Application of dihydroquinoline derivative in preparation of product for preventing or treating fatty liver

Abstract

The invention provides application of a specific dihydroquinoline derivative in preparation of a product for preventing or treating fatty liver. It is found for the first time that the specific dihydroquinoline derivative significantly reduces the liver triglyceride level, so that alcohol-induced liver fatty degeneration is relieved, and the dihydroquinoline derivative has a good clinical transformation prospect.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine, and specifically to use of a dihydroquinoline derivative in preparing a product for preventing or treating fatty liver. Background Art

[0002] Currently, there is a lack of effective targeted therapeutics for fatty liver disease, such as alcoholic fatty liver disease (ALD). Clinically, alcohol abstinence and supportive care are the primary treatments. PPARα is a key nuclear receptor that regulates fatty acid β-oxidation, but its nuclear transport is impaired in ALD, affecting its transcriptional activity and leading to lipid accumulation. Summary of the Invention

[0003] In order to solve the above problems, the present invention uses specific dihydroquinoline derivatives to provide therapeutic effects on fatty liver, especially alcoholic fatty liver.

[0004] Specifically, the present application discloses the use of a dihydroquinoline derivative in the preparation of a product for preventing or treating fatty liver. The structure of the dihydroquinoline derivative is: or a salt thereof, wherein R represents a C1-C4 alkyl group and X represents a halogen.

[0005] In the structural formula of the dihydroquinoline derivative, R is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.

[0006] In the structural formula of the dihydroquinoline derivative, X is F or Cl.

[0007] Further, the dihydroquinoline derivative structure is or a salt thereof (abbreviated as the compound is Fos in this application).

[0008] The products include pharmaceuticals.

[0009] 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.

[0010] Furthermore, the fatty liver is alcoholic fatty liver.

[0011] The position of X in the benzene ring is meta relative to the dihydroquinolinyl group.

[0012] The salt is one or more of sodium salt, lithium salt or potassium salt.

[0013] The dosage of the dihydroquinoline derivative, especially Fos, is 1-20 mg / kg / day, preferably 10 mg / kg / day.

[0014] The present invention discovered for the first time that dihydroquinoline derivatives significantly reduce liver triglyceride levels, thereby alleviating alcohol-induced hepatic steatosis, and has good prospects for clinical transformation. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 In the Lieber-DeCarli alcoholic fatty liver model, plasma ALT showed that liver damage was alleviated after Fos treatment; Figure 2 In the Lieber-DeCarli alcoholic fatty liver model, plasma AST showed that liver damage decreased after Fos treatment; Figure 3 H&E staining of the liver in the Lieber-DeCarli alcoholic fatty liver model showed that liver lipid accumulation decreased after Fos treatment; Figure 4 Oil red O staining of the liver in the Lieber-DeCarli alcoholic fatty liver model showed that hepatic lipid accumulation decreased after Fos treatment.

[0016] Figure 5 Liver liposuction in the Lieber-DeCarli alcoholic fatty liver model showed that hepatic triglyceride accumulation decreased after Fos treatment. DETAILED DESCRIPTION

[0017] Example 1: Experimental methods and grouping: 8-week-old C57BL / 6J female mice were divided into groups and fed a Lieber-DeCarli alcohol liquid diet for 2 weeks. They were then given a solvent (abbreviated as control) and Fos (10 mg / kg / day, abbreviated as Fos) for 2 weeks.

[0018] Liver tissue was taken for HE staining and Oil Red O staining, and the results showed that Fos could significantly reduce liver fat content; liver liposuction results showed that triglycerides in the liver were also significantly reduced.

[0019] Plasma was collected to test liver damage markers alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The results showed that Fos treatment significantly reduced the levels of ALT and AST, improved liver damage, and improved liver damage.

[0020] An automated biochemical analyzer was used to measure alanine aminotransferase (ALT) levels in mouse serum. ALT levels were significantly lower in the Fos (Fos)-treated group compared to the control group, suggesting that the drug has a protective effect against alcoholic liver damage.

[0021] An automated biochemical analyzer was used to measure serum aspartate aminotransferase (AST) levels in mice. Similar to ALT, Fos monotherapy decreased AST, suggesting that Fos can improve liver function abnormalities.

[0022] Paraffin sections were sectioned and stained with hematoxylin and eosin (HE), and changes in hepatocyte structure and inflammation were observed under a light microscope. The control group showed disorganized hepatocytes and fatty degeneration; the Fos group showed pathological improvement.

[0023] Frozen sections were then stained with Oil Red O to detect neutral fat deposition. Significant lipid droplet deposition was observed in the control group, but this was reduced in the Fos group, suggesting that Fos can effectively reduce hepatic lipid deposition.

[0024] Liver triglyceride (TG) levels were quantitatively measured using a biochemical kit, and the results were standardized to mg / g liver tissue. Liver TG levels were significantly elevated in the control group, but decreased in the Fos group, suggesting that Fos significantly improves hepatic lipid metabolism.

[0025] Figure 1 :Serum alanine aminotransferase (ALT) level, test method: biochemical analyzer to detect ALT activity (U / L).

[0026] Identifier: Control: control group, Fos: Fos monotherapy group ALT levels increased in the control group, indicating liver damage, while ALT levels decreased significantly in the Fos group, suggesting that Fos can improve alcoholic liver damage and produce a synergistic effect with fenofibrate.

[0027] Figure 2 :Serum aspartate aminotransferase (AST) level, test method: biochemical analyzer to detect AST activity (U / L).

[0028] AST levels were elevated in the control group and significantly decreased after Fos treatment, further demonstrating that Fos can effectively improve alcoholic liver damage.

[0029] Figure 3 :HE staining (structural changes of liver tissue), test method: paraffin section, hematoxylin-eosin staining, observation under a microscope.

[0030] Control: The liver cells in the control group were arranged in disorder and fatty degeneration was obvious. Fos: Fatty degeneration was alleviated in the Fos-treated group It was shown that Fos significantly improved alcohol-induced liver tissue pathological damage.

[0031] Figure 4 :Oil red O staining (lipid deposition detection), test method: frozen section, Oil red O staining, detection of neutral fat.

[0032] Lipid droplet deposition was extensive in the control group, while it was reduced in the Fos group. These results suggest that Fos can effectively inhibit alcohol-induced lipid accumulation.

[0033] Figure 5 : Liver triglyceride (TG) content, test method: quantitative detection by kit, results expressed in mg / g liver. mg / g liver: Triglyceride content per gram of liver tissue Hepatic TG levels increased in the control group, but decreased in the Fos group. This result was consistent with Oil Red O staining, further demonstrating that Fos alleviates hepatic lipid accumulation.

[0034] In summary, the attached figures demonstrate from multiple perspectives, including serological indicators, histological observations, lipid staining, and biochemical quantification, that Fos can significantly alleviate alcohol-induced liver damage and lipid accumulation.

[0035] Figure 1 、 Figure 2 (Serum ALT and AST activity) Conditions: C57BL / 6J mice were fed an alcohol-induced model (usually Lieber-DeCarli liquid diet or acute alcohol gavage) and divided into a control group and a Fos group.

[0036] Methods: Blood was collected from the orbit, and after serum separation, ALT and AST were detected using an automatic biochemical analyzer.

[0037] Figure 3 (HE staining, liver histological changes) Conditions: Same as above, mouse liver tissue was fixed in 4% paraformaldehyde and embedded in paraffin.

[0038] Methods: The sections (4 μm) were sliced ​​and stained with hematoxylin and eosin (H&E), and the hepatocyte arrangement, ballooning degeneration, and inflammatory infiltration were observed under a light microscope.

[0039] Figure 4 (Oil Red O staining, lipid droplet deposition) Conditions: Same as above, liver was freshly harvested and frozen sections (7 μm) were made.

[0040] 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.

[0041] Figure 5 (Liver triglyceride TG content) Conditions: Same as above, liver tissue homogenate.

[0042] Methods: Colorimetric detection was performed using a commercial kit, and the results were standardized to mg TG / g liver.

[0043] Explanation of symbols in the figure ns: no significant difference; *: p < 0.05; **: p < 0.01; ***: p < 0.001; ****: p < 0.0001 Figure 1 (Serum alanine aminotransferase (ALT) level) In alcohol-fed mice, 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 damage.

[0044] Figure 2 (Serum aspartate aminotransferase AST level) AST levels in alcohol-induced mice are significantly elevated, indicating increased hepatocyte membrane permeability. Fos significantly reduces AST levels, suggesting that the mitigating effect of Fos on alcoholic liver injury is closely related to improving hepatocyte integrity.

[0045] Figure 3 (HE staining, liver histology) HE staining revealed that the hepatocytes of the control mice showed disordered arrangement and significant fatty degeneration. However, the Fos-treated group showed reduced pathological damage, with significant improvement in lipid droplet deposition and inflammatory infiltration, further demonstrating its protective effect at the histological level.

[0046] Figure 4 (Oil red O staining, hepatic lipid droplet deposition) Oil red O staining results showed that red lipid droplets were widely deposited in the hepatocytes of the control group. Fos alone could reduce the number and size of lipid droplets, suggesting that the drug can effectively improve alcohol-induced lipid accumulation in the liver and has a complementary effect with lipid metabolism regulating drugs.

[0047] Figure 5 (Liver triglyceride TG content) Liver tissue test results showed that the TG level in the control group was significantly increased, while Fos treatment significantly reduced the TG content in the liver.

[0048] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. Use of a dihydroquinoline derivative in preparing a product for preventing or treating fatty liver, characterized in that: The structure of the dihydroquinoline derivative is: or a salt thereof, wherein R represents a C1-C4 alkyl group and X represents a halogen.

2. The use according to claim 1, characterized in that: The fatty liver is selected from one of alcoholic fatty liver, non-alcoholic fatty liver, malnutrition-induced fatty liver and drug-induced fatty liver.

3. The use according to claim 1, characterized in that: The fatty liver is alcoholic fatty liver.

4. 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.

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

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

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

8. The use according to claim 1, characterized in that: The dihydroquinoline derivative is or a salt thereof.

9. The use according to any one of claims 1 to 8, characterized in that: The dosage of the dihydroquinoline derivative is 1-20 mg / kg / day.

10. The use according to claim 9, characterized in that: The dosage of the dihydroquinoline derivative is 10 mg / kg / day.

Images