Transcriptome and Gut Microbiota Profiling Analysis of ANIT-Induced Cholestasis and the Effects of Da-Huang-Xiao-Shi Decoction Intervention

Wang, Wang; Jiang, Shujun; Xu, Chengcheng; Tang, Lili; Liang, Yan; Zhao, Yang; Zhu, Guoxue

doi:10.1128/spectrum.03242-22

Cited by 4 publications

(3 citation statements)

References 57 publications

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“…Such disruption could further exacerbate liver damage (Pollheimer et al, 2014). This model is now extensively employed to identify potential compounds for liver protection and the treatment of cholestasis (Song et al, 2023; Wang et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Allocholic acid protects against α‐naphthylisothiocyanate‐induced cholestasis in mice by ameliorating disordered bile acid homeostasis

Han,

Lin,

Liu

et al. 2023

J of Applied Toxicology

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Cholestasis is a pathological condition characterized by disruptions in bile flow, leading to the accumulation of bile acids (BAs) in hepatocytes. Allocholic acid (ACA), a unique fetal BA known for its potent choleretic effects, reappears during liver regeneration and carcinogenesis. In this research, we investigated the protective effects and underlying mechanisms of ACA against mice with cholestasis brought on by α‐naphthylisothiocyanate (ANIT). To achieve this, we combined network pharmacology, targeted BA metabolomics, and molecular biology approaches. The results demonstrated that ACA treatment effectively reduced levels of serum AST, ALP, and DBIL, and ameliorated the pathological injury caused by cholestasis. Network pharmacology analysis suggested that ACA primarily regulated BA and salt transport, along with the signaling pathway associated with bile secretion, to improve cholestasis. Subsequently, we examined changes in BA metabolism using UPLC‐MS/MS. The findings indicated that ACA pretreatment induced alterations in the size, distribution, and composition of the liver BA pool. Specifically, it reduced the excessive accumulation of BAs, especially cholic acid (CA), taurocholic acid (TCA), and β‐muricholic acid (β‐MCA), facilitating the restoration of BA homeostasis. Furthermore, ACA pretreatment significantly downregulated the expression of hepatic BA synthase Cyp8b1, while enhancing the expression of hepatic efflux transporter Mrp4, as well as the renal efflux transporters Mdr1 and Mrp2. These changes collectively contributed to improved BA efflux from the liver and enhanced renal elimination of BAs. In conclusion, ACA demonstrated its potential to ameliorate ANIT‐induced liver damage by inhibiting BA synthesis and promoting both BA efflux and renal elimination pathways, thus, restoring BA homeostasis.

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Section: Discussionmentioning

confidence: 99%

Allocholic acid protects against α‐naphthylisothiocyanate‐induced cholestasis in mice by ameliorating disordered bile acid homeostasis

Han,

Lin,

Liu

et al. 2023

J of Applied Toxicology

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“…Surprisingly, almost all cholestasis-specific pathways regulated by ZYP involve Cyp enzymes. Prior studies indicate that Cyp1a1, Cyp1a2, and Cyp2b1 are potential targets for treating of cholestasis ( Ding et al, 2014 ; Ibrahim, 2015 ; Wang et al, 2022 ). Cyp2c11 exhibits significant catalytic activity in the metabolism of arachidonic acid, but its activity is diminished in various inflammation models, leading to lipid accumulation and liver injury ( Sugatani et al, 2006 ; Zordoky et al, 2011 ).…”

Section: Discussionmentioning

confidence: 99%

The zhuyu pill relieves rat cholestasis by regulating the mRNA expression of lipid and bile metabolism associated genes

Han,

Wu,

Wen

et al. 2023

Front. Pharmacol.

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Background: The Zhuyu pill (ZYP), composed of Coptis chinensis Franch. and Tetradium ruticarpum (A. Jussieu) T. G. Hartley, is an effective traditional Chinese medicine with potential anti-cholestatic effects. However, the underlying mechanisms of ZYP remain unknown.Objective: To investigate the mechanism underlying the interventional effect of ZYP on mRNA-seq analysis in cholestasis rat models.Materials and methods: This study tested the effects of a low-dose (0.6 g/kg) and high-dose (1.2 g/kg) of ZYP on a cholestasis rat model induced by α-naphthyl-isothiocyanate (ANIT, 50 mg/kg). Serum biochemistry and histopathology results were used to evaluate the therapeutic effect of ZYP, and mRNA-Seq analysis was performed and verified using real-time fluorescence quantitative PCR (qRT-PCR). GO, KEGG, and GSEA analyses were integrated to identify the mechanism by which ZYP impacted cholestatic rats.Results: ZYP was shown to significantly improve abnormal changes in the biochemical blood indexes and liver histopathology of cholestasis rats and regulate pathways related to bile and lipid metabolism, including fatty acid metabolism, retinol metabolism, and steroid hormone biosynthesis, to alleviate inflammation, cholestasis, and lipid metabolism disorders. Relative expression of the essential genes Cyp2a1, Ephx2, Acox2, Cyp1a2, Cyp2c11, and Sult2a1 was verified by qRT-PCR and showed the same trend as mRNA-seq analysis.Conclusion: ZYP has a significant anti-cholestatic effect by regulating bile metabolism and lipid metabolism related pathways. These findings indicate that ZYP is a novel and promising prospect for treating cholestasis.

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“…There have been many pharmacology and molecular mechanism researches on Chinese herbal medicine treat cholestatic hepatitis. Wang et al ( Wang et al, 2022 ) explored the therapeutic effect of Da-Huang-Xiao-Shi Decoction on cholestasis; Wu et al ( Wu et al, 2022 ) explored the therapeutic effect of combination of resveratrol and luteolin on cholestasis by regulating bile acid homeostasis and inhibiting oxidative stress to improve disease occurrence. Hypericum japonicum is a dried whole plant of Hypericum japonicum Thunb., and has been widely applied to cure infectious hepatitis, acute and chronic hepatitis in traditional medicine.…”

Section: Introductionmentioning

confidence: 99%

Quercetin 7-rhamnoside protects against alpha-naphthylisothiocyanate (ANIT)-induced in cholestatic hepatitis rats by improving biliary excretion and inhibiting inflammatory responses

et al. 2023

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Objective: To explore the pharmacological effects and molecular mechanism of quercetin 7-rhamnoside (Q7R) in the treatment of cholestatic hepatitis induced by alpha-naphthylisothiocyanate (ANIT).Methods: ANIT-induced cholestatic hepatitis rat model was used to investigate the hepatoprotective effects of three different doses of Q7R (1.25 mg/kg; 2.5 mg/kg; 5 mg/kg). Serum biochemical indices were detected using commercial kits. H&E and masson staining were used to observe hepatic tissue damage and collagen deposition in hepatocytes. The metabolism of bile acid-related substances was detected via HPLC-MS/MS by 5-(diisopropylamino) amylamine (DIAAA) derivative method. Hepatocyte injury, cholestasis, and inflammation were detected at the mRNA and protein levels using reverse transcription-polymerase chain reaction (RT-PCR) and western blotting, respectively.Results: Q7R can decrease the level of CYP7A1, and increase FXR, CYP27A1 so then improving abnormal bile acid secretion. Furthermore, Q7R can also ameliorating inflammation by reduce TNF-α, IL-1β, PTGS1, PTGS2, NCOA2, NF-κB level. Therefore, Q7R had an effective therapeutic effect on ANIT-induced cholestatic hepatitis, improving abnormal bile acid secretion, and inhibiting inflammatory responses.Conclusion: The results demonstrated that Q7R treat cholestatic hepatitis by regulating bile acid secretion and alleviating inflammation.

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Transcriptome and Gut Microbiota Profiling Analysis of ANIT-Induced Cholestasis and the Effects of Da-Huang-Xiao-Shi Decoction Intervention

Abstract: Cholestasis is a serious manifestation of liver diseases resulting in liver injury, fibrosis, and liver failure with limited therapies. To date, only ursodeoxycholic acid (UDCA) has been approved by the U.S.

Cited by 4 publications

References 57 publications

Allocholic acid protects against α‐naphthylisothiocyanate‐induced cholestasis in mice by ameliorating disordered bile acid homeostasis

Allocholic acid protects against α‐naphthylisothiocyanate‐induced cholestasis in mice by ameliorating disordered bile acid homeostasis

The zhuyu pill relieves rat cholestasis by regulating the mRNA expression of lipid and bile metabolism associated genes

Quercetin 7-rhamnoside protects against alpha-naphthylisothiocyanate (ANIT)-induced in cholestatic hepatitis rats by improving biliary excretion and inhibiting inflammatory responses

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