Bie Jia Jian pill ameliorates BDL-induced cholestatic hepatic fibrosis in rats by regulating intestinal microbial composition and TMAO-mediated PI3K/AKT signaling pathway
As a compound of traditional Chinese medicine (TCM), Bie Jia Jian pill (BJJP) is extensively used to treat the clinical chronic liver disease. Nevertheless, the specific mechanism through which BJJP affects hepatic fibrosis (HF) remains unknown. To explore the role and potential mechanism of BJJP in...
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| creator | Cui, Xiaoyan Zhang, Ronghua Li, Yufeng Li, Ping Liu, Yankun Yu, Xiaohan Zhou, Jing Wang, Luyao Tian, Xuetao Li, Hongjie Zhang, Shukun Lan, Tao Li, Xin Zhang, Guangling Li, Jingwu Liu, Zhiyong |
| description | As a compound of traditional Chinese medicine (TCM), Bie Jia Jian pill (BJJP) is extensively used to treat the clinical chronic liver disease. Nevertheless, the specific mechanism through which BJJP affects hepatic fibrosis (HF) remains unknown.
To explore the role and potential mechanism of BJJP involved in treating HF.
HF model of Sprague-Dawley (SD) rats was induced by a bile duct ligation (BDL). The function of BJJP involved in the intestinal microbiota (IM) and its metabolites in BDL-induced HF rats were explored through the 16S rRNA sequencing and untargeted metabolomics technologies. Network pharmacology was used to forecast mechanism underlying BJJP's anti-HF effects, which were validated in BDL-induced rats and trimethylamine N-oxide (TMAO)-induced LX-2 and HSC-T6 cells.
BJJP effectively ameliorated pathological liver damage, inflammation, and fibrosis of the BDL-induced HF rats. BJJP regulated IM diversity and composition and interfered with trimethylamine (TMA)-flavin monooxygenase 3 (FMO3)-TMAO process. In vitro, BJJP significantly inhibited the TMAO-induced activation of hepatic stellate cells (HSCs) (rat HSC cell line, HSC-T6; human HSC cell line, LX-2). Network pharmacology results demonstrated that PI3K/AKT signal pathway is crucially involved in BJJP treatment of HF. Further research revealed that BJJP inhibited the PI3K/AKT signal pathway in BDL-induced HF rats. Moreover, TMAO activated the PI3K/AKT pathway, whereas BJJP suppressed TMAO-induced activation. Subsequent intervention with 740Y-P (the PI3K agonist) successfully neutralized the repression effect on PI3K/AKT signal pathway by BJJP.
These results clearly show that BJJP attenuates HF by regulating the IM, as well as inhibiting PI3K/AKT pathway mediated by TMAO.
[Display omitted]
•Effects of BJJP on hepatic fibrosis were evaluated in BDL-induced rats and TMAO-induced HSCs.•BJJP significantly reduced BDL-induced rats liver damage and inhibited the activation of HSCs.•BJJP improved the imbalance of the intestinal microbiota composition and affected TMA-FMO3-TMAO process.•BJJP attenuated BDL-induced hepatic fibrosis by inhibiting TMAO-mediated PI3K/AKT signaling pathway. |
| doi_str_mv | 10.1016/j.jep.2024.118910 |
| format | Article |
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To explore the role and potential mechanism of BJJP involved in treating HF.
HF model of Sprague-Dawley (SD) rats was induced by a bile duct ligation (BDL). The function of BJJP involved in the intestinal microbiota (IM) and its metabolites in BDL-induced HF rats were explored through the 16S rRNA sequencing and untargeted metabolomics technologies. Network pharmacology was used to forecast mechanism underlying BJJP's anti-HF effects, which were validated in BDL-induced rats and trimethylamine N-oxide (TMAO)-induced LX-2 and HSC-T6 cells.
BJJP effectively ameliorated pathological liver damage, inflammation, and fibrosis of the BDL-induced HF rats. BJJP regulated IM diversity and composition and interfered with trimethylamine (TMA)-flavin monooxygenase 3 (FMO3)-TMAO process. In vitro, BJJP significantly inhibited the TMAO-induced activation of hepatic stellate cells (HSCs) (rat HSC cell line, HSC-T6; human HSC cell line, LX-2). Network pharmacology results demonstrated that PI3K/AKT signal pathway is crucially involved in BJJP treatment of HF. Further research revealed that BJJP inhibited the PI3K/AKT signal pathway in BDL-induced HF rats. Moreover, TMAO activated the PI3K/AKT pathway, whereas BJJP suppressed TMAO-induced activation. Subsequent intervention with 740Y-P (the PI3K agonist) successfully neutralized the repression effect on PI3K/AKT signal pathway by BJJP.
These results clearly show that BJJP attenuates HF by regulating the IM, as well as inhibiting PI3K/AKT pathway mediated by TMAO.
[Display omitted]
•Effects of BJJP on hepatic fibrosis were evaluated in BDL-induced rats and TMAO-induced HSCs.•BJJP significantly reduced BDL-induced rats liver damage and inhibited the activation of HSCs.•BJJP improved the imbalance of the intestinal microbiota composition and affected TMA-FMO3-TMAO process.•BJJP attenuated BDL-induced hepatic fibrosis by inhibiting TMAO-mediated PI3K/AKT signaling pathway.</description><identifier>ISSN: 0378-8741</identifier><identifier>ISSN: 1872-7573</identifier><identifier>EISSN: 1872-7573</identifier><identifier>DOI: 10.1016/j.jep.2024.118910</identifier><identifier>PMID: 39369915</identifier><language>eng</language><publisher>Ireland: Elsevier B.V</publisher><subject>Animals ; Bie Jia Jian pill ; Cell Line ; Cholestasis - complications ; Cholestasis - drug therapy ; Cholestasis - metabolism ; Disease Models, Animal ; Drugs, Chinese Herbal - pharmacology ; Drugs, Chinese Herbal - therapeutic use ; Gastrointestinal Microbiome - drug effects ; Hepatic fibrosis ; Humans ; Intestinal microbiota ; Liver Cirrhosis - drug therapy ; Liver Cirrhosis - metabolism ; Male ; Methylamines - pharmacology ; Phosphatidylinositol 3-Kinases - metabolism ; PI3K/AKT pathway ; Proto-Oncogene Proteins c-akt - metabolism ; Rats ; Rats, Sprague-Dawley ; Signal Transduction - drug effects ; Trimethylamine N-Oxide</subject><ispartof>Journal of ethnopharmacology, 2025-01, Vol.337 (Pt 2), p.118910, Article 118910</ispartof><rights>2024 Elsevier B.V.</rights><rights>Copyright © 2024 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c235t-cd0de740b06146369e8e1dd07bb16c5a0e33d176c95afdc1c18553243e971d4a3</cites><orcidid>0000-0002-4975-2372 ; 0009-0007-8903-0888 ; 0000-0002-7851-5624 ; 0000-0002-8913-5723 ; 0000-0002-9542-4986</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.jep.2024.118910$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39369915$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cui, Xiaoyan</creatorcontrib><creatorcontrib>Zhang, Ronghua</creatorcontrib><creatorcontrib>Li, Yufeng</creatorcontrib><creatorcontrib>Li, Ping</creatorcontrib><creatorcontrib>Liu, Yankun</creatorcontrib><creatorcontrib>Yu, Xiaohan</creatorcontrib><creatorcontrib>Zhou, Jing</creatorcontrib><creatorcontrib>Wang, Luyao</creatorcontrib><creatorcontrib>Tian, Xuetao</creatorcontrib><creatorcontrib>Li, Hongjie</creatorcontrib><creatorcontrib>Zhang, Shukun</creatorcontrib><creatorcontrib>Lan, Tao</creatorcontrib><creatorcontrib>Li, Xin</creatorcontrib><creatorcontrib>Zhang, Guangling</creatorcontrib><creatorcontrib>Li, Jingwu</creatorcontrib><creatorcontrib>Liu, Zhiyong</creatorcontrib><title>Bie Jia Jian pill ameliorates BDL-induced cholestatic hepatic fibrosis in rats by regulating intestinal microbial composition and TMAO-mediated PI3K/AKT signaling pathway</title><title>Journal of ethnopharmacology</title><addtitle>J Ethnopharmacol</addtitle><description>As a compound of traditional Chinese medicine (TCM), Bie Jia Jian pill (BJJP) is extensively used to treat the clinical chronic liver disease. Nevertheless, the specific mechanism through which BJJP affects hepatic fibrosis (HF) remains unknown.
To explore the role and potential mechanism of BJJP involved in treating HF.
HF model of Sprague-Dawley (SD) rats was induced by a bile duct ligation (BDL). The function of BJJP involved in the intestinal microbiota (IM) and its metabolites in BDL-induced HF rats were explored through the 16S rRNA sequencing and untargeted metabolomics technologies. Network pharmacology was used to forecast mechanism underlying BJJP's anti-HF effects, which were validated in BDL-induced rats and trimethylamine N-oxide (TMAO)-induced LX-2 and HSC-T6 cells.
BJJP effectively ameliorated pathological liver damage, inflammation, and fibrosis of the BDL-induced HF rats. BJJP regulated IM diversity and composition and interfered with trimethylamine (TMA)-flavin monooxygenase 3 (FMO3)-TMAO process. In vitro, BJJP significantly inhibited the TMAO-induced activation of hepatic stellate cells (HSCs) (rat HSC cell line, HSC-T6; human HSC cell line, LX-2). Network pharmacology results demonstrated that PI3K/AKT signal pathway is crucially involved in BJJP treatment of HF. Further research revealed that BJJP inhibited the PI3K/AKT signal pathway in BDL-induced HF rats. Moreover, TMAO activated the PI3K/AKT pathway, whereas BJJP suppressed TMAO-induced activation. Subsequent intervention with 740Y-P (the PI3K agonist) successfully neutralized the repression effect on PI3K/AKT signal pathway by BJJP.
These results clearly show that BJJP attenuates HF by regulating the IM, as well as inhibiting PI3K/AKT pathway mediated by TMAO.
[Display omitted]
•Effects of BJJP on hepatic fibrosis were evaluated in BDL-induced rats and TMAO-induced HSCs.•BJJP significantly reduced BDL-induced rats liver damage and inhibited the activation of HSCs.•BJJP improved the imbalance of the intestinal microbiota composition and affected TMA-FMO3-TMAO process.•BJJP attenuated BDL-induced hepatic fibrosis by inhibiting TMAO-mediated PI3K/AKT signaling pathway.</description><subject>Animals</subject><subject>Bie Jia Jian pill</subject><subject>Cell Line</subject><subject>Cholestasis - complications</subject><subject>Cholestasis - drug therapy</subject><subject>Cholestasis - metabolism</subject><subject>Disease Models, Animal</subject><subject>Drugs, Chinese Herbal - pharmacology</subject><subject>Drugs, Chinese Herbal - therapeutic use</subject><subject>Gastrointestinal Microbiome - drug effects</subject><subject>Hepatic fibrosis</subject><subject>Humans</subject><subject>Intestinal microbiota</subject><subject>Liver Cirrhosis - drug therapy</subject><subject>Liver Cirrhosis - metabolism</subject><subject>Male</subject><subject>Methylamines - pharmacology</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>PI3K/AKT pathway</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Signal Transduction - drug effects</subject><subject>Trimethylamine N-Oxide</subject><issn>0378-8741</issn><issn>1872-7573</issn><issn>1872-7573</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2025</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UU2P0zAQtRCILQs_gAvykUu6njiJE3Hq7vKxbNFyKGfLsaftVPkiTkD9S_xKpnThyGE0I897b_z0hHgNagkKiqvD8oDDMlVptgQoK1BPxAJKkyYmN_qpWChtyqQ0GVyIFzEelFIGMvVcXOhKF1UF-UL8uiaUn8mdqpMDNY10LTbUj27CKK9v1wl1YfYYpN_3DcbJTeTlHoc_fUv12EeKkjrJjCjroxxxNze87Xb8yiI8uUa25Me-Jp583w7MmajvpOuC3HxZPSQtBuKLQX690_dXq_uNjLRj3kmFT-1_uuNL8WzrmoivHvul-Pbh_ebmU7J--Hh3s1onPtX5lPigAppM1aqArGCfWCKEoExdQ-Fzp1DrAKbwVe62wYOHMs91mmmsDITM6Uvx9qw7jP33mf9vW4oem8Z12M_RagBtskJVOUPhDGVvMY64tcNIrRuPFpQ9RWQPliOyp4jsOSLmvHmUn2t2_Y_xNxMGvDsDkE3-IBxt9IQdR0Aj-smGnv4j_xs5JaOW</recordid><startdate>20250130</startdate><enddate>20250130</enddate><creator>Cui, Xiaoyan</creator><creator>Zhang, Ronghua</creator><creator>Li, Yufeng</creator><creator>Li, Ping</creator><creator>Liu, Yankun</creator><creator>Yu, Xiaohan</creator><creator>Zhou, Jing</creator><creator>Wang, Luyao</creator><creator>Tian, Xuetao</creator><creator>Li, Hongjie</creator><creator>Zhang, Shukun</creator><creator>Lan, Tao</creator><creator>Li, Xin</creator><creator>Zhang, Guangling</creator><creator>Li, Jingwu</creator><creator>Liu, Zhiyong</creator><general>Elsevier B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-4975-2372</orcidid><orcidid>https://orcid.org/0009-0007-8903-0888</orcidid><orcidid>https://orcid.org/0000-0002-7851-5624</orcidid><orcidid>https://orcid.org/0000-0002-8913-5723</orcidid><orcidid>https://orcid.org/0000-0002-9542-4986</orcidid></search><sort><creationdate>20250130</creationdate><title>Bie Jia Jian pill ameliorates BDL-induced cholestatic hepatic fibrosis in rats by regulating intestinal microbial composition and TMAO-mediated PI3K/AKT signaling pathway</title><author>Cui, Xiaoyan ; Zhang, Ronghua ; Li, Yufeng ; Li, Ping ; Liu, Yankun ; Yu, Xiaohan ; Zhou, Jing ; Wang, Luyao ; Tian, Xuetao ; Li, Hongjie ; Zhang, Shukun ; Lan, Tao ; Li, Xin ; Zhang, Guangling ; Li, Jingwu ; Liu, Zhiyong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c235t-cd0de740b06146369e8e1dd07bb16c5a0e33d176c95afdc1c18553243e971d4a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2025</creationdate><topic>Animals</topic><topic>Bie Jia Jian pill</topic><topic>Cell Line</topic><topic>Cholestasis - complications</topic><topic>Cholestasis - drug therapy</topic><topic>Cholestasis - metabolism</topic><topic>Disease Models, Animal</topic><topic>Drugs, Chinese Herbal - pharmacology</topic><topic>Drugs, Chinese Herbal - therapeutic use</topic><topic>Gastrointestinal Microbiome - drug effects</topic><topic>Hepatic fibrosis</topic><topic>Humans</topic><topic>Intestinal microbiota</topic><topic>Liver Cirrhosis - drug therapy</topic><topic>Liver Cirrhosis - metabolism</topic><topic>Male</topic><topic>Methylamines - pharmacology</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>PI3K/AKT pathway</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Signal Transduction - drug effects</topic><topic>Trimethylamine N-Oxide</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cui, Xiaoyan</creatorcontrib><creatorcontrib>Zhang, Ronghua</creatorcontrib><creatorcontrib>Li, Yufeng</creatorcontrib><creatorcontrib>Li, Ping</creatorcontrib><creatorcontrib>Liu, Yankun</creatorcontrib><creatorcontrib>Yu, Xiaohan</creatorcontrib><creatorcontrib>Zhou, Jing</creatorcontrib><creatorcontrib>Wang, Luyao</creatorcontrib><creatorcontrib>Tian, Xuetao</creatorcontrib><creatorcontrib>Li, Hongjie</creatorcontrib><creatorcontrib>Zhang, Shukun</creatorcontrib><creatorcontrib>Lan, Tao</creatorcontrib><creatorcontrib>Li, Xin</creatorcontrib><creatorcontrib>Zhang, Guangling</creatorcontrib><creatorcontrib>Li, Jingwu</creatorcontrib><creatorcontrib>Liu, Zhiyong</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of ethnopharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cui, Xiaoyan</au><au>Zhang, Ronghua</au><au>Li, Yufeng</au><au>Li, Ping</au><au>Liu, Yankun</au><au>Yu, Xiaohan</au><au>Zhou, Jing</au><au>Wang, Luyao</au><au>Tian, Xuetao</au><au>Li, Hongjie</au><au>Zhang, Shukun</au><au>Lan, Tao</au><au>Li, Xin</au><au>Zhang, Guangling</au><au>Li, Jingwu</au><au>Liu, Zhiyong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Bie Jia Jian pill ameliorates BDL-induced cholestatic hepatic fibrosis in rats by regulating intestinal microbial composition and TMAO-mediated PI3K/AKT signaling pathway</atitle><jtitle>Journal of ethnopharmacology</jtitle><addtitle>J Ethnopharmacol</addtitle><date>2025-01-30</date><risdate>2025</risdate><volume>337</volume><issue>Pt 2</issue><spage>118910</spage><pages>118910-</pages><artnum>118910</artnum><issn>0378-8741</issn><issn>1872-7573</issn><eissn>1872-7573</eissn><abstract>As a compound of traditional Chinese medicine (TCM), Bie Jia Jian pill (BJJP) is extensively used to treat the clinical chronic liver disease. Nevertheless, the specific mechanism through which BJJP affects hepatic fibrosis (HF) remains unknown.
To explore the role and potential mechanism of BJJP involved in treating HF.
HF model of Sprague-Dawley (SD) rats was induced by a bile duct ligation (BDL). The function of BJJP involved in the intestinal microbiota (IM) and its metabolites in BDL-induced HF rats were explored through the 16S rRNA sequencing and untargeted metabolomics technologies. Network pharmacology was used to forecast mechanism underlying BJJP's anti-HF effects, which were validated in BDL-induced rats and trimethylamine N-oxide (TMAO)-induced LX-2 and HSC-T6 cells.
BJJP effectively ameliorated pathological liver damage, inflammation, and fibrosis of the BDL-induced HF rats. BJJP regulated IM diversity and composition and interfered with trimethylamine (TMA)-flavin monooxygenase 3 (FMO3)-TMAO process. In vitro, BJJP significantly inhibited the TMAO-induced activation of hepatic stellate cells (HSCs) (rat HSC cell line, HSC-T6; human HSC cell line, LX-2). Network pharmacology results demonstrated that PI3K/AKT signal pathway is crucially involved in BJJP treatment of HF. Further research revealed that BJJP inhibited the PI3K/AKT signal pathway in BDL-induced HF rats. Moreover, TMAO activated the PI3K/AKT pathway, whereas BJJP suppressed TMAO-induced activation. Subsequent intervention with 740Y-P (the PI3K agonist) successfully neutralized the repression effect on PI3K/AKT signal pathway by BJJP.
These results clearly show that BJJP attenuates HF by regulating the IM, as well as inhibiting PI3K/AKT pathway mediated by TMAO.
[Display omitted]
•Effects of BJJP on hepatic fibrosis were evaluated in BDL-induced rats and TMAO-induced HSCs.•BJJP significantly reduced BDL-induced rats liver damage and inhibited the activation of HSCs.•BJJP improved the imbalance of the intestinal microbiota composition and affected TMA-FMO3-TMAO process.•BJJP attenuated BDL-induced hepatic fibrosis by inhibiting TMAO-mediated PI3K/AKT signaling pathway.</abstract><cop>Ireland</cop><pub>Elsevier B.V</pub><pmid>39369915</pmid><doi>10.1016/j.jep.2024.118910</doi><orcidid>https://orcid.org/0000-0002-4975-2372</orcidid><orcidid>https://orcid.org/0009-0007-8903-0888</orcidid><orcidid>https://orcid.org/0000-0002-7851-5624</orcidid><orcidid>https://orcid.org/0000-0002-8913-5723</orcidid><orcidid>https://orcid.org/0000-0002-9542-4986</orcidid></addata></record> |
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| subjects | Animals Bie Jia Jian pill Cell Line Cholestasis - complications Cholestasis - drug therapy Cholestasis - metabolism Disease Models, Animal Drugs, Chinese Herbal - pharmacology Drugs, Chinese Herbal - therapeutic use Gastrointestinal Microbiome - drug effects Hepatic fibrosis Humans Intestinal microbiota Liver Cirrhosis - drug therapy Liver Cirrhosis - metabolism Male Methylamines - pharmacology Phosphatidylinositol 3-Kinases - metabolism PI3K/AKT pathway Proto-Oncogene Proteins c-akt - metabolism Rats Rats, Sprague-Dawley Signal Transduction - drug effects Trimethylamine N-Oxide |
| title | Bie Jia Jian pill ameliorates BDL-induced cholestatic hepatic fibrosis in rats by regulating intestinal microbial composition and TMAO-mediated PI3K/AKT signaling pathway |
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