[go: up one dir, main page]

WO2024228949A1 - Compositions pour moduler l'expression d'aquaporines dans le diabète et les états associés - Google Patents

Compositions pour moduler l'expression d'aquaporines dans le diabète et les états associés Download PDF

Info

Publication number
WO2024228949A1
WO2024228949A1 PCT/US2024/026804 US2024026804W WO2024228949A1 WO 2024228949 A1 WO2024228949 A1 WO 2024228949A1 US 2024026804 W US2024026804 W US 2024026804W WO 2024228949 A1 WO2024228949 A1 WO 2024228949A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
aquaporins
group
subject
expression
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.)
Pending
Application number
PCT/US2024/026804
Other languages
English (en)
Inventor
Anju Majeed
Shaheen Majeed
Anjali Pandey
Sarang Bani
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of WO2024228949A1 publication Critical patent/WO2024228949A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention in general relates to compositions comprising compounds of Formula I. More specifically, the invention relates io compositions comprising either Gingerenone A or Hirsutenone. Further specifically, the invention relates to a composition comprising either Gmgerenone A or Hirsutenone and methods thereof for use in modulating the expression of Aquaporins (AQP) in diabetes and for the management of diabetes and related complications thereof.
  • AQP Aquaporins
  • Water is the single largest constituent in the body weighing about 55-66% of the total body weight, distributed between the intracellular and extracellular components.
  • the solutes in the water determine the osmotic pressure of the cell, which should be equal between intracellular and extracellular fluids.
  • osmotic stress hypererosmolarity and hypoosmolality
  • Hyperosmolarity triggers cell shrinkage, oxidative stress, protein carbonylation, mitochondrial depolarization, DNA damage, and cell cycle arrest, thus rendering cells susceptible to apoptosis.
  • Hypoosmotic stress can act as an inflammatory stimulus and is also associated with a number of disorders, including acetaminophen toxicity and brain edema (Brocker et al., The role of hyperosmotic stress in inflammation and disease. Biomol Concepts. 2012 Aug: 3(4): 345 364 ⁇ . Thus, maintaining a stable water homeostasis is important to sustain a constant osmotic balance of the cells for maintaining general health and wellbeing.
  • Aquaporins are part of the family of the integral membrane proteins with a function to transport water, glycerol, ammonia, urea, H2O2, and other small molecules across the biological membranes.
  • the expression levels of AQPs are essential for maintaining water homeostasis and they have a relevant role in the development of many diseases. Recent discoveries suggest, that AQPs play an important role in the process of fat accumulation, regulation of oxidative stress, and two crucial aspects of insulin resistance, type-2 diabetes and obesity.
  • AQPs viz AQP1, AQP4, AQP9, AQP17 have been implicated in diseases like diabetes, insulin resistance, neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, loss of vision, loss of skin barrier function, kidney diseases, xerostomia (dry mouth), and the edema that follows stroke or trauma to the brain or spinal cord etc (Salman el al., Recent breakthroughs and future directions in drugging aquaporins, Trends in Pharmacological Sciences, Volume 43, Issue 7, January 2022, Pages 30-42). Modulating the expression of these aquaporins has been advocated as a possible drug target for the management of these diseases.
  • the present invention solves the unmet need by disclosing a natural plant based compounds for modulating the expression of different aquaporins and in the management of aquaporin related diseases like neurodegenerative diseases, metabolic syndrome, cardiovascular diseases, cancer, inflammatory diseases, allergy, diabetes, insulin resistance, renal disorders, skin hydration, brain edema, immune system disorders, obesity', and liver steatosis, more specifically, for the management of diabetes and related conditions like insulin resistance, diabetes, pancreatitis, pancreatic steatosis, diabetic nephropathy, atherosclerosis, diabetic cardiomyopathy, diabetic neuropathy' and diabetic retinopathy, hyperglycemia, dyslipidemia, hypercholesterolemia, obesity, liver steatosis, kidney dysfunction, and glaucoma.
  • a natural plant based compounds for modulating the expression of different aquaporins and in the management of aquaporin related diseases like neurodegenerative diseases, metabolic syndrome, cardiovascular diseases, cancer, inflammatory diseases, allergy, diabetes, insulin
  • composition comprising compounds of Formula I, wherein Ri is selected from the group consisting of methyl and H.
  • composition comprising compounds of Formula I and methods thereof for management of diabetes and related complications in a subject.
  • the present invention solves the above-mentioned objects and provides further related advantages.
  • the invention discloses a composition comprising compounds of Formula I
  • the compounds of Formula I wherein Ri is selected from the group consisting of methyl and H.
  • the invention discloses a composition comprising compounds of Formula I and methods thereof for modulating the expression of aquaporins in a subject.
  • the compound is selected from the group consisting of Gingerenone A (STR#2) or Hirsutenone (STR#3).
  • the invention discloses a composition comprising compounds of Formula I and methods thereof for increasing the pancreatic P-cell function in a subject.
  • the compound is selected from the group consisting of Gingerenone A and Hirsutenone.
  • the invention discloses a composition comprising compounds of Formula I and methods thereof for therapeutic management of diabetes and related complications in a subject.
  • the compound is selected from the group consisting of Gingerenone A,and Hirsutenone.
  • Fig. 1 is a graphical representation showing the modulation of expression of aquaporin 7 in pancreatic cell supernatant of different groups of experimental animals fed with High fat diet and administered with Gingerenone, Hirsutenone and Metformin (control).
  • FIG. 2 is a graphical representation showing the modulation of expression of aquaporin 12 in pancreatic cell supernatant of different groups of experimental animals fed with High fat diet and administered with Gingerenone, Hirsutenone and Metformin (control).
  • FIG. 3 is a graphical representation showing the modulation of expression of NLRP-3 in pancreatic cell supernatant of different groups of experimental animals fed with High fat diet and administered with Gingerenone, Hirsutenone and Metformin (control).
  • Fig. 4 is a graphical representation showing the modulation of cystatin C levels in blood of different groups of experimental animals fed with High fat diet and administered w'ith Gingerenone, Hirsutenone and Metformin (control).
  • treatment or management of a condition refers to effectively ameliorating conditions disclosed in the invention.
  • An effective dose refers to positive or modulatory effects of a condition in a subject covered under this invention.
  • the invention discloses a composition comprising compounds of Formula I
  • the compound is selected from the group consisting of Gingerenone A ( STR#2) and Hirsutenone. (STR#3).
  • Gingerenone A and Hirsutenone are isolated from plant sources or chemically synthesised.
  • the plant source is preferably, but not limited to, Zingiber officinale, Alnus hirsuta, Alnus sibirica, Alnus glutinosa, Alnus formosana, Alnus japonica, Alnus nepalensis, Viscum cruciatum.
  • the composition further comprises carriers and excipients.
  • the composition is formulated with pharmaceutically/nutraceutically acceptable excipients, adjuvants, diluents or carriers, and administered orally in the form of tablets, capsules, syrups, gummies, powders, suspensions, emulsions, chewables, candies, and eatables.
  • the invention discloses a method for modulating the expression of aquaporins in a subject with a disease condition comprising a) identifying the subject with the disease condition, b) administering an effective dose of a composition comprising compounds of Formula 1 to the said subject to bring about a change in the expression of aquaporins.
  • the compound is selected from the group consisting of Gingerenone A (STR#2) and Hirsutenone (STR#3).
  • the aquaporins are selected from the group consisting of AQPO, AQPI, AQP2, AQP3, AQP4, AQP5, AQP6, AQP8, AQP7, AQP9, AQP10, AQP11, AQP12, and combinations thereof.
  • modulating tire expression of aquaporins improves water homeostasis in the subject.
  • the disease condition is selected from the group consisting of neurodegenerative diseases, metabolic syndrome, cardiovascular diseases, cancer, inflammatory diseases, allergy, diabetes, insulin resistance, renal disorders, skin hydration, brain edema, immune system disorders, obesity, and liver steatosis.
  • modulating the expression of aquaporins is useful for management of diseases and disorders selected from the group consisting of neurodegenerative diseases, diabetes, and insulin resistance.
  • the effective dose of the compounds is in the range 2.5 - 40 mg/kg body weight of the subject.
  • the subject is a mammal.
  • the composition is formulated with pharmaceutically/nutraceutically acceptable excipients, adjuvants, diluents or carriers, and administered orally in the form of tablets, capsules, syrups, gummies, powders, suspensions, emulsions, chewables, candies, and eatables.
  • the invention discloses a composition comprising compounds of Formula I for use in modulating the expression of aquaporins in a subject with a disease condition.
  • the compound is selected from the group consisting of Gingerenone A (STR#2) and Hirsutenone (STR#3).
  • the aquaporins is selected from the group consisting of AQPO, AQPI, AQP2, AQP3, AQP4, AQP5, AQP6, AQP8, AQP7, AQP9, AQP10, AQP11, AQP12, and combinations thereof.
  • modulating the expression of aquaporins improves water homeostasis in the subject.
  • the disease condition is selected from the group consisting of neurodegenerative diseases, metabolic syndrome, cardiovascular diseases, cancer, inflammatory diseases, allergy, diabetes, insulin resistance, renal disorders, skin hydration, brain edema, immune system disorders, obesity, and liver steatosis.
  • modulating the expression of aquaporins is useful for management of diseases and disorders selected from the group consisting of neurodegenerative diseases, diabetes, and insulin resistance.
  • the effective dose of the compounds is in the range 2.5 - 40 mg/kg bodyweight of the subject.
  • the subject is a mammal.
  • the composition is formulated with pharmaceutically/nutraceutically acceptable excipients, adjuvants, diluents or carriers, and administered orally in the form of tablets, capsules, syrups, gummies, powders, suspensions, emulsions, chewables, candies, and eatables. .
  • the invention discloses use of a composition comprising compounds of Formula I for modulating the expression of aquaporins in a subject with a disease condition, m a related embodiment of the invention, the compound is selected from the group consisting of Gingerenone A (STR&2) and Hirsutenone (STR#3).
  • the aquaporins is selected from the group consisting of AQPO, AQP1, AQP2, AQP3, AQP4, AQP5, AQP6, AQP8, AQP7, AQP9, AQP10, AQP11, AQP12, and combinations thereof.
  • modulating the expression of aquaporins improves water homeostasis in the subject.
  • the disease condition is selected from the group consisting of neurodegenerative diseases, metabolic syndrome, cardiovascular diseases, cancer, inflammatory diseases, allergy, diabetes, insulin resistance, renal disorders, skin hydration, brain edema, immune system disorders, obesity, and liver steatosis.
  • modulating the expression of aquaporins is useful for management of diseases and disorders selected from the group consisting of neurodegenerative diseases, diabetes, and insulin resistance.
  • the effective dose of the compounds is in the range 2.5 - 40 mg/kg bodyweight of the subject.
  • the subject is a mammal.
  • the composition is formulated with phannaceutically/nutraceutically acceptable excipients, adjuvants, diluents or carriers, and administered orally in the form of tablets, capsules, syrups, gummies, powders, suspensions, emulsions, chewables, candies, and eatables.
  • the invention discloses a method for increasing pancreatic P-cell function in a subject with a disease condition, comprising a) identifying the subject in need of improving pancreatic [3-cell function, b) administering an effective dose of a composition comprising compounds of Formula I to the subject to increase p-cell function by improving water homeostasis.
  • the compound is selected from the group consisting of Gingerenone A (STR#2 ⁇ and Hirsutenone (STR#.3).
  • the improvement of P-cell function and water homeostasis is brought about by modulating the expression of aquaporins (AQPs).
  • the aquaporins are selected from tire group consisting of AQPO. AQP1, AQP2, AQP3, AQP4, AQP5. AQP6, AQP8, AQP7, AQP9, AQP10, AQP1 1, AQP12, and combinations thereof.
  • the aquaporins are selected from the group consisting of AQP7 and AQP12.
  • altering the pancreatic p-cell function results in modulating the proliferation, adhesion and migration of pancreatic p-cells, decreases the levels of inflammatory cytokines and regularizes insulin secretion.
  • the effective dose of the compounds is 2.5 - 40 mg/kg bodyweight of the subject. In a preferred embodiment of the invention, the effective dose is 10-20 mg/kg bodyweight of the subject.
  • the diseases condition is selected from the group consisting of, insulin resistance, diabetes, pancreatitis, pancreatic steatosis, diabetic nephropathy, atherosclerosis, diabetic cardiomyopathy, diabetic neuropathy and diabetic retinopathy, hyperglycemia, dyslipidemia, hypercholesterolemia, obesity, liver steatosis, kidney dysfunction, and glaucoma. In a related aspect the subject is a mammal.
  • the composition is formulated with pharmaceutically/nutraceutically acceptable excipients, adjuvants, diluents or carriers, and administered orally in the form of tablets, capsules, syrups, gummies, powders, suspensions, emulsions, chewables, candies, and eatables.
  • the invention discloses a composition comprising compounds of Formula I for use in increasing pancreatic p-cell function in a subject with a disease condition, wherein increase in p-cell function by the composition is brought about by improving water homeostasis.
  • the compound is selected from the group consisting of Gingerenone A (STR#2) and Hirsutenone (STR#3).
  • the improvement of p-cell function and water homeostasis is brought about by modulating the expression of aquaporins (AQP).
  • AQP aquaporins
  • the aquaporins are selected from the group consisting of AQPO, AQP1, AQP2, AQP3.
  • the aquaporins are selected from the group consisting of AQP7 and AQP 12.
  • altering the pancreatic P-cell function results in modulating the proliferation, adhesion and migration of pancreatic P-cells, decreases the levels of inflammatory cytokines and regularizes insulin secretion.
  • the effective dose of the compounds is 2.5 - 40 mg/kg bodyweight of the subject. In a preferred embodiment of the invention, the effective dose is 10-20 mg/kg bodyweight subject.
  • the disease condition is selected from the group consisting of, insulin resistance, diabetes, pancreatitis, pancreatic steatosis, diabetic nephropathy, atherosclerosis, diabetic cardiomyopathy, diabetic neuropathy and diabetic retinopathy, hyperglycemia, dyslipidemia, hypercholesterolemia, obesity, liver steatosis, kidney dysfunction, and glaucoma.
  • the subject is a mammal.
  • the composition is formulated with pharmaceutically/nutraceutically acceptable excipients, adjuvants, diluents or carriers, and administered orally in tire form of tablets, capsules, syrups, gummies, powders, suspensions, emulsions, chewables, candies, and eatables.
  • the invention discloses use of a composition comprising compounds of Formula I in increasing pancreatic [3-cell function in a subject with a disease condition, wherein increase in p-cell function by the composition is brought about by improving water homeostasis.
  • the compound is selected from the group consisting of Gingerenone A (STR#2) and Hirsutenone (STR#3).
  • the improvement of P-cell function and water homeostasis is brought about by modulating the expression of aquaporins (AQPs ).
  • the aquaporins are selected from the group consisting of AQPO, AQP1 , AQP2, AQP3, AQP4, AQP5, AQP6, AQP8, AQP7, AQP9, AQP10, AQP11, AQP12, and combinations thereof.
  • the aquaporins are selected from the group consisting of AQP7 and AQP 12.
  • altering the pancreatic P-cell function results in modulating the proliferation, adhesion and migration of pancreatic P-cells, decreases the levels of inflammatory'' cytokines and regularizes insulin secretion.
  • the effective dose of the compounds is 2.5 - 40 mg/kg bodyweight of the subject. In a preferred embodiment of the invention, the effective dose is 10-20 mg/kg body weight subject.
  • the diseases condition is selected from the group consisting of, insulin resistance, diabetes, pancreatitis, pancreatic steatosis, diabetic nephropathy, atherosclerosis, diabetic cardiomyopathy, diabetic neuropathy and diabetic retinopathy, hyperglycemia, dyslipidemia, hypercholesterolemia, obesity, liver steatosis, kidney dysfunction, and glaucoma. In a related aspect the subject is a mammal.
  • composition is formulated with pharmaceutically/nutraceutically acceptable excipients, adjuvants, diluents or carriers, and administered orally in the form of tablets, capsules, syrups, gummies, powders, suspensions, emulsions, chewables, candies, and eatables.
  • the invention discloses a method for therapeutic management of diabetes and related complications in a subject comprising a) identifying the subject with diabetes, b) administering an effective dose of a composition comprising compounds of Formula I to the subject.
  • the compound is selected from the group consisting of Oingereaone A (STR#2) and Hirsutenoue (S T.R#3).
  • management of diabetes is brought about by increasing the pancreatic [3-cell function, decreasing circulating levels of creatinine, and albumin, decreasing hyperlipidemia, decreasing blood cystatin C levels, and reducing expression of NLRP-3 inflammasomes.
  • the alteration of P-cell function is brought about by modulating the expression of aquaporins (AQP).
  • AQP aquaporins
  • the aquaporins are selected from the group consisting of AQP0, AQP1 , AQP2, AQP3, AQP4, AQP5, AQP6, AQP8, AQP7, AQP9, AQP10, AQP1 1 , AQP12, and combinations thereof.
  • the aquaporins are selected from the group consisting of AQP7 and AQP12.
  • hyperlipidemia is reduced by decreasing the levels of triglycerides, total cholesterol, free fatty acids and phospholipids.
  • the effective dose of the compounds is 2.5 - 40 mg/kg bodyweight of the subject. In a preferred embodiment of the invention, the effective dose is 10-20 mg/kg bodyweight of the subject.
  • the related complications are selected from the group consisting of. insulin resistance, diabetes, pancreatitis, pancreatic steatosis, diabetic nephropathy, atherosclerosis, diabetic cardiomyopathy, diabetic neuropathy and diabetic retinopathy, hyperglycemia, dyslipidemia, hypercholesterolemia, obesity, liver steatosis, kidney dysfunction, and glaucoma. In a related aspect the subject is a mammal.
  • composition is formulated with pharmaceutically/nutraceutically acceptable excipients, adjuvants, diluents or carriers, and administered orally in the form of tablets, capsules, syrups, gummies, powders, suspensions, emulsions, chewables, candies, and eatables.
  • the invention discloses a composition comprising compounds of Formula I for use in the therapeutic management of diabetes and related complications in a subject.
  • the compounds are selected from the group consisting of Gingerenone A (STR#2) and Hirsutenone (STR#3 ).
  • management of diabetes is brought about by increasing the pancreatic P-cell function, decreasing circulating levels of creatinine, and albumin, decreasing hyperlipidemia, decreasing blood cystatin C levels, and reducing expression of NLRP-3 inflammasomes.
  • the alteration of [3-cell function is brought about by modulating the expression of aquaporins (AQP).
  • the aquaporins are selected from the group consisting of AQPO, AQP1, AQP2, AQP3, AQP4, AQP5, AQP6, AQP8, AQP7, AQP9, AQP 10, AQP I L AQP 12. and combinations thereof.
  • the aquaporins are selected from the group consisting of AQP7 and AQP12.
  • hyperlipidemia is reduced by decreasing the levels of triglycerides, total cholesterol, free fatty acids and phospholipids.
  • the effective dose of the compounds is 2.5 - 40 mg/kg bodyweight of the subject.
  • the effective dose is 10-20 mg/kg bodyweight of the subject.
  • the related complications are selected from the group consisting of, insulin resistance, diabetes, pancreatitis, pancreatic steatosis, diabetic nephropathy, atherosclerosis, diabetic cardiomyopathy, diabetic neuropathy and diabetic retinopathy, hyperglycemia, dyslipidemia, hypercholesterolemia, obesity, liver steatosis, kidney dysfunction, and glaucoma.
  • the subject is a mammal.
  • the composition is formulated with pharmaceutically/nutraceutically acceptable excipients, adjuvants, diluents or carriers, and administered orally in the form of tablets, capsules, syrups, gummies, powders, suspensions, emulsions, chewables, candies, and eatables.
  • the invention discloses use of a composition comprising compounds of Formula I for the therapeutic management of diabetes and related complications in a subject.
  • the compounds are selected from the group consisting of Gingerenone A (STR#2) and Hirsutenone (STR#3).
  • management of diabetes is brought about by increasing the pancreatic p-cell function, decreasing circulating levels of creatinine, and albumin, decreasing hyperlipidemia, decreasing blood cystatin C levels, and reducing expression of NLRP-3 inflammasomes.
  • the alteration of p-cell function is brought about by modulating the expression of aquaporins (AQP).
  • the aquaporins are selected from the group consisting of AQPO, AQP1, AQP2, AQP3, AQP4, AQP5, AQP6, AQP8. AQP7, AQP9, AQP 10, AQP1 1, AQP 12, and combinations thereof.
  • the aquaporins are selected from the group consisting of AQP7 and AQP 12.
  • hyperlipidemia is reduced by decreasing the levels of triglycerides, total cholesterol, free fatty acids and phospholipids.
  • the effective dose of the compounds is 2.5 - 40 mg/kg body weight of the subj ect.
  • the effective dose is 10-20 mg/kg body weight of the subject.
  • the related complications are selected from the group consisting of, insulin resistance, diabetes, pancreatitis, pancreatic steatosis, diabetic nephropathy, atherosclerosis, diabetic cardiomyopathy, diabetic neuropathy and diabetic retinopathy, hyperglycemia, dyslipidemia, hypercholesterolemia, obesity', liver steatosis, kidney dysfunction, and glaucoma.
  • the subject is a mammal.
  • the composition is formulated with pharmaceutically/nutraceutically acceptable excipients, adjuvants, diluents or carriers, and administered orally in the form of tablets, capsules, syrups, gummies, powders, suspensions, emulsions, chewables, candies, and eatables.
  • Gingerenone A (STR#2) and Hirsutenone (STR#3) are evaluated for their ability to modify the expression of aqaaporins in a diabetic animal model
  • Different methods and processes are available in the literature for the chemical synthesis of Gingerenone A (STR#2 ) and Hirsutenone ( STR#3).
  • These compounds can also be isolated from a plant source, preferably, but not limited to. Zingiber officinale, Alnus hirsuta. Alnus sibirica, Alnus glutinosa, Alnus formosana. Alnus japonica, Alnus nepalensis, Viscum cruciatum using conventionally known extraction processes.
  • Example 2 Effect of Gingerenone A and Hirsutenone on pancreatic P-cell function
  • the rats were randomly divided into normal control and experimental groups.
  • the experimental group received high-fat diet (consisting of 70 % standard laboratory chow, 15 % carbohydrates, 10 % lard, and 5 % yolk powder) to establish an insulin resistance model, while the normal control group received standard chow.
  • the experimental group rats were induced with diabetes by a single intraperitoneal injection of STZ (35 mg'kg, dissolved in 0.01 M sodium citrate buffer, pH 4.4), while the Normal group rats were injected with the same dose of citrate buffer.
  • STZ 35 mg'kg, dissolved in 0.01 M sodium citrate buffer, pH 4.4
  • the Normal group rats were injected with the same dose of citrate buffer.
  • the random blood glucose levels of rats were measured to confirm the successful establishment of the diabetes model.
  • Rats with random blood glucose level > 150 mg/dl were indicative of the establishment of the diabetes and were selected for further pharmacological studies. All rats were fed their respective diets until the end of the study. All drags were administered orally once daily between 9:00 and 11 :00 a.m., continuously for 12 weeks. Table 1 discloses the groups of rats used for the experimentation.
  • Aquaporin 7 (AQP7) and aquaporin 12 (AQP12) are implicated in diabetes and beta cell function.
  • AQP7 is the most representative glycerol channel expressed in pancreatic (3-cells, the endocrine cells responsible for insulin production, regulating the blood glucose uptake. Glycerol uptake is followed by a fast [3-cell reswelling, volume- regulated anion channels activation and insulin release. Glycerol kinase phosphorylates glycerol to glycerol-3-phosphate, which is used as a substrate in the glycerol-3- phosphate shuttle, the process that reduces equivalents into mitochondria to be used in oxidative phosphorylation and ATP production.
  • AQP12 is expressed in pancreatic acinar cells and is localized on tire membrane of intracellular organelles.
  • the intracellular localization of AQP 12 in pancreatic acinar cells suggests a potential role in the maturation and exocytosis of zymogen granule and it has been proposed as a marker of pancreatic damage.
  • AQP12-null mice show increased susceptibility to acute pancreatitis, probably due to a defect in the secretion of zymogens .
  • AQP 12 is upregulated in pancreatic steatosis and related to markers of insulin resistance.
  • AQP12 increases cellular adhesion, increases insulin secretion and decreases pro-inflammatory cytokines (da Silva et al., Aquaporin-7 and aquaporin-12 modulate the inflammatory’ phenotype of endocrine pancreatic beta-cells, Archives of Biochemistry and Biophysics, Volume 691, 30 September 2020, 108481).
  • NLRP3 Nod-like receptor protein 3
  • IL- ip interleukin
  • the increase of these inflammasomes can trigger metabolic changes in diabetes including insulin resistance, hyperlipidaemia and hyperglycaemia and there is subsequent development of diabetic complications including diabetic nephropathy, atherosclerosis, diabetic cardiomyopathy, diabetic neuropathy and diabetic retinopathy.
  • Serum cystatin C has been well established as an early and accurate biomarker of CKD ⁇ Benoit et al., Cystatin C as a biomarker of chronic kidney disease: latest developments, Expert Rev Mol Diagn. 2020 Oct; 20(10): 1019- -1026). Diabetes has a toll of the kidney function and there is a choric decrease in kidney function with time.
  • the concentration of serum Cystatin C is mainly determined by glomerular filtration, which makes Cystatin C an endogenous marker of glomerular filtration rate.
  • a possible advantage of cystatin C with minor glomerular damage is that, being a large molecule, blood levels of cystatin C rises sooner than creatinine and is an effective biomarker.
  • cystatin C were elevated in high fat diet and STZ rats which was reduced by administration of Gingerenone A (STR#2) and Hirsutenone (STR#3 ) (Fig. 4), indicating the nephroprotective effects of the compounds.
  • the compounds prevent diabetic related complications such as nephropathy, kidney dysfunction etc.
  • the compounds also reduced the levels of creatinine and albumin (Table 3) thereby showing its effect as a complete nephr oprotective agents.
  • Gingerenone A (STR#2) and Hirsutenone (STR#3 (increased the expression of AQP7 and AQPI2, associated with P-cell proliferation, adhesion and migration which are reduced in diseased state.
  • the AQP12 expression was also increased which makes the cells resistant to inflammation, revealing lower levels of proinflammatory markers.
  • Gingerenone A & Himstenone reduced the expression of NLRP3 Inflammasomes in turn reduce Diabetic Complications arising due to inflammation.
  • Gingerenone A & Hirustenone can be used effectively for the management of diabetes and related complications.
  • Tables 5-18 provide illustrative examples of nutraceutical formulations Table 5: Tablet

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Psychology (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Botany (AREA)
  • Mycology (AREA)
  • Nutrition Science (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une composition comprenant des composés de Formule I pour une utilisation dans la modulation et le maintien de l'homéostasie de l'eau par modulation de l'expression d'aquaporines. Plus spécifiquement, l'invention concerne l'utilisation de la Gingérénone A et de l'Hirsuténone pour augmenter la fonction des cellules P pancréatiques par augmentation de l'expression de l'aquaporine 7 (AQP7) et de l'aquaporine 12 (AQP12), ainsi que leur autre autre utilisation dans la gestion du diabète et des complications associées.
PCT/US2024/026804 2023-04-29 2024-04-29 Compositions pour moduler l'expression d'aquaporines dans le diabète et les états associés Pending WO2024228949A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202341030814 2023-04-29
IN202341030814 2023-04-29

Publications (1)

Publication Number Publication Date
WO2024228949A1 true WO2024228949A1 (fr) 2024-11-07

Family

ID=93333354

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/US2024/026804 Pending WO2024228949A1 (fr) 2023-04-29 2024-04-29 Compositions pour moduler l'expression d'aquaporines dans le diabète et les états associés
PCT/US2024/026820 Pending WO2024228954A2 (fr) 2023-04-29 2024-04-29 Compositions pour moduler l'expression d'aquaporines dans des troubles neurodégénératifs

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/US2024/026820 Pending WO2024228954A2 (fr) 2023-04-29 2024-04-29 Compositions pour moduler l'expression d'aquaporines dans des troubles neurodégénératifs

Country Status (1)

Country Link
WO (2) WO2024228949A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN120754256A (zh) * 2025-09-09 2025-10-10 天津医科大学朱宪彝纪念医院(天津医科大学代谢病医院、天津代谢病防治中心) Aqp1在制备治疗高胰岛素血症心肌损伤药物中的应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100190862A1 (en) * 2009-01-28 2010-07-29 Chung-Ang University Industry Academic Cooperation Foundation Composition for treating atopic dermatitis comprising hirsutenone as an active ingredient
US20110124740A1 (en) * 2008-06-05 2011-05-26 Jeong Chan Ra Novel diaryl hepatonoid-based compounds and use thereof
US20160074338A1 (en) * 2011-12-29 2016-03-17 Snu R&Db Foundation Food composition for preventing obesity, pharmaceutical composition for treating obesity, and animal medicine for treating obesity, containing gingernone a

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110124740A1 (en) * 2008-06-05 2011-05-26 Jeong Chan Ra Novel diaryl hepatonoid-based compounds and use thereof
US20100190862A1 (en) * 2009-01-28 2010-07-29 Chung-Ang University Industry Academic Cooperation Foundation Composition for treating atopic dermatitis comprising hirsutenone as an active ingredient
US20160074338A1 (en) * 2011-12-29 2016-03-17 Snu R&Db Foundation Food composition for preventing obesity, pharmaceutical composition for treating obesity, and animal medicine for treating obesity, containing gingernone a

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN120754256A (zh) * 2025-09-09 2025-10-10 天津医科大学朱宪彝纪念医院(天津医科大学代谢病医院、天津代谢病防治中心) Aqp1在制备治疗高胰岛素血症心肌损伤药物中的应用

Also Published As

Publication number Publication date
WO2024228954A2 (fr) 2024-11-07
WO2024228954A3 (fr) 2025-01-23

Similar Documents

Publication Publication Date Title
Hoong et al. SGLT2 inhibitors as calorie restriction mimetics: insights on longevity pathways and age-related diseases
Sharma et al. Caulerpa lentillifera extract ameliorates insulin resistance and regulates glucose metabolism in C57BL/KsJ-db/db mice via PI3K/AKT signaling pathway in myocytes
Fan et al. Betaine supplementation protects against high-fructose-induced renal injury in rats
Meng et al. Anti-hyperuricemic and nephroprotective effects of rhein in hyperuricemic mice
Nie et al. Rutaecarpine ameliorates hyperlipidemia and hyperglycemia in fat-fed, streptozotocin-treated rats via regulating the IRS-1/PI3K/Akt and AMPK/ACC2 signaling pathways
Park et al. The combination of luteolin and l-theanine improved Alzheimer disease–like symptoms by potentiating hippocampal insulin signaling and decreasing neuroinflammation and norepinephrine degradation in amyloid-β–infused rats
Kimura et al. Endoplasmic reticulum stress inhibits STAT3-dependent suppression of hepatic gluconeogenesis via dephosphorylation and deacetylation
Liu et al. Protective effect of thymoquinone improves cardiovascular function, and attenuates oxidative stress, inflammation and apoptosis by mediating the PI3K/Akt pathway in diabetic rats
Abd El-Hameed Polydatin-loaded chitosan nanoparticles ameliorates early diabetic nephropathy by attenuating oxidative stress and inflammatory responses in streptozotocin-induced diabetic rat
CA2555296A1 (fr) Composition de diterpenes du type labdane extraite de andrographis paniculata, utilisee pour traiter les maladies auto-immunes et la maladie d'alzheimer par activation des recepteurs ppr-gamma
Lu et al. Astragalus polysaccharides decrease muscle wasting through Akt/mTOR, ubiquitin proteasome and autophagy signalling in 5/6 nephrectomised rats
Li et al. Neuroprotective effects of exendin-4 in rat model of spinal cord injury via inhibiting mitochondrial apoptotic pathway
Mao et al. A polysaccharide extract from the medicinal plant Maidong inhibits the IKK–NF-κB pathway and IL-1β–induced islet inflammation and increases insulin secretion
Obafemi et al. Antidiabetic property of miracle fruit plant (Synsepalum dulcificum Shumach. & Thonn. Daniell) leaf extracts in fructose-fed streptozotocin-injected rats via anti-inflammatory activity and inhibition of carbohydrate metabolizing enzymes
Tang et al. Protective effect of Ginkgo biloba leaves extract, EGb761, on myocardium injury in ischemia reperfusion rats via regulation of TLR-4/NF-κB signaling pathway
Li et al. Suppression of hyperglycemia and hepatic steatosis by black-soybean-leaf extract via enhanced adiponectin-receptor signaling and AMPK activation
Li et al. Toxicology studies of furosine in vitro/in vivo and exploration of the related mechanism
Hwang et al. Glucosamine enhances body weight gain and reduces insulin response in mice fed chow diet but mitigates obesity, insulin resistance and impaired glucose tolerance in mice high-fat diet
Liu et al. Nifuroxazide improves insulin secretion and attenuates high glucose-induced inflammation and apoptosis in INS-1 cells
WO2024228949A1 (fr) Compositions pour moduler l'expression d'aquaporines dans le diabète et les états associés
Chen et al. Astilbin attenuates hyperuricemia and ameliorates nephropathy in fructose-induced hyperuricemic rats
Lee et al. Anti-inflammatory activity of lobaric acid via suppressing NF-κB/MAPK pathways or NLRP3 inflammasome activation
Zhao et al. Taurine reduces apoptosis mediated by endoplasmic reticulum stress in islet β-cells induced by high-fat and-glucose diets
CN108697723B (zh) 鬼针草对增加肌肉和减少脂肪的有益效果
Liu et al. The herbal medicine cordyceps sinensis protects pancreatic beta cells from streptozotocin-induced endoplasmic reticulum stress

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24800407

Country of ref document: EP

Kind code of ref document: A1