Oasis of Hope Hospital

Tijuana, Mexico

Oasis of Hope Hospital

Tijuana, Mexico
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McCarty M.F.,Oasis of Hope Hospital | Barroso-Aranda J.,Oasis of Hope Hospital | Contreras F.,Oasis of Hope Hospital
Medical Hypotheses | Year: 2010

There is considerable evidence that activated microglia play a central role in the pathogenesis of many prominent neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. The elevated NADPH oxidase activity of these microglia contributes importantly to their pathogenic impact, collaborating with increased iNOS activity to generate the cytotoxic oxidant peroxynitrite. Phycocyanobilin (PCB), a chromophore derived from biliverdin that constitutes up to 1% of the dry weight of spirulina, has recently been shown to be a potent inhibitor of NADPH oxidase. The possibility that orally administered PCB could reach the brain parenchyma in sufficient concentrations to influence microglial function is consistent with the findings of two rodent studies: orally administered C-phycocyanin (the spirulina holoprotein that includes PCB) suppresses the neurotoxic impact of the excitotoxin kainite in rats, and a diet high in spirulina ameliorates the loss of dopaminergic neurons in the MPTP-induced Parkinsonian syndrome in mice. Hence, supplemental PCB may have considerable potential for preventing or slowing the progression of a range of neurodegenerative disorders. Some of the central physiological effects of PCB may also reflect inhibition of neuronal NADPH oxidase, which is now known to have a modulatory impact on neuron function, and can mediate neurotoxicity in certain circumstances. Neuronal NADPH oxidase activation is an obligate mediator of the central pressor effect of angiotensin II, and there is suggestive evidence that it may also play a role in inflammatory hyperalgesia; these findings point to possible antihypertensive and analgesic applications for PCB. The likely favorable effects of PCB on vascular health may also protect the brain by decreasing stroke risk, and inhibition of NADPH oxidase in rodents has been shown to lessen the neurotoxic impact of temporary cerebral ischemia. PCB may thus have versatile potential for preserving the healthful function of the central nervous system into advanced old age - albeit optimal neuroprotection may require more complex regimens that incorporate PCB along with other well tolerated nutraceuticals and drugs, in conjunction with prudent lifestyle modifications. © 2009 Elsevier Ltd.


McCarty M.F.,Oasis of Hope Hospital | Barroso-Aranda J.,Oasis of Hope Hospital | Contreras F.,Oasis of Hope Hospital
Medical Hypotheses | Year: 2010

Many cancers are deficient in catalase activity, and maintain a moderate level of oxidative stress to aid their proliferation and survival. It may prove feasible to achieve substantial selective tumor kill with a three-pronged strategy for acutely exacerbating oxidative stress in cancer cells: inducing increased production of oxidants in tumors with sustained high-dose infusions of sodium ascorbate and menadione, while concurrently undercutting the antioxidant defenses of cancer cells by imposing glucose deprivation - as with 2-deoxyglucose administration or a hypoglycemic insulin clamp - and by suppressing hypoxia-inducible factor-1 activity with available agents such as salicylate, rapamycin, and irinotecan. Inhibition of pyruvate dehydrogenase-1 with dichloroacetate may also promote oxidative stress in hypoxic cancer cells. Cell culture studies could be employed to devise effective protocols that could be tested in xenografted rodents and, ultimately, in exploratory clinical trials. © 2010 Elsevier Ltd.


McCarty M.F.,Oasis of Hope Hospital | Barroso-Aranda J.,Oasis of Hope Hospital | Contreras F.,Oasis of Hope Hospital
Medical Hypotheses | Year: 2010

The utility of anti-angiogenic strategies for cancer control is strongly compromised by hypoxia-driven phenotypic changes in cancer cells, which make cancer cells more invasive and more prone to give rise to metastases. A key mediator of this phenotypic shift is the transcription factor hypoxia-inducible factor-1 (HIF-1), which acts directly and indirectly to promote the epidermal-mesenchymal transition, boost cancer invasiveness, increase production of angiogenic factors, and induce chemoresistance. In some cancers, HIF-1 activity is constitutively elevated even in aerobic environments, making the cancer harder to treat and control. Practical strategies for suppressing HIF-1 activation may include the following: inhibiting NF-kappaB activation with salicylic acid and/or silibinin, which should decrease transcription of the HIF-1alpha gene; suppressing translation of HIF-1alpha mRNA with drugs that inhibit mTOR or topoisomerase I; supporting the effective activity of prolyl hydroxylases - which promote proteasomal degradation of HIF-1alpha under aerobic conditions - with antioxidant measures, alpha-ketoglutarate, and possibly dichloroacetate; promoting the O2-independent proteasomal degradation of HIF-1alpha with agents that inhibit the chaperone protein Hsp90; and blocking HIF-1 binding to its DNA response elements with anthracyclines. The utility of various combinations of these strategies should be tested in cancer cell cultures and rodent xenograft models; initial efforts in this regard have yielded encouraging results. Comprehensive strategies for suppressing HIF-1 activity can be expected to complement the efficacy of cancer chemotherapy and of effective anti-angiogenic regimens. © 2010 Elsevier Ltd.


McCarty M.F.,Oasis of Hope Hospital | Barroso-Aranda J.,Oasis of Hope Hospital | Contreras F.,Oasis of Hope Hospital
Medical Hypotheses | Year: 2010

Recent studies show that ingestion of flavanol-rich cocoa powder provokes increased endothelial production of nitric oxide - an effect likely mediated by epicatchin - and thus may have considerable potential for promoting vascular health. The Kuna Indians of Panama, who regularly consume large amounts of flavanol-rich cocoa, are virtually free of hypertension and stroke, even though they salt their food. Of potentially complementary merit is the cyanobacterium spirulina, which has been used as a food in certain cultures. Spirulina is exceptionally rich in phycocyanobilin (PCB), which recently has been shown to act as a potent inhibitor of NADPH oxidase; this effect likely rationalizes the broad range of anti-inflammatory, cytoprotective, and anti-atherosclerotic effects which orally administered spirulina has achieved in rodent studies. In light of the central pathogenic role which NADPH oxidase-derived oxidant stress plays in a vast range of disorders, spirulina or PCB-enriched spirulina extracts may have remarkable potential for preserving and restoring health. Joint administration of flavanol-rich cocoa powder and spirulina may have particular merit, inasmuch as cocoa can mask the somewhat disagreeable flavor and odor of spirulina, whereas the antioxidant impact of spirulina could be expected to amplify the bioactivity of the nitric oxide evoked by cocoa flavanols in inflamed endothelium. Moreover, there is reason to suspect that, by optimizing cerebrovascular perfusion while quelling cerebral oxidant stress, cocoa powder and spirulina could collaborate in prevention of senile dementia. Thus, food products featuring ample amounts of both high-flavanol cocoa powder and spirulina may have considerable potential for health promotion, and merit evaluation in rodent studies and clinical trials. © 2009 Elsevier Ltd. All rights reserved.


McCarty M.F.,Oasis of Hope Hospital | Barroso-Aranda J.,Oasis of Hope Hospital | Contreras F.,Oasis of Hope Hospital
Medical Hypotheses | Year: 2010

An impairment of glucose-stimulated insulin secretion - reflecting decreased glucokinase expression - and a moderate decrease in beta cell mass attributable to increased apoptosis, constitute the key features of beta cell failure in type 2 diabetes. Oxidative stress, provoked by prolonged exposure to excessive levels of glucose and/or fatty acids (glucolipotoxicity), appears to be a key mediator of these defects. Oxidant-provoked JNK activation induces nuclear export of the PDX-1 transcription factor, required for expression of glucokinase and other beta cell proteins. Conversely, increases in cAMP induced by incretin hormones promote the nuclear importation of PDX-1, counteracting the diabetogenic impact of oxidant stress; this may explain the utility of measures that slow dietary carbohydrate absorption for diabetes prevention. The ability of oxidative stress to boost apoptosis in beta cells is poorly understood, but may also entail JNK activation. Recent work establishes a phagocyte-type NADPH oxidase as the chief source of glucotoxicity-mediated oxidative stress in beta cells. Since bilirubin is now known to function physiologically as an inhibitor of NADPH oxidase, and phycocyanobilin (PCB) derived from spirulina likewise can inhibit this enzyme complex, supplemental PCB may have utility in the prevention and control of diabetes, and Gilbert syndrome, associated with chronically elevated free bilirubin, may be associated with decreased diabetes risk. © 2009 Elsevier Ltd.


McCarty M.F.,Oasis of Hope Hospital | Whitaker J.,Dartmouth College
Alternative Medicine Review | Year: 2010

Manipulation of the extracellular and/or intracellular pH of tumors may have considerable potential in cancer therapy. The extracellular space of most tumors is mildly acidic, owing to exuberant production of lactic acid. Aerobic glycolysis - attributable largely to chronic activation of hypoxia-inducible factor-1 (HIF-1) - as well as tumor hypoxia, are chiefly responsible for this phenomenon. Tumor acidity tends to correlate with cancer aggressiveness; in part, this reflects the ability of HIF-1 to promote invasiveness and angiogenesis. But there is growing evidence that extracellular acidity per se boosts the invasiveness and metastatic capacity of cancer cells; moreover, this acidity renders cancer cells relatively resistant to the high proportion of chemotherapeutic drugs that are mildly basic, and may impede immune rejection of tumors. Thus, practical strategies for raising the extracellular pH of tumors may have therapeutic utility. In rodents, oral administration of sodium bicarbonate can raise the extracellular pH of tumors, an effect associated with inhibition of metastasis and improved responsiveness to certain cytotoxic agents; clinical application of this strategy appears feasible. As an alternative approach, drugs that inhibit proton pumps in cancer cells may alleviate extracellular tumor acidity while lowering the intracellular pH of cancer cells; reduction of intracellular pH slows proliferation and promotes apoptosis in various cancer cell lines. Well-tolerated doses of the proton pump inhibitor esomeprazole have markedly impeded tumor growth and prolonged survival in nude mice implanted with a human melanoma. Finally, it may prove feasible to exploit the aerobic glycolysis of cancers in hyperacidification therapies; intense intracellular acidification of cancer cells achieved by induced hyperglycemia, concurrent administration of proton pump inhibitor drugs, and possibly dinitrophenol, may have the potential to kill cancer cells directly, or to potentiate their responsiveness to adjunctive measures. A similar strategy, but without proton pump inhibition, could be employed to maximize extracellular tumor acidity, enabling tumor-selective release of cytotoxic drugs encased in pH-sensitive nanoparticles.


McCarty M.F.,Oasis of Hope Hospital | Contreras F.,Oasis of Hope Hospital
Frontiers in Oncology | Year: 2014

Low millimolar concencentrations of ascorbate are capable of inflicting lethal damage on a high proportion of cancer cells lines, yet leave non-transformed cell lines unscathed. Extracellular generation of hydrogen peroxide, reflecting reduction of molecular oxygen by ascorbate, has been shown to mediate this effect. Although some cancer cell lines express low catalase activity, this cannot fully explain the selective sensitivity of cancer cells to hydrogen peroxide. Ranzato and colleagues have presented evidence for a plausible new explanation of this sensitivity - a high proportion of cancers, via NADPH oxidase complexes or dysfunctional mitochondria, produce elevated amounts of superoxide. This superoxide, via a transition metal-catalyzed transfer of an electron to the hydrogen peroxide produced by ascorbate, can generate deadly hydroxyl radical (Haber-Weiss reaction). It thus can be predicted that concurrent measures which somewhat selectively boost superoxide production in cancers will enhance their sensitivity to i.v. ascorbate therapy. One way to achieve this is to increase the provision of substrate to cancer mitochondria. Measures which inhibit the constitutive hypoxia-inducible factor-1 (HIF-1) activity in cancers (such as salsalate and mTORC1 inhibitors, or an improvement of tumor oxygenation), or that inhibit the HIF-1-inducible pyruvate dehydrogenase kinase (such as dichloroacetate), can be expected to increase pyruvate oxidation. A ketogenic diet should provide more lipid substrate for tumor mitochondria. The cancer-killing activity of 42°C hyperthermia is to some degree contingent on an increase in oxidative stress, likely of mitochondrial origin; reports that hydrogen peroxide synergizes with hyperthermia in killing cancer cells suggest that hyperthermia and i.v. ascorbate could potentiate each other's efficacy. A concurrent enhancement of tumor oxygenation might improve results by decreasing HIF-1 activity while increasing the interaction of ascorbic acid with oxygen. An increased pool of labile iron in cancer cells may contribute to the selective susceptibility of many cancers to i.v. ascorbate; antagonism of NF-kappaB activity with salicylate, and intravenous iron administration, could be employed to further elevate free iron in cancers. © 2014.


McCarty M.F.,Oasis of Hope Hospital | Barroso-Aranda J.,Oasis of Hope Hospital | Contreras F.,Oasis of Hope Hospital
Medical Hypotheses | Year: 2010

The most foolproof way to promote survival in epidemics of potentially lethal influenza is to target, not highly mutable viral proteins, but rather intracellular signaling pathways which promote viral propagation or lung inflammation. NF-kappaB, activated in influenza-infected lung epithelial cells and macrophages, is one likely target in this regard, as it plays a role both in viral replication and in the excessive lung inflammation often evoked by influenza infection. Indeed, salicylates, which suppress NF-kappaB activation, have been shown to reduce the lethality of H5N1 avian-type influenza in mice. Another potential target is NADPH oxidase, as this may be a major source of influenza-evoked oxidant stress in lung epithelial cells as well as in phagocytes attracted to lung parenchyma. A number of studies demonstrate that oxidant stress contributes to overexuberant lung inflammation and lethality in influenza-infected mice. The documented utility of N-acetylcysteine, a glutathione precursor, for promoting survival in influenza-infected mice, and diminishing the severity of influenza-like infections in elderly humans, presumably reflects a key role for oxidative stress in influenza. The lethality of influenza is also reduced in mice pretreated with adenovirus carrying the gene for heme oxygenase-1; this benefit may be mediated, at least in part, by the ability of bilirubin to inhibit NADPH oxidase. It may be feasible to replicate this benefit clinically by administering biliverdin or its homolog phycocyanobilin, richly supplied by spirulina. If this latter speculation can be confirmed in rodent studies, a practical and inexpensive regimen consisting of high-dose salicylates, spirulina, and N-acetylcysteine, initiated at the earliest feasible time, may prove to have life-saving efficacy when the next killer influenza pandemic strikes. © 2009 Elsevier Ltd. All rights reserved.


PubMed | Oasis of Hope Hospital
Type: Journal Article | Journal: Medical hypotheses | Year: 2010

Many cancers are deficient in catalase activity, and maintain a moderate level of oxidative stress to aid their proliferation and survival. It may prove feasible to achieve substantial selective tumor kill with a three-pronged strategy for acutely exacerbating oxidative stress in cancer cells: inducing increased production of oxidants in tumors with sustained high-dose infusions of sodium ascorbate and menadione, while concurrently undercutting the antioxidant defenses of cancer cells by imposing glucose deprivation - as with 2-deoxyglucose administration or a hypoglycemic insulin clamp - and by suppressing hypoxia-inducible factor-1 activity with available agents such as salicylate, rapamycin, and irinotecan. Inhibition of pyruvate dehydrogenase-1 with dichloroacetate may also promote oxidative stress in hypoxic cancer cells. Cell culture studies could be employed to devise effective protocols that could be tested in xenografted rodents and, ultimately, in exploratory clinical trials.


PubMed | Oasis of Hope Hospital
Type: | Journal: Frontiers in oncology | Year: 2014

Low millimolar concentrations of ascorbate are capable of inflicting lethal damage on a high proportion of cancer cells lines, yet leave non-transformed cell lines unscathed. Extracellular generation of hydrogen peroxide, reflecting reduction of molecular oxygen by ascorbate, has been shown to mediate this effect. Although some cancer cell lines express low catalase activity, this cannot fully explain the selective sensitivity of cancer cells to hydrogen peroxide. Ranzato and colleagues have presented evidence for a plausible new explanation of this sensitivity - a high proportion of cancers, via NADPH oxidase complexes or dysfunctional mitochondria, produce elevated amounts of superoxide. This superoxide, via a transition metal-catalyzed transfer of an electron to the hydrogen peroxide produced by ascorbate, can generate deadly hydroxyl radical (Haber-Weiss reaction). It thus can be predicted that concurrent measures which somewhat selectively boost superoxide production in cancers will enhance their sensitivity to i.v. ascorbate therapy. One way to achieve this is to increase the provision of substrate to cancer mitochondria. Measures which inhibit the constitutive hypoxia-inducible factor-1 (HIF-1) activity in cancers (such as salsalate and mTORC1 inhibitors, or an improvement of tumor oxygenation), or that inhibit the HIF-1-inducible pyruvate dehydrogenase kinase (such as dichloroacetate), can be expected to increase pyruvate oxidation. A ketogenic diet should provide more lipid substrate for tumor mitochondria. The cancer-killing activity of 42C hyperthermia is to some degree contingent on an increase in oxidative stress, likely of mitochondrial origin; reports that hydrogen peroxide synergizes with hyperthermia in killing cancer cells suggest that hyperthermia and i.v. ascorbate could potentiate each others efficacy. A concurrent enhancement of tumor oxygenation might improve results by decreasing HIF-1 activity while increasing the interaction of ascorbic acid with oxygen. An increased pool of labile iron in cancer cells may contribute to the selective susceptibility of many cancers to i.v. ascorbate; antagonism of NF-kappaB activity with salicylate, and intravenous iron administration, could be employed to further elevate free iron in cancers.

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