Cellular Oxidative Stress & Chronic Inflammation, Part 2

1. Cellular Oxidative Stress &Chronic Inflammation, Part 2 W. Jean Dodds, DVM AHVMA 2016 Columbus, OH

2. Cellular Oxidative Stress & Cell Homeostasis • Cells are in homeostatic equilibrium when in oxidative balance • Occurs when the antioxidants (reducing agents) are balanced with the oxidants (oxidizing agents) • When oxidant levels exceed antioxidants (termed cell redox) , the cell undergoes oxidative stress • Basic mechanism of all sickness and chronic disease (Mandelker, JAHVMA 41: 22-24, Winter, 2016)

3. Cellular Optimal Health • Even with chronic health conditions, cells still have a remarkable ability to repair, regenerate and renew • Creating optimum health at the cellular level involves two key nutritional steps: • feeding a diet rich in functional foods that tells the epigenome to initiate healthy gene expression; and • reducing or removing foods sending harmful messages to the epigenome, and causing unhealthy gene expression • Ideal diet contains Three Keys -- • variety, nutrient-dense, whole foods

4. Nutritional Ecology • Study of animal nutrition based on ecology and evolution • Science that spans many fields including ecology, nutrition, behavior, morphology, physiology, life history, and evolutionary biology • Focuses not specifically on the organism or its environment, but rather on the dynamic interface between organism and environment (Raubenhemer & Simpson Ann Rev Nutr 36:603-626, 2016)

5. Nutritional Geometry • Framework for examining how mixtures of nutrients (and other dietary components) influence biological outcomes such as health and disease • Differs from studying a particular nutrient in isolation • Focus on mixtures allows for modeling how nutrients interact to determine the nutritional properties of foods and how foods in turn combine into meals, diets, anddietary patterns that influence health (Raubenhemer & Simpson Ann Rev Nutr 36:603-626, 2016)

7. Overweight = Increased Health Risk • Cardiorespiratory diseases: airway obstruction in brachycephalic breeds, and laryngeal paralysis • Endocrine disorders: hyperadrenocorticism (Cushing’s disease) and hypothyroidism • Functional alterations, like decreased respiratory capacity, exercise intolerance, heat intolerance/stroke and decreased immune functions • Metabolic abnormalities, like hyperlipidemia and dyslipidemia • Neoplasia, including transitional cell carcinoma (TCC)of the bladder • Orthopedic disorders, like osteoarthritis, anterior cruciate ligament rupture and intervertebral disk disease • Urogenital system conditions, including TCC of bladder

9. Obesity Regulates Gene Expression • Poor diet leads to health problems by creating fat, but also changes the expression of obesity-related genes • Foods that suppress genomic expression for obesity may not only result in weight loss, but also reduced risk of obesity-related diseases • More fat cells create more cytokine secretion ( pro-inflammatory cell messengers) leading to more chronic, systemic inflammation • Fat regulating hormones = adiponectinthat  modulates metabolic processes like glucose regulation and fatty acid oxidation, and leptin, that acts on the brain to regulate food intake and body weight, and signals satiety • Green tea enhances adiponectin.

10. Oxidative Stress & Chronic Inflammation = CANCERS Background • Cancer responsible for about half the canine and feline deaths in the USA. • Leading cause of death in dogs older than two years. • No definitive conclusion why some individuals get cancer. • Estimated 5 -10% of all cancer cases originate purely from genetic predisposition, but 90-95% are the result of lifestyle & environmental factors. • “Basically, cancer is often a fatal disease caused by mutations in the genes of certain susceptible cells. These genetic mutations, usually caused by inflammation or excessive oxidation, convert normal cells into cancer cells that divide rapidly and grow uncontrollably, pushing their way into the surrounding tissues composed of otherwise normal cells”. Dr. Shawn Messonnier, 2006.

11. Cancer & Immune Surveillance • Cancer cells are created in the body every day • Healthy immune system distinguishes these mutated cells from normal cells and kills them • Compromised immune system allows these cells to live and divide until they create cancerous tumors • Cancer cells exist in a ‘wound healing’ environment, which they help create, and are energy hungry • Cancer cells preferentially use protein for energy and prefer certain amino acids, like arginine, at the expense of the host • Cancer diets often contain arginine to replenish and repair depleted sources

12. More Behavior of Cancer Cells • Cancer cells preferentially metabolize glucose for energy • Different pathway than normal cells; form lactate causing local acid environment • Body must expend energy to convert lactate back to glucose • Cancer diets should thus be low in carbohydrates • But, end-stage cancer diets need carbohydrates to replace depleted energy stores • Most cancer cells cannot oxidize fats, so cancer diets need high quality, high fat content, especially omega-3 fatty acids • But, these high fat diets are unsuitable for pets prone to pancreatitis or liver disease. • Provide bioavailable vitamins & minerals

13. Cancer Cell

14. T-Lymphocytes Attacking Cancer Cell

15. Breast Cancer Cell SEM

16. Lymphoma Cell

17. Leukemic Cells in Blood

18. Melanoma Cell

19. Predisposing Factors & Cancer • Obesity • Foods with high Glycemic Index (GI) • Glutens (release zonulin from bowel) • Fluoride (accumulates in bones; osteosarcoma risk) • Environmental toxins • PBDE (polybrominated diphenyl ethers)(flame retardants; especially toxic for cats) • Secondhand smoke • Topical flea/tick preventives • Adverse vaccine reactions

20. Obesity & Cancer • Obesity alters metabolism of hormones that maintain and control balance of cell proliferation, differentiation, and apoptosis • Pro-inflammatory cytokines produced by fat cells activate transcription factor (NK-fB) that promotes carcinogenesis and other inflammatory diseases • NK-fB activated by hyperglycemia of obesity • Link between gene expression in fat and insulin resistance = high risk for type 2 diabetes and cancer • 15 types of cancer in people are linked to long term obesity, especially bowel cancer that occurs later in life

21. High Glycemic Index Carbs & Cancer • Promote carcinogenesis and hyperinsulinemia • High risk for type 2 diabetes and colon-rectal cancer • Avoid refined sugars and flours Glutens & Cancer • Releases zonulin from bowel which causes “leaky gut” • Immune attack of inflammatory invader proteins triggers diseases (IBD) and cancers • Avoid glutens in animal cancer diets

22. Fluoride & Cancer • Fluoride accumulates in bones, results in high risk for osteosarcoma • Dogs 10 times more likely to have osteosarcoma than people • High fluoride levels in food and fluoridated water • Dry dog foods have 1.6-2.5 times EPA‘s safe fluoride level • Pet foods contain bone meal, meat meal and meat by-product meal • Promotes mitosis and rapid growth of osteoblasts • Dogs with cancer should avoid bone meal and animal byproducts, and drink fluoride-free water

23. Environmental Toxins & Cancer Common environmental toxins include: • Lawn and garden pesticides, herbicides, fertilizers, swimming pool products • Household cleaning, carpet and laundry products • Construction materials • Automotive products including antifreeze • Batteries and battery acids • Personal care and hygiene products • Pet care and grooming products

24. PBDEs (polybrominated diphenyl ethers)& Cancer • Flame-retardant chemicals used in clothing, furniture and electronics for 40 years • Leak into environment; known disruptors of endocrine function, especially thyroid gland • Linked to developmental problems, and even cancer, in animals • Residues found in serum, foods and house dust of cats and dogs PBDE levels in cats were 20 -100 times those in humans, while levels in dogs were 5-10 times higher-- -- as dogs metabolize them faster than cats, and have an enzyme that helps detox them See Environmental Working Group (www.ewg.org)

25. Secondhand Smoke & Cancer • Research studies found that dogs exposed to large amounts of second-hand smoke eventually have substantial changes to their lung tissue • Changes range from fibrosisto pre-cancerous and even cancerous lesions Topical Flea/Tick Preventives & Cancer • Products used to eradicate, like monthly spot treatments squeezed between the shoulder blades, contain toxic chemicals that pose both immediate and chronic health • risks to dogs—including death

26. Topical Flea/Tick Preventives & Cancer(cont’d) • In 1989, Purdue University Veterinary School found that dogs receiving 1-2 topical pesticides per year had 60% increased risk of bladder cancer. Dogs given more than 2 applications per year were 3.5 times more likely to develop bladder cancer. The risk was increased even more in overweight or obese dogs • Use veterinary prescribed products rather than OTC or pet store supplies, as should be safer • Organophosphates, carbamates and pyrethrins/pyrethroids pose severe health risks; clearly not for dogs with cancer • Use common sense preventives measures instead (bathing dog and bedding, combing, keeping grass short, natural repellants)

27. Adverse Vaccine Reactions & Cancer • Both MLV and inactivated, killed vaccines can produce serious adverse reactions including death in susceptible animals • Injection-site sarcomas can occur at sites of vaccination in both dogs and cats • Removal of the tumor can still result in recurrence – which has promoted worldwide policies to vaccinate pets in certain preferred locations on the body and to record where vaccines were given • Most commonly associated with rabies, feline leukemia, but can occur after any vaccination • Affected pets should not be revaccinated; for rabies, need to receive written exemption/ waivers instead

28. Toxic Exposures & Cancer Example:Bispenol-A (BPA), chemical used to make plastics and resins harden but stay flexible • Despite known hazards, used in plastic water bottles, food containers, and to line inner surface of canned goods • 95% of population has BPA exposure • Leaches into food & beverages it contacts • Has estrogenic properties • Affects many body tissues and functions: prostate, testes, mammary glands, brain; body size, and behavior • Only use canned goods labelled BPA-free. But related compounds are being used like Bisphenol-F and -S

29. Diet & Cancer • Dietary changes can prevent 30-40% of all cancers • Remove harmful foods that block effects of functional food • Promote DNA methylation (turmeric = curcumin, folate, cruciferous vegetables, SAMe, vitamin B-12) • Green leafy & yellow orange vegetables • Herbs & Ginger • Milk thistle (Silybum marianum); has active flavonoids • Berries (blueberries, cranberries, aronia); Pomegranates • Medicinal Mushrooms • Prebiotics (Spirulina) & Probiotics • Vitamin D • Omega-3 fatty acids

30. Supplements & Cancer • Anti-oxidants (reduce free radical damage) • Vitamins A, C, E and Co-Enzyme Q10 • Pro-oxidants (increase free radicals; enhance cancer cell death) • High dose curcumin (turmeric) • Anti-angiogenic (reduce cancer’s blood supply) • Fractionated pectin and shark cartilage • Immune modulators(increase or decrease immune system needs) • Mushrooms like Coriolus versicolor and Cordycepssinensis • Specific gene expression/ chemical pathway modulators • Quercetin down-regulates mutant p53 gene and functions in tumor suppression; but also promotes cell division and cancer. Quercetin suppresses expression of the RAS gene which can cause cancer

31. Phytochemical Nutrients & Cancer • Phytochemicals[plant chemicals that help prevent disease], including carotenoids (e.g. beta-carotene, lutein, zeaxanthin), flavonoids (e.g. quercetin, resveratrol, rutin), and phytosterols • Green leafy vegetables like spinach, broccoli, kale, lettuce, Italian parsley, Swiss chard, collards, bok choy or turnip greens • Yellow orange vegetables like squashes, carrots, pumpkin, yellow beets, yams, and sweet potatoes • Both the green leafy and yellow orange vegetables when given 3 times a week or more decrease canine TCC bladder cancer risk by 92%

32. Anti-Angiogenic Foods Beneficial in mast cell tumors • Apples • Artichokes • Berries(blackberries, blueberries, raspberries) • Bok choy • Cherries • Curcumin(turmeric) • Ginseng • Kale • Lavender • Maitake mushrooms • Olive oil • Parsley ♣ Pumpkin

33. Herbs & Cancer Herbs that enhance immune function (Fougère, 2012) • Cordycepssinensis • Echinacea • Astragalus • Withania • Siberian ginseng • Essiac • Cats claw • Pau d’Arco • Shitake and Reishi mushrooms

34. Supplements for Balancing the Immune System • Immune function requires zinc, selenium and vitamin E, vitamin B6 , and linoleic acid; and carotenoids, especially lutein and beta-carotene • Sterols + Sterolins in combination = immune balancing and stress modulating fats from fruits, vegetables and medicinal plants (e.g. ModuCare by Thorne) • Natural antioxidants and preservatives (e.g. vitamins E and C, citric acid, rosemary, turmeric, oregano, blueberries, cranberries, pomegranates)

35. Dietary Supplements • Novel or restricted protein source diet, pre-biotics (spirulina), probiotics (FOS, MOS) , antioxidants • Carotenoids, kelp, garlic, high fiber foods, nutritional herbs • Medicinal herbs, vitamins E and C, apple cider vinegar • Essential oils, flower essences, unpasteurized yogurt • Taurine and DMG for epileptics, milk thistle or denosyl methionine as liver cleanse, herbal pain remedies

36. Herbs / Nutrients to Use with Caution • Rosemary, Oregano, Fennel and Sage– added today as pet food preservative and antioxidant. NOT to be given to epileptics. (Peppermint Oil can help protect epileptics) • Grapes and Raisins – toxic to dogs; acute renal failure • Corn, Corn Starch, Fructose from Corn – associated with food sensitivity, intolerance • Wheat and Wheat gluten -- associated with food sensitivity, intolerance • Onions – cause Heinz body hemolytic anemia; Garlic , safe in moderation • Vasoactive Amines – tuna, mackerel, skipjack, bonito

37. “Let food be thy medicine and medicine be thy food.” Hippocrates