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

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Post by Cr6 on Sat Mar 31, 2018 1:29 am

See also:
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


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 ( Cool, 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.

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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.


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Post by Cr6 on Sat Mar 31, 2018 10:34 pm

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 (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.


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Post by Cr6 on Sun Apr 01, 2018 11:39 pm

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.


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
Endothelial cell proliferation and differentiation Promotes angiogenesis


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

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



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.


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.


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Post by Cr6 on Tue Apr 03, 2018 1:53 am

Uncoupling protein-2 modulates the lipid metabolic response
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}

Diabetes 2013 May; 62(5): 1623-1633.


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...)


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;

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)


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–Cool. 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...)


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 2007

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.


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Post by Cr6 on Tue Apr 03, 2018 1:57 am

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


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.


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Post by Cr6 on Sun Apr 15, 2018 4:37 am

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:

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

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.


(related) (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.
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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.


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
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This article has been cited by other articles in PMC.
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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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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].


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Post by Cr6 on Sun Apr 15, 2018 4:57 am

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.

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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.


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.


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.


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.
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.

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.

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.

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

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.


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Post by Cr6 on Sun Apr 15, 2018 5:09 am

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.


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.

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.

Last edited by Cr6 on Mon Aug 20, 2018 1:30 am; edited 5 times in total


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Post by Cr6 on Fri May 04, 2018 12:56 am

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].

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.

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


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.

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


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–Cool. 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.

Second link:


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


The glucokinase (EC 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.


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Post by Cr6 on Wed May 09, 2018 2:42 am

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:
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.

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...


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Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor) - Page 2 Empty BioCancer: R library for DNA influences

Post by Cr6 on Sun May 20, 2018 2:26 am

An interesting R library from BioConductor:

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.


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

bioCancer focuses on Cancer Genomics data visualisation and Genes Classifications.

Circomics: Pull User genetic profiles with existing Cancer studies

Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor) - Page 2 Circomics_demo


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Post by Cr6 on Mon May 21, 2018 1:58 am

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.
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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..... )
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.

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.....


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Post by Cr6 on Fri Jun 15, 2018 1:56 am

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:


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]


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Post by Cr6 on Fri Jun 29, 2018 1:40 am

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.


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
Cited by: 94
W. Becker, Institute of Pharmacology and Toxicology, RWTH Aachen University, Wendlingweg 2, 52074 Aachen, Germany



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.


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Post by Cr6 on Fri Jun 29, 2018 1:43 am

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". ​​


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Post by Cr6 on Wed Jul 11, 2018 12:49 am

Crystal structure reveals how curcumin impairs cancer

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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."


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Post by Cr6 on Mon Aug 20, 2018 1:27 am

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).
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


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–Cool. 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.
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.


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Post by Cr6 on Mon Aug 20, 2018 1:43 am

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.


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Post by Cr6 on Sun Sep 02, 2018 1:03 am

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.

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.



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.

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.

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.


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.

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Post by Cr6 on Sun Sep 02, 2018 1:09 am

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


→ 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.

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Post by Cr6 on Sat Sep 29, 2018 12:07 am

Ancient Chinese medicine for the cancer win (anti-hangover too):

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

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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.

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, Cool. 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.


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Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor) - Page 2 Empty Re: Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor)

Post by Cr6 on Sat Sep 29, 2018 12:10 am

Anti-Inflammatory is this Chinese medicine...taps the human body's use of the Charge Field:
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

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; and Longhuo Wu;

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.


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 (Cool.
Figure 1: The structure of dihydromyricetin (1) and its metabolites (2–Cool.

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].


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Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor) - Page 2 Empty Re: Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor)

Post by Cr6 on Sat Sep 29, 2018 1:11 am

| 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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Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor) - Page 2 Empty Re: Cancer and ATP: The Photon Energy Pathway (DCA as anti-tumor)

Post by Cr6 on Fri Nov 23, 2018 8:09 pm

Some more details on UCP2 mentioned in earlier posts (Warburg Effect)

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,*
Author information Article notes Copyright and License information Disclaimer
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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

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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Post by Cr6 on Fri Nov 23, 2018 8:11 pm

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.


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