TOXICOLOGY IN VITRO
·
2025
·
IF 2.7
Yuhui Yan,Wenyu Wang,Aiwen Yan,Haonan Zhu,Qiang Meng
Cholestasis, a condition marked by bile acid accumulation in the liver and body systems, leads to liver dysfunction and cirrhosis. Currently, ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are the only two FDA-approved drugs for Cholestasis. Thus, new therapeutic approaches need to be developed. In this study, we validated the liver-protective properties of β-sitosterol (SIT), a key bioactive element abundant in plants, against hepatic toxicity and cholestasis induced by alpha-naphthylisothiocyanate(ANIT), while elucidating its mechanisms of action both in vivo and in vitro. SIT's FXR activation was confirmed via molecular docking and dual-luciferase assays. In the mechanisms of SIT hepatoprotection, the expression levels of bile salt export pump (Bsep) and multidrug resistance protein2 (Mrp2) which are bile acid efflux transporter, and sulfate transferase 2a1 (Sult2a1) which is a bile acid metabolizing enzyme were all increased by SIT, whereas the expression of uptake transporter sodium taurocholate transporting polypeptide (Ntcp), bile acid synthesis enzyme cholesterol 7α-hydroxylase (Cyp7a1) and oxysterol 12α-hydroxylase (Cyp8b1) was decreased by SIT. In addition, SIT alleviated liver inflammation by suppressing inflammatory factor expression. However, FXR antagonist guggulsterone and FXR siRNA abolished SIT's improvements in liver histology, bile acid transporters, and enzymes. Conclusively, through activating FXR, SIT provides a protective effect against hepatotoxicity and cholestasis. SIT might serve as a new potential therapeutic strategy for the treatment of cholestatic liver diseases.
研究领域:
药理学
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分子生物学
·
肝脏疾病
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
·
2024
·
IF 2.7
Hang Yang,Tingting Yang,Jiaxin Ding,Xue Wang,Xi Chen,Jia Liu,Ting Shu,Ziteng Wu,Lixin Sun,Xin Huang,Zhenzhou Jiang,Luyong Zhang
Bile acid homeostasis is crucial for the normal physiological functioning of the liver. Disruptions in bile acid profiles are closely linked to the occurrence of cholestatic liver injury. As part of our diagnostic and therapeutic approach, we aimed to investigate the disturbance in bile acid profiles during cholestasis and its correlation with cholestatic liver injury. Before the occurrence of liver injury, alterations in bile acid profiles were detected in both plasma and liver between 8 and 16 h, persisting up to 96 h. TCA, TCDCA, and TUDCA in the plasma, as well as TCA, TUDCA, TCDCA, TDCA, TLCA, and THDCA in the liver, emerged as early sensitive and potential markers for diagnosing ANIT-induced cholestasis at 8–16 h. The distinguishing features of ANIT-induced liver injury were as follows: T-BAs exceeding G-BAs and serum biochemical indicators surpassing free bile acids. Notably, plasma T-BAs, particularly TCA, exhibited higher sensitivity to cholestatic hepatotoxicity compared with serum enzyme activity and liver histopathology. Further investigation revealed that TCA exacerbated ANIT-induced liver injury by elevating liver function enzyme activity, inflammation, and bile duct proliferation and promoting the migration of bile duct epithelial cell. Nevertheless, no morphological changes or alterations in transaminase activity indicative of liver damage were observed in the rats treated with TCA alone. Additionally, there were no changes in bile acid profiles or inflammatory responses under physiological conditions with maintained bile acid homeostasis. In summary, our findings suggest that taurine-conjugated bile acids in both plasma and liver, particularly TCA, can serve as early and sensitive markers for predicting intrahepatic cholestatic drugs and can act as potent exacerbators of cholestatic liver injury progression. However, exogenous TCA does not induce liver injury under physiological conditions where bile acid homeostasis is maintained.
研究领域:
药理学
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肝脏病学
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毒理学
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产品关联
DOI
PubMed
高影响因子
CURRENT DRUG METABOLISM
·
2023
·Vol. 24
·期 4
·303-311
·
IF 2.3
Tian Qiru,Jin Huan,Huo Xiaokui,Zhao Yupu,Wu Wenhui,Xu Lei,Wang Yinan,Yang Xiaobo,Sun Chengpeng,Deng Sa,Shu Xiaohong
Background: Scoparone, the principal natural active ingredient of Artemisia capillaries (Yin Chen), can effectively treat cholestatic diseases, but the pharmacokinetic properties of scoparone are rarely studied in intrahepatic cholestatic rats. Objective: A sensitive
and rapid LC-MS/MS method was established to detect scoparone and its metabolite of scopoletin in rat plasma and then compare their plasma pharmacokinetic differences between the normal and ANITinduced cholestasis rats. Methods: Positive ionization was used to separate scoparone and scopoletin
using acetonitrile and 0.1 % formic acid water as the mobile phase on a Hypersil ODS-BP column. Results: The calibration curves presented good linearity (R=0.9983 and 0.9989) in the concentration range of 10- 10000 ng/mL and 0.5-500 ng/mL for scoparone and scopoletin, respectively. The
precision of ≤ 9.4% and the accuracy ranged from -6.4% to 6.8% were recorded over three validation runs, and the recovery was higher than 83.9%. Under different storage conditions, scoparone and scopoletin were stable. Therefore, we studied the pharmacokinetic properties of scoparone and
scopoletin in rats after a single oral administration with the above method. According to the results, the pharmacokinetic parameters of AUC, t1/2, and Cmax values of scoparone in the ANIT group were increased by 106%, 75%, and 44%, respectively,
while these values of scopoletin were increased by 142%, 62%, and 65%. Conclusion: The findings indicated that the pharmacokinetic properties of scoparone and scopoletin were significantly different between the normal and ANIT-induced cholestasis rats, which suggested that the clinical
application dosage of scoparone should be adjusted according to the liver function of patients.
研究领域:
药理学
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肝病学
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分析化学
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DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2023
·
IF 4.3
Peng Cao,Jun Gan,Sanlan Wu,Yixin Hu,Bin Xia,Xiaoyue Li,Hongan Zeng,Bingyu Cheng,Huifan Yu,Fei Li,Luqin Si,Jiangeng Huang
Cholestatic liver injury is caused by toxic action or allergic reaction , resulting in abnormality of bile formation and excretion. Few effective therapies have become available for the treatment of cholestasis . Herein, we found that tectorigenin (TG), a natural isoflavone , showed definite protective effects on alpha-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury, significantly reversing the abnormality of plasma alanine/aspartate aminotransferase, total/direct bilirubin and alkaline phosphatase , as well as hepatic reactive oxygen species , catalase and superoxide dismutase . Importantly, the targeted metabolomic determination found that BA homeostasis could be well maintained in TG-treated cholestatic mice, especially the levels of glycocholic acid , tauromuricholic acid, taurocholic acid , taurolithocholic acid , tauroursodeoxycholic acid and taurodeoxycholic acid . Overall, primary/secondary and amidated/unamidated bile acid (BA) levels were significantly altered upon ANIT stimulation but could be restored by TG intervention to certain extents. In addition, TG boosted the expression of farnesoid x receptor (FXR), which in turn upregulated multidrug resistance protein 2 (MRP2) and bile salt export pump (BSEP) to accelerate the excretion of BA. Meanwhile, TG enhanced the expression of Nrf2 and its upstream genes PI3K/Akt and downstream target genes HO-1, NQO1, GCLC and GCLM to strengthen the antioxidant capacity . Taken together, TG plays a vital role in maintaining BA homeostasis and ameliorating cholestatic liver injury through regulating FXR-mediated BA efflux and Nrf2-mediated antioxidative pathways.
研究领域:
药理学
·
肝病学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Guoqiang Guan,Houkang Cao,Zixuan Tang,Kefeng Zhang,Mingli Zhong,Rui Lv,Weimin Wan,Fengyue Guo,Yongwang Wang,Ya Gao
Ethnopharmacological relevance Polygala fallax Hemsl. is a traditional folk medicine commonly used by ethnic minorities in the Guangxi Zhuang Autonomous Region, and has a traditional application in the treatment of liver disease. Polygala fallax Hemsl . polysaccharides (PFPs) are of interest for their potential health benefits. Aim of this study This study explored the impact of PFPs on a mouse model of cholestatic liver injury (CLI) induced by alpha-naphthyl isothiocyanate (ANIT), as well as the potential mechanisms. Materials and methods A mouse CLI model was constructed using ANIT (80 mg/kg) and intervened with different doses of PFPs or ursodeoxycholic acid. Their serum biochemical indices, hepatic oxidative stress indices, and hepatic pathological characteristics were investigated. Then RNA sequencing was performed on liver tissues to identify differentially expressed genes and signaling pathways and to elucidate the mechanism of liver protection by PFPs. Finally, Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to verify the differentially expressed genes. Results Data analyses showed that PFPs reduced the levels of liver function-related biochemical indices, such as ALT, AST, AKP, TBA, DBIL, and TBIL. PFPs up-regulated the activities of SOD and GSH, down-regulated the contents of MDA, inhibited the release of IL-1β, IL-6, and TNF-α, or promoted IL-10. Pathologic characterization of the liver revealed that PFPs reduced hepatocyte apoptosis or necrosis. The RNA sequencing indicated that the genes with differential expression were primarily enriched for the biosynthesis of primary bile acids, secretion or transportation of bile, the reactive oxygen species in chemical carcinogenesis, and the NF-kappa B signaling pathway. In addition, the results of qRT-PCR and Western blotting analysis were consistent with those of RNA sequencing analysis. Conclusions In summary, this study showed that PFPs improved intrahepatic cholestasis and alleviated liver damage through the modulation of primary bile acid production, Control of protein expression related to bile secretion or transportation, decrease in inflammatory reactions, and inhibition of oxidative pressure. As a result, PFPs might offer a hopeful ethnic dietary approach for managing intrahepatic cholestasis.
研究领域:
药理学
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分子生物学
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肝病学
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民族药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Yanru Liu,Hui Chen,Gongjun Yang,Fang Feng
Ethnopharmacological relevance Yin-Chen-Si-Ni Decoction is a classical traditional Chinese medicine (TCM) prescription that is used clinically for treating cholestatic liver injury (CLI) and other hepatic diseases. However, the material basis and underlying mechanisms of YCSND are not clear. Aim of the study : To investigate effective components and mechanisms of YCSND in the treatment of CLI using serum pharmacochemistry, metabolomics, and network pharmacology. Materials and methods Biochemical indicators, liver index, and histopathology analysis were adopted to evaluate the protective effect of YCSND on ANIT-induced CLI rats. Then, a UPLC-Q-Exactive Orbitrap MS/MS analysis of the migrant components in serum and liver including prototype and metabolic components was performed in YCSND. In addition, a study of the endogenous metabolites using serum and liver metabolomics was performed to discover potential biomarkers, metabolic pathways, and associated mechanisms. Further, the network pharmacology oriented by in vivo migrant components was also used to pinpoint the active ingredients, core targets, and signaling pathways of YCSND. Finally, molecular docking and molecular dynamics simulation (MDS) were used to predict the binding ability between components and core targets, and a real-time qPCR (RT-qPCR) experiment was used to measure the mRNA expression of the core target genes. Results Pharmacodynamic studies suggest that YCSND could exert obvious hepatoprotective effects on CLI rats. Furthermore, 68 compounds, comprising 32 prototype components and 36 metabolic components from YCSND, were found by serum pharmacochemistry analysis. Network pharmacology combining molecular docking and MDS showed that apigenin, naringenin, 18β-glycyrrhetinic acid, and isoformononetin have better binding ability to 6 core targets (EGFR, AKT1, IL6, MMP9, CASP3, PPARG). Additionally, PI3K, TNF-α, MAPK3, and six core target genes in liver tissues were validated with RT-qPCR. Metabolomics revealed the anti-CLI effects of YCSND by regulating four metabolic pathways of primary bile acid and biosynthesis, phenylalanine, tyrosine and tryptophan biosynthesis, taurine and hypotaurine metabolism, and arachidonic acid metabolism. Integrating metabolomics and network pharmacology identified four pathways related to CLI, including the PI3K-Akt, HIF-1, MAPK, and TNF signaling pathway, which revealed multiple mechanisms of YCSND against CLI that might involve anti-inflammatory and apoptosis. Conclusion The research based on serum pharmacochemistry, network pharmacology, and metabolomics demonstrates the beneficial hepatoprotective effects of YCSND on CLI rats by regulating multiple components, multiple targets, and multiple pathways, and provides a potent means of illuminating the material basis and mechanisms of TCM prescriptions.
研究领域:
药理学
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中医药学
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分子生物学
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代谢研究
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产品关联
DOI
PubMed
高影响因子
Redox Biology
·
2022
·
IF 10.787
Meng Song,Zijun Chen,Ruian Qiu,Tingwei Zhi,Wenmin Xie,Yingya Zhou,Nachuan Luo,Fuqian Chen,Fang Liu,Chuangpeng Shen,Sheng Lin,Fengxue Zhang,Yong Gao,Changhui Liu
The excessive accumulation of bile acids (BA) in hepatocytes can trigger inflammatory response and recruit macrophages, thereby accelerating cholestatic liver injury. The crosstalk between hepatocytes and macrophages has been recently implicated in the pathogenesis of cholestasis; however, the underlying mechanisms remain unclear. Here, we demonstrated that BA initiate NLRP3 inflammasome activation in hepatocytes to release proinflammatory cytokines and promote the communication between hepatocytes and macrophages, thus enhancing liver inflammation in an NLRP3-dependent manner. NLRP3-inhibition by geniposidic acid (GPA), a novel NLRP3-specific covalent inhibitor that directly interacts with NLRP3, in hepatocytes and macrophages abated BA-induced inflammation. Moreover, NLRP3 -deletion or its inhibition mitigated ANIT-induced cholestatic inflammation, whereas disrupting the crosstalk between hepatic macrophages and hepatocytes attenuated the hepatoprotective effect of GPA against ANIT-induced cholestatic inflammation. Therefore, blocking this crosstalk by suppressing NLRP3 inflammasome activation may represent a novel therapeutic strategy for cholestasis.
研究领域:
肝病学
·
免疫学
·
药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2025
·
IF 5.4
Lin Jing,Yixuan Liao,Honghong Zhan,Qianyu Chen,Xiaodong Wei,Yinda Qiu,Fancheng Meng,Zhihua Liao,Min Chen
Ethnopharmacology relevance Herpetrione, an active lignan isolated from Herpetospermum pedunculosum , a traditional Tibetan medicinal plant renowned for its use in hepatobiliary diseases, has been long applied in the treatment of jaundice, hepatitis, hepatic fibrosis and other conditions, demonstrating remarkable hepatoprotective efficacy. Aim of the study Based on the traditional efficacy of Herpetospermum pedunculosum as well as the hepatoprotective activity of herpetrione, we aim to investigate the therapeutic effects and molecular mechanisms of herpetrione against α-naphthylisothiocyanate (ANIT)-induced cholestasis in mice. Materials and methods Therapeutic effects of herpetrione were evaluated in ANIT-induced cholestatic mice and Fxr knockout mice. Molecular interactions with FXR were validated using CETSA, SIP, ITC, and SPR assays, with binding sites confirmed via molecular docking and amino acid mutation analyses. FXR-regulated signaling was explored in HepG2 cells treated with guggulsterone/lithocholic acid, using Co-IP, yeast one-hybrid, and dual-luciferase assays to clarify mechanisms. Results Herpetrione significantly alleviated ANIT-induced cholestatic liver injury, evidenced by reduced serum biomarkers of bile acid accumulation and liver damage, improved hepatobiliary pathology, and decreased hepatic inflammatory infiltration. Mechanistically, it directly bound the ligand-binding domain (Glu467/Ile317/Leu464) of FXR, then ligand-bound FXR recruit coactivator SRC-1 to trigger transcriptional upregulation of BSEP/MRP2/SHP to enhance bile acid excretion while inhibiting synthesis, thereby restoring hepatic and bile acid homeostasis. Notably, herpetrione-activated FXR directly binds the promoter region of NFKB1 to inactivate NF-κB signaling and suppress inflammation. Importantly, the therapeutic effects of herpetrione were abrogated in Fxr knockout mice. Conclusion This dual regulation of bile acid homeostasis and inflammatory signaling through targeting the FXR highlights the therapeutic potential of herpetrione in cholestatic injury.
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产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2017
·
IF 3.778
Tingting Yang,Huifang Mei,Dengqiu Xu,Wang Zhou,Xiaoyu Zhu,Lixin Sun,Xin Huang,Xue Wang,Ting Shu,Jia Liu,Jiaxin Ding,H.M. Hassan,Luyong Zhang,Zhenzhou Jiang
Hepatocyte polarization is essential for biliary secretion, and loss of polarity causes bile secretory failure and hepatotoxicity. Here, we showed that alpha-naphthyl isothiocyanate (ANIT)-induced liver injury was accompanied by the dynamic interruption of bile acid homeostasis in rat plasma, liver and bile, which was characterized by the redistribution of bile acids in plasma and bile and a small range of fluctuations in the liver. Molecular mechanism studies indicated that these factors are dynamically mediated by the disruption of bile acid transporters and hepatic tight junctions. Dynamic changes in tight junction (TJ) permeability were observed by hepatobiliary barrier function assessment. Hepatocyte polarization was disrupted by ANIT before the development of cholestatic hepatotoxicity and alteration of bile acid metabolic profiles, which were assayed by high-performance liquid chromatography-tandem mass spectrometry, further verifying TJ deficiency. S1PR1 activation with SEW2871 reduced ANIT-induced liver injury by reducing the total serum bile acid concentration, liver functional enzyme activity and inflammation. Our data suggest that hepatocyte polarization plays an important role in maintaining bile acid homeostasis before the development of cholestatic hepatotoxicity and that TJs were more prominent in the early stage of cholestasis . S1PR1 may be a potential target for the prevention of drug-induced cholestatic liver injury.
研究领域:
药理学
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毒理学
·
肝病学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2025
·
IF 5.4
Su Li,Caolin Zhong,Wei Jiang,Baojun Zheng,Ruoxin Xiang,Beixuan Yang,Chaozhan Lin,Chenchen Zhu,Meiqi Wang
Ethnopharmacological relevance Huzhang Erjin Decoction (HED) is a Traditional Chinese Medicine (TCM) Formula that possesses the efficiency of clearing heat, eliminating dampness, purging the liver and gallbladder. It has been clinically used in the treatment of inflammation related to hepatobiliary disease, including cholestasis, cholecystitis and jaundice. However, the mechanism of HED for its therapeutic effects has not been explored. Aim of the study This study aimed to investigate the potential mechanism of HED in ameliorating cholestatic hepatitis based on an integrative approach with metabolomics and network pharmacology. Materials and methods In this study, the pharmacodynamic effect of HED was evaluated based on alpha-naphthylisothiocyanate (ANIT)-induced cholestatic hepatitis mice. Furthermore, network pharmacology analysis was conducted to explore the potential mechanism of HED. Meanwhile, serum metabolomics analysis was performed to investigate the key metabolic pathways and biological processes regulated by HED. Furthermore, related targets and pathways were focused, according to a comprehensive analysis combined with metabolomics and network pharmacology. Molecular docking simulations were performed to evaluate the interactions between components of HED and the targets against cholestatic hepatitis. Finally, the regulatory effects of HED on the expression levels of key proteins in the peroxisome proliferator-activated receptor gamma (PPARγ) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3) pathways were investigated both in vitro and in vivo . Results Our research findings demonstrate that HED significantly enhances liver function and alleviates liver injury in cholestatic hepatitis mice, including bile acid accumulation, hepatic necrosis and inflammatory infiltration. Furthermore, according to the combined enrichment of network pharmacology analysis and metabolomics study, HED primarily modulates cholestatic hepatitis via the regulation of lipid metabolism and bile acid metabolism to intervene in cholestatic hepatitis. Additionally, molecular docking studies revealed a high affinity and activity between the hub gene PPARG (PPARγ) and emodin in HED. Furthermore, the in vivo and in vitro results demonstrated that HED significantly promoted the expression of PPARγ and decreased the expression levels of NLRP3 and its associated proteins. In vitro , suppression of PPARγ attenuated the efficacy of HED. These findings suggested that HED modulated the PPARγ/NLRP3 signaling pathway, thereby improving cholestatic hepatitis and alleviating liver injury. Conclusion This study systematically assessed the efficacy of HED in the intervention of cholestatic hepatitis and explored the targets by integrating metabolomics and network pharmacology approaches, then elucidated its mechanism based on experiments both in vitro and in vivo . It was demonstrated that HED ameliorated cholestatic hepatitis in mice by regulating the PPARγ/NLRP3 pathway.
研究领域:
中药学
·
药理学
·
代谢组学
·
生物信息学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2023
·
IF 5.4
Qianyan Gao,Guodong Li,Yue Zu,Yanjiao Xu,Congyi Wang,Dong Xiang,Wenxi He,Tianze Shang,Xinwei Cheng,Dong Liu,Chengliang Zhang
Ethnopharmacological relevance Ginseng ( Panax ginseng C. A. Mey) is a common traditional Chinese medicine used for anti-inflammation, treating colitis, type 2 diabetes, diarrhea, and recovering hepatobiliary function. Ginsenosides, the main active components isolated from ginseng, possess liver and gallbladder diseases therapeutic potential. Aims of the study Cholestatic liver injury (CLI) is a liver disease induced by intrahepatic accumulation of toxic bile acids and currently lacks clinically effective drugs. Our previous study found that ginsenosides alleviated CLI by activating sirtuin 1 (SIRT1), but the effective ingredients and the underlying mechanism have not been clarified. This study aimed to identify an effective ingredient with the most significant activation effect on SIRT1 from the five major monomer saponins of ginsenosides: Rb1, Rd, Rg1, 20s-Rg3, and Rc further explore its protective effects on CLI, and elaborate its underlying mechanism. Materials and methods Discovery Studio 3.0 was used to conduct molecular docking between monomer saponins and SIRT1, and further detect the influence of monomer saponins on SIRT1 activity in vitro. Finally, it was determined that Rg1 had the most significant stimulative effect on SIRT1, and the hepatoprotective activity of Rg1 in CLI was explored in vivo. Wild-type mice were intragastrically α-naphthylisothiocyanate (ANIT) to establish an experimental model of intrahepatic cholestasis and Rg1 intervention, and then liver injury and cholestasis related indexes were detected. In addition, Liver-specific SIRT1 gene knockout (SIRT1 -/- ) mice were administered with ANIT and/or Rg1 to further investigate the mechanism of action of Rg1. Results The results of molecular docking and in vitro experiments showed that all the five ginsenoside monomers could bind to the active site of SIRT1 and promote SIRT1 activity in HepG2 cells. Among them, Rg1 exhibited the most significant stimulation of SIRT1 activity in cholestasis. Besides, it could ameliorate ANIT-induced inflammation and oxidative stress in HepG2 cells. Therefore, we investigated the hepatoprotective effect and mechanism of Rg1 on CLI. Results showed that Rg1 reversed the ANIT-induced increase in biochemical parameters, improved liver pathological injury, and decreased liver lipid accumulation, reactive oxygen species and pro-inflammatory factor levels. Mechanistically, Rg1 induced SIRT1 expression, followed by promoted the activity of Nrf2 and suppressed the activation of NF-κB. Interestingly, the hepatoprotective effect of Rg1 was blocked in SIRT1 -/- mice. Conclusion Rg1 mitigated ANIT-induced CLI via upregulating SIRT1 expression, and our results suggested that Rg1 is a candidate compound for treating CLI.
研究领域:
药理学
·
肝病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Microbiology Spectrum
·
2022
·
IF 9.043
Wang Wang,Shujun Jiang,Chengcheng Xu,Lili Tang,Yan Liang,Yang Zhao,Guoxue Zhu
Cholestasis is characterized by bile acid (BA) circulation disorders, which is usually related to damage of hepatocyte barrier function. Currently, patients with cholestasis face several obstacles in seeking diagnosis and therapy. Da-Huang-Xiao-Shi decoction (DHXSD) is an ancient classic formula that has been used clinically for cholestasis treatment. Nevertheless, the underlying biological activities and therapeutic mechanisms remain unclear. In this study, an alpha-naphthylisothiocyanate (ANIT)-induced cholestasis rat model was established to examine the anticholestatic effects of DHXSD using histopathological and molecular analyses. Transcriptomic analysis combined with 16S rRNA gene sequencing analysis was systematically applied to study the mechanism of action of DHXSD. Simultaneously, the effect of DHXSD on gut microbiota, short-chain fatty acids (SCFAs), and intestinal barrier function were evaluated based on the ANIT-induced cholestasis model in rats. The results showed that DHXSD effectively attenuated ANIT-induced cholestasis by reducing liver function indicators (alanine transaminase [ALT], P < 0.05; alkaline phosphatase [ALP], P < 0.05; total bile acid [TBA], P < 0.01; γ-glutamyl transpeptidase [GGT], P < 0.001) and levels of hepatotoxicity-related enzymes (P < 0.05), thus improving the recovery of histopathological injuries, and regulating levels of inflammatory cytokines (P < 0.05). In addition, 16S rRNA gene sequencing analysis combined with intestinal barrier function analysis revealed that the DHXSD significantly ameliorated ANIT-induced gut microbiota dysbiosis. Significantly altered genes in the model and treatment groups were screened using transcriptomic analysis. Sixty-eight genes and four microbial genera were simultaneously altered with opposing trends in variation after ANIT and DHXSD treatments. We built a framework for predicting targets and host-microbe interaction mechanisms, as well as identifying alternative treatment for cholestasis, which should be validated further for clinical application. In conclusion, DHXSD appears to be a promising agent for protection against liver injury.IMPORTANCE 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. Food and Drug Administration for the treatment of cholestasis. However, approximately one-third of patients with cholestasis are unresponsive to UDCA. Therefore, it is urgent to search for appropriate therapeutic agents for restoring stoppage status of the bile components to treat cholestasis. In this study, we investigated how the microbiome and transcriptome data sets correlated with each other to clarify the role of microbiome alterations in host metabolism. In combination, this research offers potential molecular biomarkers that should be validated for more accurate diagnosis of cholestasis and the clinical utilisation of gut microbiota as a target for treatment.
研究领域:
药理学
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分子生物学
·
微生物学
·
病理学
·
胃肠病学
✓ 已验证
DOI
PubMed
高影响因子
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