15]. Overexpression of Sirt1 was frequently observed in all kinds of non-melanoma skin cancers including squamous cell carcinoma, basal cell carcinoma, Bowen's disease, and actinic keratosis [16]. Based on the elevated levels of Sirt1 in cancers, it was hypothesized that Sirt1 serves as a tumor promoter [17]. The first evidence of Sirt1 as a tumor promoter came from experiments showing that Sirt1 physically interacts with p53 and attenuates p53-mediated functions through deacetylation of p53 at its C-terminal Lys382 residue [18, 19]. In addition, two recent studies demonstrated that DBC1 (deleted in breast cancer-1), which was initially cloned from a region (8p21) homozygously deleted in breast cancer, forms a stable complex with Sirt1 and inhibits Sirt1 activity, leading to increased levels of p53 acetylation and upregulation of p53-mediated function. Consistently, knockdown of DBC1 by RNA interference (RNAi) promoted Sirt1 mediated deacetylation of p53 and inhibited p53-mediated apoptosis induced by genotoxic stress. These effects were reversed in cells by concomitant RNAi-mediated knockdown of endogenous Sirt1 [20, 21]. Sirt1 is also involved in epigenetic silencing of DNA-hypermethylated tumor suppressor genes (TSGs) in cancer cells (Figure 1). Inhibition of Sirt1 by multiple approaches (pharmacologic, over expression of a dominant negative protein or short interfering RNA) leads to TSG re-expression and a block in tumor-causing networks of cell signaling that are activated by loss of the TSGs in a wide range of cancers. Furthermore, Sirt1 inhibition causes re-expression of the E-cadherin gene (in breast and colon cancer cell lines), whose protein product complexes with β-catenin, and this gene reactivation collectively may suppress the constitutive activation of the WNT signaling pathway [22]. Sirt1 acts as a critical modulator of endothelial angiogenic functions. Inhibition of endogenous Sirt1 gene expression prevents the formation of a vascular-like network in vitro. Overexpression of wild-type Sirt1, but not of a deacetylase-defective mutant of Sirt1 (Sirt1 H363Y) [18, 19], increased the sproutforming and migratory activity of endothelial cells [23].

.........
Cell Sci. 2010 February 15; 123(4): 578–585.
Published online 2010 January 26. doi:  10.1242/jcs.060004
PMCID: PMC2818195
Degradation of an intramitochondrial protein by the cytosolic proteasome
Vian Azzu1 and Martin D. Brand1,2,

Abstract

Mitochondrial uncoupling protein 2 (UCP2) is implicated in a wide range of pathophysiological processes, including immunity and diabetes mellitus, but its rapid degradation remains uncharacterized. Using pharmacological proteasome inhibitors, immunoprecipitation, dominant negative ubiqbiquitiuitin mutants, cellular fractionation and siRNA techniques, we demonstrate the involvement of the ubiquitin-proteasome system in the rapid degradation of UCP2. Importantly, we resolve the issue of whether intramitochondrial proteins can be degraded by the cytosolic proteasome by reconstituting a cell-free system that shows rapid proteasome-inhibitor-sensitive UCP2 degradation in isolated, energised mitochondria presented with an ATP regenerating system, ubiquitin and 26S proteasome fractions. These observations provide the first demonstration that a mitochondrial inner membrane protein is degraded by the cytosolic ubiquitin-proteasome system.

Introduction

The proteasome is a cytosolic multicatalytic protein degradation system involved in concerted degradation pathways in the cell, including those for the proteolysis of cytosolic, endoplasmic reticulum (Klausner and Sitia, 1990) and mitochondrial outer membrane proteins (Neutzner et al., 2007). This proteolytic pathway is largely, but not solely, mediated by the regulated recognition of proteins and the addition of polyubiquitin chains, which target proteins for proteasomal destruction (Chau et al., 1989; Murakami et al., 1992). One proteasomal pathway that has not convincingly been shown is the degradation of intramitochondrial proteins that are not directly in contact with the cytosol. To date, no mitochondrial protein export machinery has been identified, raising the question of how intramitochondrial proteins could be accessed by a cytosolic degradation machinery given the ostensible barrier of the outer membrane. Here, we identify uncoupling protein 2 (UCP2) as an example of a mitochondrial inner membrane protein that is degraded by this unusual pathway.

UCP2 regulates the bioenergetics of diverse mammalian tissues including the kidney, spleen, pancreas and central nervous system (Brand and Esteves, 2005; Mattiasson and Sullivan, 2006). UCP2 has a broad distribution and is implicated in a variety of processes, including regulation of reactive oxygen species production (Arsenijevic et al., 2000), food intake (Andrews et al., 2008), insulin secretion (Zhang et al., 2001) and immunity (Arsenijevic et al., 2000) as well as pathologies including atherosclerosis (Blanc et al., 2003), cancer (Derdak et al., 2008), diabetes (Zhang et al., 2001) and neuronal injury (Sullivan et al., 2003). UCP2 levels vary dynamically in response to nutrients and this is achieved by varied expression rates against a background of a very short UCP2 protein half-life of ~1 hour (Rousset et al., 2007; Giardina et al., 2008; Azzu et al., 2008). This rapid turnover is not a general result of mitochondrial inner membrane proteolysis or whole mitochondrial turnover by autophagy, since the adenine nucleotide translocase (ANT) — a related carrier also integral to the mitochondrial inner membrane − is not degraded in the same time period. In contrast to the situation in cells, UCP2 is stable in isolated mitochondria, suggesting that extramitochondrial factors may be involved in the UCP2 degradation pathway (Azzu et al., 2008).

http://europepmc.org/articles/PMC2818195

......

https://www.deccanchronicle.com/lifestyle/health-and-wellbeing/220118/longevity-protein-may-help-treat-diabetes-cancer-says-study.html

Longevity protein may help treat diabetes, cancer, says study

PTI

Published Jan 22, 2018, 9:17 am IST
Updated Jan 22, 2018, 9:17 am IST
Named after the Greek goddess who spun the thread of life, Klotho proteins are located on the surface of cells of specific tissues.

The proteins bind to a family of hormones, designated endocrine Fibroblast growth factors (FGFs), that regulate critical metabolic processes in the liver, kidneys, and brain, among other organs. (Photo: Pixabay)
The proteins bind to a family of hormones, designated endocrine Fibroblast growth factors (FGFs), that regulate critical metabolic processes in the liver, kidneys, and brain, among other organs. (Photo: Pixabay)

New York: Scientists have revealed the three-dimensional structure of longevity protein that may help develop therapies to treat diabetes, obesity and certain cancers.

Named after the Greek goddess who spun the thread of life, Klotho proteins are located on the surface of cells of specific tissues.


The proteins bind to a family of hormones, designated endocrine Fibroblast growth factors (FGFs), that regulate critical metabolic processes in the liver, kidneys, and brain, among other organs.

Researchers from Yale University in the US found that beta-Klotho is the primary receptor that binds to FGF21, a key hormone produced upon starvation.

FGF21 stimulates insulin sensitivity and glucose metabolism, causing weight loss. This new understanding of beta-Klotho and FGF21 can guide the development of therapies for conditions such as type 2 diabetes in obese patients, the researchers said.

"Like insulin, FGF21 stimulates metabolism including glucose uptake," said Joseph Schlessinger, from Yale University.

"In animals and in some clinical trials of FGF21, it shows that you can increase burning of calories without changing food intake, and we now understand how to improve the biological activity of FGF21," Schlessinger said.

In the study, published in the journal Nature, the researchers also described a new variant of FGF21 that has 10 times higher potency and cellular activity.

By developing drugs that enhance the pathway, Schlessinger said, researchers can target diabetes and obesity.

(more at link...)

Re-defining the problem of how these proteins work in terms of the charge field is important to future working cures. How epi-genetics turn on/off genetic factors with the charge field -- especially with human protein formation ---  is critical to future cures. The randomness and manner in which cells are turned "on/off" as cancerous within the same cancer body...distinctively hints at "charge field" effects with mitochondria.  Overall, this is not too different from the charge field and superconducting with graphene/halogens under pressure.

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The Biology of Mitochondrial Uncoupling Proteins

   Sophie Rousset, Marie-Clotilde Alves-Guerra, Julien Mozo, Bruno Miroux, Anne-Marie Cassard-Doulcier, Frédéric Bouillaud and Daniel Ricquier

Diabetes 2004 Feb; 53(suppl 1): S130-S135. https://doi.org/10.2337/diabetes.53.2007.S130

Abstract

Uncoupling proteins (UCPs) are mitochondrial transporters present in the inner membrane of mitochondria. They are found in all mammals and in plants. They belong to the family of anion mitochondrial carriers including adenine nucleotide transporters. The term “uncoupling protein” was originally used for UCP1, which is uniquely present in mitochondria of brown adipocytes, the thermogenic cells that maintain body temperature in small rodents. In these cells, UCP1 acts as a proton carrier activated by free fatty acids and creates a shunt between complexes of the respiratory chain and ATP synthase. Activation of UCP1 enhances respiration, and the uncoupling process results in a futile cycle and dissipation of oxidation energy as heat. UCP2 is ubiquitous and highly expressed in the lymphoid system, macrophages, and pancreatic islets. UCP3 is mainly expressed in skeletal muscles. In comparison to the established uncoupling and thermogenic activities of UCP1, UCP2 and UCP3 appear to be involved in the limitation of free radical levels in cells rather than in physiological uncoupling and thermogenesis. Moreover, UCP2 is a regulator of insulin secretion and UCP3 is involved in fatty acid metabolism.

ROS, reactive oxygen species
UCP, uncoupling protein

Mitochondria are the cellular organelles where respiration occurs. They contain two compartments bounded by inner and outer membranes. The outer membrane is permeable to small metabolites, whereas the permeability of the inner membrane is controlled to maintain the high electrochemical gradient created by the mitochondrial respiratory chain that is necessary for energy conservation and ATP synthesis in mitochondria. The inner membrane transports anion substrates such as ADP, ATP, phosphate, oxoglutarate, citrate, glutamate, and malate. The reactions of the citric acid cycle, fatty acid oxidation, and several steps of urea synthesis and gluconeogenesis also take place in mitochondria. Energy produced by mitochondrial respiration is used for ATP synthesis by a complex mechanism referred to as “oxidative phosphorylation.” In addition to oxidative phosphorylation and metabolic pathways, mitochondria are involved in thermogenesis, radical production, calcium homeostasis, protein synthesis, and apoptosis. Although respiration is coupled with ADP phosphorylation, this coupling is less than perfect and may be partially or very partially loose. The uncoupling proteins (UCPs) are particular mitochondrial transporters of the inner membrane that appear to be controlling the level of respiration coupling. Several reviews devoted to UCPs have been published in the last few years (1–14). This article is an attempt to summarize recognized as well as putative biological functions of the UCPs.

BIOLOGY OF RESPIRATION UNCOUPLING

It has long been known that respiration and mitochondrial ATP synthesis are coupled. The observation that decreased ATP utilization inhibited oxygen consumption and that respiration rate increased when mitochondria synthesized more ATP led to the concept of respiratory control by ADP phosphorylation. In fact, there is a link between mitochondrial ATP synthesis and cellular ATP demand by a feedback mechanism controlling ATP synthesis induced by mitochondrial respiration. After the seminal proposal made by Peter Mitchell (chemi-osmotic theory), it was demonstrated that the mitochondrial electrochemical proton gradient, generated as electrons are passed down the respiratory chain, is the primary source for cellular ATP synthesis. The mitochondrial respiratory chain is made of five complexes. Complexes I, III, and IV pump protons outside the inner membrane during reoxidation of coenzymes and generate a proton gradient that is consumed by complex V, which catalyzes ATP synthesis (Fig. 1). In addition to reentry of protons through ATP synthase, a proton leak represents another mechanism consuming the mitochondrial proton gradient. Mitchell’s theory predicted that any proton leak not coupled with ATP synthesis would provoke uncoupling of respiration and thermogenesis. A well-known example of such an uncoupling of respiration to ADP phosphorylation is represented by the mitochondrial uncoupling protein of brown adipocytes (UCP1), which dissipates energy of substrate oxidation as heat (15–18). Besides adaptive thermogenesis, uncoupling of respiration allows continuous reoxidation of coenzymes that are essential to metabolic pathways. In fact, partial uncoupling of respiration prevents an exaggerated increase in ATP level that would inhibit respiration.

UNCOUPLING PROTEINS History.

Morphologists and physiologists identified the brown adipose tissue as a particular form of adipose tissue in hibernators and small mammals and observed its thermogenic activity in infants at birth, rodents exposed to the cold, and hibernators during arousal (15–17). Brown adipocytes differ from white adipocytes by a direct sympathetic innervation, a central nucleus, many triglyceride droplets, and numerous mitochondria. Original studies of isolated brown fat mitochondria revealed an elevated respiratory rate and an uncoupled respiration not controlled by ADP. A rapid respiration not coupled with ATP synthesis represents a powerful thermogenic process. It was also established that activation of brown adipocytes by norepinephrine was immediately followed by increased respiration and heat production, a marked increase in blood flow, and evacuation of warmed blood toward the brain and cardiac regions. It appeared that fatty acids generated by stimulated lipolysis were directly activating a specific proton pathway not coupled with ADP phosphorylation in the inner mitochondrial membrane. The protein explaining this proton pathway was identified as a 33-kDa UCP (15–18). Brown fat mitochondrial UCP is unique to brown adipocytes. The UCP content reflects the thermogenic activity of brown fat deposits: the elevated thermogenic capacity of brown fat of rats adapted to cold parallels the increased UCP in mitochondria. Decrease in brown fat thermogenic capacity during postnatal development in many mammals is accompanied by a declining UCP content. The brown fat UCP belongs to the family of the anion carriers present in the inner membrane of mitochondria. Like the mitochondrial adenine nucleotide transporters, the phosphate carrier, or the citrate carrier, UCP has a triplicate structure and every third is made of two transmembrane domains attached by a more hydrophilic domain (Fig. 2).


FIG. 1.

The mitochondrial proton gradient generated by complexes of respiratory chain is used by F0-F1-ATP synthase to phosphorylate ADP. Another mechanism consuming the gradient and lowering ATP synthesis is proton leak (yellow arrow). The reentry of protons in the matrix noncoupled with ATP synthesis is an energy-dissipating mechanism. The brown fat UCP1 is an example of mitochondrial proton leak. Cyt C, cytochrome C; ΔμH+, proton electrochemical gradient; e−, electron; F0, membranous part of ATP-synthase; F1, catalytic part of ATP-synthase.

http://diabetes.diabetesjournals.org/content/53/suppl_1/S130
(more at link...)

REFERENCES

   ↵Garlid KD, Jaburek M: The mechanism of proton transport mediated by mitochondrial uncoupling proteins. FEBS Lett438 :10 –14,1998
   OpenUrlCrossRefPubMedWeb of Science
   ↵Diehl AM, Hoek JB: Mitochondrial uncoupling: role of uncoupling protein anion carriers and relationship to thermogenesis and weight control “The benefits of losing control.” J Bioenerg Biomembr31 :493 –505,1999
   OpenUrlCrossRefPubMedWeb of Science
   ↵Ricquier D, Miroux B, Cassard-Doulcier AM, Lévi-Meyrueis C, Gelly C, Raimbault S, Bouillaud F: Contribution to the identification and analysis of the mitochondrial uncoupling proteins. J Bioenerg Biomembr31 :407 –418,1999
   OpenUrlCrossRefPubMed
   Kozak LP, Harper ME: Mitochondrial uncoupling proteins in energy expenditure. Annu Rev Nutr20 :339 –363,2000
   OpenUrlCrossRefPubMedWeb of Science
   ↵Ricquier D, Bouillaud F: The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP. Biochem J345 :161 –179,2000
   Boss O, Hagen T, Lowell BB: Uncoupling proteins 2 and 3: potential regulators of mitochondrial energy metabolism. Diabetes49 :143 –156,2000
   OpenUrlAbstract

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Tuesday, 4 March 2014

The role of UCP2 & UCP4 in stem cells

An embryonic stem cell differentiating into a neuronal cell under the microscope.

Credit: Anne Rupprecht/Vetmeduni Vienna

Cells have a metabolism that can be altered according to its function and requirements. If cellular metabolism is disturbed, it can lead to disease of the entire organism. Now, researchers at the University of Veterinary Medicine in Vienna say that they have discovered that the uncoupling proteins UCP2 and UPC4 are involved in different types of cellular metabolism.

The proteins provide information about the condition of cells. As a result, cell alterations can now be detected much earlier than it was previously possible.

UCPs or uncoupling proteins are present in mitochondria, the powerhouses of each cell in our body. The functions of most of the five known UCPs remain mysterious (UCP2-UCP5), whereby only the distinct function for UCP1 has thus far been discovered. UCP1 is responsible for heat production when muscle activity is deficient such as is the case with babies and animals in hibernation.

The researchers at the Department of Physiology and Biophysics at the University of Veterinary Medicine in Vienna were able to provide a fundamental explanatory concept for the function of UCP2 and UPC4 for the first time. Each of these proteins are involved in different types of cell metabolism.

UCP2 in Stem Cells and Cancer Cells

In earlier studies of immune cells, lead author, Anne Rupprecht, had already shown that UCP2 could be involved in increased metabolism. Embryonic stem cells (ESCs), precisely exhibit such an increased metabolism, as they rapidly and continually divide, just like cancer cells. Rupprecht searched for various UCPs in  ESCs of mice and in effect found UCP2. "Very high amounts of UCP2 even indicated an especially strong increase in metabolism. In other studies UCP2 had also already been detected in cancer cells," according to Rupprecht.

UCP4 in Nerve Cells

In contrast to UCP2, UCP4 is only found in nerve cells. Nerve cells have a completely different metabolism. They seldom divide, unlike stem cells and cancer cells. The research team of Prof. Elena Pohl therefore examined ESCs that differentiated to nerve cells in culture. On the basis of this model system, the researchers could show that UCP2 is still existent in the quickly reproducing stem cells, yet at the moment of differentiation are replaced by UPC4.

   "In our work, we have examined the natural process of cell differentiation from stem cells to neurons. We know that metabolism changes during differentiation. The fact that we found UCP2 in one case and in the other UCP4 proves for the first time that these proteins are associated with varying types of cell metabolism." said Elena Pohl.


The researchers, for example, found only UCP2 in neuroblastoma cells -- nerve cells that have malignant changes. UCP4, the usual protein of nerve cells was not detectable. UPC4 apparently got lost in the changed nerve cells that were on their way to becoming rapidly reproductive cancer cells.

(more at link....)

http://www.stemcellsfreak.com/2014/03/UCP2-UPC4-embryonic-stem-cells.html

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Superoxide-mediated activation of uncoupling protein 2 causes pancreatic β cell dysfunction
Stefan Krauss,1 Chen-Yu Zhang,1 Luca Scorrano,2 Louise T. Dalgaard,1 Julie St-Pierre,3 Shane T. Grey,4 and Bradford B. Lowell1

First published December 15, 2003 - More info

See the related Commentary beginning on page 1788.

   Abstract

   Failure to secrete adequate amounts of insulin in response to increasing concentrations of glucose is an important feature of type 2 diabetes. The mechanism for loss of glucose responsiveness is unknown. Uncoupling protein 2 (UCP2), by virtue of its mitochondrial proton leak activity and consequent negative effect on ATP production, impairs glucose-stimulated insulin secretion. Of interest, it has recently been shown that superoxide, when added to isolated mitochondria, activates UCP2-mediated proton leak. Since obesity and chronic hyperglycemia increase mitochondrial superoxide production, as well as UCP2 expression in pancreatic β cells, a superoxide-UCP2 pathway could contribute importantly to obesity- and hyperglycemia-induced β cell dysfunction. This study demonstrates that endogenously produced mitochondrial superoxide activates UCP2-mediated proton leak, thus lowering ATP levels and impairing glucose-stimulated insulin secretion. Furthermore, hyperglycemia- and obesity-induced loss of glucose responsiveness is prevented by reduction of mitochondrial superoxide production or gene knockout of UCP2. Importantly, reduction of superoxide has no beneficial effect in the absence of UCP2, and superoxide levels are increased further in the absence of UCP2, demonstrating that the adverse effects of superoxide on β cell glucose sensing are caused by activation of UCP2. Therefore, superoxide-mediated activation of UCP2 could play an important role in the pathogenesis of β cell dysfunction and type 2 diabetes.

https://www.jci.org/articles/view/19774

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Summary of Berberine
Primary Information, Benefits, Effects, and Important Facts

Berberine is an alkaloid extracted from various plants used in traditional Chinese medicine.

Berberine is supplemented for its anti-inflammatory and anti-diabetic effects. It can also improve intestinal health and lower cholesterol. Berberine is able to reduce glucose production in the liver. Human and animal research demonstrates that 1500mg of berberine, taken in three doses of 500mg each, is equally effective as taking 1500mg of metformin or 4mg glibenclamide, two pharmaceuticals for treating type II diabetes. Effectiveness was measured by how well the drugs reduced biomarkers of type II diabetes.

Berberine may also synergize with anti-depressant medication and help with body fat loss. Both of these benefits need additional evidence behind them before berberine can be recommended specifically for these reasons.

Berberine’s main mechanism is partly responsible for its anti-diabetic and anti-inflammatory effects. Berberine is able to activate an enzyme called Adenosine Monophosphate-Activated Protein Kinase (AMPK) while inhibiting Protein-Tyrosine Phosphatase 1B (PTP1B).

Berberine has a high potential to interact with a medications, and some interactions may be serious.

Berberine is one of the few supplements in the Examine.com database with human evidence that establishes it to be as effective as pharmaceuticals.

https://examine.com/supplements/berberine/?PageSpeed=noscript

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(NOT ADVOCATING THIS...just found it interesting....)

Get Metformin-Like AntiCancer Activity Without A Prescription (Berberine)

Feb 23, 2013 Brian D. Lawenda, M.D.

Huang Lian

What Is Berberine?

Berberine is one of the active alkaloid extracts, derived from a variety of plants (i.e. Oregon grape, barberry, tree turmeric, goldenseal, Amor cork tree, Chinese goldthread or “huanglian” or “Coptis chinensis”, etc.), that have been traditionally used in Ayurvedic and Chinese medicines for the treatment of diabetes, infections and gastrointestinal problems.

Studies* have demonstrated a wide-range of benefits of berberine:

*(human, in-vivo and/or  in-vitro)
   liver protection (protects against chemotherapy injury)
   anti-inflammatory
   anti-angiogenesis
   anti-depressant
   anti-Alzheimer’s disease
   anti-bacterial
   anti-osteoporosis
   anti-rheumatoid arthritis
   anti-viral
   anti-parastic
   anti-diabetic  (randomized trial found that berberine is as effective as the drug metformin); that should be no surprise, as berberine has many of the same effects as metformin (i.e. AMP kinase activator, increases insulin sensitivity, decreases gluconeogenesis, reduces glucose absorption in the gut, etc.)…so, if your physician won’t write you that prescription for metformin for its’ anti-cancer benefits, maybe berberine is a good alternative. (Read more about metformin on my prior blog post)
   anti-cancer (causes cancer cell death, slows cancer growth and increases the effectiveness of radiation therapy and chemotherapy)
   Inhibits the development of cancer from carcinogen exposure
   promotes weight loss
   cholesterol & triglyceride lowering (in one randomized study: lowering triglycerides by 36%, LDL cholesterol by 21%, and total cholesterol by 18%)
   anti-hypertension
   improves post-operative ileus
   protects against radiation-induced gastrointestinal symptoms (this study used a dose of 300 mg, three-times per day during radiation therapy)
   reduces colitis

How Does It Work?

It slows cancer growth and causes cancer cell death through a variety of mechanisms: tumor cell apoptosis and cell cycle arrest, inhibits blood vessel growth to tumors, inhibition of tumor cellular invasion and metastases (spread), etc.

One of the main anti-cancer targets that is inhibited by berberine is NF-kappaB. NF-kappa B is one of the most important proteins in our cells, acting as a key switch in the development and progression of inflammation and cancer.

•   Cancer (and precancerous cells) often have a permanently activated NF-kappa B, which keeps the cells proliferating and prevents them from dying (apoptosis.)
     Chronic inflammation can also be a result of activated NF-kappa B, and we know that chronic inflammation can lead to cancer growth (learn more about this on my previous blog post.)
  

Additionally, berberine is a radio-sensitizer of tumor cells, but not of normal cells (in fact, it may protect normal cells.) Therefore, berberine may make radiation therapy more effective.

Berberine also inhibits the tendency of cancer cells to become drug resistant over time by inhibiting the cellular membrane proteins that pump drugs out of the cell.

When berberine is taken with numerous chemotherapy drugs, studies have shown that they work synergistically against cancer cells.

As with other promising anti-cancer plant compounds (i.e. green tea, turmeric, etc.), there are data suggesting that using the whole plant extract (Coptidis rhizoma or “huanglian”) may be more effective than simply taking berberine, alone. This is potentially due to synergistic effects of the many known and unknown anti-cancer compounds in the whole plant.
Contraindications

   Displaces bilirubin and should not be administered to jaundiced neonates (may increase bilirubin levels due to displacement of bilirubin from albumin)
   May cause a prolonged QT interval (a variable in cardiac electrical conduction) in patients with underlying heart disease

Herb-Drug Interactions

   Berberine inhibits liver enzymes called “cytochromes P450“ (specifically these enzymes: CYP2D6, CYP2D6, CYP2C9, and CYP3A4): taking a drug or supplement that also inhibits these liver enzymes can increase the blood levels of both compounds, increasing the risk of toxicity.
   Always discuss your use of supplements with your physicians first, before starting them.
   Here’s an abbreviated list of some of the more common drugs that also interact with the cytochromes p450 enzymes.

....
(Reputed Cyc-C interactions)

Cancer and Berberine

There is an inflammatory enzyme called cyclooxygenase-2 (COX-2) that is abundantly expressed in colon cancer cells. It also plays a key role in colon tumorigenesis (new cancer growth). Therefore, compounds inhibiting COX-2 transcriptional activity (gene RNA replication) potentially have a chemopreventive property. Finding natural compounds to inhibit COX-2 pathways should prove exciting and promising.

In a recent study, an assay method for estimating COX-2 transcriptional activity in human colon cancer cells was established using a β-galactosidase reporter gene system. The study examined effects made of various medicinal herbs and their ingredients for an inhibitory effect on COX-2 transcriptional activity.

They found that berberine, an isoquinoline alkaloid present in plants of the genera Berberis and Coptis from Oregon grape root and Bayberry, effectively inhibits COX-2 transcriptional activity in colon cancer cells in a dose- and time-dependent manner at concentrations higher than 0.3 μM. These findings may further explain the mechanism of anti-inflammatory and anti-tumor promoting effects of berberine.

Berberine and Breast Cancer

Berberine has many other biological activities including the ability to induce cell cycle arrest and apoptosis, making it a potentially useful agent for targeting cancer cells other than just the colon. Another study analyzed the effects of berberine on MCF-7 breast cancer cells. Berberine was added to MCF-7 cells in culture, and proliferation, side population (SP) cells and expression of ABCG2 were examined resulting in very promising results:

1. Berberine caused a dose-dependent reduction in proliferation (new cancer growth).
2. Berberine treatment caused a decrease in SP cells (cells that become circulating tumor cells or cancer stem cells) relative to untreated controls.
3. In addition, berberine treatment was associated with a decrease in expression of ABCG2 relative to untreated controls (ABCG2 expression is associated with increased resistance to chemotherapeutic agents).

These results indicate that the growth inhibitory effects of berberine treatment on MCF-7  Cancer cells may be reason in itself for use.
Berberine limits Metastasis and Angiogenesis

Metastasis and angiogenesis is to be avoided at all cost. There is increasing evidence that two chemicals, urokinase-type plasminogen activator (u-PA) and matrix metalloproteinases (MMPs) play an important role in cancer spread and vasculization. Inhibition of u-PA and MMPs could suppress migration and invasion of cancer cells. Berberine reported to have anti-cancer effects in different human cancer cell lines by inhibiting u-PA and MMPs according to another study.

The treatment of human prostate cancer cells (PC-3) with berberine was shown to induce dose-dependent apoptosis.   Berberine-induced apoptosis was associated with the disruption of the mitochondrial membrane potential, release of apoptogenic molecules (cytochrome c and Smac/DIABLO) from mitochondria and cleavage of caspase-9,-3 and PARP proteins. In xenograft in vivo studies, berberine reduced tumor weights and volumes accompanied with apoptotic cell death and increased expression of apoptotic cell death proteins.

   Berberine can stimulate a Th1 reaction so use with caution.

(more at link...)
http://www.connersclinic.com/cancer-and-berberine/

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Berberine hydrochloride: anticancer activity and nanoparticulate delivery system

Wen Tan, Yingbo Li, Meiwan Chen, and Yitao Wang
Author information ► Copyright and License information ► Disclaimer
This article has been cited by other articles in PMC.

Abstract

Background

Berberine hydrochloride is a conventional component in Chinese medicine, and is characterized by a diversity of pharmacological effects. However, due to its hydrophobic properties, along with poor stability and bioavailability, the application of berberine hydrochloride was hampered for a long time. In recent years, the pharmaceutical preparation of berberine hydrochloride has improved to achieve good prospects for clinical application, especially for novel nanoparticulate delivery systems. Moreover, anticancer activity and novel mechanisms have been explored, the chance of regulating glucose and lipid metabolism in cancer cells showing more potential than ever. Therefore, it is expected that appropriate pharmaceutical procedures could be applied to the enormous potential for anticancer efficacy, to give some new insights into anticancer drug preparation in Chinese medicine.
Methods and results

We accessed conventional databases, such as PubMed, Scope, and Web of Science, using “berberine hydrochloride”, “anti-cancer mechanism”, and “nanoparticulate delivery system” as search words, then summarized the progress in research, illustrating the need to explore reprogramming of cancer cell metabolism using nanoparticulate drug delivery systems.

Conclusion

With increasing research on regulation of cancer cell metabolism by berberine hydrochloride and troubleshooting of issues concerning nanoparticulate delivery preparation, berberine hydrochloride is likely to become a natural component of the nanoparticulate delivery systems used for cancer therapy. Meanwhile, the known mechanisms of berberine hydrochloride, such as decreased multidrug resistance and enhanced sensitivity of chemotherapeutic drugs, along with improvement in patient quality of life, could also provide new insights into cancer cell metabolism and nanoparticulate delivery preparation.
Keywords: berberine hydrochloride, anticancer mechanisms, nanoparticulate drug progress

Introduction

Berberine hydrochloride is an isoquinoline alkaloid (see Figure 1) isolated from a variety of Chinese herbs, including Coptidis rhizoma, Phellodendron chinense schneid, and Phellodendron amurense, and has diverse pharmacological actions. It has antidiabetic and antilipid peroxidation activity, as well as an anti-atherosclerotic action, and also has neuroprotective properties and improves polycystic ovary syndrome.1–5 Berberine hydrochloride is widely used as an antibacterial, antifungal, and anti-inflammatory drug, and has been used as a gastrointestinal remedy for thousands of years in China.6,7

(more at link...)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3173044/

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Molecules 2014, 19(, 12349-12367; doi:10.3390/molecules190812349
Review

Berberine, an Epiphany Against Cancer

Luis Miguel Guamán Ortiz 1,2, Paolo Lombardi 3, Micol Tillhon 1 and Anna Ivana Scovassi 1,*1
Istituto di Genetica Molecolare CNR, Via Abbiategrasso 207, Pavia 27100, Italy2
Departamento de Ciencias de la Salud, Universidad Técnica Particular de Loja, San Cayetano Alto, Calle París, Loja 1101608, Ecuador3
Naxospharma, Via Giuseppe di Vittorio 70, Novate Milanese 20026, Italy*
Author to whom correspondence should be addressed; Tel.: +39-0382-546-334; Fax: +39-0382-422-286.
Received: 27 June 2014; in revised form: 6 August 2014 / Accepted: 11 August 2014 / Published: 15 August 2014

Abstract:
Alkaloids are used in traditional medicine for the treatment of many diseases. These compounds are synthesized in plants as secondary metabolites and have multiple effects on cellular metabolism. Among plant derivatives with biological properties, the isoquinoline quaternary alkaloid berberine possesses a broad range of therapeutic uses against several diseases. In recent years, berberine has been reported to inhibit cell proliferation and to be cytotoxic towards cancer cells. Based on this evidence, many derivatives have been synthesized to improve berberine efficiency and selectivity; the results so far obtained on human cancer cell lines support the idea that they could be promising agents for cancer treatment. The main properties of berberine and derivatives will be illustrated.

Keywords:
apoptosis; autophagy; berberine; cancer; traditional medicine

1. Introduction

Natural compounds have been used for centuries because of their availability; those present in plants are employed in the so-called Traditional Medicine, which translates theories, beliefs and experiences into knowledge, skills and practices applied to prevent, diagnose and treat physical and mental disorders [1]. Being recognized as an integral part of the culture and traditions of populations, Traditional Medicine has been recommended by the World Health Organization as an effective complementary and alternative medicine for different diseases [2].

Plants have wide biological and medicinal properties, and are characterized by high safety, availability, accessibility and low cost, thus representing an invaluable source of chemicals with potential therapeutic effects [3,4]. Secondary metabolites of plants, such as flavonoids, saponins, tannins, steroids and alkaloids, display a number of properties, including hormonal mimicry, antioxidant, antibacterial, anti-inflammatory, immunomodulating, detoxificant effects [5] and even anticancer activity [3,4,6].

2. Berberine

Among the several plant secondary metabolites, alkaloids possess a variety of pharmacological properties. Berberine (BBR, C20H19NO5, Figure 1, a 5,6-dihydro-dibenzo[a,g]quinolizinium derivative) is an isoquinoline quaternary alkaloid isolated from many kinds of medicinal plants such as Hydrastis canadensis, Berberis aristata, Coptis chinensis, Coptis japonica, Phellondendron amurense and Phellondendron chinense Schneid [7,8]. BBR has antioxidant effects and multiple pharmacological properties. It has been found to be effective against gastroenteritis, diarrhea, hyperlipidemia, obesity, fatty liver and coronary artery diseases, hypertension, diabetes and metabolic syndrome, polycystic ovary [8,9,10,11] and Alzheimer’s disease [12,13]. Recently, in vitro studies using cancer cell lines have shown that BBR inhibits cancer cell proliferation and migration, and induces apoptosis in a variety of cancer cell lines [8,14,15,16], stimulating further development of derivatives for drug-base cancer prevention and treatment.

Many groups are actively working to depict the molecular mechanism of action of BBR; although many results suggest that the molecular structure of BBR is able to bind DNA, other nuclear and cytoplasmic targets have been identified (see below).
Molecules 19 12349 g001 1024
Figure 1. Chemical structure of berberine chloride.

3. Molecular Targets of Berberine

BBR interacts directly with nucleic acids and with several proteins, including telomerase, DNA topoisomerase I, p53, NF-kB, MMPs and estrogen receptors. In general, BBR treatment promotes cell cycle arrest and death in human cancer cell lines, coupled to an increased expression of apoptotic factors [8,15,16]. The main known targets of BBR are below described.


4. Berberine and Cancer

The search for new drugs that induce apoptosis in tumors refractory to the conventional therapy is crucial to develop efficient anticancer therapies. Several mechanisms by which BBR inhibits the proliferation of different cancer cell lines have been reported. Among them, the killing of cancer cells by the activation of apoptosis is the best characterized.

In this context, several groups have reported the pro-apoptotic effect of BBR mediated by the impact on mitochondria. In fact, BBR was proved to alter the mitochondrial membrane potential (MMP), inhibit mitochondrial respiration leading to mitochondrial dysfunction and regulate the expression of Bcl-2 family members, as Mcl-1 [45,47]. Alterations in mitochondrial membrane stimulate the release of cytochrome c promoting the formation of reactive oxygen species (ROS) that trigger apoptosis that requires the activation of caspases and poly(ADP-ribose) polymerase-1 (PARP-1) cleavage [64]. Some examples of the pro-apoptotic effect of BBR are shown in Table 1 (see references therein).
Table
Table 1. Examples of the multiple effects of BBR leading to apoptosis in different cancer cell lines.

BBR pro-apoptotic effects could be mediated through the modulation of the HER2/PI3K/Akt [71,72] and/or JNK/p38 signaling pathway [76] an impact of BBR on the NF-kB pathway, leading to inactivation of this factor with consequent triggering of the apoptotic process, cell cycle and invasion pathway arrest, was reported [85]. The inhibition of the transcription factor AP-1 by BBR caused apoptosis in human hepatoma [86], oral [87], breast [88] and colon [89] cancer cells.

BBR modulates the activity of the Bcl-2 family members; increased expression of pro-apoptotic protein Bax (Bcl-2-associated X protein) together with decrease of Bcl-2/Bcl-xL after BBR treatment was observed not only in human prostate epithelial (PWR-1E) or carcinoma cells (DU145, PC-3 and LNCaP), but also in promyelocytic leukemia, gastric carcinoma and lung cancer cells, inducing cell death (Table 1).

Caspase-dependent apoptosis was reported in colon carcinoma cells treated with 13-arylalkyl BBR derivatives [33]. BBR has been used to treat TRAIL-sensitive breast cancer cells, and found to be able to sensitize also TRAIL-resistant breast cancer cells to apoptosis [48,49]. BBR suppresses HPV transcription in dose and time dependent manner in cervical cancer cell lines [84].

(more at link...)
http://www.mdpi.com/1420-3049/19/8/12349/htm

See also: https://milesmathis.forumotion.com/t484-100-year-old-tech-could-accelerate-electric-vehicle-boom#4402
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Mitochondrial Uncoupling and the Warburg Effect: Molecular Basis for the Reprogramming of Cancer Cell Metabolism
Ismael Samudio, Michael Fiegl and Michael Andreeff
DOI: 10.1158/0008-5472.CAN-08-3722 Published March 2009

Abstract

The precise mitochondrial alterations that underlie the increased dependence of cancer cells on aerobic glycolysis for energy generation have remained a mystery. Recent evidence suggests that mitochondrial uncoupling—the abrogation of ATP synthesis in response to mitochondrial membrane potential—promotes the Warburg effect in leukemia cells, and may contribute to chemoresistance. Intriguingly, leukemia cells cultured on bone marrow–derived stromal feeder layers are more resistant to chemotherapy, increase the expression of uncoupling protein 2, and decrease the entry of pyruvate into the Krebs cycle—without compromising the consumption of oxygen, suggesting a shift to the oxidation of nonglucose carbon sources to maintain mitochondrial integrity and function. Because fatty acid oxidation has been linked to chemoresistance and mitochondrial uncoupling, it is tempting to speculate that Warburg's observations may indeed be the result of the preferential oxidation of fatty acids by cancer cell mitochondria. Therefore, targeting fatty acid oxidation or anaplerotic pathways that support fatty acid oxidation may provide additional therapeutic tools for the treatment of hematopoietic malignancies. [Cancer Res 2009;69(6)–6]

The Warburg Effect and Mitochondrial Uncoupling

More than half a century ago, Otto Warburg ( 1) proposed that cancer cells originated from non-neoplastic cells acquired a permanent respiratory defect that bypassed the Pasteur effect, i.e., the inhibition of fermentation by oxygen. This hypothesis was based on results of extensive characterization of the fermentation and oxygen consumption capacity of normal and malignant tissues—including mouse ascites and Earle's cells of different malignancies but same genetic origin—that conclusively showed a higher ratio of fermentation to respiration in the neoplastic cells. Moreover, the data indicated that the more malignant Earle's cancer cells displayed a higher ratio of fermentation to respiration than their less malignant counterparts, suggesting to Warburg and his colleagues that a gradual and cumulative decrease in mitochondrial activity was associated with malignant transformation. Interestingly, the precise nature of these gradual and cumulative changes has eluded investigators for nearly 80 years, albeit Warburg's observations of an increased rate of aerobic glycolysis in cancer cells have been reproduced countless times—not to mention the wealth of positron emission tomography images that support an increased uptake of radiolabeled glucose in tumor tissues.

It is noteworthy that although Warburg's hypothesis remains a topic of discussion among cancer biologists, Otto Warburg himself had alluded to an alternative hypothesis put forth by Feodor Lynen—one which did not necessitate permanent or transmissible alterations to the oxidative capacity of mitochondria—that suggested the possibility that the increased dependence of cancer cells on glycolysis stemmed not from their inability to reduce oxygen, but rather from their inability to synthesize ATP in response to the mitochondrial proton gradient (ΔΨM; ref. 1). Lynen's hypothesis was partly based on his work ( 2) and the previous work of Ronzoni and Ehrenfest ( 3) using the prototypical protonophore 2,4-dinitrophenol, which causes a “short circuit” in the electrochemical gradient that abolishes the mitochondrial synthesis of ATP, and decreases the entry of pyruvate into the Krebs cycle. Subsequent work showed that mitochondrial uncoupling (i.e., the abrogation of ATP synthesis in response to ΔΨM) results in a metabolic shift to the use of nonglucose carbon sources to maintain mitochondrial function ( 4, 5). Given the elusiveness of permanent transmissible alterations to the oxidative capacity of cancer cells that could broadly support Warburg's hypothesis, could Lynen's hypothesis better explain the dependence of cancer cells on glycolysis for ATP generation?

Over the past several decades, it has become increasingly clear that mitochondrial uncoupling occurs under physiologic conditions, such as during cold acclimation in mammals, and is mediated, at least in part, by uncoupling proteins (UCP; ref. 6, 7). UCP1 was the first UCP identified, and was shown to play a role in energy dissipation as heat in mammalian brown fat ( 6). During cold acclimation, UCP1 accumulates in the inner mitochondrial membrane and short circuits ΔΨM (created by the mitochondrial respiratory chain) by sustaining an inducible proton conductance ( 7). Other UCPs have been identified in humans (UCP2-4), although their functions may be unrelated to the maintenance of core body temperature, and instead involved in the reprogramming of metabolic pathways. For instance, recent work shows that UCP2 is necessary for efficient oxidation of glutamine ( , and may promote the metabolic shift from glucose oxidation to fatty acid oxidation ( 4). Likewise, UCP3 has also been shown to promote fatty acid oxidation in muscle tissue via, in part, an increased flux of fatty acid anions ( 9); however, such as for UCP2, the nature of its proton conductance remains controversial (reviewed in ref. 10). More interesting, perhaps, are recent observations that UCP2 is overexpressed in various chemoresistant cancer cell lines and primary human colon cancer, and that overexpression of this UCP leads to an increased apoptotic threshold ( 11), suggesting that in addition to metabolic reprogramming, UCPs may ipso facto provide a prosurvival advantage to malignant cells.

It is important to point out that physiologic fatty acid oxidation has been shown to be associated with an uncoupling and/or thermogenic phenotype in various cell types (reviewed in ref. 12). In addition, it is also significant that glycolysis-derived pyruvate, as well as α-ketoglutarate derived from glutaminolysis, may be necessary to provide anaplerotic substrates (i.e., those that replenish intermediates in metabolic cycles) for efficient Krebs cycle use of fatty acid-derived acetyl CoA ( 13), suggesting the possibility that in certain cell types, high rates of aerobic glycolysis may be necessary for efficient mitochondrial oxidation of fatty acids (“fats burn in the fire of carbohydrates”). The above support the concept—and indirectly, Lynen's hypothesis—that the Warburg effect may, in fact, be the result of fatty acid and/or glutamine oxidation in favor of pyruvate use.

Mitochondrial Uncoupling in Leukemia Cells

We have recently reported that leukemia cells cultured on bone marrow–derived mesenchymal stromal cells (MSC) show increased aerobic glycolysis and reduced ΔΨM ( 14). A priori we hypothesized that MSC decreased mitochondrial function in leukemia cells; however, our experiments revealed that the oxygen consumption capacity of leukemia cells was not affected and, in fact, displayed a transient (∼6–8 h) increase after exposure to MSC. In addition, leukemia cells cultured on MSC were less sensitive to the ΔΨM-dissipating effects of oligomycin and, as previously reported ( 15, 16), more resistant to apoptosis induced by a variety of chemotherapeutic agents, suggesting that leukemia cells cultured on MSC feeder layers were displaying a prosurvival mitochondrial metabolic shift, rather than a compromised mitochondrial function. Additionally, it was observed that in contrast to hypoxia (∼6% oxygen), which markedly increased the uptake of glucose, and a fluorescent glucose derivative from the medium, MSC feeder layers did not increase the uptake of glucose in leukemia cells, further supporting the notion that the increased accumulation of lactate in the medium of MSC-leukemia cocultures is indicative of reduced entry of pyruvate into the Krebs cycle of leukemia cells.

Because the above observations supported the possibility that MSC may induce mitochondrial uncoupling in leukemia cells, we investigated whether MSC feeder layers were modulating the expression of UCPs (UCP1–4). We observed that leukemia cells only expressed UCP2 and that MSC induced pronounced accumulation of this UCP. Surprisingly, siRNA silencing of UCP2 expression did not completely overcome the dissipation of ΔΨM induced by MSC, albeit decreased expression of this protein markedly decreased the accumulation of lactate in the medium of MSC-leukemia cocultures. Moreover, although leukemia cells rapidly lost ΔΨM when exposed to MSC feeder layers (∼30 minutes), maximal expression of UCP2 did not occur until 24 to 48 hours after coculture, and conversely, the rapid dissipation of ΔΨM was insensitive to inhibition of protein synthesis with cycloheximide. Taken together, the above results suggest that although UCP2 expression may contribute to the observed loss of ΔΨM, it is likely that other factor(s) may initiate the dissipation of the electrochemical gradient; however, the data reported support the notion that UCP2 is indeed involved in metabolic reprogramming away from the oxidation of pyruvate, a phenomenon that may, in turn, facilitate the maintenance of a reduced ΔΨM.

Our data using the protonophore CCCP also supported the notion that, at least in leukemia cells, dissipation of the proton gradient per se opposed the onset of apoptosis. Likewise, MSC feeder layers protected OCI-AML3 cells from apoptosis, but not the growth inhibitory effects of mitoxanthrone, AraC, and vincristine. It is noteworthy that leukemia cells that did not increase the expression of UCP2 when cultured with MSC feeder layers did not increase lactate generation, did not dissipate ΔΨM, and were not protected from the cytotoxic effects of chemotherapy when cultured with MSC, suggesting that the observed metabolic reprogramming in OCI-AML3 cells is associated with chemoresistance. It is thus provoking to speculate that targeting UCP2, as well as the metabolic reprogramming involved in initiating and maintaining the dissipation of ΔΨM (increased glutamine and/or fatty acid metabolism, etc.), could be exploited therapeutically to overcome microenvironment-induced chemoresistance.

Implications of Mitochondrial Uncoupling

The metabolic shift from the oxidation pyruvate to the uncoupled oxidation of glutamine or fatty acids highlights two critical concepts. First, glycolysis remains the critical pathway by which cancer cells meet their energy demands, not because of permanent transmissible alterations to the oxidative capacity of cells, but rather because of the inability of uncoupled mitochondria to generate ATP. Second, the continued reduction of oxygen, in the absence of pyruvate oxidation, suggests that anaplerotic reactions from nonglucose carbon skeletons must be replenishing critical intermediates from the Krebs cycle—reactions that may be amenable to therapeutic intervention, and that may critically depend on highly conserved UCPs—to in turn support the oxidation of fatty acids or glutamine ( Fig. 1 ). Curiously, anaplerotic reactions have recently been reported to support the activity of the Krebs cycle in glioma cells ( 17), which use most of their glutamine carbon skeletons to regenerate α-ketoglutarate, while at the same time using glucose carbon skeletons to synthesize fatty acids. Moreover, the required NADPH (the biosynthetic reducing equivalent) for fatty acid synthesis was provided by conversion of glutamate-derived malate to pyruvate and, to a lesser extent, from the activity of the pentose phosphate shunt, further highlighting the importance of glutamine metabolism via the Krebs cycle ( 17). In the above study, it was evident that the metabolism of glucose was largely anaerobic, although the cells maintained the ability to consume oxygen, as well as an active Krebs cycle, suggesting the possibility that mitochondrial uncoupling and UCPs may promote the observed metabolic pattern.

Figure 1.Figure 1.

   Download figureOpen in new tabDownload powerpoint

Figure 1.

Mitochondrial uncoupling mediates the metabolic shift to aerobic glycolysis in cancer cells. A, coupled mitochondria (blue) oxidize pyruvate through the Krebs cycle. B, uncoupled mitochondria (orange) display a metabolic shift to the oxidation of other carbon sources, supported in part by fatty acid and glutamine metabolism that may depend on UCP2 expression. C, uncoupled mitochondria are more resistant to cytotoxic insults and oppose the activation of the intrinsic apoptotic pathway.

Notably, a recent report showed that the entry of pyruvate into the Krebs cycle, via pyruvate dehydrogenase, is supressed in cancer cells, and that the reactivation of pyruvate dehydrogenase activity by dichloroacetate induced cell death in several solid tumor cell lines and xenografts ( 18), supporting the notion that mitochondrial glucose oxidation may be incompatible with cancer cell survival. Likewise, it is interesting that pharmacologic inhibition of fatty acid oxidation has been shown to potentiate apoptosis induced by a variety of chemotherapeutics in cancer cell lines ( 19), as well as palmitate-induced apoptosis in hematopoietic cells ( 20), suggesting a priori that the metabolism of fatty acids in the mitochondria may be linked to cell survival. In light of the above, it is intriguing to propose that targeting the mitochondrial metabolism of fatty acids and/or glutamine may hold therapeutic promise for the treatment of human malignancies. Conversely, given the important role of UCPs in the metabolic shift associated with increased fatty acid and glutamine metabolism in favor of glucose oxidation, it would be of great interest to develop therapeutic strategies that targeted these proteins.

http://cancerres.aacrjournals.org/content/69/6/2163.long


Also:

https://themedicalbiochemistrypage.org/glycolysis.php

Apparent mouse cure for Lymphoma:
-----
A Cancer 'Vaccine' Cured 97% of Tumors in Mice. What's That Mean for People?
By Rachael Rettner, Senior Writer | March 29, 2018 07:13am ET

https://www.livescience.com/62161-cancer-vaccine-trial.html (more at link...)


A Cancer 'Vaccine' Cured 97% of Tumors in Mice. What's That Mean for People?
Credit: Shutterstock

A promising new cancer "vaccine" that cured up to 97 percent of tumors in mice will soon be tested in humans for the first time — but experts say that we're still a long way off from this type of drug being prescribed to cancer patients.

Researchers from Stanford University will test the therapy in about 35 people with lymphoma by the end of the year, according to SFGate, a local news outlet in San Francisco. The treatment stimulates the body's immune system to attack cancer cells. In studies in mice with various cancers — including lymphoma, breast cancer and colon cancer — the treatment eliminated cancer tumors in 87 out of 90 mice, even when the tumors had spread to other parts of the body, the researchers said.

Dr. Alice Police, the regional director of breast surgery at Northwell Health Cancer Institute in Westchester, New York, who was not involved in the study, said that the news of a human trial to test this treatment is "exciting." However, she cautioned that results in animal studies don't always translate to people.

"We've been able to cure a lot of cancers in mice for a long time," Police told Live Science. What's more, the current human trials are for patients with lymphoma, and so it could be many years before doctors know if this treatment works for other cancers, such as breast and colon cancer, Police said. [10 Do's and Don'ts to Reduce Your Risk of Cancer]

A cancer vaccine?

The new treatment is not technically a vaccine, a term used for substances that provide long-lasting immunity against disease. But the treatment does involve a vaccine-like injection, SFGate reported. (According to the American Society of Clinical Oncology, a "cancer vaccine" can refer to a treatment that's used to prevent cancer from coming back and destroys cancer cells that are still in the body.)

Instead, the treatment is a type of immunotherapy. It contains a combination of two agents that stimulate T cells, a type of immune cell, to attack cancer. Normally, the body's T cells recognize cancer cells as abnormal and will infiltrate and attack them. But as a tumor grows, it suppresses the activity of the T cells so that these cells can no longer keep the cancer at bay.

Makes me wonder how Ayahuasca and Syrian Rue work in the brain?  Perhaps they suppress this generation of the MIF in the pituitary gland?
---------
QJM. 2010 Nov; 103(11): 831–836.
Published online 2010 Aug 30. doi:  10.1093/qjmed/hcq148
PMCID: PMC2955282
PMID: 20805118

Inflammation and cancer: macrophage migration inhibitory factor (MIF)—the potential missing link
H. Conroy, L. Mawhinney, and S. C. Donnelly

Author information ► Copyright and License information ► Disclaimer
This article has been cited by other articles in PMC.

Abstract

Macrophage migration inhibitory factor (MIF) was the original cytokine, described almost 50 years ago and has since been revealed to be an important player in pro-inflammatory diseases. Recent work using MIF mouse models has revealed new roles for MIF. In this review, we present an increasing body of evidence implicating the key pro-inflammatory cytokine MIF in specific biological activities related directly to cancer growth or contributing towards a microenvironment favouring cancer progression.
...
The discovery that MIF was secreted from corticotrophic pituitary cells led to its classification as a hormone as well as a cytokine. Its release coincides with, and is induced by adrenocorticotrophic hormone and its ability to override the anti-inflammatory effects of this hormone suggested an inbuilt regulatory mechanism.9 This ability to promote inflammation while hindering the anti-inflammatory effects of glucocorticoids was implicated in the pathogenesis of acute respiratory distress syndrome (ARDS).12 Direct association between MIF expression levels and degrees of disease pathogenesis in a number of inflammatory diseases was revealed through analysis of genetic variation within the MIF gene.13–15 Allelic variation within a repeat region found upstream of the MIF promoter, determines efficiency of expression of the protein. Individuals carrying five copies of the CATT repeat element were found to display lower MIF levels, with those possessing increasing numbers of repeats (6, 7 or 8 ) having a corresponding increase in expression. In cystic fibrosis patients, this increase in MIF production associated with carrying the 6 and 7 repeat variants was associated with enhanced end-organ injury. Rheumatoid arthritis patients carrying the 6 and 7 repeat variants had both higher basal levels of MIF and higher levels following stimulation with forskolin or serum. The higher levels of MIF associated with this particular variant also correlated with progressive disease.16 In relation to malignant diseases, individuals carrying the seven-repeat allele were also found to have an increased incidence of prostate cancer.17 MIF biological activity has also been implicated in the pathogenesis of atherosclerosis and abdominal aortic aneurysm.18 In the context of atherosclerosis, MIF has also been identified as a non-cognate receptor of CXCR2 and CXCR4 and has functional chemokine activity in evolving atherosclerosis mediating monocyte arrest and the formation of plaques.19 Additionally, as part of this disease process MIF can induce the CXCR ligand, Interleukin (IL)-8 and regulators of macrophage infiltration ICAM-1 and CD44, confirming its relevance in this disease.20

Mounting evidence suggests that inflammation is closely associated with many types of cancer. 21 Inflammatory pathways designed to defend against infection and injury can promote an environment which favours tumour growth and metastasis. Chronic inflammatory conditions and infections have been directly linked to specific cancers, see Table 1. Supporting this observation, treatment with non-steroidal anti-inflammatory drugs has been shown to reduce the risk of developing colon cancer.22 Consequently, there is heightened interest both within academia and industry, to define key regulatory events within the inflammatory process which predispose individuals to enhanced cancer risk. This would provide the rational for significant investment in these high-value therapeutic targets for drug development.
MIF and cancer

MIF’s unique biological activities have the potential to contribute to an in vivo microenvironment favouring tumour growth and invasiveness. These functional activities include: tumour suppressor downregulation, COX-2 and PGE2 upregulation, potent induction of angiogenesis and enhanced tumour growth, proliferation and invasiveness (summarized in Table 2).

Table 2

MIF biological activities which favour tumour pathogenesis
MIF functional activities Role in tumourigenesis
P53 inhibition Accumulation of mutation
Inhibition of apoptosis
Proliferation of cells
Sustained ERK activation Promotes invasion
Inhibits cell death
COX-2/PGE-2 induction Tumour Growth
Viability
Metastasis
Endothelial cell proliferation and differentiation Promotes angiogenesis

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2955282/

.......

Hypoxia stimulates the expression of macrophage migration inhibitory factor in human vascular smooth muscle cells via HIF-1α dependent pathway

   Hua Fu1, 2, Fengming Luo2, 3, Li Yang4, Wenchao Wu2 and Xiaojing Liu2Email author
BMC Cell Biology201011:66
https://doi.org/10.1186/1471-2121-11-66

 Fu et al; licensee BioMed Central Ltd. 2010
Received: 21 April 2010
Accepted: 20 August 2010
Published: 20 August 2010

Abstract

Background

Hypoxia plays an important role in vascular remodeling and directly affects vascular smooth muscle cells (VSMC) functions. Macrophage migration inhibitory factor (MIF) is a well known proinflammatory factor, and recent evidence suggests an important role of MIF in the progression of atherosclerosis and restenosis. However, the potential link between hypoxia and MIF in VSMC has not been investigated. The current study was designed to test whether hypoxia could regulate MIF expression in human VSMC. The effect of modulating MIF expression on hypoxia-induced VSMC proliferation and migration was also investigated at the same time.

Results

Expression of MIF mRNA and protein was up-regulated as early as 2 hours in cultured human VSMCs after exposed to moderate hypoxia condition (3% O2). The up-regulation of MIF expression appears to be dependent on hypoxia-inducible transcription factor-1α(HIF-1α) since knockdown of HIF-1α inhibits the hypoxia induction of MIF gene and protein expression. The hypoxia induced expression of MIF was attenuated by antioxidant treatment as well as by inhibition of extracellular signal-regulated kinase (ERK). Under moderate hypoxia conditions (3% O2), both cell proliferation and cell migration were increased in VSMC cells. Blocking the MIF by specific small interference RNA to MIF (MIF-shRNA) resulted in the suppression of proliferation and migration of VSMCs.

https://bmccellbiol.biomedcentral.com/articles/10.1186/1471-2121-11-66

Uncoupling protein-2 modulates the lipid metabolic response
www.jimmunol.org/content/183/10/6313.full.pdf
http://www.physiology.org/doi/full/10.1152/ajpgi.00016.2008
....
UCP2 Regulates the Glucagon Response to Fasting and Starvation

Emma M. Allister1, Christine A. Robson-Doucette1, Kacey J. Prentice1, Alexandre B. Hardy1, Sobia Sultan1, Herbert Y. Gaisano1, Dong Kong2, Patrick Gilon3, Pedro L. Herrera4, Bradford B. Lowell2 and Michael B. Wheeler1⇑

Corresponding author: Michael B. Wheeler, michael.wheeler{at}utoronto.ca.

Diabetes 2013 May; 62(5): 1623-1633. https://doi.org/10.2337/db12-0981


Abstract

Glucagon is important for maintaining euglycemia during fasting/starvation, and abnormal glucagon secretion is associated with type 1 and type 2 diabetes; however, the mechanisms of hypoglycemia-induced glucagon secretion are poorly understood. We previously demonstrated that global deletion of mitochondrial uncoupling protein 2 (UCP2−/−) in mice impaired glucagon secretion from isolated islets. Therefore, UCP2 may contribute to the regulation of hypoglycemia-induced glucagon secretion, which is supported by our current finding that UCP2 expression is increased in nutrient-deprived murine and human islets. Further to this, we created α-cell–specific UCP2 knockout (UCP2AKO) mice, which we used to demonstrate that blood glucose recovery in response to hypoglycemia is impaired owing to attenuated glucagon secretion. UCP2-deleted α-cells have higher levels of intracellular reactive oxygen species (ROS) due to enhanced mitochondrial coupling, which translated into defective stimulus/secretion coupling. The effects of UCP2 deletion were mimicked by the UCP2 inhibitor genipin on both murine and human islets and also by application of exogenous ROS, confirming that changes in oxidative status and electrical activity directly reduce glucagon secretion. Therefore, α-cell UCP2 deletion perturbs the fasting/hypoglycemic glucagon response and shows that UCP2 is necessary for normal α-cell glucose sensing and the maintenance of euglycemia.

Elevated basal glucagon levels and reduced hypoglycemia-induced glucagon secretion are underappreciated and poorly understood aspects of type 1 and type 2 diabetes (1–3). Although high plasma glucose normally inhibits glucagon secretion, it remains unclear whether this in vivo response is mediated by glucose sensing, neuronal modulation, paracrine/endocrine control, or a combination thereof (4–10). Uncoupling protein 2 (UCP2), an inner mitochondrial membrane protein, is expressed in pancreatic α-cells (11), and its expression can be induced in adipose tissue by a ketogenic diet (12), suggesting a role in the fasting response. While the precise physiological function of UCP2 in islet cells is still debated, it can mildly dissipate the proton motive force generated during mitochondrial electron transport and limit ATP synthesis under certain conditions (13–15). Additionally, UCP2 can limit mitochondrial reactive oxygen species (ROS) production, which can alter associated signaling pathways and/or protect against oxidative stress (16–18). In β-cells, UCP2 deletion elicits only small changes in mitochondrial membrane potential (ΔΨm) with limited effect on ATP (18,19) but rather increases ROS production, which amplifies insulin secretion (18,20). α-Cells, like β-cells, have glucose-sensing machinery that center on KATP channel activity, cellular depolarization, and calcium influx, triggering exocytosis; however, unlike β-cells, they are electrically active and secretory at low glucose concentrations (5,21–24). UCP2 in α-cells could therefore be an important regulator of glucagon secretion via regulation of ATP production, plasma membrane potential, and ROS levels.

Previously, we showed that islets from mice globally lacking UCP2 (UCP2−/−) displayed higher basal glucagon secretion and impaired low glucose–mediated glucagon secretion (11). Due to UCP2’s wide expression profile in glucose-sensitive tissues, these changes in α-cell function in UCP2−/− mice could be the result of β-cell and/or extra-pancreatic deletion. To decipher the role of UCP2 in α-cells and in the response to fasting, we created an α-cell–specific UCP2 knockout (UCP2AKO) deletion mouse model. These mice displayed reduced fasting plasma glucagon levels and impaired glucagon secretion, due in part to elevated ROS, enhanced glucose-induced hyperpolarization of the ΔΨm, and depolarization of plasma membrane potential. Therefore, we conclude that α-cell UCP2 plays a key role in the hypoglycemic response.

(more at link...)

http://diabetes.diabetesjournals.org/content/62/5/1623

......


UCP2 is highly expressed in pancreatic α-cells and influences secretion and survival
Jingyu Diao, Emma M. Allister, Vasilij Koshkin, Simon C. Lee, Alpana Bhattacharjee, Christine Tang, Adria Giacca, Catherine B. Chan and Michael B. Wheeler
PNAS August 19, 2008. 105 (33) 12057-12062; https://doi.org/10.1073/pnas.0710434105

Edited by Donald F. Steiner, University of Chicago, Chicago, IL, and approved May 21, 2008

↵*J.D. and E.M.A. contributed equally to this work. (received for review November 6, 2007)

Abstract

In pancreatic β-cells, uncoupling protein 2 (UCP2) influences mitochondrial oxidative phosphorylation and insulin secretion. Here, we show that α-cells express significantly higher levels of UCP2 than do β-cells. Greater mitochondrial UCP2-related uncoupling was observed in α-cells compared with β-cells and was accompanied by a lower oxidative phosphorylation efficiency (ATP/O). Conversely, reducing UCP2 activity in α-cells was associated with higher mitochondrial membrane potential generated by glucose oxidation and with increased ATP synthesis, indicating more efficient metabolic coupling. In vitro, the suppression of UCP2 activity led to reduced glucagon secretion in response to low glucose; however, in vivo, fasting glucagon levels were normal in UCP2−/− mice. In addition to its effects on secretion, UCP2 played a cytoprotective role in islets, with UCP2−/− α-cells being more sensitive to specific death stimuli. In summary, we demonstrate a direct role for UCP2 in maintaining α-cell function at the level of glucose metabolism, glucagon secretion, and cytoprotection.

ATP glucagon islet mitochondria diabetes

Blood-glucose levels are tightly regulated by the islet hormones insulin and glucagon. Insulin is secreted from β-cells when glucose levels are high to increase glucose utilization, whereas glucagon is secreted from α-cells when glucose levels are low to elevate blood glucose. It is well established that β-cell dysfunction, resulting in a lack of insulin secretion, is a key event in the development of hyperglycemia that is associated with both type 1 and 2 diabetes (1, 2). In type 2 diabetes, β-cell dysfunction can in part be explained by the loss of proper glucose sensing, leading to abnormal insulin secretion. However, in both forms of diabetes, glucagon secretion can be dysregulated during hyper- and hypoglycemia (3, 4), suggesting that glucose sensing by the α-cell is also impaired. For this reason, it is important to understand mechanistically how glucagon is regulated by glucose in normal and diseased states.

High plasma levels of glucose inhibit glucagon secretion; however, it is still unclear whether this in vivo response is mediated directly via glucose sensing or indirectly by neuronal modulation and/or paracrine/endocrine effects (5–. Pancreatic α-cells, like β-cells, possess ATP-dependent K+ (KATP) channels; however, the metabolism/oxidation of glucose resulting in closure of the KATP channels causes inhibition of glucagon secretion (9, 10). It is suggested that N-type Ca2+ channels modulate this alternate excitability downstream of KATP-channel closure (10). Glucose metabolism in α-cells generates a proton-motive force (pmf) in the inner mitochondria that drives the synthesis of ATP via ATP synthase. Uncoupling proteins (UCPs) are mitochondrial carrier proteins that can dissipate the proton gradient to prevent the pmf from becoming excessive when there is nutrient overload, which can reduce reactive oxygen species (ROS) produced by electron transport (11). There are five mitochondrial UCP homologues in mammals (12). The closely related UCPs are UCP1–3. UCP1 is mainly expressed in brown adipose tissue and UCP3 in muscle and adipose tissue, whereas UCP2 has been found in liver, brain, pancreas, and adipose tissue and immune cells (13, 14). Specifically, UCP2 is expressed in pancreatic islets where its β-cell overexpression increases mitochondrial uncoupling, decreases mitochondrial membrane potential (ΔΨm), reduces mitochondrial ROS production and cytoplasmic ATP content, and therefore attenuates glucose stimulated insulin secretion (GSIS) by antagonizing the KATP-channel pathway (15–17). Uncoupling processes have not been studied in α-cells where they could regulate ATP production and glucagon secretion. UCP2 may be cytoprotective in some cell types, such as macrophages, cardiomyocytes, and neurons (18, 19), and thus expression of UCP2 in α-cells may modulate susceptibility to stress stimuli and influence cell survival (20). This study aims to identify whether UCP2 is expressed in α-cells, and if so, to characterize the role it plays in regulating glucagon secretion and cell survival.

(more at link...)

http://www.pnas.org/content/105/33/12057.long

...

Uncoupling protein-2 controls proliferation by promoting fatty acid oxidation and limiting glycolysis-derived pyruvate utilization
Claire Pecqueur
, Thi Bui
, Chantal Gelly
, Julie Hauchard
, Céline Barbot
, Frederic Bouillaud
, Daniel Ricquier
, Bruno Miroux
, and Craig B. Thompson

Published Online:13 Sep 2007https://doi.org/10.1096/fj.07-8945com
Abstract

Uncoupling protein-2 (UCP2) belongs to the mitochondrial carrier family and has been thought to be involved in suppressing mitochondrial ROS production through uncoupling mitochondrial respiration from ATP synthesis. However, we show here that loss of function of UCP2 does not result in a significant increase in ROS production or an increased propensity for cells to undergo senescence in culture. Instead, Ucp2−/− cells display enhanced proliferation associated with a metabolic switch from fatty acid oxidation to glucose metabolism. This metabolic switch requires the unrestricted availability of glucose, and Ucp2−/− cells more readily activate autophagy than wild-type cells when deprived of glucose. Altogether, these results suggest that UCP2 promotes mitochondrial fatty acid oxidation while limiting mitochondrial catabolism of pyruvate. The persistence of fatty acid catabolism in Ucp2+/+ cells during a proliferative response correlates with reduced cell proliferation and enhances resistance to glucose starvation-induced autophagy.—Pecqueur, C., Bui, T., Gelly, C., Hauchard, J., Barbot, C., Bouillaud, F., Ricquier, D., Miroux, B., Thompson, C. B. Uncoupling protein-2 controls proliferation by promoting fatty acid oxidation and limiting glycolysis-derived pyruvate utilization.

http://www.fasebj.org/doi/abs/10.1096/fj.07-8945com?journalCode=fasebj

Keep in mind that a lot of type-1 diabetics become alcoholic/heavy-drinkers over the years.
.....
Uncoupling protein 2 (UCP2) lowers alcohol sensitivity and pain threshold

Balazs Horvath, Claudia Spies, Gyongyi Horvath, Wolfgang J. Kox, Suzanne Miyamoto, Sean Barry, Craig H. Warden, Ingo Bechmann, Sabrina Diano, Jill Heemskerk, Tamas L. Horvath

   Hematology and OncologyGeneral Pediatrics

Research output: Contribution to journal › Article

   27 Citations

Abstract

Abuse of ethanol is a major risk factor in medicine, in part because of its widespread effect on the activity of the central nervous system, including behavior, pain, and temperature sensation. Uncoupling protein 2 (UCP2) is a mitochondrial protonophore that regulates cellular energy homeostasis. Its expression in mitochondria of axons and axon terminals of basal forebrain areas suggests that UCP2 may be involved in the regulation of complex neuronal responses to ethanol. We employed a paradigm in which acute exposure to ethanol induces tolerance and altered pain and temperature sensation. In UCP2 overexpressing mice, sensitivity to ethanol was decreased compared to that of wild-type animals, while UCP2 knockouts had increased ethanol sensitivity. In addition, UCP2 expression was inversely correlated with the impairment of pain and temperature sensation induced by ethanol. Taken together, these results indicate that UCP2, a mitochondrial uncoupling protein previously associated with peripheral energy expenditure, is involved in the mediation of acute ethanol exposure on the central nervous system. Enhancement of UCP2 activation after acute alcohol consumption might decrease the time of recovery from intoxication, whereas UCP2 inhibition might decrease the tolerance to ethanol.


https://ucdavis.pure.elsevier.com/en/publications/uncoupling-protein-2-ucp2-lowers-alcohol-sensitivity-and-pain-thr

Focuses on Iron. Like Malaria...Absinthe tends to affect parasitical/fermentation cell action towards Iron as a source of novel energy (ATP/Charge flows). Iron in a women's breast can be prone to cancer in certain situations:

https://www.ncbi.nlm.nih.gov/pubmed/22311047

Mol Biol Rep. 2012 Jul;39(7):7373-9. doi: 10.1007/s11033-012-1569-0. Epub 2012 Feb 5.
Artemisia absinthium (AA): a novel potential complementary and alternative medicine for breast cancer.
Shafi G1, Hasan TN, Syed NA, Al-Hazzani AA, Alshatwi AA, Jyothi A, Munshi A.
Author information
Abstract

Natural products have become increasingly important in pharmaceutical discoveries, and traditional herbalism has been a pioneering specialty in biomedical science. The search for effective plant-derived anticancer agents has continued to gain momentum in recent years. The present study aimed to investigate the role of crude extracts of the aerial parts of Artemisia absinthium (AA) extract in modulating intracellular signaling mechanisms, in particular its ability to inhibit cell proliferation and promote apoptosis in a human breast carcinoma estrogenic-unresponsive cell line, MDA-MB-231, and an estrogenic-responsive cell line, MCF-7. Cells were incubated with various concentrations of AA, and anti-proliferative activity was assessed by MTT assays, fluorescence microscopy after propidium iodide staining, western blotting and cell cycle analysis. Cell survival assays indicated that AA was cytotoxic to both MDA-MB-231 and MCF-7 cells. The morphological features typical of nucleic staining and the accumulation of sub-G1 peak revealed that the extract triggered apoptosis. Treatment with 25 μg/mL AA resulted in activation of caspase-7 and upregulation of Bad in MCF-7 cells, while exposure to 20 μg/mL AA induced upregulation of Bcl-2 protein in a time-dependent response in MDA-MB-231 cells. Both MEK1/2 and ERK1/2 was inactivated in both cell lines after AA treatment in a time-dependent manner. These results suggest that AA-induced anti-proliferative effects on human breast cancer cells could possibly trigger apoptosis in both cell lines through the modulation of Bcl-2 family proteins and the MEK/ERK pathway. This might lead to its possible development as a therapeutic agent for breast cancer following further investigations.

PMID:
   22311047
DOI:
   10.1007/s11033-012-1569-0

(related)

https://en.wikipedia.org/wiki/Oligonol (lychee fruit with other additives)
....

Eur J Cancer Prev. 2007 Aug;16(4):342-7.
Induction of apoptosis in MCF-7 and MDA-MB-231 breast cancer cells by Oligonol is mediated by Bcl-2 family regulation and MEK/ERK signaling.
Jo EH1, Lee SJ, Ahn NS, Park JS, Hwang JW, Kim SH, Aruoma OI, Lee YS, Kang KS.
Author information

Abstract

Oligonol is a novel catechin-rich biotechnology product. The role of oligonol in modulating intracellular signaling mechanisms was investigated with the view of demonstrating its potential chemopreventive effect and the ability to inhibit cell proliferation using the estrogen-responsive MCF-7 and the estrogen-unresponsive MDA-MB-231 human breast cancer cell lines. Cell survival assay indicated that Oligonol was cytotoxic to both cells. Oligonol triggered apoptosis as revealed by the morphological features typical of nucleus staining and the accumulation of sub-G1 peak. Treatment with 25 microg/ml Oligonol resulted in an activation of caspase-7 and up-regulation of Bad on MCF-7 cells, while the Oligonol (20 microg/ml) induced up-regulation of Bcl-2 protein in a time-response manner on MDA-MB-231 cells. ERK1/2 in both cells were inactivated after Oligonol treatment in a time-dependent manner, and also inactivated upstream MEK1/2. Oligonol triggers apoptosis in MCF-7 and MDA-MB-231 cells through the modulation of pro-apoptotic Bcl-2 family proteins and MEK/ERK signaling pathway.

PMID:
   17554207
DOI:
   10.1097/01.cej.0000236247.86360.db
....


The effect of Oligonol intake on cortisol and related cytokines in healthy young men
Jeong-Beom Lee, Young-Oh Shin,corresponding author Young-Ki Min, and Hun-Mo Yang
Author information ► Article notes ► Copyright and License information ► Disclaimer
This article has been cited by other articles in PMC.
Go to:

Abstract

This study investigated the effects of Oligonol intake on cortisol, interleukin (IL)-1β, and IL-6 concentrations in the serum at rest and after physical exercise loading. Nineteen healthy sedentary male volunteers participated in this study. The physical characteristics of the subjects were: a mean height of 174.2 ± 2.7 cm, a mean weight of 74.8 ± 3.6 kg and a mean age of 22.8 ± 1.3 years. Each subject received 0.5 L water with Oligonol (100 mg/day) (n = 10) or a placebo (n = 9) daily for four weeks. The body composition, the white blood cell (WBC) and differential counts as well as the serum cortisol, IL-1β, and IL-6 concentrations were measured before and after Oligonol intake. The cortisol concentration and serum levels of IL-1β and IL-6 after Oligonol intake were significantly decreased compared to before treatment (P < 0.01, respectively). In addition, the rate of increase of these factors after exercise was decreased compared to the placebo group. There was no change in the WBC and differential cell counts. These results suggest that oral Oligonol intake for four weeks had a significant effect on inhibition of inflammatory markers in healthy young men.

Keywords: Oligonol, cortisol, interleukin-1β, interleukin-6
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Introduction

The plants, vegetables, herbs and spices used in traditional medicine have been widely studied for their prophylactic and chemopreventive effects on human disease; in addition, they have been used for drug discovery and development [1-2]. Oligonol is a novel compound produced from the oligomerization of polyphenol. It is an optimized phenolic product containing catechin-type monomers and oligomers (dimer, trimer, and tetramer) of proanthocyanidin that are easily absorbed [3]. Oligonol is composed of 50% oligomers whereas a typical polyphenol polymer contains less than 10%. Thus, polyphenol polymers are not as efficiently bioactive or easily absorbed as Oligonol because of their high molecular weight.

Extracts or other purified preparations of phenolic rich foods have antioxidant, antibacterial, anti-inflammatory, antiallergic, hepatoprotective, antithrombotic, antiviral, anticarcinogenic, vasodilatory, and neuroprotective properties [4-7]. Nagakawa et al. [8] examined the effects of proanthocyanidin-rich extracts in rats subjected to renal ischemia-reperfusion. Their results suggested that Oligonol might play a role in modulating the cerebral and renal ischemia associated with oxidative stress. It has been shown that Oligonol exhibits significant protection against b-amyloid- and high glucose-induced cytotoxicity in rat pheochromocytoma PC12 cells and in the porcine proximal tubule cell line LLC-PK1, respectively [9,10].

In spite of the findings of recent studies on Oligonol, except for the study reported by Fujii and colleagues [11], there has been no study demonstrating the anti-inflammatory and anti-oxidative effects of Oligonol in humans. Thus, the purpose of the present study was to examine the effects of Oligonol intake for four weeks on cortisol and related cytokines, such as interleukin (IL)-6 and IL-1β, in healthy male subjects.

Exercise-induced stress was evaluated in this study. Exercise has acute and chronic effects on the systemic immunity and inflammatory response. It causes changes in stress hormones and cytokine concentrations. Following prolonged running at high intensity, the concentration of serum cortisol has been shown to be significantly elevated above control levels for several hours; this has been related to many of the cell trafficking changes that occur during recovery. Exercise that causes muscle cell injury can result in sequential release of pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-6 [12,13]. The inflammatory cytokines help regulate the rapid migration of neutrophils, and then later monocytes, into the areas of injured muscle cells and other metabolically active tissues to initiate repair [14].

BMC Complement Altern Med. 2014 Jul 18;14:252. doi: 10.1186/1472-6882-14-252.
Synergistic anticancer effects of a bioactive subfraction of Strobilanthes crispus and tamoxifen on MCF-7 and MDA-MB-231 human breast cancer cell lines.
Yaacob NS1, Kamal NN, Norazmi MN.

Author information
Abstract

BACKGROUND:

Development of tumour resistance to chemotherapeutic drugs and concerns over their toxic effects has led to the increased use of medicinal herbs or natural products by cancer patients. Strobilanthes crispus is a traditional remedy for many ailments including cancer. Its purported anticancer effects have led to the commercialization of the plant leaves as medicinal herbal tea, although the scientific basis for its use has not been established. We previously reported that a bioactive subfraction of Strobilanthes crispus leaves (SCS) exhibit potent cytotoxic activity against human breast cancer cell lines. The current study investigates the effect of this subfraction on cell death activities induced by the antiestrogen drug, tamoxifen, in estrogen receptor-responsive and nonresponsive breast cancer cells.

METHODS:

Cytotoxic activity of SCS and tamoxifen in MCF-7 and MDA-MB-231 human breast cancer cells was determined using lactate dehydrogenase release assay and synergism was evaluated using the CalcuSyn software. Apoptosis was quantified by flow cytometry following Annexin V and propidium iodide staining. Cells were also stained with JC-1 dye to determine changes in the mitochondrial membrane potential. Fluorescence imaging using FAM-FLICA assay detects caspase-8 and caspase-9 activities. DNA damage in the non-malignant breast epithelial cell line, MCF-10A, was evaluated using Comet assay.

RESULTS:

The combined SCS and tamoxifen treatment displayed strong synergistic inhibition of MCF-7 and MDA-MB-231 cell growth at low doses of the antiestrogen. SCS further promoted the tamoxifen-induced apoptosis that was associated with modulation of mitochondrial membrane potential and activation of caspase-8 and caspase-9, suggesting the involvement of intrinsic and extrinsic signaling pathways. Interestingly, the non-malignant MCF-10A cells displayed no cytotoxicity or DNA damage when treated with either SCS or SCS-tamoxifen combination.

CONCLUSIONS:

The combined use of SCS and lower tamoxifen dose could potentially reduce the side effects/toxicity of the drug. However, further studies are needed to determine the effectiveness and safety of the combination treatment in vivo.

https://www.ncbi.nlm.nih.gov/pubmed/25034326
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Artemisia Cancer Cure?
Posted on February 24, 2011 | 39 Comments

I had recently come across a testimony from a Doctor who treated a boy with cancer with artemisia, among other things, and he stated that it produced a prompt remission. So I looked into Artemisia.

Artemisia cure for cancer?

In an archeological dig in China in the 1970’s, many ancient herbal remedies were uncovered. Among them was one for malaria using Artemisia. As a result, this herb began to be used widely for malaria treatment. Of note, this is Artemisia Annua, also known as Sweet Annie or Qing Hao in Chinese, not Artemisia Absinthe, which is known as Wormwood and is commonly used in anti-parasite cures.

But what’s more, in 1995, bioengineering professors Henry Lai and Nahendra Singh from the University of Washington began studying its potential as an anti-cancer drug and found it killed cancer cells in vitro in a matter of hours, and was even able to cure a dog from bone cancer withing 5 days.
After pumping the cancer cells with maximum amounts of iron using something called holotransferrin, Lai and Singh introduced artemisinin to selectively kill the cancer cells.
http://www.utne.com/2002_si/CouldWormwoodbetheCureforCancer.aspx

If you go to Prof Lai’s page at the U of W, you will see that his research is focused on
biological effects of electromagnetic fields and cancer treatment using Artemisinin and synthetic compounds. He has an entire page dedicated to Artemisinin information.
http://depts.washington.edu/bioe/research/research_artemisinin.html

Of course, it comes with a warning that the FDA has not approved Artemisia for use in the treatment of cancer, that more research is needed and that you should consult with your doctor (who will, in accordance with the FDA, recommend that you be poisoned and irradiated).

But below that, you will find a list of 206 studies going back as far as 1996, showing that artemisinin induces apoptosis, aka cell death, in cancer tumors and basically cures cancer.
http://depts.washington.edu/bioe/people/core/lai.html

You would think that after over 15 years of such promising research in vitro and in animals, someone would have done a human study by now- but no. I guess it would be considered unethical to deprive someone of ‘standard of care’, but you would think that surely they could find someone to volunteer to delay his murderous standard treatment by a couple of weeks to see if Artemisia would work as well for him as it does for the mice. I’m sure this could be done, but who will fund it? The problem is always funding because it all comes down to money. Investment vs return. If you use cheap herbs to actually restore people’s health, you lose out on some big bucks. That’s the bottom line for Big Pharma.

Instead of funding studies with natural herbs, research has taken the direction of studying a synthetic, patentable version of artemisinin as well as nanotechnology that could be used to deliver it. Is this really necessary? The plain of herbs worked for the dog, who I hear was still alive two years after the study, and that’s about 14 dog-years. Pretty good long-term survival, I would say.

We are told that cancer is some mysterious, horrible, incurable condition that can only be addressed with toxic, expensive pharma treatments. I used to work as a transcriptionist in an Oncology dept and I had full confidence in standard treatment. Day after day, I typed out reports of people improving, going into remission, being declared cancer-free. It never occurred to me that I never got to type reports about patients dying because once they died, their files were handled by the morgue. We are told that ‘cancer’ is this incurable mystery, but if you look into it a little more, you will find that cancer is no mystery and it is certainly curable, or at least manageable in other cases. Doctors who use alternative treatments to cure people from cancer are often persecuted, even run out of the country.

The fact is, there is a cure for cancer. Not one cure, actually, but many. ‘Cancer’ is nothing but an umbrella term used to describe about 100 conditions that involve abnormal cell proliferation and tumors, which can have many causes and to which there are many remedies. I would recommend “Knockout” by Suzanne Somers as a primer in alternative cancer treatments. Yes, Chrissie from Three’s Company. No, she’s not playing doctor, she’s interviewing doctors. You can get more info at http://suzannesommers.com

Preventing people’s access to natural cancer treatments is done under the pretense of ethics, but nothing could be more unethical than forcing people to undergo horrendous toxic treatments which have a very low success rate. But the word is getting out and people are saying Enough is Enough! We have been lied to! We demand real medicine! We demand health freedom! We will not allow you to profit off our sickness and death!

Note: Dr Lai’s experiments involved artemisinin and holotransferrin. This should not be interpreted to mean you can cure yourself of cancer at home using Artemisia Annua.

https://thetruthergirls.wordpress.com/2011/02/24/artemisia-cancer-cure/

Basically to activities to help cure cancer:

1. Go on a fasts (water only) so that the body uses Ketones for fuel
2. Drink Absinthe (Mephisto from Austria with full Grande Sage wormwood)
3. Filter soaked/boiled Methanol extracts of powdered Syrian Rue seeds with White Vinegar/Alcohol -- (use Mephisto)
4. DCA - DichloroAcetate (mentioned earlier)
5. Eliminate all forms of Fructose/Corn Syrup from the diet. Fructose feeds cancer directly.
6. Use cordecyps mushroom as an oxidation action.
7. Curcumin with Manuka Honey (attacks the fermentation cycle)
8. Cell mitochondria enhancers (NAD+, NMN, Oaxacletate, ATP pills, Oligonol (Korean lychee drink),  etc...)
9. Get Metformin or Berberine
10. Take BPOV (Bis Picolinato Oxo Vanadium) in a product such as VPX's Shotgun5. This can dramatically increase insulin sensitivity.
11. Get ATP pills from MuscleTech or other makers along with Nitric Oxide/L-Citrulline or get Shotgun5 mentioned above. Take this with Curcumin/Syrian Rue also mentioned above while on a fast.



Results

We show that metformin decreases mitochondrial respiration, causing an increase in the fraction of mitochondrial respiration devoted to uncoupling reactions. Thus, cells treated with metformin become energetically inefficient, and display increased aerobic glycolysis and reduced glucose metabolism through the citric acid cycle. Conflicting prior studies proposed mitochondrial complex I or various cytosolic targets for metformin action, but we show that the compound limits respiration and citric acid cycle activity in isolated mitochondria, indicating that at least for these effects, the mitochondrion is the primary target. Finally, we demonstrate that cancer cells exposed to metformin display a greater compensatory increase in aerobic glycolysis than nontransformed cells, highlighting their metabolic vulnerability. Prevention of this compensatory metabolic event in cancer cells significantly impairs survival.
Conclusions

Together, these results demonstrate that metformin directly acts on mitochondria to limit respiration and that the sensitivity of cells to metformin is dependent on their ability to cope with energetic stress.
https://cancerandmetabolism.biomedcentral.com/articles/10.1186/2049-3002-2-12

Background on how TB rewires ATP usage like Cancer does. Syrian Rue reportedly is effective against TB in manner that it is said to be effective against many cancers -- ATP generation in the UV range is increased with Harmine.

Harmine (banisterine). C13H12ON2 - It is present in P. harmala and in some species of Banisteia, viz., B. caapi, Spruce., B. lutea and B. metallicolor. The alkaloid is optically inactive and forms colorless rhombic prisms from methanol. It is slightly soluble in water, alcohol or ether. Solutions of its salts show a deep blue fluorescence. The hydrochloride has been found to be highly active against Mycobacterium tuberculosis [7].

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An adenosine triphosphate-independent proteasome activator contributes to the virulence of Mycobacterium tuberculosis

Mycobacterium tuberculosis encodes a proteasome that is highly similar to eukaryotic proteasomes and is required to cause lethal infections in animals. The only pathway known to target proteins for proteasomal degradation in bacteria is pupylation, which is functionally analogous to eukaryotic ubiquitylation. However, evidence suggests that the M. tuberculosis proteasome contributes to pupylation-independent pathways as well. To identify new proteasome cofactors that might contribute to such pathways, we isolated proteins that bound to proteasomes overproduced in M. tuberculosis and found a previously uncharacterized protein, Rv3780, which formed rings and capped M. tuberculosis proteasome core particles. Rv3780 enhanced peptide and protein degradation by proteasomes in an adenosine triphosphate (ATP)-independent manner. We identified putative Rv3780-dependent proteasome substrates and found that Rv3780 promoted robust degradation of the heat shock protein repressor, HspR. Importantly, an M. tuberculosis Rv3780 mutant had a general growth defect, was sensitive to heat stress, and was attenuated for growth in mice. Collectively, these data demonstrate that ATP-independent proteasome activators are not confined to eukaryotes and can contribute to the virulence of one the world’s most devastating pathogens.

Authors:
   Jastrab, Jordan B. [1] ; Wang, Tong [2] ; Murphy, J. Patrick [3] ; Bai, Lin [2] ; Hu, Kuan [4] ; Merkx, Remco [5] ; Huang, Jessica [6] ; Chatterjee, Champak [6] ; Ovaa, Huib [5] ; Gygi, Steven P. [3] ; Li, Huilin [4] ; Darwin, K. Heran [1]
   + Show Author Affiliations

Publication Date:
   2015-03-23

https://www.osti.gov/pages/biblio/1215607-adenosine-triphosphate-independent-proteasome-activator-contributes-virulence-mycobacterium-tuberculosis


.........
Extracellular Adenosine Triphosphate Affects the Response of Human Macrophages Infected With Mycobacterium tuberculosis

Abstract

Granulomas are the hallmark of Mycobacterium tuberculosis infection. As the host fails to control the bacteria, the center of the granuloma exhibits necrosis resulting from the dying of infected macrophages. The release of the intracellular pool of nucleotides into the surrounding medium may modulate the response of newly infected macrophages, although this has never been investigated. Here, we show that extracellular adenosine triphosphate (ATP) indirectly modulates the expression of 272 genes in human macrophages infected with M. tuberculosis and that it induces their alternative activation. ATP is rapidly hydrolyzed by the ecto-ATPase CD39 into adenosine monophosphate (AMP), and it is AMP that regulates the macrophage response through the adenosine A2A receptor. Our findings reveal a previously unrecognized role for the purinergic pathway in the host response to M. tuberculosis. Dampening inflammation through signaling via the adenosine A2A receptor may limit tissue damage but may also favor bacterial immune escape.

All living cells sense and respond to changes in their external environment. This is particularly true of cells of the immune system. These cells express receptors that recognize both conserved structural motifs on microbes, known as pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), resulting from tissue damage [1, 2]. In studies on infectious diseases, much attention has been paid to the role of PAMPs and the responses they induce. However, the DAMPs released by necrotic cells are also very likely to affect the host immune response. These molecules, which include high-mobility group box 1 protein, uric acid, heat shock proteins, and nucleotides, have been described to promote and to exacerbate inflammation by activating the NF-κB pathway [1]. A high concentration of extracellular adenosine triphosphate (eATP) serves as a danger signal to alert the immune system to tissue damage [3]; it promotes adhesion of neutrophils to the vascular endothelium, increases secretion of inflammatory cytokines by monocytes or macrophages, induces maturation of dendritic cells, and stimulates effector T-cell function [3].

Tuberculosis research is not an exception to this rule; it has been mainly focused on the role of PRRs and mycobacterial PAMPs at the expense of the role of DAMPs. Mycobacterium tuberculosis, the etiologic agent of this disease has been described to interact with a multitude of PRRs, including Toll-like receptor 2 (TLR2), TLR4, TLR9, NOD-like receptor 2, and some C-type lectins (mannose receptor, DC-SIGN, dectin-1, and Mincle) [4]. Upon ligation of these receptors, macrophages secrete cytokines and chemokines that orchestrate the formation of granulomas. Tuberculosis is characterized by a caseous necrosis in tissues, and, interestingly, M. tuberculosis favors necrosis over apoptosis in infected macrophages [5]. Infected phagocytes are thus exposed to molecules usually present in the cytosol or in the nucleus of the cell. Surprisingly, little is known about how these DAMPs modulate antimycobacterial responses. It has been shown that eATP induces apoptosis of M. tuberculosis–infected phagocytes and mycobacterial killing via phagosome-lysosome fusion and autophagy induction in a P2X7-dependent manner [6–9]. However, the consequences of an eATP-rich microenvironment for mycobacterial killing remain controversial [10]. The concentration of ATP required to limit bacterial growth in macrophages is very high (3 mM) [6–9, 11], well above physiological concentrations. Indeed, in the extracellular space, the steady state concentration of ATP is between 1 and 10 nM [12], although in various pathological situations, such as inflammation, the concentration of eATP may be in the 100-μmol/L range [3].

Here, we report an investigation of whether eATP, at concentrations likely to be present at the site of infection, influences the response of human monocyte-derived macrophages upon M. tuberculosis infection. We found that stimulation of M. tuberculosis–infected macrophages with ATP is accompanied by changes in expression of genes associated mainly with the immune response. In particular, ATP strongly decreased the secretion of inflammatory mediators such as tumor necrosis factor α (TNF-α) and chemokines responsible for the recruitment of innate effector cells, and it increases the expression of tissue-repair-associated genes like VEGF and transforming growth factor α (TGF-α). Alternative activation of macrophages by eATP required its degradation by the ectonucleotidase CD39, and we provide strong evidence that the resulting adenosine monophosphate (AMP) mediated the observed effect through the stimulation of the adenosine A2A receptor. These various findings show that an extracellular AMP-rich microenvironment, similar to that probably prevailing in granulomas, modulates the macrophage response to M. tuberculosis infection and may favor bacterial persistence by dampening the host immune response.
https://academic.oup.com/jid/article/210/5/824/2908522

...
Structure of the mycobacterial ATP synthase Fo rotor ring in complex with the anti-TB drug bedaquiline

INTRODUCTION

Tuberculosis (TB) killed more than 1.3 million people in 2012 (1). The
sharply increasing infection rates documented in the latest World
Health Organization Global Tuberculosis Report (2) pose a threat to
global TB eradication programs (3), making the development of new
and alternative antibiotics, particularly against multidrug-resistant (MDR)
Mycobacterium tuberculosis, an urgent priority. Bedaquiline (BDQ; marketed
as Sirturo) is a novel antitubercular compound that belongs to
the chemical class of diarylquinolines. It was shown to equally inhibit the
growth of drug-sensitive and drug-resistant M. tuberculosis in active TB
infections (4). In vitro–generated BDQ-resistant mutants suggested the
rotor ring of the organism’s F1Fo-ATP synthase as the drug target (4).
The F1Fo-ATP synthase is a macromolecular, membrane-embedded protein
complex that uses the transmembrane electrochemical ion (H+ or
Na+) gradient to convert adenosine diphosphate (ADP) and inorganic
phosphate (Pi) into adenosine triphosphate (ATP) by a rotary mechanism
(5–. The membrane-embedded Fo domain of the complex
harbors the rotor ring of the F-type ATP synthase; usually in bacteria,
it consists of identical copies of c-subunits, forming an hourglass-shaped
cylinder with a central pore (the c-ring) (9). It shuttles ions across the
membrane and thereby powers the synthesis of ATP within the three
catalytically active sites of the F1 headpiece.

http://advances.sciencemag.org/content/advances/1/4/e1500106.full.pdf

https://www.researchgate.net/publication/51332213_Bioluminescence_assay_of_adenosine_triphosphate_in_drug_susceptibility_testing_of_Mycobacterium_tuberculosis

Second link:
https://research.pasteur.fr/en/publication/extracellular-adenosine-triphosphate-affects-the-response-of-human-macrophages-infected-with-mycobacterium-tuberculosis/
https://en.wikipedia.org/wiki/ATP_phosphoribosyltransferase

.....


Involvement of tryptophan(s) at the active site of polyphosphate/ATP glucokinase from Mycobacterium tuberculosis

Pei Chung Hsieh, Bhami C. Shenoy, F. Carl Haase, Joyce E. Jentoft, Nelson F B Phillips

Abstract

The glucokinase (EC 2.7.1.63) from Mycobacterium tuberculosis catalyzes the phosphorylation of glucose using inorganic polyphosphate (poly(P)) or ATP as the phosphoryl donor. The nature of the poly(P) and ATP sites was investigated by using N-bromosuccinimide (NBS) as a probe for the involvement of tryptophan in substrate binding and/or catalysis. NBS oxidation of the tryptophan(s) resulted in fluorescence quenching with concomitant loss of both the poly(P)- and ATP-dependent glucokinase activities. The inactivation by NBS was not due to extensive structural changes, as evidenced by similar circular dichroism spectra and fluorescence emission maxima for the native and NBS-inactivated enzyme. Both phosphoryl donor substrates in the presence of xylose afforded ∼65% protection against inactivation by NBS. The Km values of poly(P) and ATP were not altered due to the modification by NBS, while the catalytic efficiency of the enzyme was decreased, suggesting that the essential tryptophan(s) are involved in the catalysis of the substrates. Acrylamide quenching studies indicated that the tryptophan residue(s) were partially shielded by the substrates against quenching. The Stern-Volmer quenching constant (Ksv) of the tryptophans in unliganded glucokinase was 3.55 M-1, while Ksv values of 2.48 and 2.57 M-1 were obtained in the presence of xylose+poly(P)5 and xylose+ATP, respectively. When the tryptophan-containing peptides were analyzed by peptide mapping, the same peptide was found to be protected by xylose+poly(P)5 and xylose+ATP against oxidation by NBS. The two protected peptides were determined to be identical by N-terminal sequence analysis and amino acid composition. It is proposed from these results that one or both of the tryptophans present in the protected peptide may be located at a common catalytic center and that this peptide may constitute part of the poly(P) and ATP binding regions.

https://cwru.pure.elsevier.com/en/publications/involvement-of-tryptophans-at-the-active-site-of-polyphosphateatp-2

Came across this quote on Garcinia Cambogia. Interesting that (ATP) adenosine triphosphate-citrate-lyase was mentioned as a factor in cancer growth in another article mentioned earlier:
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1. Weight Loss

The key active ingredient found in the rind of garcinia cambogia is hydroxycitric acid (HCA), which some research suggests can help certain people lose weight. (1)

Some studies have found that garcinia cambogia might, in fact, be able to help with low amounts of fat loss, plus some of the other health concerns mentioned above, although its effectiveness is rarely strong or consistent. For example, research suggests that HCA works by blocking a certain enzyme called adenosine triphosphate-citrate-lyase, which contributes to the formation of fat cells. But studies comparing GC’s effects to controls have found that it might only increase weight loss by a mere one to two pounds on average.
https://draxe.com/garcinia-cambogia/
....
Abstract

1-Oncogenes express proteins of "Tyrosine kinase receptor pathways", a receptor family including insulin or IGF-Growth Hormone receptors. Other oncogenes alter the PP2A phosphatase brake over these kinases.
2-Experiments on pancreatectomized animals; treated with pure insulin or total pancreatic extracts, showed that choline in the extract, preserved them from hepatomas.
Since choline is a methyle donor, and since methylation regulates PP2A, the choline protection may result from PP2A methylation, which then attenuates kinases.
3-Moreover, kinases activated by the boosted signaling pathway inactivate pyruvate kinase and pyruvate dehydrogenase. In addition, demethylated PP2A would no longer dephosphorylate these enzymes. A "bottleneck" between glycolysis and the oxidative-citrate cycle interrupts the glycolytic pyruvate supply now provided via proteolysis and alanine transamination. This pyruvate forms lactate (Warburg effect) and NAD+ for glycolysis. Lipolysis and fatty acids provide acetyl CoA; the citrate condensation increases, unusual oxaloacetate sources are available. ATP citrate lyase follows, supporting aberrant transaminations with glutaminolysis and tumor lipogenesis. Truncated urea cycles, increased polyamine synthesis, consume the methyl donor SAM favoring carcinogenesis.
4-The decrease of butyrate, a histone deacetylase inhibitor, elicits epigenic changes (PETEN, P53, IGFBP decrease; hexokinase, fetal-genes-M2, increase)
5-IGFBP stops binding the IGF - IGFR complex, it is perhaps no longer inherited by a single mitotic daughter cell; leading to two daughter cells with a mitotic capability.
6-An excess of IGF induces a decrease of the major histocompatibility complex MHC1, Natural killer lymphocytes should eliminate such cells that start the tumor, unless the fever prostaglandin PGE2 or inflammation, inhibit them...

https://molecular-cancer.biomedcentral.com/articles/10.1186/1476-4598-10-70

An interesting R library from BioConductor:

https://kmezhoud.github.io/bioCancer/


bioCancer - Interactive Multi-OMICS Cancers Data Visualization and Analysis

Travis-CI Build Status releaseVersion develVersion Bioc total

bioCancer is a browser-based interface for Cancer Genomics Data analysis and visualization developped by R, and based on the Shiny package.

Interactivities

bioCancer is listening user setting. Results are updated immediately when inputs are changed (i.e., no separate dialog boxes).
Context

bioCancer focuses on Cancer Genomics data visualisation and Genes Classifications.

Circomics: Pull User genetic profiles with existing Cancer studies

Article by Sam Apple (journalist who helped popularize the Warburg Effect again):
-----------

It's getting clearer — the diet-cancer connection points to sugar and carbs
By Sam Apple
Oct 27, 2017 | 4:00 AM

In August of 2016, the New England Journal of Medicine published a striking report on cancer and body fat: Thirteen separate cancers can now be linked to being overweight or obese, among them a number of the most common and deadly cancers of all — colon, thyroid, ovarian, uterine, pancreatic and (in postmenopausal women) breast cancer.

Earlier this month, a report from the Centers for Disease Control and Prevention added more detail: Approximately 631,000 Americans were diagnosed with a body fat-related cancer in 2014, accounting for 40% of all cancers diagnosed that year.

Increasingly, it seems not only that we are losing the war on cancer, but that we are losing it to what we eat and drink.

These new findings, while important, only tell us so much. The studies reflect whether someone is overweight upon being diagnosed with cancer, but they don't show that the excess weight is responsible for the cancer. They are best understood as a warning sign that something about what or how much we eat is intimately linked to cancer. But what?

When insulin rises to abnormally high levels and remains elevated, it can promote the growth of tumors directly and indirectly.
Share quote & link

The possibility that much of our cancer burden can be traced to diet isn't a new idea. In 1937, Frederick Hoffman, an actuary for the Prudential Life Insurance Co., devoted more than 700 pages to a review of all the medical thinking on the topic at the time. But with little in the way of evidence, Hoffman could only guess at which of the many theories might be correct. If we've made little progress since then in pinpointing specific foods that cause cancer, it's in large part because nutrition studies aren't well-suited to cracking the problem.

A cancer typically arises over years, or decades, making the type of study that might definitively establish cause and effect — an experiment in which people are randomly assigned to different diets — nearly impossible to carry out. The next-best option — observational studies that track what a specific group of individuals eats and which members of the group are later diagnosed with cancer — tends to generate as much confusion as knowledge. One day we read that a study has linked eating meat to cancer; a month later, a new headline declares the exact opposite.

And yet researchers have made progress in understanding the diet-cancer connection. The advances have emerged in the somewhat esoteric field of cancer metabolism, which investigates how cancer cells turn the nutrients we consume into fuel and building blocks for new cancer cells.

Largely ignored in the last decades of the 20th century, cancer metabolism has undergone a revival as researchers have come to appreciate that some of the most well-known cancer-causing genes, long feared for their role in allowing cancer cells to proliferate without restraint, have another, arguably even more fundamental role: allowing cancer cells to "eat" without restraint. This research may yield a blockbuster cancer treatment, but in the meantime it can provide us with something just as crucial — knowledge about how to prevent the disease in the first place.

Lewis Cantley, the director of the cancer center at Weill Cornell Medicine, has been at the forefront of the cancer metabolism revival. Cantley's best explanation for the obesity-cancer connection is that both conditions are also linked to elevated levels of the hormone insulin. His research has revealed how insulin drives cells to grow and take up glucose (blood sugar) by activating a series of genes, a pathway that has been implicated in most human cancers.

The problem isn't the presence of insulin in our blood. We all need insulin to live. But when insulin rises to abnormally high levels and remains elevated (a condition known as insulin resistance, common in obesity), it can promote the growth of tumors directly and indirectly. Too much insulin and many of our tissues are bombarded with more growth signals and more fuel than they would ever see under normal metabolic conditions. And because elevated insulin directs our bodies to store fat, it can also be linked to the various ways the fat tissue itself is thought to contribute to cancer.


(more at link..... http://www.latimes.com/opinion/op-ed/la-oe-apple-cancer-and-diet-20171027-story.html )
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An Old Idea, Revived: Starve Cancer to Death

In the early 20th century, the German biochemist Otto Warburg believed that tumors could be treated by disrupting their source of energy. His idea was dismissed for decades — until now.

SAM APPLE
MAY 12, 2016
Continue reading the main story
The story of modern cancer research begins, somewhat improbably, with the sea urchin. In the first decade of the 20th century, the German biologist Theodor Boveri discovered that if he fertilized sea-urchin eggs with two sperm rather than one, some of the cells would end up with the wrong number of chromosomes and fail to develop properly. It was the era before modern genetics, but Boveri was aware that cancer cells, like the deformed sea urchin cells, had abnormal chromosomes; whatever caused cancer, he surmised, had something to do with chromosomes.

Today Boveri is celebrated for discovering the origins of cancer, but another German scientist, Otto Warburg, was studying sea-urchin eggs around the same time as Boveri. His research, too, was hailed as a major breakthrough in our understanding of cancer. But in the following decades, Warburg’s discovery would largely disappear from the cancer narrative, his contributions considered so negligible that they were left out of textbooks altogether.

Unlike Boveri, Warburg wasn’t interested in the chromosomes of sea-urchin eggs. Rather, Warburg was focused on energy, specifically on how the eggs fueled their growth. By the time Warburg turned his attention from sea-urchin cells to the cells of a rat tumor, in 1923, he knew that sea-urchin eggs increased their oxygen consumption significantly as they grew, so he expected to see a similar need for extra oxygen in the rat tumor. Instead, the cancer cells fueled their growth by swallowing up enormous amounts of glucose (blood sugar) and breaking it down without oxygen. The result made no sense. Oxygen-fueled reactions are a much more efficient way of turning food into energy, and there was plenty of oxygen available for the cancer cells to use. But when Warburg tested additional tumors, including ones from humans, he saw the same effect every time. The cancer cells were ravenous for glucose.

Warburg’s discovery, later named the Warburg effect, is estimated to occur in up to 80 percent of cancers. It is so fundamental to most cancers that a positron emission tomography (PET) scan, which has emerged as an important tool in the staging and diagnosis of cancer, works simply by revealing the places in the body where cells are consuming extra glucose. In many cases, the more glucose a tumor consumes, the worse a patient’s prognosis.

In the years following his breakthrough, Warburg became convinced that the Warburg effect occurs because cells are unable to use oxygen properly and that this damaged respiration is, in effect, the starting point of cancer. Well into the 1950s, this theory — which Warburg believed in until his death in 1970 but never proved — remained an important subject of debate within the field. And then, more quickly than anyone could have anticipated, the debate ended. In 1953, James Watson and Francis Crick pieced together the structure of the DNA molecule and set the stage for the triumph of molecular biology’s gene-centered approach to cancer. In the following decades, scientists came to regard cancer as a disease governed by mutated genes, which drive cells into a state of relentless division and proliferation. The metabolic catalysts that Warburg spent his career analyzing began to be referred to as “housekeeping enzymes” — necessary to keep a cell going but largely irrelevant to the deeper story of cancer.

“It was a stampede,” says Thomas Seyfried, a biologist at Boston College, of the move to molecular biology. “Warburg was dropped like a hot potato.” There was every reason to think that Warburg would remain at best a footnote in the history of cancer research. (As Dominic D’Agostino, an associate professor at the University of South Florida Morsani College of Medicine, told me, “The book that my students have to use for their cancer biology course has no mention of cancer metabolism.”) But over the past decade, and the past five years in particular, something unexpected happened: Those housekeeping enzymes have again become one of the most promising areas of cancer research. Scientists now wonder if metabolism could prove to be the long-sought “Achilles’ heel” of cancer, a common weak point in a disease that manifests itself in so many different forms.

There are typically many mutations in a single cancer. But there are a limited number of ways that the body can produce energy and support rapid growth. Cancer cells rely on these fuels in a way that healthy cells don’t. The hope of scientists at the forefront of the Warburg revival is that they will be able to slow — or even stop — tumors by disrupting one or more of the many chemical reactions a cell uses to proliferate, and, in the process, starve cancer cells of the nutrients they desperately need to grow.

Even James Watson, one of the fathers of molecular biology, is convinced that targeting metabolism is a more promising avenue in current cancer research than gene-centered approaches. At his office at the Cold Spring Harbor Laboratory in Long Island, Watson, 88, sat beneath one of the original sketches of the DNA molecule and told me that locating the genes that cause cancer has been “remarkably unhelpful” — the belief that sequencing your DNA is going to extend your life “a cruel illusion.” If he were going into cancer research today, Watson said, he would study biochemistry rather than molecular biology.

“I never thought, until about two months ago, I’d ever have to learn the Krebs cycle,” he said, referring to the reactions, familiar to most high-school biology students, by which a cell powers itself. “Now I realize I have to.”
(more at link.....
https://www.nytimes.com/2016/05/15/magazine/warburg-effect-an-old-idea-revived-starve-cancer-to-death.html
)

Just wanted to add this... may explain why Metformin is effective for some cancers and makes DCA's effects more potent in some Lactic Acid/Lactate driven cancers:

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https://en.wikipedia.org/wiki/Pyruvate_dehydrogenase_kinase

Disease Relevance

Some studies have shown that cells that lack insulin (or are insensitive to insulin) overexpress PDK4.[10] As a result, the pyruvate formed from glycolysis cannot be oxidized which leads to hyperglycaemia due to the fact that glucose in the blood cannot be used efficiently. Therefore, several drugs target PDK4 hoping to treat type II diabetes.[11]

PDK1 has shown to have increased activity in hypoxic cancer cells due to the presence of HIF-1. PDK1 shunts pyruvate away from the citric acid cycle and keeps the hypoxic cell alive.[12] Therefore, PDK1 inhibition has been suggested as an antitumor therapy since PDK1 prevents apoptosis in these cancerous cells.[13] Similarly, PDK3 has been shown to be overexpressed in colon cancer cell lines.[14] Three proposed inhibitors are AZD7545 and dichloroacetate which both bind to PDK1, and Radicicol which binds to PDK3.[15]

Mutations in the PDK3 gene are a rare cause of X-linked Charcot-Marie-Tooth disease (CMTX6).[16][17]

A harmine-derived beta-carboline displays anti-cancer effects in vitro by targeting protein synthesis.
Eur J Pharmacol.  2017; 805:25-35 (ISSN: 1879-0712)

Carvalho A; Chu J; Meinguet C; Kiss R; Vandenbussche G; Masereel B; Wouters J; Kornienko A; Pelletier J; Mathieu V

Growing evidence indicates that protein synthesis is deregulated in cancer onset and progression and targeting this process might be a selective way to combat cancers. While harmine is known to inhibit DYRK1A and intercalate into the DNA, tri-substitution was shown previously to modify its activity profile in favor of protein synthesis inhibition. In this study, we thus evaluated the optimized derivative CM16 in vitro anti-cancer effects unfolding its protein synthesis inhibition activity. Indeed, the growth inhibitory profile of CM16 in the NCI 60-cancer-cell-line-panel correlated with those of other compounds described as protein synthesis inhibitors. Accordingly, CM16 decreased in a time- and concentration-dependent manner the translation of neosynthesized proteins in vitro while it did not affect mRNA transcription. CM16 rapidly penetrated into the cell in the perinuclear region of the endoplasmic reticulum where it appears to target translation initiation as highlighted by ribosomal disorganization. More precisely, we found that the mRNA expression levels of the initiation factors EIF1AX, EIF3E and EIF3H differ when comparing resistant or sensitive cell models to CM16. Additionally, CM16 induced eIF2α phosphorylation. Those effects could explain, at least partly, the CM16 cytostatic anti-cancer effects observed in vitro while neither cell cycle arrest nor DNA intercalation could be demonstrated. Therefore, targeting protein synthesis initiation with CM16 could represent a new promising alternative to current cancer therapies due to the specific alterations of the translation machinery in cancer cells as recently evidenced with respect to EIF1AX and eIF3 complex, the potential targets identified in this present study.

https://www.medscape.com/medline/abstract/28322844

==============


https://www.researchgate.net/publication/316773136_Data_in_support_of_a_harmine-derived_beta-carboline_in_vitro_effects_in_cancer_cells_through_protein_synthesis


Harmine specifically inhibits protein kinase DYRK1A and interferes with neurite formation
Nora Göckler
Guillermo Jofre
Chrisovalantis Papadopoulos
Ulf Soppa
Francisco J. Tejedor
Walter Becker
First published: 01 October 2009
https://doi.org/10.1111/j.1742-4658.2009.07346.x
Cited by: 94
W. Becker, Institute of Pharmacology and Toxicology, RWTH Aachen University, Wendlingweg 2, 52074 Aachen, Germany

E‐mail: wbecker@ukaachen.de
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Abstract

DYRK1A is a dual‐specificity protein kinase that autophosphorylates a conserved tyrosine residue in the activation loop but phosphorylates exogenous substrates only at serine or threonine residues. Tyrosine autophosphorylation of DYRKs is a one‐off event that takes place during translation and induces the activation of the kinase. Here we characterize the beta‐carboline alkaloid harmine as a potent and specific inhibitor of DYRK1A both in vitro and in cultured cells. Comparative in vitro assays of four kinases of the DYRK family showed that harmine inhibited substrate phosphorylation by DYRK1A more potently than it inhibited substrate phosphorylation by the closely related kinase DYRK1B [half maximal inhibitory concentrations (IC50) of 33 nm versus 166 nm, respectively] and by the more distant members of the family, DYRK2 and DYRK4 (1.9 μm and 80 μm, respectively). Much higher concentrations of harmine were required to suppress tyrosine autophosphorylation of the translational intermediate of DYRK1A in a bacterial in vitro translation system (IC50 = 1.9 μm). Importantly, harmine inhibited the phosphorylation of a specific substrate by DYRK1A in cultured cells with a potency similar to that observed in vitro (IC50 = 48 nm), without negative effects on the viability of the cells. Overexpression of the DYRK1A gene on chromosome 21 has been implicated in the altered neuronal development observed in Down syndrome. Here, we show that harmine interferes with neuritogenesis in cultured hippocampal neurons. In summary, our data show that harmine inhibits DYRK1A substrate phosphorylation more potently than it inhibits tyrosine autophosphorylation, and provide evidence for a role of DYRK1A in the regulation of neurite formation.

https://febs.onlinelibrary.wiley.com/doi/full/10.1111/j.1742-4658.2009.07346.x

Canadian researchers uncover new molecular mechanism to stop proliferation of cancer cells

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June 26, 2018

Canadian researchers have discovered a new and direct molecular mechanism to stop cancer cells from proliferating. In the prestigious journal Nature Cell Biology, scientists from Université de Montréal show that a disruption of a fine balance in the composition of ribosomes (huge molecules that translate the genetic code into proteins) results in a shutdown of cancer cell proliferation, triggering a process called senescence.

"Ribosomes are complex machines composed of both RNAs and proteins that make all the proteins necessary for cells to grow," said UdeM biochemistry professor Gerardo Ferbeyre, the study's senior author. Cancer cells grow and proliferate relentlessly and thus require a massive amount of ribosomes, he explained. Growing cells must coordinate the production of both ribosomal RNAs and ribosomal proteins in order to assemble them together in strict proportion to each other.

"We were surprised, however, to find that if the production of ribosomal RNA-protein proportions are driven out of balance in a cancer cell, proliferation can be shut down by in a very simple and direct manner," said Ferbeyre.

In their research, led by UdeM biochemistry researcher Frédéric Lessard and done in collaboration with biochemistry professor Marlene Oeffinger of the UdeM-affilated Montreal Clinical Research Institute, Ferbeyre and his team uncovered a new mechanism that uncouples ribosomal RNA from ribosomal protein synthesis to stop the proliferation of cells bearing oncogenic mutations. The team demonstrated an unbalanced ribosomal RNA and ribosomal protein synthesis during oncogene-induced senescence, a response that prevents cancer formation. In the lab, senescent cells shut down ribosomal RNA synthesis but kept producing ribosomal proteins. The team then showed that excess copies of a ribosomal protein called RPS14 could now bind and inhibit a key protein – cyclin-dependent kinase-4, or CDK4 – required to drive cell proliferation.

Lessard noted immediate therapeutic implications of the team's discovery. "A drug that shuts down ribosomal RNA biogenesis would immediately lead to an accumulation of ribosomal proteins outside the ribosomes, and since tumor cells make more of them, they would be preferentially affected by these kinds of drugs," he said.

Added Oeffinger: "The physical interaction of RPS14 with CDK4 is the most direct link between ribosome synthesis and cell proliferation regulatory pathways discovered to date. It is therefore likely a very specific way for cancer progression to be prevented". ​​
Source:

http://nouvelles.umontreal.ca/en/article/2018/06/25/scientists-discover-a-new-mechanism-that-prevents-the-proliferation-of-cancer-cells/

Crystal structure reveals how curcumin impairs cancer

(More at link: https://phys.org/news/2018-07-crystal-reveals-curcumin-impairs-cancer.html )
July 9, 2018, University of California - San Diego

A 3D image, obtained using x-ray crystallography, shows curcumin in yellow and red binding to kinase enzyme dual-specificity tyrosine-regulated kinase 2 (DYRK2) in white at the atomic level. Credit: UC San Diego Health

Through X-ray crystallography and kinase-inhibitor specificity profiling, University of California San Diego School of Medicine researchers, in collaboration with researchers at Peking University and Zhejiang University, reveal that curcumin, a natural occurring chemical compound found in the spice turmeric, binds to the kinase enzyme dual-specificity tyrosine-regulated kinase 2 (DYRK2) at the atomic level. This previously unreported biochemical interaction of curcumin leads to inhibition of DYRK2 that impairs cell proliferation and reduces cancer burden.

But before turning to curcumin or turmeric supplements, Sourav Banerjee, Ph.D., UC San Diego School of Medicine postdoctoral scholar, cautions that curcumin alone may not be the answer.

"In general, curcumin is expelled from the body quite fast," said Banerjee. "For curcumin to be an effective drug, it needs to be modified to enter the blood stream and stay in the body long enough to target the cancer. Owing to various chemical drawbacks, curcumin on its own may not be sufficient to completely reverse cancer in human patients."

Writing in the July 9 issue of the Proceedings of the National Academy of Sciences, Banerjee and colleagues report that curcumin binds to and inhibits DYRK2 leading to the impediment of the proteasome—the cellular protein machinery that destroys unneeded or damaged proteins in cells—which in turn reduces cancer in mice.

"Although curcumin has been studied for more than 250 years and its anti-cancer properties have been previously reported, no other group has reported a co-crystal structure of curcumin bound to a protein kinase target until now," said Banerjee, first author on the study. "Because of their work on the crystallography, our collaborators at Peking University, Chenggong Ji and Junyu Xiao, helped us to visualize the interaction between curcumin and DYRK2."

"The enzyme kinases IKK and GSK3 were thought to be the prime curcumin-targets that lead to anti-cancer effect but the co-crystal structure of curcumin with DYRK2 along with a 140-panel kinase inhibitor profiling reveal that curcumin binds strongly to the active site of DYRK2, inhibiting it at a level that is 500 times more potent than IKK or GSK3."

Working alongside Jack E. Dixon, Ph.D., Distinguished Professor of Pharmacology, Cellular and Molecular Medicine, Chemistry and Biochemistry at UC San Diego, Banerjee and team have been looking for regulators of proteasomes to inhibit tumor formation by proteasome-addicted cancers like triple-negative breast cancer (TNBC) and the plasma cell malignancy called multiple myeloma.

Using biochemical, mouse cancer models and cellular models the team found that curcumin is a selective inhibitor of DYRK2 and that this novel molecular target has promising anticancer potential for not only chemo-sensitive but also proteasome inhibitor resistant/adapted cancers.

"Our results reveal an unexpected role of curcumin in DYRK2-proteasome inhibition and provide a proof-of-concept that pharmacological manipulation of proteasome regulators may offer new opportunities for hard-to-treat triple-negative breast cancer and multiple myeloma treatment," said Dixon, who was co-senior author with Zhejiang University's Xing Guo, Ph.D., on the paper. "Our primary focus is to develop a chemical compound that can target DYRK2 in patients with these cancers."

https://phys.org/news/2018-07-crystal-reveals-curcumin-impairs-cancer.html

BPOV in VPX's Shotgun 5 or Synthase pre-workout drinks is a very effective and active form of Bis-Piclonato Oxo vanadium. It can dramatically increase insulin sensitivity. (note this is not an advertisement or promotion merely a mention of product that contains this active form of vanadium).
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Role of Vanadium in Cellular and Molecular Immunology: Association with Immune-Related Inflammation and Pharmacotoxicology Mechanisms

Olga Tsave,1 Savvas Petanidis,1 Efrosini Kioseoglou,1 Maria P. Yavropoulou,2 John G. Yovos,2 Doxakis Anestakis,3,4 Androniki Tsepa,4,5 and Athanasios Salifoglou1

https://www.hindawi.com/journals/omcl/2016/4013639/

Abstract

Over the last decade, a diverse spectrum of vanadium compounds has arisen as anti-inflammatory therapeutic metallodrugs targeting various diseases. Recent studies have demonstrated that select well-defined vanadium species are involved in many immune-driven molecular mechanisms that regulate and influence immune responses. In addition, advances in cell immunotherapy have relied on the use of metallodrugs to create a “safe,” highly regulated, environment for optimal control of immune response. Emerging findings include optimal regulation of B/T cell signaling and expression of immune suppressive or anti-inflammatory cytokines, critical for immune cell effector functions. Furthermore, in-depth perusals have explored NF-κB and Toll-like receptor signaling mechanisms in order to enhance adaptive immune responses and promote recruitment or conversion of inflammatory cells to immunodeficient tissues. Consequently, well-defined vanadium metallodrugs, poised to access and resensitize the immune microenvironment, interact with various biomolecular targets, such as B cells, T cells, interleukin markers, and transcription factors, thereby influencing and affecting immune signaling. A synthetically formulated and structure-based (bio)chemical reactivity account of vanadoforms emerges as a plausible strategy for designing drugs characterized by selectivity and specificity, with respect to the cellular molecular targets intimately linked to immune responses, thereby giving rise to a challenging field linked to the development of immune system vanadodrugs.

1. Introduction

In the past decades, several metallodrugs have been developed to target human pathophysiologies, with platinum, copper, vanadium, gold, ruthenium, and yttrium, among select metal ions, serving as the basis of such pharmaceuticals [1, 2]. Representative examples of therapeutic metallodrugs include Y-90 (Zevalin) used in the treatment of non-Hodgkin’s lymphoma, sodium aurothiomalate (Myochrysine, Myocrisin, and Tauredon) or aurothioglucose (Aureotan, Solganal, Solganol, and Auromyose) used in rheumatoid arthritis patients, and bismuth subsalicylate (Pepto-Bismol), a widely used drug for the treatment of gastrointestinal disorders [1]. Beyond those, the successful platinum-based metallodrugs (cisplatin, carboplatin, and oxaliplatin) as antitumor agents were burdened by undesirable toxic side effects and appearance of chemoresistance. Both of them emerged as dire problems forcing the development of alternative metallodrugs with distinct modes of action and fewer or no side effects [3]. Vanadium is a known metal of high physiological, environmental, and industrial importance. It is an early first-row transition metal (Group 5 with ), with an electronic configuration of [Ar]3d34s2, having two natural isotopes, 51V and 50V. Its presence in biological systems in the marine and terrestrial environment has been well-established over the years [4]. It is encountered, among others, in vanadium-dependent haloperoxidases and alternative nitrogenases [5]. Moreover, various vanadium species have been found to exhibit significant effects as external cofactors, inhibiting the function of a wide range of enzymes (glyceraldehyde-3-phosphate dehydrogenase, lipoprotein lipase, tyrosine phosphorylase, glucose-6-phosphate dehydrogenase, glycogen synthase, adenylate cyclase, and cytochrome oxidase) and stimulating the function of others (Na+-K+-ATPase, H+/K+-ATPase, myosin ATPase, dynein, adenylate kinase, phosphofructokinase, and choline esterase) [6, 7]. From the biological point of view, the oxidation states V(IV) and V(V) appear to be of strong interest, with cationic and anionic complexes thereof forming in the physiological pH range (pH 2–. In vivo, a key redox interplay emerges between the physiologically relevant V(V) and V(IV) oxidation states, with medium equilibria defining their distribution intra- and extracellularly. V(III), on the other hand, is present in ascidians and fan worms, but it is not present in higher organisms [8, 9]. Its emergence in biological media under reduced conditions, however, leaves a lot to be scrutinized with respect to potential roles in bioprocesses [10, 11] currently elusive or unknown. Nevertheless, the majority of mammalian tissues contain approximately 20 nM vanadium. Consequently, involvement of a biogenic metal ion, such as vanadium, in immune-regulating mechanisms, including immune suppression and inflammation downregulation, formulates a well-defined platform for research into future effective and efficient immunotherapy [12, 13]. In this respect, the herein elaborated account presents new facets of the merit that vanadium holds as a metallodrug in immunotherapy, based on currently held views and knowledge emerging from ongoing research in the fields of (bio)chemical and medical interest (Figure 1). The various forms of vanadium thus far employed in immune-related pathologies (a) necessitate an orderly account of its (bio)chemical activity at the cellular and molecular level, (b) signify a structure-based elaboration of its involvement in immune system interactions and responses, and (c) point out significant factors entering future design of new vanadodrugs capable of atoxically, selectively, and specifically targeting cellular molecular loci, intimately influencing immunophysiology and contributing to immunopharmaceuticals in a host of relevant diseases (Figure 2).

Figure 1: Vanadium forms exhibiting immunogenic activity.

Figure 2: Vanadium influences several immune-related pathways, thereby sculpturing immune response.

5. Targeting the NF-κB Signaling Pathway

In recent years, several studies have demonstrated that NF-κB might be a very important target for vanadium with regard to the influence of cell signaling mechanisms and gene expression. Vanadium has the ability to interact with several transcription factors and influence the activity of the cell cycle, oncogenes, or tumor suppressor genes. V(IV) complex species (Figure 1) seem to promote differentiation and mineralization of the mesenchymal stem cells via activation of the NF-κB/ERK signaling pathway and subsequent enhancement of the NF-κB mediated action. Moreover, it has been demonstrated that ERK is implicated in the rise of the transcriptional activity of NF-κB. Thus, it is possible that V(IV) modulates both ERK and NF-κB pathways, and each pathway would act in concert to stimulate osteoblasts [28]. Likewise, bis(peroxido)vanadium species (Bpv) (Figure 1) (Table 1), a phosphotyrosine phosphatase inhibitor, induces myogenic cells to acquire a gene expression profile and differentiation potential consistent with the phenotype of circulating precursors, while maintaining their myogenic potential. These effects are mediated by NF-κB activation through the Tyr42-IκB-alpha phosphorylation, as shown by the expression of the dominant negative mutant form of the p50 NF-κB subunit [29]. Moreover, treatment of macrophages with sodium metavanadate results in the activation of both NF-κB and c-Jun N-terminal kinase (JNK) [30]. The activity of IκB kinase-beta (IKKbeta) was significantly elevated concurrently with the increased degradation of IκB-α and enhanced NF-κB activity in cells exposed to metavanadate. Thus, both IKK and SAPK/ERK kinase 1 (SEK1), an intermediate kinase within the MEKK1 to c-Jun N-terminal kinase (JNK) cascade, are involved in vanadate-induced NF-κB activation. Finally, “pervanadate” (V(V)-peroxido) was also shown to activate the DNA-binding activity of NF-κB, through (a) tyrosine phosphorylation and (b) expression of the T cell tyrosine kinase , but not degradation of IκB-α [31] (Table 1). Evidently, suitably configured vanadium species of both oxidation states (V(IV) and V(V)) are in a position to support distinct influence patterns of reactivity in key NF-κB signaling pathways.
6. Subverting Toll-Like Receptor Signaling

Toll-like receptors (TLRs) constitute a distinct type of pattern recognition receptors (PRR) playing a crucial role in innate immune response [32]. Triggering TLRs to generate an immune response is therefore a primary goal in immunotherapy. To this end, certain metallodrugs are able to elicit an immune response in various immune cell types via Τoll-like receptors (TLRs) and, correspondingly, their receptor agonists [33, 34]. Recently, texture-specific vanadium-containing alloy materials (mmnTi-Al-V), reflecting implant materials, were shown to diminish TLR expression, exhibiting an 8-fold reduction in mRNAs for Τoll-like receptor-4. Treated cells had reduced levels of proinflammatory interleukins and higher mRNAs for factors strongly associated with cell apoptosis [35] (Figure 1) (Table 1). Under normal conditions, TLR ligation and dimerization activate signaling cascades and subsequent production of proinflammatory cytokines, interferons, ROS, and proteases. Signaling involves recruitment of adaptor proteins MyD88, MAL, TRIF, or TRAM. The MyD88-dependent pathway is required for all TLRs except for TLR3, and MyD88 signaling involves a serine kinase (IL-1R)-associated kinase (IRAK), TNFR-associated factor 6 (TRAF6), and (TGF-β)-activated kinase 1 (TAK-1) sequence followed by activation of nuclear factor NF-κB and activator protein 1 (AP-1) transcription factors via the IKK and MAPK pathways, respectively [36]. TLR-targeting therapies, employing metallodrugs currently under development and clinical trials, and better understanding of the mechanisms of TLR-targeting therapies are thus expected to allow more specific treatments to be developed, thereby improving treatment options for immunoinflammatory disorders.

7. Role in Inflammation-Related Immunopathology

Activation of the inflammatory cascade involves immune cell mediators, transcription factors, and chemokines [37]. Inflammation is characterized by upregulation in the systemic concentrations of inflammation-related cytokines such as IL-6, IL-8, IL-18, TNF-α, and C-reactive protein (CRP) [38, 39]. Accumulating evidence reveals that vanadium can downregulate inflammatory reactions both in vitro and in vivo. To this end, recent findings have shown that vanadium administration reduced serum creatinine and blood urea nitrogen levels, suggesting amelioration of renal dysfunction [40]. Moreover, vanadium(III)-(L-cysteine) (VC-III) (Figure 1) (Table 1) treatment significantly prevented CDDP (cis-diamminedichloroplatinum(II))-induced generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and onset of lipid peroxidation in kidney tissues of experimental mice. In addition, vanadium also substantially restored CDDP-induced depleted activities of the renal antioxidant enzymes, such as superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, and glutathione (reduced) levels. Histopathological analysis also confirmed reduced expression of proinflammatory mediators such as NF-κB, COX-2, and IL-6. VC-III administration also stimulated the Nrf2-mediated antioxidant defense system through promotion of downstream antioxidant enzymes, such as HO-1. Moreover, vanadium treatment significantly enhanced CDDP-mediated cytotoxicity in MCF-7 and NCI-H520 human cancer cell lines. Thus, VC-III can serve as a suitable chemoprotectant and increase the therapeutic window of CDDP in cancer patients. Furthermore, bis(peroxido)vanadium is able to prevent neuronic inflammation on cerebral ischemia. Data reveal that bis(peroxido)vanadium (Bpv), a specific inhibitor of PTEN’s phosphatase activity, exhibits powerful neuroprotective properties [41]. Treatment with Bpv significantly increased IL-10 levels and decreased TNF-α concentration in the ischemic boundary zone of the cerebral cortex. Likewise, vanadium(III)-(L-cysteine) treatment significantly reduced PTEN mRNA and protein levels and increased PI3K, Akt, and p-GSK-3β protein expression in the ischemic boundary zone of the cerebral cortex. These results (a) demonstrate the neuroprotective effects of bis(peroxido)vanadium on cerebral ischemia and reperfusion injury of ischemic stroke rats and (b) show that vanadium is associated with reduction of inflammatory mediator production and upregulation of PTEN downstream proteins PI3K, Akt, and p-GSK-3β
.
8. Pharmacotoxicology Mechanisms

Increasing evidence shows that complex vanadium species possess structural characteristics that justify their chemical reactivity at the biological level, thereby rendering them viable candidates for immune system disease metallodrugs [42, 43]. In order for vanadium compounds to be effective, atoxic well-defined forms of that metal ion encompassing selected physicochemical characteristics should be examined carefully in terms of their availability, selectivity, and specificity, followed by long-term epidemiological studies and controlled clinical trials. For such well-defined forms to emerge as immunomodulatory agents, key factors should be taken into consideration in the design and subsequent synthetic efforts. Such factors include (a) the nature of vanadium itself (inorganic forms at various oxidation states, metal-organic complex species, organometallic forms, etc.), (b) the nature of ligands-substrates bound to vanadium (e.g., peroxido, oxido, and nonperoxido organic chelators of variable O,N-containing tethers), (c) the oxidation state of vanadium (with V(IV) and V(V) representing the well-established physiological forms in human biological fluids, and V(III) awaiting further perusal), (d) the hydrophilicity-hydrophobicity of the ligands-substrates as well as the arising vanadium complex inorganic-organic species, thereby allowing access to specified molecular loci of action, and (e) the binary and ternary complex metal-organic nature of vanadium bestowing appropriate chemical reactivity where and when such is needed to counteract carcinogenic activity. The aforementioned collective properties formulate the chemical profile of vanadium that will configure its biological reactivity and consequently adhere to the selectivity and specificity needs of the immune system target site(s) of anti-inflammatory action. The need for such approaches to new atoxic vanadium compounds exemplifies the motivation for commensurate research efforts currently underway (Figure 4). In line with the emergence of select vanadium species, capable of delivering immunogenic activity, studies on the identification of immune system specific sites of interaction of vanadium with biomolecular targets in the cell should be conducted, shedding light onto the chemistry associated with the biological activity of vanadium in its various selected atoxic forms (Table 1). Current research data presented in this review highlight vanadium’s synthetic and structural bioinorganic profile along with its biological activity attributes, collectively formulating the significant potential of unique structure-based and immune process-specific vanadodrugs for the detection, prevention, and treatment of immune system aberrations.

Figure 4: Current obstacles to overcome by specifically designed vanadium metallodrugs in cancer immunotherapeutics.

9. Conclusions

Overall, specified vanadium complex species are involved in key mechanisms of immune regulation and can be used as promising metallodrugs toward future immunotherapy. Therefore, significant merit emerges toward further studies attempting to (a) design new vanadodrugs and (b) decipher the potential role that vanadium species have in interactions with immune system modulators as well as other transcription factors influencing immune signaling. Concurrently, vanadium regulation of B and T cell signaling emerges as a useful tool in probing modulatory mechanisms of inflammation suppression and their (in)direct implication in immunotherapeutic approaches. In addition, activation of certain interleukins, including IL-2, IL-4, IL-6, and IL-10 by vanadium denotes their specific contribution to immunometabolic processes, thereby warranting further perusal into the development of diagnostic and immunotherapeutic tools in immunopathological disorders. Numerous advances have contributed to the understanding of the cellular and molecular pathways involved in immune-related inflammation and stand as groundwork toward further investigations linking interleukin involvement to inflammation-driven immune response. Sculpting the immune response using metallodrugs may thus be a challenging goal toward future immunotherapies. The collective data mentioned in the current review reflect apt examples of vanadium-based approaches in cancer immunotherapy and related diseases. To this end, better understanding of the molecular signaling pathways used by vanadium interjection in immune surveillance, immune-driven inflammation, and immune cells stands as a well-defined platform for targeted research into future effective and efficient vanadium-based immunotherapy. Defined into such a well-formulated framework, vanadium-linked approaches in immunotherapy have merit, deserve due attention, and warrant further investigation.
Abbreviations
ATPase: Adenosine triphosphatase
GTPase: Guanosine triphosphatase
AP-1: Activator protein 1
LPLs: Lamina propria lymphocytes
IELs: Intraepithelial lymphocytes
IFN-γ: Interferon-gamma
TCR: T cell receptor
TNF-α: Tumor necrosis factor alpha
MHC: Major histocompatibility complex
PGE2: Prostaglandin E2
ERK: Extracellular signal-regulated kinases
IKKB: Inhibitor of nuclear factor kappa-B kinase subunit beta
JNK: c-Jun N-terminal kinase
MEKK1: Mitogen-activated protein kinase kinase kinase 1
SAPK: Stress-activated protein kinase
NF-κB: Nuclear factor of kappa light polypeptide gene enhancer in B cells
NFAT: Nuclear factor of activated T cells
CDDP: cis-Diamminedichloroplatinum(II)
MYD-88: Myeloid differentiation primary response gene 88
COX-2: Cyclooxygenase-2
Nrf-2: Nuclear factor (erythroid-derived 2)-like 2
CRP: C-reactive protein
Bpv: Bis(peroxido)vanadium
PTEN: Phosphatase and tensin homolog
PI3K: Phosphoinositide 3-kinase
Akt: Serine-threonine kinase-protein kinase B
p-GSK-3β: Phosphorylated glycogen synthase kinase 3 beta
mmnTi-Al-V: Macro-/micro-/nanotextured rough Ti-Al-V.

Related. Cancer and Diabetes tends to rise as people move to "developed" nation status and away from working with dirt and the bacteria in it. This isn't the pollution related cancers which also arise. With higher leisure time, insulin sensitivity can drop as people gain weight from sitting around watching screens.

https://www.independent.co.uk/life-style/health-and-families/health-news/child-diabetes-watch-tv-three-hours-a-day-screen-time-how-much-archives-of-disease-in-childhood-a7627121.html

Nature Partner Journals: Aging and Mechanisms of Disease Publishes Elysium’s Clinical Trial Studying Basis

It’s now possible to boost declining levels of NAD+, a molecule required for fundamental chemical reactions in the human body. Read the results of our study in Nature Partner Journals: Aging and Mechanisms of Disease.

https://www.nature.com/articles/s41514-017-0016-9

Elysium is committed to conducting rigorous scientific research and sharing it with our customers, which is why we publish our work in open access, peer-reviewed journals. The results of our recent clinical trial on the safety and efficacy of Basis were published in Nature Partner Journals: Aging and Mechanisms of Disease, a journal that provides a forum for the world’s most important research in the field of aging.

Here, we take you through the most important elements of the trial.

   Abstract
   Introduction
   Results
   Discussion
   Methods

Abstract

The first-in-humans, double-blind, placebo-controlled, randomized study assessed the safety and efficacy of taking repeat doses of Basis — a combination of nicotinamide riboside (NR) and pterostilbene — in a population of 120 healthy adults ages 60-80. The results? Regular doses of Basis increased NAD+ levels by an average of 40 percent.
Introduction

Metabolism, Aging, and NAD+

A properly functioning metabolism is essential to health and longevity. In the scientific sense of the word, metabolism refers to the sum of every chemical reaction that happens inside the body, an enormous web of interactions on the molecular level that aim to keep the you in what biologists call homeostasis: a state of balance, best illustrated by our near constant body temperature, which persists even in a wide range of circumstances. This is all made possible by an elegant choreography between coenzymes (or, “helper molecules”) and specific proteins acting as metabolic sensors, attuned to, and responding to ambient conditions in the cell and the body as a whole. The coenzyme nicotinamide adenine dinucleotide (NAD+) and a family of proteins called sirtuins make up an important part of this choreography.

NAD+ in Energy Creation, Genome Integrity, and More

First discovered in 1906, NAD+ is a coenzyme found in all living cells, and it has two main categories of roles in the body. One is is turning nutrients into energy. In that process NAD+ transfers electrons in redox reactions to help synthesize ATP, the energy currency of the cell. Importantly, NAD+ isn’t “used up” or consumed in creating energy. In the other category of roles, NAD+ works with proteins to carry out essential biological processes like DNA damage repair, mitochondrial function, maintaining chromosomal integrity, gene expression, epigenetic and posttranslational modifications, and calcium signaling. Sirtuins are some of the proteins that regulate these processes, especially those that help keep the cell healthy during stressful conditions, including aging.

Several things are important to know about the relationship between NAD+ and sirtuins. Sirtuins require NAD+ to function, and NAD+ is used up in this process (and in all the other processes except energy creation). This means that the body needs to constantly synthesize it. Finally, NAD+ is known to decline in organisms, including humans, as they age. This led researchers to the notion that restoring NAD+ levels, on the one hand, and activating sirtuins, on the other, could have health benefits.

NAD+ Replenishment Improves Health in Animal Studies

And so far the preclinical research supports this idea. In fact, using NAD+ precursors, including one of the two primary ingredients in Basis, nicotinamide riboside, has shown significant value in maintaining robust health and preventing age-related health problems animal studies. For example, one study demonstrated that mitochondrial dysfunction, a hallmark of aging, was caused by declining NAD+ levels in old animals leading to a breakdown of communication between the nucleus and the mitochondria. Remarkably, one week of NMN (another NAD+ precursor) administration in old mice was shown to reverse the observed mitochondrial dysfunction in a manner requiring one of the sirtuins. In another study, NR was shown to reverse the decline in the number and function of adult stem cells in mice, and to increase the lifespan of these animals. Likewise, the polyphenol resveratrol has been demonstrated to be a potent sirtuin activator with poor bioavailability in humans; pterostilbene, the other ingredient in Basis, is a natural analog with better bioavailability.
Results

The Trial: Basis Increases NAD+ in Humans

Basis combines the ingredients nicotinamide riboside and pterostilbene with the goal of synergistically supporting metabolic health by increasing NAD+ levels and activating sirtuins. Since human data on NAD+ supplementation is limited — one previous study on 12 participants showed that NR could increase NAD+ levels in the blood over a 24-hour period — this study by Elysium sought to determine whether NAD+ levels could be sustained over a longer time period: eight weeks, thereby extending the base of safety and efficacy data on the ingredients.

We did that in a placebo-controlled trial of 120 healthy adults between the ages of 60 and 80, the first repeat-dose trial for NR as well as the first test of the combination of NR and pterostilbene in humans. The results? Participants taking the recommended dose of Basis (250 mg of NR; 50 mg of pterostilbene) saw NAD+ levels increase by an average of 40 percent over baseline after 30 days, a number that was sustained at 60 days. Participants taking twice the recommended dose of Basis saw their NAD+ levels increase by 90 percent over baseline after 30 days and 55 percent at 60 days. And those taking the placebo had no NAD+ increase at all. There were no serious adverse events reported in the study.

Discussion

Topics for Future Study: Liver Enzymes, Blood Pressure, Lipids

The science of NAD+ is thriving. The strength of this study is in the demonstration that NAD+ levels in whole blood can be significantly increased in humans in a safe and sustainable way by taking Basis. While secondary and exploratory endpoints of the trial suggested a possible role of Basis in liver health, blood pressure, and mobility (see complete study for details), the data isn’t sufficiently powered to draw definitive conclusions. This study represents an important first step that future clinical studies can build upon — and these trials are underway.

(more at link:  https://www.elysiumhealth.com/en-us/basis/human-clinical-trial-results  )

This Scientist Discovered That One Molecule Makes Naked Mole Rats Immune to Cancer. Will it Work in Humans?

An interview with Dr. Vera Gorbunova, whose lab at the University of Rochester, NY, studies aging, DNA repair, and cancer.
Photography by Maciek Jasik

https://www.elysiumhealth.com/en-us/knowledge/endpoints

Highlights:

→ How evolution prepared long-lived animals, especially naked mole rats, to be the ideal research models

→ High-molecular-weight hyaluronan, which is responsible for the animal's incredible near-immunity to cancer

→ The "longevity quotient," a metric that determines if an animal is long-lived

→ The role of DNA repair in health and disease

→ How the role of telomeres differs in animals and humans

Vera Gorbunova’s office sits on the fourth floor of a brutalist building overlooking the Genesee River on the University of Rochester campus. Her test subjects — and her muses — reside one floor below, scurrying through mazes of plastic-tube tunnels in a lab where the thermostat is cranked up to 90 degrees Fahrenheit, humidity at 50 percent. “It’s very tropic in the naked mole rat room,” Gorbunova says. “I like being in there. And they live for 30 years, so it must be good for you.”

But it’s not temperature and humidity that make naked mole rats extraordinary winners in the game of survival. Gorbunova, who has made several groundbreaking discoveries on the molecular science of aging by studying the creatures, knows this more than most.
University of Rochester, NY.

The daughter of two physicists from St. Petersburg, Russia, Gorbunova became intrigued by the study of aging before direct research on its mechanisms were being fully explored. So she took the long way round by necessity, first studying DNA repair and transposable elements (gene sequences that can change their position in the genome) at the Weizmann Institute in Rehovot, Israel, and then working on cellular senescence and telomeres at Baylor College of Medicine. “Only after I defended my postdoctoral thesis was I finally able to focus on aging itself,” she said. “But what I did before that was very important, because now I’ve connected DNA repair with aging, and more recently I started to look at transposable elements, and they’re related to aging, too. So it all kind of comes together.”

Specifically, it all comes together for Gorbunova in her lab, where she studies comparative biology using a wide range of rodents that aren’t mice or rats. While the mouse model is traditional, highly honed and efficient for many studies, it isn’t the ideal subject for insights on longevity. The standard lab mouse survives two, maybe three years, whereas a number of larger rodents — squirrels, beavers, porcupines — live for at least 20, or like naked mole rats, even longer. “Evolution already prepared these animals as research models,” she says. “We can take all the knowledge we have from mice and rats and try to apply it to these longer lived rodents, and see how they are different from each other.”
Naked mole rats at the Gorbunova Lab. Photos by CK.

In the naked mole rat, Gorbunova made her most stunning discovery yet: that a molecule called high-molecular-weight hyaluronan (HMW-HA) seems to be responsible for their incredible near-immunity to cancer. Humans also produce hyaluronan, but not enough, or the right type, to ward off cancer. We spent an afternoon with Gorbunova, discussing her wrinkled muses, how pathways of longevity evolved differently in different long-lived animals, and the ways we might use her discoveries to make humans live longer, healthier lives.

Finding Molecular Strategies for Longevity

When you were growing up, in St. Petersburg, both your parents were physicists. Do you think their worldview — seeing life through the lens of physical laws — rubbed off on you and the way you looked at studying animals?

I’m not sure I really saw this connection. To me, in living organisms the complexity was so many orders of magnitude higher. In physics, there are certain laws. If you drop something, it always falls down. But in biology, five percent of the time, when you drop something it flies upward. And that’s fine!

   The system is so much more complex. Things don’t always work the same way. That’s what fascinated me. Physics was cold. Biology felt alive, and so complicated.

Which biologists inspired you in those early years?

I read a book by Konrad Lorenz, an Austrian biologist who was a founder of ethology [the scientific and objective study of animal behavior], when I was around 12. The books he wrote were very beautifully written. He studied animals that lived around his house — geese, crows that were nesting on the trees nearby. And to me that was just imagining your life as being surrounded by science, not really separating work and home. It was all the same.

From ethology, what I was interested in evolved. I went to college and realized animal behavior wasn’t what I wanted to do. I wanted to dig deeper, into what the molecular mechanisms of these animals were.
The model that you use applies molecular study to long-lived animals. How did you get into this field?

During my postdoc, I started thinking I wanted to do something different. Most people at the time were taking this approach that they need to find a very simple organism that lives a very short life and use it as a model. You can find some important genes this way. But that’s when I began thinking about longer-lived organisms. They’re more difficult to study, but that’s where the interesting findings are.

Steve Austad was the one who initially introduced the idea. Before him, pretty much no one was looking at long-lived species on a mechanistic level. People examined their life histories, but didn’t move much past that. I wanted to bring them as research models into the lab and apply all the molecular tools we have to them.

A good tool for understanding what makes an animal long-lived is called the Longevity Quotient. Can you explain it?

The Longevity Quotient is metric that Steve Austad came up with. He plotted lifespan versus size for hundreds of different species. There was a diagonal line that most species were scattered along. So for a certain size, you expect an animal to have a certain lifespan. The longevity quotient is how much an animal deviates from that expected lifespan. Elephants, for example, live for about 80 years. They fall almost directly on this diagonal line — an animal the size of an elephant you’d expect to live for around 80 years.

Now humans also live for around 80 years. So we are outliers there. Because to live as long as we do, you’d expect us to be the size of an elephant.

The naked mole rat is similarly an outlier: To live as long as they actually do, which is 30 years, you’d expect them to be perhaps the size of a goat. And there are a few other species that are also outliers. Bats are outliers — they live longer than expected. Marsupials are outliers in a different way. They live shorter than you’d expect. Opossums are a pretty sizeable animal, but they live like two years, and that’s it.

Given what we know about these long-lived animals, why do we age?

That’s a difficult question. If you’d ask me how we age, I’d say there is an accumulation of damage. Our repair systems don’t keep up. But why? If you look at different species, every species evolves a lifespan that kind of makes sense for that organism. A mouse usually doesn’t live past its first year in the wild, because somebody will eat it. So the mouse evolved a short lifespan, and even if you take them to a lab and pamper them, they can make it maybe two or three years at most. But they’re really at their prime in the first year. In the wild, that’s as long as they make it. So they reproduce in the first year; they are healthy and vigorous. There is no point for a mouse to have the capacity to live 10 years because it will never in the wild do that.

But if you take porcupine, it’s much harder to kill it. It can evolve longer lifespan, and reproduce for a longer span of time. So then it evolves all those mechanisms to support its life for longer time.
You’ve said something in the past that I find very interesting: That in every long-lived animal we’ve found a different pathway to longevity. How are these animals evolving along different pathways to live longer?

What we keep finding is that there are perhaps two classes of mechanisms being used. There are conserved mechanisms that we tend to find in all longer lived species. DNA repair is probably one. We find that most longer-lived species that we look at have an enhanced version of that mechanism.

Then there are mechanisms that are different in every species. If you think about how animals evolved long lifespan, it happened independently. The naked mole rat used to live above ground, but when it adopted a subterranean lifestyle, it started living longer and longer. That’s a very different evolutionary environment than a squirrel, which lived on the ground and had a shorter life, but when it started climbing trees it became harder to catch, so it then evolved a longer lifespan. But that’s a very different ecological niche. So it then uses very different molecular strategies for longevity. It has a whole different set of conditions where longevity will evolve.

There are so many mechanisms that are not conserved in different individuals. That to me makes them even more interesting. Because that means if we really learn the mechanisms, and we learn how to import them into humans, then we can benefit from them.

Naked mole rats are very interesting animals.

They are. They live in East Africa, and spend almost their entire lives underground. And their social lifestyle is fascinating: In every colony there is only one breeding female, which we call the queen, and maybe one or two males that are chosen to breed. So far, in most conditions, it’s been found that their social structure is most close to a social insect colony.

What about their biology? They have incredible longevity.

They live very long, some upwards of 30 years, but they stay very fit to the end of their lives. There was a paper that just came out recently summarizing many many years of statistics on naked mole rats. It said that their mortality — their chance of death — doesn’t increase as they get older. Which is crazy, because it tells us they don’t age.

(LEFT GRAPH) Age-specific mortality hazard for naked mole-rats (cyan), calculated for 200 day intervals; for mice (pink), calculated for 50 day intervals using the control-mouse survival data reported by Miller (Miller et al., 2014); for human females (orange), by year, as reported for the 1900 birth cohort by Bell and Miller (Bell and Miller, 2005); and for horses (yellow), by year, calculated from life insurance tables reported by Valgren (Valgren, 1945). Calculations begin after Tsex for each species (red). (RIGHT GRAPH) Hazard plots from (left chart) panels, re-scaled on the x-axis to the time it takes each organism to reach Tsex from birth. The definition of Tsex is more nuanced than that of body weight: ambiguity exists around how the age of sexual maturity should be marked, whether Tsex should include gestation time, and how Tsex relates to other developmental milestones. Tsex also lacks independence from both body weight and phylogeny.
That is a common definition of what aging is.

Exactly — an increase in mortality rates year over year. Our colony is not that old, so I can’t add anything from my own observations. Our animals are around fifteen years old. And that’s pretty young for naked mole rat. In this study, they looked for several decades, but seemingly they don’t have increased mortality. So that means either they don’t age, or maybe they do age but they can live much longer than 30 years. Thirty years may be just how long we have been able to observe them alive.

So if they’re not getting cancer, and they don’t have increasing mortality, what are they dying of when they do die at age thirty?

They don’t die very often. We’ve had the same animals for a decade. In our colony, most deaths are from fighting, which happens if there is unrest in the colony — if a female tries to challenge the queen, they fight. They can puncture each others lungs with their teeth.

Is it likely that they can live longer than the max age we have recorded?

I think it can be longer. We’ve only had one animal that was close to that age, which was the original founder. We got him when he was 27, and he was 29 when he died. At that age, he was slower than the other animals. So I cannot say he was as spry as the youngsters, but he was generally healthy. He died of a liver condition. Around the same time, we also had one younger animal from a different colony die from a similar condition. We thought it might be from eating something that wasn’t fresh enough, so we changed our procedures and started cleaning our vegetables better, and it never happened again. So maybe he didn’t even die of old age. Other than those two deaths, we have not had any other animals die from health-related issues. It was all fighting.

So it’s not just cancer that they’re resisting.

Right, they are resistant to all sorts of diseases. We tried to induce arthritis in them, using a surgical procedure to model human arthritis in mice. Mice develop it within weeks. We did the same surgery on the naked mole rat, and it was just fine. They are also resistant to heart disease. So it’s amazing just how healthy these animals are. In terms of what humans can take home from that, there is a lot. We can look for mechanisms related to multiple degenerative conditions.

One of your major discoveries with naked mole rats is how they use this molecule, hyaluronan, for cancer resistance. First of all, what is hyaluronan?

Hyaluronan was discovered a long time ago. It’s a major non-protein component of extracellular matrix, which is whatever is between cells and provides structure for our tissues. It also holds water, so it makes our tissues hold water and not collapse. It also interacts with the cell receptors. So it’s really an integral part of the tissue.

And you found it in naked mole rats for the first time?

Yes. I knew hyaluronan was this thing within the space between cells, but that was it. When we started studying cancer resistance in naked mole rats and were culturing their cells, we found that their cells made the culture medium, the plate, very viscous. And we don’t see that viscosity with human cells or mouse cells — so we were like, what’s the goo?

We were looking for some kind of secreted molecule that was responsible for cancer resistance, because we had clues from our other experiments. So we decided to figure out what the goo was. It took us a while, but then we found it was hyaluronan.

Why was it causing cancer resistance?

What we found at first when we started culturing naked mole rat cells was that they don’t grow as densely as human or mouse cells. Those form what’s called a monolayer on the plate. Every cell would sit very tight next to the other cell. Naked mole rat cells would still leave space. So we were wondering if that’s what’s important for the anti-cancer effect, because in a tumor, cells really start to crowd. Here, cells were keeping their distances. Something wasn’t letting the cells crowd too much. So we thought, whatever prevents this crowding may be important for cancer resistance. So when we noticed the goo, we thought, well, maybe it’s something they secrete that will let the cells know it’s too crowded.

And that’s what we found. If we prevented naked mole rat cells from making hyaluronan, then they’d start to grow in more crowded ways. It’s not a physical barrier, because some cells can squeeze past each other. It’s more of a signalling barrier, because the cells have receptors, and hyaluronan interacts with those receptors and triggers a signaling pathway that tells the cell, Okay, stop dividing. And how exactly this pathway works we actually don’t know.

Do humans have hyaluronan, too? Does it have the same qualities as this hyaluronan in naked mole rats?

Hyaluronan was a very serendipitous finding, because it has the same structure in both humans and naked mole rats. So it’s already a part of our bodies. The big difference is that naked mole rats have a lot of hyaluronan, and the molecules are longer than ours. Naked mole rats upregulate it at high levels. For humans, it’s just a structural component of our tissues, and it degrades very quickly. But the structural units are the same. So if we find ways to upregulate it in humans, then maybe we could get the same benefits as naked mole rats do.

Have there been any studies or advances in treatments for humans?

We are working on that. The simplest thing is you’d just inject it where it was needed. But that is not very practical, because it would stay local. And people do use injections for arthritis, but it’s not going to address systemic conditions. So what we are working on now is developing small-molecule drugs that will slow down degradation of hyaluronan in the human body, so that we can systematically increase the levels.

   “DNA gets damaged all the time, from oxidation, from radiation and free radicals, from strands that get broken during the replication of DNA. It’s easy to break. That damage happens a lot — every day.”

You’ve noted that there are other pathways to longevity that naked mole rats use, including efficient DNA repair. What is that?

They do have more efficient DNA repair. DNA gets damaged all the time, from oxidation, from radiation and free radicals, from strands that get broken during the replication of DNA. It’s easy to break. That damage happens a lot — every day.

There are special enzymes that work like a handyman to go in and put the pieces back together. There are multiple pathways for DNA repair, so for every type of lesion there will be different “crew” or handyman.
How are certain animals different in their DNA repair? Do they have enzymes that others don’t, or do we all have the same, but theirs are more efficient?

The second is more true. If we look at mammals, we would pretty much all have the same “handyman” enzymes, but some are more efficient than others. This is still really what my group is focused on, trying to understand what enzymes have improved DNA repair activity in long-lived species, and how that works. Because if we can understand that, maybe we can enhance it.

What are direct results of inefficient DNA repair?

There are two things. Cancer is an obvious one — due to a high rate of accumulation of mutations. For cancer to occur there must be multiple mutations of certain kinds put together to transform the cell. A more common outcome is that every cell gets a little bit derailed in different ways. Every cell starts to work not optimally. When people look at single cells and measure the expression of many genes, in a young organism, every cell of the same tissue would express the same set of genes. But in old age, it’s all over the place.
What are the hurdles to finding the mechanisms of efficient DNA repair out, and translating them to humans?

It’s been very difficult to make DNA repair more efficient. It’s much easier to make it less efficient. You’re mutating a protein and then you get an animal that ages prematurely in many cases, because it accumulates a lot of DNA damage.

But people were skeptical in assigning a role for DNA repair in longevity, and saying, it’s easy to screw things up — you mutate it, you get premature aging — but it doesn’t mean that it limits normal lifespan. This is when we started looking at multiple species, and we saw that long-lived species actually have better DNA repair, so for the first time we could connect long lifespan with better DNA repair, and not just mutated proteins with short lifespan.

What are the biggest hurdles for your field?

I think what’s really important now in biology is for scientists to keep open mind. There was a lot of progress achieved with model organisms. You take yeast cell and can mutate every gene you want, and shuffle them the way you want. It’s a very defined system. This idea was keeping many scientists from working on something like a naked mole rat — that you can’t make a transgenic animal, that you can’t modify just one gene. But that’s really something we have to get away from. People have to think broader, and not limit themselves to these traditional systems. What I mean is: Don’t keep searching for the keys only under the streetlight, because it’s easy to look there. Go where you think you lost the keys.

Illustration by Esther Sarto

For years, scientists believed that telomeres, or the section of repeating nucleotide sequences (TTAGGG) that cap the chromosome within DNA, had a vital impact on aging — and even, after it was found that they shorten as humans age, that they were a main mechanism of the aging process. “People found that human cells cannot grow forever, and they stop growing,” says Gorbunova. “And the shortening of telomeres became a clock for that.”

Gorbunova was perplexed by a comparative biological question: she found that relative to humans, lab mice maintained extremely long telomeres their entire lives, yet they had extremely short lifespans. She began studying telomere length across a variety of animals.

   “We found that it really depends on the size of the animal,” she says. “Up to 10 kilograms, there is one kind of telomere maintenance. And in animals bigger than ten kilos, it’s more human like. Then we came up with a model to explain that.”

That model has become standard in comparative biology. The shortening of telomeres and suppression of the enzyme that lengthens telomeres, telomerase, while important to the aging process, seems to mainly be an anti-cancer mechanism. It causes senescence, an end to cell growth, which keeps pre-malignant tumors from becoming malignant. But in small animals that are likely to be eaten by predators early in life, like mice, a disease like cancer that occurred later in life was not a major concern for health. Instead, by keeping their telomeres long and their telomerase active, they gained benefits like faster cell growth and regeneration.

(more at link:  https://endpoints.elysiumhealth.com/vera-gorbunova-profile-f94c08dddec9?gi=906c0dfa9139 )

Ancient Chinese medicine for the cancer win (anti-hangover too):
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Dihydromyricetin Activates AMP-Activated Protein Kinase and P38MAPK Exerting Antitumor Potential in Osteosarcoma

Zhiqiang Zhao, Jun-qiang Yin, Man-si Wu, Guohui Song, Xian-biao Xie, Changye Zou, Qinglian Tang, Yuanzhong Wu, Jinchang Lu, Yongqian Wang, Jin Wang, Tiebang Kang, Qiang Jia and Jingnan Shen
DOI: 10.1158/1940-6207.CAPR-14-0067 Published September 2014

ArticleFigures & DataInfo & Metrics
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Abstract

Numerous patients with osteosarcoma either are not sensitive to chemotherapy or develop drug resistance to current chemotherapy regimens. Therefore, it is necessary to develop several potentially useful therapeutic agents. Dihydromyricetin is the major flavonoid component derived from Ampelopsis grossedentata, which has a long history of use in food and medicine. The present study examined the antitumor activity both in vitro and in vivo without noticeable side effects and the underlying mechanism of action of dihydromyricetin in osteosarcoma cells. We found that dihydromyricetin induced increased p21 expression and G2–M cell-cycle arrest, caused DNA damage, activated ATM–CHK2–H2AX signaling pathways, and induced apoptosis in osteosarcoma cells as well as decreasing the sphere formation capability by downregulating Sox2 expression. Mechanistic analysis showed that the antitumor potential of dihydromyricetin may be due to the activation of AMPKα and p38MAPK, as the activating AMPKα led to the inactivation of GSK3β in osteosarcoma cells. Moreover, GSK3β deletion or GSK3β inhibition by LiCl treatment resulted in increased p21 expression and reduced Sox2 expression in osteosarcoma cells. Taken together, our results strongly indicate that the antitumor potential of dihydromyricetin is correlated with P38MAPK and the AMPKα–GSK3β–Sox2 signaling pathway. Finally, immunohistochemical analysis indicated that some patients had a lower p-AMPK expression after chemotherapy, which supports that the combination of dihydromyricetin and chemotherapy drug will be beneficial for patients with osteosarcoma. In conclusion, our results are the first to suggest that dihydromyricetin may be a therapeutic candidate for the treatment of osteosarcoma. Cancer Prev Res; 7(9); 927–38. 2014 AACR.
Introduction

Osteosarcoma is the most common primary malignant bone tumor in childhood and adolescence (1).The clinical outcome of patients with osteosarcoma can be improved with chemotherapy, and the 5-year survival rate has reached 60% to 70% (2). However, there is currently a need to identify effective agents for the treatment of this deadly disease and to develop new therapeutic strategies with less severe side effects, because numerous patients with osteosarcoma are either not sensitive to chemotherapy or develop drug resistance with current chemotherapy regimens.

Ampelopsis grossedentata, a vine plant in South China, is a popular and multipurpose traditional Chinese medicinal herb and has a long history of being used as food and medicine (3). Dihydromyricetin, a 2,3-dihydroflavonol compound, is the main bioactive component extracted from Ampelopsis grossedentata, is one kind of flavonoids that has many biologic effects, including antialcohol intoxication, reducing blood pressure, antibacterial, antioxidant, and antitumor properties (4–6). Recently, it has been shown in some cancer cells that dihydromyricetin possesses antitumor effects, such as antiproliferation, cell-cycle arrest, induction of apoptosis, and increased sensitivity to chemotherapeutic drugs (7, . Moreover, dihydromyricetin has shown potential in ameliorating chemotherapy-induced side effects (9). However, very little is known about its effects on osteosarcoma, and the underlying mechanisms of dihydromyricetin's anticancer effects are still under investigation.

AMP-activated protein kinase (AMPK), a serine/threonine protein kinase and a member of the Snf1/AMPK protein kinase family, is a metabolic checkpoint protein downstream of the LKB1 tumor suppressor and integrates growth factor receptor signaling with cellular energy status. AMPK is activated by metabolic stresses and xenobiotic compounds that cause a cellular energy imbalance (10). Evidence suggesting that AMPK can inhibit cell-cycle progression in human hepatocellular carcinoma cells (11), and that AMPK activation requires the presence of LKB1, led us to hypothesize that AMPK activators might be useful in the prevention and/or treatment of cancer. It is possible that AMPK has many downstream targets whose phosphorylation mediates dramatic changes in cell metabolism, cell growth, and other functions. 5-Aminoimidazole-4-carboxamide riboside (AICAR) and metformin are pharmacologically active, potent AMPK activators and have become the focus of much research in carcinogenesis due to their regulation of various signaling pathways, such as the inhibition of mTOR signaling and blocking of the growth of glioblastoma cells that express the activated EGFR mutant, as well as their ability to control the levels of p53, p21, cyclin D1, and caspases (12, 13). In addition, metformin has been found to be an effective antitumor agent due to induction of DNA damage and apoptosis in osteosarcoma (14).

The p38MAPK and JNK protein kinases affect a variety of intracellular responses, such as inflammation, cell-cycle regulation, cell death, development, differentiation, senescence, and tumorigenesis; as such, these kinases have been exploited for the development of therapeutics to treat a variety of different diseases, including cancer (15, 16). Constitutive activation of JNK or p38MAPK has been implicated in the induction of many forms of neuronal apoptosis in response to a variety of cellular injuries (17). Moreover, p38MAPK phosphorylation by anandamide treatment subsequently activated caspase-3, leading to apoptosis in osteosarcoma cells (18).

In this study, we have investigated the antitumor activity of dihydromyricetin in osteosarcoma and examined its effects on cell-cycle progression, the induction of DNA damage and apoptosis, and sphere formation. Furthermore, we have investigated the changes in AMPK/GSK3β/Sox2 and p38MAPK cell signaling in osteosarcoma cells treated with dihydromyricetin. This study is the first to demonstrate the effect of dihydromyricetin on osteosarcoma cells and has identified the mechanism of its action, through activating AMPK and p38MAPK signaling pathways, which may help guide the clinical use of dihydromyricetin.

http://cancerpreventionresearch.aacrjournals.org/content/7/9/927

Anti-Inflammatory is this Chinese medicine...taps the human body's use of the Charge Field:
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Basic Study
Copyright The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 7, 2018; 24(13): 1398-1409
Published online Apr 7, 2018. doi: 10.3748/wjg.v24.i13.1398
vidence-Based Complementary and Alternative Medicine
Volume 2017, Article ID 1053617, 10 pages
https://doi.org/10.1155/2017/1053617

Review Article
The Versatile Effects of Dihydromyricetin in Health
Hongliang Li,1 Qisheng Li,2 Zhaowen Liu,1 Kai Yang,1 Zhixi Chen,1 Qilai Cheng,1 and Longhuo Wu1

1College of Pharmacy, Gannan Medical University, Ganzhou 341000, China
2Jiangxi Health Vocational College, Nanchang 330052, China

Correspondence should be addressed to Qilai Cheng; cql_57@126.com and Longhuo Wu; longhwu@hotmail.com

Received 24 May 2017; Accepted 27 July 2017; Published 30 August 2017

Academic Editor: Siyaram Pandey

Copyright 2017 Hongliang Li et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Dihydromyricetin is a flavonoid isolated from Ampelopsis grossedentata, which is traditionally used in China. Dihydromyricetin exhibits health-benefiting activities with minimum adverse effects. Dihydromyricetin has been demonstrated to show antioxidative, anti-inflammatory, anticancer, antimicrobial, cell death-mediating, and lipid and glucose metabolism-regulatory activities. Dihydromyricetin may scavenge ROS to protect against oxidative stress or potentiate ROS generation to counteract cancer cells selectively without any effects on normal cells. However, the low bioavailability of dihydromyricetin limits its potential applications. Recent research has gained positive and promising data. This review will discuss the versatile effects and clinical prospective of dihydromyricetin.

1. Introduction

Dihydromyricetin, also known as ampelopsin belonging to flavonoid family, is isolated from Ampelopsis grossedentata, which grows widely in the south of China. Traditionally, Ampelopsis grossedentata is used as tea in Yao people in China to treat pyretic fever and cough, pain in pharynx and larynx, and jaundice hepatitis. It is also used in nephritis, hepatitis, halitosis, and polyorexia prevention and treatment [1]. Dihydromyricetin is the richest component found in Ampelopsis grossedentata. Biologically, recent studies have demonstrated that dihydromyricetin shows multiple health-benefiting activities, including antioxidative, anti-inflammatory, anticancer, antimicrobial, cell death-mediating, and lipid and glucose-metabolism-regulatory activities. In this review article, these biological activities will be discussed comprehensively.

2. Chemical Characteristics of Dihydromyricetin

Structurally, due to the highly hydrophilic character, dihydromyricetin shows poor bioavailability and significantly limits its potential medicinal applications. The solubility of dihydromyricetin may be enhanced with temperature increasing from 0.2 mg/ml at 25°C to 0.9 mg/ml at 37°C. The diagrams of phase-solubility show that dihydromyricetin solubility is positively correlated with the concentration of hydroxypropyl-β-cyclodextrin, PVP K30, and PEG6000. Thus, the solubility of dihydromyricetin increases to 2.8 mg/ml at 25°C and 9.6 mg/ml at 37°C, respectively [2]. In addition, enzyme-acylated product of dihydromyricetin improves its lipid-solubility and also exhibits a good antioxidative activity [3]. The poor bioavailability is further supported by the pharmacokinetic characteristics, which show (21.63 ± 3.62 ng/mL) and t1/2 (3.70 ± 0.99 h) after oral administration [4]. Similar results are obtained but show different pharmacokinetic characteristics of dextroisomer and racemate in dihydromyricetin: (81.3 and 107 ng/mL), AUC0-∞ (42.8 and 32.0 mg × min/L), and t1/2 (288 and 367 min), respectively [5].

However, the low bioavailability of dihydromyricetin may be also partially attributed to its poor structural stability. Dihydromyricetin decomposes when exposing to light, pH buffer, pepsin, and pancreatin enzymes. Generally, the metabolites of flavonoids are produced by hydrolysis, ring fission, and reduction [6]. Dihydromyricetin can be transformed into seven metabolites in rats [7] (Figure 1). They are 5,7,3′,5′-tetrahydroxyflavanonol (2), 5,7,4′,5′-tetrahydroxy-3′-methoxyflavone (3), 5,7,3′,5′-tetrahydroxy-4′-methoxyflavone (4), 5,7,3′,4′,5′-pentahydroxyflavanone (5), 3,4,5,7,3′,4′,5′-hepthydroxyflavan (6), (2R,3S)-5,7,3′,4′,5′-pentahydroxyflavanonol (7), and dihydromyricetin-O-5-β-D-glucuronide (.
Figure 1: The structure of dihydromyricetin (1) and its metabolites (2–.

3. Oxidative Stress-Mediating Activity

Oxidative stress is a state of cellular homeostasis imbalance, characterized as reactive oxygen species (ROS) production overweighting the antioxidant enzyme system. Excessive ROS contributes to mitochondria-dependent apoptosis. The mechanistic chemistry in radical scavenging ability of dihydromyricetin has been approved in protection against mesenchymal stem cells damage [8]. The antioxidative activity of dihydromyricetin is also confirmed by two model systems, including cooked ground beef and soybean oil [9]. Excessive ROS may acts as a dominant factor contributing to myocardial fibrosis. Cardiac fibroblast may be activated by angiotensin II through induction of ROS production, promoting proliferation, and collagen synthesis. Dihydromyricetin restores these adverse effects induced by angiotensin II, as indicating by decreased levels of ROS and MDA, attenuated expression of (a subunit of NADPH oxidase), and increased total antioxidant capacity [10]. Similar results are showed in the antioxidative effect of dihydromyricetin on attenuating angiotensin II-induced cardiomyocyte hypertrophy [11].

Excessive ROS is also correlated with neurogenerative diseases. 3-Nitropropionic acid may induce motor dysfunction and learning and memory impairments through hyperactivation of ROS production. Dihydromyricetin significantly restores metabolic abnormality in striatum, improves the expression of antioxidant system, and inhibits mitochondria-dependent apoptosis [12]. Memory impairments are also subject to hypobaric hypoxia, which often induces oxidative stress in the brain. Dihydromyricetin has been showed to suppress ROS production and attenuate lipid peroxidation in the hippocampus, promoting mitochondrial biogenesis and improving mitochondrial functions (Table 1). In addition, dihydromyricetin protects neurons from hypobaric hypoxia through amelioration of Sirt3-FOXO3a signaling-induced oxidative stress [13].
Table 1: The biological activities of dihydromyricetin.

Oxidative stress has been considered as the critical factor correlating with nephrotoxicity induced by cisplatin. In HK-2 cells, dihydromyricetin may protect against such nephrotoxicity through attenuation of oxidative stress and inflammatory stress, leading to inhibition of apoptosis [14]. ROS in osteocytes contributes to osteoporosis formation. In MG63 cells, dihydromyricetin effectively exhibits antioxidative activity to scavenge ROS and leads to attenuation of caspase-3 and caspase-9 and inhibition of cell apoptosis [15]. In HUVECs, dihydromyricetin ameliorates H2O2-induced oxidative stress against apoptosis mitochondria dependently [16]. In addition, dihydromyricetin may increase the total antioxidant capacity and attenuate ROS generation and NOX2 expression. Thus, dihydromyricetin ameliorates the cytotoxicity induced by oxLDL, as indicated by monocytes adhesion and oxidative stress [17].

P62 has been demonstrated to competitively bind to Keap1, which plays a negative role in modulating Nrf2 activity. The complex p62-Keap1-LC3II promotes Keap1 degradation, which further activates Nrf2 in a positive feedback loop. Dihydromyricetin significantly induces p62 expression and subsequent Nrf2 and HO-1 activation, leading to attenuation of oxidative stress and hepatoprotection against toxicity induced by ethanol [18].

4. Anti-Inflammatory Activity

NF-κB signaling has been demonstrated to play a critical role in regulating the expression of target genes relating to inflammation. The subunit IκBα, as a negative controller, can be degraded after phosphorylation modification, leading to activation and nuclear translocation of p65 and subsequent promotion of NF-κB target genes expression. The computational docking assays show that dihydromyricetin binds to a novel binding site IKKβ-Cys46, which plays a pivotal role in the pathogenesis of inflammation. The delayed-type hypersensitivity and an IKKβC46A transgenic mouse model confirm that Cys46 is the binding site for dihydromyricetin to be responsible for suppression of NF-κB signaling [55]. In LPS-induced RAW2264.7 microphages, dihydromyricetin attenuates IKKβ activity and IKKα/β phosphorylation, leading to inhibiting p65 phosphorylation and nuclear translocation and suppressing target genes expression, including COX-2 and iNOS [19]. Similar results showed that dihydromyricetin inhibits the phosphorylation of NF-κB, p38, and JNK, but not ERK1/2 in LPS-induced RAW2264.7 microphages [20].

Dihydromyricetin has been reported to inhibit TNF-α-induced inflammation through inactivation of NF-κB signaling in HeLa cells. Specifically, dihydromyricetin dephosphorylates and inhibits the degradation of IκBα, inactivates p65 nuclear translocation and downregulates the TNF-α-induced expression of TRAF2 and RIP1. In addition, dihydromyricetin also downregulates the expression of NF-κB target genes, including c-IAP2, Bcl-2, TRAF1, iNOS, cyclin D1, COX-2, ICAM-1, MMP-9, and VEGF [21] (Table 1). In asthmatic mouse model, ovalbumin promotes the secretion of proinflammatory cytokines, IgE, and IgG1 and the infiltration of inflammatory cells into the bronchoalveolar lavage. Dihydromyricetin has been demonstrated to significantly reduce ovalbumin-induced inflammatory activities [22].

5. Anticancer Activity

ROS may act as a messenger to balance redox signaling to determine cell fates. Higher ROS production and oxidative stress are positively correlating with carcinogenesis. Interestingly, dihydromyricetin may regulate cell death potentially through mediating ROS generation. Dihydromyricetin, in a dose-dependent manner, promotes ROS generation and activation of mitochondria-dependent apoptosis in human hepatocarcinoma HepG2 cells [23]. Mechanistically, dihydromyricetin triggers mitochondria-dependent apoptotic pathway through downregulating Akt/Bad signaling. More specific, dihydromyricetin inhibits the phosphorylation of Akt-Ser473 and Bad-Ser112/Ser136 and enhances Bax and Bad proteins expression, leading to formation of Bcl-2/Bcl-xL heterodimers and activation of Bax-stimulated mitochondrial apoptosis in HepG2 cells [24]. In mouse hepatocellular carcinoma Hepal-6 cells, dihydromyricetin dose-dependently induces cell apoptosis through downregulation of TGFβ/Smad3 pathway and NOX4/ROS pathway [27]. In addition, dihydromyricetin significantly inhibits the expression of MMP-9, but not MMP-2, which is the key factor responsible for the migration and invasion of SK-Hep-1 cells. This underlying mechanism of dihydromyricetin in antimetastasis is related to the decreased phosphorylation levels of p38, ERK1/2, and JNK, and the increased expression of PKC-δ [28] (Table 1).

In A2780 and SKOV3 cell lines, dihydromyricetin dose- and time-dependently inhibits cellular proliferation and causes cell cycle arrest in G0/G1 and S phases. The activation of p53 signaling and the suppression of survivin expression are involved in dihydromyricetin-induced ovarian cancer cell apoptosis. Survivin, an inhibitors of apoptosis proteins (IAPs) family, is a key factor in cellular chemotherapy-related resistance. Thus, dihydromyricetin may promote the resistant ovarian cancer cells to resensitize to paclitaxel and doxorubicin through suppression of survivin expression [29]. On molecular mechanism of drug resistance in colorectal cancer HCT116/L-OHP cells, dihydromyricetin significantly inhibits the promoter activity and the expression of multidrug resistance protein 2 (MRP2), leading to chemosensitivity of cells to oxaliplatin. In addition, dihydromyricetin also attenuates the nuclear translocation of erythroid 2 p45 related factor 2, a MRP2 regulator [30].

In osteosarcoma, dihydromyricetin may upregulate the expression of p21 and cause cell cycle arrest in G2-M phage, leading to cell apoptosis. The molecular mechanism is associated with dihydromyricetin-induced activation of AMPKα-GSK-3β-Sox2 signaling pathway [31] (Table 1). In human melanoma SK-MEL-28 cells, dihydromyricetin promotes the expression of p21 and p53 and attenuates the expression of cdc2, p-cdc-2, and cdc25A, causing cell cycle arrest in G1/S phase. In addition, dihydromyricetin activates cell apoptosis through upregulation of the proapoptotic factor Bax and downregulation of NF-κB pathway and p38 pathway [32]. In HepG2 and Hep3B cell lines, dihydromyricetin may cause cell cycle arrest in G2/M phase through activation of Chk1/Chk2/cdc25C. However, deficiency of p53 and Chk1 does not cause dihydromyricetin-induced G2/M arrest [33].

6. Cell Death-Mediating Activity

Apoptosis is a process of programmed cell death, which exhibits a critical role in cellular physiopathology of various tissues and organs. Dihydromyricetin, in a dose-dependent manner, downregulates the expression of p53 and upregulation Bcl-2 expression, leading to activation of apoptosis in gastric cancer cell [34]. Interestingly, dihydromyricetin promotes cell apoptosis through reduction of TGFβ and activation of p53 signaling pathways in HepG2 cells [25]. Consistently, dihydromyricetin downregulates Bcl-2 expression and increases Bax/Bcl-2 ratio through upregulation of p53 signaling pathway in HepG2 cells [56]. Dihydromyricetin exhibits a selective cytotoxicity against non-small-cell lung cancer (NSCLC) cells (A549 and H1975), but not against normal cells (WI-38). This might be related to dihydromyricetin-triggered ROS generation, which causes a mitochondria-dependent apoptosis. In addition, dihydromyricetin promotes ROS-induced ERK1/2 and JNK1/2 signaling pathways, which can be reversed by N-acetylcysteine [35].

Dihydromyricetin can induce not only apoptosis but also autophagy in human melanoma (SK-MEL-28) cells. Dihydromyricetin potentiates ROS generation, which can be counteracted by N-acetyl-L-cysteine (NAC). The mechanism of dihydromyricetin-induced autophagy is related to upregulation of NF-κB phosphorylation induced by ROS [36]. Similarly, dihydromyricetin induces cardiac autophagy and protects against apoptosis in STZ-induced diabetic mice, as indicated by upregulation of Beclin1, Atg7, and Bcl-2 expression and LC3 II/LC3 I ratio and downregulation of p62, caspase-3/-9 levels. Further, dihydromyricetin may promote AMPK and ULK1 phosphorylation, improve mitochondrial functions, and subsequently prevent diabetic cardiomyopathy [37]. mTOR, a master regulator belonging to PI3K related kinase family, regulates the activation of autophagy. mTOR can be phosphorylated and regulated by PI3K/Akt, ERK1/2, and AMPK through regulating TSC2 and TSC1/2 phosphorylation. Dihydromyricetin has been reported to activate AMPK and attenuate the expression of p-ERK1/2 and p-Akt, leading to inhibition of mTOR and activation of autophagy in HepG2 cell lines [26] (Table 1).

AMPK increases the transcriptional activity of FOXO3a through the phosphorylation at Ser588. In liver I/R injury, dihydromyricetin also increases the mRNA expression of autophagy-related genes, such as BECN1, LC3, Atg5, and Atg12, protecting liver cell against apoptosis. This might be associated with upregulation of FOXO3a protein expression, nuclear translocation, and phosphorylation at Ser588 induced by dihydromyricetin [38]. FOXO3a activity is also mediated by its acetylation induced by p300/CBP or Sirt. However, the acetylation levels of FOXO3a are not changed in the cytosol, indicating that FOXO3a acetylation does not play an important role in dihydromyricetin-induced autophagy [38]. In head and neck squamous cell carcinoma (HNSCC), dihydromyricetin promotes the phosphorylation and activation of STAT3 and subsequent induction of autophagy through producing ROS. Specifically, dihydromyricetin induces the upregulation of autophagic markers such as Beclin1, LC3, and p62. In addition, dihydromyricetin also promote HNSCC cells apoptosis [39] (Table 1).

7. Metabolism-Mediating Activity

Flavonoids are also partial agonists of PPARγ, which exhibits an inhibitory effect on diabetes. Upregulation of diabetogenic adipokines expression and downregulation of adiponectin expression are mediated by PPARγ-Ser273 phosphorylation, which is regulated by ERK/CDK5 signaling pathway. In Zucker diabetic fatty rats, dihydromyricetin may inhibit the phosphorylation of PPARγ-Ser273 through attenuation of ERK/CDK5 signaling pathway, leading to retardation of hyperglycemia onset and amelioration of insulin resistance without weight gain [40]. Management of insulin resistance in skeletal muscle becomes a strategy for type II diabetes (T2D) treatment. Dihydromyricetin increases skeletal muscle insulin sensitivity, as indicated by upregulation of p-IRS-1 and p-AKT expression, by inducing formation of autophagosomes partially through activation of AMPK-PGC-1α-Sirt3 pathway in C2C12 myotubes [41, 42] (Table 1).

In LDL receptor knockout (LDLr−/−) mice, dihydromyricetin decreases high-fat diet-induced serum levels of ox-LDL, IL-6, and TNF-α and increases PPARα, LXRα, and ABCA1 expression, leading to amelioration of hyperlipidemia, suppression of hepatic lipid accumulation, and inhibition of foam cell formation and cholesterol efflux [17]. This is supported by the ApoE−/− mouse model, which shows that dihydromyricetin can significantly prevent the development of weight gain, hyperlipidemia, and atherosclerosis induced by a Western diet (high cholesterol, high sucrose, and high-fat) [57]. Dyslipidemia constitutes a major health problem in inducing atherosclerosis. Many flavonoids including naringenin, quercetin, and dihydromyricetin are involved in glucose and lipid profiles improvement. Synergized with benzo[a]pyrene (BaP), β-naphthoflavone (BNF) activates CYP1A1 expression and CYP1A1-mediated 7-ethoxyresorufin O-deethylation (EROD). Dihydromyricetin has been demonstrated to promote tumorigenesis induced by BaP in small intestine [58]. However, dihydromyricetin alone does not show any significant effects on metabolic activity of CYP1A1/2 and CYP2B1 enzymes [59].

Irisin is a new myokine derived from the fibronectin type III domain-containing protein 5 (FNDC5). PGC-1α regulates the expression of FNDC5 mRNA and the metabolism of irisin, which is correlated with body mass index (BMI). Dihydromyricetin has been demonstrated to increase irisin levels in serum and upregulate the FNDC5 expression through partially activating PGC-1α pathway, leading to amelioration of metabolic diseases [44]. Palmitate has been identified as a major inducer of insulin resistance in obesity. Also, palmitate can downregulate the expression of slow-twitch fiber proportion, AMPK, and PGC-1α and upregulate the expression of folliculin-interacting protein 1 (FNIP1) and folliculin in C2C12 myotubes. These effects induced by palmitate could be abrogated by dihydromyricetin administration [43].

8. Neuroprotective Activity

MicroRNAs (miRs) have been demonstrated to be involved in the development of Alzheimer’s disease (AD). Sirt, a direct substrate of miR-34a, can promote cell tolerance to aging through induction of autophagy. In aging models, dihydromyricetin downregulates the D-gal-induced expression of miR-34a and p53/p21 pathways and upregulates Sirt1 expression. mTOR negatively modulates autophagy activation. Dihydromyricetin may increase the phosphorylation of mTOR at Ser2448 and inactivate it in D-gal-induced models, leading to activation of autophagy [45]. In Parkinson’s disease (PD), dihydromyricetin also exhibits neuroprotective activity in behavioral tests through attenuation of MPTP-induced cytotoxicity, ROS generation, and GSK-3β activation dose- and time-dependently [46] (Table 1). L-Dopa has been implicated in PD management. Catechol O-methyltransferase (COMT) may decrease the bioavailability of L-dopa. Dihydromyricetin has been demonstrated to benefit PD management through inhibition of COMT activity dose-dependently [60].

Dihydromyricetin is also the main component of Hovenia, which is traditionally used for treatment of alcohol hangovers. It has been demonstrated that dihydromyricetin may exhibit the protective effects against alcohol intoxication and alcohol tolerance. The molecular mechanism might be associated with competitively binding of dihydromyricetin to BZ sites on GABAARs [61]. Fetal alcohol exposure (FAE) promotes long-lasting alternations in behavior and physiology, which might be related to dysfunction of GABAARs in hippocampi. In rat models, dihydromyricetin effectively prevents FAE disorders through regulation of GABAARs [62]. Dysfunction of GABAARs in neurotransmission also contributes to AD development. In transgenic (TG2576) and Swedish transgenic (TG-SwDI) mice, dihydromyricetin may reduce Aβ peptide production and restore gephyrin levels, GABAergic transmission, and functional synapses, leading to improvement of clinical symptoms [63].

9. Miscellaneous Section

Dihydromyricetin also exhibits anti-bacterial activity against Staphylococcus aureus. The possible mechanism is that dihydromyricetin may disrupt the integrity and the fluidity of membrane. In addition, dihydromyricetin also binds to intracellular DNA through the groove-binding mode in S. aureus [64]. This is inconsistent with reports from Huang et al. (2015) that dihydromyricetin does not significantly inhibit S. aureus PriA, which is an important helicase for DNA replication restart [65]. Dihydropyrimidinase, a key member in the chain of pyrimidine catabolism, plays an important role in metabolism of DNA base in Pseudomonas aeruginosa PAO1. Abrogation of dihydropyrimidinase may lead to inhibition of bacterial growth and promotion of death. Dihydromyricetin substrate-dependently docks into the active site of dihydropyrimidinase and inhibits its activity with IC50 value of 80 μM [66].

Dihydromyricetin decreases the expression of MDA, blood urea nitrogen, and kidney tissue molecule-1 and inhibits cell apoptosis, protecting against kidney injury induced by LPS. [47]. On protection against acute liver injury, dihydromyricetin exhibits anti-inflammatory, antiapoptotic, and proliferation-accelerating activities in carbon tetrachloride- (CCl4-) induced hepatocytes through upregulation of JNK expression [48]. Melanogenesis is positively regulated by MAPK pathway, cAMP/PKA pathway, and PKC pathway through upregulating of CREB/MITF axis. Dihydromyricetin has been demonstrated to attenuate the activities of these three signaling pathways and inhibits the expression of CREB and MITF, leading to blockage of melanogenesis in B16F10 melanoma cells [49] (Table 1). Wnt/β-catenin signaling pathway plays a pivotal role in mediating osteogenic differentiation in bone mesenchymal stem cells (BMSCs). Evidences show that dihydromyricetin decreases the expression of kickkopf-1 and sclerostin and increase β-catenin transcriptional activity, resulting in enhancing osteogenic differentiation in vitro [67].

10. Clinical Prospective

It is well proved that high-fat diet may severely cause hyperlipidemia, hepatic steatosis, and type II diabetes. In high-fat diet rats, dihydromyricetin improves glucose uptake, promotes glucose transporter 1 (GLU1) translocation, and enhances Krebs cycle activity, leading to amelioration of insulin resistance. Specifically, dihydromyricetin reverses the decreased levels of CS, SDHA, and DLST induced by high-fat diet. Similarly, the increased levels of serine, leucine, asparagine, SSA, 5-L-glutamyl-alanine, and L-methylhistidine are also restored by dihydromyricetin. These are associated with downregulation of phosphorylation of IRS-Ser612 and upregulation of Akt and AMPK, resulting in inhibitory phosphorylation of GSK-3β and reduction of G6Pase and PEPCK expression [50] (Table 1). Nonalcoholic fatty liver disease is characterized by accumulation of TG and TC in the cytoplasm of hepatocytes. Dihydromyricetin exhibits inhibitory effects on this accumulation and ROS generation, which are related to regulation of AMPK, AKT, and PPARγ pathways in oleic acid-induced L02 and HepG2 cells [51]. In a double-blind clinical trial, either two dihydromyricetin or two placebo capsules are applied for twice daily and three months. Dihydromyricetin supplementation may significantly ameliorate the serum levels of glucose, LDL-C, GGT, alanine, AST, and Apo B, resulting in dihydromyricetin-enhanced metabolism of glucose and lipid. In addition, dihydromyricetin also downregulates the expression of TNF-α, CK-18 fragment, and FGF21 [52].

Oxidative stress may exaggerate ischemia and reperfusion (I/R) injury, leading to cell apoptosis. In rats in vivo and H9c2 cardiomyocytes in vitro, dihydromyricetin provides effective protection against I/R-induced injury through activation of PI3K/Akt and HIF1α signaling pathways, leading to augment of cellular antioxidant capacity and inhibition of apoptosis. These are characterized by upregulation of antiapoptotic factors Bcl-2 and Bcl-XL and downregulation of proapoptotic factors Bax, Bnip3, cleaved caspase-3/-9, and cytochrome c [53]. Methylglyoxal (MG), an endogenous toxic compound from the glycolytic pathway, may accumulate and impair cognitive dysfunction in metabolic diseases. MG may potentiate oxidative stress and calcium overload, leading to activation of mitochondrial apoptosis in PC12 cells. This might be associated with impairing of BLUT4 translocation and downregulating the expression of glyoxalase 1 and p-AMPKα. Dihydromyricetin exhibits a protective role in treating diabetic encephalopathy through ameliorating MG toxicity [54].

Combined with nedaplatin, dihydromyricetin synergistically induces apoptosis in p53/Bcl-2 signaling-dependent manner in hepatocellular carcinoma (SMMC7721 and QGY7701) cells. In addition, dihydromyricetin selectively protects normal hepatocytes (HL7702) against damage induced by nedaplatin [68]. Similarly, dihydromyricetin has been reported to show no cytotoxicity to normal hepatocytes but significant inhibition of cellular proliferation and activation of apoptosis in a p53-dependent manner in HCC cells [69]. Dihydromyricetin selectively induces tumor cells mitochondrial apoptosis and synergistically potentiates the cytotoxicity of cisplatin in HepG2 and SMMC-7721. This is possibly related to dihydromyricetin-induced enhancement of p53 phosphorylation at Ser15 [70]. Adriamycin causes serious cardiotoxicity, as indicated by increased levels of ALT, LDH, and CKMB in the serum, leading to activation of apoptosis. Dihydromyricetin exhibits the cardioprotective activity that it ameliorates adriamycin-induced cardiotoxicity and synergistically potentiates anticancer activity of adriamycin p53-dependently [71].

https://www.hindawi.com/journals/ecam/2017/1053617/

| Jun 9, 2018
| BioCentury | Product Development

POC for cytokines
Cytokines are emerging as a logical combination partner to boost PD-1 responses
by Emily Cukier, Senior Writer

A body of clinical evidence is emerging that two different approaches to immune-stimulating cytokine therapies could increase efficacy of PD-1 inhibitors in both hot and cold tumors.

Oncologists who spoke to BioCentury said, taken together, data presented for Nektar Therapeutics’ NKTR-214 at the American Society of Clinical Oncology (ASCO) meeting and data published on NantWorks LLC’s N-803 suggest that cytokines that signal through a common heterodimeric receptor can increase responses to PD-1 inhibitors beyond what would be expected from the inhibitors alone.

The doctors cautioned against reading too much into the apparent decline in response rates to NKTR-214 as the trial progresses, and pointed instead to multiple signs in the data that the product is having the biological effect expected of IL-2.

Both candidates signal through the intermediate-affinity IL-2 receptor, which comprises the IL-2 receptor beta chain (CD122; IL2RB) and gamma chain (CD132; IL2RG).

Selective activation of the intermediate-affinity receptor triggers activation and proliferation of CD8+ T cells and NK cells needed to carry out an anticancer response, but spares Treg expansion and toxicities mediated by the high-affinity IL-2 receptor.

NKTR-214 is an IL-2 that contains six conjugated PEG moieties that extend half-life and release over time in a way that biases the molecule to signal through the intermediate-affinity receptor instead of the high-affinity receptor.

N-803 is a mutant version of IL-15 complexed to an Fc fusion protein of IL-15 receptor alpha chain (IL-15RA). IL-15 signals through the intermediate-affinity IL-2 receptor only in the presence of IL-15RA. Fusing IL-15 to IL-15RA keeps the needed receptor close at hand and improves the construct’s stability. NantWorks gained N-803 through last year’s acquisition of Altor Bioscience Corp. for an undisclosed sum.

“All our data suggest they are likely to benefit with deepening responses and increasing responses over time.”

Jonathan Zalevsky, Nektar

The oncologists did say that the bigger opportunity for these candidates may be in tumor types that have not typically responded well to PD-1 monotherapy. Early data showed the cytokines can flip tumors from PD-L1-negative to -positive, leading to responses comparable to those in tumors that were PD-L1-positive at baseline.

But Nektar and partner Bristol-Myers Squibb Co. will move into Phase III first in melanoma with NKTR-214 plus Opdivo nivolumab, followed by first-line renal cell carcinoma (RCC) and cisplatin-ineligible urothelial carcinoma. These are indications where checkpoint inhibitors are approved and produce substantial responses, which may make demonstrating an additive effect for the cytokine a high hurdle to clear.

N-803 is in Phase II development for non-small cell lung cancer (NSCLC), including a Phase II study in NSCLC that has progressed after responding to a PD-1 inhibitor. It also is in testing in combination with other immunotherapies in bladder, pancreatic, head and neck, breast, colorectal, liver, chordoma and hematologic cancer indications.

Posters with early data for Armo Biosciences Inc.’s pegilodecakin (AM0010) showed an alternative cytokine approach could also be effective in augmenting the efficacy of PD-1 inhibitors.

Pegilodecakin is a long-acting, pegylated form of recombinant IL-10 that stimulates a different population of cancer-fighting immune cells than are stimulated by cytokines that signal through the IL-2 intermediate-affinity receptor.

Armo is being acquired by Eli Lilly and Co. in a $1.6 billion deal expected to close this quarter.

While Armo’s data for pegilodecakin plus PD-1 inhibitors also showed better response rates than would be expected for PD-1 inhibitor monotherapy, the oncologists who spoke with BioCentury wanted to see more data on how the molecule achieves its effects.

Because endogenous IL-10 has an immunosuppressive profile, they were unsure how to interpret the clinical results in cancer. In the absence of a full biological explanation for how AM0010 fights tumors, they had less confidence in its ability to potentiate checkpoint inhibitors without confirmation in larger studies.

Data for two Phase II studies of pegilodecakin in combination with anti-PD-1 mAbs are expected late this year.

Merck KGaA presented yet another alternative approach at ASCO that involved blocking rather than stimulating cytokine signaling (see “Two in One”).

Sidebar: Two in one

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https://www.biocentury.com/biocentury/product-development/2018-06-08/cytokines-are-emerging-logical-combination-partner-boost-

Some more details on UCP2 mentioned in earlier posts (Warburg Effect)
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4905249/

Mol Cell Oncol. 2015 Jan-Mar; 2(1): e975024.
Published online 2014 Dec 1. doi:  [10.4161/23723556.2014.975024]
PMCID: PMC4905249
PMID: 27308391

UCP2 induces metabolic reprogramming to inhibit proliferation of cancer cells

Pauline Esteves,1,2,3,† Claire Pecqueur,4,5,† and Marie-Clotilde Alves-Guerra1,2,3,*
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Abstract

Invalidation of uncoupling protein 2 (Ucp2) increases glucose utilization and proliferation in normal cells. We recently reported that cancer cells that overexpress UCP2 become less tumorigenic while switching their metabolism from glycolysis to oxidative phosphorylation. UCP2 appears to be a key regulator of cellular metabolism with a relevant function against tumorigenesis.
Keywords: uncoupling protein 2, mitochondria, cancer, proliferation, metabolism reprogramming

Metabolic remodeling associated with cancer is the subject of renewed research interest that integrates multiple aspects of bioenergetic adaptation. The maintenance of mitochondrial function during cell growth and development is tightly associated with mitochondria–nuclear crosstalk. Because of the quantitatively predominant role of the nuclear genome in mitochondria biogenesis, much attention over the past several decades has been directed to the analysis of anterograde regulation. However, recent studies have revealed that mitochondria are also engaged in retrograde regulation, which can be defined as cellular responses, mostly changes in nuclear gene expression, to changes in the functional state of mitochondria. This retrograde signaling is for the most part an adaptive response and its outcome is usually a recasting of metabolic, regulatory, or stress-related pathways.

Uncoupling protein 2 (UCP2) is a mitochondrial carrier whose protein expression is tightly related to changes in cell proliferation, and as such is a crucial player in the cascade of mitochondrial molecular events associated with carcinogenesis. Indeed, Ucp2 invalidation is associated with increased cell proliferation both in primary embryonic fibroblasts (MEF) and in activated T cells isolated from Ucp2−/− mice.1 In our recent report in Cancer Research2 we showed that direct manipulation of mitochondrial activity through expression of this inner membrane carrier induces a feed-forward loop from mitochondria to the adenosine monophosphate-activated protein kinase (AMPK)/hypoxia inducible factor (HIF) axis that modifies cancer cell proliferation (Fig. 1). Using different cancer cell lines that overexpress UCP2, we showed that UCP2 protein expression level correlates closely and negatively with tumor proliferation in vitro and in vivo. This decrease in proliferation is associated with metabolic remodeling, i.e., decreased glycolysis and increased oxidative phosphorylation. We showed that the antitumor effect of UCP2 is associated with an increase in AMPK signaling and a decrease in HIF. Our study indicated that a reduced fumarate level driven by UCP2 could be the link between AMPK activation and the significant decrease in HIF2-α expression. Indeed, cancers carrying mutations in enzymes involved in the tricarboxylic acid cycle (TCA), specifically succinate dehydrogenase (SDH) and fumarate hydratase (FH), show intracytoplasmic accumulation of fumarate and succinate that inhibits the prolyl hydroxylase domain proteins (PHD), thus allowing stabilization of HIF.3 Furthermore, other studies have shown that AMPK activity is decreased in renal cancer cells deficient in FH enzyme, which also accumulate fumarate.4

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4905249/figure/f0001/

UCP2-induced metabolic reprogramming involves the HIF/AMPK axis to inhibit proliferation of cancer cells. Tumor cells with low protein levels of endogenous uncoupling protein 2 (UCP2) proliferate rapidly and express high levels of hexokinase 2 (HK2) and pyruvate kinase isoform 2 (PKM2) enzymes. In these cells, UCP2 overexpression triggers a metabolic reprogramming favoring oxidative metabolism with increased expression of pyruvate dehydrogenase (PDH) and oxidative phosphorylation (OXPHOS), and conversely decreased expression of HK2 and PKM2. This reprogramming is associated with decreased hypoxia inducible factor (HIF) signaling and increased adenosine monophosphate-activated protein kinase (AMPK) activity. This feed-forward loop from mitochondria to AMPK/HIF axis driven by UCP2 decreases the tumorigenic properties of tumor cells.
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Tuesday, 4 March 2014
The role of UCP2 & UCP4 in stem cells

An embryonic stem cell differentiating into a neuronal cell under the microscope.

http://www.stemcellsfreak.com/2014/03/UCP2-UPC4-embryonic-stem-cells.html

Credit: Anne Rupprecht/Vetmeduni Vienna

Cells have a metabolism that can be altered according to its function and requirements. If cellular metabolism is disturbed, it can lead to disease of the entire organism. Now, researchers at the University of Veterinary Medicine in Vienna say that they have discovered that the uncoupling proteins UCP2 and UPC4 are involved in different types of cellular metabolism.

The proteins provide information about the condition of cells. As a result, cell alterations can now be detected much earlier than it was previously possible.

UCPs or uncoupling proteins are present in mitochondria, the powerhouses of each cell in our body. The functions of most of the five known UCPs remain mysterious (UCP2-UCP5), whereby only the distinct function for UCP1 has thus far been discovered. UCP1 is responsible for heat production when muscle activity is deficient such as is the case with babies and animals in hibernation.

The researchers at the Department of Physiology and Biophysics at the University of Veterinary Medicine in Vienna were able to provide a fundamental explanatory concept for the function of UCP2 and UPC4 for the first time. Each of these proteins are involved in different types of cell metabolism.

UCP2 in Stem Cells and Cancer Cells
In earlier studies of immune cells, lead author, Anne Rupprecht, had already shown that UCP2 could be involved in increased metabolism. Embryonic stem cells (ESCs), precisely exhibit such an increased metabolism, as they rapidly and continually divide, just like cancer cells. Rupprecht searched for various UCPs in ESCs of mice and in effect found UCP2. "Very high amounts of UCP2 even indicated an especially strong increase in metabolism. In other studies UCP2 had also already been detected in cancer cells," according to Rupprecht.

UCP4 in Nerve Cells
In contrast to UCP2, UCP4 is only found in nerve cells. Nerve cells have a completely different metabolism. They seldom divide, unlike stem cells and cancer cells. The research team of Prof. Elena Pohl therefore examined ESCs that differentiated to nerve cells in culture. On the basis of this model system, the researchers could show that UCP2 is still existent in the quickly reproducing stem cells, yet at the moment of differentiation are replaced by UPC4.