Phytonutrients & Inflammation
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1 Phytonutrients & Inflammation Zhaoping Li, M.D., Ph.D. Professor of Medicine David Geffen School of Medicine, UCLA VA Greater Los Angeles Health Care System
2 TIME Feb. 23, 2004
3 Role of Inflammation in Human Diseases Pulmonary diseases Cancer Cardiovascular diseases Neurological diseases INFLAMMATION Alzheimer s disease Autoimmune diseases Arthritis Diabetes II
4 Inflammation: a reaction to injurious agents characterised by disturbed function. Can be: - biological ( metaflammation )* - ecological ( ecoflammation ) Hotomisligil G.Nature Dec. 2006; 444 Egger G. Obesity Reviews 2008
5 An inflamed body in an inflamed environment Garry Egger, Centre for Health Promotion & Research & Southern Cross University
6 Diets Then and Now 50,000 Years Ago Today Fruits, nuts, seeds, roots, tubers, flowers, leaves, stalks, beans 1/2 the fat 2-3x the protein No dairy or refined flour No processed foods No alcohol, no tobacco Potato, refined pasta & cereals white rice & flour, corn Added fat and sugar High fat proteins Ice cream, cheese and whole milk Processed foods
7 Instead of these colors..
8 We eat these colors
9 Phytochemicals/Phytonutrients Non-nutrient plant compounds Provide health benefits against certain chronic human illnesses such as cancer, heart disease, neurodegenerative diseases, etc.
10
11 Diet and Exercise Intervention Controlled Dietary Intervention 30% protein 7 servings of fruits and vegetables 20% fat 50% carbohydrates with grams of fiber per day Controlled Exercise Intervention Exercise program individually tailored Weight training Aerobic exercise Exercise training performed on-site at UCLA Fit Center South Gym
12 Preliminary Results Leptin from Serum Leptin ng/ml
13 Preliminary Results Estrone-S from Serum Estrone-S ng/ml
14 Preliminary Results Content of Estradiol in Nipple Lavage Fluid Estradiol (pmoll/l)
15 High Intake of Carotenoid-rich Vegetables and Fruit Reduces Plasma CRP Watzl et al AJCN 2005
16
17
18 Golden Triangle Modern Technology Traditional Knowledge (Traditional Chinese Medicine Ayurvedic Medicine Egyptian Medicine Kampo) Modern Knowledge (Allopathic Medicine) Aggarwal BB, et al Expert Opin Ther Targets. 2006;10:
19 Structure of Curcumin From turmeric (Curry Powder) O O CH3O OCH3 HO OH Diferuloylmethane Milobedzka J., von Kostnecki St, and Lampe V: ZurKenntnis des curcumins. Ber Deutsch ChemGes, 1910, 43,
20 PROFILE OF COMMERCIAL CURCUMIN 77 % Diferuloylmethane (curcumin) 17 % Demethoxycurcumin 6 % Bisdemethoxycurcumin
21
22 Molecular targets downregulated ELAM-1 ER-α EPCR EGFR DR-5 CXCR4 VCAM-1 ICAM-1 AHR Fas R H2R IAP-1 HER-2 IL-8 R AR Bcl-2 ITR PDGF Bcl-xL DEF-40 Cyclin D1 IR LDLR TF Hsp-70 MDRP HGF NGF TGF- 1 upa p53 Receptors CTGF EGF VEGF Others Notch-1 EGR-1 Growth factors FGF WT-1 -catenin AP-1 Nrf-2 PPAR- STAT-4 CREB-BP NF- B HIF-1 Transcriptional factors Curcumin IL-1R AK ERK JAK Pp60c-tk PAK FAK Kinases Ca2+PK PhK PKA STAT-1 STAT-3 ERE STAT-5 AAPK MAPK EGFR-K PKB JNK IL-1 IL-18 IL-2 MCP Inflammatory cytokines Telomerase PTK MIP Desaturase Enzymes DNA pol Src-2 TMMP-3 IL-5 FPT MaIP TNF-α GST Molecular targets upregulated IL-6 GCL MMP inos NQO-1 GlCL ODC IL-8 IL-12 AATF-1 ATFase ATPase COX-2 5-LOX PhP D Anand etal, CL, 2008
23 CURCUMIN HAS POOR PK PROPERTIES In humans, curcumin shows: Extremely poor oral absorption. A 8 g dose of curcumin produces averaged serum concentrations (as metabolites) of only ca. 120 ng/ml High rate of metabolic conjugation (sulfation and glucuronydation) Rapid clearance from the body In general, pharmacokinetics data from animal experiments have a poor human translation Mol. Pharmaceutics 4 (6), (2007)
24 CURCUMIN IS HYDROLITICALLY UNSTABLE AT INTESTINAL ph MeO O O OMe HO OH t 1/2 < 10 min ph 7.2, 37 C MeO HO a O a O b + b O OMe OH O OH OMe OH MeO O OH MeO O HO HO Wang, Y. J. J. Pharm. Biomed. Anal. 1997, 15,
25 STRATEGIES TO IMPROVE THE PK OF CURCUMIN 1. Increased resistance to metabolic inactivation: addition of piperine, an intestinal glucuronidases inhibitor, and quercetin as adjuvants 1. Increased absorption and resistance to hydrolytic and metabolic inactivation by complexation (nanoparticles, mycelles, liposomes and phytosome) Mol. Pharmaceutics 4 (6), (2007)
26 Piperine Enhance Curcumin Bioavailability Planta Med May;64(4):353-6.
27 PHYTOSOMES CHAPERONE POLYPHENOLICS INTO BIOMEMBRANES Phytosomes are made up by phospholipids, and cell membrane contain phospholipids. They can merge, shuttling polyphenolics into the cell membranes of enteric cells.
28 MERIVA HUMAN PK STUDY 30 fold higher bioavailability of Curcuminoids 60 fold higher bioavailability of Demethoxycurcumin Curcuminoids 376 mg 209 mg 1800 mg J Nat Prod Mar 17
29 THERACUMIN Human PK Study
30 Curcumin Increase Insulin Response Wickenberg et al. Nutrition Journal 2010, 9:43
31 Serum Lipid level Changes in serum lipid levels in healthy subjects by curcumin 500 mg/day x 7days; N=10 Lipid Peroxide (nmoles/ml) Total Cholesterol (mg/100ml) HDL-C (nmoles/ml) Triglycerides (nmoles/ml) Pre Post Pre Post 50 Pre Post 100 Pre Post Sony & Kuttan, 1992
32
33 UCLA Ongoing Trial Head to head comparison of different curcumin preparations Bioavaialbility Bioactivity on inflammation
34 Supplements Research results: promising, preliminary Unknown: optimal therapeutic dosage, compounds synergies.
35 CONCLUSIONS Fruits and vegetables contain high levels and a wide diversity of phytonutrients Phytonutrients show anti-inflammatory, antioxidant, anticancer, anti-atherosclerotic and anti-neurodegenerative properties. Phytonutrients may function synergistically in its natural matrix
36 Questions?
Impact of Phytonutrients on Inflammation
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