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Innate glutathione production

Innate glutathione production. Glutathione levels are the highest for about six hours after each meal. Our lowest level of glutathione is in the morning before our first meal.

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Innate glutathione production

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  1. Innate glutathione production • Glutathione levels are the highest for about six hours after each meal. • Our lowest level of glutathione is in the morning before our first meal. • While healthy children and young adults tend to have sufficient glutathione, glutathione production decreases as we age. • Once we reach the age of 45, production declines precipitously. • Add to this, glutathione depleting activities, and our glutathione stores can become seriously depleted

  2. Dietary glutathione

  3. Stress-induced glutathione depletion • Chronic neuroendocrine stress leads to the elevation of cortisol, norepinephrine and epinephrine and increased metabolic rate - which is frequently accompanied by oxidative damage and depleted antioxidants • High levels of stress hormones promote lipid storage as organ fat rather than subcutaneous fatty tissue. • Organ adipocytes secrete proinflammatory cytokines, which increase oxidation, leading to a depletion of antioxidants, especially glutathione, and ultimately to cell injury, organ damage and disease. Djordjevic J, et al. Cell Mol Neurobiol. 2010;30(5):693. Abraham NG, et al. Ann N Y Acad Sci. 2007 Oct;1113:256-75

  4. Cell signaling: Psychological Stress

  5. Stress & Cancer Progression • Clinical and epidemiological studies over the last 30 years have identified psychosocial factors especially stress, chronic depression and feelings of isolation as risk factors for cancer progression. • Chronicity of negative affect, as manifested by depressed mood or hopelessness/pessimism, appears to have stronger relationships with outcomes than do stressful events. • This suggests that sustained activation of negative affective pathways may provide the strongest links to cancer progression. Moreno-Smith M. et al. Future Oncol. 2010 Dec;6(12):1863-81

  6. Stress, Depression and Renal cell carcinoma • 217 participants with newly diagnosed metastatic RCC (MD Anderson Cancer Center) with life expectancy of greater than 4 months, good performance status (<2) and no major concurrent diseases. • Baseline: Depression questionnaires, Salivary cortisol, blood sample for genomic analysis • The following factors were associated with survival time: • CES-D scores • SF-36 PCS scores • cortisol slope • risk category Cohen L. PLoS One. 2012;7(8):e42324.

  7. Stress, Depression and RCC • Gene Ontology analyses identified upregulation of genes involved in inflammation, immune response, and negative regulation of programmed cell death (all p<.0001) and down- regulation of genes involved in cell trafficking, adhesion, oxygen transport, and hemostasis (all p<.05).

  8. Cancer Determinant: Signal transduction, or extrinsic carcinogenesis Upregulated signal transduction results in abnormal rate of gene transcription which will ultimately destabilize chromosomes leading to further methylation changes and malignant transformation. Devita VT, et al. Hellman and Rosenberg’s Cancer: Principles & Practice of Oncology, 9thed, 2011: www.lwwoncology.com

  9. Sensitivity of signal transduction • Cells are exquisitely sensitive to ligands (picomolar to nanomolar range) • Very few receptors are required to transmit a signal • i.e. only 10 receptors on a T-cell need to be stimulated to activate a maximal response • Given the small number of receptors involved in most actions, the signals are amplified intracellularly. • Relatively small changes in the tissue mileau can profoundly affect signal transduction. • Hormones, interleukins and prostaglandins are some of the most influential of these ligands.

  10. Aberrant cell signaling: chronic inflammation Aggarwal BB, et al. BiochemPharmacol. 2006;72(11):1605-21.

  11. Genes, Inflammation and Cancer

  12. NF-kB, IL-6 and breast cancer stem cells • Malignant stem cells are the result of one stable cell type changing into another stable cell type without any modifications to the genetic sequence of the cell – an epigenetic phenomenon. • Inflammatory response activates NF-kB • NF-kB activation decreases mRNA (Let-7 mRNA) thereby releasing repression of IL-6 • IL-6 signaling pathways are induced leading to the intrinsic self-renewal capacity characteristic of breast cancer stem cells Shostak K and Chariot A. . Breast Cancer Research. 2011;13(4):214.

  13. IL-6: Breast Cancer survival IL-6 < 55 pg/mL IL-6 > 55 pg/mL Bachelot T, et al. Br J Cancer. 2003 Jun 2;88(11):1721-6.

  14. CRP: Prostate cancer survival Beer TM, et al. Cancer. 2008 Jun;112(11):2377-83.

  15. Plant food and NF-kB signaling Anand P. et al. Pharmacetuical Research, 2008;25(9):2097.

  16. NFkB inhibition: anthocyanidins • Anthocyanins isolated from bilberries and black currants (Medox) efficiently suppressed LPS-induced activation of NF-kappaB in cultured monocytes. • Parallel-designed, placebo-controlled clinical trial (n = 120 men and women aged 40-74 y) (23) • Intervention consisted of Medox, 300 mg/d for 3 wk • Decreases in the NF-kappaB-controlled pro-inflammatory chemokines and IFNalpha (an inducer of NF-kappaB activation) in the Medox group • 45% and 40% respective decreases from baseline vs. placebo group with 20% and 15% decreases from baseline) (P < 0.050) Karlsen A et al. J Nutr. 2007 Aug;137(8):1951-4

  17. Walnuts and VEGF • The aim of the present study was to examine the effect of dietary walnuts on colorectal cancer in vivo and to comparatively evaluate their efficacy in relation to flaxseed oil. • METHODS: HT-29 human colon cancer cells were injected in 6-wk-old female nude mice. After a 1-wk acclimation period, mice (n = 48) were randomized to diets containing ~ 19% of total energy from walnuts, flaxseed oil, or corn oil (control) and were subsequently studied for 25 d. • RESULTS: Tumor growth rate was significantly slower in walnut-fed and flaxseed-fed mice compared with corn oil-fed animals (P < 0.05) by 27% and 43%, respectively. • Accordingly, final tumor weight was reduced by 33% and 44%, respectively (P < 0.05 versus control); the differences between walnut and flaxseed diets did not reach significance. • Dietary walnuts significantly decreased angiogenesis (CD34 staining; P = 0.017 versus control), whereas this effect did not reach significance in the flaxseed oil group (P = 0.454 versus control). Nagel JM, et al. Nutrition. 2012. 28(l):67-75.

  18. IL-6: Immune shift • IL-6, also known as B cell stimulatory factor-2 (BSF-2), is a terminal differentiation factor for B cells that is produced by monocytes and lymphocytes as part of Th2 immune activation. • Shifting immune activity away from Th2 and towards Th1 will decrease PBMC production of IL-6. • Increase Th1 with (examples): • PSK from Coriolus (Trametes) versicolor • Melatonin • Probiotics • Lower Th2 by eliminating dietary allergens Giannoulia-Karantana A, et al. Neuroimmunomodulation. 2006;13(3):133-44. Carrillo-Vico A, et al. FASEB J. 2004 Mar;18(3):537-9.

  19. Plant flavonoids and anti-inflammatory Nrf-2 • The transcription factor Nrf2 is kept sequestered in cytoplasm as an inactive complex with its cytosolic repressor Keap-1. • Chemopreventivephytochemicals activate diverse upstream kinases, which in turn stimulate dissociation of Nrf2 from Keap-1. • Once released from Keap-1 repression, Nrf2 translocates to nucleus, forms heterodimer with small Maf protein, and binds to ARE/EpRE sequences located in the promoter region of genes encoding antioxidant and detoxifying enzymes. Surh Y-J. Journal Nutr. 2005;135: 2993S–3001S.

  20. Flavonoids and colon cancer • Controlled trial of 87 patients • 36 patients with resected colon cancer • 51 patients after polypectomy • Entire group was divided into 2 groups: one group was treated with a flavonoid mixture (daily standard dose 20 mg apigenin and 20 mg epigallocathechin-gallate, n = 31) and compared with a matched control group (n = 56). • Both groups were observed for 3-4 years by surveillance colonoscopy and by questionnaire. • Among the flavonoid-treated patients with resected colon cancer (n = 14), there was no cancer recurrence and one adenoma developed. • The cancer recurrence rate of the 15 matched untreated controls was 20% (3 of 15) and adenomas evolved in 4 of those patients (27%). • The combined recurrence rate for neoplasia was 7% (1 of 14) in the treated patients and 47% (7 of 15) in the controls (P = 0.027). H. Hoensch, et al. World J Gastroenterol. 2008 Apr 14;14(14):2187-93.

  21. Green tea • Male patients who consumed over 10 cups of green tea daily died 3.6 years later than did their male counterparts who drank less than 3 cups daily. • Female patients who consumed over 10 cups of green tea daily died 7.8 years later than did their female counterparts who drank less than 3 cups daily. • In addition, the age at onset of cancer was 3.0 years later in men and 8.7 years later among women who drank over 10 cups of green tea daily than those drinking less than 3 cups of green tea daily. • The difference between male and females was explained by the higher tobacco use by men. • Finally, in an extension of this same study, the researchers determined that women who drank over 10 cups of green tea daily showed a lower relative risk of cancers of the lung, colon, and liver. Imai K, et al. Prev Med,1997 Nov-Dec;26(6):769-75

  22. Green tea and Breast cancer Histologically confirmed invasive breast carcinoma n = 472 Japanese premenopausal women Stages I – III Followed for 7 years post surgery Ave. = 2 cups/d P < 0.05 Ave. = 8 cups/d Nakachiet al, Jpn J Cancer Res, 1998 Mar;89(3):254-61.

  23. Green tea and breast cancer • A prospective cohort study conducted over a 9-year period from 1990 to 1999. • In 1990, 1160 new surgical cases of invasive breast cancer in female patients at a Japanese cancer center were enrolled in the study. • During 5264 person-years of follow-up (average 4.5 years per subject), 133 subjects (12%) experienced recurrence. Average consumption = 5 cups/d Inoue, et al, Cancer Lett, 2001 Jun 26;167(2):175-82.

  24. Lycopene and Prostate cancer • Demonstrated effectiveness in pre-clinical studies • The prostate gland concentrates lycopene • Highest serum levels of lycopene compared to the lowest is associated with an 83% reduction in PCa. • Majority of clinical studies in men with PCa show improvements in PSA kinetics and disease stabilization. Trottier G. et al. Nat Rev Urol. 2010 Jan; 7(1);21-30 Lu QY, et al. Cancer Epidemiol Biomarkers Prev. 2001 Jul; 10(7):749-56.

  25. Lycopene • 26 men with newly diagnosed localized PCa. • Randomized to 30mg lycopene or no supplement prior to radical prostatectomy. • Lycopene group: • Smaller tumors: 84% vs. 45% with tumors <4mL • Clean margins: 73% vs. 18% • PIN: 67% vs. 100% • PSA: -18% vs. +14% • 41 men with Gleason score 6 and rising PSA • Treated with 5mg lycopene BID x 1y • PSA velocity decreased in 71% • PSA slope was negative in 21% Kucuk O. et al. Exp. Biol. Med (Maywood). 2002 Nov;227(10):881-5. Zhang X. et al. Chin Med J (Engl). 2010 Aug;123(16):2231-6.

  26. Flaxseed • 25 men with PCa treated with low fat diet + 30g flaxseeds for an average of 34d prior to prostatectomy. • Matched to historic controls • In men with Gleason < 6, PSA reduced (7.1 vs. 6.4 ng/mL) • Prostate cancer cells had significantly decreased proliferation and increased apoptosis compared to controls. • Follow-up study with 161 men • Randomized to Flaxseed, Flaxseed+low fat diet or usual diet • Cancer cell proliferation significantly lower for flaxseed (51%) and flaxseed + low fat diet (54%) compared to controls. Demark-Wahnefried W. et al. Urology. 2001 Jul;58(1):47-52 Denmark-Wahnefried W. et al. Cancer Epid. Biomarkers Prev. 2008 Dec;17(12):3577-87.

  27. Deadly Signaling Trio: Obesity, Insulin Resistance and Inflammation • IR arises from either increased dietary glucose and/or defects in the insulin signaling pathway • Cancer cells are saturated with insulin receptors • Insulin is a direct growth factor in cancer cells. • When insulin is elevated, so is IGF-1, another tumorigenic growth factor. Van Kruijsdijk RC, et al. Cancer Epidemiol Biomarkers Prev. 2009;18:2569-78 27

  28. Obesity is a carcinogenic state Van Kruijsdijk RC, et al. Cancer Epidemiol Biomarkers Prev. 2009;18:2569-78

  29. Weight • Being overweight or obese is responsible for one in six cancer deaths in the United States • Weight, weight gain, and obesity account for approximately 20% of all cancer cases. • Excess weight increases the chance of dying of prostate cancer by 34% • Being overweight more than doubles the risk of dying of breast cancer • According to the WCRF, the strongest evidence exists for an association of obesity with the following cancer types: • endometrial, esophageal adenocarcinoma, colorectal, postmenopausal breast, prostate, renal, leukemia, non-Hodgkin’s lymphoma, multiple myeloma, malignant melanoma, and thyroid tumors Wolin et al. The Oncologist. 2010;15:556–565 Magheli et al. Urology. 2008;72(6):1246-51. WCRF, Food NutrPhysActivPrev Cancer, 2007. AICR, 2nd ed. 2007

  30. Adult Energy Imbalance Excess Caloric Intake Inactivity Stress Visceral Obesity Insulin Resistance Increased IGF-1/ Insulin Signaling (IGF-1, IR-IGF-1R Hybrid R) Tumor Cell Proliferation Tumor Growth Tumor Sensitivity to Treatment Cancer Recurrence Cancer Survival

  31. Cell signaling: Insulin Resistance Ulanet DB et al. ProcNatlAcadSci U S A. 2010 Jun 15;107(24):10791-8.

  32. IR and Cancer risk Increased Cancer Mortality FBS >100 mg/dl NEJM. 2011;364:829-41 Esposito K, et al. Dia Care. 2012;35:2402-2411 32

  33. Diabetes and cancer cell mebolism

  34. Lowering Insulin and IGF-1 • IGF-1 lowering interventions: • Low glycemic load diet • Blood sugar balancing nutrients and herbs • Exercise • Weight loss • PPAR agonists: Metformin, Berberine • IGF-1 trivia: Prunes increase IGF-1 levels

  35. Glycemic Load and Colon cancer • Prospective, observational study of 1011 stage III colon cancer patients reporting dietary intake during and 6 months after participation matched to 253 controls in an adjuvant chemotherapy trial. • The median follow-up from the time of completion of Q1 was 7.3 years. • Higher dietary glycemic load was associated with statistically significant worse disease-free, recurrence-free, and overall survival. • Stage III colon cancer patients in the highest quintile of dietary glycemic load experienced an adjusted hazard ratio (HR) for disease recurrence of 1.79 (95% confidence interval [CI] = 1.29 to 2.48), compared with those in the lowest quintile (HR = 1) (Ptrend across quintiles <.001). • Increased glycemic load was associated with decreased overall survival (Ptrend across quintiles <.001). • These associations were strongest for overweight patients (BMI > 25; HR 2.26) Meyerhardt J, et al. J NatlCancerInst. 2012 Nov 21;104(22):1702-11

  36. Nutritional influences on IGF-1: Walnuts • An elevated fat (20% of energy as fat) diet containing 155 g of whole walnuts were compared to those of an elevated fat (20% of energy as soy bean oil) diet with matched macronutrients, tocopherols as well as a low-fat (8 % of energy as soy bean oil) dietin the transgenic adenocarcinoma of the mouse prostate (TRAMP) cancer model. • No differences were observed in whole animal growth rates in either high-fat (HF) diet group, but prostate tumor weight and growth rate were reduced in the walnut diet group. • Walnut diet group prostate weight, plasma insulin-like growth factor 1, resistin and LDL were lower at 18 weeks. • The walnut diet's beneficial effects probably represent the effects of whole walnuts’ multiple constituents and not via a specific fatty acid or tocopherols. Davis PA, et al. Br J Nutr. 2012 Nov 28;108(10):1764-72.

  37. Cinnamon and IR • Cinnamon promotes insulin signaling via selective phosphorylation of the IR, thereby reinstating insulin sensitivity • This causes increased cellular uptake of glucose • Activates peroxisome proliferator-activated receptors (PPARs). • PPARs regulate insulin resistance and PPAR agonists are used in the treatment of DB2 and IR. • Cinnamon reduces inflammation by decreasing IL-1B, IL-6, and TNFa mRNA. 37 Huang B. et al. J Agric Food Chem. 2011 Apr 27;59(8):3666-73.

  38. Clinical studies with cinnamon Rafehi H. et al. Diab Obesity Metab. 2012;14:493-99

  39. Blueberries and IR • Six week DBRCT of 32 obese, nondiabetic, insulin-resistant subjects. • Randomized to consume a smoothie with 22.5g blueberry bioactives from freeze dried whole blueberry powder or equivalent smoothie without the blueberry twice daily • Provided equivalent of 2 cups fresh whole blueberries • Insulin sensitivity improved more in blueberry group than in placebo group (p=0.04) 39 Stull A. et al. J Nutr. 2010;140(10):1764-8

  40. Berberine • Berberine restores insulin sensitivity via: • Activation of AMPk • Reduction of hepatic gluconeogenesis (epigenetic effect) • Inhibition of fatty acid synthesis in liver (and decrease of fatty liver) • RCT of 36 adults with DB2 x 3mo • Randomized to 500mg Berberine TID or 500mg Metformin TID • There were equivalent blood glucose lowering effects (P<0.01) • Continued use of Berberine resulted in improvement of HOMA-IR reduced by 44.7% (P<0.001), lowered FBG, HgA1c, LDL-C. Xia X. et al. Plos One. 2011;6(2):e16556 Yin J. et al. Metabolism. 2008;57:712-17

  41. Tocotrienols • Tocotrienols, vitamin E isomers, with increased flexibility and smaller (less methylated) heads, allowing for increased antioxidant and anti-inflammatory activity over tocopherols. • Tocotrienols reduce triglyceride accumulation (thereby reducing increased adiposity) • Tocotrienols improve glucose and insulin tolerance and reduce inflammatory cell infiltration in a rodent model of human metabolic syndrome. • Tocotrienols activate PPAR which increases insulin sensitivity by restoring Akt pathway function. • Tocotrienols also exert direct antiinflammatory effects: • Reduce NFkB, TNFa, COX-2 Wong WY et al. Nutrients. 2012;4(10):1527-41 Fang F et al. MolNutr Res. 2010;54(3):345-52 Yam ML et al. Lipids. 2009;44(9):787-97

  42. Cancer Determinant: Immunity • The body’s first and last line of defense • Cancer, arising from self, is likely to create immune tolerance. • Cancer cells secrete IL-10 which activates T regulatory (suppressor) cells and downregulates dendritic type 1 cells Huang RP, et al. Cancer Res 1995;55(21):5054-62.

  43. A tumor’s immunological fate

  44. Th1: counterweight against tumor-derived immune escape • Stimulation of IL-12 producing DC (APC) with subsequent activation of tumor specific cytotoxic T cells (CD8) is the goal of immunologic tumor destruction.

  45. The pivotal role of the type 1 Dendritic cell • Immuno-suppression associated with cancer leads away from Dendritic cell type 1 towards Dendritic cell type 2 development • This shift promotes regulatory T cell activation and recruitment into tumor sites, suppresses T helper 1 (TH1)-dependent, cytotoxic T lymphocyte responses. Rissoan MC, et al. Science, 1999;283(5405):1183-6. Whiteside TL, Semin Cancer Biol, 2006;16(1):3-15.

  46. Immune-mediated tumor destruction Lysed Tumor cell Ag-presenting Immune cell Ab-dept. Cellular cytotoxcity CD4 helper T-cell NK cell MHC II Activation of CD4 T-cell TH2 cytokines: IL4-6, IL10 Uptake of tumor cell protein fragments TH1 cytokines: IL-2, IFN-γ, TNF-β B cell Mushrooms Melatonin Glutathione Nature NK cell Lysis MHC I Lysed Tumor cell Tumor cell CD8 cytotoxic T-cell

  47. Melatonin • Over 1534 scientific publications on melatonin and cancer • Over 88 human clinical trials on melatonin in cancer • 41 Randomized Clinical Trials • In a meta analysis of 8 RCT’s in solid tumor cancers (n=761), 20mg of melatonin po nightly in conjunction with chemo or radiation. • Melatonin significantly improved the complete and partial remission (16.5% vs. 32.6%; RR = 1.95, 95% CI, 1.49-2.54; P < 0.00001) • Melatonin improved 1-year survival rate over control (52.2% vs. 28.4%; RR = 1.90; 95% CI, 1.28-2.83; P = 0.001) • Melatonin significantly decreased radiochemotherapy-related side effects including: • thrombocytopenia (19.7 vs. 2.2%; RR = 0.13; 95% CI, 0.06-0.28; P < 0.00001) • neurotoxicity (15.2 vs. 2.5%; RR = 0.19; 95% CI, 0.09-0.40; P < 0.0001) • fatigue (49.1 vs. 17.2%; RR = 0.37; 95% CI, 0.28-0.48; P < 0.00001). • Effects were consistent across different types of cancer. No severe adverse events were reported. Wang et al. Cancer ChemotherPharmacol. 2012 May;69(5):1213-20.

  48. Medicinal mushrooms • Systematic review and meta-analysis of 13 trials that met inclusion criteria • Cumulatively, there was 1,284 patients in the PSK/PSP group (49.6%) and 1,303 in comparison groups(50.4%) • Overall survival at 5 years was improved in the PSK/PSP group P<0.00001; RR=1.14 • Over all cancers, there was a 9% absolute reduction in 5-year mortality (one additional patient alive for every 11 pts treated) • Effects were more evident for breast, gastric or colorectal cancer versus esophageal or nasopharyngeal LY Eliza W, et al. Recent Patents Inflamm& Allergy Drug Discovery. 2012;6(1):78-87.

  49. Antioxidant status: Polarizing the immune response • Glutathione (GSH) is the most important intracellular antioxidant. • Depletion of GSH results in lowered Th1 and increased Th2 activity. • Conversely, repletion of GSH increases Th1 and decreases Th2 activity. • Thus, the antioxidant status of the cell influences the Th1 polarization of the immune response. Peterson JD, Herzenberg LA, Vasquez K et al. Proc Nat Acad Sci USA,1998 Murata Y, et al., IntImmunol, 2002.

  50. Forest Bathing

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