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Anti-liver fibrosis effects of the total flavonoids of litchi semen on CCl₄-induced liver fibrosis in rats associated with the upregulation of retinol metabolism.

ABSTRACT:

Context

The litchi semen are traditional medications for treating liver fibrosis (LF) in China. The mechanism remains unclear.

Objective

This study investigates the anti-liver fibrotic mechanism of the total flavonoids of litchi semen (TFL).

Materials and methods

Sprague-Dawley rats with carbon tetrachloride-induced LF were treated with TFL (50 and 100 mg/kg) for 4 weeks. The anti-liver fibrotic effects of TFL were evaluated and the underlying mechanisms were investigated via histopathological analysis, proteomic analysis and molecular biology technology.

Results

Significant anti-LF effects were observed in the high-TFL-dose group (TFL-H, p < 0.05). Five hundred and eighty-five and 95 differentially expressed proteins (DEPs) were identified in the LF rat model (M group) and TFL-H group, respectively. The DEPs were significantly enriched in the retinol metabolism pathway (p < 0.0001). The content of 9-cis-retinoic acid (0.93 ± 0.13 vs. 0.66 ± 0.10, p < 0.05, vs. the M group) increased significantly in the TFL-H group. The upregulation of RXRα (0.50 ± 0.05 vs. 0.27 ± 0.13 protein, p < 0.05), ALDH2 (1.24 ± 0.09 vs. 1.04 ± 0.08 protein, p < 0.05), MMP3 (0.89 ± 0.02 vs. 0.61 ± 0.12 protein, p < 0.05), Aldh1a7 (0.20 ± 0.03 vs. 0.03 ± 0.00 mRNA, p < 0.05) and Aox3 (0.72 ± 0.14 vs. 0.05 ± 0.01 mRNA, p < 0.05) after TFL treatment was verified.

Conclusions

TFL exhibited good anti-liver fibrotic effects, which may be related to the upregulation of the retinol metabolism pathway. TFL may be promising anti-LF agents with potential clinical application prospects.

SUBMITTER: Yan J

PROVIDER: S-EPMC9262366 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Penthorum chinense Pursh (PCP) is widely utilized in China to treat a variety of liver diseases. It has been shown that flavonoids inhibit inflammation and have the potential to attenuate tissue damage and fibrosis. However, the mechanisms underlying how total flavonoids isolated from PCP (TFPCP) exert their anti-fibrotic effects remain unclear. Methods: The chemical composition of TFPCP was determined using UHPLC-Q-Orbitrap HRMS. Subsequently, rats were randomly assigned to a control group (Control), a carbon tetrachloride (CCl4)-induced hepatic fibrosis model group (Model), a positive control group [0.2 mg/(kg∙day)] of Colchicine), and three TFPCP treatment groups [50, 100, and 150 mg/(kg∙day)]. All substances were administered by gavage and treatments lasted for 9 weeks. Simultaneously, rats were intraperitoneally injected with 10%-20% CCl4 for 9 weeks to induce liver fibrosis. At the end of the experiment, the liver ultrasound, liver histomorphological, biochemical indicators, and inflammatory cytokine levels were tested respectively. The underlying mechanisms were assessed using Western blot, immunohistochemistry, immunofluorescence, RT-qPCR, and metabolomics. Results: Fourteen flavonoids were identified in TFPCP. Compared with control animals, CCl4-treated rats demonstrated obvious liver injury and fibrosis, manifested as increases in gray values, distal diameter of portal vein (DDPV) and a decrease in blood flow velocity (VPV) in the ultrasound analysis; increased biochemical index values (serum levels of ALT, AST, TBIL, and ALP); marked increases in the contents of fibrotic markers (PC III, COL4, LN, HA) and inflammatory factors (serum TNF-α, IL-6, and IL-1β); and significant pathological changes. However, compared with the Model group, the ultrasound parameters were significantly improved and the serum levels of inflammatory cytokines were reduced in the TFPCP group. In contrast, the expression of TGF-β1, TLR4, and MyD88, as well as the p-P65/P65 and p-IκBα/IκBα ratios, were considerably reduced following TFPCP treatment. In addition, we identified 32 metabolites exhibiting differential abundance in the Model group. Interestingly, TFPCP treatment resulted in the restoration of the levels of 20 of these metabolites. Conclusion: Our findings indicated that TFPCP can ameliorate hepatic fibrosis by improving liver function and morphology via the inactivation of the TLR4/MyD88-mediated NF-κB pathway and the regulation of liver metabolism.

Project description:BackgroundRifaximin is a poorly absorbed broad-spectrum antibiotic used for hepatic encephalopathy. Although increased Lactobacillaceae and decreased Bacteroidetes abundance are characteristic of hepatic encephalopathy, rifaximin does not dramatically alter the stool microbiota. As the antimicrobial effect of rifaximin increases by micellization with bile acids, we hypothesized that rifaximin alters the microbiota in the duodenum and jejunum, where the levels of bile acids are abundant.Methods and resultsEight-week-old BALB/c mice were injected with carbon tetrachloride (CCl4) intraperitoneally for 12 weeks to induce liver fibrosis. The mice were grouped into the control (n = 9), CCl4 (n = 13), and rifaximin group in which mice were treated with rifaximin for two weeks after CCl4 administration (n = 13). We analyzed the microbiota of the duodenum, jejunum, ileum, cecum, and stool using 16S ribosomal RNA gene analysis. The content of Lactobacillaceae, the most abundant bacterial family in the duodenum and small intestine, increased in the CCl4 group, especially in the jejunum (median 67.0% vs 87.8%, p = 0.03). Rifaximin significantly decreased Lactobacillaceae content in the duodenum (median 79.4% vs 19.0%, p = 0.006) and jejunum (median 87.8% vs 61.3%, p = 0.03), but not in the ileum, cecum, and stool. Bacteroidetes abundance tended to decrease on CCl4 administration and increased following rifaximin treatment in the duodenum and jejunum. S24_7, the most abundant family in Bacteroidetes, demonstrated a significant inverse correlation with Lactobacillaceae (duodenum, r = - 0.61, p < 0.001; jejunum, r = - 0.72, p < 0.001). In the ileum, cecum, and stool, the effect of rifaximin on the microbiota was minimal, with changes within the same phylum. The percentage of bacterial families, such as Lactobacillaceae and S24_7 in the duodenum and small intestine, did not correlate with that in the stool.ConclusionsThe abundance of Lactobacillaceae increased in the jejunum of mice with CCl4-induced liver fibrosis, while rifaximin significantly reduced it in the duodenum and jejunum. Thus, rifaximin possibly exerts its effect by altering the duodenal and jejunal microbiota. Furthermore, changes in the duodenal and small intestinal microbiota were not associated with that of stool, suggesting that the analysis of stool microbiota is insufficient to evaluate upper intestinal microbiota.

Dataset Information

Anti-liver fibrosis effects of the total flavonoids of litchi semen on CCl₄-induced liver fibrosis in rats associated with the upregulation of retinol metabolism.

Context

Objective

Materials and methods

Results

Conclusions

Similar Datasets

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Dataset Information

Anti-liver fibrosis effects of the total flavonoids of litchi semen on CCl4-induced liver fibrosis in rats associated with the upregulation of retinol metabolism.

Context

Objective

Materials and methods

Results

Conclusions

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Anti-liver fibrosis effects of the total flavonoids of litchi semen on CCl₄-induced liver fibrosis in rats associated with the upregulation of retinol metabolism.