Extraordinary Nutrients:

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Flavonoids And Other Polyphenols

POLYPHENOL ABSORPTION

  • Polyphenols are abundant micronutrients in our diet, and evidence for their role in the prevention of degenerative diseases is emerging. Bioavailability differs greatly from one polyphenol to another, so that the most abundant polyphenols in our diet are not necessarily those leading to the highest concentrations of active metabolites in target tissues.

  • Gallic acid and isoflavones are the most well-absorbed polyphenols, followed by catechins, flavanones, and quercetin glucosides, but with different kinetics. The least well-absorbed polyphenols are the proanthocyanidins, the galloylated T catechins, and the anthocyanins.

  • Bacteria in the gut can perform reactions that transform more complex plant phenols such as anthocyanins, procyanins, flavanones, flavonols, tannins, and isoflavones into simple phenolic metabolites. The colon is thus a rich source of potentially active phenolic acids that may impact both locally and systemically on gut health. Both the small and large intestine contain absorption sites for phenolic acids, but low post-prandial concentrations in plasma indicate minimal absorption early in the GI tract, and/or rapid hepatic metabolism and excretion. Therefore, any bioactivity that contributes to gut health occurs predominantly in the colon. Several phenolic acids affect the expression and activity of enzymes involved in the production of inflammatory mediators of pathways thought to be important in the development of gut disorders including colon cancer. ----- supplementing with IMMUNO-SYNBIOTIC is the only way to assure bioavailability of flavonoids.

  • Controlled human intervention studies with beverages such as red wine that are rich in polyphenolic compounds have yielded conflicting results. The biological effect of such beverages may be a balance between the pro-oxidant effects of alcohol and its metabolism and the antioxidant effects of polyphenolic constituents.

  • There is a long-standing controversy over whether flavonoids are absorbed as the intact glycoside, or whether they have to be hydrolyzed to the free aglycon prior to absorption. Analyses of 12 dietary flavonoids in human urine showed that no flavonoid glycosides are excreted, and that the citrus flavanones and phloretin are excreted in higher amounts than the flavonols. In other words, the benefits of flavonoids do not derive from the flavonoids themselves but from metabolites produced by the liver, or by colonic bacteria acting upon those flavonoids.

 

HESPERIDIN

  • Improves capillary integrity (250 mg) = decreases excess capillary permeability and associated edema

  • Flavonoids reduce lipid peroxidation, with rutin being more effective than hesperidin, which is more effective than quercetin; flavonoids are protective against auto-oxidation of rat cerebral membranes, with quercetin being more effective than rutin, which is more effective than hesperidin.

  • Rutin and quercetin (flavonols) and hesperidin (flavanone) in intraperitoneal doses of 80 mg/kg inhibit both acute and chronic phases of inflammation. Rutin is the most active in the chronic phase of inflammation, but is only effective in the chronic process, principally in adjuvant arthritis. On neurogenic inflammation induced by xylene, only hesperidin (and hesperetin) is effective, and the flavanones are the most effective in subchronic inflammatory processes. The most important flavonoid in reducing acute inflammation and swelling induced by carrageenan is quercetin.

 

QUERCETIN

  • One of the major polyphenol constituents of red wine (along with catechin)

  • Non-citrus

  • 250 mg constitutes a therapeutic dose

  • Histamine inhibitor

  • Controls excess release of Mast Cells

  • Controls excess release of Leukotrienes and Prostaglandins

  • Quercetin inhibits LPS-induced PGE2 production in vitro.

  • Increases efficacy and decreases toxicity of chemotherapy

  • Improves Intestinal Barrier function

  • Maintains presynaptic acetylcholine retention at neuromuscular junctions of the GI tract

  • Protects DNA from oxidation; quercetin = 78%, luteolin = 91%, myricetin = 90%, vitamin C = 12% but additive with quercetin

  • Inhibits protein kinase C (carcinogenic process); inhibits tyrosine kinase (tumor spread)

  • Xanthine oxidase and xanthine dehydrogenase (uric acid production in the liver) inhibition

  • Flavonoids reduce lipid peroxidation, with rutin being more effective than hesperidin, which is more effective than quercetin; flavonoids are protective against auto-oxidation of rat cerebral membranes, with quercetin being more effective than rutin, which is more effective than hesperidin.

  • In mice, quercetin shows no protective effect against LDL oxidation or atherosclerotic lesion formation, while the glycoside quercetin 3-(6-malonylglucoside) is very effective.

  • Quercetin attenuates the development of atherosclerosis by reducing the susceptibility of LDL to aggregation. It has no direct antioxidant effects on LDL, but reduces its tendency to oxidize by binding LDL particles into aggregates.

  • Quercetin inhibits LPS-induced Nitric Oxide production in macrophages through suppression of Nitric Oxide Synthase expression.

  • Quercetin (as well as apigenin and luteolin) inhibit platelet aggregation by binding to thromboxane A2 receptors.

  • Rutin and quercetin (flavonols) and hesperidin (flavanone) in intraperitoneal doses of 80 mg/kg inhibit both acute and chronic phases of inflammation.
    Rutin is the most active in the chronic phase of inflammation, but is only effective in the chronic process, principally in adjuvant arthritis. On neurogenic inflammation induced by xylene, only hesperidin (and hesperetin) is effective, and the flavanones are the most effective in subchronic inflammatory processes. The most important flavonoid in reducing acute inflammation and swelling induced by carrageenan is quercetin.

  • Quercetin and rutin (7.5 mg/kg, per os) decrease both the immediate and late-phase increase in airway resistance in asthma. These flavonoids also significantly inhibit histamine (15 mg/kg) production as well as recruitment of neutrophils and eosinophils during the late-phase response. Quercetin and rutin are about half as effective as dexamethasone (3 mg/kg).

  • Photosensitized hemolysis of human RBCs is suppressed by quercetin and rutin, accompanied by inhibition of lipid peroxidation. --- Indicating that flavonols can function as antioxidants in biological systems by terminating radical chain reactions and removing singlet molecular oxygen. This antioxidant function is a mechanism by which quercetin and rutin decrease excess permeability and fragility of capillaries.

  • Two week quercetin supplementation (1,000 mg daily) of trained cyclists resulted after a 3 day period of heavy exertion in increased granulocyte oxidative burst activity, and a significant decrease of C-reactive protein and Interleukin-6 and Interleukin-10.

  • Supplementation with quercetin decreased upper respiratory tract infections in trained cyclists during a 2 week period after intensified exercise.

 

RUTIN

  • Improves capillary integrity = decreases excess capillary permeability and associated edema

  • Decreases platelet aggregation

  • Binds Iron = antioxidant --- prevents Fe+2 from binding to H2O2

  • Inhibits VEGF (angiogenesis)

  • Anti-inflammatory

  • Decreases cytotoxic effect of oxidized LDL

  • Molds (Aspergillus) = rutin catabolic pathway

  • 350 mg of rutin administered by intraperitoneal route results in significant drop in triglycerides. Rutin combined with nicotinic acid also lowers cholesterol better than nicotinic acid alone.

  • Flavonoids reduce lipid peroxidation, with rutin being more effective than hesperidin, which is more effective than quercetin; flavonoids are protective against auto-oxidation of rat cerebral membranes, with quercetin being more effective than rutin, which is more effective than hesperidin.

  • In rats with induced myocardial infarct, pre-treatment with rutin protected against increased heart weight, prevented increased heart concentrations of cholesterol, triglycerides, and free fatty acids, and a decrease of phospholipids. In these myocardial infarct rats, rutin also prevented the increase in serum cholesterol, triglycerides, phospholipids, LDL cholesterol, vLDL cholesterol, and the decrease in HDL cholesterol. Rutin had no effect on these parameters in normal control rats.

  • Rutin and quercetin (flavonols) and hesperidin (flavanone) in intraperitoneal doses of 80 mg/kg inhibit both acute and chronic phases of inflammation. Rutin is the most active in the chronic phase of inflammation, but is only effective in the chronic process, principally in adjuvant arthritis. On neurogenic inflammation induced by xylene, only hesperidin (and hesperetin) are effective, and the flavanones are the most effective in subchronic inflammatory processes. The most important flavonoid in reducing acute inflammation and swelling induced by carrageenan is quercetin.

  • Quercetin and rutin (7.5 mg/kg, per os) decrease both the immediate and late-phase increase in airway resistance in asthma. These flavonoids also significantly inhibit histamine (15 mg/kg) production as well as recruitment of neutrophils and eosinophils during the late-phase response. Quercetin and rutin are about half as effective as dexamethasone (3 mg/kg).

  • Rutin has antiradical and antioxidant activity in both iron- and ascorbate-driven fenton systems, radiation, xanthine/xanthine oxidase systems, and, has DPPH radical scavenging activities.

  • Superoxide anion scavenging activity is strongest with rutin, and second strongest with quercetin (and naringin), and only moderate with hesperidin. The superoxide anions are strong inhibitors of prostacyclin production, so, flavonoids facilitate anti-aggregatory PGI2 formation.

  • Supplementation with rutosides was given to patients with chronic venous insufficiency (CVI) without diabetes (1500 mg/day) and patients with CVI plus diabetes (2 g/d). In the CVI patients without diabetes, there was a statistically significant decrease in capillary filtration rate, and an even greater decrease in capillary filtration rate in the diabetic patients taking a somewhat larger dose of rutosides. During the 5 year study, venous edema reduced substantially and deterioration of the distal venous system was prevented. There was also prevention of ulcerations. Rutoside supplementation after only 4-8 weeks caused an increase in subnormal PO2 and a decrease in elevated PCO2, indicating microcirculatory improvement. There was a significant decrease in ankle swelling of 41% after 8 weeks.

  • Intravenous arachidonic acid and serotonin increase vascular permeability (an indication of inflammation), and that increase is reduced by aspirin. It is also totally abolished by vitamin C and the flavonoid compound troxerutin (100 mg/kg), whereas vitamin E has only a partial effect (40-100% inhibition). The anti-inflammatory potential of flavonoids is highlighted here.

  • Photosensitized hemolysis of human RBCs is suppressed by quercetin and rutin accompanied by inhibition of lipid peroxidation. --- Indicating that flavonols can function as antioxidants in biological systems by terminating radical chain reactions and removing singlet molecular oxygen. This antioxidant function is a mechanism by which quercetin and rutin decrease excess permeability and fragility of capillaries.

  • Flavonoids such as rutins decrease inflammatory edema. The benefit of decreasing excess vascular permeability is associated with inhibiting the leakage of albumen from the serum into the interstitium.

  • Rutosides decrease vascular permeability associated with excess histamine, bradykinin, and fibrin degradation products.