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WO2009039195A1 - Compositions contenant du resvératrol destinées à moduler la concentration ou l'activité d'un produit génique - Google Patents

Compositions contenant du resvératrol destinées à moduler la concentration ou l'activité d'un produit génique Download PDF

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Publication number
WO2009039195A1
WO2009039195A1 PCT/US2008/076707 US2008076707W WO2009039195A1 WO 2009039195 A1 WO2009039195 A1 WO 2009039195A1 US 2008076707 W US2008076707 W US 2008076707W WO 2009039195 A1 WO2009039195 A1 WO 2009039195A1
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lgx
res
resveratrol
containing composition
gene
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PCT/US2008/076707
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English (en)
Inventor
William F. Sardi
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Resveratrol Partners, Llc
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Priority to CA2699908A priority Critical patent/CA2699908C/fr
Priority to EP08831905A priority patent/EP2197434A4/fr
Priority to JP2010525922A priority patent/JP2010540444A/ja
Publication of WO2009039195A1 publication Critical patent/WO2009039195A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a resveratrol-containing composition capable of modulating gene expression to an extent greater than that observed with resveratrol alone or with calorie restriction.
  • the invention particularly pertains to such resveratrol-containing compositions that comprise resveratrol, a chelator, hyaluronic acid, and/or vitamin D and which, upon administration to a recipient, increases the concentration or activity of a survival/longevity gene product and/or decreases the concentration or activity of a gene product that induces or causes cellular damage.
  • the invention particularly relates to the use of such compositions in the treatment or prevention of cancer, cardiovascular disease, diseases associated with aging, and other conditions and illnesses.
  • Resveratrol (3,4',5-trihydroxy-?r ⁇ «,y-stilbene) is a naturally occurring phenolic compound found, for example in grape skins, that has been demonstrated to have beneficial properties relating to health of humans (Das, S. et al. (2007) “Resveratrol: A Therapeutic Promise For Cardiovascular Diseases " Recent Patents Cardiovasc. Drug Discov. 2(2): 133- 138; Mancuso, C. et al. (2007) "Natural antioxidants in Alzheimer's disease " Expert Opin. Investig. Drugs. 16(12): 1921-1931 ; Baumann L. (2007) “Botanical Ingredients In Cosmeceuticals " J. Drugs Dermatol.
  • resveratrol is believed to be beneficial to the functioning of the heart and in extending the life of human cells.
  • Resveratrol when used in dietary supplements, is generally produced as an alcohol extract from plant sources.
  • Calorie restricted diets have been shown to enhance survival and longevity by up- regulating survival/longevity genes or down-regulating genes whose expression enhances cellular damage (Edwards, M.G. et al. (2007) "Gene Expression Profiling Of Aging Reveals Activation Of A P53-Mediated Transcriptional Program," BMC Genomics 8:80; Anderson, R.M. et al. (2006) “Calorie Restriction: Progress During Mid-2005-Mid-2006 " Exp. Gerontol. 41(12): 1247-1249; Weindruch, R. et al. (2001) "Microarray Profiling of Gene Expression in Aging and Its Alteration by Caloric Restriction in Mice," J.
  • mice have been used extensively as a model for genetic expression comparisons with humans. Without limitation, the validity of murine models to human gene expression reflects the fact that 98% of human and murine gene are homologous, and that mice and humans have about the same number of genes (e.g., approximately 30,000).
  • the present invention relates to a resveratrol-containing composition capable of modulating gene expression to an extent greater than that observed with resveratrol alone or with calorie restriction.
  • the invention particularly pertains to such resveratrol-containing compositions that comprise resveratrol, a chelator, hyaluronic acid, and/or vitamin D and which, upon administration to a recipient, increases the concentration or activity of a survival/longevity gene product and/or decreases the concentration or activity of a gene product that induces or causes cellular damage.
  • the resveratrol-stabilizing composition will comprise the chelator phytic acid (inositol hexaphosphate; IP6), hyaluronic acid, and vitamin D.
  • IP6 chelator phytic acid
  • the invention further pertains to the use of such compositions to up- regulate a survival/longevity gene or down-regulate a gene whose expression enhances cellular damage upon administration to a recipient.
  • the invention particularly relates to the use of such compositions in the treatment or prevention of cancer, cardiovascular disease, diseases associated with aging, and other conditions and illnesses.
  • the invention provides a resveratrol-containing composition that, upon administration to a recipient, modulates the concentration or activity, relative to resveratrol alone or calorie restriction, of the product of a survival/longevity gene or the product of a gene whose expression enhances cellular damage.
  • Administration is preferably by oral ingestion.
  • the invention further provides the embodiments of such compositions wherein the modulation alters:
  • the invention further provides the embodiments of such compositions wherein the gene product is a survival/longevity gene product, and especially wherein the gene product is sSirtuin 1, or the forkhead Foxol transcription factor.
  • the invention further provides the embodiments of such compositions wherein the gene product is a gene product that enhances cellular damage, and especially wherein the gene product is encoded by the uncoupling protein 3, Pgc-1, or pyruvate dehydrogenase kinase 4 genes.
  • composition comprises:
  • the invention further provides a method of ameliorating a symptom associated with an existing disease of an individual or for preventing the onset of the symptom in an individual prior to the occurrence of the disease in the individual, which comprises administering to the individual, a resveratrol-containing composition that modulates the concentration or activity, relative to resveratrol alone or calorie restriction, of the product of a survival/longevity gene or the product of a gene whose expression enhances cellular damage, wherein the resveratrol is provided in an amount effective to cause a modulation of the concentration or activity of the gene that ameliorates the symptom of the disease, and wherein the disease is selected from the group consisting of: cardiovascular disease, cancer, macular degeneration, a disease associated with aging, and inflammation.
  • the invention further provides the embodiments of such method wherein the modulation alters:
  • the invention further provides the embodiments of such method wherein the survival/longevity gene product is Sirtuin 1 or the forkhead Foxol transcription factor.
  • the invention further provides the embodiments of such method wherein the gene whose expression enhances cellular damage encodes uncoupling protein 3 or pyruvate dehydrogenase kinase 4.
  • composition comprises:
  • the invention further provides the embodiments of such method wherein the disease is cancer, or a disease associated with aging (especially a neurodegenerative disease).
  • the invention further provides the embodiments of such method wherein the composition additionally comprises quercetin, hyaluronic acid and/or vitamin D. [0019] The invention further provides the embodiments of such method wherein the modulation is relative to resveratrol alone or wherein the modulation is relative to calorie restriction.
  • the invention further provides the embodiments of such methods wherein the gene product is a survival/longevity gene product, and especially wherein the gene product is Sirtuin 1 , or the forkhead Foxo 1 transcription factor.
  • the invention further provides the embodiments of such methods wherein the gene product is a gene product that enhances cellular damage, and especially wherein the gene product is encoded by the uncoupling protein 3, Pgc-1, or pyruvate dehydrogenase kinase 4 gene.
  • Figure 1 shows the change in body weight of mice administered resveratrol or a composition of the present invention (Longevinex®) relative to control animals and animals maintained on a calorie restricted diet.
  • Figure 2 shows the serum insulin level of mice administered resveratrol or a composition of the present invention (Longevinex®) relative to control animals and animals maintained on a calorie restricted diet.
  • Figure 4 shows a schematic of a mechanism of action that is consistent with the observed biological activities of the compositions of the present invention.
  • the present invention relates to a resveratrol-containing composition (and especially a resveratrol-containing dietary composition (i.e., a composition amenable for oral ingestion by a recipient)) capable of modulating gene expression to an extent greater than that observed with resveratrol alone or with calorie restriction.
  • the invention particularly pertains to such resveratrol-containing compositions that comprise resveratrol, a chelator, hyaluronic acid, and/or vitamin D and which up-regulate a survival/longevity gene or down-regulate a gene whose expression enhances cellular damage upon administration to a recipient.
  • the resveratrol-stabilizing composition will comprise the chelator phytic acid (inositol hexaphosphate; IP6), hyaluronic acid, and vitamin D.
  • IP6 chelator phytic acid
  • the invention further pertains to the use of such compositions to up-regulate a survival/longevity gene or down-regulate a gene whose expression enhances cellular damage upon administration to a recipient.
  • the mineral chelators of the present invention provide anti-aging effects, as evidence in differentiation of the genome.
  • resveratrol refers to the phytoalexin: 3,4',5-trihydroxy- trans-stilbcnc having the structure:
  • Resveratrol has been ascribed multiple beneficial biological effects (see, United States Patent No. 7,345,178, which listing of disclosed effects is herein incorporated by reference), including preventing or treating cardiovascular disease (see, e.g., Das, S. et al. (2007) “Resveratrol: A Therapeutic Promise For Cardiovascular Diseases " Recent Patents Cardiovasc. Drug Discov. 2(2): 133- 138), Opie, L.H. et al. (Epub 2007 Jun 7) "The Red Wine Hypothesis: From Concepts To Protective Signaling Molecules " Eur. Heart J. 28(14): 1683- 1693; Bertelli, A. A.
  • Reseveratrol may be synthesized chemically (Farina, A. et al. (2006) “An Improved Synthesis Of Resveratrol,” Nat. Prod. Res. 20(3):247-252), or, more preferably, may be extracted from plant sources. Resveratrol is found in at least 72 species of plants distributed among 31 genera and 12 families (see, Counet, C. et al. (2006) “Chocolate And Cocoa: New Sources Of Trans-Resveratrol And Trans-Piceid,” Food Chem. 98:649-657; Jang, M. et al.
  • the invention pertains to compositions that, upon administration to a recipient, increase the concentration or activity of a survival/longevity gene product and/or decrease the concentration or activity of a gene product that induces or causes cellular damage.
  • increase (or decrease) in concentration or activity may be accomplished by any mechanism.
  • increase (or decrease) may reflect a modulation of gene expression resulting in either increased (or decreased) expression of the gene encoding the survival/longevity gene product, or a gene that regulates (e.g., induces or represses) or whose product regulates such expression or activity.
  • such increase (or decrease) in concentration or activity may reflect a modulation of the recipient's ability to degrade or stabilize any such gene products.
  • such increase (or decrease) in concentration or activity may reflect a modulation of the recipient's ability to enhance, accelerate, repress or decelerate the activity of any such gene products.
  • the modulation of concentration or activity discussed above may be a modulation of intracellular, intercellular and/or tissue concentration or activity of such survival/longevity gene products or such gene products that induce or cause cellular damage.
  • Such modulation may be identified by assays of DNA expression, assays of gene product activity, assays of the level of gene product, assays of the rate of gene product turnover, etc. conducted in one or more types of cells, tissues, etc.
  • An increase in the concentration of a survival/longevity gene product may result from, for example, increased transcription of the gene that encodes the survival/longevity gene product, increased transcription of a gene that induces the expression of the gene that encodes the survival/longevity gene product, decreased transcription of a gene that represses the expression of the gene that encodes the survival/longevity gene product, decreased degradation or enhanced stabilization of expressed molecules of the survival/longevity gene product (leading to the enhanced accumulation of the survival/longevity gene product).
  • a decrease in the concentration of a survival/longevity gene product may result from, for example, decreased transcription of the gene that encodes the survival/longevity gene product, decreased transcription of a gene that induces the expression of the gene that encodes the survival/longevity gene product, increased transcription of a gene that represses the expression of the gene that encodes the survival/longevity gene product, increased degradation or decreased stabilization of expressed molecules of the survival/longevity gene product (leading to the enhanced dissipation of the survival/longevity gene product).
  • One aspect of the present invention thus relates to the use of resveratrol and resveratrol-containing compositions to modulate gene expression, and in particular, to modulate the expression of "survival/longevity" genes and/or "damage inducing" genes.
  • a compound is said to "modulate” gene expression if its administration results in a change in expression (relative to a control) of such genes of at least 10%. Modulation may involve an increase in expression ("up-regulation") or it may involve a decrease in expression (“down- regulation").
  • up-regulate thus denotes an increase of expression of at least 10%, at least 20%, at least 50%, at least 2-fold, at least 5-fold, or most preferably at least 10-fold (relative to a control).
  • down-regulate conversely denotes a decrease of expression of at least 10%, at least 20%, at least 50%, at least 2-fold, at least 5-fold, or most preferably at least 10-fold (relative to a control).
  • a second aspect of the present invention thus relates to the use of resveratrol and resveratrol-containing compositions to modulate the concentration or activity of expressed products of "survival/longevity" genes and/or "damage inducing" genes.
  • a compound is said to "modulate” the concentration or activity of such expressed products if its administration results in a change in an intracellular, intercellular or tissue concentration or activity (relative to a control) of such gene products of at least 10%.
  • Modulation may, for example, involve an "enhanced accumulation” or an “enhanced activity” or, for example, it may involve a “diminished accumulation” or a “diminished activity.”
  • the term “enhanced accumulation” (or “enhanced activity”) denotes an increase in concentration (or activity) of at least 10%, at least 20%, at least 50%, at least 2-fold, at least 5-fold, or most preferably at least 10-fold (relative to a control).
  • diminished accumulation or “diminished activity.” conversely denotes a decrease in concentration (or activity) of at least 10%, at least 20%, at least 50%, at least 2-fold, at least 5-fold, or most preferably at least 10-fold (relative to a control).
  • a "survival/longevity" gene is a gene whose expression contributes to an increase in the survival or longevity of a subject (e.g., a mammal, and particularly a human) expressing such gene.
  • a “damage inducing” gene is a gene whose expression contributes to DNA, cellular, or tissue damage in such subject.
  • Such genes are responders to biological stressors, they initiate action in response to stressors such as radiation (e.g., sunlight, gamma rays, UV light, etc.), radiomimetic agents (e.g., vitamin D), heat, near starvation (calorie restriction, or its mimetic, resveratrol) by modulating their expression.
  • Examples of survival/longevity genes are provided in Table 1. Examples of genes whose expression enhances cellular damage are provided in Table 2. These Tables provide the gene's NCBI "ENTREZGENE” accession number. Most preferably, such genes are human genes.
  • the Sirtuin 1 gene is known to control the rate of aging of living organisms by virtue of its ability to produce DNA repair enzymes and mimics the beneficial effects of calorie restriction.
  • the trans form of resveratrol (but not czs-resveratrol) activates the Sirtuin 1 gene (Alcendor, R.R.
  • the invention particularly pertains to compositions that increase the concentration of the Sirtuin 1 survival/longevity gene product.
  • the invention further particularly pertains to compositions that increase the concentration of the forkhead Foxol (daf-16, dFoxO) transcription factor survival/longevity gene product.
  • the invention particularly pertains to resveratrol-containing compositions in which the specific activity of the resveratrol has been stabilized or enhanced.
  • specific activity refers to the ratio of the extent of gene modulation (relative to control) per amount (mass) of administered resveratrol.
  • compositions will comprise a chelator, hyaluronic acid, and/or vitamin D.
  • the invention particularly pertains to such compositions that comprise resveratrol (preferably, the compositions of the present invention will provide a composition dosage of from about 10 mg to about 2 g, more preferably from about 100 mg to about 500 mg), and at least one compound selected from the group consisting of an antioxidant (chelator), hyaluronic acid, and vitamin D.
  • the compositions of the present invention will contain resveratrol, an antioxidant, hyaluronic acid, and vitamin D.
  • chelator refers to an organic compound that bonds with and removes free metal ions from solution.
  • suitable chelators include ethylenediaminetetraacetic acid (EDTA), histidine, antibiotic drugs of the tetracycline family, pyridoxal 2-chlorobenzoyl hydrazone, desferrioxamine, dexrazoxane, deferasirox, pyoverdine, pseudan, citrate, NDGA (nordihydroguaiaretic acid: l,4-bis[3,4-dihydroxyphenyl]2,3- dimethylbutane), ferulic acid and phytic acid.
  • the compositions of the present invention will provide a composition dosage of chelator of from about 1 g to about 15 g, more preferably from about 2 g to about 12 g.
  • Phytic acid is a particularly preferred chelator for the purposes of the present invention.
  • the term “phytic acid” refers to inositol hexaphosphate ((2,3,4,5,6- pentaphosphonooxycyclohexyl) dihydrogen phosphate; also known as "IP6";) (see, Thome Research, Inc. (2002) “Inositol Hexaphosphate. Monograph,” Altern. Med. Rev. 7(3):244-248; Vucenik, I. et al. (2006) “Protection against Cancer By Dietary IP6 And Inositol,” Nutr. Cancer. 55(2): 109-125; Lopez, M.A. et al.
  • IP6 is an Anti-Neoplastic And Lipid-Lowering Agent
  • IP6 is an Anti-Neoplastic And Lipid-Lowering Agent
  • IP6 is an Anti-Neoplastic And Lipid-Lowering Agent
  • Phytic acid is found in substantial amounts in whole grains, cereals, legumes, nuts, and seeds, and is the primary energy source for the germinating plant (Graf, E. (1983) " Applications of Phytic Acid,” J. Am. Oil. Chem. Soc 60: 1861-1867). Phytic acid and its lower phosphorylated forms (such as IP3) are also found in most mammalian cells, where they assist in regulating a variety of important cellular functions (Szwergold, B. S. et al. (1987) "Observation Of Inositol Pentakis- And Hexakisphosphates In Mammalian Tissues By 31 P NMR,” Biochem. Biophys. Res. Commun. 264:874-881).
  • Phytic Acid is preferably provided in the form of rice bran (Srinivasan, M. (2007) "Ferulic Acid' Therapeutic Potential Through Its Antioxidant Property " J. Clin. Biochem. Nutr. (2007) 40(2):92-100; Kim, MJ. et al. (2007) "Ferulic Acid Supplementation Prevents Tnmethyltin-Induced Cognitive Deficits in Mice," Biosci. Biotechnol. Biochem. (2007) 71(4): 1063-1068).
  • Phytic acid is reported to function as an antioxidant by chelating divalent cations such as copper and iron, thereby preventing the generation of reactive oxygen species responsible for cell injury and carcinogenesis (Harland, B.F. et al. (1987) "Phytate In Foods " World Rev. Nutr. Diet 52:235-259).
  • the preferred composition dosage of phytic acid (for example, as rice bran) is in the range of 2000-12,000 mg.
  • hyaluronic acid also known as hyaluronan refers to linear polymer composed of repeating disaccharides of D-glucuronic acid and D-N- acetylglucosamine, linked together via alternating ⁇ -1,4 and ⁇ - 1,3 glycosidic bonds ([- ⁇ (1,4)- GlcUA- ⁇ (l,3)-GlcNAc-] n ).
  • Hyaluronic acid can be 25,000 disaccharide repeats (n) in length:
  • Hyaluronic acid is a water-retaining molecule that is generated naturally in the human body but in decreasing amounts as the body ages.
  • Hyaluronic acid is a multifunctional glycosaminoglycan that forms the basis of the pericellular matrix of cells.
  • Hyaluronic acid is synthesized by 3 different but related enzymes (hyaluronan synthases: HASl, HAS2 and HAS3 (Weigel, P.H. et al. (1997) "Hyaluronan Synthases,” J. Biol. Chem. 272:13997-14000; Tammi, M.I. et al. (2002) “Hyaluronan And Homeostasis' A Balancing Act,” J. Biol. Chem.
  • Hyaluronic acid has been traditionally extracted from rooster combs, from bovine or fish vitreous humor, from microbial production or from other sources (Rangaswamy, V. et al. (Epub 2007 Oct 24) "An Efficient Process For Production And Purification Of Hyaluronic Acid From Streptococcus Equi Subsp. Zooepidemicus," Biotechnol. Lett. 30(3):493-496; Gao, F. et al. (2006) "Preparation And Characterization Of Hyaluronan Oligosaccharides For Angiogenesis Study " J. Biomed. Mater. Res. B Appl. Biomater. 78(2):385-392; Blank, L.M.
  • the hyaluronic acid of the present invention is obtained from rooster combs.
  • Hyaluronic acid is widely available commercially, and such preparations are suitable for the purposes of the present invention.
  • the compositions of the present invention will provide a composition dosage of hyaluronic acid of from about 1 mg to about 400 mg, more preferably from about 50 mg to about 200 mg.
  • Vitamin D refers to a fat-soluble prohormone.
  • vitamin D 2 ergocalciferol
  • vitamin D 3 cholecalciferol
  • Vitamin D exhibits many biological actions. While vitamin D is widely known for its ability to stave off bone disease (rickets in growing children, osteoporosis in senior adults), it is becoming a central player in the battle against cancer. Regarding the role of vitamin D in immunity and cancer, vitamin D improves the chemotactic (affinity for) neutrophils to mobilize and migrate. Patients with rickets due to vitamin D deficiency are observed to have sluggish neutrophils that cannot migrate properly. Vitamin D stimulates the maturation of monocytes to macrophages. This results in an enlarged army of immune fighting cells to mount against tumors. Vitamin D is widely available commercially, and such preparations are suitable for the purposes of the present invention.
  • Vitamin D is essential for optimal muscle, bone, brain, immune and cardiovascular health and is undergoing re-discovery by aging researchers worldwide. Vitamin D supplementation up to 2000 IU has been shown to significantly reduce mortality rates, thus adding vitamin D to the lineup of molecules now considered to be true longevity factors (Autier, P. et al. (2007) "Vitamin D Supplementation And Total Mortality: A Meta-Analysis Of Randomized Controlled Trials," Arch Intern Med. 167(16):1730-1737). Its anti-calcifying properties (Zittermann, A. et al. (2007) “Vitamin D And Vascular Calcification,” Curr. Opin.
  • Lipidology 18(l):41-46) qualify vitamin D as another powerful agent that inhibits progressive overmineralization in the human body with advancing age and parallels the action of other mineral chelators in the compositions of the present invention. While the 1200 IU dose is three times more than the Recommended Daily Allowance, it is well within the Safe Upper Limit established by the National Academy of Sciences (2000 IU) and corresponds with a supplemental dosage recently found to be beneficial in a human clinical trial (Lappe, J.M. et al. (2007) "Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial," Amer. J. Clin. Nutr. 85(6):1586-1591).
  • compositions of the present invention will provide a composition dosage of vitamin D of from about 100 IU to about 100,000 IU, more preferably from about 1,000 IU to about 50,000 IU.
  • compositions of the present invention may contain additional components, including additional active components that act to enhance resveratrol biological activity and inactive compounds (e.g., flavorants, sweeteners, dyes, vitamins, amino acids (e.g., lysine, proline, etc.), minerals, nutrients, etc.).
  • additional active components e.g., flavorants, sweeteners, dyes, vitamins, amino acids (e.g., lysine, proline, etc.), minerals, nutrients, etc.).
  • quercetin (3,3',4',5,7-pentahydroxy-2-phenylchromen-4-one)
  • Resveratrol is glucuronated in the human liver, which may reduce its bioavailability.
  • Flavonoids such as quercetin, inhibit resveratrol glucuronidation and thus may act to improve resveratrol bioavailability (see, de Santi, C. et al. (2000) "Glucuronidation Of Resveratrol, A Natural Product Present In Grape And Wine, In The Human Liver," Xenobiotica 30(11):1047- 1054); De Santi, C. et al. (2000) “Sulphation Of Resveratrol, A Natural Compound Present In Wine, And Its Inhibition By Natural Flavonoids," Xenobiotica 30(9):857-866; De Santi, C.
  • Quercetin may also act synergistically with resveratrol or independently of resveratrol to provide beneficial function (Kampk ⁇ tter, A. et al. (Epub 2007 Oct 16) "Increase Of Stress Resistance And Lifespan Of Caenorhabditis Elegans By Quercetin,” Comp. Biochem. Physiol. B Biochem. MoI. Biol. 149(2):314-323). (See also, Kaindl, U. et al.
  • Emulsifiers, fillers, binding agents, and the like may also be included in the compositions of the present invention.
  • compositions of the present invention comprise a novel combination of: small molecules such as quercetin and resveratrol with widespread preventive and therapeutic health properties; and/or collagen-building nutrients (such as vitamin C- ascorbate, lysine, proline, etc.); and a glycosaminoglycan such as a shortened (low molecular weight) chain of hyaluronic acid (HA) or its singular components (glucosamine, glucuronate) or chondroitin sulfate, which are linear disaccharides (sugar-like molecules) that serve as structural components of cartilage, but in this combination serve as synergistic co-healing agents in non-cellular (connective) tissue that surrounds living cells.
  • small molecules such as quercetin and resveratrol with widespread preventive and therapeutic health properties
  • collagen-building nutrients such as vitamin C- ascorbate, lysine, proline, etc.
  • a glycosaminoglycan such as a shortened (
  • glycosaminoglycans hyaluronan, glucuronate or chondroitin
  • ascorbate lysine or proline
  • the combination of the present invention is intended for human or animal oral intake as a dietary supplement.
  • such compositions may comprise a combination of resveratrol and hyaluronan in a dietary supplement that serves to heal a variety of illnesses including some cancers.
  • Resveratrol is known to be an anti-cancer molecule and to have other healing and longevity enhancing properties.
  • Hyaluronan (hyaluronic acid, HA) is taken as an oral supplement or can be given intravenously to target cancer cells. When combined with or attached to other molecules, hyaluronan will deliver other anti-cancer and healing agents such as resveratrol to tumor sites.
  • the combination may or may not include a chelating agent, an antioxidant and/or an emulsifier as described in my above-referenced co- pending patent application.
  • resveratrol and HA When encapsulated or otherwise applied together, with or without those additives, resveratrol and HA have powerful healing properties for animals and humans.
  • compositions of the present invention stabilize resveratrol specific activity such that the resveratrol of the compositions has a specific activity that is greater than that of resveratrol maintained in the presence of oxygen gas, or maintained in the absence of a chelator, hyaluronic acid, or vitamin D.
  • the amounts of the non- resveratrol constituents of the compositions will stabilize the composition's resveratrol so that it exhibits at least 10% more activity, at least 20% more activity, at least 50% more activity, at least 2-times the activity, at least 5-times the activity, or at least 10-times the activity of resveratrol maintained in the presence of oxygen gas, or maintained in the absence of a chelator, hyaluronic acid, or vitamin D and so that it remains capable of exhibiting such specific activity over extended periods (for example, 1, 2, 4, 6, 10, 12, 18, 24, or 36 months or longer) at ambient conditions of temperature and humidity (i.e., without need for special precautions as to temperature or humidity).
  • extended periods for example, 1, 2, 4, 6, 10, 12, 18, 24, or 36 months or longer
  • Resveratrol is typically unstable to light and oxidation (Shaanxi University of Science & Technology, Xianyang China (2007) "Study On The Stability Of Resveratrol In Rhizoma Polygoni cuspidate “ Zhong Yao Cai. 30(7):805-80).
  • the resveratrol of the present invention is preferably prepared, packaged and/or stored in a manner that maximizes its specific activity. It is preferred to prepare, package and/or store resveratrol in low light (or in the dark) and/or in low oxygen, so as to minimize light-induced degradation (e.g., photo- isomerization) or oxygen-induced degradation.
  • compositions of the present invention are formulated as dietary supplements for oral ingestion in the form of a pill, lozenge, capsule, elixir, syrup, etc.
  • Other modalities of administration may alternatively be employed (e.g., intranasal, parenteral, intravenous, intraarterial, topical, etc.).
  • the compositions of the present invention are formulated as air-tight capsules in which encapsulation is conducted so as to prevent or minimize exposure to oxygen.
  • such encapsulation is conducted in an oxygen-free environment.
  • the components of the compositions of the present invention may be inserted into a capsule in an inert gas (e.g., nitrogen, argon, etc.) environment.
  • an inert gas e.g., nitrogen, argon, etc.
  • a nitrogen bubble e.g., 5-20% of the capsule volume
  • That international application has a corresponding U. S. patent application.
  • Suitable capsules useful in the encapsulation of resveratrol and other oxidation prone ingredients of dietary supplements include Licaps® (Capsugel), an air-tight gelatin capsule.
  • Licaps® Capsugel
  • phytic acid which has the ability to protect the components from metal-induced oxidation, augments such anti- oxidation precautions.
  • a particularly preferred example of such a resveratrol-containing composition is Longevinex® (Resveratrol Partners, LLC, San Dimas, CA), which comprises resveratrol and phytic acid.
  • Longevinex® contains as active ingredients (per capsule): 5 mg Vitamin E (as mixed tocopherols), 215 mg total resveratrol (obtained from French red wine and giant knotwood (Polygonum cuspidatum), and providing 100 mg of trans-resveratrol), 25 mg quercetin dihydrate, 75 mg phytic acid (rice bran extract), 380 mg rice bran oil, 55 mg sunflower lecithin.
  • an oxygen absorbing packette is preferably employed to reduce the presence of free oxygen. Vacuum or nitrogen-flushed packaging (bottles, pill cases, etc.) in air-tight materials is desirable.
  • the components and compositions of the present invention may be prepared as a microencapsulated process (see, generally, Rubiana, M. et al. (2004) "Drug Delivery Systems: Past, Present, and Future," Current Drug Targets, 5(5):449- 455).
  • Micro-encapsulation is a process by which tiny particles or droplets (ranging in size from a few nanometers to one micron) are coated with a protective layer to create small capsules with controlled properties.
  • Suitable micron-sized, encapsulated, preparations can be obtained using the microencapsulation processes of Maxx Performance Inc. (Chester, NY), Blue California (Rancho Santa Margarita, CA), Southwest Research Institute (San Antonio, TX), Coating Place, Inc.
  • the present invention further comprises a practical method of stabilizing quercetin and other easily oxidized dietary supplement ingredients which may come in contact with oxidizing metals.
  • compositions of the present invention enhance resveratrol's specific activity.
  • the compositions of the present invention therefore find utility in the treatment of diseases (or in the amelioration of the symptoms of diseases) such as cardiovascular disease, cancer, macular degeneration, aging, neurodegenerative diseases (e.g., Alzheimer's Disease, Parkinson's Disease, etc.) and inflammation in which the modulation of expression of "survival/longevity" genes and/or “damage inducing" genes is desired.
  • diseases or in the amelioration of the symptoms of diseases
  • diseases such as cardiovascular disease, cancer, macular degeneration, aging, neurodegenerative diseases (e.g., Alzheimer's Disease, Parkinson's Disease, etc.) and inflammation in which the modulation of expression of "survival/longevity" genes and/or “damage inducing” genes is desired.
  • diseases or in the amelioration of the symptoms of diseases
  • diseases such as cardiovascular disease, cancer, macular degeneration, aging, neurodegenerative diseases (e.g., Alzheimer's Disease
  • Macular degeneration is a progressive, age-related disease that can be broken down into four stages:
  • RPE retinal pigment epithelia
  • Bruch's membrane an underlying cellophane -thin retinal layer called Bruch's membrane, which resides between the RPE and the blood supply layer (choroid). While drusen that forms within the retina is partially composed of cholesterol, this lipid does not originate from the blood circulation or the liver where most cholesterol is produced. Calcifications within Bruch's membrane further impairs the exit of lipids (fats), protein, and cellular debris, from the photoreceptor layer, which results in the formation of yellow spots called drusen on the retina. Drusen can be observed during an eye examination using an ophthalmoscope. There is currently no method of removing drusen.
  • the death of the RPE cells is the third stage of this progressive disease. This is sometimes called RPE dropout. As the RPE cells are either impaired or have died, and Bruch's membrane is clogged with calcium, the photoreceptors then cannot be nourished and also begin to die off. There is currently no treatment for stages 1 -3 of macular degeneration. Stage 1-3 is called the "dry" form of macular degeneration because it has not resulted in hemorrhage or edema or new blood vessel formation. About 85% of macular degeneration patients have the "dry" form of this disease. 4.
  • the cell cleansing process facilitated by the lysosomes cannot keep up with the accumulation of metabolic waste over a lifetime.
  • the parafoveal ring where rod cell density is highest, and therefore more discs of used-up vitamin A are shed, is where macular degeneration begins, and where the highest concentration of lipofuscin is observed in the retina.
  • the RPE cells die off with advancing age, which increases the burden on the remaining RPE cells to maintain a healthy retina.
  • lipofuscin has been considered a harmless wear-and-tear byproduct of cellular metabolism.
  • One aspect of the present invention relates to the recognition that lipofuscin, which forms from iron and copper-induced oxidation, and hardens within lysosomal bodies within retinal pigment epithelial cells, sensitizes the retina to damage by mild amounts of radiation and oxidation.
  • the retina becomes increasingly sensitive to blue-light damage with advancing age.
  • Drusen formation within the retina is associated with RPE cell inability to produce superoxide dismutase, an endogenous antioxidant enzyme. Mice deficient in superoxide dismutase develop features that are typical of age-related macular degeneration in humans. Superoxide dismutase protects retinal cells against unbound (free) iron. High iron diets and cellular environments have been shown to reduce superoxide dismutase activity.
  • Retinal photoreceptors and retinal pigment epithelial cells are believed to be especially vulnerable to damage by low-molecular weight complexes of iron. Since antioxidants in the blood circulation may not always be able to cross the blood-retinal barrier, the retina produces its own protective antioxidants that bind iron. Iron chelators inhibit the adverse effects of unbound (free) iron (not bound to proteins). Heme oxygenase also serves in a similar manner to iron chelators to prevent retinal damage induced by loose iron.
  • Sorbinil has been shown to partially reduce lipofuscin deposits in the retinal pigment epithelium cells of rodents.
  • Hydergine is a drug used to treat senile dementia. In a rodent study, hydergine was reported to have reduced brain lipofuscin levels, but also led to the early demise of the animals.
  • the East Indian spice turmeric contains an antioxidant molecule called curcumin. Curcumin has been used in an experimental mouse study to reduce lipofuscin in the brain.
  • Purslane is a flowering plant rich in magnesium, beta carotene and omega-3 oil. The provision of purslane to mice has been shown to reduce lipofuscin deposition in the brain of mice.
  • lipoic acid a natural metabolic antioxidant
  • Lipoic acid a natural antioxidant produced within living tissues, and also available as a dietary supplement, has been shown to protect RPE cells from oxidative damage in lab dish studies.
  • Lipofuscin formation dramatically increases in brain tissues following alcohol consumption. Supplementation with high-dose grape seed flavonols prevents increase lipofuscin formation. Lipofuscin is an end-product of lipid peroxidation which dramatically increases following ethanol consumption.
  • Epigallocatechin-3-gallate (EGCG) the major constituent of green tea, upregulates the activity of heme oxygenase in lab dish studies.
  • Heme oxygenase is a protective enzyme against iron-induced oxidation, which occurs in the retina.
  • U. S Patent No. 5,747,536 describes the combined therapeutic use of L-carnitine, lower alkanoyl L-carnitines or the pharmacologically acceptable salts thereof, with resveratrol, resveratrol derivatives or resveratrol-containing natural products, for producing a medicament for the prophylaxis and treatment of cardiovascular disorders, peripheral vascular diseases and peripheral diabetic neuropathy.
  • Melanin is an iron-binding antioxidant in the retina. As melanin levels decline in the retina with advancing age, there is a greater accumulation of lipofuscin.
  • the present invention relates to a composition comprising a combination of:
  • a chelator such as inositol hexaphosphate (IP6), trans resveratrol, quercetin, or any polyphenol or bioflavonoid for metal(s) such as iron, copper, heavy metals;
  • a calcium chelator such as inositol hexaphosphate (IP6);
  • a heme oxygenase activator such as trans resveratrol, piceatannol, or any of resveratrol's natural analogs, or similar small molecules such as fisetin, myricetin, quercetin or other bioflavonoids;
  • IP6 inositol hexaphosphate
  • antioxidants such as vitamin E, lutein/zeaxanthin, alpha lipoic acid.
  • a major challenge in cancer therapy is to selectively target cytotoxic agents to tumor cells (Luo, Y. et al. (2000) "A Hyaluronic Acid-Taxol Antitumor Bioconjugate Targeted To Cancer Cells " Biomacromolecules l(2):208-218).
  • cytotoxic agents to tumor cells
  • a major challenge in cancer therapy is to selectively target cytotoxic agents to tumor cells (Luo, Y. et al. (2000) "A Hyaluronic Acid-Taxol Antitumor Bioconjugate Targeted To Cancer Cells " Biomacromolecules l(2):208-218).
  • cytotoxic agents to tumor cells
  • a macromolecular carrier and in particular with hyaluronic acid
  • the present invention relates to a resveratrol- and hyaluronic acid-containing composition for the treatment of cancer comprising: resveratrol, hyaluronan, and optionally vitamin D and/or IP6. It is believed that these components act synergistically with one another to mediate an effect in curing and/or in preventing cancer in humans and/or in improving immunity (e.g., immune system response) in patients threatened by tumors.
  • This aspect of the present invention is based in part upon the recognition that natural molecules can boost cancer immunity, possibly in a manner similar to that observed in cancer-proof mice.
  • the sentinels of the innate immune system, dendritic cells can be alerted and neutrophils, macrophages and natural killer cell activity can be significantly enhanced.
  • the enhancement of vitamin D receptors via resveratrol is yet another major advantage of a combination approach to treat or prevent cancer. This approach appears to be more appropriate for senior adults, the highest risk group for cancer, who are often immune-compromised due to poor nutrition or lack of nutrient absorption. The fact that this therapy can now be immediately measured for effectiveness by non-invasive cancer cell counting technology means that expensive and equivocal tests on animals may not be required to prove efficacy.
  • Vitamin D exhibits many biological actions. While vitamin D is widely known for its ability to stave off bone disease (rickets in growing children, osteoporosis in senior adults), it is becoming a central player in the battle against cancer. Only recently is it also gaining attention as an antibiotic. Vitamin D-deficient mice exhibit a defective response from phagocyte cells in the face of infection or inflammation. Vitamin D deficiency is frequently associated with recurrent infections. Only about half of the macrophage cells accumulate at the site of inflammation in vitamin D-deficient animals compared to animals whose vitamin D levels are adequate.
  • vitamin D improves the chemotactic (affinity for) neutrophils to mobilize and migrate. Patients with rickets due to vitamin D deficiency are observed to have sluggish neutrophils that cannot migrate properly. Vitamin D stimulates the maturation of monocytes to macrophages. This results in an enlarged army of immune fighting cells to mount against tumors. Greater attention is now being given to vitamin D as an anti-cancer weapon because of studies which show supplemental vitamin D drastically reduces the risk for all types of cancer. A study that employed 1100 IU of vitamin D3 produced a 60-77% reduction in cancer risk among women in California in just a 4-year period.
  • Vitamin D's ability to inhibit cancer may be heightened when it is aided by weak estrogen-like molecules in the diet.
  • Resveratrol an estrogen-like molecule commonly found in red wine, upregulates the vitamin D receptor in breast cancer cells without increasing cancer growth.
  • Resveratrol in effect, can sensitize breast cancer cells to the anti-cancer properties of vitamin D.
  • resveratrol by itself has been shown to calm the response of phagocytes to foreign invaders like germs and tumor cells. Resveratrol dampens production of reactive oxygen species (free radicals) and normalizes particle ingestion in macrophage cells. Therefore, resveratrol prevents the over-response of immune cells that can produce autoimmunity.
  • Resveratrol blocks cancer in so many ways that it is difficult to find a pathway for cancer that is not obstructed by resveratrol.
  • Resveratrol induces the cell energy compartments in tumor cells, called mitochondria, to release an enzyme called cytochrome C oxidase that usually leads to a cascade of other enzymes that induce programmed cell death, called apoptosis.
  • cytochrome C oxidase an enzyme that usually leads to a cascade of other enzymes that induce programmed cell death, called apoptosis.
  • autophagy a process where enzymes produced inside the tumor cell actually digest its innards (kind of a form of intracellular cannibalism). This is a form of cell suicide that resveratrol activates in tumor cells, but not healthy cells.
  • IP6 inositol hexaphosphate
  • IP6 In examining the immune enhancing properties of IP6 it has been shown that it boosts production of free radicals (superoxide) and the cell digesting action of neutrophils in the presence of bacteria. IP6 increases the release of interleukin-8.
  • the action of natural killer cells, which are involved in tumor cell destruction, is enhanced by IP6.
  • the hyaluronic acid of such composition is conjugated to a chemotherapeutic agent.
  • the invention particularly pertains to such compositions in which the chemotherapeutic agent is taxol.
  • the invention particularly pertains to such compositions that additionally and preferably comprise a chelator, and/or vitamin D.
  • Most malignant solid tumors contain elevated levels of Hyaluronic Acid (Rooney, P. et al. (1995) "The Role Of Hyaluronan In Tumour Neovascularization (Review) " Int. J.
  • a preferred method of conjugation entails forming an NHS (N-hydroxy- succimimide derivative of the chemotherapeutic agent.
  • NHS N-hydroxy- succimimide derivative of the chemotherapeutic agent.
  • Such a derivative can be made by adding a molar excess of dry pyridine to a stirred solution of Taxol and succinic anhydride in CH 2 CI 2 at room temperature. The reaction mixture is then stirred for several days at room temperature and then concentrated in vacuo. The residue is dissolved in 5 ml Of CH 2 Cl 2 and the produced Taxol-2'-hemisuccinate can be purified on silica gel (washed with hexane; eluted with ethyl acetate) to give the desired product (Luo, Y. et al. (1999) "Synthesis And Selective Cytotoxicity Of A Hyaluronic Acid-Antitumor Bioconjugate," Bioconjug. Chem. 10(5):755- 763).
  • N-hydroxy-succimimide derivative of the chemotherapeutic agent is then conjugated to adipic dihydrazido-functionalized hyaluronic acid.
  • Adipic dihydrazido- functionalized hyaluronic acid is preferably prepared as described by Pouyani, T. et al. (1994) ("Functionalized Derivatives Of Hyaluronic Acid Oligosaccharides - Drug Carriers And Novel Biomaterials " Bioconjugate Chem. 5:339-347); Pouyani, T. et al. (1994) ("Novel Hydrogels Of Hyaluronic Acid: Synthesis, Surface Morphology, And Solid-State NMR," J. Am. Chem. Soc.
  • hyaluronic acid is preferably dissolved in water and an excess of adipic dihydrazide (ADH).
  • ADH adipic dihydrazide
  • the pH of the reaction mixture is adjusted to 4.75 by addition acid.
  • 1 equivalent of l-Ethyl-3-[3-(dimethylamino)-propyl]carbodiimide (EDCI) is added in solid form. The pH of the reaction mixture is maintained at 4.75 by addition of acid.
  • reaction is quenched by addition of 0.1 N NaOH to adjust the pH of reaction mixture to 7.0.
  • the reaction mixture is then transferred to pretreated dialysis tubing (Mw cutoff 3,500) and dialyzed exhaustively against 100 mM NaCl, then 25% EtOH/H2O and finally water.
  • the solution is then filtered through 0.2 m cellulose acetate membrane, flash frozen, and lyophilized (Luo, Y. et al. (1999) "Synthesis And Selective Cytotoxicity Of A Hyaluronic Acid- Antitumor Bioconjugate " Bioconjug. Chem. 10(5):755-763).
  • Calcification and rusting are major accelerators of aging.
  • the human body is composed of cells that must continually be replaced or renewed from within, and a gooey substance that fills space between cells called collagen or connective tissue which also must be continually regenerated.
  • As the human body ages at the cellular level there is a slow accumulation of cellular debris called lipofuscin.
  • the formation of lipofuscin is facilitated by the progressive accumulation of iron and calcium within cell bodies called lysosomes and mitochondria.
  • a cell cleansing and renewal process called autophagy prevents the accumulation of lipofuscin.
  • Progressive inability to remove cellular debris results in declining cell function and then premature death of the cell.
  • a young cell efficiently removes debris from within. An old cell cannot efficiently remove debris and accumulates lipofuscin.
  • compositions of the present invention inhibit and/or reverse cellular aging and/or connective tissue aging, and in particular, inhibit and/or reverse cellular aging and/or connective tissue aging caused by an accumulation of major minerals (e.g., iron, calcium, etc.). As a consequence, recipients of the compositions of the present invention exhibit enhanced longevity and enhanced cellular and connective tissue health and structure.
  • major minerals e.g., iron, calcium, etc.
  • fibroblasts The human body ages within connective tissue by failure of cells called fibroblasts to regenerate collagen and hyaluronic acid, the latter being a space-filling, water-holding molecule. Collagen formation is facilitated by vitamins and amino acids in the diet (vitamin C, lysine, proline). Fibroblasts can be stimulated to produce hyaluronic acid by estrogen, made naturally in the body, and by estrogen-like molecules found in plants, called phytoestrogens, provided in the diet of by hyaluronic acid itself. Young females, by virtue of the ability to produce estrogen, exhibit thicker hair, smoother skin and more flexible joints, due to the abundance of hyaluronic acid. All of these being attributes of youthfulness.
  • the present invention invention addresses both cellular and extracellular (connective tissue) aging, thus (a) preserving youthful function of living cells by removal of excess minerals, largely calcium and iron, from cells, this facilitating autophagy (cleanup of cellular debris, such as lipofuscin, via lysosomal enzymes) and (b) invigorating and preserving production of hyaluronan by stimulation of fibroblasts by HA, phytoestrogens (resveratrol, quercetin, genistein, are a few), to inhibition of degradation of HA by provision of metal chelators, such as phytic acid, ferulate, quercetin, resveratrol, etc.
  • metal chelators such as phytic acid, ferulate, quercetin, resveratrol, etc.
  • the present invention is a dietary supplement that addresses both cellular and non-cellular aging by its ability to:
  • metal chelating molecules that help maintain youthful lysosomal function are identified as antioxidants, like vitamin E or vitamin C, lipoic acid, metal chelators like IP6 phytate, quercetin, bioflavonoids or polyphenols, resveratrol.
  • Resveratrol works by its ability to stimulate production of heme oxygenase, an enzyme that helps to control iron.
  • hyaluronic acid hyaluronic acid, glucosamine, chondroitin, or estrogen-like molecules such as genistein, lignans, hydroxytyrosol, or other molecules configured like estrogen.
  • Orally consumed HA stimulates greater HA and chondroitin synthesis.
  • glucosamine stimulate fibroblasts to produce HA.
  • glucosamine stimulates synovial production of hyaluronic acid, which is primarily responsible for the lubricating and shock- absorbing properties of synovial fluid" (McCarty, M.F. (1998) "Enhanced Synovial Production Of Hyaluronic Acid May Explain Rapid Clinical Response To High-Dose Glucosamine In Osteoarthritis " Medical Hypotheses 50:507-510, 1998).
  • (f) orally consumed molecules that stimulate production of collagen are vitamin C, proline and lysine.
  • the present invention relates to a resveratrol and hyaluronic acid-containing dietary supplement that restores youthful function and appearance to human cells and tissue.
  • the invention particularly pertains to such compositions that additionally comprise a chelator, and/or vitamin D.
  • the composition will comprise the chelator phytic acid (inositol hexaphosphate; IP6).
  • IP6 chelator phytic acid
  • the compositions of the present invention synergistically enhance the specific activity of the resveratrol and/or hyaluronic acid, and thus the compositions of the present invention provide an enhancement of activity above and beyond that obtained with the components administered individually.
  • the invention relates to a method for restoring youthful function and appearance to human cells and tissues comprising the following steps: (a) stimulating renewal of living cells from within via enzymatic degradation of cellular debris by intracellular lysosomal bodies (preferably by providing a metal chelating molecule that helps maintain youthful lysosomal function, such molecules comprising antioxidants, such as vitamin E or vitamin C, lipoic acid, metal chelators like IP6 phytate, quercetin, bioflavonoids or polyphenols, and/or resveratrol); and
  • stimulating fibroblasts to produce hyaluronic acid comprises providing orally consumed molecules that stimulate fibroblasts to produce hyaluronic acid, such orally consumed molecules comprising, for example, hyaluronic acid, glucosamine, chondroitin, and/or estrogen-like molecules such as genistein, lignans, hydroxytyrosol, or other molecules configured like estrogen).
  • such stimulation is achieved by the dietary administration of a composition comprising the stated compounds, more preferably in combination with an orally consumable molecule that stimulates production of collagen, such molecules comprising, for example, vitamin C, proline and/or lysine.
  • a composition comprising the stated compounds, more preferably in combination with an orally consumable molecule that stimulates production of collagen, such molecules comprising, for example, vitamin C, proline and/or lysine.
  • Vitamin D3 works as an agent that mimics the response to a biological stressor, solar radiation.
  • vitamin D3 upregulates protective genes involved in activation of the immune system, particularly neutrophil count and motility, and aids in overcoming the decline in endogenous vitamin D3 production with advancing age due to thickening of the skin, which reduces sun/skin production of vitamin D.
  • vitamin D3 works synergistically to breakdown IP6 to IP3, thought to be a major active molecule.
  • Resveratrol also works synergistically to sensitize cells to vitamin D3 (sensitizes the vitamin D receptor on the cell surface).
  • Vitamin D serves to break down IP6 to IP3, which is its primary active form.
  • Vitamin D is also believed to act as an immune system enhancing agent, boosting innate immunity in humans. In this capacity, vitamin D has been shown experimentally to have important cancer-preventive and cancer-curing properties.
  • Resveratrol increases the sensitivity of the vitamin D receptor on the surface of cells, and thus is believed to act as an enhancing agent for vitamin D and as an anti-cancer agent. Resveratrol up-regulates the vitamin D receptor on the surface of cancer cells, and sensitizes cancer cells to vitamin D (Wietzke, J.A. et al. (2003) "Phytoestrogen Regulation Of A Vitamin D3 Receptor Promoter And 1,25- Dihydroxyvitamin D3 Actions In Human Breast Cancer Cells," J. Steroid Biochem. Molec. Biol. 84(2-3):149-157; Wietzke, J.A. et al.
  • Resveratrol is also believed to be a monoamine oxidase inhibitor (MAO Inhibitor).
  • Hyaluronic acid is the water gelling molecule of the human body which serves as its scaffolding and hydrating agent. As aging progresses, less Hyaluronic acid is produced, resulting in wrinkled skin, thinning hair, unlubricated joints.
  • the chelators of the present composition also help to preserve hyaluronic acid in the body.
  • the hyaluronic acid component and the mineral chelating components e.g., resveratrol, quercetin, phytic acid IP6, ferulate
  • Hyaluronic acid is believed to have an affinity to cancer cells.
  • hyaluronic acid to the compositions of the present invention is believed to activate fibroblast cells in the human body to produce additional hyaluronic acid, thus serving to preserve connective tissue (collagen) in a youthful state (Yadav, A.K. et al. (2008) "An Insight On Hyaluronic Acid In Drug Targeting And Drug Delivery;' J. Drug Target.
  • Phytic Acid preferably in the form of rice bran, is believed to act as an iron and copper chelator and as an inhibitor of calcium cystallization. Phytic Acid also is believed to reduce the availability of metallic minerals that serve as growth factors in tumor cells. It is also believed to serve as a neutrophil priming and motility agent. Additionally, phytic acid has been found to be neuroprotective, and thus to attenuate the severity of conditions associated with neurodegenerative diseases (especially Parkinson's Disease, camptocormia, and Alzheimer's Disease) (Xu, Q. et al.
  • compositions of the present invention are believed to enhance such neuroprotection.
  • the iron chelator, quercetin, if present, is believed to serve to increase immediate bioavailability of resveratrol by permitting more passes through the liver before it is metabolized.
  • the individual components of the composition are believed to act synergistically to enhance the effect of, for example, resveratrol. Without intending to be limited thereby, it is proposed that the body's control or chelation of iron and calcium regulates the rate of aging after full growth has been achieved.
  • all the iron and calcium are directed towards production of new bone and new red blood cells (hemoglobin).
  • the cessation of childhood growth results in excess iron, copper and calcium, which then progressively (a) calcifies and (b) rusts tissues.
  • the lysosomes begin to accumulate iron and calcium, which results in their dysfunction.
  • the mitochondria begin to malfunction as they also progressively rust and calcify.
  • compositions of the present invention are believed to be capable of limiting or slowing the progressive rusting and calcification of cells and cellular organelles to thereby facilitate a slowing or reversal of the aging process.
  • the chelation is what controls the genes. Genes are then favorably upregulated or downregulated. Resveratrol and a copper chelator are believed to act: (1) as controllers of calcium concentration via upregulation of osteocalcin, the hormone that helps retain calcium in bones and (2) as controllers of iron concentration via heme oxygenase, an antioxidant enzyme.
  • MAO inhibitors and iron chelators have been proposed as treatments for Parkinson' s disease (Youdim, M.B. et al. (2004) "Novel Bifunctional Drugs Targeting Monoamine Oxidase Inhibition And Iron Chelation As An Approach To Neuroprotection In Parkinson 's Disease And Other Neurodegenerative Diseases," J. Neural. Transm. 111(10-11): 1455-1471 ; Yanez, M. et al. (2006) "(-)-Trans-Epsilon-Viniferin, A Polyphenol Present In Wines, Is An Inhibitor Of Noradrenaline And 5-Hydroxytryptamine Uptake And Of Monoamine Oxidase Activity " Eur. J. Pharmacol.
  • compositions of the present invention which contain the MAO inhibitor and copper chelator, resveratrol, the iron chelator and MAO inhibitor, quercetin, and the broad metal chelator, phytic acid are particularly preferred for the treatment of neurodegenerative diseases (especially Parkinson's Disease, camptocormia, and Alzheimer's Disease) or in the amelioration of the symptoms of such diseases.
  • compositions of the present invention were more effective than resveratrol alone in mediating a resveratrol biological activity, an analysis of gene expression was conducted, comparing the modulation of gene expression achieved by calorie restriction to the modulation of gene expression achieved by the compositions of the present invention.
  • mice Male B6CHF1 mice (2 months of age) were thus either placed on a 40% calorie restricted diet, provided commercially obtained trans-resveratrol (Sigma Chemical; 1.25 mg/kg per day), provided a resveratrol-containing composition of the present invention (Longevinex®; Resveratrol Associates, LLC; 100 mg ?ra «,y-resveratrol containing capsule per 80 kg human per day (i.e., 2.5 mg/kg per day of resveratrol (1.25 mg/kg per day ?r ⁇ «,y-resveratrol) 0.31 mg/kg per day quercetin dihydrate, 0.94 mg/kg per day rice bran extract, 4.75 mg/kg per day rice bran oil and 0.70 mg/kg per day sunflower lecithin)). The mice were monitored until they had reached five months of age.
  • trans-resveratrol Sigma Chemical
  • a resveratrol-containing composition of the present invention Longevinex®; Resveratrol Associates, LLC;
  • FC is calculated as the mean of the treated group divided by the mean of the control group, and this value is then log-transformed (base 2) for statistical purposes.
  • base 2 a gene that is expressed at 100 in the control and 200 in a treated group would be have an Fc of 2 (i.e., a twofold increase in expression); a gene that is expressed at 100 in the control and 50 in the treated group, would have an Fc of -2 (i.e., a twofold decrease in expression).
  • Probe Set ID Treatment mean mean mean mean mean mean CR Res 4 X Entrez Info
  • Probe Set ID Treatment mean mean mean mean mean mean CR Res Lcjx Entrez Info
  • Probe Set ID Treatment mean mean mean mean mean mean CR Res Lcjx Entrez Info
  • Probe Set ID Treatment mean mean mean mean mean mean CR Res Lcjx Entrez Info
  • Probe Set ID Treatment mean mean mean mean mean mean CR Res Lcjx Entrez Info
  • Probe Set ID Treatment mean mean mean mean mean mean CR Res 4 X Entrez Info
  • Probe Set ID Treatment mean mean mean mean mean mean CR Res 4 X Entrez Info
  • Probe Set ID Treatment mean mean mean mean mean mean CR Res 4 X Entrez Info
  • Probe Set ID Treatment mean mean mean mean mean mean CR Res Lcjx Entrez Info
  • Probe Set ID Treatment mean mean mean mean mean mean CR Res 4 X Entrez Info
  • Probe Set ID Treatment mean mean mean mean mean mean CR Res 4 X Entrez Info
  • Probe Set ID Treatment mean mean mean mean mean mean CR Res 4 X Entrez Info
  • Probe Set ID Treatment mean mean mean mean mean mean CR Res Lcjx Entrez Info
  • Probe Set ID Treatment mean mean mean mean mean mean CR Res Lcjx Entrez Info
  • Probe Set ID Treatment mean mean mean mean mean mean CR Res Lcjx Entrez Info
  • Probe Set ID Treatment mean mean mean mean mean mean CR Res Lcjx Entrez Info
  • Probe Set ID Treatment mean mean mean mean mean mean CR Res 4 X Entrez Info

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Abstract

La présente invention concerne une composition contenant du resvératrol capable de moduler l'expression d'un gène dans une mesure plus importante que celle observée avec le resvératrol seul ou avec une restriction de calories. L'invention concerne particulièrement de telles compositions contenant du resvératrol qui renferment du resvératrol, un chélateur, de l'acide hyaluronique et/ou de la vitamine D et qui après administration à un receveur, augmentent la concentration ou l'activité d'un produit génique de survie/longévité et/ou diminuent la concentration ou l'activité d'un produit génique qui induit ou provoque des dommages cellulaires. Idéalement, la composition stabilisant le resvératrol renfermera de l'acide phytique chélateur (inositol hexaphosphate ; IP6), de l'acide hyaluronique et de la vitamine D. L'invention concerne en outre l'utilisation de telles compositions dans le traitement ou la prévention du cancer, de maladies cardiovasculaires, de maladies associées au vieillissement et d'autres affections et pathologies.
PCT/US2008/076707 2007-09-20 2008-09-17 Compositions contenant du resvératrol destinées à moduler la concentration ou l'activité d'un produit génique WO2009039195A1 (fr)

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CA2699908A CA2699908C (fr) 2007-09-20 2008-09-17 Compositions contenant du resveratrol destinees a moduler la concentration ou l'activite d'un produit genique
EP08831905A EP2197434A4 (fr) 2007-09-20 2008-09-17 Compositions contenant du resvératrol destinées à moduler la concentration ou l'activité d'un produit génique
JP2010525922A JP2010540444A (ja) 2007-09-20 2008-09-17 遺伝子産物の濃縮または活性を調節するためのレスベラトロールを含む組成物

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Cited By (14)

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JP2011079797A (ja) * 2009-10-09 2011-04-21 Yamada Bee Farm Corp 抗老化剤
WO2011089168A3 (fr) * 2010-01-21 2011-12-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Composition particuliere pour son application comme medicament
US20120058088A1 (en) * 2010-06-28 2012-03-08 Resveratrol Partners, Llc Resveratrol-Containing Compositions And Methods Of Use
WO2012138467A1 (fr) * 2011-04-05 2012-10-11 Hallstar Innovations Corp. Photostabilisation du resvératrol par des composés alcoxycrylènes
CN102908338A (zh) * 2012-11-20 2013-02-06 晨光生物科技集团天津有限公司 白藜芦醇微胶囊的制备方法
WO2013074948A1 (fr) * 2011-11-16 2013-05-23 Resveratrol Partners, Llc Compositions contenant du resvératrol et des nucléotides
WO2015057726A1 (fr) * 2013-10-14 2015-04-23 Biomarker Pharmaceuticals, Inc. Combinaisons de nutriments pour avoir une incidence sur un processus de vieillissement
JP2016153427A (ja) * 2016-05-20 2016-08-25 株式会社山田養蜂場本社 抗老化剤
JP2018052982A (ja) * 2017-12-26 2018-04-05 株式会社山田養蜂場本社 抗老化剤
US10352947B2 (en) 2012-09-12 2019-07-16 Berg Llc Use of markers in the identification of cardiotoxic agents and in the diagnosis and monitoring of cardiomyopathy and cardiovascular disease
US10702571B2 (en) 2015-12-03 2020-07-07 The University Of North Carolina At Pembroke Materials for cathepsin B enhancement and methods of use
US11479802B2 (en) 2017-04-11 2022-10-25 Regeneron Pharmaceuticals, Inc. Assays for screening activity of modulators of members of the hydroxy steroid (17-beta) dehydrogenase (HSD17B) family
US11485958B2 (en) 2017-01-23 2022-11-01 Regeneron Pharmaceuticals, Inc. HSD17B13 variants and uses thereof
US11702700B2 (en) 2017-10-11 2023-07-18 Regeneron Pharmaceuticals, Inc. Inhibition of HSD17B13 in the treatment of liver disease in patients expressing the PNPLA3 I148M variation

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JP5608629B2 (ja) * 2011-11-28 2014-10-15 アピオン・ジャパン有限会社 サーチュイン１（ｓｉｒｔ１）遺伝子活性化剤及びテロメラーゼ逆転写酵素（ｔｅｒｔ）遺伝子活性化剤
JP5933633B2 (ja) * 2014-06-18 2016-06-15 アピオン・ジャパン有限会社 サーチュイン１（ｓｉｒｔ１）遺伝子活性化剤及びテロメラーゼ逆転写酵素（ｔｅｒｔ）遺伝子活性化剤
EP4212449A1 (fr) * 2014-12-23 2023-07-19 Intelligent Packaging Pty Ltd. Récipient pour produit consommable revêtu d'une couche contenant du resvératrol

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Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011079797A (ja) * 2009-10-09 2011-04-21 Yamada Bee Farm Corp 抗老化剤
WO2011089168A3 (fr) * 2010-01-21 2011-12-29 INSERM (Institut National de la Santé et de la Recherche Médicale) Composition particuliere pour son application comme medicament
JP2013529685A (ja) * 2010-06-28 2013-07-22 レスベラトロル パートナーズ， エルエルシー レスベラトール含有組成物および使用方法
US20120058088A1 (en) * 2010-06-28 2012-03-08 Resveratrol Partners, Llc Resveratrol-Containing Compositions And Methods Of Use
EP2584897A4 (fr) * 2010-06-28 2014-01-22 Resveratrol Partners Llc Compositions contenant du resvératrol et procédés d'utilisation
EP2584897A1 (fr) * 2010-06-28 2013-05-01 Resveratrol Partners, Llc Compositions contenant du resvératrol et procédés d'utilisation
US20140011889A1 (en) * 2010-06-28 2014-01-09 Resveratrol Partners, Llc Resveratrol-Containing Compositions and Methods of Use for Cardiac-Related Diseases
WO2012138467A1 (fr) * 2011-04-05 2012-10-11 Hallstar Innovations Corp. Photostabilisation du resvératrol par des composés alcoxycrylènes
WO2013074948A1 (fr) * 2011-11-16 2013-05-23 Resveratrol Partners, Llc Compositions contenant du resvératrol et des nucléotides
US8916528B2 (en) 2011-11-16 2014-12-23 Resveratrol Partners, Llc Compositions containing resveratrol and nucleotides
US9226937B2 (en) 2011-11-16 2016-01-05 Resveratrol Partners, Llc Compositions containing resveratrol and nucleotides
US10352947B2 (en) 2012-09-12 2019-07-16 Berg Llc Use of markers in the identification of cardiotoxic agents and in the diagnosis and monitoring of cardiomyopathy and cardiovascular disease
CN102908338A (zh) * 2012-11-20 2013-02-06 晨光生物科技集团天津有限公司 白藜芦醇微胶囊的制备方法
US9138453B2 (en) 2013-10-14 2015-09-22 Biomarker Pharmaceuticals, Inc. Nutrient combinations for affecting an aging process
US10016476B2 (en) 2013-10-14 2018-07-10 Biomarker Pharmaceuticals, Inc. Nutrient combinations for affecting an aging process
WO2015057726A1 (fr) * 2013-10-14 2015-04-23 Biomarker Pharmaceuticals, Inc. Combinaisons de nutriments pour avoir une incidence sur un processus de vieillissement
US10702571B2 (en) 2015-12-03 2020-07-07 The University Of North Carolina At Pembroke Materials for cathepsin B enhancement and methods of use
JP2016153427A (ja) * 2016-05-20 2016-08-25 株式会社山田養蜂場本社 抗老化剤
US11485958B2 (en) 2017-01-23 2022-11-01 Regeneron Pharmaceuticals, Inc. HSD17B13 variants and uses thereof
US11753628B2 (en) 2017-01-23 2023-09-12 Regeneron Pharmaceuticals, Inc. HSD17B13 variants and uses thereof
US11845963B2 (en) 2017-01-23 2023-12-19 Regeneron Pharmaceuticals, Inc. HSD17B13 variants and uses thereof
US11479802B2 (en) 2017-04-11 2022-10-25 Regeneron Pharmaceuticals, Inc. Assays for screening activity of modulators of members of the hydroxy steroid (17-beta) dehydrogenase (HSD17B) family
US11702700B2 (en) 2017-10-11 2023-07-18 Regeneron Pharmaceuticals, Inc. Inhibition of HSD17B13 in the treatment of liver disease in patients expressing the PNPLA3 I148M variation
JP2018052982A (ja) * 2017-12-26 2018-04-05 株式会社山田養蜂場本社 抗老化剤

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