Application of chrysin in preparation of medicine for treating alcoholic liver disease

Abstract

The invention belongs to the technical field of biological medicines, and discloses application of chrysin in preparation of a medicine for treating alcoholic liver diseases. Wherein chrysin is used for treating the alcoholic liver disease by improving intestinal flora disorder of ALD mice. The research proves that chrysin has a relatively good protective effect on ALD mice from analysis of mouse liver function indexes, blood fat indexes, and richness and diversity of intestinal flora.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedicine, and specifically relates to the application of chrysin in preparing a medicine for treating alcoholic liver disease. Background Art

[0002] Alcoholic liver disease (ALD) is a disease in which alcohol is metabolized by a series of enzymes in the liver to produce acetaldehyde, which leads to cell dysfunction and damage. [1] The initial pathological manifestation of the liver is alcoholic fatty liver, which develops into alcoholic hepatitis as cell damage continues to worsen. Under the continuous stimulation of inflammation, cell fibrosis intensifies and develops into alcoholic liver fibrosis, which eventually deteriorates and develops into cirrhosis and liver cancer. [2] If drug intervention is given before liver fibrosis occurs, there is still a possibility of recovery.

[0003] Intestinal flora is the largest micro-ecological system in the human body. [3] Recent studies have found that intestinal microorganisms can participate in the metabolism of human substances, are also part of the biological barrier, and are closely related to immune regulation and host defense functions. [4] The liver's well-developed portal vein system is the "first stop" for microorganisms to enter the body. A large number of studies have shown that intestinal flora plays a key role in the progression of ALD. [5] Studies have shown that substances such as lipopolysaccharide and peptidoglycan produced by intestinal bacteria can activate neutrophils and hepatocytes through the portal vein system and induce the liver to release inflammatory mediators, directly leading to liver damage. [6] In recent years, the "gut-liver axis" theory has been widely recognized. Studies have found that an abnormal "gut-liver axis" is one of the important reasons for the increase of inflammatory indicators, changes in intestinal permeability, and decreased expression of related genes, and this phenomenon exacerbates the occurrence and development of ALD. It is speculated that intestinal microecological imbalance can cause dual damage to the intestinal barrier and liver through the "gut-liver axis" pathway. [7] .

[0004] Chrysin is a flavonoid compound extracted from the plant Oroxylum indica of the Bignoniaceae family. It is the main active ingredient of the Chinese medicine propolis capsule. [8] Our team's previous research found that chrysin regulates AMP-activated kinase (AMPK)-NOD-like receptor protein (NLRP3) pathway to mediate cell pyroptosis and has a protective effect on liver fibrosis. [9] In addition, chrysin has anti-inflammatory, antioxidant, anti-diabetic, anti-cancer, and liver and kidney protection effects. [10-11], but there is no direct report on the effect of chrysin on intestinal flora in ALD. Summary of the invention

[0005] In order to overcome the shortcomings of the prior art, the present invention provides the use of chrysin in the preparation of drugs for the treatment of alcoholic liver disease, establishes an ALD mouse model, and evaluates the regulatory effect of chrysin on the intestinal flora of ALD mice based on 16S rDNA technology, and preliminarily explores the mechanism of action of chrysin in improving ALD from the perspective of intestinal flora.

[0006] The above object of the present invention is achieved through the following technical scheme: application of chrysin in the preparation of a drug for treating alcoholic liver disease.

[0007] Furthermore, the chrysin is used in the preparation of a drug for treating alcoholic liver disease, wherein the chrysin in the drug for treating alcoholic liver disease treats alcoholic liver disease by improving the intestinal flora disorder of ALD mice.

[0008] Furthermore, the chrysin alleviates ethanol-induced hepatocyte fatty degeneration and inflammatory response by reducing inflammatory cell infiltration in mouse liver.

[0009] Furthermore, the chrysin treats alcoholic liver disease by significantly increasing the richness of the intestinal flora of mice and restoring the diversity of the intestinal flora.

[0010] Furthermore, the drug for treating alcoholic liver disease is a drug for mammals.

[0011] In a further preferred embodiment of the present invention, the drug for treating alcoholic liver disease is a drug for human use.

[0012] Another object of the present invention is to protect a drug for treating alcoholic liver disease, which comprises chrysin and the dosage of chrysin is 25-50 mg / kg.

[0013] The beneficial effects of the present invention compared with the prior art are: This study confirmed that chrysin has a good protective effect on ALD mice from the analysis of mouse liver function indicators, blood lipid indicators, richness and diversity of intestinal flora. In addition, PICRUSt12 functional prediction shows that chrysin improves ethanol-induced intestinal flora disorders in mice, which may be related to the effects of the pentose phosphate pathway and the pyruvate metabolic pathway. In summary, chrysin can improve ethanol-induced intestinal flora disorders in mice by upregulating beneficial flora and downregulating harmful flora, providing a reference for the treatment of ALD and the development and application of innovative drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments.

[0015] Figure 1is a schematic diagram of the pathological morphology of mouse liver tissue (×200);

[0016] Figure 2 is a dilution curve diagram of each sample in the embodiment (n=6);

[0017] Figure 3 is a PCoA analysis of chrysin on the intestinal flora of ethanol-induced mice in the Example (n=6);

[0018] Figure 4 is a graph of the relative abundance analysis of chrysin on the ethanol-induced intestinal flora of mice at the phylum (A) and genus (B) levels in the Example;

[0019] Figure 5 This is a graph showing the difference in LEfSe between chrysin and the intestinal flora of alcohol-induced mice in the embodiment;

[0020] Figure 6 This is a PICRUSt1 functional prediction analysis diagram of chrysin on the intestinal flora of alcohol-induced mice in the example. DETAILED DESCRIPTION

[0021] The present invention is described in detail below by specific examples, but the protection scope of the present invention is not limited. Unless otherwise specified, the experimental methods used in the present invention are all conventional methods, and the experimental equipment, materials, reagents, etc. used can be obtained from commercial channels.

[0022] The following examples use the ALD mouse model as a research object to preliminarily explore the effect of chrysin on the intestinal flora of mice.

[0023] Example 1 Materials and Methods

[0024] 1.1 Animals Specific pathogen-free (SPF) C57BL / 6 male mice, 6-8 weeks old, weighing 22-24 g, were used, provided by Liaoning Changsheng Biotechnology Co., Ltd., with a certificate number of SCXK (Liao) 2020-0001. The animal experiments were approved by the Ethics Committee of Zhongshan Hospital Affiliated to Dalian University (approval number: DWLL2019060).

[0025] 1.2 Drugs and reagents Chrysin (batch number: HY-14589) was purchased from MCE Shanghai Haoyuan Biopharmaceutical Technology Co., Ltd.; silymarin (batch number: SS8540) was purchased from Beijing Solaibao Technology Co., Ltd.; Lieber-DeCarli ethanol liquid feed was purchased from Nantong Trofi Company. Aspartate aminotransferase (AST) kit (batch number: C010-2-1), alanine aminotransferase (ALT) kit (batch number: C009-2-1), triglyceride (TG) kit (batch number: A110-1-1) were purchased from Nanjing Jiancheng Bioengineering Institute.

[0026] 1.3 Animal modeling The Gao-Binge model was used to establish the mouse ALD model [4] C57BL / 6 mice were randomly divided into a normal control group, an ALD model group, a silymarin group, and a low-dose and high-dose chrysin group, with 8 mice in each group. The mice were adaptively fed with a Lieber-DeCarli control liquid feed for 7 days, the normal control group was fed with a control liquid feed for 8 weeks, and maltodextrin was gavaged once a week, and the other 4 groups were fed with a Lieber-DeCarli ethanol liquid feed for 8 weeks, and ethanol was gavaged once a week at 5g / kg. The low-dose and high-dose chrysin groups were gavaged with 25 and 50mg.kg chrysin. -1 , silymarin group was gavaged with silymarin 100mg.kg -1 , administered once a day, and continued until the 8th week.

[0027] 1.4 Determination of serum biochemical indices At the 8th week of the experiment, 9 hours after intragastric administration of ethanol, blood was collected from the orbital venous plexus and centrifuged to obtain serum. The levels of AST, ALT, and TG in the serum were determined according to the method specified in the kit.

[0028] 1.5 Detection of pathological changes in liver tissue Hematoxylin and eosin (HE) staining was used to stain paraffin sections of liver tissue to observe its pathological changes.

[0029] 1.6 Stool sampling and detection After the administration, the mice were sterilely dissected, and the contents of the rectal segment of each mouse were collected and placed in a sterilized cryopreservation tube and stored in a -80°C refrigerator for 16S rDNA gene sequencing. 30 samples of mouse intestinal contents (6 samples per group) were taken and sent to Lianchuan Biotechnology Co., Ltd. for 16SrDNA sequencing.

[0030] 1.7 Analysis of sequencing data The sequencing data were analyzed using the Lianchuan Bio Cloud Platform. The QIIME2 method was used to detect the significant abundance difference characteristics between species in the intestinal contents of mice, screen the groups with significant differences in abundance, and analyze the magnitude of the effect of the abundance of each group (species) on the difference effect and the relative abundance. On this basis, α diversity and β diversity analysis were performed. Based on the Lianchuan Bio Cloud Platform, the linear discriminant analysis effect size (LEfSe) multi-level species difference discrimination of the intestinal contents of mice was performed, and the functional enrichment of the Kyoto encyclopedia of genes and genomes (KEGG) was combined for analysis.

[0031] 1.8 Statistical methods GraphPad Prism 9.0 software was used for statistical analysis, and the data were expressed as mean ± standard deviation. The differences among the groups were analyzed by univariate and multivariate analysis, and P < 0.05 was considered statistically significant.

[0032] Example 2 Analysis Results

[0033] 2.1 Effects of chrysin on serum transaminases and blood lipids in mice

[0034] The results are shown in Table 1. Compared with the normal control group, the levels of AST, ALT, and TG in the serum of mice in the ALD model group were significantly increased (P<0.01), indicating that the ALD model of mice was successfully established. Compared with the ALD model group, the levels of AST, ALT, and TG in the low-dose and high-dose chrysin groups and the silymarin group were significantly reduced (all P<0.01), and the levels of AST, ALT, and TG in the serum of mice after administration of chrysin were reduced in a dose-dependent manner.

[0035] Table 1 Comparison of serum AST, ALT, TG content in each group

[0036]

[0037]

[0038] ①Compared with the normal control group, t=-6.01~-2.16, P<0.05; ②Compared with the ALD model group, t=2.20-7.34, P<0.05.

[0039] ①Compared with normal control group,t=-6.01—-2.16,P<0.05; ②Compared with ALD model group,t=2.20—7.34,P<0.05.

[0040] 2.2 Effect of chrysin on pathological changes of mouse liver tissue HE staining results showed that the normal control group mice had no obvious liver lesions, while the ALD model group mice had obvious fatty degeneration of liver cells, with punctate and lamellar necrosis and inflammatory cell infiltration. After the intervention of silymarin and chrysin, the inflammatory cell infiltration of mouse liver was significantly reduced, indicating that chrysin can alleviate the fatty degeneration of liver cells and inflammatory response caused by ethanol.

[0041] 2.3 Evaluation of intestinal flora species in each group of mice from the dilution curve ( Figure 2 ) analysis showed that when the number of sequencing increased, the dilution curves of the Shannon diversity index of the mouse intestinal content samples were basically flat, indicating that this sequencing could basically cover most of the microbial species in the mouse intestinal contents. It also showed the rationality of the sequencing data results and the good uniformity of the samples.

[0042] 2.4 Effect of chrysin on the diversity of intestinal flora in ethanol-induced mice The results of β-diversity analysis are shown in Figure 3 The contribution rates of the five groups in PCoA1 and PCoA2 were 28.66% and 11.86%, respectively. The intestinal flora composition of the ALD model group and the normal control group was far apart in PCoA2, while the intestinal flora composition of the chrysin group and the silymarin group was mainly separated from the ALD model group in PCoA1, indicating that ethanol intake significantly changed the composition structure of the intestinal flora of mice, indicating that studying ALD from the perspective of microorganisms is very promising.

[0043] 2.5 Effect of chrysin on the composition of intestinal flora in ethanol-induced mice Chrysin showed a regulatory effect on intestinal flora in the sequencing results. Further comparative analysis of the abundance of flora species showed that Figure 4As shown in A, at the phylum level, the structure of the intestinal flora of mice was mainly composed of Firmicutes (48%), Bacteroidota (35%), Proteobacteria (7%), Verrucomicrobiota (13%), Desulfobacterota (11.5%), and Actinobacteriota (5.5%). The normal control group had Bacteroidetes (39.09%) and Firmicutes (40.63%) as the dominant phyla. The ratio of Firmicutes to Bacteroidetes was 0.96. The ALD model group had Bacteroidetes (23.84%), Firmicutes (43.28%), Verrucomicrobiota (17.03%), and Proteobacteria (11.5%) as the main dominant phyla. The ratio of Firmicutes to Bacteroidetes was 1.81. In the silymarin group, the main dominant phyla were Bacteroidetes (55.85%), Firmicutes (26.64%), and Desulfobacteria (8.25%), with a Firmicutes / Bacteroidetes ratio of 0.47. In the low-dose chrysin group, the dominant phyla were Bacteroidetes (53.06%), Firmicutes (33.94%), and Desulfobacteria (5.33%), with a Firmicutes / Bacteroidetes ratio of 0.63. In the high-dose chrysin group, the dominant phyla were Bacteroidetes (47.08%), Firmicutes (28.19%), Proteobacteria (9.23%), and Verrucomicrobia (8.84%), with a Firmicutes / Bacteroidetes ratio of 0.59. In addition, the proportion of Bacteroidetes and Firmicutes in the intestinal flora in the normal control group, silymarin group, and high- and low-dose chrysin groups exceeded 75%.

[0044] like Figure 4As shown in B, at the genus level, the top three dominant genera in the control group were Muribaculaceae_unclassified (20.87%), Monoglobus (23.04%), and Desulfovibrionaceae_unclassified (4.96%); the top three dominant genera in the ALD model group were Monoglobus (23.84%), Akkermansia (17.03%), and Muribaculaceae_unclassified (14.61%); the top three dominant genera in the silymarin group were Muribaculaceae_unclassified (20.87%), Monoglobus (23.04%), and Desulfovibrionaceae_unclassified (4.96%). classified genera (28.29%), Monoglobus (11.2%), and Parabacteroides (7.43%); the top three dominant genera in the low-dose chrysin group were Muribaculaceae_unclassified (23.22%), Monoglobus (13%), and Parabacteroides (8.68%); the top three dominant genera in the high-dose chrysin group were Muribaculaceae (21.90%), Monoglobus (12.89%), and Akkermansia (8.84%).

[0045] 2.6 Multi-level species difference analysis of chrysin on LEfSe intestinal flora of ethanol-induced mice

[0046] Results Figure 5 . The LEfSe multi-level species difference discriminant analysis was used to study the bacterial group structure with significant differences in intestinal microbial abundance in different groups of mice. It was found that there were 43 bacterial groups in the normal control group, 15 in the ALD model group, 33 in the silymarin group, 59 in the low-dose chrysin group, and 16 in the high-dose chrysin group. At the genus level, the differentially dominant genera in the normal control group were Coriobacteriia-unclassified and Lactobacillaceae; the differentially dominant genera in the ALD model group were Akkermansia muciniphila and Escherichia coli; the differentially dominant genera in the silymarin group were Muribaculaceae and Desulfovibrionaceae; the differentially dominant genera in the low-dose chrysin group were Oscillospirales and g-Firmicutes-unclassified; the differentially dominant genera in the high-dose chrysin group were Alloprevotella and Dorea.

[0047] 2.7 PICRUSt2 functional prediction analysis of chrysin on ethanol-induced mouse intestinal flora PICRUSt2 was used to predict the function of the bacterial community in the mouse intestine, and the abundance prediction table of KO (KEGG Orthology) function and KEGG metabolic pathway (KEGG pathway) abundance table were obtained with reference to the KEGG database. Figure 6 A The results showed that there was no significant difference in the abundance of genes in the primary functional layer. Figure 6 B The results show that there are differences in the abundance of functional genes in the secondary functional layer, especially in metabolism, cellular processes and signaling pathways. Figure 6 The results of C showed that in the tertiary functional layer, especially in the pentose phosphate pathway and pyruvate metabolic pathway, the relative abundance of chrysin low and high groups was significantly increased compared with the ALD model group. The above results suggest that chrysin regulation of intestinal microorganisms may be a potential biological pathway to improve ALD.

[0048] Example 3 Results Discussion

[0049] The liver is the main organ for ethanol metabolism. When the ethanol content in the liver is too high, a large amount of acetaldehyde will accumulate in the liver cells, inducing cell damage.

[12] The metabolites of ethanol in the liver include ethanol, acetaldehyde and acetic acid. This process can aggravate the inflammatory response in the liver and cause liver damage.

[13] Therefore, reducing liver damage and reducing liver inflammation are crucial to the treatment of ALD. As research continues to deepen, changes in the composition, function, and metabolism of intestinal microorganisms will also have an important impact on the occurrence, development, and outcome of liver disease.

[14] Therefore, the regulation of intestinal flora plays an important role in the development of liver disease and subsequent treatment. Our team’s previous research has confirmed that chrysin has a certain protective effect on ethanol-induced liver damage.

[15] This study further found that chrysin can improve intestinal flora disorders in ALD mice.

[0050] In this study, an ALD mouse model was established, and the regulatory effect of chrysin on the intestinal flora of ALD mice was evaluated based on 16S rDNA technology, and the mechanism of action of chrysin in improving ALD was preliminarily explored from the perspective of intestinal flora. The results showed that the community composition of the intestinal flora of ethanol-induced mice was significantly different from that of normal mice. According to the α diversity results, the richness of the intestinal flora of mice in the ALD model group was significantly reduced compared with the normal group, and the richness of the intestinal flora was significantly increased after treatment with silymarin and chrysin. According to the analysis results of β diversity, it can be seen that ethanol can reduce the diversity of the intestinal flora of mice, and the treatment of silymarin and chrysin can restore the diversity of the intestinal flora.

[0051] At the genus level, compared with the intestinal flora of mice in the normal control group, the number of harmful bacteria such as Escherichia Shigella and Akkermansia muciniphila in the intestinal tract of mice in the ALD model group increased significantly. Akkermansia muciniphila is a bacterium that can degrade mucin, which is an important component of the intestinal barrier.

[16] When excessive Akkermansia muciniphila proliferates abnormally, it will degrade the intestinal mucin and mucus layer, leading to damage to the intestinal barrier, causing intestinal inflammation, and lipopolysaccharide entering the blood through the intestinal barrier, thus causing the occurrence of the disease.

[17] . However, the number of core intestinal bacteria such as Pseudomonas and Bacteroides decreased significantly. At the phylum level, the beneficial Firmicutes in the mouse intestine decreased significantly, which is similar to the genus level. Among them, the Metamycetes contains many beneficial bacteria, such as Lactobacillus. They can produce acetate, lactic acid, etc. to prevent pathogens from colonizing the intestine.

[18] In addition, butyrate is also one of the main energy sources for intestinal cells, which is closely related to maintaining the normal function of intestinal cells and maintaining the integrity of the intestinal barrier. This component is also produced by Firmicutes.

[19] After treatment with silymarin and chrysin, the imbalance of intestinal flora in mice was significantly improved.

[0052] This study confirmed that chrysin has a good protective effect on ALD mice based on mouse liver function indicators, blood lipid indicators, richness and diversity of intestinal flora. In addition, PICRUSt12 function prediction showed that chrysin improved ethanol-induced intestinal flora disorders in mice, which may be related to the pentose phosphate pathway and pyruvate metabolic pathway. In summary, chrysin can improve ethanol-induced intestinal flora disorders in mice by upregulating beneficial flora and downregulating harmful flora, providing a reference for the treatment of ALD and the development and application of innovative drugs.

[0053] The above-described embodiments are only preferred embodiments of the present invention, but not all feasible embodiments of the present invention. For those skilled in the art, any obvious changes made thereto without departing from the principles and spirit of the present invention should be considered to be included in the scope of protection of the claims of the present invention.

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Claims

1. Application of chrysin in the preparation of drugs for the treatment of alcoholic liver disease.

2. The use of chrysin according to claim 1 in the preparation of a drug for treating alcoholic liver disease, characterized in that: Chrysin in the drug for treating alcoholic liver disease treats alcoholic liver disease by improving the intestinal flora disorder of ALD mice.

3. The use of chrysin according to claim 1 in the preparation of a drug for treating alcoholic liver disease, characterized in that: The chrysin alleviates ethanol-induced hepatocyte fatty degeneration and inflammatory response by reducing inflammatory cell infiltration in rat liver.

4. The use of chrysin in the preparation of a drug for treating alcoholic liver disease according to claim 1, characterized in that: The chrysin treats alcoholic liver disease by significantly increasing the richness of the intestinal flora of mice and restoring the diversity of the intestinal flora.

5. The use of chrysin in the preparation of a drug for treating alcoholic liver disease according to claim 1, characterized in that: The drug for treating alcoholic liver disease is a drug for mammals.

6. The use of chrysin in the preparation of a drug for treating alcoholic liver disease according to claim 5, characterized in that: The drug for treating alcoholic liver disease is a drug for human use.

7. A drug for treating alcoholic liver disease, characterized in that: Chrysin is included and the amount of chrysin is 25-50 mg / kg.

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