CN117085020A - Application of theobromine in preparing medicament for treating and/or preventing lipid metabolism abnormality related diseases - Google Patents
Application of theobromine in preparing medicament for treating and/or preventing lipid metabolism abnormality related diseases Download PDFInfo
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- CN117085020A CN117085020A CN202311310252.XA CN202311310252A CN117085020A CN 117085020 A CN117085020 A CN 117085020A CN 202311310252 A CN202311310252 A CN 202311310252A CN 117085020 A CN117085020 A CN 117085020A
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- theobromine
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- lipid metabolism
- treating
- liver
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- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 title claims abstract description 88
- 229960004559 theobromine Drugs 0.000 title claims abstract description 44
- 201000010099 disease Diseases 0.000 title claims abstract description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 15
- 230000037356 lipid metabolism Effects 0.000 title claims abstract description 15
- 239000003814 drug Substances 0.000 title claims abstract description 14
- 230000005856 abnormality Effects 0.000 title claims abstract description 12
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims abstract description 21
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims abstract description 19
- 210000004185 liver Anatomy 0.000 claims abstract description 14
- 206010022489 Insulin Resistance Diseases 0.000 claims abstract description 8
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 8
- 230000006372 lipid accumulation Effects 0.000 claims abstract description 6
- 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 description 12
- 210000002966 serum Anatomy 0.000 claims description 11
- 235000012000 cholesterol Nutrition 0.000 claims description 6
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 6
- 208000004930 Fatty Liver Diseases 0.000 claims description 4
- 206010067125 Liver injury Diseases 0.000 claims description 4
- 231100000753 hepatic injury Toxicity 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 claims description 3
- 108010082126 Alanine transaminase Proteins 0.000 claims description 3
- 108010003415 Aspartate Aminotransferases Proteins 0.000 claims description 3
- 102000004625 Aspartate Aminotransferases Human genes 0.000 claims description 3
- 206010016654 Fibrosis Diseases 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 230000002159 abnormal effect Effects 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 230000004761 fibrosis Effects 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- 235000003599 food sweetener Nutrition 0.000 claims description 2
- 208000006454 hepatitis Diseases 0.000 claims description 2
- 231100000283 hepatitis Toxicity 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 239000003765 sweetening agent Substances 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 235000013599 spices Nutrition 0.000 claims 1
- 239000000375 suspending agent Substances 0.000 claims 1
- 208000019425 cirrhosis of liver Diseases 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 6
- 210000004369 blood Anatomy 0.000 abstract description 2
- 239000008280 blood Substances 0.000 abstract description 2
- 241000699670 Mus sp. Species 0.000 description 20
- 230000014509 gene expression Effects 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 230000037213 diet Effects 0.000 description 5
- 235000005911 diet Nutrition 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 201000010063 epididymitis Diseases 0.000 description 4
- 108020004999 messenger RNA Proteins 0.000 description 4
- 210000003486 adipose tissue brown Anatomy 0.000 description 3
- 238000003304 gavage Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 231100000240 steatosis hepatitis Toxicity 0.000 description 3
- 230000003442 weekly effect Effects 0.000 description 3
- 239000005715 Fructose Substances 0.000 description 2
- 206010019708 Hepatic steatosis Diseases 0.000 description 2
- 108010028554 LDL Cholesterol Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 210000000593 adipose tissue white Anatomy 0.000 description 2
- 230000007882 cirrhosis Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 208000010706 fatty liver disease Diseases 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 238000007410 oral glucose tolerance test Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 1
- 206010057573 Chronic hepatic failure Diseases 0.000 description 1
- 208000010334 End Stage Liver Disease Diseases 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 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 1
- 206010061218 Inflammation Diseases 0.000 description 1
- NPGIHFRTRXVWOY-UHFFFAOYSA-N Oil red O Chemical compound Cc1ccc(C)c(c1)N=Nc1cc(C)c(cc1C)N=Nc1c(O)ccc2ccccc12 NPGIHFRTRXVWOY-UHFFFAOYSA-N 0.000 description 1
- 230000035508 accumulation Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 208000011444 chronic liver failure Diseases 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000028974 hepatocyte apoptotic process Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 230000007863 steatosis Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses application of theobromine in preparing medicaments for treating and/or preventing diseases related to lipid metabolism abnormality, wherein the theobromine inhibits liver lipid accumulation through FXR-SHP-SREBP1c axis, and has the effects of improving nonalcoholic steatohepatitis, reducing blood fat, improving liver fibrosis and improving insulin resistance. The invention discovers the effect of theobromine on improving the nonalcoholic steatohepatitis caused by lipid metabolism abnormality for the first time, and provides more choices for treating diseases related to lipid metabolism abnormality.
Description
Technical Field
The invention relates to application of theobromine, in particular to application of the theobromine in preparing a medicament for treating and/or preventing diseases related to lipid metabolism abnormality.
Background
Nonalcoholic fatty liver disease (Non-alcoholic fatty liver disease, NAFLD) is a disease characterized by accumulation of intrahepatic lipids, and includes a range of histologically altered diseases, mainly simple fatty liver, nonalcoholic steatohepatitis (nonalcoholic steatohepatitis, NASH), liver fibrosis, cirrhosis and liver cancer. NASH is an advanced stage of NAFLD, simple fatty liver can be reversed to normal liver, and after progression to NASH, steatosis will be accompanied by inflammation, hepatocyte apoptosis and various degrees of liver fibrosis. Liver fibrosis is highly associated with the occurrence of end-stage liver disease, and serious NASH can cause cirrhosis or liver cancer, endangering human lives. At present, there is no clinically effective means for treating NASH and liver fibrosis, in addition to controlling body weight and limiting diet.
Theobromine (Theobromine), also known as 3, 7-dimethylxanthine, has a formula of C 7 H 8 N 4 O 2 The molecular weight is 180.164, and the chemical structural formula is as follows:
the application of theobromine in preparing medicaments for treating and/or preventing diseases related to lipid metabolism abnormality is not reported in the prior art, and the research on the novel application of the theobromine in the field of medicaments is needed to overcome larger technical difficulty and has important significance.
Disclosure of Invention
The invention aims to: the invention aims to provide an application of theobromine with the functions of improving nonalcoholic steatohepatitis, reducing blood fat, improving liver fibrosis and improving insulin resistance in preparing a medicine for treating and/or preventing diseases related to lipid metabolism abnormality.
The technical scheme is as follows: the theobromine can be applied to the preparation of medicines for treating and/or preventing diseases related to lipid metabolism abnormality. Theobromine can inhibit liver lipid accumulation through FXR-SHP-SREBP1c axis, thereby effectively reducing body weight of mice with nonalcoholic steatohepatitis induced by high-fat, high-fructose and high-cholesterol diet, and improving cholesterol and triglyceride levels in serum, liver fibrosis and insulin resistance thereof.
Further, the disease associated with abnormal lipid metabolism is nonalcoholic steatohepatitis.
The invention also provides application of the pharmaceutical composition containing theobromine in preparing medicines for treating and/or preventing diseases related to lipid metabolism abnormality.
Further, the composition is a pharmaceutical preparation prepared by taking theobromine as an active ingredient and adding pharmaceutically acceptable carriers or auxiliary materials. The pharmaceutical preparation is tablet, capsule, syrup, suspension or injection. The adjuvants are perfume, sweetener, liquid/solid filler or diluent.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages:
(1) Theobromine can inhibit liver lipid accumulation through FXR-SHP-SREBP1c axis, thereby effectively improving liver steatosis, liver injury, hepatitis and fibrosis of a non-alcoholic steatohepatitis model mouse, reducing the contents of cholesterol, triglyceride, glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase in serum of the non-alcoholic steatohepatitis model mouse, and improving glucose tolerance and insulin resistance of the non-alcoholic steatohepatitis model mouse;
(2) The theobromine medicine composition has wide application and is expected to be developed into a biological medicine preparation for treating the nonalcoholic steatohepatitis aiming at the activity of the theobromine medicine composition in animals.
Drawings
FIG. 1 is the experimental results of mouse body weight;
FIG. 2 is the experimental results of liver weights of mice;
FIG. 3 is an experimental result of the weight of epididymal white fat of mice;
FIG. 4 is an Oral Glucose Tolerance Test (OGTT) result;
FIG. 5 is the area under the oral glucose tolerance test curve
FIG. 6 is an insulin resistance test (ITT) result;
FIG. 7 is an area under insulin resistance test curve
FIG. 8 is an experimental result of Total Cholesterol (TC) in serum;
FIG. 9 is an experimental result of Triglyceride (TG) in serum;
FIG. 10 is the experimental results of low density cholesterol (LDL-C) in serum;
FIG. 11 shows the results of experiments on glutamic-oxaloacetic transaminase (AST) in serum;
FIG. 12 is the experimental results of glutamic pyruvic transaminase (ALT) in serum;
FIG. 13 is a pathological section of the liver of a mouse, epididymal fat and brown fat;
FIG. 14 is a pathological section of the heart, muscle, spleen, lung and kidney of the mice;
FIG. 15 is the experimental results of the mRNA level of FXR in the liver of mice;
FIG. 16 is an experimental result of the mRNA level of SHP in the liver of mice;
FIG. 17 shows the results of experiments on mRNA levels of SHP and SREBP1c before and after FXR knockdown in liver primary cells.
Detailed Description
The technical scheme of the invention is further described below by referring to examples.
Examples: theobromine effect on nonalcoholic steatohepatitis.
1. Experimental method
a) Animal experiment
Normal group (Control): c57BL/6J male mice with the size of 8 weeks are fed with common feed. After 12 weeks, 0.1% cmc-Na was administered daily by gavage at the same time for 8 weeks. Body weight was recorded weekly.
Model set (HFFC): male mice of C57BL/6J 8 weeks old were fed HFFC diet (HFFC, fat content 40%, fructose content 20%, cholesterol content 2%). After 12 weeks, 0.1% cmc-Na was administered daily by gavage at the same time for 8 weeks. Body weight was recorded weekly.
Drug administration group: c57BL/6J male mice 8 weeks old were fed HFFC diet. The low dose (50 mg/kg), medium dose (100 mg/kg) and high dose (200 mg/kg) groups of theobromine were administered daily at the same time by gavage for 8 weeks after 12 weeks. Body weight was recorded weekly.
b) Cell experiment
Taking 12-week-old male mice, extracting liver primary cells, and 1×10 per well with six-well plate 6 Individual cells were plated. After extraction of cellular mRNA after administration of theobromine or transfected FXR-siRNA in a time-gradient, gene expression levels of FXR, SHP and SREBP1c were determined by q-PCR.
2. Experimental results
The weight of the theobromine high dose group was reduced by 6.5g compared to HFFC fed mice (fig. 1). In addition, the liver weight of the theobromine high dose administration group was reduced by 0.73g compared to the HFFC model group (FIG. 2). Consistent with the above results, the weight of epididymal fat was reduced by 1.55g in mice in the high dose theobromine dosing group compared to the HFFC model group (FIG. 3). Glucose tolerance and insulin resistance were significantly improved in HFFC-fed mice treated with the compound theobromine (fig. 4-7). Furthermore, serum TC was reduced by 1.07mM in the mice of the theobromine high dose administration group compared to the HFFC model group (fig. 8). Serum TG levels were reduced by 1.82mM in mice from the theobromine high dose dosing group compared to mice from the HFFC model group (fig. 9). Serum LDL-C was reduced by 3.28mM in theobromine-dosed mice compared to HFFC model group (fig. 10). Subsequently, further examination of the common indices of clinical liver injury, ALT and AST, revealed a significant decrease in ALT and AST content in the theobromine-administered group (FIGS. 11-12). HE. Pathological section staining with oil red O, sirius scarlet showed lower lipid accumulation, reduced liver injury, and reduced liver fibrosis in mice treated with compound theobromine compared to HFFC model group mice (fig. 13). Histological analysis showed that the compound theobromine reduced the cell size of mouse epididymal white adipose tissue (eWAT) and Brown Adipose Tissue (BAT) (FIG. 13). Whereas HE sections of heart, muscle, spleen, lung and kidney showed that the compound theobromine had no significant toxic side effects (fig. 14). In terms of mechanism, the present invention explored the expression of lipid metabolism-related genes after theobromine administration, and found that the expression level of FXR was significantly increased after theobromine administration and had a dose-dependency (fig. 15). The FXR-SHP-SREBP1c axis reduced liver lipid accumulation, and the present invention further examined the expression of SHP, a direct target gene for FXR, and found that SHP expression was also elevated after theobromine administration (FIG. 16). Further, FXR knockdown in NASH mice liver primary cells, it was found that the effect of SHP expression increase after theobromine administration was reversed, while the expression level of SHP-inhibited SREBP1c was increased (fig. 17), indicating that lipid synthesis was increased after FXR knockdown.
In conclusion, theobromine improves HFFC diet-induced nonalcoholic steatohepatitis in C57BL/6J mice through FXR-SHP-SREBP1C axis, and has excellent safety.
Claims (10)
1. Use of theobromine in preparing medicament for treating and/or preventing lipid metabolism abnormality related diseases.
2. The use according to claim 1, characterized in that: the lipid metabolism abnormality related disease is non-alcoholic steatohepatitis.
3. The use according to claim 2, characterized in that: theobromine inhibits liver lipid accumulation through FXR-SHP-SREBP1c axis, thereby effectively improving nonalcoholic steatohepatitis.
4. The use according to claim 2, characterized in that: theobromine can effectively improve liver steatosis, liver injury, hepatitis and fibrosis.
5. The use according to claim 2, characterized in that: theobromine can reduce the content of cholesterol, triglyceride, glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase in serum.
6. The use according to claim 2, characterized in that: theobromine can improve glucose tolerance and insulin resistance.
7. Use of a pharmaceutical composition containing theobromine for preparing a medicament for treating and/or preventing diseases associated with abnormal lipid metabolism.
8. The use according to claim 7, characterized in that: the pharmaceutical composition is a pharmaceutical preparation prepared by taking theobromine as an active ingredient and adding a pharmaceutically acceptable carrier or auxiliary material.
9. The use according to claim 8, characterized in that: the pharmaceutical preparation is a tablet, a capsule, syrup, a suspending agent or an injection.
10. The use according to claim 8, characterized in that: the auxiliary materials are spice, sweetener, liquid/solid filler or diluent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311310252.XA CN117085020A (en) | 2023-10-10 | 2023-10-10 | Application of theobromine in preparing medicament for treating and/or preventing lipid metabolism abnormality related diseases |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311310252.XA CN117085020A (en) | 2023-10-10 | 2023-10-10 | Application of theobromine in preparing medicament for treating and/or preventing lipid metabolism abnormality related diseases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117085020A true CN117085020A (en) | 2023-11-21 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311310252.XA Pending CN117085020A (en) | 2023-10-10 | 2023-10-10 | Application of theobromine in preparing medicament for treating and/or preventing lipid metabolism abnormality related diseases |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117085020A (en) |
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2023
- 2023-10-10 CN CN202311310252.XA patent/CN117085020A/en active Pending
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