CN117530957A - Application of ammonium tetrathiomolybdate in preparation of medicines for treating metabolic-related fatty liver diseases - Google Patents
Application of ammonium tetrathiomolybdate in preparation of medicines for treating metabolic-related fatty liver diseases Download PDFInfo
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- CN117530957A CN117530957A CN202311709578.XA CN202311709578A CN117530957A CN 117530957 A CN117530957 A CN 117530957A CN 202311709578 A CN202311709578 A CN 202311709578A CN 117530957 A CN117530957 A CN 117530957A
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- ZKKLPDLKUGTPME-UHFFFAOYSA-N diazanium;bis(sulfanylidene)molybdenum;sulfanide Chemical compound [NH4+].[NH4+].[SH-].[SH-].S=[Mo]=S ZKKLPDLKUGTPME-UHFFFAOYSA-N 0.000 title claims abstract description 48
- 208000010706 fatty liver disease Diseases 0.000 title claims abstract description 43
- 230000002503 metabolic effect Effects 0.000 title claims abstract description 29
- 239000003814 drug Substances 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 229940079593 drug Drugs 0.000 title abstract description 7
- 210000004185 liver Anatomy 0.000 claims abstract description 26
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 22
- 235000012000 cholesterol Nutrition 0.000 claims abstract description 11
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 claims abstract description 10
- 108010082126 Alanine transaminase Proteins 0.000 claims abstract description 10
- 108010003415 Aspartate Aminotransferases Proteins 0.000 claims abstract description 10
- 102000004625 Aspartate Aminotransferases Human genes 0.000 claims abstract description 10
- 230000037396 body weight Effects 0.000 claims abstract description 10
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims abstract description 8
- 229930182817 methionine Natural products 0.000 claims abstract description 8
- 210000002966 serum Anatomy 0.000 claims abstract description 8
- 208000004481 Choline Deficiency Diseases 0.000 claims abstract description 6
- 208000021752 choline deficiency disease Diseases 0.000 claims abstract description 6
- 238000011282 treatment Methods 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 7
- 239000000463 material Substances 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 4
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 4
- 239000006186 oral dosage form Substances 0.000 claims description 4
- 239000006187 pill Substances 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 208000010002 alcoholic liver cirrhosis Diseases 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000008298 dragée Substances 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 239000007902 hard capsule Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 2
- 239000007901 soft capsule Substances 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 238000013268 sustained release Methods 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 150000003626 triacylglycerols Chemical class 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims 2
- 206010009208 Cirrhosis alcoholic Diseases 0.000 claims 1
- 208000021017 Weight Gain Diseases 0.000 claims 1
- 230000007882 cirrhosis Effects 0.000 claims 1
- 239000012730 sustained-release form Substances 0.000 claims 1
- 239000003826 tablet Substances 0.000 claims 1
- 230000004584 weight gain Effects 0.000 claims 1
- 235000019786 weight gain Nutrition 0.000 claims 1
- 235000005911 diet Nutrition 0.000 abstract description 27
- 230000037213 diet Effects 0.000 abstract description 27
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 abstract description 12
- 230000004060 metabolic process Effects 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 6
- 238000002474 experimental method Methods 0.000 abstract description 6
- 206010061218 Inflammation Diseases 0.000 abstract description 5
- 230000004054 inflammatory process Effects 0.000 abstract description 5
- 208000004930 Fatty Liver Diseases 0.000 abstract description 3
- 231100000240 steatosis hepatitis Toxicity 0.000 abstract description 3
- 206010019708 Hepatic steatosis Diseases 0.000 abstract 2
- 241000699670 Mus sp. Species 0.000 description 24
- 239000002904 solvent Substances 0.000 description 6
- 102000004889 Interleukin-6 Human genes 0.000 description 4
- 108090001005 Interleukin-6 Proteins 0.000 description 4
- 108700012920 TNF Proteins 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 238000013424 sirius red staining Methods 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- 229930091371 Fructose Natural products 0.000 description 3
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 3
- 239000005715 Fructose Substances 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 208000019425 cirrhosis of liver Diseases 0.000 description 3
- 230000037406 food intake Effects 0.000 description 3
- 235000012631 food intake Nutrition 0.000 description 3
- 108020004999 messenger RNA Proteins 0.000 description 3
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- 108090000340 Transaminases Proteins 0.000 description 2
- 102000003929 Transaminases Human genes 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 210000005228 liver tissue Anatomy 0.000 description 2
- 230000017074 necrotic cell death Effects 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 235000010692 trans-unsaturated fatty acids Nutrition 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 206010014486 Elevated triglycerides Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 206010033307 Overweight Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 230000003818 metabolic dysfunction Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000007863 steatosis Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- -1 tabletting Substances 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Dermatology (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses application of ammonium tetrathiomolybdate in preparation of a medicament for treating metabolic-related fatty liver diseases. The ammonium tetrathiomolybdate disclosed by the invention is applied to the preparation of medicines for treating methionine choline deficiency diet-induced metabolism-related fatty liver inflammation or medicines for treating AMLN diet-induced metabolism-related fatty liver inflammation. Experiments are respectively carried out on a methionine choline deficiency diet-induced metabolism-related fatty liver disease model and an AMLN diet-induced metabolism-related fatty liver disease model, and the results show that the ammonium tetrathiomolybdate can obviously reduce the ratio of liver weight to body weight, reduce the levels of serum alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST), and reduce the levels of Total Cholesterol (TC) and Triglyceride (TG) in the liver, so that the ammonium tetrathiomolybdate has obvious effect of resisting the metabolism-related fatty liver disease.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to application of ammonium tetrathiomolybdate, and in particular relates to application of ammonium tetrathiomolybdate in preparation of a medicament for treating metabolic-related fatty liver diseases.
Background
Metabolic-related fatty liver disease is a pathology characterized by excessive intracellular fat accumulation, usually accompanied by overweight or obesity, type 2 diabetes, metabolic dysfunction, manifested by elevated levels of transaminases, triglycerides and total cholesterol in the blood, excessive accumulation of liver fat, and the occurrence of insulin resistance. Metabolic-related fatty liver disease is closely related to the onset of various diseases such as liver fibrosis, liver cancer, type two diabetes and atherosclerosis. Ammonium tetrathiomolybdate is a copper chelator that reduces the uptake of copper by cells. However, the use of ammonium tetrathiomolybdate in the preparation of a medicament for the treatment of metabolic-related fatty liver disease has not been reported.
Disclosure of Invention
The invention aims to provide application of ammonium tetrathiomolybdate, and particularly aims to provide application of ammonium tetrathiomolybdate in preparation of medicines for treating metabolic-related fatty liver diseases.
In a first aspect, the invention provides the use of ammonium tetrathiomolybdate in the manufacture of a medicament for the treatment of metabolic-related fatty liver disease.
In the above application, the metabolism related fatty liver disease is at least one of non-alcoholic simple fatty liver disease, non-alcoholic steatohepatitis and liver cirrhosis.
In a second aspect, the invention provides the use of ammonium tetrathiomolybdate in the manufacture of a medicament for the treatment of methionine choline deficiency induced metabolic-related fatty liver disease.
In a third aspect, the invention provides the use of ammonium tetrathiomolybdate in the manufacture of a medicament for the treatment of AMLN-diet-induced metabolic-related fatty liver disease.
In a fourth aspect, the invention provides the use of ammonium tetrathiomolybdate in the manufacture of a product for the treatment of increased liver weight to body weight ratio associated with metabolic-related fatty liver disease.
In a fifth aspect the present invention provides the use of ammonium tetrathiomolybdate in the preparation of a product for the treatment and/or prophylaxis of an increase in aspartate aminotransferase and/or alanine aminotransferase in serum from an organism afflicted with a metabolic-related fatty liver disease.
In a sixth aspect the present invention provides the use of ammonium tetrathiomolybdate in the manufacture of a product for the treatment and/or prophylaxis of elevated triglycerides and/or total cholesterol in the liver of a subject suffering from a metabolic-related fatty liver disease.
The seventh aspect of the present invention provides a medicament for treating metabolic-related fatty liver disease, comprising a active ingredient and an adjuvant;
the active ingredient is ammonium tetrathiomolybdate.
In the above-mentioned medicine, the dosage form of said medicine is oral dosage form or injection dosage form.
In the medicines, the oral dosage form is selected from hard capsules, soft capsules, sustained and controlled release capsules, tabletting, sugar-coated tablets, powder, granules, dripping pills, water-honeyed pills, syrup or oral liquid;
the injection is selected from solution type, suspension type, emulsion type or freeze-dried powder.
In the above medicine, the auxiliary material is pharmaceutically acceptable auxiliary material.
In the invention, the preparation method of the medicine comprises the following steps: the ammonium tetrathiomolybdate and the pharmaceutical auxiliary agent are prepared into corresponding pharmaceutical preparations according to the conventional preparation method of the pharmaceutical preparations.
The invention has the following advantages:
experiments are respectively carried out on a methionine choline deficiency diet-induced metabolism-related fatty liver disease model and an AMLN diet-induced metabolism-related fatty liver disease model, and the results show that the ammonium tetrathiomolybdate can obviously reduce the ratio of liver weight to body weight, reduce the levels of serum alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST), and reduce the levels of Total Cholesterol (TC) and Triglyceride (TG) in the liver, so that the ammonium tetrathiomolybdate has obvious effect of resisting the metabolism-related fatty liver disease.
Drawings
FIG. 1 shows the solvent group (Vehicle) and ammonium tetrathiomolybdate dosing group (TTM) serum alanine Aminotransferase (ALT) and serum aspartate Aminotransferase (AST) of methionine choline deficient diet (MCD diet) fed mice.
FIG. 2 is a graph showing the ratio of liver weight to body weight of solvent (Vehicle) and ammonium tetrathiomolybdate dosing (TTM) groups of MCD diet fed mice.
Fig. 3 is the Total Cholesterol (TC) and Triglyceride (TG) levels in the liver of solvent (Vehicle) and ammonium tetrathiomolybdate dosing groups (TTM) of MCD diet fed mice.
FIG. 4 is a graph of hematoxylin-eosin (HE) staining and sirius red staining of a control group and an ammonium tetrathiomolybdate dosing group of MCD diet fed mice.
Figure 5 is NAS score of liver HE staining of MCD diet fed mice.
FIG. 6 shows the mRNA expression levels of IL-6, TNFa, IL-1b in the control group and the ammonium tetrathiomolybdate group of MCD diet fed mice.
FIG. 7 is a graph of hematoxylin-eosin (HE) staining and sirius red staining of a control group and an ammonium tetrathiomolybdate dosing group of high-fat high fructose high cholesterol diet (AMLN diet) fed mice.
Fig. 8 is total liver cholesterol (TC), triglyceride (TG) content of control group (Vehicle) and ammonium tetrathiomolybdate dosing group (TTM) of AMLN diet fed mice.
Detailed Description
The experimental methods used in the following examples are conventional methods unless otherwise specified.
Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
The invention is further illustrated by the following examples, which should not be taken to limit the scope of the invention.
The materials used in the examples below were all commercially available, C57BL/6J mice, male, 8 weeks, 20-22g, purchased from Vetong Lihua corporation; methionine choline deficiency model feed (MCD feed): purchased from synergistic biology company, cat number XTMCD; AMLN feed: dai Ci biotech (tin-free) high trans fat (40% kcal) high cholesterol (2%) high fructose (22%) feed, cat: AMLN. All animal experiments are strictly in accordance with the guidelines for administration and use of laboratory animalsIs required and licensed by the laboratory animal management committee of the university of capital medical science. Ammonium tetrathiomolybdate, purchased from milin, CAS number 15060-55-6, molecular weight: 260.28, molecular formula: (NH) 4 ) 2 MoS 4 。
In the invention, when C57BL/6J mice are dosed, a dosing group (TTM) is ammonium tetrathiomolybdate solution which is dissolved in normal saline and is dosed into the mice, and the dosing dose is 5mg/Kg; the solvent (Vehicle) group was physiological saline administered to mice.
EXAMPLE 1 model experiment of Methocholine deficiency diet-induced Met-related fatty liver disease
Wild type mice were fed with methionine choline deficient diet (MCD diet) for 8 weeks, and the body weight, food intake, were monitored. After 7 weeks of MCD diet, a model of metabolic-related fatty liver disease in mice was developed, manifested by elevated transaminases and altered liver histology, characterized by steatosis, focal inflammation, hepatocyte necrosis, and fibrosis. The mice with MCD diet-induced metabolic-related fatty liver disease were randomly divided into two groups, each day of intraperitoneal injection of a solvent (physiological saline, vehicle group) or an ammonium tetrathiomolybdate solution (physiological saline-soluble ammonium tetrathiomolybdate solution, 5mg/Kg dose, TTM administration group) for one week, during which MCD diet was continuously administered to the mice, and the weight and intake of the mice were monitored. One week after dosing, the mice were fasted for 12 hours, liver tissue was collected and weighed, and the liver/body weight ratio was calculated. The left lobe of the liver of each mouse was fixed with 4% paraformaldehyde at 0.1 cm. Times.0.1 cm. Times.0.6 cm specimen for use.
Serum ALT, AST, liver homogenate TG, TC content was detected. The test results are shown in FIGS. 1, 2 and 3.
From the results in fig. 1, serum ALT and AST were significantly decreased in mice after administration.
From the results in fig. 2, the ratio of liver weight to body weight was significantly decreased after administration.
From the results in fig. 3, the liver TC and TG contents were significantly reduced after administration.
Liver left leaf specimens from the above mice were stained with Hematoxylin and Eosin (HE) (i.e., hematoxylin-eosin (HE)) and sirius red, respectively.
From the results in fig. 4, hematoxylin-eosin (HE) staining and sirius red staining showed reduced lipid droplets after administration and reduced liver fibrosis, indicating that ammonium tetrathiomolybdate has a significant effect against metabolic-related fatty liver disease.
Liver NAS score (NAFLD Activity Score) is a scoring system used to evaluate the extent of non-alcoholic fatty liver disease inflammation and cellular injury. From the results in fig. 5, it can be seen that the liver NAS score was reduced after administration, indicating that ammonium tetrathiomolybdate was able to alleviate liver steatosis, reduce the degree of inflammation and the degree of cell necrosis.
In FIG. 6, the mRNA expression levels of IL-6, TNFa, IL-1b in the liver were measured, and IL-6, TNFa, IL-1b were pro-inflammatory cytokines, and the mRNA expression of IL-6, TNFa, IL-1b was decreased after administration; illustrating that the ammonium tetrathiomolybdate has anti-inflammatory effect * P<0.05， ** P<0.01， *** P<0.001)。
EXAMPLE 2 model experiments on AMLN diet-induced metabolism-related fatty liver disease
Wild-type mice were fed high trans fat (40% Kcal), high cholesterol (2%), high fructose (22%) (AMLN diet) for 24 weeks, and mice were monitored for body weight, food intake. After 24 weeks of AMLN diet, mice were developed with a metabolic-related fatty liver disease model. Mice with AMLN diet-induced metabolic-related fatty liver disease were randomly divided into two groups, each day of intraperitoneal injection of solvent (normal saline, vehicle group) or ammonium tetrathiomolybdate solution (ammonium tetrathiomolybdate solution in normal saline, 5mg/Kg dose, TTM administration group) for seven weeks, during which time AMLN diet was continued to the mice, and body weight and food intake were monitored. Mice liver tissue was collected after a week of dosing with a fasting of 12 hours. The left lobe of the liver of each mouse was sampled at 0.1 cm. Times.0.1 cm. Times.0.6 cm and fixed with 4% paraformaldehyde. Each specimen was stained with hematoxylin-eosin (HE), sirius red, respectively.
The test results are shown in FIGS. 7-8.
From the results in fig. 7, hematoxylin-eosin (HE) staining and sirius red staining showed significant improvement of liver pathology after administration, lipid drop reduction, and liver fibrosis reduction, indicating that ammonium tetrathiomolybdate has significant effect against metabolism-related fatty liver disease.
From the results shown in fig. 8, it is evident that the Total Cholesterol (TC) and Triglyceride (TG) contents in the liver significantly decreased after administration, indicating that the ammonium tetrathiomolybdate of the present invention has a significant effect of resisting metabolic-related fatty liver disease. ( * P<0.05, ** P<0.01)。
The embodiments described above are some of the embodiments of the present invention, but the embodiments of the present invention are not limited by the embodiments described above, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (10)
1. Use of ammonium tetrathiomolybdate in the preparation of a medicament for treating metabolic-related fatty liver disease.
2. The use according to claim 1, wherein the metabolic-related fatty liver disease is at least one of non-alcoholic simple fatty liver disease, non-alcoholic steatohepatitis and cirrhosis.
3. Use of ammonium tetrathiomolybdate in the manufacture of a medicament for the treatment of methionine choline deficiency induced metabolic-related fatty liver disease.
4. Use of ammonium tetrathiomolybdate in the manufacture of a medicament for the treatment of AMLN-diet-induced metabolic-related fatty liver disease.
5. Use of ammonium tetrathiomolybdate in the manufacture of a product for the treatment of weight gain of the liver relative to body weight in the case of metabolic-related fatty liver disease.
6. Use of ammonium tetrathiomolybdate for the preparation of a product for the treatment and/or prevention of an increase in aspartate aminotransferase and/or alanine aminotransferase in serum of a body suffering from a metabolic-related fatty liver disease.
7. Use of ammonium tetrathiomolybdate for the preparation of a product for the treatment and/or prevention of an increase in triglycerides and/or total cholesterol of the liver of a subject suffering from a metabolic-related fatty liver disease.
8. A medicament for treating metabolic-related fatty liver disease, which is characterized by comprising active ingredients and auxiliary materials;
the active ingredient is ammonium tetrathiomolybdate.
9. The medicament according to claim 8, wherein the dosage form of the medicament is an oral dosage form or an injection dosage form.
10. The medicament according to claim 9, wherein the oral dosage form is selected from the group consisting of hard capsules, soft capsules, sustained release capsules, tablets, dragees, powders, granules, dripping pills, water-honeyed pills, syrups or oral liquids;
the injection is selected from solution type, suspension type, emulsion type or freeze-dried powder.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311709578.XA CN117530957A (en) | 2023-12-13 | 2023-12-13 | Application of ammonium tetrathiomolybdate in preparation of medicines for treating metabolic-related fatty liver diseases |
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|---|---|---|---|
| CN202311709578.XA CN117530957A (en) | 2023-12-13 | 2023-12-13 | Application of ammonium tetrathiomolybdate in preparation of medicines for treating metabolic-related fatty liver diseases |
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