CN115607546A - Isarubrolone C, pharmaceutical composition containing Isarubrolone C and application - Google Patents

Isarubrolone C, pharmaceutical composition containing Isarubrolone C and application Download PDF

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Publication number
CN115607546A
CN115607546A CN202211321596.6A CN202211321596A CN115607546A CN 115607546 A CN115607546 A CN 115607546A CN 202211321596 A CN202211321596 A CN 202211321596A CN 115607546 A CN115607546 A CN 115607546A
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liver
pharmaceutical composition
pharmaceutically acceptable
isarubrolone
isarbrolone
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Inventor
陈博
张靖溥
张苗青
张锐
刘馨妍
马媛媛
韩莹
武临专
李书芬
江冰娅
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Institute of Medicinal Biotechnology of CAMS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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

Abstract

The invention belongs to the technical field of medicines, and particularly relates to Isarubrolone C, pharmaceutically acceptable salts or stereoisomers thereof, a pharmaceutical composition containing Isarubrolone C and application thereof in preparation of medicines for preventing and/or treating liver diseases. In particular, isarbrolone C and the pharmaceutical composition thereof according to the present invention have an excellent effect of preventing and/or treating liver diseases, particularly non-alcoholic fatty liver disease or non-alcoholic steatohepatitis.

Description

Isarubrolone C, pharmaceutical composition containing Isarubrolone C and application
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to Isarubrolone C, pharmaceutically acceptable salt or stereoisomer thereof, a pharmaceutical composition containing Isarubrolone C and application thereof in preparation of medicines for preventing and/or treating liver diseases.
Background
With the increase of living standard, patients with liver diseases including non-alcoholic fatty liver disease (NAFLD) are rapidly increasing due to unhealthy lifestyle, nutrient excess, and the like. Non-alcoholic fatty liver disease (NAFLD) refers to the condition of excessive accumulation of fat in the liver of a human who has little or no alcohol consumption. The course of NAFLD is manifested as liver lesions of varying degrees, ranging from simple fatty liver without any inflammation to severe inflammatory reactions with marked fibrosis and even cirrhosis, mainly including simple fatty liver (NAFL), steatohepatitis (NASH), steatocirrhosis type 3 [1].
Some nonalcoholic steatohepatitis (NAFLD) patients may develop a more serious disease, nonalcoholic steatohepatitis (NASH). Pathologically, NASH refers to adiposis of hepatocytes, with intralobular or assembler inflammation and ballooning and necrosis of the hepatocytes. In NASH, fat accumulation in the liver is associated with inflammation and scarring to varying degrees. NASH is a potentially serious disease with a great risk of developing end-stage liver disease, cirrhosis and hepatocellular carcinoma. Some patients with cirrhosis are at risk of liver failure and may eventually require liver transplantation [2].
The number of patients suffering from NAFLD is on the rise. Research shows that the prevalence rate of NAFLD in general population of Asian countries is about 25%. Without effective intervention, about one quarter of patients with NAFLD progress to NASH, with a incidence of cirrhosis as high as 15-25% within 10-15 years. Therefore, NASH has become a serious global public health problem, and is one of the leading causes of the growing cirrhosis and liver cancer [3,4].
The hepatic stearoyl-coa desaturase SCD1 is a key lipogenic enzyme. Increased expression of SCD1 in mice with hyperlipidemia or obese/type II diabetic patients. SCD1 is a potential therapeutic target for metabolic-related diseases such as obesity, NAFLD/NASH [5]. The drug Aramchol targeting SCD1 for NASH treatment has entered phase 3 clinical trials [6].
Autophagy is a conserved metabolic program of cells that maintain cellular homeostasis by bulk degradation of abnormal contents. The autophagy process requires the involvement of tens of autophagy-related proteins, where changes in LC3B-II levels are often indicative of autophagosome formation. The process of autophagy to degrade intracellular lipid droplets is also referred to as lipophagy, and several studies support autophagy to regulate intracellular lipid droplet metabolism and to exert anti-NAFLD effects [7].
At present, no medicine for preventing or treating NAFLD or NASH on the market is approved in China. No clinically recognized effective drug is recommended for routine treatment of NASH patients.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides Isarubrolone C, pharmaceutically acceptable salts or stereoisomers thereof, a pharmaceutical composition containing Isarubrolone C and application thereof in preparing medicines for preventing and/or treating liver diseases.
In order to achieve the purpose, the invention adopts the following technical scheme:
according to one aspect of the present invention, there is provided the use of isarbrolone C, a pharmaceutically acceptable salt or a stereoisomer thereof in the manufacture of a medicament for the prevention and/or treatment of liver disease.
According to one embodiment of the invention, the liver disease is selected from hepatitis, fatty liver, cirrhosis, liver failure.
According to one embodiment of the invention, the hepatitis is selected from non-alcoholic steatohepatitis, non-alcoholic fatty liver disease.
According to one embodiment of the present invention, there is provided a use of isalubronone C, a pharmaceutically acceptable salt or a stereoisomer thereof in the preparation of a medicament for preventing and/or treating hepatitis, fatty liver, liver cirrhosis, liver failure diseases.
According to one embodiment of the present invention, there is provided a use of isarbrolone C, a pharmaceutically acceptable salt or a stereoisomer thereof for the manufacture of a medicament for the prevention and/or treatment of non-alcoholic steatohepatitis, non-alcoholic fatty liver disease.
According to an aspect of the present invention, there is provided a pharmaceutical composition for preventing and/or treating liver diseases, comprising said isarbrolone C, a pharmaceutically acceptable salt or a stereoisomer thereof, and at least one pharmaceutically acceptable adjuvant.
According to an aspect of the present invention, there is provided a pharmaceutical composition for preventing and/or treating liver diseases, comprising said isarbrolone C, a pharmaceutically acceptable salt or a stereoisomer thereof, and one or more second therapeutically active agents; optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
According to an aspect of the present invention, there is provided a pharmaceutical composition for preventing and/or treating liver diseases, comprising said isarbrolone C, a pharmaceutically acceptable salt or a stereoisomer thereof, and one or more second therapeutically active agents; and one or more pharmaceutically acceptable auxiliary materials.
According to one embodiment of the invention, the adjuvant is selected from one or several of a carrier, a diluent, an excipient or an adjuvant.
According to an aspect of the present invention, there is provided a use of the pharmaceutical composition as described above for the manufacture of a medicament for the prevention or treatment of liver diseases.
According to one embodiment of the invention, the liver disease is selected from hepatitis, fatty liver, cirrhosis, liver failure.
According to one embodiment of the invention, the hepatitis is selected from non-alcoholic steatohepatitis, non-alcoholic fatty liver disease.
According to an embodiment of the present invention, there is provided a use of the pharmaceutical composition as described above for the preparation of a medicament for preventing or treating hepatitis, fatty liver, liver cirrhosis, liver failure.
According to an embodiment of the present invention, there is provided a use of the pharmaceutical composition as described above for preparing a medicament for preventing and/or treating non-alcoholic steatohepatitis, non-alcoholic fatty liver disease.
According to an aspect of the present invention, there is provided a method for preventing and/or treating liver diseases, comprising administering to a patient in need thereof a therapeutically effective amount of isarubilone C, a pharmaceutically acceptable salt or a stereoisomer thereof;
optionally, the liver disease is selected from hepatitis, fatty liver, cirrhosis, liver failure;
optionally, the hepatitis is selected from non-alcoholic steatohepatitis, non-alcoholic fatty liver disease.
According to an aspect of the present invention, there is provided a method for preventing and/or treating liver diseases, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising said isaubrolone C, a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable adjuvant;
optionally, the liver disease is selected from hepatitis, fatty liver, cirrhosis, liver failure;
optionally, the hepatitis is selected from non-alcoholic steatohepatitis, non-alcoholic fatty liver disease.
According to one aspect of the present invention, there is provided a method for preventing and/or treating liver diseases, comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising said isarbrolone C, a pharmaceutically acceptable salt or stereoisomer thereof, and one or more second therapeutically active agents; and one or more pharmaceutically acceptable adjuvants;
optionally, the liver disease is selected from hepatitis, fatty liver, cirrhosis, liver failure;
optionally, the hepatitis is selected from non-alcoholic steatohepatitis, non-alcoholic steatohepatitis.
Has the advantages that: the isarbrolone C, pharmaceutically acceptable salts or stereoisomers thereof and pharmaceutical compositions thereof according to the present invention have excellent effects of preventing and/or treating liver diseases, particularly, non-alcoholic fatty liver diseases or non-alcoholic steatohepatitis. According to the invention, researches show that Isarubrolone C can inhibit lipogenesis by reducing SCD1, activate autophagy, obviously reduce triglyceride level in a cell lipid toxicity model, reduce triglyceride level in an animal high-fat model, obviously improve hepatic steatosis and protect liver injury.
Drawings
FIG. 1 is a cell fat fluorescence staining diagram of a human L02 hepatocyte model drug activity test experiment with high lipid.
FIG. 2 is a diagram showing the level of triglyceride in the human L02 liver cell model drug activity test.
FIG. 3 is a diagram of Western blotting results in a human L02 hepatocyte high-lipid model pharmacological mechanism experiment.
FIG. 4 is a diagram of the real-time quantitative PCR result in a human L02 hepatocyte model high lipid pharmacological mechanism experiment.
FIG. 5 is a liver oil red O staining pattern in a zebra fish NAFLD model drug activity test experiment.
FIG. 6 is a liver slice HE staining diagram in a zebra fish NAFLD model drug activity test experiment.
Fig. 7 is a graph of triglyceride levels in a zebrafish NAFLD model drug activity test experiment.
Detailed Description
The molecular formula of Isarubrolone C in the invention is as follows: c 24 H 25 NO 9 Molecular weight: 471, the chemical structural formula is as shown in formula (1):
Figure BDA0003910745390000031
by "pharmaceutically acceptable" is meant that the molecular entity and combination drug do not produce adverse, allergic, or other untoward reactions when properly administered to an animal or human.
The "pharmaceutically acceptable salt" refers to pharmaceutically acceptable acid and base addition salts, such as metal salts, ammonium salts, salts with organic acids, salts with organic bases, salts with inorganic acids, salts with acidic amino acids or basic amino acids, and the like.
By "stereoisomer" is meant a compound that contains one or more asymmetric centers that each independently give rise to two optical isomers. The scope of the present invention includes all possible optical isomers and mixtures thereof. All enantiomers, diastereomers, racemates, meso, cis-trans isomers, tautomers, geometric isomers, epimers, mixtures thereof and the like of the compounds are included within the scope of the present invention.
The "pharmaceutically acceptable adjuvant" should be compatible with isarbrolone C, its pharmaceutically acceptable salts or stereoisomers, i.e. capable of being blended therewith without substantially reducing the effectiveness of the pharmaceutical composition under normal circumstances.
The "carrier", "diluent", "excipient" or "adjuvant" may include a solvent, diluent, dispersant, suspending agent, surfactant, isotonic agent, thickener, emulsifier, binder, lubricant, stabilizer, hydrating agent, emulsification accelerator, buffer, absorbent, colorant, ion exchanger, mold release agent, coating agent, flavor, antioxidant and the like which are conventional in the pharmaceutical field. If necessary, a flavor, a preservative, a sweetener and the like may be further added to the pharmaceutical composition.
Specific examples of some substances that may serve as "pharmaceutically acceptable excipients" are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium methylcellulose, ethylcellulose and methylcellulose; gelatin; talc; a solid lubricant; a polyol; an emulsifier; a colorant; a flavoring agent; tabletting agents, stabilizers; an antioxidant; a preservative; pyrogen-free water; isotonic saline solution. These materials are used as needed to aid in the stability of the formulation or to aid in the enhancement of the activity or its bioavailability or to produce an acceptable mouth feel or odor in the case of oral administration.
In the present invention, unless otherwise specified, the dosage form is not particularly limited, and may be prepared into injection, oral liquid, tablet, capsule, dripping pill, spray, granule, etc. by a conventional method, and the dosage form is selected to match the administration mode. The administration may be, for example, oral, parenteral, rectal or pulmonary administration, and the like.
As used herein, a "therapeutically effective amount" refers to an amount of the compound, pharmaceutical composition, which, when administered to a patient, is capable of at least alleviating the symptoms of the condition in the patient. The actual amount comprising a "therapeutically effective amount" will vary depending on a variety of circumstances, including, but not limited to, the particular condition being treated, the severity of the condition, the physical and health of the patient, and the route of administration. The appropriate amount can be readily determined by the skilled medical practitioner using methods known in the medical arts.
The present invention is described in further detail below with reference to specific embodiments, which are given for the purpose of illustration only and are not intended to limit the scope of the invention. The experimental procedures in the examples described below are, unless otherwise specified, all conventional procedures; the materials, reagents, instruments, etc. used are commercially available unless otherwise specified.
Isarubrolone C used in examples of the present invention was prepared by the method described in reference [8 ].
Example 1 model of human L02 liver cell hyperlipidemia
Human Normal liver cell line L02 cells were cultured in 10% FBS-containing DMEM (thermal fisher scientific) medium, 5% CO 2 Culturing in a cell culture box under the condition. Human normal liver cell line L02 cells were divided into five groups: the first group is a normal control group, and cells are normally cultured without any special treatment; the second group was a model group, cells were treated with palmitic acid: oleic acid (1; the third to fifth groups were Isarubrolone C groups, cells were pretreated with Isarubrolone C (0.1. Mu.M, 1. Mu.M, 10. Mu.M) for 12h and then added with palmitic acid: the incubation with oleic acid (1.
Cells were harvested for lipid staining, biochemical markers, cellular proteins, and cellular mRNA level analysis, respectively. Statistical analysis: data are presented as mean ± standard deviation. The multiple comparisons were performed using one-way analysis of variance and t-test for the two groups. P <0.05 is statistically significant.
The results of the cell fat fluorescent staining are shown in fig. 1, and the hepatocytes of the normal control group have almost no green lipid fluorescent staining, while the hepatocytes of the model group have large-area green lipid fluorescent staining. The area/intensity of fluorescent staining of green lipids in hepatocytes was significantly reduced in isarbrolone C pretreated group (10 μ M) compared to the model group. The results suggest that isalubrone C significantly reduced intracellular lipid levels.
Cellular triglyceride levels as shown in fig. 2, the levels of triglyceride in the model group hepatocytes were significantly increased (P < 0.05) compared to the normal control group hepatocytes. Isarubrolone C (1. Mu.M, 10. Mu.M) pretreatment significantly reduced the triglyceride level in hepatocytes (P < 0.05).
In addition, the relevant pharmacological mechanisms were analyzed by western blotting and real-time quantitative PCR, respectively, and the results are shown in fig. 3 and 4.
LC3II is one of the autophagy marker proteins. In fig. 3, LC3II in the model group cells was significantly reduced compared to the normal control group cells. Different concentrations of isarubilone C pretreated cells increased cellular LC3II levels to different extents compared to the model group. SCD1 is a key enzyme in lipogenesis. Compared with the normal control group cells, the SCD1 protein level in the model group cells is obviously increased. When the cells were pretreated with isarbrolone C at different concentrations, the SCD1 protein level in the cells was reduced to different degrees compared to the model group. The results suggest that isalubronone C may promote autophagy by increasing LC3II protein levels, and inhibit adipogenesis by inhibiting SCD 1.
cd36, fasn, scd1 are adipogenesis associated genes. In FIG. 4, the levels of cd36, fasn, scd1 mRNA in the model cells were significantly higher (P < 0.05) compared to the normal control cells. In comparison with the model group, isarubrolone C can significantly reduce cd36, fasn, scd1 mRNA level (P < 0.05) of cells after pretreatment of the cells. The results suggest that isarubilone C may affect adipogenesis pathways by decreasing adipogenesis-associated gene expression.
Example 2 Zebra fish NAFLD model
The AB line zebra fish embryos were normally raised to 5dpf and were randomly divided into three groups. The first group was a normal control group, zebrafish were fed (30 mg/day) juvenile fish feed AP100 (Larval-AP 100, zeigler Bros, inc., USA); the second group is a model group, young fish feed AP100 is fed to zebra fish (180 mg/day), and the feeding is continued for 10 days; the third group was the isalubrone C group, which was fed (180 mg/day) with juvenile fish feed AP100 to zebrafish and given isalubrone C (10 μ M) treatment daily for 10 days. One day prior to the end of the experiment, fasted overnight, and after the end of the experiment, some zebrafish were fixed with 4% paraformaldehyde and liver histology was analyzed using oil red O staining and hematoxylin/eosin (HE) staining. And collecting part of zebra fish, freezing in liquid nitrogen, and measuring biochemical indexes.
The results of oil red O staining are shown in FIG. 5, where there was almost no oil red staining in the liver of the normal control group (within the black dashed box), and a large area of red staining in the liver of the model group, which indicates a large amount of liver fat accumulation. In comparison to the model group, isalubrone C treatment significantly reduced fatty red staining of zebrafish liver. The results suggest that isarbrolone C can significantly improve NAFLD in zebrafish and improve liver lipid accumulation.
The result of hematoxylin/eosin (HE) staining is shown in fig. 6, and the liver cells of the normal control group have clear outlines and uniformly filled cytoplasm. The liver cell outline of the model group is fuzzy, a large number of lipid vacuoles appear, and cytoplasm is sparse and uneven. In contrast to the model group, isarbrolone C treatment relegated liver histological features to normal. The results suggest that isarbrolone C improves liver injury and steatosis in a zebrafish NAFLD model.
Triglyceride levels as shown in fig. 7, the triglyceride levels in the zebrafish tissues of the model group were significantly increased (P < 0.05) compared to the normal control group. Isarubrone C (10. Mu.M) treatment significantly reduced the triglyceride levels in zebrafish tissues compared to the model group (P < 0.05).
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that various changes and modifications can be made by those skilled in the art without departing from the spirit of the invention, and these changes and modifications are all within the scope of the invention. Therefore, the protection scope of the present invention should be subject to the appended claims.
Reference documents
1.Kasper,P.,et al.,NAFLD and cardiovascular diseases:a clinical review.Clin Res Cardiol,2021.110(7):p.921-937.
2.Loomba,R.and L.A.Adams,The 20％ Rule of NASH Progression:The Natural History of Advanced Fibrosis and Cirrhosis Caused by NASH.Hepatology,2019. 70(6):p.1885-1888.
3.Fan,J.G.,S.U.Kim,and V.W.Wong,New trends on obesity and NAFLD in Asia.J Hepatol,2017.67(4):p.862-873.
4.Zhou,F.,et al.,Unexpected Rapid Increase in the Burden of NAFLD in China From 2008to 2018:A Systematic Review and Meta-Analysis.Hepatology,2019.70(4):p. 1119-1133.
5.Ascenzi,F.,et al.,SCD1,autophagy and cancer:implications for therapy.J Exp Clin Cancer Res,2021.40(1):p.265.
6.Ratziu,V.,et al.,Aramchol in patients with nonalcoholic steatohepatitis:a randomized,double-blind,placebo-controlled phase 2b trial.Nat Med,2021.27(10): p.1825-1835.
7.Qian,H.,et al.,Autophagy in liver diseases:A review.Mol Aspects Med,2021.82:p. 100973.
8.Li,L.,et al.,Isarubrolones Containing a Pyridooxazinium Unit from Streptomyces as Autophagy Activators.J Nat Prod,2019.82(5):p.1149-1154.

Claims (9)

  1. Use of isarbrolone C, a pharmaceutically acceptable salt or a stereoisomer thereof in the manufacture of a medicament for the prevention and/or treatment of liver disease.
  2. 2. A pharmaceutical composition for preventing and/or treating liver diseases, which comprises said isarbrolone C, a pharmaceutically acceptable salt or a stereoisomer thereof, and at least one pharmaceutically acceptable adjuvant.
  3. 3. A pharmaceutical composition for preventing and/or treating liver diseases, comprising said isarbrolone C, a pharmaceutically acceptable salt or stereoisomer thereof, and one or more second therapeutically active agents; optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
  4. 4. The pharmaceutical composition according to claim 2 or 3, wherein the adjuvant is selected from one or more of a carrier, a diluent, an excipient or an adjuvant.
  5. 5. The pharmaceutical composition according to claim 2 or 3, wherein the liver disease is selected from hepatitis, fatty liver, cirrhosis, liver failure.
  6. 6. The pharmaceutical composition according to claim 5, wherein the hepatitis is selected from non-alcoholic steatohepatitis, non-alcoholic fatty liver disease.
  7. 7. Use of a pharmaceutical composition according to claim 2 or 3 in the manufacture of a medicament for the prevention or treatment of liver disease.
  8. 8. Use according to claim 1 or 7, wherein the liver disease is selected from hepatitis, fatty liver, cirrhosis, liver failure.
  9. 9. The use of claim 8, wherein the hepatitis is selected from the group consisting of non-alcoholic steatohepatitis, non-alcoholic fatty liver disease.
CN202211321596.6A 2022-10-26 2022-10-26 Isarubrolone C, pharmaceutical composition containing Isarubrolone C and application Pending CN115607546A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104258414A (en) * 2014-08-25 2015-01-07 中国医学科学院医药生物技术研究所 Function and application of autophagy-related genes ATG10 to participation of RNA virus replication
CN112794895A (en) * 2021-01-06 2021-05-14 中国医学科学院医药生物技术研究所 Application of exogenous ATG10S protein in preparation of antiviral drugs

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104258414A (en) * 2014-08-25 2015-01-07 中国医学科学院医药生物技术研究所 Function and application of autophagy-related genes ATG10 to participation of RNA virus replication
CN112794895A (en) * 2021-01-06 2021-05-14 中国医学科学院医药生物技术研究所 Application of exogenous ATG10S protein in preparation of antiviral drugs

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
LINLI LI等: "Isarubrolones Containing a Pyridooxazinium Unit from Streptomyces as Autophagy Activators", JOURNAL OF NATURAL PRODUCTS, vol. 82, pages 1150 *
MIAOQING ZHANG等: "Structure and Biosynthesis of Isatropolones, Bioactive Amine- Scavenging Fluorescent Natural Products from Streptomyces Gç66", JOURNAL OF NATURAL PRODUCTS, vol. 85, pages 1018 *
SURYAKANT NITURE等: "Emerging Roles of Impaired Autophagy in Fatty Liver Disease and Hepatocellular Carcinoma", INTERNATIONAL JOURNAL OF HEPATOLOGY, pages 2 - 3 *

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