Recommended
Recommended
More Related Content
What's hot
What's hot (20)
Viewers also liked
Viewers also liked (20)
Similar to Plant Derived Therapeutics for Treating Metabolic Syndrome
Similar to Plant Derived Therapeutics for Treating Metabolic Syndrome (20)
Recently uploaded
Recently uploaded (20)
Plant Derived Therapeutics for Treating Metabolic Syndrome
- 1. Plant Derived Therapeutics for the treatment Metabolic Syndrome William T. Cefalu, M.D. Pennington Biomedical Research Center
- 2. Changing Nutrition/Health Paradigm s What food is required for me? ä Nutritional deficiency: ä Iron - Anemia ä Iodine – Thyroid goiter ä Vitamin D - Rickets ä Identifying essential nutrients required for promoting growth and sustaining life. ä Vitamins ä Essential minerals – Calcium ä Essential amino acids 1920s-1980s
- 3. Changing Nutrition/Health Paradigm s What does food do to me? ä Nutritional excess and imbalances ä Calories - obesity ä Fiber – Colon cancer ä Identifying nutrients and components that contribute to premature death ä Saturated fat ä Cholesterol ä Sodium 1950s-1990s
- 4. Seven Countries Study: CHD Events are Correlated with Saturated Fat 0 5 10 15 20 % Calories from Saturated Fat 0 1 2 3 4 5 CHDDeathsandMI/100 R = 0.84 V M C D G S W B Z U N E K Keys, 1970
- 5. Changing Nutrition/Health Paradigm s What does food do for me? ä Nutritional optimization of quality of life ä Identification of physiological active components to prevent or delay premature onset of chronic disease ä Phytochemicals ä Pre/Probiotics ä Fiber 1990s-Today! Identification of Phytochemicals
- 6. Phytochemicals as Functional Components s Individual compounds in plants that have evolved in part as protective mechanisms against environmental insult s Phytochemicals with biological activity have had great utility as pharmaceuticals and pest- management agents. s Very few of these potentially active compounds have been examined thoroughly.
- 7. Functional Foods s Definition ä Generic description of foods, that when ingested, provide demonstrated physiological health benefits beyond simple nutritional value s Expanded Definition ä Similar in appearance to conventional foods; Are consumed as part of a usual diet
- 8. How to Be a Functional Food s A natural food product can be engineered to become a functional food by ä Increasing specific components (Phytochemicals) to reach a concentration more likely to express health benefits ä Adding components not normally present but having a beneficial effect ä Replacing a component that is excessive and harmful with one having a beneficial effect ä Improving the bioavailability of components having desired health benefits
- 9. Phytochemicals and Reported Sources
- 10. Polyphenols ä Epicatechin ä Epigallocatechin ä Epigallocatechin gallate s Source: Green tea; grapes, red wine s Benefits: Anti-cancer; CHD protective s Function: Inhibit chemical carcinogenesis and tumor formation; inhibit cancer cell growth; antioxidant; reduces free radical/oxidative damage
- 11. Isoflavones ä Genistein ä Daidzein s Source: Soybean, flaxseed s Benefits: Relieves menopausal symptoms; prevents osteoporosis; anti-cancer; CHD protective s Function: Estrogen-like activity; inhibit growth of breast cancer cells; stimulate Ca absorption; lower cholesterol levels Genistein
- 12. Phytosterols ä -sitosterol ä Campesterol ä -sitostanol s Source: Plant oils s Benefits: CHD protective s Function: Inhibit cholesterol absorption -sitosterol
- 13. Carotenoids ä Lycopene ä -carotene ä -cryptoxanthin ä Lutein s Source: Tomatoes, carrots, yams, cantaloupe, spinach, sweet potatoes; citrus fruits s Benefits: Anti-cancer; CHD protective s Function: Antioxidant; free radical scavenger; induction of cell-cell communication and growth control; inhibit tumor growth -carotene
- 14. n3-Fatty Acids ä -linoleic acid ä Docosahexaenoic acid ä Eicosapentaenoic acid s Source: Flaxseed oil, fish oil s Benefits: CHD protective; anti-cancer; anti- inflammatory s Function: Lower triglycerides; inhibit platelet aggregation; affect eicosanoid production DHA
- 15. Flavonoids ä Quercetin ä Apigenin ä Luteolin ä Myricetin s Source: Citrus fruits; vegetables s Benefits: Anti-cancer; CHD protective s Function: Antioxidant; inhibit platelet aggregation; inhibit cancer cell growth and proliferation; cytotoxic to cancer cells Luteolin
- 16. The Promise of Plant Therapeutics s Better health through improved nutrition can: ä Increase quality of life ä Enhance productivity ä Reduce health-care costs - by preventing or delaying the onset of chronic disease, i.e diabetes - or improving metabolic factors related to the disease, i.e. glucose Health claims need to be verified with carefully controlled studies
- 17. O Type 2 diabetes Years from diagnosis 0 5-10 -5 10 15 Pre-diabetes Onset Diagnosis Insulin resistance Post-Meal glucose Fasting glucose “Nutraceutical (Botanical/Bioactive) Strategies”
- 18. “Pre-Diabetes” Type 2 diabetes Years from diagnosis 0 5-10 -5 10 15 Pre-diabetes Onset Diagnosis Insulin secretion Insulin “inefficiency Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789 Nathan DM. N Engl J Med. 2002;347:1342-1349 Post-Meal glucose Fasting glucose Pancreas function Progressive -Cell Failure Natural History of Type 2 Diabetes
- 19. RelativeRiskofMIorStroke 0 1 2 3 4 5 6 7 Nondiabetic Throughout 2.4 >15 Yr Before Dx 10-14.9 Yr Before Dx 3.64 <10 Yr Before Dx Diabetic Throughout 5.02 3.19 1.0 Hu FB, et al. Diabetes Care. 2002;25:1129-1134. Non-Diabetic Diabetes Cardiovascular Risk in Pre-diabetes Pre-Diabetes
- 20. Type 2 diabetes Years from diagnosis 0 5-10 -5 10 15 Pre-diabetes Onset Diagnosis Insulin resistance Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789 Nathan DM. N Engl J Med. 2002;347:1342-1349 Post-Meal glucose Fasting glucose Natural History of Type 2 Diabetes “Nutraceutical (Botanical/Bioactive) Strategies”
- 21. Phytochemicals and Reported Sources
- 22. Blueberries as a Therapy for Type 2 Diabetes • Literature Review – Blueberries are a folk remedy in Canada for treatment of diabetes (Martineau LC et al., Phytomedicine, 2006) – Blueberries have been found to: • Reduce blood glucose concentrations in rats and humans (Abidov M et al, 2006 ; DeFuria J et al, 2009) • Increase glucose uptake in muscle and fat cells (Tri Vuong et al, 2006) • Protect against obesity in rats (DeFuria J et al, 2009)
- 23. PBRC Blueberry Research Study • Primary Objective – To evaluate the effect of blueberry bioactives on improving a pathophysiologic parameter contributing to the development of type 2 diabetes in humans • Hypothesis – Increased consumption of blueberry bioactives will result in an increase in whole body insulin action, i.e. insulin sensitivity, in pre-diabetic individuals
- 24. Study Design Baseline Blueberry Group Placebo (Control) Screening Insulin Sensitivity Test 1 2 3 4 5 6 7 8 9 End End Visits (Weeks) *Randomized *Started consuming smoothies Hyperinsulinemic Euglycemic Clamp “Gold Standard” for objectively assessing whole body insulin action
- 25. Nutritional Value (per 16oz) Bioactives Placebo Energy, kcal 239 234 Carbohydrate, g 48.5 48.6 Fiber, g 4.2 4.3 Protein, g 11.9 11.1 Fat, g 0.08 0.08 Saturated Fat, g 0.05 0.05 Each subject consumed two 16oz smoothies per day 16 oz Smoothie (Bioactives) = Nutritional Value of Intervention Placebo Smoothie Stull AJ et al. J Nutr. 2010 Oct;140(10):1764-8.
- 26. The Ability of Insulin to Work in All Participants From Beginning to End of Study -30 -20 -10 0 10 20 30 40 50 60 70 80 90 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 %∆InsulinSensitivity Subject Numbers Bioactives Group Placebo 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Placebo (Control) Group Bioactives Group Individual Response in Insulin Sensitivity Technical Variability
- 27. Blueberry Bioactives Improved Insulin Sensitivity 22.2 4.9 0 5 10 15 20 25 Blueberry Placebo %∆InsulinSensitivity ∆ insulin Sensitivity = ability of insulin to work from week 0 to week 6 4-Fold
- 28. Botanicals showing Promise to Favorably modulate Carbohydrate Metabolism • Bitter Melon ( Momordica charantia) • Hoodia (Hoodia gordonii) • Artemisia dracunculas and related sp.
- 29. 0.0 0.5 1.0 1.5 2.0 2.5 0 6 12 LFD HFD BM * *** # Insulin(ng/ml) Weeks 0 50 100 150 200 250 0 6 12 LFD HFD BM Glucose(mg/dl) ** # Weeks A B C Figure 3 100 150 200 250 300 350 400 0 20 40 60 80 100 120 HFD BM Glucose(mg/dl) Time (min) IPGTT *** *** *** ***# # # D 0 50 100 150 200 0 20 40 60 80 100 120 HFD BM LFD Glucose(mg/dl) Time (min) IPITT # # *** *** *** *** *** E F 0 3000 6000 9000 12000 15000 LFD HFD BM Plasma leptin concentration in mice(pmol/ml) Groups *** *** ## 0.0 0.5 1.0 1.5 0 6 12 LFD HFD BM HOMA-IR * *** ### *** Weeks Bitter Melon and Glucose tolerance
- 30. IRS-2 IRS-1 -actin Group LFD HFD BM IR GLUT4 PI 3K Akt1 Akt2 Skeletal muscle IRS-1 p (Tyr612) Akt1 p (ser473) Insulin - + - + - + Group LFD HFD BM IRS-1 Akt1 Akt2 Akt2 p (ser474) Mouse # 1 2 3 4 8 9 7 11 13 15 16 18 Insulin - + - + - + - + - + - + Group LFD HFD BM 0.0 0.5 1.0 1.5 2.0 2.5 LFD HFD BM Basal Insulin FoldofLFDatbasal ** ** * ### Bitter Melon and Glucose tolerance
- 31. Figure 4. A B 0 5 10 15 20 25 30 C14:2 C14:1 C14-OH C16 C18-OH LFD HFD BM Acylcarnitine(pmol/mgprotein) Long chain acyl carnitine in muscle tissues *** ### ##*** ### 0 5 10 15 20 25 C3 C4 C4-DC C6 C8:1 C12-OH LFD HFD BM Acylcarnitine(pmol/mgprotein) Short/medium chain acyl carnitine in muscle tissues # *** ### # # ## *** * * Bitter Melon Modulates Intracellular lipids
- 32. Hoodia gordonii and Asclepias incarnata (Swamp milkweed) Belong to the Same Plant Family cellhealthmakeover.com abnativeplants.com
- 33. 12-hydroxy (lineolon) 12-acetyl 12-nicotinoyl 12-tigloyl 12-benzoyl 12-cinnamoyl In collaboration with Analyticon Natural Diversity of Pregnanes Isolated from A. incarnata Extract ikemagenin
- 34. An approach to the study of Phytochemicals and Human Health
- 35. Phytochemicals and Carbohydrate Metabolism Alcoholic Extract of Artemisia dracunculus L. Russian Tarragon (PMI 5011) Ribnicky DM, et al. Am J Physiol Endocrinol Metab. 2007
- 36. • Agriculture SOPs must be developed for each crop (Germination; Plant nutrition Pest management) Sourcing and Standardization of Phytochemicals
- 37. Artemisia dracunculus in Hydroponics at ARC Greenhouses
- 38. • Agriculture SOPs must be developed for each crop (Germination; Plant nutrition Pest management) • Optimization of activity and composition Sourcing and Standardization of Phytochemicals
- 39. Phytochemicals and Carbohydrate Metabolism Flowering Artemisia dracunculus
- 40. LC-MS Comparison of PMI-5011 Extracts Made from Plants at Different Stages of Development Flowering Stage Growth/ Non-flowering Stage
- 41. • Agriculture SOPs must be developed for each crop (Germination; Plant nutrition Pest management) • Optimization of activity and composition • Identification of the active components for standardization (Bioactivity guided Fractionization) Sourcing and Standardization of Phytochemicals
- 42. 5011 ADEX ADEX ADEX Bioactivity Guided Fractionization Identification and Isolation of Phytochemicals
- 43. BMI 29.5 0 4 6 8 12 hoursType 2 DM subjects: BMI 31.1 BMI 36.8 PTP-1B -actin PTP-1B -actin PTP-1B -actin PTP1B Levels and Artermisa sp (5011) Human Skeletal Muscle Time Course Studies: 5011
- 44. IRS-1 IRS-2 PTP 1B IR PI 3 -Actin Fraction7 Contr 2 3 4 5 6 7 8 9 10 11 5011D Akt-p Insulin Signaling Parameters Human Skeletal Muscle Culture 5011 Fractions Phosphatase Wang ZQ et al. Metabolism. 2008 Jul;57(7 Suppl 1):S58-64. Ribnicky DM et al. Am J Clin Nutr. 2008;87(2):472S-5S.
- 45. Isolated Compounds ALR2 PTP-1B PEPCK 4,5-di-O-caffeoylquinic acid * ◊ ○ A - - Davidigenin * ◊ † ‡ A - - A - A 2′,4′-dihydroxy- 4- methoxydihydrochalcone * ◊ ○ † ‡ § A A A 2,4-dihydroxy- 4- methoxydihydrochalcone * ◊ ○ † ‡ - A - - A - 6-demethoxycapillarisin * ◊ ○ Sakuranetin ▪ ◊ ○ * - confirmed with NMR ◊ - new compound to A . dracunculus ○ - activity reported for the first time A - active † - dihydrochalcone ‡ - new compound to genus Artemisia § - first report as a constituent of plants ▪ - flavonoids ALR2- Aldose reductase PTP-1B - Protein tyrosine phosphatase - 1B PEPCK - Phosphoenolpyruvate carboxykinase Bioactives Isolated from Artemisia dracunculus and PMI-5011 by Activity-Guided Fractionation
- 46. *2′, 4′–dihydroxy-4-methoxydihydrochalcone 0 50 100 150 200 250 Labrasol 50 mg/kg chalcone 150 mg/kg chalcone 300 mg/kg chalcone metformin 300 mg/kg bloodglucose(mg/dl) 0 hr 6 hr * * ** * All treatments provided with 66% Labrasol The Pure Active DMC-2* from Artermisia is Validated in vivo with Comparable Activity to Metformin
- 47. • Agriculture SOPs must be developed for each crop (Germination; Plant nutrition Pest management) • Optimization of activity and composition • Identification of the active components for standardization (Bioactivity Guided Fractionization) • Standardized for Active Components Sourcing and Standardization of Phytochemicals
- 48. • Agriculture SOPs must be developed for each crop (Germination; Plant nutrition Pest management) • Optimization of activity and composition • Identification of the active components for standardization (Fingerprinting) • Standardized for Active Components • Stability Assessed Sourcing and Standardization of Phytochemicals
- 49. -20ºC freezer 22ºC open container 22ºC desiccator 37ºC open oven Stability of the Extract PMI-5011 is stable under various storage conditions Stability was investigated a period of 7 months by validated HPLC method HPLC-Chromatograms of PMI-5011, stored under different conditions
- 50. Sourcing and Standardization of Phytochemicals Assuring Supply of materials for research • in vitro studies • Toxicology • in vivo preclinical • clinical
- 51. Animals Received 5011 Placebo Intervention Animals: KK-Ay Intervention: 5011 Total Extract vs control conditions Endpoint: Insulin and Glucose levels, Muscle signaling Baseline • Insulin Stimulation/Muscle Insulin Signaling • Serial Insulin/Glucose Baseline Study Design: In vivo Mechanism
- 52. Ribnicky DM, et al. Phytomedicine. 2006 Sep;13(8):550-7. Body Weight/Food Intake
- 53. Plasma insulin 0 2 4 6 8 0 5 10 15 20 Control 5011 Weeks of Study Insulin(pg/ml) Mean + SEM, * P<0.05, ** P<0.01. ** * * Plasma Insulin
- 54. Akt-p Akt-1 Akt-2 AS160 Mice # 1 2 3 9 10 11 5011 - - - + + + Glut 4 -Actin Control 5011 Insulin Signaling Parameters Skeletal Muscle
- 55. Bench to Bedside Cells tested with Botanical Human Testing in Several Phases Animal Testing to Monitor Safety and Effectiveness
- 56. Screening Screening 5011 Placebo Intervention Subjects: Obese, Insulin Resistant, n = 28 Intervention: 5011 Total Extract vs Placebo Endpoint: Insulin Sensitivity (Clamp Procedure) •Hyperinsulinemic Euglycemic Clamps •Body Composition Baseline Baseline Clinical Trial Study Design
- 57. 4 5 6 7 8 9 10 11 12 Pre Post Pre Post 5011 4 6 8 10 5011Placebo InsulinSensitivity(mg/min/FFM) Placebo Baseline End of Study * * P < .05 Clinical Response Insulin Sensitivity
- 58. Analysis of Compounds from PMI-5011 in SIM for active compounds in PMI-5011 Standards 6-demethoxycapillarisin & davidigenin Standards sakuranetin & 2′, 4–dihydroxy-4′-methoxydihydrochalcone SIM plasma analysis SIM = Selected Ion Monitoring 285 257 271 285 Phytochemical Characterization In Plasma by LC-MS-SIM
- 59. Time Course of Appearance 0 1 2 3 4 5 6 7 0 45 120 180 240 Minutes after Ingestion Abundance(X107) Plasma Appearance of Phytochemical
- 60. Mean Levels over 4 hours 0 1 2 3 4 5 6 7 5011 Placebo Ion 257: davidigenin Ion 271 sakuranetin Ion 285: chalcone Undetectable Abundance(x107) Plasma Abundance 5011 Metabolites
- 61. Potential Nutraceutical (Phytochemical) Markets 1. Joint health (n3-fatty acids, glucosamine, chondroitin sulfate) 2. Gastrointestinal health (ginger, pepermint, fennel, prebiotics, probiotics) 3. Blood lipids (n3-fatty acids, oat bran, phytosterols) 4. Bone density and skeletal health (phytoestrogens, Ca, Zn) 5. Hormone replacement (isoflavones, arginine, yohimbe)
- 62. 6. Body fat/Weight (herbal phen-fen, Cr, garcinia cambogia) 7. Optimal vision (lutein, zeaxanthin) 8. Stress and insomnia (St. John’s Wort, tryptophan) 9. Breast and prostate health (fruits, vegetables, saw palmetto) 10. Carbohydrate Metabolism (Chalcones, Cinnamon polyphenols) Potential Nutraceutical (Phytochemical) Markets
- 63. The most studied Phytochemical: Wine 0 0.2 0.4 0.6 0.8 1 1.2 1.4 0 <0.1 0.1 - 0.3 0.3 - 1 1.0 - 2.0 >2.0 Drinks per Day Relative Risk CVD Non-CVD s Over 40 prospective studies have documented an inverse relationship between alcohol intake and heart disease prevention
- 64. We Can’t Put Our Heads in the Sand any Longer !!! Regarding Plant Therapeutics and Human Health…..