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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/12—Ketones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• the present invention relates to a curcuminoid composition and its therapeutic applications thereof. More specifically the invention relates to the composition comprising Tetrahydrocurcuminoids (THC), Hexahydrocurcuminoids (HHC) and Octahydrocurcuminoids (OHC) and their potential in alleviating symptoms of metabolic syndrome.
• THC Tetrahydrocurcuminoids
• HHC Hexahydrocurcuminoids
• OOC Octahydrocurcuminoids
• Metabolic syndrome is a cluster or combination of metabolic disorders that increase a person's risk for heart disease, diabetes, and stroke.
• the term metabolic refers to the biochemical processes occurring in the body. According to National Institutes of Health (NIH), it is a serious global health challenge with 23% of adult population exposed to increased risk of cardiovascular disease, diabetes, and stroke. A person will be at increased risk for cardiovascular problems if he/she presents with these conditions together than any one factor presenting alone (Metabolic Syndrome, National Heart, Lung and Blood institute, U.S. Dept of Health and Human Sendees, nlilbi.nih.gov/health-topics/metabolic-syndrome).
• curcumin such as tetrahydrocurcumin, as represented by STR#1, hexahydrocurcumin as represented by STR#2 and octahydrocurcumin as represented by STR#3 are yet to be proven and tapped for industrial application.
• the reductive metabolites also include tetrahydro-demethoxy curcumin (STR#4), tetrahydrobis-demethoxycurcumin (STR#5), hexahydro-demethoxycurcumin (STR#6), hexahydrobis-demethoxycurcumin (STR#7), octahydro-demethoxy'curcumin (STR#8) and octahydrobis-demethoxycurcumin (STR#9).
• STR#4 tetrahydro-demethoxy curcumin
• STR#5 tetrahydrobis-demethoxycurcumin
• STR#6 hexahydro-demethoxycurcumin
• STR#7 hexahydrobis-demethoxycurcumin
• octahydro-demethoxy'curcumin octahydrobis-demethoxycurcumin
• the present invention discloses a composition comprising metabolites of curcuminoids, specifically tetrahydrocurcumin, hexahydrocurcumin and octahydrocurcumin and its therapeutic potential in the management of metabolic syndrome.
• curcuminoids specifically tetrahydrocurcumin, hexahydrocurcumin and octahydrocurcumin and its therapeutic potential in the management of metabolic syndrome.
• the invention discloses a method for the therapeutic management of metabolic syndrome in mammals, said method comprising step of administering an effective dose, based on the body weight of said mammal, a composition comprising 70%-80% w/w tetrahydrocurcuminoids, 10%-20% w/w hexahydrocurcuminoids and 5%-10% w/w octahydrocurcuminoids to mammals in need of such therapeutic management.
• the invention discloses the use of a composition comprising 70%-80% w/w tetrahydrocurcuminoids, 10%-20% w/w hexahydrocurcuminoids and 5%-10% w/w octahydrocurcuminoids in the therapeutic management of metabolic syndrome in mammals.
• the invention discloses a method for the therapeutic management of hyperlipidemia in mammals, said method comprising step of administering an effective dose, based on the body weight of said mammal, a composition comprising 70%-80% w/w tetrahydrocurcuminoids, 10%-20% w/w hexahydrocurcuminoids and 5%-10% w/w octahydrocurcuminoids to mammals in need of such therapeutic management to bring about an effect of reducing the levels of a) total cholesterol, b) LDL aand c) triglycerides and increasing the levels of HDL in said mammals.
• the invention discloses a method for the therapeutic management of diabetes and associated hyperglycemia in mammals, said method comprising step of administering an effective dose, based on the body weight of said mammal, a composition comprising 70%-80% w/w tetrahydrocurcuminoids, 10%-20% w/w hexahydrocurcuminoids and 5%- 10% w/w octahydrocurcuminoids to mammals in need of such therapeutic management.
• the invention discloses a method for the therapeutic management of liver dysfunction in mammals, said method comprising step of administering an effective dose, based on the body weight of said mammal, a composition comprising 70%- 80% w/w tetrahydrocurcuminoids, 10%-20% w/w hexahydrocurcuminoids and 5%-10% w/w octahydrocurcuminoids to mammals in need of such therapeutic management to reduce the elevated levels of liver enzymes.
• the invention discloses a method for inhibiting adipogenesis in mammalian cells, said method comprising step bringing into contact, mammalian adipocytes with a composition comprising 70%-80% w/w tetrahydrocurcuminoids, 10%-20% w/w hexahydrocurcuminoids and 5%-10% w/w octahydrocurcuminoids to bring about inhibition in adipogenesis.
• Fig. 1 is a graphical representation showing the reduction in serum insulin test animals administered with a composition comprising tetrahydrocurcuminoids hexahydrocurcuminoids and octahydrocurcuminoids. **, P ⁇ 0.01
• Fig. 2 is a graphical representation showing the reduction in glucose levels in test animals administered with a composition comprising tetrahydrocurcuminoids hexahydrocurcuminoids and octahydrocurcuminoids. **, P ⁇ 0.01
• Fig. 2 is a graphical representation showing the reduction in body weight of test animals administered with a composition comprising tetrahydrocurcuminoids hexahydiOCurcuminoids and octahydiOCurcuminoids. **, P ⁇ 0.01
• Fig. 4 is a graphical representation showing the reduction in lipid accumulation in 3T3 cells incubated with a composition comprising tetrahydrocurcuminoids hexahydrocurcuminoids and octahydrocurcuminoids.
• Fig. 5 is a Oil Red O (ORO) staining of mouse 3T3 cells showing the inhibiting of adipogenesis by the composition comprising tetrahydrocurcuminoids hexahydrocurcuminoids and octahydrocurcuminoids.
• ORO Oil Red O
• the invention discloses a method for the therapeutic management of metabolic syndrome in mammals, said method comprising step of administering an effective dose, based on the body weight of said mammal, a composition comprising 70%-80% w/w tetiahydrocurcuminoids, 10%-20% w/w hexahydrocurcuminoids and 5%-10% w/w octahydrocurcuminoids to mammals in need of such therapeutic management.
• the tetrahydrocurcuminoids comprise of tetrahydrocurcumin, tetrahydro-demethoxycurcumin and tetrahydro bis-demethoxycurcumin.
• the hexahydrocurcuminoids further comprise of hexahydrocurcumin, hexahydro- demethoxycurcumin and hexahydro bis-demethoxycurcumin.
• octahydrocurcuminoids further comprise of octahydrocurcumin, octahydro- demethoxycurcumin and octahydrobis-demethoxycurcumin.
• the therapeutic effect of managing metabolic syndrome is brough about by normalising elevated lipids levels, normalising elevated liver enzymes, reducing elevated glucose levels and inhibiting adipogenesis.
• the metabolic syndrome is induced by high fat fructose diet.
• the effective dose of the composition is 25- 50 mg/kg body weight.
• the composition further comprises of stabilizing agents, bioavailability enhancers and antioxidants, pharmaceutically or nutraceutically or cosmeceutically accepted excipients and enhancers.
• the mammal is human.
• the invention discloses the use of a composition comprising 70%-80% w/w tetrahydrocurcuminoids, 10%-20% w/w hexahydrocurcuminoids and 5%-10% w/w octahydrocurcuminoids in the therapeutic management of metabolic syndrome in mammals.
• the tetrahydrocurcuminoids comprise of tetrahydrocurcumin, tetrahydro-demethoxycurcumin and tetrahydrobis-demethoxycurcumin.
• the hexahydrocurcuminoids further comprise of hexahydr ocurcumin, hexahydro-demethoxycurcumin and hexahydro bis- demethoxycurcumin.
• octahydrocurcuminoids further comprise of octahydrocurcumin, octahydro-demethoxycurcumin and octahydrobis- demethoxycurcumin.
• the therapeutic effect of managing metabolic syndrome is brough about by normalising elevated lipids levels, normalising elevated liver enzymes, reducing elevated glucose levels and inhibiting adipogenesis.
• the metabolic syndrome is induced by high fat fructose diet.
• the effective dose of the composition is 25-50 mg/kg body weight.
• the composition further comprises of stabilizing agents, bioavailability enhancers and antioxidants, pharmaceutically or nutraceutically or cosmeceutically accepted excipients and enhancers.
• the mammal is human.
• the invention discloses a method for the therapeutic management of hyperlipidemia in mammals, said method comprising step of administering an effective dose, based on the body weight of said mammal, a composition comprising 70%-80% w/w tetrahydrocurcuminoids, 10%-20% w/w hexahydrocurcuminoids and 5%-10% w/w octahydrocurcuminoids to mammals in need of such therapeutic management to bring about an effect of reducing the levels of a) total cholesterol, b) LDL aand c) triglycerides and increasing the levels of HDL in said mammals.
• the tetrahydrocurcuminoids comprise of tetrahydrocurcumin, tetrahydro-demethoxycurcumin and tetrahydrobis-demethoxycurcumin.
• the hexahydrocurcuminoids further comprise of hexahydrocurcumin, hexahydro-demethoxycurcumin and hexahydrobis- demethoxycurcumin.
• octahydrocurcuminoids further comprise of octahydrocurcumin, octahydro-demethoxycurcumin and octahydrobis- demethoxycurcumin.
• hyperlipidemia is associated with high fat fructose diet induced metabolic syndrome.
• the effective dose of the composition is 25-50 mg/kg body weight.
• the composition further comprises of stabilizing agents, bioavailability enhancers and antioxidants, pharmaceutically or nutraceutically or cosmeceutically accepted excipients and enhancers.
• the mammal is human.
• the invention discloses a method for the therapeutic management of diabetes and associated hyperglycemia in mammals, said method comprising step of administering an effective dose, based on the body weight of said mammal, a composition comprising 70%-80% w/w tetrahydrocurcuminoids, 10%-20% w/w hexahydrocurcuminoids and 5%-10% w/w octahydrocurcuminoids to mammals in need of such therapeutic management.
• the tetrahydrocurcuminoids comprise of tetrahydrocurcumin, tetrahydro-demethoxycurcumin and tetrahydrobis-demethoxycurcumin.
• the hexahydrocurcuminoids further comprise of hexahydrocurcumin, hexahydro-demethoxycureumin and hexahydrobis-demethoxycurciimin.
• octahydrocnrcuminoids further comprise of octahydrocurcumin, octahydro-demethoxycurcumin and octahydrobis-demethoxycurcumin.
• diabetes and hyperglycemia are associated with high fat fructose diet induced metabolic syndrome.
• the therapeutic effect of managing diabetes is brought about by decreasing elevated levels of glucose and insulin.
• the effective dose of the composition is 25-50 mg/kg body weight.
• the composition further comprises of stabilizing agents, bioavailability enhancers and antioxidants, pharmaceutically or nutraceutically or cosmeceutically accepted excipients and enhancers.
• the mammal is human.
• the invention discloses a method for the therapeutic management of liver dysfunction in mammals, said method comprising step of administering an effective dose, based on the body weight of said mammal, a composition comprising 70%- 80% w/w tetrahydrocurcuminoids, 10%-20% w/w hexahydrocurcuminoids and 5%-10% w/w octahydrocurcuminoids to mammals in need of such therapeutic management to reduce the elevated levels of liver enzymes.
• the tetrahydrocurcuminoids comprise of tetrahydrocurcumin, tetrahydro-demethoxycurcumin and tetrahydrobis-demethoxycurcumin.
• the hexahydrocurcuminoids further comprise of hexahydrocurcumin, hexahydro-demethoxycureumin and hexahydrobis-demethoxycurcumin.
• octahydrocurcuminoids further comprise of octahydrocurcumin, octahydro-demethoxycurcumin and octahydrobis-demethoxycurcumin.
• liver dysfunction is associated with high fat fructose diet induced metabolic syndrome.
• the liver enzymes are selected from the group consisting of Alanine transaminase and aspartate transminase.
• the effective dose of the composition is 25-50 mtykg body weight.
• the composition further comprises of stabilizing agents, bioavailability enhancers and antioxidants, pharmaceutically or nutraceutically or cosmeceutically accepted excipients and enhancers.
• the mammal is human.
• the invention discloses a method for inhibiting adipogenesis in mammalian cells, said method comprising step bringing into contact, mammalian adipocytes with a composition comprising 70%-80% w/w tetrahydrocurcuminoids, 10%-20% w/w hexahydrocurcuminoids and 5%-10% w/w octahydrocurcuminoids to bring about inhibition in adipogenesis.
• the tetrahydrocurcuminoids comprise of tetrahydrocurcumin, tetrahydro-demethoxycurcumin and tetrahydrobis-demethoxycurcumin.
• the hexahydrocurcuminoids further comprise of hexahydrocurcumin, hexahydro-demethoxycurcumin and hexahydrobis- demethoxycurcumin.
• octahydrocurcuminoids further comprise of octahydrocurcumin, octahydro-demethoxycurcumin and octahydrobis- demethoxycurcumin.
• the composition further comprises of stabilizing agents, bioavailability enhancers and antioxidants, pharmaceutically or nutraceutically or cosmeceuticaliy accepted excipients and enhancers.
• the mammal is human.
• bioavailability enhancer is selected from the group consisting of, but not limited to, pipeline, quercetin, garlic extract, ginger extract, and naringin.
• one or more anti-oxidants and anti-inflammatory agents are selected from the group consisting of, but not limited to, vitamin A, D, E, K, C, B complex, rosmarinic acid, Alpha Lipoic Acid, Eilagic Acid, Glycyrrhizinic Acid, Epigallocatechin Gallate, plant polyphenols, Glabridin, moringa oil, oleanolic acid, Oleuropein, Carnosic acid, urocanic acid, phytoene, lipoid acid, lipoamide, ferritin, desferal, billirubin, billiverdin, meianins, ubiquinone, ubiquinol, ascorbyl palmitate, Mg ascorbyl phosphate, ascorbyl acetate, tocopherols and derivatives such as vitamin E acetate, uric acid, a-glucosyirutin, calalase and the superoxide dismutase, glutathione, selenium compounds, but
• Tetrahydocurcumin along with its analogues tetrahydrodemethoxycurcumin, tetrahydrobisdemethoxycurcumin has been isolated from Zingiber sp. and Curcuma sp. (Peng et al, Chemical constituents of Zingiber officinale (Zingeberaceae). Yunnan Zhiwu Yanjiu, 2007; 29( 1): 125-128).
• Tetrahydrodemethoxycurcumin and tetrahydrobisdemethoxycurcumin has been reported to be present in the rhizome of Thai Zeodary (Curcuma zedoaria) (Matsuda et al., Anti-allergic principles from Thai zedoary: structural requirements of curcuminoids for inhibition of degranulation and effect on the release of TNF-alpha and IL-4 in RBL-2H3 cells. Bioorg med hem, 2004; 12(22):5891-5898).
• Tetrahydrocurcumin is also obtained by biotransformation from THC (Shimoda et al., Formation of tetrahydrocurcumin by reduction of curcumin with cultured plant cells of Marchantia polymmrpha, Nat Prod Commun, 2012, 7(4):529-530).
• Hexahydrocurcuminoids is also a naturally occurring plant metabolite found in the roots and rhizomes of Curcuma. Zingiber and Alpina. Hexahydrocurcuminoids have been isolated from rhizomes of fresh ginger (Peng et al.. Cytotoxic, cytoprotective and antioxidant effects of isolated phenolic compounds from fresh ginger, Fitorick, 2012, 83(3):568-585). Hexahydrocurcuminoids are reported to occur in either of the two enatiomeric forms (S&R) and also as a racemic mixture (Majeed et al., Reductive Metabolites of Curcuminoids, Nutriscience Publishers LLC, 2019).
• Octahydrocurcuminoids are also isolated from the rhizomes of C. xanthorrhiza (Uehara et al., Diarylheptanoids from the rhizomes of Curcuma xanthorrhiza and Alpinia officinarum, Chem Pharm Bull, 1987, 35(8): 3298-3304). Octahydrocurcumin is also prepared by hydrogenation form tetrahydrocurcumin, in-vivo and microbial biotransformation (Majeed et al., Reductive Metabolites of Curcuminoids, Nutriscience Publishers LLC, 2019) [Para0037] The composition claimed in the present invention was formulated using the following hydrogenation process:
• Curcuminoids are reduced in solvent acetone under hydrogen pressure in the presence of Palladium/carbon at room temperature till the absence disappearance of the starting material.
• the product is isolated at off-white powder comprising Tetrahydrocurcumin, Tetrahydro demethoxycurcumin and Tetrahydro bisdemethoxy curcumin.
• the tetrahydrocurcuminoids are reduced selectively to Hexahydrocurcuminoids in solvent ethanol under specific temperatur e and hydr ogen pressur e in the presence of Palladium/carbon till the absence disappearance of the starting material.
• the product is isolated as off-white powder comprising Hexahydrocurcuminoids and ⁇ 5% of Octahydrocurcuminoids.
• Tetrahydrocurcuminoids are reduced to Octahydrocurcuminoids in solvent ethanol under high temperature and hydrogen pressure in the presence of Palladium/carbon till the complete conversion of the starting material.
• the product is isolated as off-white powder as essentially Octahydrocurcuminoids with traces of Hexahydrocurcuminoids.
• composition is also available commercially as C3 Reduct® Special from Sami Labs Limited.
• Example 2 Therapeutic potential of the Composition comprising Tetrahydrocurcuminoids, Hexahydrocurcuminoids and Octahydrocurcuminoids
• the therapeutic potential of the composition comprising Tetrahydrocurcuminoids, Hexahydrocurcuminoids and Octahydrocurcuminoids was tested by evaluating its ORAC and ROS & DPPH scavenging potential compared to curcuminoids, tetrahydrocurcuminoids, hexahydrocurcuminoids and octahydrocurcuminoids per se.
• ORAC Oxygen Radical Absorption Capacity Assay
• AUC (1 + f1/f0+ f2/f0 + . +f35/ f0)
• DPPH (2,2-diphenyl-1-picryl-hydrazyl-hydrate) free radical assay [Para0047] The test sample was dissolved in DMSO and diluted in 50% methanol for the assay. Different concentrations of pterostUlbene were mixed with DPPH solution in methanol in a 96 well plate. The plate was incubated in the dark for 15 min, and the absorbance was measured at 540 nm using a microplate reader (TECAN Ltd, Gurnnedorf, Switzerland). Blanks (DMSO, methanol) and standard (Trolox solution in DMSO) were recorded simultaneously. [Para0048] The free radical scavenging activity was calculated as follows,
• B is the Absorbance of reference solution
• C is the Absorbance of reference solution blank (Methanol only)
• S is the Absorbance of the test solution
• C is the Absorbance of test solution blank.
• Table 2 ORAC and DPPH scavenging potential of the composition comprising tetrahydrocurcuminoids, hexahydrocurcuminoids and octahydrocurcumioids (THO Composition)
• composition comprising tetrahydrocurcuminoids, hexahydrocurcuminoids and octahydrocurcumioids showed better ORAC and DPPH scavenging compared to curcuminoids and individual actives of the composition, indicating higher therapeutic efficacy of the composition. Further therapeutic activities were evaluated for the composition.
• Example 3 In vivo study for metabolic syndrome disease
• CPCSEA Committee for the Purpose of Control and Supervision of Experiments on Animals
• Blood TC cholesterol levels were determined by Trinder CHOD/POD End Point method under the principle of enzymatic determination of TC using the following reactions: Cholesterol ester is converted into cholesterol and fatty acids in the presence of cholesterol esterase. Cholesterol is oxidized in the presence of cholesterol oxidase to produce hydrogen peroxide. Hydrogen peroxide reacts with Phenol and 4-Aminoantipyrin in the presence of peroxidases to give Quinone and water molecule to produce red colour. The optical density is read at 500 nm against blank.
• TGF w ere determined by GPO/POD method.
• TGL are hydrolyzed by lipase to glycerol and free fatty acids.
• Glycerol is phosphorylated by ATP in the presence of glycerol kinase to Glycerol-3-phosphate w hich is oxidized by the enzyme Glycerol-3-phosphate oxidase producing hydrogen peroxide.
• Hydrogen peroxide so formed reacts w ith 4-Aminoantipyrine and 4-Chlorophenol in the presence of enzyme peroxidases to produce red Quinoneimine.
• the intensity of color developed is proportional to the TGL concentration.
• HDF and LDL parameter were measured with Direct Reagent Kit (Beacon).
• Liver parameters The enzyme levels alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine phosphatase were determined by standard kinetic methods. The catalytic activity of an enzyme is measured by determination of the conversion rate of catalyzed chemical reaction using a specific measurement procedure. It is expressed as the amount of substance converted per unit time, in international units (IU). The catalytic concentration is the catalytic activity contained in a volume of sample and is expressed in U/L.
• Glucose level was estimated by glucose oxidase / Peroxidase (GOD / POD Method).
• Glucose oxidase (GOD) catalyzes the oxidation of glucose to gluconic acid.
• the formed hydrogen peroxide (H202) is detected by a chromogenic oxygen acceptor, phenol- aminophenazone in the presence of peroxidase (POD).
• the intensity of the color formed is proportional to the glucose concentration in the sample.
• Serum insulin level The serum or plasma samples were prepared by adding 150 L of the reagent and phosphate-buffered saline plus 0.05% Tween-20. The sample was further diluted 1:100 diluents. The samples, insulin control solutions, and calibrators were also prepared as well as sufficient micro plate wells to accommodate calibrators and samples in duplicates. Exactly 350 L of wash solution was added into each well, and the wash solution discarded and tapped firmly several times against absorbent paper to remove excess liquid. The mixtures were incubated for 2 h at room temperature with rigorous shaking at 300-1000 g. The plate was placed on the shaker for approximately 5 s to ensure mixture.
• the absorbance of the supernatant was measured at 450 nm within 30 min, and value of insulin was expressed in ng/mL (Clark and Hales, 1994).
• Insulin tolerance Test ITT After fasting for 6 h, blood samples were collected from the test animals. Then the animals were injected intraperitoneally with 1.2 U/kg bw of insulin suspended in normal saline*.
• Cells were induced to differentiate after two days of reaching 100% confluency by supplementing DMEM media with 10% fetal bovine serum, 0.25 ⁇ M dexamethasone, 0.5 mM methyl isobutyl xanthine, and insulin (1 ⁇ g/mL) together with or without various concentrations of sample. After 48 hrs of differentiation, the media was replaced with DMEM containing 10% fetal bovine serum, insulin (1 ⁇ g/mL) and sample on alternate days until the cells were harvested on day 6.
• the lipid content in the adipocytes was determined by staining them with Oil Red O (ORO) staining (ORO). Briefly, the cells were fixed with 10% formalin for 30 min and stained with ORO working solution [0.3%] for 60 min at room temperature and visualized by an inverted phase-contrast microscope (Olympus, Tokyo, Japan,). The lipids stained with ORO were extracted from the cells using 4% triton X-100 in isopropanol and quantified at a wavelength of 520 nm.
• ORO Oil Red O
• composition comprising tetrahydrocurcuminoids, hexahydrocurcuminoids and octahydrocurcuminoids was tested for its potential in inhibiting adipogenesis. The results indicated that the composition was effective in reducing adipogenesis in 3T3 preadipocytes, (Fig.4 and Fig. 5) indicating the potential of the composition for use as an anti-obesity agent.
• composition comprising tetrahydrocurcuminoids, hexahydrocurcuminoids and octahydrocurcuminoids was effective in managing metabolic syndrome by normalizing lipid levels, glucose and insulin levels in blood, reducing the elevated liver enzymes and inhibiting adipogenesis. The composition is very suitable for use as a supplement for the management of diet induced metabolic syndrome.

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