Resveratrol

Absorbce

• Buccal delivery
• Without swallowing
• One milligram of resveratrol in 50 ml 50% alcohol/ water solution in the mouth for one minute before swallowing
• 37 ng/ml of free resveratrol was measured in plasma two minutes later

• Level of unchanged resveratrol in blood
• Achieved with 250 mg of resveratrol taken in a pill form [1]

• Low aqueous solubility of the molecule
• Absorbed transmucosally
• Must be in free-form or dissolved [1]

• 70% of orally administered resveratrol is absorbed
• Oral bioavailability is approximately 0.5%
• Extensive hepatic glucuronidation and sulfation [1]

• Resveratrol in a proprietary formulation SRT-501 (3 or 5 g) - Sirtris Pharmaceuticals
• 5-8 x higher blood levels
• Concentration necessary to exert the effects shown in animal models and in vitro experiments [1]

• Rats
• Less than 5% of the oral dose was observed as free resveratrol in blood plasma [1]

• Resveratrol from wine
• Could have higher bioavailability than resveratrol from a pill [1]

• Human oral administration of 500 mg over 13 weeks
• Resveratrol was detected in cerebrospinal fluid
• Crossed the blood-brain barrier [1]

Biosyntéza

• In plants
• Resveratrol synthase [1]

Biotransformation

• Grapevine fungal pathogen Botrytis cinerea
• Oxidise resveratrol into metabolites showing attenuated antifungal activities
• Resveratrol dimers restrytisol A, B, C,
• Resveratrol trans-dehydrodimer
• Leachinol F
• Pallidol [1]
• The soil bacterium Bacillus cereus
• Can be used to transform resveratrol into
• Piceid (resveratrol 3-O-beta-D-glucoside) [1]

Dávkování

• The lower end of supplementation
• 5-10mg daily
• Otherwise healthy
• 150-445 mg have been used
• With no clear indication for what is the optimal dose

• For cerebral blood flow
• Dose in the 250-500mg/d range

• For aromatase inhibition
• 500mg /d

• Refers to trans-resveratrol exclusively [2]

History

• 1. mention of resveratrol in a Japanese article in 1939
• Michio Takaoka
• Isolated it from Veratrum album
• Variety grandiflorum
• 1963 isol. from the roots of Japanese knotweed [1]

Interakce

Interakce vhodné

• Synergické působení na stimulaci imunity s betaglukany a vit. C
• Combination of glucan, resveratrol and vitamin C demonstrates strong anti-tumor potential.
• ß-Glucans powerful immunomodulators
• Additional bioactive molecules have synergistic effects with glucan
• Anticancer properties of glucan, resveratrol, vitamin C combination
• Combination was the strongest activator of phagocytosis and antibody formation
• Strongly suppressed the growth of breast and lung tumors
• Most likely due to the stimulation of apoptosis [4]

Metabolismus resveratrolu

• Extensively metabolized in the body
• Liver and lungs as the major sites [1]

Resveratrol

Synonyma

• Trans-3,5,4'-Trihydroxystilbene;
• 3,4',5-Stilbenetriol;
• 3,5,4'-trihydroxy-trans-stilbene
• Trans-Resveratrol;

(E)-5-(p-Hydroxystyryl)resorcinol;(E)-5-(4-hydroxystyryl)benzene-1,3-diol [1]

Zařazení

• Stilbenoid
• Derivative of stilbene
• Type of natural phenol
• Phytoalexin [1]

Chemické formy

• Two geometric isomers: cis- (Z) and trans- (E)
• Free or bound to glucose [1]

Trans- form

• Can undergo isomerization to the cis- form
• When exposed to ultraviolet irradiation
• Photoisomerization [1]

• Ultraviolet irradiation to cis-resveratrol
• Induces further photochemical reaction
• Fluorescent molecule named "Resveratrone" [1]

• Trans-resveratrol in the powder
• Stable under "accelerated stability" conditions
• 75% humidity
• 40 °C
• In the presence of air [1]

• Trans isomer is also stabilized
• By the presence of transport proteins

• Stable after fermentation and stored for a long period in the
• Skins of grapes
• Pomace [1]

Related compounds

• Dihydro-resveratrol different resveratrol dimers
• Epsilon-viniferin
• Pallidol
• Quadrangularin A
• Trans-diptoindonesin B
• Resveratrol trimer
• Hopeaphenol
• Resveratrol tetramer
• Oxyresveratrol
• Aglycone of mulberroside A
• In Morus alba, the white mulberry [1]
• Piceatannol
• Active metabolite of resveratrol found in red wine
• Piceid
• Resveratrol glucoside
• Pterostilbene
• Doubly methylated resveratrol
• 4'-Methoxy-(E)-resveratrol 3-O-rutinoside
• In the stem bark of Boswellia dalzielii [1]

Dietary supplements

• No studies to show that resveratrol supplements are beneficial in humans [1]
• Sales of resveratrol supplements increased in 2006 after studies on non-humans [1]
• Harvard University scientist and professor David Sinclair
• Co-founded Sirtris Pharmaceuticals
• Initial product of which was a resveratrol formulation
• Sinclair became known for making statements about resveratrol like
• “(It's) as close to a miraculous molecule as you can find....
• One hundred years from now, people will maybe be taking these molecules on a daily basis to prevent heart disease, stroke, and cancer.” [1]
• Most of the anti-aging field was more cautious
• What else resveratrol might do in the body
• Its lack of bioavailability [1]
• Supplements vary in purity
• Can contain anywhere from 50 - 99 % resveratrol [1]

Nežádoucí účinky

• 2010, GlaxoSmithKline small clinical trial of SRT501 - proprietary form of resveratrol
• Terminated the study later that year
• Microparticles (< 5 µm) intended to enhance absorption
• Dose 5 grams per day
• Gastrointestinal disorders and
• Diarrhea in many subjects

• Clinical study of Alzheimer's disease
• Well-tolerated
• Side effects from daily intake of up to 2 grams
• Nausea, diarrhea
• Weight loss [1]

Studie

Prodloužení života

• 2011 no good evidence that consuming resveratrol affects life expectancy or human health [1]

Kardiovaskulární choroby

• No evidence of benefit from resveratrol in those who already have heart disease [1]
• 2014 Chinese meta-analysis found weak evidence that high-dose resveratrol supplementation could reduce systolic blood pressure.[1]

Cancer

• 2016 - no evidence of an effect of resveratrol on cancer in humans [1]
• 2014 - results of studies on laboratory animals or human clinical trials concerning the effects of resveratrol on cancer
• Inconsistent, even if massive doses [1]

Metabolism

• No conclusive human evidence for an effect of resveratrol on metabolism.[1]

Neurological studies

• One-year clinical trial of subjects with Alzheimer's disease
• 2 grams of resveratrol daily
• Well-tolerated
• Reduced some disease biomarkers in cerebrospinal fluid and blood
• Other biomarkers and progressive dementia were unaffected
• Other preliminary human studies short-term ingestion of resveratrol
• Increased cerebral blood flow in normal subjects and in people with diabetes [1]
• Under study for its potential to limit secondary damage after ischemic stroke or acute brain trauma [1]

Antidiabetic studies

• In vitro, resveratrol was shown to act as an agonist of Peroxisome proliferator-activated receptor gamma
• A nuclear receptor under pharmacological research as a potential treatment for type 2 diabetes
• One systematic review and meta-analysis
• Resveratrol is a "leading candidate" compound for serving as an adjunct pharmacotherapy for type 2 diabetes
• There is little evidence for its use as a possible treatment for diabetes [1]

Skin

• No evidence that resveratrol taken orally or topically has any effect on human skin [1]

Účinky resveratrolu

• Resveratrol activates sirtuin 1[1]
• Aktivates PGC-1alfa
• Ovlivňuje functioning of mitochondria [1 ]

• Cells treated with resveratrol
• Increase in the action of MnSOD (SOD2)
• Increase in GPER activity [1]

• Less effective than the antioxidants quercetin and epicatechin found in red wine [3]

• Reduced platelet aggregation
• Could contribute to prevention of atherosclerosis [3]

• Can affect the initiation, promotion, and progression of cancer

• Some of the same effects as calorie-restricted diets
• Reduced the incidence of age-related diseases in animals [3]

• GlaxoSmithKline acquired Sirtris for $720 million in 2008
• Hopes to develop drugs that target the sirtuins
• Group of enzymes associated with the aging process [3]

Research Misconduct

• 2012, the University of Connecticut
• Dipak K. Das, Ph.D., a professor in its Department of Surgery and director of the Cardiovascular Research Center
• Guilty of 145 counts of fabrication and falsification of data
• University had notified 11 journals about this problem
• Das had gained attention for his reports on allegedly beneficial properties of resveratrol
• 2014, journals had retracted 20 of his papers
• Many of which were repeatedly cited by others
• Das died in 2013 [3]

• Although laboratory tests have demonstrated that resveratrol might help
• There are several reasons why a population-wide increase would be premature.
• Research on resveratrol has focused on
• Its short-term effects
• Dominated by in vitro (laboratory) studies
• On non-human models
• Not enough is known about the
• Absorption and clearance of resveratrol
• Identities of its metabolic products
• Its effects on the liver [3]

• Resveratrol's role as a potentiator of breast carcinomas may significantly limit its use.
• Taking resveratrol pills is certainly safer than heavy wine consumption
• Supplementing with unproven substances is generally unwise
• Epidemiologic studies can find associations between the consumption of foods or dietary supplements and various health outcomes
• Only human clinical trials can determine whether supplementation is useful for humans
• Most clinical trials of other antioxidants have failed to demonstrate the benefits suggested by preliminary studies
• Some substances—most notably beta-carotene—have even produced adverse effects [3]
• Prior to 2010, resveratrol had not been tested in clinical trials
• Since that time some, most of which were small, short-term (a year of less)
• Designed to evaluate possible therapeutic effects rather than disease-preventive effects [3]

Sources of resveratrol

• Produced by several plants
• In response to
• Injury
• Cutting
• Crushing
• Ultraviolet radiation [1]
• Bacteria or fungi [1]
• Knotweeds
• Pine trees
• Scots pine
• Eastern white pine
• Grape vines
• Peanut plants
• Cocoa bushes
• Vaccinium shrubs that produce berries
• Blueberries, raspberries, mulberries, cranberries, and bilberries
• ++ in the skin [1]

• Eucalyptus
• Spruce
• Lily
• Mulberries and peanuts
• Vitis vinifera
• Labrusca, and muscadine grapes
• In the vines, roots, seeds, and stalks
• Highest concentration is in the skin
• 50-100 ug/g suché hmoty

• Class of antibiotic compounds produced as a part of a plant's defense system against disease
• P-coumaroyl CoA
• Malonyl CoA

• Fungal infections are more common in cooler climates
• Higher concentration [1]

• Grape juice
• Not a fermented beverage
• Not a significant source of resveratrol
• Wine is the most notable dietary source
• Presence of resveratrol in the human diet is almost negligible [1]

Obsahy resveratrolu ve vínech

• In a 2007 review of published resveratrol concentrations
• Average in red wines is 1.9±1.7 mg trans-resveratrol/L
• 8.2±7.5 µM
• From nondetectable levels to 14.3 mg/l (62.7 µM) trans-resveratrol
• Cis-resveratrol - same trend as trans-resveratrol [1]
• Wines made from grapes with highest level of trans-resveratrol:
• Pinot Noir
• St. Laurent varieties
• No wine or region can yet be said to produce wines with significantly higher concentrations than any other wine or region

• Champagne and vinegar
• Also contain appreciable levels of resveratrol [1]

• Red wine
• 0.2 and 5.8 mg/l - the grape variety [1]

• White wine
• Much less
• Because red wine is fermented with the skins
• Allowing the wine to extract the resveratrol [1]

• Extraction of resveratrol from grapes
• Depends on duration of the skin contact
• Resveratrol 3-glucosides are in part hydrolysed
• Both trans- and cis-resveratrol [1]

Obsahy resveratrolu v jídle

• Peanuts have about 25% as much resveratrol as red wine
• 2.3 - 4.5 ug/g - before sprouting
• 11.7 - 25.7 ug/g - after sprouting dle druhu [1]
• Mulberries
• Especially the skin
• 50 ug of resveratrol /g suché váhy [1]

Zpracování

Literatura:

[1] en.wikipedia.org/wiki/Resveratrol
[2] examine.com/supplements/resveratrol/
[3] www.quackwatch.org/01QuackeryRelatedTopics/DSH/resveratrol.html
[4] www.ncbi.nlm.nih.gov/pubmed/22213291
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====

:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====

:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====

:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====

:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====

:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====
:::: ====