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

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

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

Mitochondrial Uncoupling and the Warburg Effect: Molecular Basis for the Reprogramming of Cancer Cell Metabolism
Ismael Samudio, Michael Fiegl and Michael Andreeff
DOI: 10.1158/0008-5472.CAN-08-3722 Published March 2009

Abstract

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

The Warburg Effect and Mitochondrial Uncoupling

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

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

Over the past several decades, it has become increasingly clear that mitochondrial uncoupling occurs under physiologic conditions, such as during cold acclimation in mammals, and is mediated, at least in part, by uncoupling proteins (UCP; ref. 6, 7). UCP1 was the first UCP identified, and was shown to play a role in energy dissipation as heat in mammalian brown fat ( 6). During cold acclimation, UCP1 accumulates in the inner mitochondrial membrane and short circuits ΔΨM (created by the mitochondrial respiratory chain) by sustaining an inducible proton conductance ( 7). Other UCPs have been identified in humans (UCP2-4), although their functions may be unrelated to the maintenance of core body temperature, and instead involved in the reprogramming of metabolic pathways. For instance, recent work shows that UCP2 is necessary for efficient oxidation of glutamine ( 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.

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


Also:

https://themedicalbiochemistrypage.org/glycolysis.php

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

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

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

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


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

Credit: Shutterstock

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

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

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

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

A cancer vaccine?

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

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

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

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?
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QJM. 2010 Nov; 103(11): 831–836.
Published online 2010 Aug 30. doi:  10.1093/qjmed/hcq148
PMCID: PMC2955282
PMID: 20805118

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

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

Abstract


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

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

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

Table 2

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

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

.......

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


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

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

Abstract

Background

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

Results

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

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

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

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


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

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

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

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


Abstract

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

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

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

(more at link...)

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

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UCP2 is highly expressed in pancreatic α-cells and influences secretion and survival

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

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

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

Abstract

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

ATP glucagon islet mitochondria diabetes

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

High plasma levels of glucose inhibit glucagon secretion; however, it is still unclear whether this in vivo response is mediated directly via glucose sensing or indirectly by neuronal modulation and/or paracrine/endocrine effects (5–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...)

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

...

Uncoupling protein-2 controls proliferation by promoting fatty acid oxidation and limiting glycolysis-derived pyruvate utilization

Claire Pecqueur
, Thi Bui
, Chantal Gelly
, Julie Hauchard
, Céline Barbot
, Frederic Bouillaud
, Daniel Ricquier
, Bruno Miroux
, and Craig B. Thompson

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

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

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

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

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

Abstract

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


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

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

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:

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

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

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

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

(related)

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

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

Abstract

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

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


The effect of Oligonol intake on cortisol and related cytokines in healthy young men

Jeong-Beom Lee, Young-Oh Shin,corresponding author Young-Ki Min, and Hun-Mo Yang
Author information ► Article notes ► Copyright and License information ► Disclaimer
This article has been cited by other articles in PMC.
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Abstract

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

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

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

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

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

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

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

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.

Author information
Abstract

BACKGROUND:

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

METHODS:

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

RESULTS:

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

CONCLUSIONS:

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

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

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

Artemisia cure for cancer?

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

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

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

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

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

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

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

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

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

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

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

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

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

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 mitocondria enhancers (NAD+, NMN, Oaxacletate, ATP pills, Oligonol (Korean lychee drink),  etc...)

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

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