[go: up one dir, main page]

WO2018174379A1 - Composition pharmaceutique comprenant un antagoniste de htr2a à titre de principe actif pour la prévention ou le traitement de la maladie du foie gras - Google Patents

Composition pharmaceutique comprenant un antagoniste de htr2a à titre de principe actif pour la prévention ou le traitement de la maladie du foie gras Download PDF

Info

Publication number
WO2018174379A1
WO2018174379A1 PCT/KR2017/015006 KR2017015006W WO2018174379A1 WO 2018174379 A1 WO2018174379 A1 WO 2018174379A1 KR 2017015006 W KR2017015006 W KR 2017015006W WO 2018174379 A1 WO2018174379 A1 WO 2018174379A1
Authority
WO
WIPO (PCT)
Prior art keywords
htr2a
fatty liver
liver
expression
mice
Prior art date
Application number
PCT/KR2017/015006
Other languages
English (en)
Korean (ko)
Inventor
김하일
남궁준
최원석
Original Assignee
한국과학기술원
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
Priority claimed from KR1020170158580A external-priority patent/KR20180108402A/ko
Application filed by 한국과학기술원 filed Critical 한국과학기술원
Publication of WO2018174379A1 publication Critical patent/WO2018174379A1/fr

Links

Images

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
    • 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
    • A23L33/13—Nucleic acids or derivatives thereof
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing

Definitions

  • the present invention was made by the task number 2014M3A9D8034464 under the support of the Ministry of Science, ICT and Future Planning, and the research management specialized organization of the project is “Korea Research Foundation”, the research project name is “Bio / Medical Technology Development Project”, and the research project title is “Cell Organ Organelle” Development of reconstruction technology for countermeasures through functional recovery ", the host institution is Korea Advanced Institute of Science and Technology, and the research period is 2016.06.26. to be.
  • the present invention was made by the task number 2016M3A9B6902871 under the support of the Ministry of Science, ICT and Future Planning, the research management specialized organization of the project is "Korea Research Foundation", the research project name “Bio / medical technology development project”, the research project title is "local Analysis of Adipose Cell Remodeling Mechanism by Cell-derived Serotonin ", Organizer is Korea Advanced Institute of Science and Technology, Research period 2016.06.26.-2017.06.25. to be.
  • the present invention relates to a pharmaceutical composition for preventing or treating fatty liver, comprising an HTR2A antagonist as an active ingredient.
  • Fatty liver is a disease in which triglycerides accumulate in liver cells. It is caused by excessive energy such as obesity and metabolic syndrome or excessive alcohol consumption. If fatty liver persists, hepatitis, cirrhosis and even liver cancer can cause a series of diseases. Recently, obesity and rural populations are rapidly increasing not only in western developed countries but also in Korea due to lack of eating habits, drinking culture, and lack of exercise, which is a serious social problem.
  • Fatty liver develops when the amount of fat accumulated in the liver exceeds the amount of fat metabolized by the liver through the fat metabolism pathway in the liver. Increased absorption of fat from the blood into the liver, increased fat production from the liver, increased triglycerides synthesized in the liver, reduced fat oxidation consumed in the liver, ultra-low-density lipoprotein (VLDL) that exports fat from the liver to the blood In addition, the reduction of very low desity lipoprotein may be seen in pathophysiology of fatty liver.
  • VLDL ultra-low-density lipoprotein
  • the present inventors have endeavored to develop a substance having anti-fatty activity, and confirmed that the HTR2A antagonist including safogrelate, ketanserine, etc. of the present invention exhibited significant fatty liver improvement effects, and completed the present invention.
  • Another object of the present invention is to provide a food composition for preventing or improving fatty liver, comprising an HTR2A (5-hydroxytrptamine receptor 2A) inhibitor as an active ingredient.
  • the test substance is determined as a candidate for preventing or treating fatty liver.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of fatty liver comprising HTR2A (5-hydroxytrptamine receptor 2A) inhibitor as an active ingredient.
  • fatty liver refers to a condition in which a greater amount of fat is accumulated in the liver than the proportion of fat (5%) in normal liver.
  • the fatty liver may be classified into alcoholic fatty liver due to excessive drinking and non-alcoholic fatty liver due to obesity, diabetes, hyperlipidemia or drugs.
  • Alcoholic fatty liver is caused by the ingestion of alcohol to promote fat synthesis and normal energy metabolism in the liver, non-alcoholic fatty liver occurs due to causes other than alcohol, the non-alcoholic fatty liver causes abnormal fat metabolism It is known to be frequently accompanied by adult disease.
  • alcoholic fatty liver refers to a state in which fat is accumulated in liver cells by ingesting excessive alcohol (excessive drinking).
  • non-alcoholic fatty liver refers to fatty liver caused by causes other than alcohol. It accounts for 57% of the total fatty liver, and is commonly known to be accompanied by the adult disease causing fat metabolism abnormality. One of the causes of adult disease is known to be excessive carbohydrate intake and obesity resulting from obesity. In fact, 75% of patients with nonalcoholic fatty liver have been reported to be obese.
  • HTR2A (5-hydroxytrptamine receptor 2A, or 5-HT2A receptor) belongs to the serotonin receptor family and is one of the subtypes of the 5-HT2 receptor, which is a G protein-coupled receptor (GPCR). HTR2A was first noticed because of its importance as a target for serotonergic hallucinogens such as LSD, and was later found to mediate the action of many antipsychotic drugs, especially atypical drugs. However, the relationship between the HTR2A and fatty liver is not known yet.
  • the prevention or treatment of fatty liver is achieved by an inhibitor of HTR2A.
  • HTR2A The inhibition of HTR2A can be done in a variety of ways.
  • the term “inhibitor” may be an antagonist.
  • Antagonists are substances that antagonize the binding of certain bioactive substances to their receptors, but do not exhibit physiological activity through their respective receptors.
  • Antagonists, blocking agents, inhibitors, etc. are substances that antagonize the binding of certain bioactive substances to their receptors, but do not exhibit physiological activity through their respective receptors.
  • Antagonists, blocking agents, inhibitors, etc. are substances that antagonize the binding of certain bioactive substances to their receptors, but do not exhibit physiological activity through their respective receptors.
  • Antagonists, blocking agents, inhibitors, etc. .
  • the antagonist herein includes an inverse agonist for the receptor.
  • the HTR2A antagonist is Sapogrelate, 5-I-R91150, 5-MeO-NBpBrT, Adatanserin, Altanserin, AMDA (9-Aminomethyl -9,10-dihydroanthracene, Amperozide, Asenapine, BL-1020, Sinanserin, Clozapine, Deramciclane, Fananserin, Plyans Flibanserin, Glemanserin, Iferanserin, Ketanserin, KML-010, Lidanserin, Lubazodone, Lumateperone, Lumeperone, LY- 367,265, Medifoxamine, Mepiprazole, MIN-101, Naphtidrofuryl, Nefazodone, Ollanzapine, Phenoxybenzamine, Pipamperone , Pruvanserin, Lauwolscine, Quetiapine, Risperidone, Ritanserin, It may be selected from the group consisting
  • the HTR2A antagonist is Ketanserin.
  • the HTR2A antagonist may be an HTR2A expression inhibitor.
  • the expression inhibitor may be an HTR2A expression inhibitor selected from the group consisting of antisense oligonucleotides, siRNAs, shRNAs and ribozymes that specifically bind to mRNA of the HTR2A gene, but is not limited thereto.
  • antisense oligonucleotide refers to DNA or RNA or derivatives thereof that contain a nucleic acid sequence complementary to a sequence of a particular mRNA and binds to the complementary sequence within the mRNA to inhibit translation of the mRNA into a protein.
  • An antisense sequence refers to a DNA or RNA sequence that is complementary to HTR2A mRNA (eg, GenBank Accession Nos. NM_000621.4 and NM_001165947.2) and capable of binding to HTR2A mRNA, and translates into HTR2A mRNA, into the cytoplasm. May inhibit the essential activity for translocation, maturation or any other overall biological function of the antisense nucleic acid, 6-100 bases in length, specifically 8-60 bases, more specifically 10 to 40 bases.
  • the antisense nucleic acid can be modified at one or more base, sugar or backbone positions to enhance efficacy (De Mesmaeker et al., Curr Opin Struct Biol., 5 (3): 343-55 (1995) ).
  • the nucleic acid backbone can be modified with phosphorothioate, phosphoroester, methyl phosphonate, short chain alkyl, cycloalkyl, short chain heteroatomic, heterocyclic intersaccharide linkages and the like.
  • antisense nucleic acids may comprise one or more substituted sugar moieties.
  • Antisense nucleic acids can include modified bases.
  • Modified bases include hypoxanthine, 6-methyladenine, 5-me pyrimidine (particularly 5-methylcytosine), 5-hydroxymethylcytosine (HMC), glycosyl HMC, gentobiosil HMC, 2-aminoadenine, 2 Thiouracil, 2-thiothymine, 5-bromouracil, 5-hydroxymethyluracil, 8-azaguanine, 7-deazaguanine, N6 (6-aminohexyl) adenine, 2,6-diaminopurine, etc. There is this.
  • the antisense nucleic acids of the present invention may be chemically bound to one or more moieties or conjugates that enhance the activity and cellular adsorption of the antisense nucleic acids.
  • Antisense oligonucleotides can be synthesized in vitro by conventional methods to be administered in vivo or to allow antisense oligonucleotides to be synthesized in vivo.
  • One example of synthesizing antisense oligonucleotides in vitro is using RNA polymerase I.
  • One example of allowing antisense RNA to be synthesized in vivo is to allow the antisense RNA to be transcribed using a vector whose origin is in the opposite direction of the recognition site (MCS). Such antisense RNA is desirable to ensure that there is a translation stop codon in the sequence so that it is not translated into the peptide sequence.
  • antisense oligonucleotides that can be used in the present invention can be readily prepared according to methods known in the art with reference to the nucleotide sequences of HTR2A mRNA known to GenBank (Weiss, B. (ed.): Antisense Oligodeoxynucleotides and Antisense RNA: Novel Pharmacological and Therapeutic Agents, CRC Press, Boca Raton, FL, 1997; Weiss, B., et al., Antisense RNA gene therapy for studying and modulating biological processes.Cell.Mol.Life Sci., 55: 334-358 (1999).
  • siRNA refers to a nucleic acid molecule capable of mediating RNA interference or gene silencing (see WO 00/44895, WO 01/36646, WO 99/32619, WO 01/29058, WO 99 / 07409 and WO 00/44914) siRNAs are provided as an efficient gene knockdown method or as a gene therapy method because they can inhibit the expression of target genes siRNA was first discovered in plants, worms, fruit flies and parasites. siRNA was developed and used in mammalian cell research.
  • the sense strand (corresponding sequence corresponding to the HTR2A mRNA sequence) and the antisense strand (sequence complementary to the HTR2A mRNA sequence) may be positioned opposite to each other to have a double-chain structure. Or may have a single chain structure with self-complementary sense and antisense strands.
  • siRNAs are not limited to completely paired double-stranded RNA moieties paired with RNA, but paired by mismatches (the corresponding bases are not complementary), bulges (there are no bases corresponding to one chain), and the like. May be included.
  • the total length is 10 to 100 bases, preferably 15 to 80 bases, more preferably 20 to 70 bases.
  • the siRNA terminal structure can be either blunt or cohesive, as long as the expression of the HTR2A gene can be suppressed by the RNAi effect.
  • the cohesive end structure is possible for both 3'-end protrusion structures and 5'-end protrusion structures.
  • an siRNA molecule may have a form in which a short nucleotide sequence (eg, about 5-15 nt) is inserted between a self-complementary sense and an antisense strand, and in this case, by expression of a nucleotide sequence
  • the formed siRNA molecules form a hairpin structure by intramolecular hybridization, and form a stem-and-loop structure as a whole. This stem-and-loop structure is processed in vitro or in vivo to produce an active siRNA molecule capable of mediating RNAi.
  • prevention refers to any action that inhibits or delays the onset of the fatty liver by administration of the composition according to the present invention
  • treatment refers to improving or beneficially modifying fatty liver by administration of the composition. It means all actions.
  • composition for preventing or treating fatty liver of the present invention can be used to suppress or improve the onset of fatty liver by administering to a subject who is likely to develop or develop fatty liver.
  • compositions and methods of treatment comprising the HTR2A antagonist of the present invention as an active ingredient include mammals such as cattle, horses, sheep, pigs, goats, camels, antelopes, dogs, cats, etc., which can cause all diseases related to fatty liver as well as humans. Can also be used for.
  • composition comprising the HTR2A antagonist of the present invention may further comprise a suitable carrier, excipient or diluent according to conventional methods.
  • Carriers, excipients and diluents that may be included in the compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • composition comprising the HTR2A antagonist of the present invention, respectively, in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, oral dosage forms, external preparations, suppositories, or sterile injectable solutions according to a conventional method.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient such as starch, calcium carbonate, sucrose ( sucrose, lactose, gelatin and the like can be mixed.
  • excipients such as starch, calcium carbonate, sucrose ( sucrose, lactose, gelatin and the like can be mixed.
  • lubricants such as magnesium stearate, talc can also be used.
  • Liquid preparations for oral use include suspensions, solvents, emulsions, and syrups, and include various excipients such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories.
  • non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.
  • As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • Preferred dosages of the active ingredients of the present invention vary depending on the patient's condition, age, weight, extent of disease, drug form, route of administration, and duration, and may be appropriately selected by those skilled in the art.
  • the active ingredient of the present invention can be administered in 0.0001 ⁇ 100 mg / kg, preferably in an amount of 0.001 ⁇ 100 mg / kg divided once to several times daily.
  • the active ingredient of the present invention in the composition should be present in an amount of 0.0001 to 10% by weight, preferably 0.001 to 1% by weight based on the total weight of the total composition.
  • the pharmaceutical dosage form of the active ingredient of the present invention may be used in the form of their pharmaceutically acceptable salts, and may be used alone or in combination with other pharmaceutically active ingredients or in a suitable collection.
  • the pharmaceutical composition of the present invention can be administered to mammals such as mice, rats, cattle, horses, pigs, domestic animals, humans, and the like by various routes. All modes of administration can be expected, for example, to be administered by oral, abdominal, rectal or intravenous, arterial, muscle, inhalation, transdermal, subcutaneous, intradermal, intrauterine, dural or intracerebroventricular injection. Can be.
  • the present invention provides a food composition for preventing or improving fatty liver comprising an HTR2A inhibitor as an active ingredient.
  • the HTR2A inhibitor of the present invention is sapogrelate (Sarpogrelate), 5-I-R91150, 5-MeO-NBpBrT, Adatanserin, Altanserin, AMDA (9-Aminomethyl-9,10-dihydroanthracene), Amperozide, Acenapine ), BL-1020, Sinanserin, Clozapine, Deramciclane, Fananserin, Flibanserin, Glemanserin, Iferanserin, Ketan Ketanserin, KML-010, Lidanserin, Lubazodone, Lumateperone, LY-367,265, Medifoxamine, Mepiprazole, MIN-101, Naphtidrofuryl, Nefazodone, Olanzapine, Phenoxybenzamine, Pipamperone, Pruvanserin, Lauwolscine, Queetiapine (Quetiapine) ), Risperidone, Ritanserin, Setoper
  • the food composition for preventing or improving fatty liver of the present invention includes the form of pills, powders, granules, tablets, capsules or liquids, and the like to which the composition of the present invention can be added, for example, various foods , For example, drinks, gum, tea, vitamin complexes, dietary supplements and the like.
  • the food composition may further include other ingredients that do not interfere with fatty liver improvement, and the type thereof is not particularly limited.
  • other ingredients that do not interfere with fatty liver improvement, and the type thereof is not particularly limited.
  • various herbal extracts, food acceptable additives, natural carbohydrates, and the like may be contained as additional ingredients, such as conventional foods.
  • natural carbohydrates examples include monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • natural flavoring agents tautin, stevia extract
  • synthetic flavoring agents saccharin, aspartame, etc.
  • the food composition of the present invention may include a health functional food.
  • the term "health functional food” refers to a food prepared and processed in the form of tablets, capsules, powders, granules, liquids and pills using raw materials or ingredients having useful functions for the human body.
  • functional means to obtain useful effects for health purposes such as nutrient control or physiological action on the structure and function of the human body.
  • the health functional food of the present invention can be prepared by a method commonly used in the art, and the preparation can be prepared by adding raw materials and ingredients commonly added in the art.
  • the preparation can be prepared by adding raw materials and ingredients commonly added in the art.
  • unlike the general medicine has the advantage that there is no side effect that can occur when taking a long-term use of the drug as a raw material, and excellent portability.
  • the mixed amount of the active ingredient may be suitably determined depending on the purpose of use (prevention, health or therapeutic treatment).
  • the HTR2A antagonist of the present invention is added at a dose of 1 to 10% by weight, preferably 5 to 10% by weight of the raw material composition.
  • it may be used at a dose below the above range.
  • Examples of the food to which the substance can be added include dairy products including meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, various soups, drinks, tea, drinks, Alcoholic beverages and vitamin complexes, and the like and include all of the health foods in the conventional sense.
  • the term " improvement" refers to parameters related to a condition in which fatty liver disease improves or alleviates with administration of a composition according to the invention, such as a decrease in triglycerides, a decrease in lipogenesis, a decrease in hepatic fat, and the like. Means any action to reduce the symptoms of fatty liver.
  • the present inventors confirmed the expression of serotonin synthase Tph1 (Tryptophan hydoxylas 1) in a fatty liver-induced mouse model to confirm the relationship between fatty liver pathophysiology and serotonin. It was confirmed that Tph1 expression was increased in the intestinal tissue, which is the main place of serotonin synthesis (see Fig. 1 and Fig. 2).
  • Tph1 gut-specific knockout (Tph1 GKO) was constructed to induce fatty liver and induced fatty liver. It was confirmed that the change was improved (see FIG. 3).
  • Ethanol-mediated fatty liver improvement in Tph1 GKO mice was confirmed by increased expression of Cpt1a, which is responsible for fatty acid oxidation in the liver, decreased expression of Cd36, which brings fatty acids into cells, and decreased expression of Lpin1, which synthesizes intracellular triglycerides. 8).
  • serotonin receptor HTR2A was administered to ketanserine, a receptor-specific antagonist, and the changes in fatty liver due to high fat diet were investigated.
  • administration of ketanserine with a high fat diet was confirmed that the effect of reducing weight gain (see FIG. 10).
  • glucose and insulin sensitivity tests confirmed that glucose tolerance and insulin resistance were improved by ketanserine (see FIG. 11).
  • the hepatocytes of the mouse were first cultured and the ketanserine was directly administered to confirm that the expression of genes related to fat production was reduced (FIG. On the contrary, it was confirmed that administration of an agonist for HTR2A, a target receptor of ketanserine, showed the opposite result (see FIG. 15).
  • the ketanserine of the present invention inhibited the expression of Acly and Me1 involved in adipogenesis in liver cells, and on the contrary, by confirming the increased expression of Acaca and Fasn by an agonist for HTR2A, a target receptor for ketanserine, Ketanserine can be usefully used in the composition for regulating liver fat metabolism.
  • liver tissue-specific HTR2A-removed mice Htr2a LKO
  • fatty liver see FIGS. 17A to 17C
  • triglycerides in liver tissue.
  • hepatic triglyceride was also found to be significantly reduced in the safogrelate administration group (see Fig. 18) was confirmed that the HTR2A gene is a gene associated with the development of fatty liver, HTR2A antagonist of the present invention composition for the prevention or treatment of fatty liver It can be usefully used.
  • Htr2a LKO liver tissue specific Htr2a-removing mouse
  • the expression level of genes related to lipogenesis and triglyceride synthesis is reduced, the expression amount of genes related to fatty acid uptake is reduced, HTR2A
  • the gene has been confirmed to be a gene associated with the development of fatty liver
  • HTR2A antagonist of the present invention can be usefully used as a composition for the prevention or treatment of fatty liver.
  • HTR2A inhibitors inhibit the expression of the HTR2A gene, a gene involved in the onset of fatty liver (expression inhibitor), or antagonize the action of the HTR2A receptor. (Receptor antagonist), it can be usefully used as a composition for the prevention or treatment of fatty liver.
  • the present invention provides a method for screening a candidate for preventing or treating fatty liver, comprising the following steps:
  • the test substance is determined as a candidate for preventing or treating fatty liver.
  • a test substance is contacted with a cell containing the HTR2A gene or protein.
  • the cells may be prepared variously, specifically hepatocytes.
  • hepatocytes of a mouse were isolated and used.
  • test material refers to an unknown substance used in screening to determine whether the expression level of HTR2A gene, or the amount or activity of HTR2A protein is affected.
  • the test substance specifically includes, but is not limited to, extracts, compounds, antisense nucleotides, and proteins.
  • Step (b): HTR2A The expression level of the gene, or HTR2A Measuring the amount or activity of a protein
  • the test substance is a candidate for preventing or treating fatty liver. Determined as a substance.
  • the measurement of the change in the expression level of the HTR2A gene can be carried out through various methods known in the art. For example, RT-PCR (Sambrook et al., Molecular Cloning. A Laboratory Manual, 3rd ed. Cold Spring Harbor Press (2001)), Northern blotting (Peter B. Kaufma et al., Molecular and Cellular Methods in Biology and Medicine , 102-108, CRC press), hybridization reaction using cDNA microarray (Sambrook et al., Molecular Cloning.A Laboratory Manual, 3rd ed. Cold Spring Harbor Press (2001)) or in situ hybridization reaction (Sambrook et al. , Molecular Cloning.A Laboratory Manual, 3rd ed.Cold Spring Harbor Press (2001)).
  • RNA is isolated from cells treated with a sample, and then a first-chain cDNA is prepared using oligo dT primers and reverse transcriptase. Subsequently, the first chain cDNA is used as a template, and PCR reaction is performed using the HTR2A gene-specific primer set. Then, PCR amplification products are electrophoresed, and the formed bands are analyzed to measure changes in the expression level of the HTR2A gene.
  • Changes in the amount of HTR2A protein can be carried out through various immunoassay methods known in the art.
  • changes in the amount of HTR2A protein include, but are not limited to, radioimmunoassay, radioimmunoprecipitation, immunoprecipitation, enzymelinked immunosorbent assay (ELISA), capture-ELISA, inhibition or hardwood assay, and sandwich assay. .
  • Fatty liver prophylactic or therapeutic candidates determined through the screening method of the present invention can be used to prevent or treat fatty liver.
  • the present invention provides a method for preventing fatty liver comprising administering to a subject a pharmaceutical composition comprising the above-described HTR2A (5-hydroxytrptamine receptor 2A) inhibitor of the present invention as an active ingredient. Or provide a method of treatment.
  • administer refers to administering a therapeutically effective amount of a composition of the invention directly to a subject (an individual) in need thereof so that the same amount is formed in the subject's body. Say that.
  • a “therapeutically effective amount” of a composition means a content of the composition that is sufficient to provide a therapeutic or prophylactic effect to a subject to which the composition is to be administered, and includes “prophylactically effective amount”.
  • the term “subject” includes, without limitation, human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, monkey, chimpanzee, baboon or rhesus monkey. Specifically, the subject of the present invention is a human.
  • the method for preventing or treating fatty liver of the present invention is a method comprising administering a pharmaceutical composition for preventing or treating fatty liver, which is an aspect of the present invention, and thus avoids excessive complexity of the present disclosure with respect to overlapping contents. To omit them.
  • the present invention provides a pharmaceutical composition for preventing or treating fatty liver, comprising an HTR2A (5-hydroxytrptamine receptor 2A) inhibitor as an active ingredient.
  • the present invention also provides a food composition for preventing or improving fatty liver, comprising an HTR2A inhibitor as an active ingredient.
  • the present invention also provides a method for screening a candidate for preventing or treating fatty liver.
  • the HTR2A inhibitor of the present invention inhibits fatty liver production induced by high fat diet and inhibits the expression of genes related to adipogenesis in hepatocytes, it may be usefully used as an active ingredient for preventing or treating fatty liver.
  • Tph1 tryptophan hydroxylase 1
  • FIG. 2 shows that the expression of Tph1, a rate-determining enzyme of serotonin synthesis, increases by ethanol intake in the intestinal tissues of mice.
  • FIG. 3 is a diagram showing that fatty liver changes by high fat diet were improved in mice in which Tph1 was specifically removed from intestinal tissue.
  • FIG. 4 is a diagram showing that the increase in triglycerides in liver tissue by high fat diet is suppressed in the tissues specifically Tph1 removed.
  • FIG. 5 is a diagram showing changes in the expression of genes associated with hepatic fat metabolism by high fat diet in mice in which Tph1 is specifically removed from intestinal tissue.
  • FIG. 6 is a diagram showing the improvement of fatty liver changes by ethanol diet in mice in which Tph1 is specifically removed from intestinal tissue.
  • FIG. 7 is a diagram showing the decrease of triglycerides in liver tissue by ethanol diet in mice in which Tph1 is specifically removed from intestinal tissue.
  • FIG. 8 is a diagram showing changes in the expression of genes related to hepatic fat metabolism by ethanol diet in mice in which Tph1 is specifically removed from intestinal tissue.
  • Figure 9 is a diagram showing the expression of serotonin receptors and serotonin metabolizing enzymes in liver tissue of the mouse.
  • FIG. 10 is a diagram showing the weight change when ketanserin was administered to a group of mice fed high fat diet.
  • Figure 11 shows the increase in glucose and insulin sensitivity when ketanserin is administered to the mouse group.
  • FIG. 12 is a graph showing the reduction of fat accumulation in liver tissue as a result of H & E tissue staining when ketanserin, a type of HTR2A antagonist of the present invention, was administered to a group of mice fed high fat diet.
  • Figure 13 is a diagram showing the reduction of hepatic triglycerides (hepatic triglycerides) when administration of ketanserin, a type of HTR2A antagonist of the present invention, to a group of mice fed high fat diet.
  • FIG. 14 is a diagram showing a decrease in expression of genes related to fat production when ketanserin is administered to liver cells of a mouse.
  • Figure 15 shows the increase in expression of genes associated with fat production when HTR2A agonist is administered to mouse liver cells.
  • FIG. 16A is a diagram illustrating a vector design for manufacturing an Htr2a floxed mouse
  • FIG. 16B is a schematic diagram showing a method of manufacturing an Htr2a LKO mouse by crossing an Htr2a floxed mouse and an Alb-Cre mouse
  • FIG. 16C is a manufactured Htr2a LKO. RT-PCR results to confirm knockout of mice.
  • Htr2a Liver Knock Out mouse Htr2a LKO
  • wild-type mice divided into normal diet group (SCD, standard chow diet), high fat diet (HFD, high fat diet)
  • SCD standard chow diet
  • HFD high fat diet
  • Figure 18 shows the results of confirming the change in triglycerides in the liver in liver tissue-specific Htr2a removal mice (Htr2a LKO).
  • FIG. 19A is a diagram confirming the change in weight of liver tissue-specific Htr2a-removed mice (Htr2a LKO), and FIG. 19B is a diagram confirming the change in weight ratio by organ to body weight.
  • FIG. 20 is a diagram confirming the changes in glucose tolerance and insulin resistance of liver tissue specific Htr2a deficient mice (Htr2a LKO) (FIG. 20B).
  • FIG. 21 shows a comparison of lipid profiles (total cholesterol, fatty acids, triglycerides, HDL cholesterol levels) in plasma of liver tissue specific Htr2a deficient mice (Htr2a LKO).
  • FIG. 22 is a diagram showing a comparison of expression levels of genes associated with lipo metabolism in liver tissue specific Htr2a-removed mice (Htr2a LKO).
  • Htr2a LKO liver tissue specific Htr2a-removed mice
  • Figure 23 is a diagram showing the weight change when a group of mice fed high fat diet was administered safogrelate, which is a kind of HTR2A antagonist of the present invention.
  • FIG. 24 is a diagram showing the reduction of fat accumulation in liver tissue as a result of H & E tissue staining when administration of safogrelate, which is a type of HTR2A antagonist of the present invention, to a group of mice fed high-fat diet (FIG. 24A: 10x; FIG. 24b: 20x).
  • Figure 25 is a diagram showing a decrease in hepatic triglycerides (hepatic triglyceride) when the administration of safogrelate, which is a type of HTR2A antagonist of the present invention, to a group of mice fed high fat diet.
  • NCD group normal chow diet
  • HFD group high-fat diet
  • NCD group In order to perform the ethanol diet, 10-week-old mice were divided into two diet groups (NCD group and ethanol diet group) and used for the experiment.
  • the NCD group was distilled water, and the ethanol group was previously described (Zhou et al., 2003, Exp . Biol . Med . 227: 214-222; Kao et al., 2012, Hepatology . 56: 594-604 Ethanol was administered according to the following method.
  • ketanserin Sigma
  • 12-week-old mice were divided into two treatment groups (control group, ketanserin group) and used in the experiment.
  • Ketanserine group was injected with ketaneserine dissolved in phosphate-buffered saline (PBS) in 1 mg / kg body weight of the mouse and the same amount of PBS daily in the control group.
  • PBS phosphate-buffered saline
  • mice were anesthetized with Zoletil® (Virbac) intraperitoneally, and then the intraperitoneal incision was taken to extract the intestines and liver.
  • Zoletil® Virbac
  • Tph1, a serotonin synthase, in the intestinal tissue was significantly increased in both the high fat diet (HFD group) and the ethanol diet (EtOH) (see FIGS. 1 and 2). Therefore, high fat diet and ethanol diet was found to increase the expression of Tph1, a serotonin synthase in the intestinal tissue.
  • Tph1 gut-specific knockout mice with Tph1 gene-specific intestinal tissues were removed according to the method described in Sumar et al., 2012, Cell Metab . 16: 588-600. Cre mice were made by crossing.
  • liver tissue of the intestinal tissue specific Tph1 removing mouse (Tph1 GKO) prepared in Example 3-1
  • the liver was extracted by the method described in Example 1-2 and fixed in 10% neutral formalin solution.
  • Paraffin embedded cut to 5 ⁇ m thickness and adhered to the slide.
  • Tph1 GKO intestinal tissue-specific Tph1-removed mice
  • the liver was extracted by the method described in Example 1-2, followed by a 5% NP-40 solution. After pulverizing in and heated to dissolve all lipid components. Triglyceride Reagent (Sigma) was used to decompose triglycerides into Glycerol, and Glycerol Reagent (Sigma) was used to quantify the amount of Glycerol by color reaction. The protein amount was measured by BCA Protein Assay Kit (Pierce) to correct the triglyceride amount to the amount of protein in the tissue.
  • Example 4 intestinal tissue specificity Tph1 Remove mouse ( Tph1 GKO ) Changes in gene expression related to fat metabolism
  • Example 2 was extracted from liver tissues extracted by the method described in Example 1-2.
  • RNA was extracted by the method described in the above, cDNA was synthesized, and realtime PCR was performed.
  • the primers used for PCR used the sequences listed in Table 2 below.
  • Example 5 intestinal tissue specificity Tph1 Remove mouse ( Tph1 GKO ) Synthesis of Serotonin Receptor and Metabolic Enzyme Expression in Liver Tissue
  • Htr1a, Htr1d, HTR2A, Htr2b, Htr3a, Htr4, Htr7, and Slc6a4 responsible for serotonin reuptake, Maoa responsible for serotonin degradation, and Maob among serotonin receptors were confirmed (see FIG. 9).
  • serotonin receptor HTR2A was administered to ketanserine, which is a receptor-specific antagonist, to investigate changes in fatty liver due to high fat diet.
  • ketanserine which is a receptor-specific antagonist
  • the administration of ketanserine with a high fat diet was confirmed that the weight gain is reduced (see Fig. 10).
  • Example 6 of the present invention Ketanserin Of mice by administration Glucose tolerance And insulin resistance
  • a general diet group ii) a general diet and a ketanserine administration group, iii) high fat, in order to confirm the effect of improving the glucose tolerance and insulin resistance of the mouse by administration of the ketanserine of the present invention Diet group, iv) high-fat diet and ketanserine-administered groups were bred, and blood was collected from the caudal vein of mice to measure blood glucose.
  • glucose solution was administered intraperitoneally with 2 g / kg body weight after fasting, and blood glucose was measured after 0, 15, 30, 45, 60, 90, and 120 minutes.
  • Insulin resistance was measured after 0.75 U / kg body weight of insulin solution after fasting and blood glucose was measured after 0, 15, 30, 45, 60, 90, 120 minutes.
  • a general diet group ii) a general diet and ketanserine administration group, iii) a high fat diet group, iv by the method described in Example 1-1
  • Breeding was divided into high fat diet and ketanserine administration group, and liver tissue was observed by H & E staining by the method described in Examples 3-2 and 3-3, and the amount of triglyceride was quantified.
  • Ketanserine was intragastrically administered.
  • hepatocytes of the mouse were isolated by a two-step perfusion method described in.
  • the hepatocytes are high glucose DMEM containing 1% antibiotic-antimycotic solution (Invitrogen, Carlsbad, CA) and 10% bovine calf serum (Invitrogen, Carlsbad, CA)
  • the growth medium incubated in a humid atmosphere of 5% carbon dioxide and 37 °C temperature conditions.
  • Ketanserine which is an HTR2A antagonist, or DOI, which is an HTR2A agonist, was treated to a concentration of 1 ⁇ M, respectively, and after 24 hours, RNA was extracted by the same method as in ⁇ Example 2> to synthesize cDNA, followed by realtime PCR. Primers used for PCR were as shown in Table 2 above.
  • Htr2a liver-specific knockout (Htr2a LKO) was generated by crossing Htr2a floxed mice and Alb-Cre mice (see FIGS. 16A and 16B). Liver tissues of the prepared Htr2a LKO mice were collected and subjected to RT-PCR for the Htr2a gene to confirm that knockout was well performed (see FIG. 16C).
  • Htr2a liver-specific knockout mice Htr2a LKO mice were examined.
  • SCD standar chow diet and high fat diet (HFD).
  • HFD high fat diet
  • liver tissue-specific Htr2a-removed mice (Htr2a LKO) and wild-type mice (WT) prepared in Example 9-1 were bred by the method described in Example 9-2, and liver was extracted by the method described in Example 1-2. It was. As a result of comparing the liver tissues of the Htr2a LKO mice fed the high fat diet and the wild type control mice (WT) fed the high fat diet, it was confirmed that the livers of the Htr2a LKO mice were smaller (FIG. 17A). The livers were also fixed in 10% neutral formalin solution to confirm histological differences, embedded in paraffin, cut to 5 ⁇ m thickness and adhered to slides.
  • Htr2a LKO liver tissue-specific Htr2a-removed mice
  • liver tissue specific Htr2a-removing mice Htr2a LKO prepared in Example 9-1
  • liver was extracted by the method described in Example 1-2, followed by 5% NP-40 solution. After pulverizing in and heated to dissolve all lipid components.
  • Triglyceride Reagent (Sigma) was used to decompose triglycerides into Glycerol, and Glycerol Reagent (Sigma) was used to quantify the amount of Glycerol by color reaction.
  • the protein amount was measured by BCA Protein Assay Kit (Pierce) to correct the triglyceride amount to the amount of protein in the tissue.
  • liver triglyceride amount was reduced in the normal diet and the high-fat diet in liver tissue-specific Htr2a-removed mice (Htr2a LKO). Therefore, it can be seen that the inhibition of expression of the Htr2a receptor of the present invention is also associated with the decrease of triglycerides in the liver.
  • Htr2a liver-specific knockout Htr2a LKO
  • WT wild-type mice
  • WT wild type mice
  • the mice were divided into normal and high-fat diets. Feed was fed and weighed for 4-20 weeks. In addition, the weight of other tissues (eWAT, epididymal white adipose tissue; iWAT, inguinal white adipose tissue; BAT, brown adipose tissue; Quadriceps; kidney) was measured.
  • eWAT epididymal white adipose tissue
  • iWAT inguinal white adipose tissue
  • BAT brown adipose tissue
  • Quadriceps kidney
  • Htr2a liver-specific knockout, Htr2a LKO liver tissue-specific knockout mice
  • i) Groups were divided into general diet wild type mouse group, ii) high fat diet wild type mouse group, iii) general diet Htr2a LKO group, and iv) high fat diet Htr2a LKO group, and blood was collected from the caudal vein of the mouse to measure blood glucose. After fasting, glucose solution was administered intraperitoneally with 2g / kg of glucose solution, and blood glucose was measured after 0, 15, 30, 60, 90, and 120 minutes (18 weeks of age).
  • Insulin resistance measured blood glucose levels after 0, 15, 30, 60, 90, and 120 minutes of intraperitoneal administration of 0.75 U or 1 U of insulin solution after fasting (19 weeks of age). As a result, it was confirmed that there was no difference in glucose tolerance (FIG. 20a) and insulin resistance between wild-type mice and Htr2a LKO mice in both the normal diet and the high-fat diet group (FIG. 20B).
  • Htr2a liver-specific knockout, Htr2a LKO liver tissue-specific Htr2a gene-depleted mice (Htr2a liver-specific knockout, Htr2a LKO) of the present invention
  • i. A) general diet wild type mouse group, ii) high fat diet wild type mouse group, iii) general diet Htr2a LKO group, and iv) high fat diet Htr2a LKO group and then raised blood from the veins of the mice to measure blood glucose.
  • Example 10 liver tissue specific Htr2a Remove mouse ( Htr2a LKO Changes in gene expression related to fat metabolism in liver tissue
  • Example 2 RNA was extracted by the method described in the above, cDNA was synthesized, and realtime PCR was performed.
  • the primer used for PCR the sequence described in Table 2 of Example 4 was used.
  • C57BL6 / J mice from 12 to 20 weeks of age i) general diet + vehicle (vehicle, phosphate buffered saline) ii) general diet + safogrerel Liver (3) high fat diet + vehicle, iv) high fat diet + safogrelate administration group, and then weighed, and weighed the liver tissue by the method described in Examples 3-2 and 3-3 above.
  • triglyceride amount was quantified.
  • the safogrelate was intragastric injection at 30 mg / kg / day.
  • liver tissue was significantly reduced in the sapogrelate administration group as well as the weight and liver tissue results (see FIG. 25).

Landscapes

  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Immunology (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Genetics & Genomics (AREA)
  • Public Health (AREA)
  • Mycology (AREA)
  • Nutrition Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Microbiology (AREA)
  • Veterinary Medicine (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Hematology (AREA)
  • Biomedical Technology (AREA)
  • General Engineering & Computer Science (AREA)
  • Cell Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biophysics (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique comprenant un inhibiteur de HTR2A à titre de principe efficace pour la prévention ou le traitement de la maladie du foie gras. L'inhibition de la production d'un foie gras induit par un régime riche en graisses et la suppression de l'expression des gènes liés à la lipogenèse dans les hépatocytes permettent à l'inhibiteur de HTR2A selon la présente invention d'être utile à titre de principe actif dans une composition pour la prévention ou le traitement du foie gras, et autres.
PCT/KR2017/015006 2017-03-24 2017-12-19 Composition pharmaceutique comprenant un antagoniste de htr2a à titre de principe actif pour la prévention ou le traitement de la maladie du foie gras WO2018174379A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR20170037833 2017-03-24
KR10-2017-0037833 2017-03-24
KR1020170158580A KR20180108402A (ko) 2017-03-24 2017-11-24 Htr2a 길항제를 유효성분으로 포함하는 지방간의 예방 또는 치료용 약학적 조성물
KR10-2017-0158580 2017-11-24

Publications (1)

Publication Number Publication Date
WO2018174379A1 true WO2018174379A1 (fr) 2018-09-27

Family

ID=63585586

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2017/015006 WO2018174379A1 (fr) 2017-03-24 2017-12-19 Composition pharmaceutique comprenant un antagoniste de htr2a à titre de principe actif pour la prévention ou le traitement de la maladie du foie gras

Country Status (1)

Country Link
WO (1) WO2018174379A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12239641B2 (en) 2018-03-27 2025-03-04 Rajeshwar MOOKERJEE Methods of treating or preventing fibrosis in non-alcoholic fatty liver disease

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150024995A1 (en) * 2009-06-05 2015-01-22 Veroscience Llc Combination Of Dopamine Agonists Plus First Phase Insulin Secretagogues For The Treatment Of Metabolic Disorders
KR101519448B1 (ko) * 2014-03-28 2015-05-13 한국과학기술원 비만 또는 당뇨 예방 및 치료용 조성물의 스크리닝 방법
KR20160108258A (ko) * 2016-06-20 2016-09-19 한국과학기술원 대사 질환의 예방 또는 치료용 조성물

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150024995A1 (en) * 2009-06-05 2015-01-22 Veroscience Llc Combination Of Dopamine Agonists Plus First Phase Insulin Secretagogues For The Treatment Of Metabolic Disorders
KR101519448B1 (ko) * 2014-03-28 2015-05-13 한국과학기술원 비만 또는 당뇨 예방 및 치료용 조성물의 스크리닝 방법
KR20160108258A (ko) * 2016-06-20 2016-09-19 한국과학기술원 대사 질환의 예방 또는 치료용 조성물

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FU, JIHUA: "Long-term stress with hyperglucocorticoidemia-induced hepatic steatosis with VLDL overproduction is dependent on both 5-HT2 receptor and 5-HT synthesis in liver", INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES, vol. 12, no. 2, 1 January 2016 (2016-01-01), pages 219 - 234, XP055608750, ISSN: 1449-2288, DOI: 10.7150/ijbs.13062 *
PEREZ-CORNAGO, AUROR A: "DNA hypermethylation of the serotonin receptor type-2A gene is associated with a worse response to a weight loss intervention in subjects with metabolic syndrome", NUTRIENTS, vol. 6, no. 6, 23 June 2014 (2014-06-23), pages 2387 - 2403, XP055608753, DOI: 10.3390/nu6062387 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12239641B2 (en) 2018-03-27 2025-03-04 Rajeshwar MOOKERJEE Methods of treating or preventing fibrosis in non-alcoholic fatty liver disease

Similar Documents

Publication Publication Date Title
KR101665846B1 (ko) Gpr119 리간드를 유효성분으로 포함하는 비알콜성 지방간 질환의 예방 또는 치료용 약학적 조성물
WO2012008788A2 (fr) Composition contenant de la sérine en tant que principe actif pour la prévention et le traitement de stéatoses hépatiques, et utilisation de celle-ci
WO2021261631A1 (fr) Nouvelle souche de picalibacterium prosnich eb-fpdk9 et utilisations associées
WO2020106048A1 (fr) Composition pharmaceutique pour la prévention ou le traitement d'une maladie neurodégénérative
WO2018174379A1 (fr) Composition pharmaceutique comprenant un antagoniste de htr2a à titre de principe actif pour la prévention ou le traitement de la maladie du foie gras
WO2016048005A2 (fr) Nouveau dérivé de pipéridine pentadiénoyl et son utilisation
WO2015147369A1 (fr) Composition pharmaceutique contenant un inhibiteur de sirt2
KR102307548B1 (ko) Htr2a 길항제를 유효성분으로 포함하는 지방간의 예방 또는 치료용 약학적 조성물
US20190008864A1 (en) Pharmaceutical composition containing gpr119 ligand as effective ingredient for preventing or treating non-alcoholic steatohepatitis
WO2009151304A2 (fr) Composition comprenant la protéine akap12 et utilisations de poisson zèbre à mutation akap12 choisi comme modèle animal
WO2015111971A1 (fr) Composition pharmaceutique contenant un ligand gpr119 comme principe actif pour prévenir ou traiter une stéatose hépatique non alcoolique
WO2016133352A1 (fr) Composition visant à prévenir, soulager ou traiter les maladies métaboliques, contenant de l'amodiaquine en tant que principe actif
WO2020032452A1 (fr) Composition comprenant un composé à base d'or en tant que principe actif visant à inhiber la différenciation des ostéoclastes
WO2019235876A1 (fr) Composition pharmaceutique comprenant un inhibiteur de l'expression ou de l'activité de c-src permettant de prévenir ou de traiter une synucléinopathie
WO2011059294A2 (fr) Composition anticancéreuse améliorant l'immunité contenant des alcaloïdes de type morphinane au titre de principes actifs
WO2017061828A1 (fr) Composition pharmaceutique pour prévenir ou traiter un cancer comprenant un inhibiteur de plrg1 (régulateur pléiotropique 1) comme principe actif
WO2021033995A1 (fr) Composition comprenant un extrait d'amomum tsaoko pour prévenir, atténuer ou traiter une maladie liée à la sarcopénie
WO2017052340A1 (fr) Composition pharmaceutique d'induction d'effets de type exercice
WO2021256837A1 (fr) Composition permettant de diagnostiquer ou de traiter une maladie rénale
WO2025048488A1 (fr) Composition comprenant une matrice extracellulaire dérivée de kératinocytes cutanés en tant que principe actif pour la prévention ou le traitement du cancer par régulation du microenvironnement tumoral
WO2023149768A1 (fr) Composition pharmaceutique comprenant un inhibiteur de la désubiquitinase pour la prévention ou le traitement de maladies associées au stress du réticulum endoplasmique
WO2023096233A1 (fr) Nouveau peptide et son utilisation
WO2023096232A1 (fr) Nouveau peptide et son utilisation
WO2020197304A1 (fr) Composition visant à prévenir, soulager ou traiter le cancer du pancréas, contenant un inhibiteur de tétraspanine-2 en tant que principe actif
WO2018074879A1 (fr) Composition pharmaceutique pour la prévention ou le traitement du diabète et/ou de l'hyperlipidémie comprenant de la midorine ou un sel pharmaceutiquement acceptable de celle-ci en tant que principe actif

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: 17901602

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17901602

Country of ref document: EP

Kind code of ref document: A1