Presentation on theme: "The Science of Resveratrol"— Presentation transcript:
1 The Science of Resveratrol Mark Lange, Ph. D.Market AmericaDirector of Quality Control
2 Important StatementThis presentation is on the latest research in the areas of longevity, cancer, and heart disease.Claims are not being made to treat disease or health conditions with dietary supplements.This research is in its infancy; please refrain from drawing conclusions based on preliminary data.
3 Berry and Fruit Extracts to be Discussed Resveravine® – whole grape extract containing resveratrolBioVin® Advanced – grape skin extract containing OPCs, anthocyanins, and resveratrolVita Blue® – wild blueberry extract containing anthocyanins
4 Resveravine®A natural extract from grape combining the synergistic biological effects of trans-resveratrol and -viniferinA standardized extract with 20% total trans-resveratrol and -viniferinThe most concentrated source of Resveratrol
5 infection and oxidative stress due to external attacks. Resveratrol is naturally produced by plants as a defense system againstinfection and oxidative stress due to external attacks.UVFungiCopperOzonetimeResveratrol level
6 Sources of Resveratrol Resveratrol is found inGrapes (only in skin)WineGrape JuicePeanutsBlueberriesBilberriesCranberries
7 Benefits of Resveratrol Induces apoptosis (programmed cell death) in unhealthy cellsPromotes normal nuclear factor kappa B and cyclooxygenase-2 activityPromotes normal activity of the SIRT-1 gene (involved in calorie restriction, fat mobilization, mitochondrial function, longevity)Promotes cardiovascular healthNormal platelet activityNormal vasorelaxationAntioxidant protection of LDL particlesPossibly Fights Obesity and Diabetes
8 ApoptosisApoptosis is programmed cell death. The lifespan of cells have genetic limitations. The apoptotic process safely disposes of old cells and cell fragments and does not trigger inflammation.
9 Microscope View of Apoptosis A. Unfertilized embryonic cell receives a biochemical signal to die.B. Cell starts to shrink as activated enzymes cut up the cytoskeleton and DNA in the nucleus.C. Cell prepares itself to be engulfed by macrophages.D. Cell fragments into blobs.
10 Apoptosis is a Normal Process Rapid turnover of white blood cells in the bodyRemodeling of the developing fetus (fingers and toes)Formation of connections (synapses) between neurons in the brainMenstruation – sloughing of the uterine lining
11 Apoptosis in Cancer Cells Unlike normal cells, cancer cells proliferate rapidly and lose the ability to respond to cell death signals and apoptosis. Resveratrol has been found to inhibit proliferation and induce apoptosis in a number of cancer cell lines.Aggarwal BB, Bhardwaj A, Aggarwal RS, Seeram NP, Shishodia S, Takada Y. Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res. 2004;24(5A):The growth of cancer cells is unchecked.
12 Importance of Apoptosis Defective cell cycle regulation may result in the propagation of mutations that contribute to the development of cancer. Resveratrol has been found to induce cell cycle arrest when added to cancer cells grown in culture.Joe AK, Liu H, Suzui M, Vural ME, Xiao D, Weinstein IB. Resveratrol induces growth inhibition, S-phase arrest, apoptosis, and changes in biomarker expression in several human cancer cell lines. Clin Cancer Res. 2002;8(3):Cancer is caused by genetic mutations.Sometimes the mutations are inherited and there is a predisposition to cancer.But most of the time, the mutations slowly accumulate over time. Cancer is caused by multiple genetic mutations.Resveratrol tells cells with genetic mutations to shut down and die, thus preventing cancer from developing.
13 Resveratrol ResearchResveratrol caused significant cytotoxicity and increased apoptosis in malignant hemorrhagic tumors.Resveratrol blocks the multi-step process of carcinogenesis at various stages: suppressing tumor initiation, promotion and progression.Resveratrol shown to delay development and reduce the metastasizing capacity of spontaneous mammary tumors in mice due to apoptosis.Resveratrol supresses tumor development and its progression. In other words, it stops cancer in its tracks.
14 NIH Resveratrol StudyNational Institutes of Health is currently sponsoring a Phase I Study of Resveratrol in Patients With Surgically Removable Colorectal Cancer
15 Increased frequency of apoptosis in two tumor cell lines induced by polyphenolic extracts Cells death rate (%)(Japanese knotweed)
16 Nuclear factor-kappa B is a protein involved in cellular responses to stress (free radicals, UV light, and bacterial or viral attack).NF-κB plays a key role in regulating the immune response to infection.Incorrect regulation of NF-κB has been linked to cancer, inflammatory and viral infection.Rheumatoid arthritis and bronchial asthma.
17 Resveratrol and NF-kBResveratrol was shown to be a potent inhibitor of NF-kB by blocking IkB kinase activityCancer Research. 60: , 2000.This study examined the anti-inflammatory effects of resveratrol on human airway epithelial cells, resveratrol inhibited NF-kBAm J Physiol Lung Cell Mol Physiol,Resveratrol has been shown to promote normal NF-kB activity in several studies.Polish Journal of Pharmacology. 53(6):557-69, 2001.
18 Resveratrol Inflammation Research Cyclooxygenase (COX) – Blocking this enzyme impedes the production of the chemical messengers (prostaglandins) that cause pain and swelling from inflammation.Suppression of COX-2 expression by blocking the activation of MAPKs and AP-1 may represent possible molecular mechanisms responsible for previously reported anti-tumor promoting effects of resveratrol on mouse skin carcinogenesis.Biofactors. 21(1-4):33-39, 2004.Study concluded in addition to other effects on gene expression, resveratrol also directly inhibited the activity of COX-2.J Biol Chem. 273(34): , 1998.
19 Non-Steroidal Anti-Inflammatory Drugs Commonly prescribed for rheumatoid arthritis and osteoarthritis.Sept. 30, 2004: Vioxx recalled due to sudden heart attacks, strokes, and blood clots.
20 Resveratrol for Cardiovascular Support Healthy Platelet ActivityStudy reported a dose-dependent inhibition of platelet aggregation (blood clotting) by resveratrol.Clin Chim Acta. 235: , 1995.Rodent study demonstrated that resveratrol protects the heart and improves heart functions after diminished blood flow, affecting developed pressure and arterial flow.Journal of Cardiovascular Pharmacology. 35(2): , 2000.Shown to inhibit platelet aggregation both in vitro and in vivoInternational Journal of Molecular Medicine. 9:77-9, 2002.Platelets are particles circulating in the blood that are necessary for blood clots to form.Blood clotting is important because it stops us from bleeding when we get cut.However, if a blood clot forms inside an artery, it blocks the flow of blood to the tissue that the artery supplies, and that can damage the tissue.For example, a blood clot in a coronary artery causes a heart attack and a blood clot that forms in an artery supplying blood to the brain causes a stroke.
21 Resveratrol Inhibits Platelet Aggregation Platelet aggregation is one of the first steps in the formation of a blood clot that can occlude a coronary or cerebral artery, resulting in myocardial infarction or stroke. Resveratrol has been found to inhibit platelet aggregation in vitro.Blood Cells Mol Dis. 2000;26(2):Clin Chim Acta. 1995;235(2):
22 Resveratrol stimulates eNOS eNOS is an enzyme that catalyzes the formation of nitric oxide (NO) by vascular endothelial cells. NO is needed to maintain arterial relaxation (vasodilation), and impaired NO-dependent vasodilation is associated with increased risk of cardiovascular disease. Resveratrol has been found to stimulate eNOS activity in cultured endothelial cells.Circulation. 2002;106(13):The endothelium is a single layer of cells which line the internal wall of blood vessels. It enables blood to flow smoothly inside the blood vessels.The endothelium has many different biological actions, but the one we’re focusing on is controlling blood pressure.Nitroglycerine patches or taking pills?
23 A study of mechanisms involved in vasodilation by Resveratrol ControlE-NOS Inhibitor (L-NNA)Endothelium RemovedEndothelium IntactArterial Relaxation (%)1551050100Red Wine Extract Concentration (μM)100806040201550100Li etal. A Study of Mechanisms Involved in Vasodilation Induced by Resveratrol in Isolated Porcine Coronary Artery. Physiol. Res. 55:365-72, 2006.
24 Cardiovascular Support Antioxidant protection of LDL particlesResveratrol was shown to protect LDL by scavenging free radicals and chelating copperFremont L et al. Antioxidant activity of resveratrol and alcohol-free wine polyphenols related to LDL oxidation and polyunsaturated fatty acids. 64(26): , 1999.Belguendouz, L., et al. Resveratrol inhibits metal ion-dependent and independent peroxidation of porcine low-density lipoproteins. Biochem Pharmacol. 53(9): , 1997.Low-density Lipoprotein Particle (LDL)
25 Resveravine protects LDL from oxidation better than synthetic resveratrol, catechin and vitamin E
26 Caloric RestrictionCaloric restriction is reducing caloric intake without malnutrition.Proven method for extending life span (30-50%) and postponing age-related functional decline and age-related disease.
27 Resveratrol Research in Extending Life Span Restricting calorie intake extends the life spans of organisms ranging from yeast cells to lab animals.Sirtuins enhance cell survival during times of stress, especially lack of food.Sirtuins are regulators of aging in virtually all living organisms.Resveratrol activates sirtuin activity without the extreme difficulty of starving oneself!
28 Sirtuins Help Cells Survive Sirtuins help rejuvenate old or dying cells by beefing up their DNA repair process and stimulating production of protective antioxidants.If a cell is at a point of deciding whether to live or die, Sirtuins push toward the survival mode by making the cell fix itself.
29 Studies Backing Resveratrol’s Activation of Sirtuins Tests on Nothobranchius furzeri, a short-lived seasonal fishResveratrol extended the maximum life span by 59% and extended the median lifespan by 56%Study also showed resveratrol supplementation improved swimming performance and delayed motor and cognitive age-related declineTrends in Pharmacological Sciences 26, 2005.Current Biology, 2006.Obese mice supplemented with resveratrol lived an average of 15% longer than obese mice not given resveratrolNature, 2006.
30 Studies Backing Resveratrol’s Activation of Sirtuins Saccharomyces cerevisiae (yeast), resveratrol mimics calorie restriction by stimulating Sir2, increasing DNA stability and extending lifespan by 70%.Howitz, K. T., et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. NatureDrosophila melanogaster, resveratrol identified as being beneficial and shown to extend lifespan under normal laboratory conditionsBauer, J. H., et al. An accelerated assay for the identification of lifespan-extending interventions in Drosophila melanogaster. Proc Natl Acad Sci U S A. 101: , 2004.
31 Resveratrol is a Superior Antioxidant Oxidative stress is implicated in numerous disease processesA lead resveratrol investigator, Dr. Milos Sovak commented, “There is no question that resveratrol is one of the best free-radical scavengers and that it has many effects whose ramifications might affect not only longevity but also general health.”
32 Resveratrol as an Antioxidant In vitro studies revealed that red wine extract is a potent antioxidant as evidenced by its ability to scavenge peroxyl radical in vitro.Sato M et al. Myocardial protection with red wine extract. J Cardiovasc Pharmacol.35(2):263-8, 2000.Olas et al demonstrated that resveratrol inhibits the production of several different reactive oxygen species (O2.-, H2O2, singlet oxygen and organic radicals in pig blood plateletsOlas B et al. Resveratrol may reduce oxidative stress induced by platinum compounds in human plasma, blood platelets and lymphocytes. Anticancer Drugs. 16(6):659-65, 2005.Resveratrol’s antioxidant capability has been demonstrated in numerous studies. READ SLIDE.
33 Protection against oxidative stress Influence of three related polyphenols on the oxidative stress of lymphocytes infected by the Epstein-Barr virus (EBV)Peroxidation rate (%)
34 Resveratrol Might Fight Obesity June 16th. Google: “Martin Wabitsch endo08 webcast”Human fat cells exposed to resveratrol or not exposed (control).Number of fat cells in control doubled. Number of fat cells exposed to resveratrol decreased by 50%.
35 Resveratrol Might Fight Obesity In addition, exposure to resveratrol also reduced the secretion of substances called interleukin 6 and 8, which may be linked to the development of diabetes and clogged arteries, both thought to be obesity-related problems.
36 Safety of ResveratrolData in humans have revealed that resveratrol is safe to ingest.Aggarwal B et al. Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res. 24(5A): , 2004.Human trials on Resveravine®Single oral doses of 1, 2.5 and 5 grams were given to 29 volunteers, and no serious adverse events were reported.
37 Possible Herb-Drug Interactions Resveratrol has been found to inhibit human platelet aggregation in vitro. Theoretically, high intakes of resveratrol (e.g., from supplements) could increase the risk of bleeding when taken with anticoagulant drugs, such as warfarin (Coumadin), and antiplatelet drugs, such as clopidogrel (Plavix), dipyridamole (Persantine), non-steroidal anti-inflamatory drugs (NSAIDs), aspirin and others.
38 As mentioned, Resveravine also provides -Viniferin, which is a dimer of Resveratrol : Naturally synthesized by the plant, it is involved in the defense system against various fungi such as Botrytis cinerea .It is naturally present in the grapes and wineLike Resveratrol, -Viniferin has also very interesting biological properties:anti-inflammatoryantioxidant effects
39 BioVin® AdvancedBioVin Advanced is a French red wine extract, offering a full 5% of pure resveratrolMade exclusively from French red wine grapes, naturally high in resveratrolContains red wine polyphenols and trans-resveratrolLet’s move on to another berrry extract—this one called BioVin® Advanced. READ SLIDE. It’s still being isolated from French red grapes like Resveravine®, but in this extract contains oligomeric proanthocyanidins (OPCs), anthocyanins, other phenolic acids and 5% naturally occurring resveratrol. Here we are looking at the possibility of more beneficial interactions among these compounds.
40 BioVin® Advanced vs. Wine Amount of Resveratrol in 200mg BioVin® AdvancedAmount required to be equivalent to 200 mg BioVin® AdvancedRed WineWhite Wine10 mg10 glasses (1500 ml)40 glasses (6000 ml)
41 Benefits of BioVin® Advanced Due to the synergistic blend of OPCs and resveratrol,BioVin Advanced offers numerous health advantagesCardiovascular healthImproves blood circulationStrengthens blood vesselsDecreases platelet aggregationCellular health (as described earlier for Resveratrol)Induces apoptosis, involvement in SIRT-1 activity, involvement in nuclear factor-kappa B and cyclooxygenase-2 activityVision healthExcellent antioxidant capabilitiesSkin health
42 VitaBlue™ Wild Blueberry Extract Through a unique proprietary process, VitaBlue™ extract has concentrated the phytochemicals of the blueberry into an extract of unmatched purity, anthocyanin content and antioxidant potency.Only the finest, ripest North American wild blueberries qualify to be used in this patented extract.12.5% Anthocyanins, 40% Polyphenolics, 6500 ORAC units, including pterostilbene.We move on to another potent berry extract, called Vita Blue™ Blueberry Extract , which concentrates anthocyanins, other polyphenolic acids, and another interesting compound pterostilbene—a close chemical cousin of resveratrol.
43 ORAC of Selected Foods 2007 U.S. Department of Agriculture Cranberry Blueberry Plum Blackberry Raspberry Strawberry Cherry Apple Pear 2941
44 Benefits of Blueberries Blueberries have been shown to be beneficial in several applicationsProvides 30 anthocyanins and pterostilbenePowerful antioxidantInhibits cellular proliferation and induces apoptosis (programmed cell death in unhealthy cells)Promotes cardiovascular healthContains COX-2 inhibitorsPromotes healthy vision
45 Blueberries and Cell Health The following review summarizes current knowledge on the various molecular evidences of cancer chemoprevention by anthocyanins including 1) antioxidant activity 2) the molecular mechanisms involved in anti-carcinogenesis 3) the molecular mechanisms involved in the induction of apoptosis in tumor cells.Hou D et al. Potential mechanisms of cancer chemoprevention by anthocyanins. Curr Mol Med. 3(2): , 2003.In this study, blueberry exhibited potential anti-carcinogenic activity as evaluated by in vitro screening tests.Bomser, J., et al. In vitro anticancer activity of fruit extracts from Vaccinium species. Planta Medica. 62(3): , 1996.
46 Hypoxia-Inducible Factor (HIF) – Why Antioxidants May Help to Prevent Cancer NORMAL CONDITIONSOXYGENHypoxiaOXYGENNat Rev Cancer Oct;3(10):721-32
47 HIF Helps Cells Survive, But Free Radicals Must Be Present HypoxiaOXYGENFREE RADICALS"HIF-1 helps an oxygen- starved cell convert sugar to energy without using oxygen and also initiates the construction of new blood vessels to bring in a fresh oxygen supply."
48 Cancer Cells Consume All The Oxygen Around Them HypoxiaOXYGENOXYGEN
49 But HIF Can’t Help the Cancer Cells Survive When Antioxidants Have Neutralized All The Free Radicals.AntioxidantsHypoxiaOXYGENFREE RADICALSHIF
50 And the Cancer Cells Die…. HypoxiaOXYGENAntioxidants
52 Conclusions about Berry Extracts and Cell Health The active chemicals in selected berries have shown promise in maintaining cardiovascular, immune, and visual health, as well as lengthening life span and using fat stores more efficiently in experimental animal models.The active chemicals are more than potent antioxidants – they interact with key enzymes and signaling pathways in cells.Research is ongoing. More to come….READ SLIDE