EP1100511A2 - Inhibierung der delta-9-desaturase wirkung mit saponinen - Google Patents

Inhibierung der delta-9-desaturase wirkung mit saponinen

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Publication number
EP1100511A2
EP1100511A2 EP99927180A EP99927180A EP1100511A2 EP 1100511 A2 EP1100511 A2 EP 1100511A2 EP 99927180 A EP99927180 A EP 99927180A EP 99927180 A EP99927180 A EP 99927180A EP 1100511 A2 EP1100511 A2 EP 1100511A2
Authority
EP
European Patent Office
Prior art keywords
saponin
mammal
composition
saponins
administering
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99927180A
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English (en)
French (fr)
Inventor
Sambasiva R. Chavali
R. Armour Forse
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Individual
Original Assignee
Individual
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Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of EP1100511A2 publication Critical patent/EP1100511A2/de
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • 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
    • 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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/258—Panax (ginseng)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn

Definitions

  • PUFA Polyunsaturated fatty acids
  • LA ar-linolenic acid
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • Saponins a heterogeneous mixture of chemically distinguishable triterpenoid or steroidal glycosides, are present in many plants and vegetables, and are generally well tolerated when consumed as foods (Marston et al, J. Ethnopharmacol 38:215- 223 (1993); Okenful, Food Chem. 6:19-40 (1981)). Moreover, orally administered saponins increase absorption of other nutrients and experimental oral vaccines into the circulation (Campbell and Peerbaye, Res. Immunol 143:526-530 (1992). When consumed as supplements along with dietary fats, saponins possessing antioxidant properties can prevent fatty acids from being oxidized (Tsujino et al, Biosc. Biotchnol Biochem.
  • saponins can increase uptake and incorporation of precursor fatty acids into the membrane phospholipids and may, consequently, affect arachidonic acid metabolism.
  • mice fed Quil A the plasma levels of the anti-inflammatory interleukin (IL)-IO were significantly elevated, and those of the proinflammatory IL- 12 were markedly reduced.
  • IL interleukin
  • SO diets supplemented with 1% ginseng saponins mice fed SO diets supplemented with 1% ginseng saponins, stearic acid levels were markedly higher with a concomitant decrease in the levels of oleic acid, and circulating levels of TNF- in response to LPS were significantly reduced.
  • the invention pertains to compositions comprising one or more saponins in an amount effective to inhibit ⁇ -9 desaturase enzyme.
  • the composition is a dietary supplement or nutritional solution, such as a dietary supplement or nutritional solution suitable for enteral or parenteral administration.
  • the saponin of the composition is essentially purified.
  • the saponin is selected from the group consisting of crude saponin extracts, semi-purified saponin fractions (such as Quil A and Quillayanin), purified saponin extracts, and ginseng saponins.
  • the saponin is derived from Quillaja saponaria, Panax t ⁇ folium, Panax quinquefolium and Glycyrrhiza glabra.
  • the composition further comprises essential fatty acids and/or essential vitamins and minerals.
  • the invention further relates to a dietary supplement or medical food comprising an effective amount of a saponin.
  • the dietary supplement or medical food can be selected from the group consisting of nutritional beverage, baked good (cookie, brownie, fudge, cake, bread, biscuit and cracker), pudding, confection, snack food, ice cream, frozen confection, and non-baked, extruded food product such as a bar.
  • the invention also pertains to a method of inhibiting ⁇ -9 desaturase enzyme activity in a mammal comprising administering a composition comprising an effective amount of one or more saponins to a mammal in need thereof.
  • the composition to be administered is a dietary supplement or nutritional solution, such as one which is suitable for enteral or parenteral administration.
  • the composition further comprises essential fatty acids and/or essential vitamins and minerals. The composition can be administered enterally or parenterally.
  • the invention also pertains to a method of inhibiting ⁇ -9 desaturase enzyme activity in a mammal comprising administering a composition comprising an effective amount of a saponin metabolite to a mammal in need thereof, as well as to compositions comprising a saponin metabolite in an amount effective to treat inflammation.
  • the invention further relates to a method of inhibiting palmitic acid or stearic acid metabolism in a mammal comprising administering to the mammal a composition comprising an effective amount of a saponin or a saponin metabolite. Inhibition of stearic acid metabolism results in inhibition of the formation of oleic acid and oleic acid metabolites, such as PGE 2 and thromboxane (Tx)B 2 .
  • the invention also relates to a method of inhibiting the formation of oleic acid in a mammal comprising administering to the mammal a composition comprising an effective amount of a saponin or a saponin metabolite.
  • the invention further relates to a method of inhibiting the level of PGE 2 , PGE l 5 PGE 1+2 , TxB 2 or proinflammatory cytokines such as IL- 12 in a mammal comprising administering to the mammal a composition comprising an effective amount of a saponin or a saponin metabolite.
  • the invention also relates to a method of enhancing the level of anti- inflammatory cytokines such as IL- 10 in a mammal comprising administering to the mammal a composition comprising an effective amount of a saponin or a saponin metabolite.
  • Saponins have several benefits and advantages for the health of mammals to which it is administered.
  • consumption of saponin-supplemented diets can improve the functions of vital organs such as heart, lungs, liver and kidneys by increasing the absorption of nutrients by the body.
  • the levels of TNF are not elevated in mice fed saponins in contrast to TNF levels with other anti-inflammatory drugs; therefore, use of saponins as anti- inflammatory agents does not induce the undesirable side effects induced by many other anti-inflammatory agents.
  • Proinflammatory mediators such as PGE 2 and IL-6 are also associated with increased mortality of patients with cancer/neoplasia and of those with sepsis and septic shock.
  • the ability of saponins to decrease the levels of one or more of these mediators without affecting the levels of TNF can positively impact therapy regimens.
  • the Figure is a schematic diagram depicting the precursors and products of ⁇ -9-desaturase enzyme.
  • proinflammatory mediators such as PGE 2 , TxB 2 , and TNF-oc, IL-6 and IL-12 is associated with severity of septic shock and plays a major role in the pathogenesis of sepsis. Attempts to ameliorate the production of these mediators have become an important strategy in the management of the critically ill patients with septic shock and other inflammatory diseases.
  • saponins to increase absorption of precursor fatty acids could affect the tissue levels of arachidonic acid and subsequently alter the production of prostaglandins and thromboxanes which play a major role during infection/inflammation.
  • palmitic acid is converted to palmitoleic acid and stearic acid is converted to oleic acid by the activity of a ⁇ -9-desaturase enzyme.
  • An increase in the oleic acid/stearic acid ratio is a common finding in several clinical conditions such as obesity, non-insulin dependent diabetes mellitus (Pan et al, J Nutr 124:1555-1565 (1994); Wahle et al, Comp Biochem Physiol 109:235-244 (1994); Pan et al, J Clin Invest 96:2802-2808 (1995)), and atherosclerosis.
  • saponins e.g., Quil A or other structurally similar saponins
  • saponins can decrease the ratio of oleic acid to stearic acid which may result from an inhibition in the activity of ⁇ -9 desaturase enzyme. Therefore, saponins, through their ability to decrease the activity of ⁇ -9 desaturase enzyme, can be useful as dietary supplements in enteral and parenteral nutrition to provide a wide array of beneficial effects by ameliorating symptoms associated with inflammatory conditions and diseases such as diabetes, obesity and atherosclerosis.
  • saponins alone or along with selected dietary fats could be mixed with oral vaccines to form stable emulsions to optimize immune responses for a specific infection in mammals, e.g., humans, while decreasing the formation of proinflammatory mediators.
  • consumption of saponins results in a significant improvement of the vital organ functions, where as administration of nonsteroidal anti-inflammatory drugs result in several serious side effects such as ulceration and liver damage.
  • all these beneficial effects are exerted in as short a period as 3-4 days, whereas other agents take as many as 6-7 days to benefit patients even after tube feeding.
  • Endogenous IL-6 plays a crucial role during sepsis (Damas et al, Ann Surg 215:356-362 (1991); Starnes, Jr., et al, J Immunol 745:4185-4191 (1990)). In the studies described herein, the levels of IL-6 were unaffected in mice fed Quil A supplemented diets.
  • Interleukin 10 is an anti-inflammatory cytokine which influences differentiation of both T and B cells (Burdin et al, J Immunol 154:2533-2544 (1995); Appelberg et al, Immunol 82:361-364 (1994); Ming et al, Clin Exp Immunol 89:148-153 (1992)), confers protection against infection and enhances humoral immunity through favoring T helper type 2 cell responses (van der Poll et al, J lmmul 758:1971-1975 (1997); Huhn et al, Clin Pharmacol Ther 62:171-180 (1997)).
  • IL-12 is a pro-inflammatory mediator which can suppress humoral immune responses, induce synthesis of TNF- ⁇ and IFN- ⁇ and favor T helper type 1 cell responses (Houssiau et al, Clin Exp Immunol 708:375-380 (1997); Pearlman et al, J Immunol 754:4658-4664 (1995)).
  • Interleukin- 10 decreases LPS- induced production of TNF- ⁇ from macrophages (Gerard et al, J Exp Med 177:541- 550 (1993)), from the whole blood (Marchant et al, Prog Clin Biol Res 388:411-423 (1994)), and in mice (Standiford et al, J Immunol 755:2222-2229 (1995)). Further, endogenous IL-10 is elevated as a protective mechanism in animals injected with LPS (Standiford et al, J Immunol 155:2222-2229 (1995)).
  • compositions comprising saponin or a saponin metabolite in an amount effective to inhibit (e.g., reduce or abolish) ⁇ -9 desaturase enzyme activity.
  • Such compositions can be used in the treatment or inhibition of obesity, atherosclerosis and diabetes mellitus and related conditions.
  • treatment or inhibition encompasses reduction in symptomology associated with a particular disorder, including complete resolution of the condition. Treatment and inhibition are also intended to include reduction or minimization of risk of the condition in a mammal at risk for such symptoms or conditions.
  • compositions comprising saponins or a saponin metabolite can be in any form suitable for administration to a mammal, including tablet, powder, capsule, liquid, injectable and suppository forms.
  • the composition is a dietary supplement or a nutritional solution.
  • the dietary supplement can contain essential fatty acids and/or essential vitamins and minerals in addition to saponins or saponin metabolites.
  • Saponins can also be used along with other dietary fats such as sesame seed oil, fish oil, or linseed oil. Such mixtures of saponins and dietary fats can be consumed as dietary supplements or as essential ingredients in consumable foods and drinks.
  • the dietary supplement can be provided in a variety of forms, such as nutritional beverages, baked goods (e.g., cookies, brownies, fudge, cake, breads, biscuits, crackers), puddings, confections (i.e., candy), snack foods (e.g., pretzels, chips), ice cream, frozen confections and novelties, or non-baked, extruded foods such as bars.
  • baked goods e.g., cookies, brownies, fudge, cake, breads, biscuits, crackers
  • puddings e.g., confections (i.e., candy), snack foods (e.g., pretzels, chips), ice cream, frozen confections and novelties, or non-baked, extruded foods such as bars.
  • the dietary supplement can provide optimal nutrition for growth and weight maintenance, and can comprise protein, carbohydrate and fat components, alone or in combination, in addition to an effective amount of one or more saponins or saponin metabolites.
  • the carbohydrate sources can include, but are not limited to, one or more of corn syrup, high fructose corn syrup, corn starch, maltodextrin, fructose, lactose, glucose, sucrose, dextrose and maltose.
  • the protein sources can include, but are not limited to, one or more of whey protein, whey protein concentrate, whey powder, egg protein, soy protein, soy protein isolate and caseinate.
  • the fat sources can include, but are not limited to, one or more of dietary fats, coconut oil, peanut oil, safflower oil, canola oil, corn oil, sesame seed oil, fish oil and vegetable oil, as well as structured triglycerides, long-chain triglycerides and medium-chain triglycerides.
  • the dietary supplement can also comprise adjunct ingredients such as emulsifiers (e.g. saponins), preservatives, artificial sweeteners, thickeners, colorings and flavors which improve the palatability, stability, shelf-life and organoleptic properties of the composition (see, for example, U.S. Patent Nos. 5,674,853 and 5,397,778).
  • the nutritional solution can be a parenteral nutritional solution, such as a total parenteral nutritional solution which contains all essential nutrients for health.
  • the composition can also comprise additional components as appropriate.
  • the saponin or saponin metabolite can be formulated with a physiologically acceptable medium to prepare a pharmaceutical composition.
  • the particular physiological medium may include, but is not limited to, water, buffered saline, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol) and dextrose solutions.
  • the saponin or saponin metabolite can also be formulated in a vaccine composition.
  • an effective amount includes an amount sufficient to show statistically significant anti-inflammatory effects.
  • the range of effective amounts will generally be from about 0.1 to about 10 mg/kg body weight of the mammal to be treated.
  • the optimum concentration of the active ingredient(s) in the chosen medium can be determined empirically, according to procedures well known in the art, and will depend on the ultimate pharmaceutical formulation desired.
  • Saponins or saponin metabolites can be present in the composition in a purified form or administered in the form of a crude or semi-purified extract.
  • the saponin is selected from the group consisting of crude saponin extracts, semi-purified saponin fractions (such as Quil A and Quillayanin), purified saponin extracts, and ginseng saponins.
  • the saponin is derived from Quillaja saponaria, Panax trifolium, Panax quinquefolium and Glycyrrhiza glabra.
  • saponins can be in either an isolated or synthetic form; that is, saponin can be isolated from a natural plant source or it can be synthesized chemically.
  • saponin is intended to include saponin metabolites as well as a saponin itself, as well as combinations of one or more saponins or saponin metabolites.
  • Saponin metabolites include any secondary metabolite produced by direct or subsequent metabolism of a saponin; that is, saponin metabolites include products produced by direct metabolism of a saponin itself (primary metabolites), as well as secondary products produced by further metabolism of the primary metabolites (secondary metabolites).
  • the determination of the metabolite or metabolites responsible for the ⁇ -9 desaturase inhibiting properties of a saponin can be determined by assessing the ability of each saponin metabolite to inhibit ⁇ -9-desaturase activity by art recognized methods such as those described herein or by methods such as those described by Shimizu et al. (Lipids 26:512-516 (1991)). Saponin metabolites which are identified as having inhibitory ability in vitro can then be studied to assess the in vivo anti-inflammatory properties of the metabolite by art recognized methods such as those described herein or those described by Shimizu et al. (Lipids 26:512-516 (1991)). Compounds which are structurally related to saponins and metabolic products thereof, such as ginsenosides, can also be used in the methods described herein.
  • the invention also relates to methods of treating obesity, atherosclerosis or diabetes, or inhibiting ⁇ -9 desaturase activity by administering a composition comprising an effective amount of a saponin to a mammal in need thereof.
  • Suitable mammals include, but are not limited to, primates (e.g., humans), dogs, cats, cows, horses, pigs, goats and rodents (e.g., rats, mice and hamsters).
  • Methods of administering such compositions include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, oral, suppository and intranasal. Particularly preferred methods of administration are enteral and parenteral administration. Other suitable methods of introduction can also include rechargeable or biodegradable devices and slow release devices.
  • the compositions of this invention can also be administered as part of a combinatorial therapy with other agents, including anti-inflammatory agents and antibiotics.
  • the methods of the present invention can also be used to reduce the incidence or symptomology of inflammation associated with infection by various organisms, as well as to reduce the occurrence or severity of inflammation associated with other conditions.
  • the methods of the present invention are useful to treat conditions such as arthritis, lyme disease, aging, breast cancer, head and neck cancer, common colds and flu and sepsis, as well as any other conditions in which a reduction of ⁇ -9 desaturase activity is desirable.
  • the invention also encompasses methods of inhibiting ⁇ -9-desaturase activity in a mammal comprising administering to the mammal a composition comprising an effective amount of a saponin or a saponin metabolite.
  • Inhibition of ⁇ -9-desaturase activity is intended to include an inhibition or reduction in levels or activities of enzymes responsible for the ⁇ -9-desaturation of stearic acid, such as ⁇ - 9-desaturase enzyme.
  • the inhibition of ⁇ -9-desaturase activity results in an increase in the level of stearic acid and palmitic acid, and a decrease in any or all of the compounds for which oleic acid or palmitoleic acid is a precursor.
  • One result of ⁇ - 9-desaturase inhibition is a decrease in proinflammatory mediators such as prostaglandins.
  • the invention also encompasses a method of inhibiting the level of PGE 2 , PGEj or PGE 1+2 in a mammal comprising administering to the mammal a composition comprising an effective amount of a saponin or a saponin metabolite.
  • the invention also relates to a method of inhibiting the activity of PLA 2 in a mammal comprising administering to the mammal a composition comprising an effective amount of a saponin or a saponin metabolite.
  • the AJN-76A fat-free powder along with 0.05%t-butyl hydroxy toluene, an antioxidant, was mixed with 5 wt% (10% Kcal) of safflower oil (Oilseeds International Ltd., Fresno, CA), partitioned into daily rations packaged in separate whirl-pack bags, flushed with N 2 , and stored at 4°C. Where mentioned, these diets were supplemented with 0.25% saponin (Quil A) obtained from Superfos Biosector a/s, Denmark.
  • liver tissues (100 mg) were homogenized and extracted with chloroform: methanol (2:1 v/v) solvent mixture containing 0.01% t-butylated hydroxytoluene as an antioxidant (Folch et al, J. Biol Chem. 226:491-509 (1957)).
  • the chloroform fractions were evaporated to dryness under N 2 and reconstituted in the same solvent.
  • the total phospholipids were separated by thin-layer chromatography on silica gel-H plates (Analtech Inc. Newark, DE), and the fatty acid methyl esters were derived (Metcalfe and Schmitz, Anal. Chem.
  • the PGE 2 antiserum has a 50% cross-reactivity with PGEj. Therefore, the actual amount of PGE 2 reported may represent up to a maximum of 50% PGE,, if present in the samples. No effort was made to correct for cross-reactivity with PGE, and the results are referred to as PGE 1+2 .
  • fatty acid composition (mean ⁇ s.d. molar %) of stearic acid, oleic acid and arachidonic acid (AA) were determined in the membrane phospholipids of livers from mice fed SO diets supplemented with Quil A saponins, and the data are summarized in Tables 1 and 2.
  • the tissue levels of oleic acid were significantly lower (p,0.05) in mice maintained on Quil A supplemented SO diets compared to those fed SO alone (Table 1).
  • Data represent the molar percents of oleic acid (OA), stearic acid (SA) and arachidonic acid (AA) in the liver membrane phospholipids. Similar data were obtained in the animals fed saponin-supplemented diets containing other dietary fats such as sesame seed oil, menhaden fish oil, or linseed oil.
  • the effects of feeding diets enriched with 5% safflower oil (SO) supplemented with 1% ginseng (Panax quinquefolium) saponins on the fatty acid composition of the liver were determined.
  • the stearic acid levels in the livers from mice fed ginseng saponin-supplemented diets were markedly higher (p ⁇ 0.01), with a concomitant decrease in the levels of oleic acid. Consequently, the oleic acid/stearic acid ratio was significantly lower (p ⁇ 0.01) in animals fed ginseng-supplemented diets compared to those fed SO alone, which suggests that consumption of ginseng saponins inhibited the ⁇ -9 desaturase enzyme activity.
  • TNF- ⁇ tumor necrosis factor
  • LPS lipopolysaccharide

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EP99927180A 1998-06-08 1999-06-03 Inhibierung der delta-9-desaturase wirkung mit saponinen Withdrawn EP1100511A2 (de)

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US9311398A 1998-06-08 1998-06-08
US93113 1998-06-08
PCT/US1999/012304 WO1999063979A2 (en) 1998-06-08 1999-06-03 Inhibition of δ-9-desaturase activity by saponins

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EP3529245A4 (de) 2016-10-24 2020-12-23 Yumanity Therapeutics, Inc. Verbindungen und verwendungen davon
MA47212A (fr) 2017-01-06 2019-11-13 Yumanity Therapeutics Inc Méthodes de traitement de troubles neurologiques
WO2019084157A1 (en) 2017-10-24 2019-05-02 Yumanity Therapeutics, Inc. COMPOUNDS AND USES THEREOF
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MA54829A (fr) 2019-01-24 2021-12-01 Yumanity Therapeutics Inc Composés et leurs utilisations
EA202192047A1 (ru) 2019-11-13 2021-12-08 Юманити Терапьютикс, Инк. Соединения и их применение

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