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  • All cells were treated with 200 ng/ml of TNFα except for Control Alexa Fluor594 conjugate of cholera toxin subunit B (CT-B) (Table 1). ThisCT-B conjugate binds to the pentasaccharide chain of plasmamembrane ganglioside GM1, which selectively partitions into lipidrafts.12,34
  • such as TNF receptor I with nSMase. The subsequent accumulation of ceramide through nSMase activation serves to coalesce lipid rafts into larger platforms involved in the signaling cascade leading to apoptosisa phosphorylation cascade induced by insulin binding to its receptor activates the phosphoinositide 3-kinases and the G protein, TC10. The later binds and recruits an exocyst protein complex (APS-CAP-Cbl) integral to the docking of Glut4 at lipid raft domains. assembly is necessary for Glut4 translocation and glucose uptake (Inoue et al., 2006). Fujimura et al. (2006) found a receptor associated with lipid rafts that bind with Epigallocatechin-3-O-gallate (EGCG), a potent flavonoid in green tea.APS is a Cbl-binding protein that is tyrosine phosphorylated by the insulin receptor kinase
  • Phytonutrients

    1. 1. Phytonutrients
    2. 2. What are functional foods? • International food information council “those foods that provide health benefits beyond basic nutrition” Bioactive Nutraceutical • Considered non-essential for growth and development • Decrease risk of chronic diseases
    3. 3. dietary supplements • Regulated as foods • Safety of supplement regulated by FDA only after they have entered the market • DSHEA states that a dietary supplement is “adulterated” only if it presents a “significant or unreasonable risk of illness or injury”
    4. 4. Dietary supplement health & education act of 1994 Definition of a supplement: “Is a product (other than tobacco) that is intended to supplement the diet that bears or contains one or more of the following dietary ingredients: a vitamin, a mineral, an herb or other botanical, an amino acid, a dietary substance for use by man to supplement the diet by increasing the total daily intake, or a concentrate, metabolite, constituent, extract, or combinations of these ingredients.” • Is intended for ingestion in pill capsule, tablet, or liquid form • Is not represented for use as a conventional food or as the soled item of a meal or diet • Is labeled as a “dietary supplement” • Includes products such as an approved new drug, certified antibiotic, or licensed biologic that was marketed as a dietary supplements or food before approval, certification, or license (unless the Secretary of Health and Human Services waives this provision).
    5. 5. the challenge of assessing dietary supplements • Need surrogate endpoints! • Example assessment of risk of cancer, inflammation • Bioactive components decrease inflammation via multiple mechanisms, i.e. activation of transcription factor and other epigenetic regulations • Act as antioxidant etc.
    6. 6. Cytochrome p450 • The superfamily of monooxygenases that catalyze the oxidation of organic substance. • Heme proteins • Substrates include metabolic intermediate, lipids, steroidal hormones, as well as xenobiotic substances such as drugs and other toxic chemicals. • Major enzymes involved in drug metabolism • The most common reaction catalyzed by cytochromes P450 is a monooxygenase reaction: RH + O2 + NADPH + H+ → ROH + H2O + NADP+
    7. 7. Cyclooxygenase • enzymes that are responsible for the formation of the paracrine hormones, eicosanoids: prostaglandins, leukotrienes and thromboxanes. • • Act on 20 carbon polyunsaturated fatty acids The target of non-steroidal, antiinflammatory drugs, such as aspirin and ibuprofen Inflammation, asthma, allergy Regulate synthesis of cAMP production  fever, pain, blood flow, and uterine contraction Produced by platelets, important in clotting and blood flow
    8. 8. Glycemic index & glycemic load • The glycemic index (GI) is a measure of how quickly 50 gram of available carbohydrate (minus fiber) in a particular type of food will increase blood sugar (glucose), compared to white bread or pure glucose • A practical limitation of the glycemic index is that it does not take into account the quality or quantity of carbohydrate actually consumed in a meal. • Glycemic load takes quantity into account by multiplying the glycemic index by the carbohydrate content of the actual serving.
    9. 9. secondary metabolites • phytonutrients content vary by location, harvest & storage • Sometimes phytonutrient cocktail is better than isolated nutrient – SYNERGY
    10. 10. carotenoids • Yellow and orange fruits, dark green leafy vegetables • α and β-carotene and β cryptoxantin – precursor to Vitamin A • lycopene, lutein, and zeaxantin – not precursors to vit A • Foods rich in carenoids may be safer than purified supplements • Typical western diet contains about 6 mg/day of carotenoids, 60% from animal sources • Bioavailability enhanced by fat
    11. 11. lycopenes • accumulates in certain tissues, such as prostate • Lycopene commonly in plasma associated with LDLs • Lutein and zeaxantin have high binding affinity to HDLs – accumulate in macula lutea of retina, act as photoreceptors
    12. 12. the benefits of salmon… astaxanthin
    13. 13. Plant sterols & stanols • Most abundant Sterols = β-sitosterol, stigmasterol, campesterol • Inhibit growth of various forms of lung, stomach, ovarian and breast cancer. • Stanols = sitostanol, campestanol • • • • Sterols essential component cell membrane Have sterol ring – differ in side chain. Stanols are saturated form of sterol Phytosterol absorption from intestine is a fraction of cholesterol
    14. 14. Sterols and stanols cont… • Cholesterol lowing effect by lowering absorption • FDA authorized health claims – must contain at least 0.65 g of plant sterols or 1.70 g stanol esters (esters have higher lipid solubility and are more easily incorporated into foods) • Typical diet  .15 - .4 g/day of sterols and stanols • To achieve 1.5 g/day, use supplement
    15. 15. Disruption of lipid rafts NT Sterol X TNF A B C • nSMase (green), lipid raft (red), colocalization of nSMase (yellow) • (A) Control, (B) TNFα (200 ng/ml), (C) Compound X isolated from AKBB (5 μg/ml) and TNFα
    16. 16. Disruption of lipid rafts by compounds in AKBB β-sitosterol Cholesterol Ursolic acid
    17. 17. Polyphenols • 1) flavanoids, 2) phenolic acids • Secondary metabolites – more than 8000 • Hydroxyl groups might provide reducing power or antioxidant potential (ROS) • Usually lots of conjugated double bonds • Usually in free form or Ο-glycosides
    18. 18. How do we measure antioxidant power? • Assays for measuring radical quenching ability: ORAC measures sample’s ability to inhibit peroxyl radical oxidization of the fluorescent probe, fluorescein. Compared to tocopherol. • Antioxidants can also chelate metals such as iron. Ferric reducing antioxidant power FRAP assay.
    19. 19. 1) flavonoids • Teas, berries, colorful fruit, red wine, dark chocolate, ginger, licorice ginseng • Antiinflammatory, antioxidative, antiallergenic, anticarcinogenic • Low molecular weight, two aromatic rings joined by 3 C chain that often incorporates O into a ring. • Subclasses: flavones, flavonols, flavanols, flavanones, anthocyanins • Proanthocyanins sometimes called tannins are oligomers of polymers of flavanol units • US ingest 20 mg/day • Database: USDA data base for the flavonoid content of selected foods and Phenol explorer
    20. 20. Anthrocyanins in Alaskan Cranberries and Blueberries mg/g of fresh weight 1.8 1.6 Cranberry 1.4 AK Cranberry 1.2 Blueberry 1 AK Blueberry 0.8 0.6 0.4 0.2 0 Anthocyanins
    21. 21. Flavonoid metabolism… • Free flavonoids can be absorbed across the small intestinal mucosa, flavonoid glycosides require hydrolysis by digestive enzymes • Flavonoids then undergo methylation and/or conjugation to glucuronic acid or sulfate before excretion • Conjugates excreted in the bile undergo deconjugation in the gut, catalyzed by microbiota, releasing flavonoid that may be reabsorbed
    22. 22. 2) Phenolic acids • Second largest subclass of polyphenols – COOH group • makes up about 1/3rd of total polyphenolics in diet. • groups based on R group on C ring: 1) hydroxycinnamic acids 2) hydroxybenzoic acids • Hydroxycinnamic acid esters shown to inhibit 5’lipoxygenases • Caffeic acid and ellagic acid shown to lower triglyceride levels and elevate insulin, lower ROS, and proinflammatory cytokines. • Typical diet range rom 0.025 – 1 g/day • Little known about bioavailability and metabolism.
    23. 23. Phytoestrogens • Majority phytoestrogens belong • to 4 subclasses: isoflavanoid, coumestans, isofl avones, lignans, stilbenes • Composed of a planar aromatic ring system with one or more hyroxyl • Phytoestrogens proposed to mimic estrogen and act as weak agonist, promoting • estrogen signaling in the absence of estrogen. favorably affect hormonedependent cancers, menopausal symptoms, glycemic control and weight maintenance, decrease thrombus and platelet aggregation, lower TGL, LDL. Recommended as alt to hormone replacement therapy. • No safety info
    24. 24. Estrogens function in growth, reproducti on, and maintenance and integrity of skeleton and CNS. ESTRADIOL
    25. 25. Phytoestrogens cont… • Founds in licorice, kudzu, soy, red clover, saw palmetto • Wine, grapes and peanuts good source of resveratrol • Flax seed, whole grain products, vegies, tea good source of lignans. • FDA approved health claim of 25 g or more soy flour for CVD
    26. 26. Indole-3-carbinol • A chemically, mechanistically, and phylogenetically separate phytoestrogen is indole-3-carbinol • does not mimic estrogen, but alters alters estrogen metabolism via a different mechanism. • Acid condensate of I-3-C binds to aryl hydrocarbon receptor which is capable of upregulating expression of cytochrome P450, which is involved in endogenous estrogen metabolism
    27. 27. Isothiocyanates • More than 120 have been identified • When cell wall is disrupted by chewing, chopping, etc, a hydrolytic enzyme, myrosinase, releases a bioactive isothiocyanate, a thiocyanate or a nitrile • Cabbage, brocolli, bok choy… • Shown to slow progression of common cancers with as little as 3 – 5 servings each week • Proposed to increase detoxification of carcinogens
    28. 28. Organosulfurs • Contains a derivative of cysteine called alliin, released when allium vegetables are crushed. • the enzyme allinase produces a lipidsoluble, unstable intermediate called allicin that decomposes to produce allyl sulfides, including diallyl sulfide (DAS, DAD and DATS) • Onions, leaks, chives, scallions, garlic (richest source)
    29. 29. Organosulfides cont… • • • • Antithrobotic effect via platelet inhibition May inhibit COX and prostaglandin synthesis Free radical scavenging activity Causes apoptosis of human bladder cancer cells through caspase activity. • Protects DNA from oxidation and prevents DNA mutagenesis. • Like cruciferous veggies, alliums contains selenocysteine methyl transferase which is what allows the plant to take up inorganic selenium. • Acute exposure to DAS, DAT inhibit cytochrome P450 but chronic exposure upregulates
    30. 30. Polyols • Sugar alcohols are used as sweeteners – Xylitol, Sorbitol, Mannitol • Fewer calories (1.5 – 3 kcal/g) and lower glycemic index due to reduced absorption by intestine • Excessive consumption of sugar alcohols lead to osmotic diarrhea – >50g of sorbitol or 20 g mannitol
    31. 31. Stevia • A natural zero calorie South American herb • Steviol contains two hydroxyl groups • Sugar residues are esterified to one or both of the –OH groups to form glycosides which are 200 – 450 times sweeter than sucrose. • Microflora in intestine release sugars and steviol • May lower blood pressure