Use of a dihydroquinoline derivative in the preparation of products for the prevention or treatment of fatty liver

Abstract

This invention provides the application of specific dihydroquinoline derivatives in the preparation of products for the prevention or treatment of fatty liver. This invention is the first to discover that specific dihydroquinoline derivatives significantly reduce liver triglyceride levels, thereby alleviating alcohol-induced hepatic steatosis, and possesses promising prospects for clinical translation.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, specifically the use of a dihydroquinoline derivative in the preparation of products for the prevention or treatment of fatty liver. Background Technology

[0002] Currently, there are no effective targeted therapies for fatty liver, such as alcoholic fatty liver disease (ALD), and clinical treatment mainly focuses on alcohol abstinence and supportive care. PPARα is a key nuclear receptor that regulates fatty acid β-oxidation, but its nuclear transport is impaired in ALD, affecting transcriptional activity and leading to lipid accumulation. Summary of the Invention

[0003] To address the aforementioned problems, this invention utilizes specific dihydroquinoline derivatives to demonstrate therapeutic effects on fatty liver, particularly alcoholic fatty liver.

[0004] Specifically, this application discloses the use of a dihydroquinoline derivative in the preparation of products for the prevention or treatment of fatty liver, wherein the structure of the dihydroquinoline derivative is as follows:

[0005] Or its salts, wherein R represents a C1-C4 alkyl group and X represents a halogen.

[0006] In the structural formula of the dihydroquinoline derivative, R is methyl, ethyl, n-propyl, isopropyl, n-butyl, or isobutyl.

[0007] In the structural formula of the dihydroquinoline derivative, X is either F or Cl.

[0008] The structure of the further dihydroquinoline derivative is as follows: Or its salt (hereinafter referred to as Fos in this application).

[0009] The products include pharmaceuticals.

[0010] Furthermore, the fatty liver is selected from one of alcoholic fatty liver, non-alcoholic fatty liver, malnutrition-induced fatty liver, and drug-induced fatty liver.

[0011] Furthermore, the fatty liver mentioned is alcoholic fatty liver.

[0012] The position of X in the benzene ring is meta relative to the dihydroquinolinyl group.

[0013] The salt is one or more of sodium, lithium, or potassium salts.

[0014] The dosage of dihydroquinoline derivatives, especially Fos, is 1-20 mg / kg / day, preferably 10 mg / kg / day.

[0015] This invention is the first to discover that dihydroquinoline derivatives significantly reduce liver triglyceride levels, thereby alleviating alcohol-induced hepatic steatosis, and has good prospects for clinical translation. Attached Figure Description

[0016] Figure 1 The Lieber-DeCarli alcoholic fatty liver model showed that plasma ALT levels reduced liver damage after Fos treatment;

[0017] Figure 2 The Lieber-DeCarli alcoholic fatty liver model showed a decrease in liver damage after Fos treatment, based on plasma AST levels.

[0018] Figure 3 The liver H&E staining of the Lieber-DeCarli alcoholic fatty liver model showed a decrease in hepatic lipid accumulation after Fos treatment;

[0019] Figure 4 Oil Red O staining of the liver in the Lieber-DeCarli alcoholic fatty liver model showed a decrease in hepatic lipid accumulation after Fos treatment.

[0020] Figure 5 The liver liposuction of the Lieber-DeCarli alcoholic fatty liver model showed a decrease in liver triglyceride accumulation after Fos treatment. Detailed Implementation

[0021] Example 1:

[0022] Experimental methods and grouping: Eight-week-old female C57BL / 6J mice were divided into groups and modeled with a Lieber-DeCarli alcoholic liquid diet for 2 weeks. Then, they were given a solvent (abbreviated as control) and Fos (10 mg / kg / day, abbreviated as Fos) for 2 weeks.

[0023] Liver tissue was stained with hematoxylin and eosin (HE) and Oil Red O. The results showed that Fos significantly reduced liver lipid content; liver liposuction also showed a significant reduction in triglycerides in the liver.

[0024] Plasma was collected to detect liver damage markers alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The results showed that Fos treatment significantly improved ALT and AST levels, thus improving liver damage.

[0025] The serum alanine aminotransferase (ALT) level in mice was measured using a fully automated biochemical analyzer. The Fos (Fos) treatment group showed a significant decrease in ALT compared to the control group, suggesting that this drug has a protective effect against alcoholic liver injury.

[0026] Serum aspartate aminotransferase (AST) levels in mice were detected using a fully automated biochemical analyzer. Similar to ALT, Fos monotherapy reduced AST, indicating that Fos can improve abnormal liver function.

[0027] After paraffin sectioning, hepatocyte structure and inflammatory changes were observed under a light microscope after hematoxylin-eosin (HE) staining. In the control group, hepatocytes showed disordered arrangement and fatty degeneration; in the Fos group, pathological improvement was observed.

[0028] After freezing, sections were stained with Oil Red O to detect neutral lipid deposition. Significant lipid droplet deposition was observed in the control group, while it was reduced in the Fos group, suggesting that Fos can effectively alleviate hepatic lipid deposition.

[0029] The level of triglycerides (TG) in liver tissue was quantitatively detected using a biochemical reagent kit, and the results were standardized to mg / g liver tissue. TG levels were significantly elevated in the control group and decreased in the Fos group, suggesting that Fos has a significant effect on improving hepatic lipid metabolism.

[0030] Figure 1 Serum alanine aminotransferase (ALT) level, test method: ALT activity (U / L) was detected by biochemical analyzer.

[0031] Labels: Control: control group; Fos: Fos monotherapy group

[0032] Elevated ALT levels in the control group indicated liver damage. Significantly decreased ALT levels in the Fos group suggest that Fos can improve alcoholic liver injury and has a synergistic effect with fenofibrate.

[0033] Figure 2 Serum aspartate aminotransferase (AST) level, test method: AST activity (U / L) was detected by biochemical analyzer.

[0034] AST levels were elevated in the control group and significantly decreased in Fos treatment, further demonstrating that Fos can effectively improve alcoholic liver injury.

[0035] Figure 3 HE staining (structural changes in liver tissue), test method: paraffin sections, hematoxylin-eosin staining, observation under a microscope.

[0036] Control group: Disordered hepatocyte arrangement and significant fatty degeneration.

[0037] Fos: Fos treatment group showed reduced fatty degeneration

[0038] Fos significantly improved alcohol-induced liver tissue pathological damage.

[0039] Figure 4Oil Red O staining (lipid deposition detection): Test method: frozen sections, Oil Red O staining, detection of neutral fats.

[0040] Extensive lipid droplet deposition was observed in the liver tissue of the control group; however, deposition was reduced in the Fos group. These results indicate that Fos can effectively inhibit alcohol-induced lipid accumulation.

[0041] Figure 5 Liver triglyceride (TG) content, test method: quantitative detection using a kit, results expressed as mg / g liver. mg / g liver: triglyceride content per gram of liver tissue.

[0042] In the control group, liver triglycerides (TG) were elevated; in the Fos group, they were decreased. These results were consistent with Oil Red O staining, further demonstrating that Fos reduces hepatic lipid accumulation.

[0043] In summary, the attached figures demonstrate from multiple perspectives—serological indicators, histological observation, lipid staining, and biochemical quantification—that Fos can significantly reduce alcohol-induced liver damage and lipid accumulation.

[0044] Figure 1 , Figure 2 (Serium ALT and AST activity)

[0045] Conditions: C57BL / 6J mice, alcohol feeding model (usually Lieber-DeCarli liquid diet or acute alcohol gavage), divided into control group and Fos group.

[0046] Methods: Blood was collected from the orbital cavity, and after serum separation, ALT and AST were detected using a fully automated biochemical analyzer.

[0047] Figure 3 (Hematologic staining, histological changes in the liver)

[0048] Conditions: Same as above, mouse liver tissue was fixed in 4% paraformaldehyde and embedded in paraffin.

[0049] Methods: Sections (4 μm) were stained with hematoxylin and eosin (H&E) and observed under an optical microscope to examine hepatocyte arrangement, ballooning degeneration, and inflammatory infiltration.

[0050] Figure 4 (Oil Red O staining, lipid droplet deposition)

[0051] Conditions: Same as above, fresh liver tissue was taken and frozen sections were prepared (7 μm).

[0052] Methods: Neutral lipids were detected by Oil Red O staining, cell nuclei were counterstained with hematoxylin, and the distribution of red lipid droplets was observed under an optical microscope.

[0053] Figure 5 (Liver triglyceride (TG) content)

[0054] Conditions: Same as above, liver tissue homogenate.

[0055] Methods: The colorimetric method using a commercial reagent kit was used for detection, and the results were standardized to mg TG / g liver.

[0056] Explanation of symbols in the diagram

[0057] ns: No significant difference; *: p<0.05; **: p<0.01; ***: p<0.001; ****: p<0.0001

[0058] Figure 1 (Serum alanine aminotransferase (ALT) level)

[0059] In mice fed with alcohol, serum ALT levels were significantly elevated in the control group, indicating hepatocellular damage. Fos significantly reduced ALT levels, suggesting that Fos can alleviate alcohol-induced liver injury.

[0060] Figure 2 (Serum aspartate aminotransferase (AST) level)

[0061] The significantly elevated AST levels in alcohol-induced liver injury model mice indicate increased hepatocyte membrane permeability. Fos significantly reduced AST levels, suggesting that the alleviating effect of Fos on alcoholic liver injury is closely related to improving hepatocyte integrity.

[0062] Figure 3 (HE staining, liver histology)

[0063] HE staining results showed that hepatocytes in the control group mice exhibited disordered arrangement and significant fatty degeneration. The Fos-treated group showed reduced pathological damage, significantly improved lipid droplet deposition and inflammatory infiltration, further demonstrating its protective effect at the histological level.

[0064] Figure 4 (Oil Red O staining, liver lipid droplet deposition)

[0065] Oil Red O staining results showed that red lipid droplets were widely deposited in hepatocytes of the control group. Fos monotherapy reduced the number and size of lipid droplets, suggesting that the drug can effectively improve alcohol-induced intrahepatic lipid accumulation and has a complementary effect with lipid metabolism regulating drugs.

[0066] Figure 5 (Liver triglyceride (TG) content)

[0067] Liver tissue analysis showed that TG levels were significantly elevated in the control group. Fos treatment significantly reduced liver TG levels.

[0068] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. The use of a dihydroquinoline derivative in the preparation of drugs for the prevention or treatment of fatty liver, characterized in that: The structure of the dihydroquinoline derivative is as follows: Or its salt, wherein R represents a C1-C4 alkyl group and X represents a halogen; the fatty liver is alcoholic fatty liver.

2. The use according to claim 1, characterized in that: In the structural formula of the dihydroquinoline derivative, R is one of methyl, ethyl, n-propyl, isopropyl, n-butyl, or isobutyl.

3. The use according to claim 1, characterized in that: In the structural formula of the dihydroquinoline derivative, X is either F or Cl.

4. The use according to claim 1, characterized in that: The position of X in the benzene ring is meta relative to the dihydroquinolinyl group.

5. The use according to claim 1, characterized in that: The salt is one or more of sodium, lithium, or potassium salts.

6. The use according to claim 1, characterized in that: The dihydroquinoline derivative is Or its salt.

7. The use according to any one of claims 1-6, characterized in that: The dosage of the dihydroquinoline derivative is 1-20 mg / kg / day.

8. The use according to claim 6, characterized in that: The dosage of the dihydroquinoline derivative is 10 mg / kg / day.

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