Da-Chai-Hu-Tang Protects From Acute Intrahepatic Cholestasis by Inhibiting Hepatic Inflammation and Bile Accumulation via Activation of PPARα
Cholestasis is caused by intrahepatic retention of excessive toxic bile acids and ultimately results in hepatic failure. Da-Chai-Hu-Tang (DCHT) has been used in China to treat liver and gallbladder diseases for over 1800 years. Here, we demonstrated that DCHT treatment prevented acute intrahepatic c...
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Frontiers Media S.A.
2022-03-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.847483/full |
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| author | Shihao Xu Xi Qiao Peike Peng Ziyi Zhu Yaoting Li Yaoting Li Mengyuan Yu Mengyuan Yu Long Chen Yin Cai Jin Xu Xinwei Shi Christopher G. Proud Christopher G. Proud Jianling Xie Jianling Xie Kaikai Shen |
| author_facet | Shihao Xu Xi Qiao Peike Peng Ziyi Zhu Yaoting Li Yaoting Li Mengyuan Yu Mengyuan Yu Long Chen Yin Cai Jin Xu Xinwei Shi Christopher G. Proud Christopher G. Proud Jianling Xie Jianling Xie Kaikai Shen |
| author_sort | Shihao Xu |
| collection | DOAJ |
| description | Cholestasis is caused by intrahepatic retention of excessive toxic bile acids and ultimately results in hepatic failure. Da-Chai-Hu-Tang (DCHT) has been used in China to treat liver and gallbladder diseases for over 1800 years. Here, we demonstrated that DCHT treatment prevented acute intrahepatic cholestasis with liver injury in response to α-naphthylisothiocyanate (ANIT) not to bile duct ligation (BDL) induced-extrahepatic cholestasis. ANIT (80 mg/kg) increased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), direct bilirubin (DBiL), total bilirubin (TBiL), and total bile acids (TBA) which was attenuated by DCHT treatment in a dose-dependent manner. DCHT treatment at high dose of 1.875 g/kg restored bile acid homeostasis, as evidenced by the recovery of the transcription of genes implicated in bile acid biosynthesis, uptake and efflux. DCHT treatment (1.875 g/kg) reversed ANIT-evoked disordered glutathione homeostasis (as determined by GSH/GSSG ratio) and increased in the mRNA levels for Il6, Il1b and Tnfa associated with liver inflammation. Using network pharmacology-based approaches, we identified 22 putative targets involved in DCHT treatment for intrahepatic cholestasis not extrahepatic cholestasis. In addition, as evidenced by dual-luciferase reporter assays, compounds from DCHT with high affinity of PPARα increased luciferase levels from a PPARα-driven reporter. PPARα agonist fenofibrate was able to mimic the cytoprotective effect of DCHT on intrahepatic cholestasis, which was abolished by the PPARα antagonist GW6471. KEGG enrichment and western blot analyses showed that signaling axes of JNK/IL-6/NF-κB/STAT3 related to PPARα might be the principal pathway DCHT affects intrahepatic cholestasis. Taken together, the present study provides compelling evidence that DCHT is a promising formula against acute intrahepatic cholestasis with hepatotoxicity which works via PPARα activation. |
| first_indexed | 2024-12-22T16:29:55Z |
| format | Article |
| id | doaj.art-cffda5410aaa405e8dde9a5aaf49133d |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-22T16:29:55Z |
| publishDate | 2022-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-cffda5410aaa405e8dde9a5aaf49133d2022-12-21T18:20:05ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-03-011310.3389/fphar.2022.847483847483Da-Chai-Hu-Tang Protects From Acute Intrahepatic Cholestasis by Inhibiting Hepatic Inflammation and Bile Accumulation via Activation of PPARαShihao Xu0Xi Qiao1Peike Peng2Ziyi Zhu3Yaoting Li4Yaoting Li5Mengyuan Yu6Mengyuan Yu7Long Chen8Yin Cai9Jin Xu10Xinwei Shi11Christopher G. Proud12Christopher G. Proud13Jianling Xie14Jianling Xie15Kaikai Shen16School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaSchool of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaSchool of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaSchool of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaSchool of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaSchool of Pharmacy, Fudan University, Shanghai, ChinaSchool of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaSchool of Biosciences, University of Birmingham, Birmingham, United KingdomExperimental Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaDepartment of Health Technology and Informatics, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, ChinaSchool of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaSchool of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaLifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA, AustraliaMolecular and Biomedical Sciences, School of Biological Sciences, University of Adelaide, Adelaide, SA, AustraliaLifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA, AustraliaFlinders Health and Medical Research Institute, Flinders University, Adelaide, SA, AustraliaSchool of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaCholestasis is caused by intrahepatic retention of excessive toxic bile acids and ultimately results in hepatic failure. Da-Chai-Hu-Tang (DCHT) has been used in China to treat liver and gallbladder diseases for over 1800 years. Here, we demonstrated that DCHT treatment prevented acute intrahepatic cholestasis with liver injury in response to α-naphthylisothiocyanate (ANIT) not to bile duct ligation (BDL) induced-extrahepatic cholestasis. ANIT (80 mg/kg) increased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), direct bilirubin (DBiL), total bilirubin (TBiL), and total bile acids (TBA) which was attenuated by DCHT treatment in a dose-dependent manner. DCHT treatment at high dose of 1.875 g/kg restored bile acid homeostasis, as evidenced by the recovery of the transcription of genes implicated in bile acid biosynthesis, uptake and efflux. DCHT treatment (1.875 g/kg) reversed ANIT-evoked disordered glutathione homeostasis (as determined by GSH/GSSG ratio) and increased in the mRNA levels for Il6, Il1b and Tnfa associated with liver inflammation. Using network pharmacology-based approaches, we identified 22 putative targets involved in DCHT treatment for intrahepatic cholestasis not extrahepatic cholestasis. In addition, as evidenced by dual-luciferase reporter assays, compounds from DCHT with high affinity of PPARα increased luciferase levels from a PPARα-driven reporter. PPARα agonist fenofibrate was able to mimic the cytoprotective effect of DCHT on intrahepatic cholestasis, which was abolished by the PPARα antagonist GW6471. KEGG enrichment and western blot analyses showed that signaling axes of JNK/IL-6/NF-κB/STAT3 related to PPARα might be the principal pathway DCHT affects intrahepatic cholestasis. Taken together, the present study provides compelling evidence that DCHT is a promising formula against acute intrahepatic cholestasis with hepatotoxicity which works via PPARα activation.https://www.frontiersin.org/articles/10.3389/fphar.2022.847483/fullDa-Chai-Hu-Tangintrahepatic cholestasisliver injurybile acid homeostasisperoxisome proliferator-activated receptor alpha |
| spellingShingle | Shihao Xu Xi Qiao Peike Peng Ziyi Zhu Yaoting Li Yaoting Li Mengyuan Yu Mengyuan Yu Long Chen Yin Cai Jin Xu Xinwei Shi Christopher G. Proud Christopher G. Proud Jianling Xie Jianling Xie Kaikai Shen Da-Chai-Hu-Tang Protects From Acute Intrahepatic Cholestasis by Inhibiting Hepatic Inflammation and Bile Accumulation via Activation of PPARα Frontiers in Pharmacology Da-Chai-Hu-Tang intrahepatic cholestasis liver injury bile acid homeostasis peroxisome proliferator-activated receptor alpha |
| title | Da-Chai-Hu-Tang Protects From Acute Intrahepatic Cholestasis by Inhibiting Hepatic Inflammation and Bile Accumulation via Activation of PPARα |
| title_full | Da-Chai-Hu-Tang Protects From Acute Intrahepatic Cholestasis by Inhibiting Hepatic Inflammation and Bile Accumulation via Activation of PPARα |
| title_fullStr | Da-Chai-Hu-Tang Protects From Acute Intrahepatic Cholestasis by Inhibiting Hepatic Inflammation and Bile Accumulation via Activation of PPARα |
| title_full_unstemmed | Da-Chai-Hu-Tang Protects From Acute Intrahepatic Cholestasis by Inhibiting Hepatic Inflammation and Bile Accumulation via Activation of PPARα |
| title_short | Da-Chai-Hu-Tang Protects From Acute Intrahepatic Cholestasis by Inhibiting Hepatic Inflammation and Bile Accumulation via Activation of PPARα |
| title_sort | da chai hu tang protects from acute intrahepatic cholestasis by inhibiting hepatic inflammation and bile accumulation via activation of pparα |
| topic | Da-Chai-Hu-Tang intrahepatic cholestasis liver injury bile acid homeostasis peroxisome proliferator-activated receptor alpha |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.847483/full |
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