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RESVERATROL UnFranchise Training

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RESVERATROL UnFranchise Training Powered By Docstoc
					   The Science of
    Resveratrol
Mark Lange, Ph. D.
Market America
Director of Quality Control
             Important Statement

   This 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.
    Berry and Fruit Extracts to be Discussed


   Resveravine® – whole grape extract containing
    resveratrol

   BioVin® Advanced – grape skin extract
    containing OPCs, anthocyanins, and resveratrol

   Vita Blue® – wild blueberry extract containing
    anthocyanins
                   Resveravine®

   A natural extract from grape combining the
    synergistic biological effects of trans-resveratrol and -
    viniferin

   A standardized extract with 20% total trans-
    resveratrol and  -viniferin

   The most concentrated source of Resveratrol
               Resveratrol is naturally produced by
               plants as a defense system against
               infection and oxidative stress due to
               external attacks.




         Resveratrol
   UV       level

 Fungi
Copper
Ozone
                       time
            Sources of Resveratrol

   Resveratrol is found in
     Grapes (only in skin)

     Wine

     Grape Juice

     Peanuts

     Blueberries

     Bilberries

     Cranberries
              Benefits of Resveratrol
   Induces apoptosis                 Promotes cardiovascular
    (programmed cell death) in         health
    unhealthy cells                     Normal platelet activity

                                        Normal vasorelaxation
   Promotes normal nuclear             Antioxidant protection of LDL
    factor kappa B and                   particles
    cyclooxygenase-2 activity
                                      Possibly Fights Obesity and
   Promotes normal activity of        Diabetes
    the SIRT-1 gene (involved in
    calorie restriction, fat
    mobilization, mitochondrial
    function, longevity)
    Apoptosis


   Apoptosis 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.
 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.
       Apoptosis is a Normal Process


   Rapid turnover of white blood cells in the body
   Remodeling of the developing fetus (fingers and
    toes)
   Formation of connections (synapses) between
    neurons in the brain
   Menstruation – sloughing of the uterine lining
           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):2783-2840.
            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):893-903.
               Resveratrol Research
   Resveratrol 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.
            NIH Resveratrol Study



   National Institutes of Health is currently
    sponsoring a Phase I Study of Resveratrol in
    Patients With Surgically Removable Colorectal
    Cancer
          Increased frequency of apoptosis in two tumor cell
          lines induced by polyphenolic extracts


                       70
                                  Caco-2                    control                              80
                       60
                                                                                                                U937
                                                                                                 70
Cells death rate (%)




                       50                                                                        60
                                                            resveratrol




                                                                          Cells death rate (%)
                       40                                                                        50
                                                                                                 40
                       30                                   resveravine
                                                                                                 30
                       20
                                                                                                 20
                       10                                   Poligonum
                                                            cuspidatum                           10
                       0                                    extract                               0
                            0,1   1            3     10
                                      µg/ml                                                           0,1   1            3   10
                                                                                                                 µg/ml




                                              (Japanese knotweed)
           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.
             Resveratrol and NF-kB
   Resveratrol was shown to be a potent inhibitor of NF-kB by blocking
    IkB kinase activity
       Cancer Research. 60:3477-3483, 2000.

   This study examined the anti-inflammatory effects of resveratrol on
    human airway epithelial cells, resveratrol inhibited NF-kB
       Am J Physiol Lung Cell Mol Physiol, 2004 .


   Resveratrol has been shown to promote normal NF-kB activity in
    several studies.
       Cancer Research. 60:3477-3483, 2000.
       Polish Journal of Pharmacology. 53(6):557-69, 2001.
    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):21875-21882, 1998.
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.
    Resveratrol for Cardiovascular Support

   Healthy Platelet Activity

       Study reported a dose-dependent inhibition of platelet aggregation
        (blood clotting) by resveratrol.
           Clin Chim Acta. 235:207-219, 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):263-268, 2000.

       Shown to inhibit platelet aggregation both in vitro and in vivo
           International Journal of Molecular Medicine. 9:77-9, 2002.
           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):144-150.
   Clin Chim Acta. 1995;235(2):207-219.
      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):1652-1658.
   A study of mechanisms involved in
   vasodilation by Resveratrol
                                     100
                  100
                                                                                      Endothelium
       Arterial Relaxation (%)




                                                                                      Intact
                                      80
                        80

                                      60
                        60                                                                          Endothelium
                                                                                                     Removed
                                      40
                        40                                                      E-NOS
                                                                               Inhibitor
                                      20                                       (L-NNA)
                        20
                                                                                                  Control
                                       0
                                 0             1           5           10                50                 100
                                           1           5   5             50        100
                                                   Red Wine Extract Concentration (μM)
                                                                     10


Li etal. A Study of Mechanisms Involved in Vasodilation Induced by Resveratrol in Isolated Porcine Coronary Artery. Physiol. Res. 55:365-72, 2006.
Cardiovascular Support
   Antioxidant protection of LDL particles
       Resveratrol was shown to protect LDL by scavenging free radicals and
        chelating copper
           Fremont L et al. Antioxidant activity of resveratrol and alcohol-free wine polyphenols
            related to LDL oxidation and polyunsaturated fatty acids. 64(26):2511-21, 1999.
           Belguendouz, L., et al. Resveratrol inhibits metal ion-dependent and independent
            peroxidation of porcine low-density lipoproteins. Biochem Pharmacol. 53(9):1347-1355,
            1997.




                                                                      Low-density
                                                                      Lipoprotein Particle
                                                                      (LDL)
Resveravine protects LDL from oxidation better
than synthetic resveratrol, catechin
and vitamin E
     Tlag (min)
        500
                                      control
        400
                                      vitamin E
        300

                                      catechin
        200

        100                           resveratrol

          0                           resveravine
               Caloric Restriction

   Caloric 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.
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!
         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.
        Studies Backing Resveratrol’s
            Activation of Sirtuins
   Tests on Nothobranchius furzeri, a short-lived seasonal fish
     Resveratrol 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 decline
       Trends in Pharmacological Sciences 26, 2005.

       Current Biology, 2006.

    Obese mice supplemented with resveratrol lived an average of
      15% longer than obese mice not given resveratrol
       Nature, 2006.
        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. Nature. 2003.

   Drosophila melanogaster, resveratrol identified as being
    beneficial and shown to extend lifespan under normal laboratory
    conditions
       Bauer, J. H., et al. An accelerated assay for the
        identification of lifespan-extending interventions in
        Drosophila melanogaster. Proc Natl Acad Sci U S A.
        101:12980-12985, 2004.
Resveratrol is a Superior Antioxidant

   Oxidative stress is implicated in numerous disease processes

   A 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.”
    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 platelets
          Olas 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.
Protection against oxidative stress

                             120
     Peroxidation rate (%)

                             100                                 Resveratrol

                             80
                                                                 Resveravine
                             60
                             40
                                                                 Polygonum
                             20                                  cuspidatum
                                                                 extract
                              0
                                   0        5               10
                                       concentration (µg)

    Influence of three related polyphenols on the oxidative stress of
          lymphocytes infected by the Epstein-Barr virus (EBV)
    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%.
    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.
                Safety of Resveratrol

   Data 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):2783-840, 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.
      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.
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
                    wine

                     Like Resveratrol,  -Viniferin has also very
                     interesting biological properties:

                            • anti-inflammatory
                            • antioxidant effects
BioVin®       Advanced

   BioVin Advanced is a French red wine extract,
    offering a full 5% of pure resveratrol

   Made exclusively from French red wine grapes,
    naturally high in resveratrol

   Contains red wine polyphenols and trans-resveratrol
BioVin® Advanced vs. Wine


                 Amount required to be
                  equivalent to 200 mg
  Amount of
                   BioVin® Advanced
Resveratrol in
200mg BioVin®
  Advanced
                   Red Wine    White Wine

                  10 glasses   40 glasses
     10 mg         (1500 ml)    (6000 ml)
 Benefits of BioVin® Advanced

Due to the synergistic blend of OPCs and resveratrol,
BioVin Advanced offers numerous health advantages
     Cardiovascular health
         Improves blood circulation
         Strengthens blood vessels
         Decreases platelet aggregation
     Cellular health (as described earlier for Resveratrol)
         Induces apoptosis, involvement in SIRT-1 activity, involvement in
          nuclear factor-kappa B and cyclooxygenase-2 activity
     Vision health
     Excellent antioxidant capabilities
     Skin health
    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.
ORAC of Selected Foods
2007 U.S. Department of Agriculture

Cranberry 9584
Blueberry 6552
Plum 6259
Blackberry 5347
Raspberry 4882
Strawberry 3577
Cherry 3365
Apple 3082
Pear 2941
Benefits of Blueberries


       Blueberries have been shown to be beneficial in several
        applications

         Provides 30 anthocyanins and pterostilbene
         Powerful antioxidant
         Inhibits cellular proliferation and induces apoptosis
          (programmed cell death in unhealthy cells)
         Promotes cardiovascular health
         Contains COX-2 inhibitors
         Promotes healthy vision
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):149-159, 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):212-216, 1996.
 Hypoxia-Inducible Factor (HIF) – Why
Antioxidants May Help to Prevent Cancer



 NORMAL                                 OXYGEN
CONDITIONS




Hypoxia                                 OXYGEN




Nat Rev Cancer. 2003 Oct;3(10):721-32
HIF Helps Cells Survive, But Free
   Radicals Must Be Present



 Hypoxia                    HIF             OXYGEN




                                       FREE 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."
Cancer Cells Consume All The Oxygen
            Around Them

   Hypoxia             OXYGEN



OXYGEN
 But HIF Can’t Help the Cancer Cells Survive When
Antioxidants Have Neutralized All The Free Radicals.

                                             Antioxidants

    Hypoxia                        OXYGEN



                                       FREE RADICALS




               HIF
 And the Cancer Cells Die….


Hypoxia             OXYGEN



                      Antioxidants
Grape Extract                                            Resveratrol



                          Cells               Longevity,
                                              Obesity?,
          Skin                                Diabetes?

                          Heart,
                        Antioxidants

                 Eyes                   Apoptosis,
                                       Inflammation




                                                      Blueberries
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….

				
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