Source: http://www.google.com/patents/US7923041?dq=5,870,513
Timestamp: 2014-03-14 08:10:01
Document Index: 779922798

Matched Legal Cases: ['art 2', 'art 1', 'art 1', 'art 3', 'art 1', 'art 2', 'art 3']

Patent US7923041 - Compositions and methods for enhancing cognitive function - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inAdvanced Patent SearchPatentsDisclosed are compositions for promoting general health and well-being, comprising an extract of a botanical raw material, wherein said extract inhibits the carboxyl demethylating activity of a protein phosphatase, and methods of making and using same....http://www.google.com/patents/US7923041?utm_source=gb-gplus-sharePatent US7923041 - Compositions and methods for enhancing cognitive functionAdvanced Patent SearchPublication numberUS7923041 B2Publication typeGrantApplication numberUS 11/890,278Publication dateApr 12, 2011Filing dateAug 3, 2007Priority dateFeb 3, 2005Also published asUS20080213406Publication number11890278, 890278, US 7923041 B2, US 7923041B2, US-B2-7923041, US7923041 B2, US7923041B2InventorsJeffry Stock, Maxwell Stock, Haoming Gu, Zhu Li, Peter WolaninOriginal AssigneeSignum Biosciences, Inc., The Trustees Of Princeton UniversityExport CitationBiBTeX, EndNote, RefManPatent Citations (101), Non-Patent Citations (305), Referenced by (1), Classifications (56), Legal Events (2) External Links: USPTO, USPTO Assignment, EspacenetCompositions and methods for enhancing cognitive functionUS 7923041 B2Abstract Disclosed are compositions for promoting general health and well-being, comprising an extract of a botanical raw material, wherein said extract inhibits the carboxyl demethylating activity of a protein phosphatase, and methods of making and using same.
1. A method to obtain a botanical extract having PP2A methylation modifying activity, the method comprising steps of:
contacting botanical raw material selected from the group consisting of coffea, gingko, garlic, bacopa, butcher's broom, flaxseed oil, ginseng, grape seed, St. John's wort, artichoke powder, tea leaf, tobacco, and cocoa, with a polar solvent to form an extract solution; and
separating the extract solution into a plurality of fractions;
assessing PP2A carboxyl methylation modifying activity in at least two fractions, so that those fractions containing PP2A carboxyl methylation modifying activity are identified; and
obtaining as a botanical extract at least one fraction or combination of fractions that
(1) is essentially free of caffeine, caffeic acid, and chlorogenic acid; and
(2) contains the carboxyl methylation modifying activity at a concentration sufficient so that, when the extract is contacted with protein phosphatase 2A (�PP2A�) and an enzyme selected from the group consisting of PP2A-specific protein methyltransferase (�PPMT�), PP2A-specific protein methylesterase (�PPME�), and combination thereof, the extent of PP2A carboxyl methylation is altered as compared with that observed absent the extract.
2. The method of claim 1, further comprising a step of adding to the botanical extract at least one ingredient selected from the group consisting of an excipient, an electrolyte, a legal stimulant, a vitamin, and a mineral.
3. The method of claim 1, wherein the botanical extract is prepared from a plant of a species of plant genus Coffea. 4. The method of claim 1, further comprising the step of combining the extract with one or more additional components to form a beverage.
5. The method of claim 4, wherein the beverage is selected from the group consisting of a drink comprising water, a fruit drink, a coffee, a tea, an energy drink, a baby formula, an adult nutritional drink, a health drink, and a sports drink.
6. The method of claim 1, further comprising the step of combining the extract with one or more additional components to form a food, a cereal, a chewing gum, or a candy.
7. The method of claim 1, wherein the botanical extract is in the form of a powder, a tablet, a pill, a capsule, or a lozenge.
8. The method of claim 1, wherein the polar solvent is ethanol, and wherein at least a portion of the ethanol is subsequently removed to form a concentrated extract.
9. The method of claim 1, further comprising discarding at least one fraction with lower levels of PP2A carboxyl methylation modifying activity after the step of assessing.
GOVERNMENT RIGHTS This invention was made with government support under Grant #5 R01GM061284 awarded by the National Institutes of Health. The government has certain rights in this invention.
BACKGROUND OF THE INVENTION Alzheimer's disease (AD) is one of the most prevalent of progressive brain disorders. Currently an estimated 4.5 million older Americans suffer from AD. According to the latest estimates of the current and future prevalence of AD, the number of older people with AD will grow dramatically as the population ages. Projections indicate that as many as 13 million older Americans will have AD by 2050 unless new ways are found to prevent or treat the disease. AD is currently the third most expensive disease after heart disease and cancer. Treatment and care of those with AD now run $100 to $150 billion a year and costs are projected to rise sharply as the population ages. Currently, pharmacological treatment of AD is primarily based on the use of acetylcholinesterase inhibitors (AChEIs), which have been reported to provide beneficial effects on cognitive, functional, and behavioral symptoms of the disease. Four of the 5 drugs approved for AD treatment in the U.S.�donepezil (Aricept�), rivastigmine (Exelon�), galantamine (Reminyl�), and tacrine (Cognex�)�are AchEIs. The fifth, Mementine (Namenda�), is an N-methyl-D-aspartate (�NMDA�) antagonist that alters glutamate signaling. Because only a small fraction of AD patients respond to this type of treatment, any new approach to the treatment or prevention of AD would have tremendous value. In spite of intensive research, there are no proven preventive agents or agents capable of limiting progression of the disease, and the few which have been used to ameliorate its symptoms have exhibited side effects of nausea, vomiting, diarrhea, and even liver damage, yet do not meaningfully slow the disease's underlying course for most patients. AD may well be the most pharmaceutically under-served major disease in the U.S.
The variable B subunits of PP2A are classified into 4 families: (1) the B family with four isoforms (α, β, γ, δ); (2) the B′ family with five isoforms (α, β, γ, δ, ∈); (3) the B″ family; and (4) the B′″ family. The PP2A ABα-C heterotrimer appears to be the major phosphatase in brain responsible for dephosphorylation of tau. (Kamibayashi, C. et al., J. Biol. Chem. 269(31):20139-148 (1994); Sontag, E., et al., J. Neuropahol. Exp. Neurol. 63(4):287-301 (2004)).
Homocysteine, a sulfur-containing amino acid that can be either recarboxyl methylated to methionine or undergo a trans-sulfuration reaction to cystathionine, plays a key role in methylation metabolism (see FIG. 1). The conversion of homocysteine to methionine occurs in all tissues. Methionine is activated by ATP in the presence of methionine adenosyl transferase (labeled as (1) in FIG. 1) to form the methyl donor, S-adenosylmethionine (�SAM�). SAM-dependent methylation reactions in the presence of SAM-dependent methyltransferases (labeled as (2) in FIG. 1) result in the formation of S-adenosylhomocysteine (�SAH�), which is cleaved by SAH hydrolase (labeled as (3) in FIG. 1) to form adenosine and homocysteine. This reaction is reversible with the equilibrium favoring the condensation of homocysteine and adenosine. Under normal conditions, homocysteine is rapidly carboxyl methylated, which favors the further cleavage of SAH. Homocysteine accumulation leads to global decreases in cellular methylation by the condensation of homocysteine with adenosine to form SAH, which acts as a product inhibitor in cellular methylation reactions. In the United States, 5-10% of the general population has elevated plasma homocysteine, and this imbalance increases to 30-40% in of the elderly. (Selub J., et al., Ann. Intern. Med. 131(5):331-39 (1999)). The enzymes cystathionine L-synthase; cystathionine Q lyase; betaine homocysteine methyltransferase; and methionine synthase are labeled as (4), (5), (6) and (7), respectively in FIG. 1. See Vafai, S. B., Stock, J. B., FEBS Lett. 2:518 (2002).
In some embodiments of these aspects of the present invention, the composition (e.g., comestible) inhibits carboxyl demethylating activity of protein phosphatase 2A specific protein methylesterase. In some embodiments, the botanical raw material comprises at least one substance selected from the group consisting of gingko, garlic, bacopa, butcher's broom, flaxseed oil, ginseng, grape seed, St. John's wort, artichoke, coffee, tea, tobacco and cocoa. In some embodiments, the botanical raw material comprises a fruit of a species of plant genus Coffea, such as coffee bean (e.g., ground beans or instant coffee). In some other embodiments, the botanical raw material comprises grape seed or cocoa.
In other embodiments, the compositions of the present invention may be prepared simply by admixing the active botanical extracts with one or more excipients that are generally regarding as pharmaceutically acceptable excipients. The composition can be formulated for administration via several conventionally acceptable routes. The compositions are prepared by admixing the active botanical extracts with one or more inert excipients (e.g., carriers, vehicles, binders, diluents etc.) suitable for the selected route of administration. The term �excipients� as used herein refers to pharmaceutically acceptable organic or inorganic substances which do not deleteriously react with the active compounds. Suitable excipients include, but are not limited to, dietary suitable starch, vegetable oil, vegetable gums, gelatins, soy extracts, sugars, grains, natural and artificial flavorings, and the like. Suitable carriers include, but are not limited to, water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil; fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidone, and the like. Suitable excipients are described in detail in Remington's Pharmaceutical Sciences, Twentieth Edition, � 2000 incorporated herein by reference.
A skilled artisan can determine a beneficial (e.g., therapeutically effective) amount of the inventive compositions by determining the unit dose. As used herein, a �unit dose� refers to the amount of inventive composition required to produce a response of 50% of maximal effect (i.e. ED50). The unit dose can be assessed by extrapolating from dose-response curves derived from in vitro or animal model test systems. The amount of compounds in the compositions of the present invention which will be effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques. (See, for example, Goodman and Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Joel G. Harman, Lee E. Limbird, Eds.; McGraw Hill, N.Y., 2001; THE PHYSICIAN'S DESK REFERENCE, Medical Economics Company, Inc., Oradell, N.J., 1995; and DRUG FACTS AND COMPARISONS, FACTS AND COMPARISONS, INC., St. Louis, Mo., 1993). The precise amount to be employed in the formulation will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances. Various administration patterns will be apparent to those skilled in the art.
As used herein to refer to assay results, the term �inhibition activity� refers to the following relationship: Inhibition activity=1−(amount of methyl-PP2A carboxyl demethylated with inhibitor)/(amount of methyl-PP2A carboxyl decarboxyl methylated without inhibitor).
Flaxseed oil�
Ginseng�100 mg of
Cocoa, unsweetened�
Extract C72-2: 62 g of ground decaffeinated coffee (Eight O'clock brand) was extracted at room temperature with 600 ml of 100% ethanol for 18 hours. The ethanol extract was filtered though a Whatman paper thimble, and then the ethanol removed using a rotovap to yield the concentrated primary extract. The primary extract was further processed to a concentrated final extract as described above for C71-2. The final yield was 252 mg.
Patent CitationsCited PatentFiling datePublication dateApplicantTitleUS2852520Jan 8, 1957Sep 16, 1958Searle & CoTrialkoxybenzoyloxyalkyl derivatives related to norharmanUS3832253Mar 21, 1973Aug 27, 1974Baxter Laboratories IncMethod of making an inflatable balloon catheterUS3854480Jun 2, 1970Dec 17, 1974Alza CorpDrug-delivery systemUS4105027Oct 26, 1976Aug 8, 1978Syntex Puerto Rico, Inc.Inhalation deviceUS4185118Jan 12, 1979Jan 22, 1980Sandoz, Inc.BenzocycloalkylamidesUS4192309Sep 5, 1978Mar 11, 1980Syntex Puerto Rico, Inc.Inhalation device with capsule openerUS4194002Mar 29, 1978Mar 18, 1980Sandoz, Inc.Cholesterol ester-reducing amides of hexahydroindolinolsUS4201785Apr 4, 1979May 6, 1980Sandoz Inc.Cyclopropanyl-bearing hydrazidesUS4227522Sep 5, 1978Oct 14, 1980Syntex Puerto Rico, Inc.Inhalation deviceUS4229463Feb 27, 1978Oct 21, 1980Sandoz, Inc.Unsaturated fatty acid hydrazidesUS4248893Feb 5, 1979Feb 3, 1981Sandoz, Inc.Arterial wall cholesterol ester reducing cyclopropanyl-bearing amidesUS4409253Aug 26, 1982Oct 11, 1983The Procter & Gamble CompanyRecovery of noncaffeine solubles in an extract decaffeination processUS4448785Jun 24, 1982May 15, 1984Sandoz, Inc.N-Unsaturated fatty acid amides of tryptophan ester homologues and anti-cholesteric use thereofUS4452775Dec 3, 1982Jun 5, 1984Syntex (U.S.A.) Inc.Cholesterol matrix delivery system for sustained release of macromoleculesUS4627432Oct 7, 1983Dec 9, 1986Glaxo Group LimitedDevices for administering medicaments to patientsUS4658063Apr 15, 1985Apr 14, 1987Nisshin Flour Milling Co., Ltd.Isoprenylamine derivativesUS4667014May 20, 1983May 19, 1987Syntex (U.S.A.) Inc.Nonapeptide and decapeptide analogs of LHRH, useful as LHRH antagonistsUS4709094Jul 10, 1986Nov 24, 1987State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of OregonSigma brain receptor ligands and their useUS4748034Apr 18, 1986May 31, 1988Nestec S.A.Preparing a heat stable aqueous solution of whey proteinsUS4811731Jul 29, 1986Mar 14, 1989Glaxo Group LimitedDevices for administering medicaments to patientsUS4900749Mar 10, 1986Feb 13, 1990Shionogi & Co., Ltd.Isoprenoidamine compounds useful as antiulcer agentsUS4906779Aug 29, 1988Mar 6, 1990State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences UniversityN,N'-disubstituted guanidines and their use as excitatory amino acid antagonistsUS4933324Feb 24, 1989Jun 12, 1990Shashoua Victor EFatty acid-neuroactive drug conjugate as a prodrugUS4935422Dec 15, 1988Jun 19, 1990E. I. Du Pont De Nemours And CompanyAcyloxypropanolaminesUS4939174Feb 26, 1988Jul 3, 1990Shashoua Victor EAppetite suppression with dopamine-fatty acid conjugatesUS4977170May 3, 1989Dec 11, 1990Shionogi & Co., Ltd.Isoprenoidamine compounds which are useful antiulcer agentsUS5035237Dec 27, 1988Jul 30, 1991Newell Robert EDevices for administering medicaments to patientsUS5075109Mar 18, 1988Dec 24, 1991Southern Research InstituteMethod of potentiating an immune responseUS5093525Mar 2, 1990Mar 3, 1992State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences UniversityN,N'-disubstituted guanidines and their use as excitatory amino acid antagonistsUS5175183Jan 25, 1990Dec 29, 1992Abbott LaboratoriesLipoxygenase inhibiting compoundsUS5189049Dec 5, 1990Feb 23, 1993SanofiHeterocyclic substituted acylaminothiazoles, their preparation and pharmaceutical compositions containing themUS5190976Mar 2, 1992Mar 2, 1993State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And University Of OregonN,N'-disubstituted guanidines and their use as excitatory amino acid antagonistsUS5239660Oct 30, 1991Aug 24, 1993Nec CorporationVector processor which can be formed by an integrated circuit of a small sizeUS5284876Jun 11, 1992Feb 8, 1994Neuromedica, Inc.Method of treating tardive dyskinesia using dopaminergic agents of prodrugs of therapeutic agentsUS5322858Feb 14, 1992Jun 21, 1994Jacobus Pharmaceutical Co. Inc.N,N'-substituted imidodicarbonimidic diamides derived from hydroxylaminesUS5502056May 27, 1994Mar 26, 1996Breitbarth; RichardCaffeine containing compositionUS5527811Jul 13, 1994Jun 18, 1996Takeda Chemical Industries, Ltd.Isoquinolinyl compounds which are useful in treating cerebral vascular disordersUS5565491Jan 31, 1994Oct 15, 1996Bristol-Myers Squibb CompanyUse of phosphotyrosine phospatase inhibitors for controlling cellular proliferationUS5585358Jul 6, 1993Dec 17, 1996Teva Pharmaceutical Industries Ltd.Derivatives of valproic acid amides and 2-valproenoic acid amides, method of making and use thereof as anticonvulsant agentsUS5585513Jun 6, 1995Dec 17, 1996Zeneca LimitedFungicidesUS5668180May 30, 1996Sep 16, 1997Adir Et CompagnieAlkoxyaryl compoundsUS5670499Jun 5, 1995Sep 23, 1997Eli Lilly And CompanyNon-peptide tachykinin receptor antagonistsUS5684033Jun 5, 1995Nov 4, 1997Eli Lilly And CompanyNon-peptide tachykinin receptor antagonistsUS5693627May 25, 1995Dec 2, 1997Bristol-Myers Squibb CompanyUse of phosphotyrosine phosphatase inhibitors for controlling cellular proliferationUS5700821Jul 30, 1996Dec 23, 1997University Of PittsburghPhosphatase inhibitors and methods of use thereofUS5714094Jul 11, 1995Feb 3, 1998Nestec S.A.Antioxidant composition and process for the preparation thereofUS5777162Nov 12, 1996Jul 7, 1998Zeneca LimitedIntermediates for the preparation of fungicidesUS5795877Dec 31, 1996Aug 18, 1998Guilford Pharmaceuticals Inc.Inhibitors of NAALADase enzyme activityUS5821261Nov 8, 1996Oct 13, 1998Merck & Co., Inc.Substituted saturated aza heterocycles as inhibitors of nitric oxide synthaseUS5824662Sep 27, 1996Oct 20, 1998Guilford Pharmaceuticals Inc.Treatment of global and focal ischemia using naaladase inhibitorsUS5849764Dec 5, 1996Dec 15, 1998Merck & Co., Inc.Antagonists of gonadotropin releasing hormoneUS5856506Aug 22, 1997Jan 5, 1999University Of PittsburghPhosphatase inhibitors and methods of use thereofUS5863536Dec 31, 1996Jan 26, 1999Guilford Pharmaceuticals Inc.Phosphoramidate derivativesUS5880132Dec 15, 1995Mar 9, 1999Merck Sharp & Dohme LimitedTachykinin antagonist and an opioid analgesic effective at treating pain or nociceptionUS5902817Apr 9, 1997May 11, 1999Guilford Pharmaceuticals Inc.Certain sulfoxide and sulfone derivativesUS5914242Oct 1, 1997Jun 22, 1999South Alabama Medical Science FoundationMethod for diminishing myocardial infarction using protein phosphatase inhibitorsUS5925660Aug 22, 1997Jul 20, 1999University Of PittsburghPhosphatase inhibitors and methods of use thereofUS5939563Mar 30, 1998Aug 17, 1999Zeneca LimitedO-methyloximes of benzopyran-3,4- and benzofuran-2,3-diones and methods for their preparationUS5962521Apr 4, 1997Oct 5, 1999Guilford Pharmaceuticals Inc.Hydroxamic acid derivativesUS5977090Jul 23, 1997Nov 2, 1999Guilford Pharmaceuticals Inc.Pharmaceutical compositions and methods of treating compulsive disorders using NAALADase inhibitorsUS5981526Oct 3, 1997Nov 9, 1999Merck Sharp & Dohme Ltd.Use of tachykinin antagonist and rizatriptanUS5985855Nov 20, 1997Nov 16, 1999Guilford Pharmaceuticals Inc.Treatment of global and focal ischemia using NAALADase inhibitorsUS5994392Jun 5, 1995Nov 30, 1999Neuromedica, Inc.Antipsychotic prodrugs comprising an antipsychotic agent coupled to an unsaturated fatty acidUS6004946Jul 8, 1997Dec 21, 1999Guilford Pharmaceuticals Inc.Treatment of global and focal ischemia using naaladase inhibitorsUS6013658Jul 17, 1997Jan 11, 2000Novo Nordisk A/SCompounds with growth hormone releasing propertiesUS6017903Jun 27, 1997Jan 25, 2000Guilford Pharmaceuticals Inc.Pharmaceutical compositions and methods of treating a glutamate abnormality and effecting a neuronal activity in an animal using NAALADase inhibitorsUS6025344May 27, 1997Feb 15, 2000Guilford Pharmaceuticals Inc.Certain dioic acid derivatives useful as NAALADase inhibitorsUS6040323Aug 22, 1997Mar 21, 2000University Of PittsburghPhosphatase inhibitors and methods of use thereofUS6046180May 27, 1997Apr 4, 2000Guilford Pharmaceuticals Inc.NAALADase inhibitorsUS6048868Mar 17, 1998Apr 11, 2000CemafMelatonin-antagonist β-carboline derivatives and analogues thereof containing naphthalenic structure, process for their preparation and their use as medicinal productsUS6054444Apr 24, 1997Apr 25, 2000Guilford Pharmaceuticals Inc.Phosphonic acid derivativesUS6071965Dec 31, 1997Jun 6, 2000Guilford Pharmaceuticals Inc.Phosphinic alkanoic acid derivativesUS6107499Jun 6, 1995Aug 22, 2000Neuromedica, Inc.Dopamine analog amideUS6132973Jan 20, 1999Oct 17, 2000Incyte Pharmaceuticals, Inc.Human regulatory moleculesUS6140324Jul 8, 1996Oct 31, 2000Merck Sharp & Dohme Ltd.Use of a tachykinin antagonist and a muscarinic antagonist and/or an antihistamine to treat motion sicknessUS6159704Mar 17, 1997Dec 12, 2000Novartis AgPhosphatase modulatorUS6180624Feb 25, 1999Jan 30, 2001Merck Sharp & Dohme LimitedTachykinin antagonist and an opioid analgesic effective at treating pain or nociceptionUS6200768Dec 7, 1992Mar 13, 2001Max-Planck-Gesellschaft Zur Forderung Der WissenschaftenMethod of screening for compounds that dissolve paired helical filamentsUS6232110Apr 16, 1999May 15, 2001Emory UniveristyCoding sequence for protein phosphatase methylesterase, recombinant DNA molecules and methodsUS6271245Jun 1, 1999Aug 7, 2001Guilford Pharmaceuticals, Inc.Hydroxamic acid derivativesUS6277566Feb 13, 1998Aug 21, 2001Phillip A. BeachyMethod for identifying a hedgehog-mediated phosphorylation state dependent transcription factorUS6288046Apr 26, 1999Sep 11, 2001Guilford Pharmaceuticals Inc.Phosphonic acid derivativesUS6300363Jul 3, 1998Oct 9, 2001Pfizer Inc.Indole compounds as COX-2 inhibitorsUS6303610Jul 8, 1998Oct 16, 2001Eli Lilly And CompanyMethod of treating gout with certain indole compoundsUS6306912Jun 7, 1995Oct 23, 2001Nps Pharmaceuticals, Inc.Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseasesUS6337344Dec 10, 1998Jan 8, 2002Aventis Pharma Deutschland GmbhIndole derivatives as inhibitors or factor XaUS6350767Nov 19, 1999Feb 26, 2002Novo Nordisk A/SCompounds with growth hormone releasing propertiesUS6353015Aug 25, 1999Mar 5, 2002St. Elizabeth's Medical CenterMethod of treating neurodegenerative disordersUS6372752Feb 7, 2000Apr 16, 2002Genzyme CorporationInha inhibitors and methods of use thereofUS6376205Mar 25, 1996Apr 23, 2002University Court Of The University Of AberdeenScreening methods for agents that modulate or inhibit tau association with tau or map2US6399796Mar 15, 2001Jun 4, 2002Roche Vitamins Inc.Activation of a Diels-Alder reaction of a sterol 5,7-dieneUS6403577Nov 17, 1993Jun 11, 2002Eli Lilly And CompanyHexamethyleneiminyl tachykinin receptor antagonistsUS6451468Apr 1, 1999Sep 17, 2002Three Bond Co., Ltd.Sealing material for fuel cellUS6458392Jul 11, 2001Oct 1, 2002Kao CorporationPreventive, alleviative or remedy for hypertensionUS6462086Jun 19, 2000Oct 8, 2002Ramot University Authority For Applied Research And Industrial Development Ltd.Non-malignant disease treatment with Ras antagonistsUS6465457Sep 9, 1992Oct 15, 2002Zeneca LimitedCarbonate, carbamate, thiocarbonate dithiocarbonate and thiocarbomate derivatives useful as fungicidesUS6492128Feb 26, 1998Dec 10, 2002Ramot University Authority For Applied Research & Industrial Development, Ltd.Drug screen targeting lipoprotein-membrane anchorageUS6503949May 16, 2000Jan 7, 2003Noro Nordisk A/SGlucagon antagonists/inverse agonistsUS6528295Apr 20, 2001Mar 4, 2003Emory UniversityProtein phosphatase methylesteraseUS20060159773 *Jan 20, 2006Jul 20, 2006Stephen HoltHerbal compositions containing hoodiaUS20090029355 *Nov 15, 2004Jan 29, 2009Wei-Qin ZhaoAbnormalities of Phosphatase 2A (PP2A) for Diagnosis and Treatment of Alzheimer's Disease* Cited by examinerNon-Patent CitationsReference1Abolhassani et al., "Hyperosmolarity Causes Inflammation through the Methylation of Protein Phosphatase 2A," Inflammation Research, 2008, 57(9), pp. 419-429, ISSN: 1023-3830.2Acker et al., "Photometric determination of shell constituents in cocoa products," 1966, Suesswaren (Hamburg), 15(10):622-4, 626-8.3Aggen et al., "The Design, Synthesis, and Biological Evaluation of Analogues of the Serine-threonine Protein Phosphatase 1 and 2A Selective Inhibitor Microcystin LA: Rational Modifications Imparting PP1 Selectivity," Bioorganic & Medicinal Chemistry, 1999, 7(3), pp. 543-564, ISSN: 0968-0896.4Albaugh et al., "Determination of distance distribution from time domain fluorometry," 1989, J of Physical Chemistry, 93(24):8013-16.5Alonso et al., "Alzheimer's disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassemles microtubules," 1996, Nat Med, 2(7):783-787.6Alonso et al., "Hyperphosphorylation induces self-assembly of T into tangles of paired helical filaments / straight filaments," 2001, Proc Natl Acad Sci U S A, 98:6923-2928.7Alonso et al., "Protein Tyrosine Phosphatases in the Human Genome," 2004, Cell, 117:699-711.8Alonso et al., "Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease," 1994, Proc Natl Acad Sci U S A, 91:5562-5566.9Appendino et al., "First 'hybrid' ligands of vanilloid TRPV1 and cannabinoid CB2 receptors and non-polyunsaturated fatty acid-derived CB2-selective ligands," 2006, FEBS Letters, 580(2):568-574.10Appendino et al., "First �hybrid� ligands of vanilloid TRPV1 and cannabinoid CB2 receptors and non-polyunsaturated fatty acid-derived CB2-selective ligands," 2006, FEBS Letters, 580(2):568-574.11Arino et al., "Human liver phosphatase 2A: cDNA and amino acid sequence of two catalytic subunit isotypes," 1988, Proc Nat'l. Acad Sci. USA, 85:4252-4256.12Ascherio et al., "Prospective Study of Caffeine Consumption and Risk of Parkinson's Disease in Men and Women," 2001, Ann Neurol, 50:56-63.13Bai et al., "Huperzine A, A Potential therapeutic Agent for Treatment of Alzheimer's Disease," 2000, Current Medicinal Chemistry, 7:355-374.14Battini et al., "Determination of N-Alkanoyl-5-Hydroxytryptamines (C-5-HT) in Coffee Beans by Means of HPLC and TLC," Annali di Chimica, 1989, 79(7-8), pp. 369-377.15Baumann, et al., "Abnormal Alzheimer-like phosphorylation of tau-protein by cyclin-dependent kinases cdk2 and cdk5," 1993, FEBS, 336(3):417-424.16Bialy et al., "Synthesis and Biological Evaluation of Cytostatin Analogues," Chemical Communications, 2003, 15, pp. 1872-1873, ISSN: 1359-7345.17Bialy et al., "Synthesis of the Protein Phosphatase 2A Inhibitor (4S,5S,6S,10S,11S,12S)-cytostatin," Angewandte Chemie, International Edition, 2002, 41(10), pp. 1748-1751, ISSN: 1433-7851.18Bialy et al., "Synthesis of the Protein Phosphatase 2A Inhibitor (4S,5S,6S,10S,11S,12S)�cytostatin," Angewandte Chemie, International Edition, 2002, 41(10), pp. 1748-1751, ISSN: 1433-7851.19Biernat et al., "Phosphorylation of Ser262 Strongly Reduces Binding of Tau to Microtubules: Distinction between PHF-like Immunoreactivity and Microtubule Binding," 1993, Neuron,11:153-163.20Billingsley et al., "Regulated phosphorylation and dephosphorylation of tau protein: effects on microtubule interaction, intracellular trafficking and neurodegeneration," 1997, Biochem J., 323:577-91.21Blickenstaff et al., "Potential radioprotective agents. 1. Homologs of melatonin," 1994, J. of Pharmaceutical Sciences, 83(2):216-18.22Blickenstaff et al., "Potential radioprotective agents. VI. Chalcones, benzophenones, acid hydrazides, nitro amines and chloro compounds. Radioprotection of murine intestinal stem cells," 1995, Bioorganic & Medicinal Chemistry 3(7):917-22.23Blickenstaff et al., "Potential radioprotective agents-V. Melatonin analogs. Oral activity of p-aminopropiophenone and its ethylene ketal," 1994, Bioorganic & Medicinal Chemistry 2(10):1057-60.24Boger et al., "Total Synthesis of Fostriecin (Cl-920)," Journal of the American Chemical Society, 2001, 123(18), pp. 4161-4167, ISSN: 0002-7863.25Borsotto et al., "PP2A-By subunit and KCNQ2K+channels in bipolar disorder," 2007, Pharmacogenomics J., 7:123-132.26Boushey et al., "A quantitative assessment of plasma homocysteine as a risk factor for vascular disease," 1995, Jama, 274:1049-1057.27Bramblett, et al, "Abnormal Tau Phosphorylation at Ser396 in alzheimer's Disease Receapitulates Development and Contributes to Reduced Microtubule Binding," 1993, Neuron, 10:1089-1099.28Breitner, John, "Inflammatory Processes and Antinflammatory Drugs in Alzheimer's Disease: A Current Appraisal," 1996, Neurobiology of Aging, 17(5):789-794.29Brookmeyer et al., "Forecasting the global burden of Alzheimer disease," 2007, Alzheimer's and Dementia, 3(3):186-191.30Bryant et al., "Methylated C-terminal Leucine Residue of PP2A Catalytic Subunit is Important for Binding of Regulatory Balpha Subunit," Biochemical Journal, 1999, 339(2), pp. 241-246, ISSN: 0264-6021.31Bryant et al., "Methylated C-terminal Leucine Residue of PP2A Catalytic Subunit is Important for Binding of Regulatory Bα Subunit," Biochemical Journal, 1999, 339(2), pp. 241-246, ISSN: 0264-6021.32Bu�e et al., "Tau protein isoforms, phosphorylation and role in neurodegenerative disorders," 2000, Brain Res. Rev., 33(1):95-130.33Buznikov et al., "5-Hydroxytryptamides and 3-hydroxytyramides of polyenoic fatty acids as a tool for studying the pre-nervous biogenic monoamines' functions," 2000, Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, 86(9):1093-1108 (English language abstract in Appendix A).34Caudill et al., "Intracellular S-Adenosylhomocysteine Concentrations Predict Gobal DNA Hypomethylation in Tissues of Methyl-Deficient Cystathionine beta-Synthase Heterozygous Mice," 2001, American Society for Nutritional Sciences, 131:2811-2818.35Caudill et al., "Intracellular S-Adenosylhomocysteine Concentrations Predict Gobal DNA Hypomethylation in Tissues of Methyl-Deficient Cystathionine β-Synthase Heterozygous Mice," 2001, American Society for Nutritional Sciences, 131:2811-2818.36Cavin et al., "Cafestol and kahweol, two coffee specific diterpenes with anticarcinogenic activity," 2002, Food and Chemical Toxicology, 40:1155-1163.37Ceulemans et al., "Functional Diversity of Protein Phosphatase-1, a Cellular Economizer and Reset Button," 2004, Physiol. Rev., 84:1-39.38Chan et al., "Folate Deprivation Increases Tau Phosphorylation by Homocysteine-induced Calcium Influx and by Inhibition of Phosphatase Activity: Alleviation by S-adenosyl Methionine," Brain Research, 2008, 1199, pp. 133-137, ISSN: 0006-8993.39Chandra et al., "Incidence Alzheimer's disease ina rural community in India," 2001, Neurology, 57(6).40Chao et al., "Structure and Mechanism of the Phosphotyrosyl Phosphatase Activator," 2006, Molecular Cell, 23(4):535-546.41Chavez et al., "Tryptamine Derived Amides and Acetogenins from the Seeds of Rollinia mucosa," 1999, J. Of Natural Products, 62(8):1119-1122.42Chen et al., "Cheritamine, a new N-fatty acyl tryptamine and other consituents from the stems of Annona cherimola," 1999, J. of the Chinese Chemical Society (Taipei), 46(1):77-86.43Chen et al., "Comparison of Protein Phosphatase Inhibition Activities and Mouse Toxicities of Microcystins," Toxicon, 2006, 47(7), pp. 742-746, ISSN: 0041-0101.44Chen et al., "Improved Synthesis and Characterization of L-histidine Norcantharimide, a Novel Potent Protein Phosphatase 2A Inhibitor," Journal of Chinese Pharmaceutical Sciences, 2008, 17(2), pp. 134-137, ISSN: 1003-1057.45Chen et al., "Lithium Inhibits Ceramide- and Etoposide-induced Protein Phosphatase 2A Methylation, BcI-2 Dephosphorylation, Caspase-2 Activation, and Apoptosis," Molecular Pharmacology, 2006, 70(2), pp. 510-517, ISSN: 0026-985X.46Chiang et al., "S-Adenosylmethionine and methylation," 1996, Faseb J, 10:471-80.47Cho & Xu, "Crystal Structure of a Protein Phosphatase 2A Heterotrimeric Holoenzyme," 2007, Nature, 445:53-57.48Christen et al., "Inhibition of Alpha Interferon Signaling by Hepatitis B Virus," Journal of Virology, 2007, 81(1), pp. 159-165, ISSN: 0022-538X.49Clarke et al., "Folate, Vitamin B12, and Serum Total Homocysteine Levels in Confirmed Alzheimer Disease," 1998, Arch Neurol, 55:1449-1155.50Clarke et al., "Hyper homocysteinemia: an independent risk factor for vascular disease,"1991k, N Engl J Med, 324:1149-1155.51Cohen et al., "Protein Phosphatases Come of Age," 1989, J. Biol. Chem., 264(36):21435-21438.52Cohen et al., "Protein serine/threonine phosphatases; an expanding family," 1990, FEBS, 268(2):355-359.53Da Baere et al., "Purification of Porcine Brain Protein Phosphatase 2A Leucine Carboxyl Methyltransferase and Cloning of the Human Homologue," Biochemistry, 1999, 38(50), pp. 16539-16547, ISSN: 0006-2960.54Delgado-Reyes et al., "Immunohistochemical Detection of Betaine-Homocysteine S-Methyltransferase in Human, Pig, and Rat Liver and Kidney," 2001, Arch Biochem Biophys, 393(1):184-186.55Deshmukh et al., "Acute Modulation of PP2A and Troponin I Phosphorylation in Ventricular Myocytes: Studies with a Novel PP2A Peptide Inhibitor," American Journal of Physiology, 2007, 292(2, Pt. 2), pp. H792-H799, ISSN: 0002-9513.56Deventer et al., "Lower Esophageal Sphincter Pressure, Acid Secretion, and Blood Gastrin after Coffee Consumption," 1992, Digestive Diseases and Sciences, 37(4):558-569.57Du, "SmI2 Mediated Aryl Radical Cyclization/Sequential Anionic Capture on Solid Support and Computational Studies on Hapalosin and its Analogs and on Inhibitors of Protein Phosphatases PP1 and PP2A," University of California, Los Angeles, 1998, 142 pp. Avail.: UMI, Order No. DA9818006, From: Diss. Abstract Int., B 1998, 58(12), pp. 6581.58Dumanchin et al., "Segregation of a missense mutation in the microtubule- associated protein tau gene with familial frontotemporal dementia and parkinsonism," 1998, Hum. Mol. Genet., 7:1825-1829.59Duong et al., "Hepatitis C Virus Inhibits Interferon Signaling through Up-regulation of Protein Phosphatase 2A," Gastroenterology, 2004, 126(1), pp. 263-277, ISSN: 0016-5085.60Duong et al., "S-adenosylmethionine and Betaine Correct Hepatitis C Virus Induced Inhibition of Interferon Signaling in Vitro," Hepatology, 2006, 43(4), pp. 796-806, ISSN: 0270-9139.61Duong et al., "Upregulation of Protein Phosphatase 2Ac by Hepatitics C Virus Modulates NS3 Helicase Activity throught Inhibition of Protein Arginine Methyltransferase 1," Journal of Virology, 2005, 79(24), pp. 15342-15350, ISSN: 0022-538X.62Duval et al., "analogues of cytotoxics squamocin using reliable reactions: new insights into the reativity and role of the alpha,beta-unsaturated lactone of the annonaceous acetogenins," 2006, Tetrahedron, 62(26):6248-6257.63Duval et al., "analogues of cytotoxics squamocin using reliable reactions: new insights into the reativity and role of the α,β-unsaturated lactone of the annonaceous acetogenins," 2006, Tetrahedron, 62(26):6248-6257.64European Search Opnion, Communication regarding the transmission of the European Search Report, and Supplementary European Search Report for EP 1843734, Aug. 7, 2008.65Evans et al., "Functional Expression of Human PP2Ac in Yeast Permits the Identification of Novel C-terminal and Dominant-negative Mutant Forms," Journal of Biological Chemistry, 1999, 274(34), pp. 24038-24046, ISSN: 0021-9258.66Evans et al., "Mutation of the C-terminal Leucine Residue of PP2Ac Inhibits PR55/B Subunit Binding and Confers Supersensitivity to Microtubule Destabilization in Saccharomyces cerevisiae," Molecular and General Genetics, 2000, pp. 264(4), pp. 425-432, ISSN: 0026-8925.67Favre et al., "Differential Inhibition and Posttranslational Modification of Protein Phosphatase 1 and 2A in MCF7 Cells Treated with Calyculin-A, Okadaic Acid, and Tautomycin," Journal of Biological Chemistry, 1997, 272(21), pp. 13856-13863, ISSN: 0021-9258.68Favre et al., "The Catalytic Subunit of Protein Phosphatase 2A is Carboxyl-Methylated In Vivo," Journal of Biological Chemistry, 1994, 269(23), pp. 16311-16317, ISSN: 0021-9258.69Finkelstein J.D., "The metabolism of homocysteine: pathways and regultion," 1998, Eur J Pediatr, 157(Suppl 2):S40-4.70Floer et al., "Carboxyl Methylation of Protein Phosphatase 2A from Xenopus Eggs is Stimulated by cAMP and Inhibited by Okadaic Acid," Biochemical and Biophysical Research Communications, 1994, 198(1), pp. 372-379, ISSN: 0006-291X.71Folstar et al., "Liquid chromatographic coffee wax analysis," 1977, Colloque Scientifique International sure le Caf�, 8:121-124.72Folstar et al., "Liquid Chromatographie Analysis of N-b)-Alkanoyl-5-Hydroxytryptamine (C-F-HT) in Green Coffee Beans," Journal of Agricultural and Food Chemistry, 1979, 27(1), pp. 12-15.73Folstar et al., "New tryptamine derivatives isolated from wax of green coffee beans", J. Agric. Food Chem., 1980, vol. 28(4), pp. 872-874.74Fowler et al., "Inhibition of Fatty Acid Amidohydrolase, the Enzyme Responsible for the Metabolism of the Endocannabinoid Anandamide, by Analogues of Arachidonoyl-serotonin," 2003, J. of Enzyme Inhibition and Medicinal Chemistry, 18(3):225-231.75Fujita, E., "A new efficient aminolysis and its application to synthesis of macrolactam alkaloids," 1981, Pure and Applied Chemistry, 53(6):1141-54.76Gentry et al., "A Novel Assay for Protein Phosphatase 2A (PP2A) Complexes In Vivo Reveals Differential Effects of Covalent Modifications on Different Saccharomyces cerevisiae PP2A Heterotrimers," Eukaryotic Cell, 2005, 4(6), pp. 1029-1040, ISSN: 1535-9778.77George et al., "Chaperonin Assisted Overexpression, Purification, and Characterisation of Human PP2A Methyltransferase," Protein Expression and Purification, 2002, 26(2), pp. 266-274, ISSN: 1046-5928.78Gibbons et al., "Expression of Human Protein Phosphatase-1 in Saccharomyces cerevisiae Highlights the Role of Phsphatase Isoforms in Regulating Eukaryotic Functions," 2007, J. Biol. Chem., 282(30):21838-21847.79Goedert et al., "p42 map kinase phophorylation sites in microtubule-associated protein tau are dephosphorylated by protein phosphatase 2A," 1992, FEBS, 312(1):95-99.80Goedert et al., "Reduced Binding of protein Phsphatase 2A to Tau Protein with Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17 Mutations," 2000, J. Neurochem, 75:2155-2162.81Goldstein et al., "Microtubule-Bases Transport Systems in Nurons: The Roles of Kinesins and Dyneins," 2000, Annu Rev Neurosci, 23:39-71.82Gong et al., "Phosphatase activity toward abnormally phosphorylated tau: decrease in Alzheimer disease brain," 1995, J. Neurochem., 65:732-738.83Gonzalez et al., "Total Synthesis of Thyrsiferyl 23-Acetate, a Specific Inhibitor of Protein Phosphatase 2A and an Anti-Leukemic Inducer of Apoptosis," Journal of the American Chemical Society, 2000, 122(38), pp. 9099-9108, ISSN: 0002-7863.84Gotz, J. et al., "Formation of Neurofibrillary Tangles in P30 1L Tau Transgenic Mice Induced by Abeta42 Fibrils," 2001, Science, 293:1491-1495.85Gotz, J. et al., "Formation of Neurofibrillary Tangles in P30 1L Tau Transgenic Mice Induced by Aβ42 Fibrils," 2001, Science, 293:1491-1495.86Gozzo et al., "Structure-activity relationships in a series of melatonin analogues with the low-density lipoprotein oxidation model," 1999, Free Radical Biology & Medicine, 22(11/12):1538-1543.87Green et al., " Molecular cloning and sequence analysis of the catalytic subunit of bovine type A protein phosphatase," 1987, Proc Nat'l Acad. Sci USA, 84:4880-4884.88Greenberg et al., " Hydrofluoric Acid-treated T PHF Proteins Display the Same biochemical Properties as Normal T*," 1992, J. Biol. Chem., 267(1):564-569.89Guenin et al., "PP2A Activity is Controlled by Methylation and Regulates Oncoprotein Expression in Melanoma Cells: A Mechanism which Participates in Growth Inhibition Induced by Chloroethylnitrosourea Treatment," International Journal of Oncology, 2008, 32(1), pp. 49-57, ISSN: 1019-6439.90Guergnon et al., "Use of Penetrating Interacting with PP1/PP2A Proteins as a General Approach for a Drug Phosphatase Technology," 2006, Mol. Pharmacol., 69(4):1115-1124.91Gulledge et al., "Linearized and Truncated Microcystin Analogues as Inhibitors of Protein Phosphatases 1 and 2A," Bioorganic & Medicinal Chemistry Letters, 2003, 13(17), pp. 2903-2906, ISSN: 0960-840X.92Gulledge et al., "Microcystin Analogues Comprised Only of Adda and a Single Additional Amino Acid Retain Moderate Activity as PP1/PP2A Inhibitors," Bioorganic & Medicinal Chemistry Letters, 2003, 13(17), pp. 2907-2911, ISSN: 0960-894X.93Guo et al., "ATM-dependent Dissociation of B55 Regulatory Subunit from Nuclear PP2A in Response to Ionizing Radiation," Journal of Biological Chemistry, 2002, 277(7), pp. 4839-4844, ISSN: 0021-9258.94Hahn et al., "Synthesis of 1-alkylisoquinolines and 1,1'-polymethylenediisoquinolines," 1938, Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen, 71B:2183-91.95Hahn et al., "Synthesis of 3-alkyl-4-carbolines and 3,3'-polymethylenedi-4-carbolines," 1938, Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen, 71B:2175-82.96Hahn et al., "Synthesis of 1-alkylisoquinolines and 1,1′-polymethylenediisoquinolines," 1938, Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen, 71B:2183-91.97Hahn et al., "Synthesis of 3-alkyl-4-carbolines and 3,3′-polymethylenedi-4-carbolines," 1938, Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen, 71B:2175-82.98Harms et al., "Carboxylic Acid 5-Hydroxytryptamides in Coffee Beans," Zeitschrift fuer Lebensmittel-Untersuchung und-Forschung, 1968, 138(2), pp. 75-80. (English Abstract provided).99Harms et al., "Carboxylic Acid 5-Hydroxytryptamides in Coffee Beans," Zeitschrift fuer Lebensmittel-Untersuchung und-Forschung, 1968, 138(2), pp. 75-80. (English Abstract provided). (English Language).100Hart et al., "Modified Norcantharidins Synthesis, Protein Phosphatases 1 and 2A Inhibition, and Anticancer Activity," Bioorganic & Medicinal Chemistry Letters, 2004, 14(8), pp. 1969-1973, ISSN: 0960-894X.101Hemmings et al., "alpha and beta Forms of 65-kDA Subunit of Protein Phosphatase 2A Have a Similar 39 Amino Acid Repealing Structure," 1990, Biochemistry, 29:3166-3173.102Hemmings et al., "α and β Forms of 65-kDA Subunit of Protein Phosphatase 2A Have a Similar 39 Amino Acid Repealing Structure," 1990, Biochemistry, 29:3166-3173.103Hendrix et al., "Analysis of Subunit Isoforms in Protein Phosphatase 2A Holoenzymes from Rabbit Xenopus," 1993, J. biol. Chem., 268:7330-7337.104Hill et al, "Heterocyclic Substituted Cantharidin and Norcantharidin Analogues-synthesis, Protein Phosphatase (1 and 2A) Inhibition, and Anti-cancer Activity," Bioorganic & Medicinal Chemistry Letters, 2007, 17(12), pp. 3392-3397, ISSN: 0960-894X.105Hombauer et al., "Generation of Active Protein Phosphatase 2A is Coupled to Holoenzyme Assembly," PLoS Biology, 2007, 5(6), pp. 1355-1365, ISSN: 1545-7885.106Hornstein et al., "Protein Phosphatase and TRAIL Receptor Genes as New Candidate Tumor Genes on Chromosome 8p in Prostate Cancer," Cancer Genomics & Proteomics, 2008, 5(2), pp. 123-136, ISSN: 1109-6535.107Huang et al., "Molecular Cloning, Expression, and Characterization of a Novel Human Serine/Threonine protein Phosphatase, PP7, that is Homologous to Drosophila Retinal Degeneration C Gene Product (rdgC)*," 1998, J. Biol. Chem., 273(3):1462-1468.108Hubert et al., "Analysis of Carboxylic Acid Hydroxytryptamides in Coffee," Fresenius' Zeitschrift fuer Analytische Chemie, 1977, 285(3), pp. 242-250.109Hug et al., "Development of a Gas-Liquid Chromatographic Method for the Analysis of Fatty Acid Tryptamides in Cocoa Products," 2006, J of Agricultural and Food Chemistry, 54(9):3199-3203.110Hunter et al., "Protein Kinases and Phosphatases: The Ying and Yang of Protein Phosphorylation and Signaling," 1995, Cell, 80:225-236.111Hunziker et al., "High-pressure Liquid Chromatographie Determination of 5-Hydroxytryptamide in Coffee," Mitteilungen aus dem Gebiete der Lebensmitteluntersuchung und Hygiene, 1979, 70(1), pp. 142-152. (English Abstract provided).112Hunziker et al., "High-pressure Liquid Chromatographie Determination of 5-Hydroxytryptamide in Coffee," Mitteilungen aus dem Gebiete der Lebensmitteluntersuchung und Hygiene, 1979, 70(1), pp. 142-152. (English Abstract provided). (English Language).113Hunziker, "Determination of 5-Hydroxytryptamide in Coffee Using High-Pressure Liquid Chromatography," Mitteilungen aus dem Gebiete der Lebensmitteluntersuchung und Hygiene, 1977, 68(2), pp. 267-274. (English Abstract provided).114Hunziker, "Determination of 5-Hydroxytryptamide in Coffee Using High-Pressure Liquid Chromatography," Mitteilungen aus dem Gebiete der Lebensmitteluntersuchung und Hygiene, 1977, 68(2), pp. 267-274. (English Abstract provided). (English Language).115Hutton et al., "Association of missense and 5′-splice site mutations in tau with the inherited dentia FTDP-17," 1998, Nature, 393:702-705.116Ikehara et al., "Baculovirus Expression, Purification, and Characterization of Human Protein Phosphatase 2A Catalytic Subunits αand β," Protein Expression and Purification, 2006, 45(1), pp. 150-156, ISSN: 1046-5928.117Ikehara et al., "Methylation of the C-terminal Leucine Residue of the PP2A Catalytic Subunit is Unncecessary for the Catalytic Activity and the Binding of Regulatory Subunit (PR55/B)," Biochemical and Biophysical Research Communications, 2007, 354(4), pp. 1052-1057, ISSN: 0006-291X.118International Search Report for PCT/US2003/07658, Aug. 11, 2003.119International Search Report for PCT/US2006/03686, Jun. 15, 2006.120International Search Report for PCT/US2007/81260, Sep. 11, 2008.121International Search Report for PCT/US2007/82833, Oct. 9, 2008.122International Search Report for PCT/US2009/41321, Jun. 1, 2009.123Jackson-Lewis et al., "Protocol for the MPTP mouse model of Parkinson's disease," 2007, Nature Protocols, 2(1):141-152.124Janssen et al., "Fatty Acid Tryptamides as shell indicators for cocoa products and as quality parameters for cocoa butter," 2002, European Food Research and Technology, 214(3):259-264.125Janssens et al., "PP2A: the expected tumor suppressor," 2005, Curr Opin. Genet. Dev., 15:34-41.126Janssens et al., "Protein Phosphatase 2A: A Highly Regulated Family of Serine/Threonine Phosphatases Implicated in Cell Growth and Signaling," Biochemical Journal, 2001, 353(3), pp. 417-439, ISSN: 0264-6021.127Jayaprakasam et al., "Potent lipid peroxidation inhibitors from withania somnifera fruits," 2004, Tetrahedron 60(13):3109-3121.128Jiang et al., "The effects of aging on gene expression in the hypothalamus and cortex of mice," 2001, Proc Natl Aced Sci U S A. 98(4):1930-1934.129Jicha et al., "Alz-50 and MC-1, a New Monoclonal Antibody Raised to Paired Helical Filaments, Recognize Conformational Epitopes on Recombinant Tau," 1997, J. Neurosci Res., 48(2):128-132.130Kalhor et al., "Protein Phosphatase Methyltransferase 1 (Ppm1p) is the Sole Activity Responsible for Modification of the Major Forms of Protein Phosphatase 2A in Yeast," Archives of Biochemistry and Biophysics, 2001, 395(2), pp. 239-245, ISSN: 0003-9861.131Kamibayashi, C. et al., J. Biol. Chem. 269 (31): 20139.132Keen et al., "Epigenetic Regulation of Protein Phosphatase 2A (PP2A), Lymphotactin (XCL1) and Estrogen Receptor Alpha (ER) Expression in Human Breast Cancer Cells," Cancer Biology & Therapy, 2004, 3(12), pp. 1304-1312, ISSN: 1538-4047.133Kele et al., Determination of serotonin released from coffee wax by liquid chromatography, 1996, J. of Chromatography, 730:59-62.134Khew-Goodall et al., "Tissue-specific expression of mRNAs encoding αand βcatalytic subunits of protein phosphatase 2A," 1988, FEBS Lett, 238:265-268.135Khil et al., "Hydrogen Peroxide Mediates Brazilin-induced Glucose Transport in Adipocytes," Journal of Applied Pharmacology, 2004, 12(4), pp. 228-234, ISSN: 1225-6110.136Kins et al., "Reduced Poteing Phosphatase 2A Activity Induces Hyperphosphorylation and Altered Compartmentalization of Tau in Transgenic Mice," 2001, J Biol Chem, 276:38193-200.137Kita et al., "Structure-activity Relationship of Okadaic Acid, a Potent Protein Phosphatases PP1 and PP2A Inhibitor: 24-Epi-Okadaic Acid and a 18-membered Lactone Analog," Heterocycles, 2008, 76(2), pp. 1033-1042, ISSN: 0385-5414.138Kloeker et al., "Carboxymethylation of Nuclear Protein Serine/Threonine Phosphatase X," Biochemical Journal, 1997, 327(2), pp. 481-486, ISSN: 0264-6021.139Kobayashi et al., "Process Formation of Podocytes: Morphogenetic Activity of Microtubules and Regulation by Protein Serine/Threonine Phosphatase PP2A," Histochemistry and Cell Biology, 2001, 115(3), pp. 255-266, ISSN: 0948-6143.140Koenig et al., "Gas Chromatography and Mass Spectrometry as Aids in Studying High-Boiling Coffee Compounds," Institut fur Organische Chemie und Biochemie, pp. 271-278; and Colloque Scientifique International sur le Cafe (1983), Volume Date 1982, 10th. (English Abstract provided).141Koenig et al., "Gas Chromatography and Mass Spectrometry as Aids in Studying High-Boiling Coffee Compounds," Institut fur Organische Chemie und Biochemie, pp. 271-278; and Colloque Scientifique International sur le Cafe (1983), Volume Date 1982, 10th. (English Abstract provided). (English Language).142Konoki et al., "Direct Observation of Binding Between Biotinylated Okadaic Acids and Protein Phosphatase 2A Monitored by Surface Plasmon Resonance," Tetrahedron Letters, 1999, 40(5), pp. 887-890, ISSN: 0040-4039.143Koren et al., "The Scaffolding A/Tpd3 Subunit and High Phosphatase Activity are Dispensable for Cdc55 Function in the Saccharomyces cerevisiae Spindle Checkpoint and in Cytokinesis," Journal of Biological Chemistry, 2004, 279(47), pp. 48598-48606, ISSN: 0021-9258.144Kowluru et al., "Carboxylmethylation of the Catalytic Subunit of Protein Phosphatase 2A in Insulin-secreting Cells: Evidence for Functional Consequences on Enzyme Activity and Insulin Secretion," Endocrinology, 1996, 137(6), pp. 2315-2323, ISSN: 0013-7227.145Kowluru et al., "Ceramide-activated Protein Phosphatase-2A Activity in Insulin-secreting Cells," FEBS Letters, 1997, 418(1, 2), pp. 179-182, ISSN: 0014-5793.146Kowluru et al., "Purine Nucleotide- and Sugar Phosphate-induced Inhibition of the Carboxyl Methylation and Catalysis of Protein Phosphatase-2A in Insulin-secreting Cells: Protection by Divalent Cations," Bioscience Reports, 1998, 18(4), pp. 171-186, ISSN: 0144-8463.147Kowluru, "Bridging the Gap Between Protein Carboxyl Methylation and Phospholipid Methylation to Understand Glucose-stimulated Insulin Secretion from the Pancreatic β Cell," Biochemical Pharmacology, 2008, 75(2), pp. 335-345, ISSN: 0006-2952.148Kraulis, "MOLSCRIPT: a program to produce both detailed and schematic plots of protein structures," 1991, J. Appl. Crystallogr., 24:946-950.149Krebs & Fisher, "Conversion of Phosphorylase β to Phosphorylase α in Muscle Extracts," 1955, J. Biol. Chem., 216:121-132.150Krebs & Fisher, "Phosphorylase Activity of Skeletal Muscle Extracts," 1955, J. Biol. Chem., 216:113-120.151Kurzrock et al., "Chromatography of Carbonic Acid-5-Hydroxyltryptamides," Institute of Food Chemistry, pp. 305-308; and Colloque Scientifique International sur le Cafe (2005), vol. Date 2004, 20th.152Lang et al., "A Versatile Method for the Quantitative Determination of bN-Alkanoy1-5-Hydroxytryptamides in Roasted Coffee," European Food Research and Technology, 2005, 220(5-6), pp. 638-643.153Laub et al., "[ADMAdda5]-microcysins in Planktothrix agardhii Strain PH-123 (Cyanobacteria)�Importance of Monitoring of Microcystins in the Environment," Environmental Toxicology, 2002, 17(4), pp. 351-357, ISSN: 1520-4081.154Lawhorn et al, "Total Synthesis of Cytostatin," Heterocycles, 2006, 70, pp. 65-70, ISSN: 0385-5414.155Lawhorn et al., "Total Synthesis and Evaluation of Cytostatin, Its Cl0-C11 Diastereomers, and Additional Key Analogues: Impact on PP2A Inhibition," Journal of the American Chemical Society, 2006, 128(51), pp. 16720-16732, ISSN: 0002-7863.156Le Bars et al., "Influence of the Severity of Cognitive Impairment on the Effect of the Ginkgo biloba Extract EGb 761 in alzheimer's Disease," 2002, Neuropsychobiology, 45:19-26.157Lechward et al., "Protein Phosphatase 2A: Variety of Forms and Diversity of Functions," Acta Biochimica Polonica, 2001, 48(4), pp. 921-933, ISSN: 0001-527X.158Lee et al., "A Specific Protein Carboxyl Methylesterase that Demethylates Phosphoprotein Phosphatase 2A in Bovine Brain," Proceedings of the National Academy of Sciences of the United States of America, 1996, 93(12), pp. 6043-6047, ISSN: 0027-8424.159Lee et al., "Leucine Carboxyl Methyltransferase-1 is Necessary for Normal Progression through Mitosis in Mammalian Cells," Journal of Biological Chemistry, 2007, 282(42), pp. 30974-30984, ISSN: 0021-9258.160Lee et al., "Mechanisms of Parkinson's Deseas Linked to Pathological α*Synuclein: New Targets for Drug Discovery," 2006, Neuron, 52:33-38.161Lee et al., "Neurodegenerative Tauopathies," 2001, Annu Rev Neurosci, 24:1121-1159.162Lee et al., "Protein Phosphatase 2A Catalytic Subunit Is Methyl-esterified at Its Carboxyl Terminus by a Novel Methyltransferase," 1993, J. Biol. Chem., 268(26):19192-19195.163Leulliot et al., "Structure of Protein Phosphatase Methyltransferase 1 (PPM1), a Leucine Carboxyl Methyltransferase Involved in the Regulation of Protein Phosphatase 2A Activity," Journal of Biological Chemistry, 2004, 279(9), pp. 8351-8358, ISSN: 0021-9258.164Lewis et al., "Enhanced Neurofibrillary Degeneration in Transgenic Mice Expressing Mutant Tau and APP," 2001, Science, 293:1487-1491.165Li et al., "Disruption of microtubule network by Alzheimer abnormally hyperphosphorylated tau," 2007, Acta Neuropathol, 113:501-11.166Li et al., "Okadaic Acid and Microcystin-LR Directly Inhibit the Methylation of Protein Phosphatase 2A by its Specific Methyltransferase," Biochemical and Biophysical Research Communcations, 1994, 202(2), pp. 1023-1030, ISSN: 0006-291X.167Li, Zhu, "Post-Translational Carboxyl Methylation of Protein Phosphatase 2A: a Therapeutic Target," 2008, Dissertation Presented to Dept. of Chemistry at Princeton University, 1-175.168Lim et al., "The Curry Spice Curcumin Redues Oxidative Damage and Amyloid Pathology in an Alzheimer Transgenic Mouse," 2001, J of Neuroscience, 21(2):8370-8377.169Lindsay et al., "Risk Factors for Alzheimer's Disease: A Prospective Analysis from the Canadian Study of Health and Aging," 2002, Am. J. Epidemiol., 156(5):445-53.170Litvan, Irene, "Update on Epidemiological Aspects of Progressive Supranulear Palsy," 2003, Movement Disorders, 18(6):S43-S50.171Liu et al., "Antiadrenergic Effects of Adenosine A1 Receptor-mediated Protein Phosphatase 2a Activation in the Heart," American Journal of Physiology. Heart and Circulatory Physiology, 2002, 283, (4, Pt. 2), H1314-H1321, ISSN: 0002-9513.172Longin et al., "Selection of Protein Phosphatase 2A Regulatory Subunits is Mediated by the C Terminus of the Catalytic Subunit," Journal of Biological Chemistry, 2007, 282(37), pp. 26971-26980, ISSN: 0021-9258.173Lucock, M., "Folic Acid: Nutritional biochemistry, Molecular Biology, and Role in Disease Processes," 2000, Mol Genet Metab, 71:121-138.174Maeda et al., "N-Fatty acyl tryptamines from Annona reticulata," 1993, Phytochemistry, 34(6):1633-5 (English language abstract in Appendix A).175Maki et al., "Catalyst-controlled Asymmetric Synthesis of Fostriecin and 8-epi-Fostriecin," Journal of the American Chemical Society, 2005, 127(48), 17111-17117, ISSN: 0002-7863.176Mancini et al., "Synthesis and Bioactivity of Linear Oligomers Related to Polymeric Alkylpyridinium Metabolites from the Mediterranean Sponge Reniera sarai," Organic & Biomolecular Chemistry, 2004, 2(9), pp. 1368-1375, ISSN: 1477-0520.177Manning et al., "The Protein Kinase Complement of the Human Genome," 2002, Science, 298:1912-1934.178Mano, M.L., "Silicic acid column chromatography in the separation of components of food fats," 1965, Revista Portuguesa de Farmacia, 15(3):398-401.179Martin De La Vega et al., "Cerebral Postischemic Reperfusion-induced Demethylation of the Protein Phosphatase 2A Catalytic Subunit," Journal of Neuroscience Research, 2002, 69(4), pp. 540-549, ISSN: 0360-4012.180Martin et al., "Identification and determination of peanut oil mixed with permissible edible oils," 1964, Medicamenta, 32(16):9-12 (English language abstract in Appendix A).181Marx, J., "Alzheimer disease: A new take on tau," 2007, Science, 316(5830):1416-1417.182Maude et al., "Design and Preparation of Serine-Threonine Protein Phosphatase Inhibitors Based Upon the Nodularin and Microcystin Toxin Structures: Part 2. Synthesis of a Functionalized Nodularin Macrocycle and a Stripped-down Microcystin Macrocycle," Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry, 1997, 17, pp. 2513-2526, ISSN: 0300-922X.183Mazanetz et al., "Untangling tau hyperphosphorylation in drug design for neurodegenerative disease," 2007, Nat. Rev. Drug Discovery, 6:464-479.184McCaddon et al., "Total Serum Homocysteine in Senile Dementia of Alzheimer Type," 1998, Int J Geriatr Psychiatry, 13:235-239.185McCluskey et al., "Anhydride Modified Cantharidin Analogues. Is Ring Opening Important in the Inhibition of Protein Phosphatase 2A?," European Journal of Medicinal Chemistry, 2000, 35(10), pp. 957-964, ISSN: 0223-5234.186McCluskey et al., "Anhydride Modified Cantharidin Analogues: Synthesis, Inhibition of Protein Phosphatases 1 and 2A and Anticancer Activity," Biorganic & Medicinal Chemistry Letters, 2000, 10(15), pp. 1687-1690, ISSN: 0960-0894X.187McCluskey et al., "The First Two Cantharidin Analogues Displaying PP1 Selectivity," Bioorganic & Medicinal Chemistry Letters, 2002, 12(3), pp. 391-393, ISSN: 0960-894X.188McCluskey et al., "The Inhibition of Protein Phosphatases 1 and 2A: A New Target for Rational Anti-Cancer Drug Design," 2001, Anti-Cancer Drug Design, 16:291-303.189Mehrotra et al., "Design and Preparation of Serine-Threonine Protein Phosphatase-inhibitors Based Upon the Nodularin and Microcystin Toxin Structures. Part 1. Evaluation of Key Inhibitory Features and Synthesis of a Rationally Stripped-down Nodularin Macrocycle," Joumal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry, 1997, 17, pp. 2495-2511, ISSN: 0300-922X.190Merrick et al., "Selective Destruction of Stable Mictotubules and Axons by Inhibitors of Protein Serine/Threonine Phosphatases in Cultured Human Neurons (NT2N Cells),"1997, J. Neurosci, 17:5726-5737.191Miyashita et al, "Synthetic Studies on Fostriecin and Related Natural Products," Yuki Gosei Kagaku Kyokaishi, 2007, 65(9), pp. 874-887, ISSN: 0037-9980. (English Abstract included).192Moller et al., "Okadaic Acid-induced, Naringin-sensitive Phosphorylation of Glycine N-methyltransferase in Isolated Rat Hepatocytes," Biochemical Journal, 2003, 373(2), pp. 505-513, ISSN: 0264-6021.193Moreno et al., "Down-Regulation of the Homeodomain Factor Cdx2 in Colorectal Cancer by Collagen Type I: An Active Role for the Tumor Environment in Malignant Tumor Progression," 2004, Cancer Res., 64:6978-6988.194Mumby, "The 3D Structure of Protein Phosphatase 2A: New Insights into a Ubiquitous Regulator of Cell Signaling," ACS Chemical Biology, 2007, 2(2), pp. 99-103, ISSN: 1554-8929.195Munch et al., "A sensitive and seletive method for the quantitative determination of fatty acid tryptamides as shell indicators in cocoa products," 1999, Zeitschrift fuer Lebensmittel-Untersuchung und-Forschung A: Food Research and Technology, 208(1):39-43.196Munch et al., "Characterization of the substances in cocoa shell. Possibilities to determine the shell percentage in cocoa products by indicators," 1999, Lebensmittelchemie, 53(6):148.197Nagao et al., "Monitored aminolysis of 3-acylthiazolidine-2-thione: a new convenient synthesis of amide," 1980, Tetrahedron Letters, 21(9):841-4.198Nagao et al., "Studies on a new synthesis of the acyclic amide and macrocyclic lactam alkaloids," 1979, Koen Yoshishu-Tennen Yuki Kagobutsu Torankai, 22nd, 554-61 (English language abstract in Appendix A).199Nagao et al., "Utilization of sulfur-containing leavng groups. Part IV. Monitored aminolysis of 3-acyl-1,3-thiazolidine-2-thiones: synthesis of amides and amide alkaloids," 1984, Chemical & Pharmaceutical Bulletin, 32(7):2687-99.200Nebesny et al., "Effect of the Roasting Method on the Content of 5-Hydroxytryptamides of Carboxylic Acids in Roasted Coffee Beans," Nahrung, 2002, 46(4), pp. 279-282.201Netland, et al., "Indomethacin Reverses the Microglial Response to Amyloid β-Protein," 1998, Neurobiology of Aging, 19(3):201-204.202Neviani et al., "FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia," 2007, J of Clinical Investigation, 17(9):2408-2421.203Nicholls et al., "Protein Folding and Association: Insights from the Interfacial and Thermodynamic Properties of Hydrocarbons," 1991, Proteins: Struct. Funct. Genet., 11:281-296.204Nien et al., "Overexpression of the mTOR Alpha4 Phosphoprotein Activates Protein Phosphatase 2A and Increases Stat1α Binding to PIAS1," Molecular and Cellular Endocrinology, 2007, 263(1-2), pp. 10-17, ISSN: 0303-7207.205Nishiyama, et al., "Ameliorative Effect of S-Allylcysteine, a Major Thioallyl Constituent in Aged Garlic Extract, on learning Deficits in Senescence-Accelerated Mice," 2001, American Society for Nutritional Sciences, 1093S-1095S.206Nowotny et al., "Association studies between common variants in prolyl isomerase Pin1 and the risk for late-onset Alzheimer's disease," 2007, Neuroscience Letters, 419(1):15-7.207Nunbhakdi-Craig et al., "Expression of Protein Phosphatase 2A Mutants and Silencing of the Regulatory Bα Subunit Induce a Selective Loss of Acetylated and Detyrosinated Microtubules," Journal of Neurochemistry, 2007, 101(4), pp. 959-971, ISSN: 0022-3042.208O'Donnell et al., "Serine-threonine Protein Phosphatase Inhibitors Derived from Nodularin: Role of the 2-methyl and 3-diene Groups in the Adda Residue and the Effect of Macrocyclic Conformational Restraint," Journal of the Chemical Society, Perkin Transactions 1, 2001, 14, 1696-1708, ISSN: 1472-7781.209Ogawa et al., "Asymmetric Synthesis of Calyculin C. 2. Synthesis of the C26-C37 Fragment and Model Wittig Couplings," 1996, Journal of Organic Chemistry, 61(18):6153-6161, ISSN: 0022-3263.210Ogawa et al., "Total Synthesis of Calyculin C," Journal of the American Chemical Society, 1998, 120(48), pp. 12435-12442, ISSN: 0002-7863.211Ogris et al., "A Protein Phosphatase Methylesterase (PME-1) is One of Several Novel Proteins Stably Associating with Two Inactive Mutants of Protein Phosphatase 2A," Journal of Biological Chemistry, 1999, 274(20), pp. 14382-14391, ISSN: 0021-9258.212Oikawa et al., "Synthetic Study of Tautomycetin and Biological Activity of Tautomycin Derivatives," Tennen Yuki Kagobutsu Toronkai Koen Yoshishu, 1997, 39th, pp. 433-438. (English Abstract included).213Oikawa, "Synthesis of Specific Protein Phosphatase Inhibitors, Tautomycin and Tautomycetin Toward Structure-activity Relationship Study," Current Medicinal Chemistry, 2002, 9(22), pp. 2033-2054, ISSN: 0929-8673.214Ortega-Gutierrez et al., "Targeted Disruption of the PME-1 Gene Causes Loss of Demethylated PP2A and Perinatal Lethality in Mice," PLoS One, 2008, 3(7), e2486, pp. 1-9, ISSN: 1932-6203.215Otvos et al., "Monoclonal Antibody PHF-1 Recognizes Tau Protein Phosphorylated at Serine Residues 396 and 404," 1994, J. Neurosci Res., 39(6):669-673.216Paterson et al, "Total Synthesis of Spirastrellolide A Methyl Ester-part 1: Synthesis of an Advanced C17-C40 Bis-spiroacetal Subunit," Angewandte Chemie, International Edition, 2008, 47(16), pp. 3016-3020, ISSN: 1433-7851.217Peng et al., "Induction of Apoptosis by Norcantharidin in Human Colorectal Carcinoma Cell Lines: Involvement of the CD95 Receptor/Ligand," Journal of Cancer Research and Clinical Oncology, 2002, 128(4), pp. 223-230, ISSN: 0171-5216.218Pihko et al., "Synthesis of the C26-C32 Oxazole Fragment of Calyculin C: A Test Case for Oxazole Syntheses," Journal of Organic Chemistry, 1998, 63(1), pp. 92-98, ISSN: 0022-3263.219Planel et al., "Inhibition of Protein Phosphatase 2A Overrides Tau Protein Kinase I/Glycogen Synthase Kinase 3βand Cyclin-dependent Kinase 5 Inhibition and Results in Tau Hyperphosphorylation in the Hippocampus of Starved mouse," 2001, J. Biol. Chem., 276(36):34298-34306.220Potter, et al., "The inflammation-induced pathological chaperones ACT and apo-E are necessary catalysts of Alzheimer amyloid formation," 2001, Neurobiology of Aging, 22:923-930.221Rajagopalan et al., "Molecular Biology of C4 Phosphoenolpyruvate Carboxylase: Structure, Regulation and Genetic Engineering," Photosynthesis Research, 1994, 39(2), pp. 115-135, ISSN: 0166-8595.222Rametti et al., "Linking Alterations in Tau Phosphorylation and Cleavage during Neuronal Apoptosis," 2004, J. Biol. Chem., 279:54518-54528.223Refsum et al., "Homocystein and Cardiovascular Disease," 1998, Annu. Rev. Medicine, 49:31-62.224Rizzu et al., "High prevalence of mutations in the microtubule-associated protein tau in a population of study of frontotemporal dementia in the Netherlands," 1999, Am. J. Hum. Genet., 64:414-421.225Roder et al., "Microtubule-associated protein tau as a therapeutic target in neurodegenerative disease," 2007, Expert Opinion ther. Targets, 11(4):435-442.226Roszkowski et al., "Enantioselective synthesis of 1-substituted tetrahydro-β-carboline derivatives via asymmetric transfer hydrogenation," 2005, J. of Molecular Catalysis A: Chemical, 232(1-2):143-149.227Rusnak et al., "Calcineurin: Form and Function," 2000, Physiological Reviews, 80(4):1483-1521.228Ryu et al., 2006, "Photo- and electroluminescent properties of cyano-substituted styryl derivatives and synthesis of CN-PPV model compounds containing an alkoxy spacer for OLEDs," Tetrahedron, 62:6236-47.229Sacher et al., "Behenic acid tryptamide, a component of cocoa shell," 1965, Zeitschrift fuer Lebensmittel-Untersuchung und-Forschung 128(5):264-7 (English language abstract in Appendix A).230Sakoff & McCluskey, "Protein Phosphatase Inhibition: Structure Based Design. Towards new Therapeutic Agents," 2004, Current Pharmaceutical Design, 10:1139-1159.231Sakoff et al., "Anticancer Activity and Protein Phosphatase 1 and 2A Inhibition of a New Generation of Cantharidin Analogues," Investigational New Drugs, 2002, 20(1), pp. 1-11, ISSN: 0167-6997.232Salit et al, "Synthetic Studies Toward Cytostatin, a Natural Product Inhibitor of Protein Phosphatase 2A," Tetrahedron, 2008, 64(28), pp. 6684-6697, ISSN: 0040-4020.233Scarlato et al., "Asymmetric Synthesis of Calyculin C. 1. Synthesis of the C1-C25 Fragment," Journal of Organic Chemistry, 1996, 61(18), pp. 6139-6152, ISSN: 0022-3263.234Schnyder et al., " Decreased Rate of Coronary Restenosis After Lowering of Plasma Homocysteine Levels," 2001, N Engl J Med, 345:1593-1600.235Schwartz et al., "Hyperosmotic Stress Contributes to Mouse Colonic Inflammation through the Methylation of Protein Phosphatase 2A," American Journal of Physiology, 2008, 295(5, Pt. 1), pp. G934-G941, ISSN: 0002-9513.236Sciortino et al., "Antiviral activity. IX. Higher acyl derivatives of sympathomimetic amines of biological significance," 1968, Bollettino Chimico Farmaceutico, 107(8):506-11.237Scott and Weir, "Folic acid, homocysteine and one-carbon metabolism: a review of the essential biochemistry," 1998, J Cardiovasc Risk, 5:223-227.238Scott B., "Protein Phosphatase 2A methylation," 2002, FEBS Letters, 518(1-3):1-4.239Selhub et al., "B vitamins, homocysteine, and neurocognitive function in the elderly," 2000, Am J Clin Nutr, 71:614S-620S.240Selhub et al., "Vitamin Status and Intake as Primary Determinants of Homocysteinemia in an Elderly Population," 1993, Jama, 270:2693-2698.241Selhub, "Homocysteine Metabolism," 1999, Annu Rev Nutr, 19:217-246.242Selhub, et al., " Serum Total Homocysteine Concentrations in the Third National Health and Nutrition Examination Survey (1991-1994): Population Reference Ranges and Contribution of Vitamin Status to High Serum Concentrations," 1999, Ann. Intern. Med., 131(5):331-339.243Selkoe, "Alzheimer's Disease: Genes, Proteins, and Therapy," 2001, Physiol Rev. 81:741-66.244Seshadri et al., "Plasma Homocystein as a Risk Factor for Dementia and Alzheimer's Disease," 2002, New England J. Of Med., 346(7):476.245Sherpina et al., "Ginkgo Biloba," 2003, American Family Physician, 68(5):923-926.246Shibasaki et al, "Synthetic Strategies of Fostriecin," Heterocycles, 2005, 66(1), pp. 727-741, ISSN: 0385-5414.247Somei et al., "The chemistry of indoles. 87. Syntheses of 1-hydroxytryptamines and serotonins having fatty acyl or (E)-3-phenylpropenoyl derivatives as a Nb-substituent, and a novel homologation on the 3-substituent of the 1-hydroxytryptamines upon treatment with diazomethane," 1998, Heterocycles 48(6):1117-1120.248Sontag et al., "A Novel Pool of Protein Phosphatase 2A Is Associated with Microtubules and Is Regulated during the Cell Cycle," 1995, J Cell Biol, 128:1131-1144.249Sontag et al., "Altered Expression Levels of the protein Phosphatase 2A ABαC Enzyme are Associated with Alzheimer Disease Pathology," 2004, Journal of Neuropathology and Experimental Neurology, 63(4):287-301.250Sontag et al., "Downregulation of Protein Phosphatase 2A Carboxyl Methylation and Methyltransferase May Contribute to Alzheimer Disease Pathogenesis," Journal of Neuropathology and Experimental Neurology, 2004, 63(10), pp. 1081-1091, ISSN: 0022-3069.251Sontag et al., "Molecular Interactions among Protein Phosphatase 2A, Tau, and Microtubules," 1999, J. Biol. Chem., 274(36):25490-25498.252Sontag et al., "Protein Phosphatase 2A Methyltransferase Links Homocysteine Metabolism with Tau and Amyloid Precursor Protein Regualtion," Journal of Neuroscience, 2007, 27(11), pp. 2751-2759, ISSN: 0270-6474.253Sontag et al., "Regulation of Phosphorylation State and Microtubule-Binding Activity of tau by Protein Phosphatase 2A," 1996, Neuron, 17:1201-1207.254Sontag, E. "Protein phosphatatase 2A: the Trojan Horse of Cellular signaling," 2001, Cell. Signaling, 13:7-16.255Stock et al., "A protein methylesterase involved in bacterial sensing," 1978, Proc. Natl. Acad. Sci. USA, 75(8):3659-3663.256Stone et al., "Molecular Cloning of cDNAs Encoding Two Isoforms of the Catalytic Subunit of Protein Phosphatase 2A," 1987, Biochemistry, 26:7215-7220.257Studer et al., "Quantitative HPTLC Determination of Carbon-5-Hydroxytryptamides and�Tryptamines in Food Products," Journal of High Resolution Chromatography & Chromatography Communications, Oct. 1982, vol. 5(No. 10358), pp. 581-582.258Sun et al., "Inhibition of Protein Phosphatase 2A- and Protein Phosphatase 1-Induced Tau Hyperphosphorylation and Impairment of Spatial Memory Retention in Rats," 2003, Neuroscience, 118:1175-1182.259Sunahori et al., "Methylation Status of CpG Islands Flanking a cAMP Response Element Motif on the Protein Phosphatase 2Acα Promoter Determines CREB Binding and Activity," Journal of Immunology, 2009, 182(3), pp. 1500-1508, ISSN: 0022-1767.260Swiatek et al., "Biochemical Characterization of Recombinant Subunits of Type 2A Protein Phosphatase Overexpressed in Pichia pastoris," European Journal of Biochemistry, 2000, 267(16), pp. 5209-5216, ISSN: 0014-2956.261Szelag et al., "Determination of the amount of hull-derived lipids in cocoa oils," 1984, Przemysl Spozywczy 38(9):355-7.262Szelag et al., "Evaluation of behenic acid tryptamide in cocoa fat on the basis of blue value dterminations," 1988, Nahrung, 32(3):285-90 .263Taylor et al., "Potent Non-peptidyl Inhibitors of Protein Tyrosine Phosphatase 1B," Bioorganic & Medicinal Chemistry, 1998, 6(9), pp. 1457-1468, ISSN: 0968-0896.264Taylor et al., "Potent Non-peptidyl Inhibitors of Protein Tyrosine Phosphatase 1B. [Erratum to document cited in CA130:3892]," Bioorganic & Medicinal Chemistry, 1998, 6(11), pp. 2235, ISSN:0968-0896.265Tolstykh et al., "Carboxyl Methylation Regulates Phosphoprotein Phosphatase 2A by Controlling the Association of Regulatory B Subunits," EMBO Journal, 2000, 19(21), pp. 5682-5691, ISSN: 0261-4189.266Travesa et al., "Distinct Phosphatases Mediate the Deactivation of the DNA Damage Checkpoint Kinase Rad53," Journal of Biological Chemistry, 2008, 283(25), pp. 17123-17130, ISSN: 0021-9258.267Tsujio et al., "Inhibitors of protein phosphatase-2A from human brain structures, immunocytological localization and activities towards dephosphorylation of the Alzheimer type hyperphosphorylated tau," 2005, FEBS Lett, 579:363-372.268Turowski et al., "Differential Methylation and Altered Conformation of Cytoplasmic and Nuclear Forms of Protein Phosphatase 2A During Cell Cycle Progression," Journal of Cell Biology, 1995, 129(2), pp. 397-410, ISSN: 0021-9525.269Tverdal et al., "Coffee Intake and Mortality from Liver Cirrhosis," 2003, AEP 13(6):419-423.270Tyas, S., "Are tobacco and alcohol use related to Alzheimer's disease? A critical assessment of the Evidence and its Implications" 1996, Addiction Biology, 1(3):237.271Urban, 1959, "Physiology of some flavonoids and oxycinnamic acid. II. Annual and diumal periodicity of formation," Planta, 52:565-82.272Vafai et al., "Protein phosphatase 2A methylation: a link between elevated plasma homocysteine and Alzheimer's Disease," 2002, FEBS Letters, 518:1-4.273Van Dam et al., "Coffee consumption and risk of type 2 diabetes mellitus," 2002, The Lancet,360:1477.274Virshup, D., "Protein phosphatase 2A:a panoply of enzymes," 2000, Curr Opin. Cell Biol., 12:180-185.275Vogelsberg-Ragaglia et al., "PP2A mRNA Expression Is Quantitatively Decreased in Alzheimer's Disease Hippocampus," 2001, Exp Neurol, 168:402-412.276Wang et al., "Inhibition of Growth and p21res Methylation in Vascular Endothelial Cells by Homocysteine but Not Cysteine," 1997, J Biol Chem, 272:25380-25385.277Webster et al., "Design and Preparation of Serine-Threonine Protein Phosphatase Inhibitors Based Upon the Nodularin and Microcystin Toxin Structures. Part 3," Journal of the Chemical Society, Perkin Transactions 1, 2001, 14, pp. 1673-1695, ISSN: 1472-7781.278Wei et al., "Carboxymethylation of the PP2A Catalytic Subunit in Saccharomyces cerevisia is Required for Efficient Interaction with the B-type Subunits Cdc55p and Rts1p," Journal of Biological Chemistry, 2001, 276(2), pp. 1570-1577, ISSN: 0021-9258.279Welch, G.N. and Loscalzo, J., "Homocysteine and Atherothrombosis," 1998, N Engl J Med, 338:1042-1050.280Wera et al., "Serine/threonine protein phosphatases," 1995, Biochem. J., 311:17-19.281Wiart et al., "Sesquiterpenes and Alkaloids from Scorodocarpus borneensis," Phytochemistry, 2001, 58(4), pp. 653-656.282Williams et al., "Spirastrellolide A: A Revised Structure, Progress Toward the Relative Configuration, and Inhibition of Protein Phosphatase 2A," Organic Letters, 2004, 6(15), pp. 2607-2610, ISSN: 1523-7060.283Witten Opinion for PCT/US09/41321, Jun. 1, 2009.284Written Opinion for PCT/US2006/003686, Aug. 2, 2007.285Written Opinion for PCT/US2007/81260, Sep. 11, 2008.286Written Opinion for PCT/US2007/82833, Oct. 9, 2008.287Wu et al., "Carboxyl Methylation of the Phosphoprotein Phosphatase 2A Catalytic Subunit Promotes its Functional Association with Regulatory Subunits in vivo," 2000, EMBO, 19(21):5672-5681.288Wu et al., "Tryptamine-Derived Amides and Alkaloids from the Seeds of Annona atemoya," 2005, J. of Natual Products, 68(3):406-408.289Wurziger at al., "Hydroxytrypatamides of Green and Roasted Coffee Beans," Presented at Association Scientifique Internationale du Cafe, 4th International Colloquium on the Chemistry of Coffee, 1969, pp. 85-91.290Wurziger et al., "Chemistry of Cocoa. Carboxylic Acid-5-Hydroxytryptamide in Cocoa Beans," 1970, Hyg. Inst., Gordian, 70(1643), Part 1:376-378. (English language abstract included on first page of document).291Wurziger et al., "Chemistry of Cocoa. Carboxylic Acid-5-Hydroxytryptamide in Cocoa Beans," 1970, Hyg. Inst., Gordian, 70(1644), Part 2:438-440. (English language abstract included on first page of reference C117).292Wurziger et al., "Chemistry of Cocoa. Carboxylic Acid-5-Hydroxytryptamide in Cocoa Beans," 1970, Hyg. Inst., Gordian, 70(1645), Part 3:470-473. (English language abstract included on first page of reference C117).293Xie and Clarke, 1993, "Methyl esterification of C-terminal leucine residues in cytosolic 36-kDa polypeptides of bovine brain," J. Biol. Chem., 268(18):13364-71.294Xie et al., "An Enzymic Activity in Bovine Brain that Catalyzes the Reversal of the C-terminal Methyl Esterification of Protein Phosphatase 2A," Biochemical and Biphysical Research Communications, 1994, 203(3), pp. 1710-1715, ISSN: 0006-291X.295Xie et al., "Protein Phosphatase 2A is Reversibly Modified by Methyl Esterification at its C-terminal Leucine Residue in Bovine Brain," Journal of Biological Chemistry, 1994, 269(3), pp. 1981-1984, ISSN: 0021-9258.296Xing et al., "Structural Mechanism of Demethylation and Inactivation of Protein Phosphatase 2A," Cell, 2008, 133(1), pp. 154-163, ISSN: 0092-8674.297Xing et al., "Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins," 2006, Cell, 127(2):341-353.298Xu et al., "Structure of the Protein Phosphatase 2A Holoenzyme," 2006, Cell, 127(6):1239-1251.299Yang et al., "S-adenosylemthionine and its Metabolite Induce Apoptosis in HepG2 Cells: Role of Protein Phosphatase 1 and Bcl-xS," Hepatology, 2004, 40(1), pp. 221-231, ISSN: 0270-9139.300Yi et al., "Increase in Plasma Homocysteine Associated with Parallel Increase in Plasma S-Adenosylhomocysteine and Lymphocyte DNA Hypomethylation," 2000, J Biol Chem, 275:29318-29323.301Yoo et al., "The α4-containing Form of Protein Phosphatase 2A in Liver and Hepatic Cells," Journal of Cellular Biochemistry, 2008, 105(1), pp. 290-300, ISSN: 0730-2312.302Yoon et al., "Methotrexate Decreases PP2A Methylation and Increases Tau Phosphorylation in Neuron," Biochemical and Biophysical Research Communications, 2007, 363(3), pp. 811-816, ISSN: 0006-291X.303Yu et al., "Methylation of the Protein Phosphatase 2A Catalytic Subunit is Essential for Association of Bα Regulatory Subunit but not SG2NA, Striatin, or Polyomavirus Middle Tumor Antigen," Molecular Biology of the Cell, 2001, 12(1), pp. 185-199, ISSN: 1059-1524.304Zhang et al., "Homocysteine Induces Tau Phosphorylation by Inactivating Protein Phosphatase 2A in Rat Hippocampus," Neurobiology of Aging, 2008, 29(11), pp. 1654-1665, ISSN: 0197-4580.305Zhou et al., "Tau Hyperphosphorylation Correlates with Reduced Methylation of Protein Phosphatase 2A," Neurobiology of Disease, 2008, 31(3), pp. 386-394, ISSN: 0969-9961.Referenced byCiting PatentFiling datePublication dateApplicantTitleUS8357422Jul 2, 2010Jan 22, 2013Rbc Life Sciences, Inc.Dietary supplementClassifications U.S. Classification424/725, 424/400, 424/439, 424/728International ClassificationA61K47/00, A61K36/00, A61K36/254, A61K9/00Cooperative ClassificationA61K36/81, A61K36/8962, A61K36/28, A23L1/296, A23L2/02, A61K36/38, A61K36/185, A61K36/74, A23F5/36, A23G4/06, A61K36/16, A23F3/16, A61K36/258, A61K36/87, A23G3/36, A23L2/38, A23L1/3002, A23F5/24, A61K45/06, A61K36/55, A23G4/068, A61K31/355, A61K36/82, A23G3/48European ClassificationA23L1/29F, A23L2/38, A23L2/02, A23F5/36, A23G4/06, A23F5/24, A23L1/30B, A23G3/36, A61K45/06, A23F3/16, A23G4/06P, A23G3/48, A61K36/258, A61K36/38, A61K31/355, A61K36/55, A61K36/74, A61K36/87, A61K36/82, A61K36/8962, A61K36/185, A61K36/28, A61K36/81, A61K36/16Legal EventsDateCodeEventDescriptionOct 13, 2010ASAssignmentOwner name: THE TRUSTEES OF PRINCETON UNIVERSITY, NEW JERSEYEffective date: 20080218Free format text: CORRECTIVE ASSIGNMENT TO CORRECT THE NAME OF ASSIGNOR JEFFRY B. 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