Parthenolide, bioactive compound of Chrysanthemum parthenium L., ameliorates fibrogenesis and inflammation in hepatic fibrosis via regulating the crosstalk of TLR4 and STAT3 signaling pathway.

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Abstract

Title:: Parthenolide, bioactive compound of Chrysanthemum parthenium L., ameliorates fibrogenesis and inflammation in hepatic fibrosis via regulating the crosstalk of TLR4 and STAT3 signaling pathway.
Authors:: Cui ZY; Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China.
Wang G; Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China.
Zhang J; Research and Development Center, Liaoning Shengjing Stem cell technology Co., Ltd, Shenyang, China.
Song J; Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China.
Jiang YC; Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China.
Dou JY; Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China.
Lian LH; Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China.
Nan JX; Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China.; Clinical Research Centre, Affiliated Hospital of Yanbian University, Yanji, China.
Wu YL; Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China.
Source:: Phytotherapy research : PTR [Phytother Res] 2021 Oct; Vol. 35 (10), pp. 5680-5693. Date of Electronic Publication: 2021 Jul 12.
Publication Type:: Journal Article
Language:: English
Imprint Name(s):: Publication: : Chichester : Wiley
Original Publication: London : Heyden & Son, c1987-
MeSH Terms:: STAT3 Transcription Factor*/metabolism
Toll-Like Receptor 4*/metabolism
Inflammation ; Liver Cirrhosis/drug therapy ; Sesquiterpenes ; Signal Transduction ; Tanacetum parthenium
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Grant Information:: 20180201065YY Department of Science and Technology of Jilin Province; 20180414048GH Department of Science and Technology of Jilin Province; 20190304084YY Department of Science and Technology of Jilin Province; 81660689 National Natural Science Foundation of China; 81760668 National Natural Science Foundation of China; 81973555 National Natural Science Foundation of China; 2020023 the Innovation and Entrepreneurship Talent Project of Jilin Province
Contributed Indexing:: Keywords: crosstalk of TLR4 and STAT3; hepatic fibrosis; hepatic stellate cells; inflammation; parthenolide
Substance Nomenclature:: 0 (STAT3 Transcription Factor)
0 (Sesquiterpenes)
0 (Toll-Like Receptor 4)
2RDB26I5ZB (parthenolide)
Entry Date(s):: Date Created: 20210712 Date Completed: 20211026 Latest Revision: 20211026
Update Code:: 20240105
DOI:: 10.1002/ptr.7214
PMID:: 34250656
: Academic Journal

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The current study focused on the regulatory effects of parthenolide (PNL), a bioactive component derived from Chrysanthemum parthenium L., against hepatic fibrosis via regulating the crosstalk of toll-like receptor 4 (TLR4) and signal transducer and activator of transcription 3 (STAT3) in activated hepatic stellate cells (HSCs). HSCs or Raw 264.7 macrophages were activated by TGF-β or LPS for 1 hr, respectively, and then treated with PNL, CLI-095 (TLR4 inhibitor), or Niclosamide (STAT3 inhibitor) for the indicated time to detect the crosstalk of TLR4 and STAT3. PNL significantly decreased the expressions of α-SMA, collagen I, and the ratio of TIMP1 and MMP13 in TGF-β-activated HSCs. PNL significantly reduced the releases of pro-inflammatory cytokines, including IL-6, IL-1β, IL-1α, IL-18, and regulated signaling P2X7r/NLRP3 axis activation. PNL obviously induced the apoptosis of activated HSCs by regulating bcl-2 and caspases family. PNL significantly inhibited the expressions of TLR4 and STAT3, including their downstream signaling. PNL could regulate the crosstalk of TLR4 and STAT3, which were verified by their inhibitors in activated HSCs or Raw 264.7 cell macrophages. Thus, PNL could decrease the expressions of fibrosis markers, reduce the releases of inflammatory cytokines, and also induce the apoptosis of activated HSCs. In conclusion, PNL could bi-directionally inhibit TLR4 and STAT3 signaling pathway, suggesting that blocking the crosstalk of TLR4 and STAT3 might be the potential mechanism of PNL against hepatic fibrosis.
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