JQ-1 ameliorates schistosomiasis liver fibrosis by suppressing JAK2 and STAT3 activation

Schistosomiasis is a serious parasitic infection caused by Schistosoma. The parasite deposits eggs in the host liver, causing inflammation that activates hepatic stellate cells (HSCs), which leads to liver fibrosis. Currently, there is no effective therapy for liver fibrosis; thus, treatments are ur...

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Autores principales:	Han Ding, Xuhan Yang, Jiaming Tian, Xinran Wang, Yongsheng Ji, Saeed El-Ashram, Cuiping Ren, Jijia Shen, Miao Liu
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Schistosoma japonicum Fibrosis JQ-1 JAK2/STAT3 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/a0e897dc1eb44c03aaff0e59bc579fb1
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spelling	oai:doaj.org-article:a0e897dc1eb44c03aaff0e59bc579fb12021-11-14T04:29:12ZJQ-1 ameliorates schistosomiasis liver fibrosis by suppressing JAK2 and STAT3 activation0753-332210.1016/j.biopha.2021.112281https://doaj.org/article/a0e897dc1eb44c03aaff0e59bc579fb12021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0753332221010659https://doaj.org/toc/0753-3322Schistosomiasis is a serious parasitic infection caused by Schistosoma. The parasite deposits eggs in the host liver, causing inflammation that activates hepatic stellate cells (HSCs), which leads to liver fibrosis. Currently, there is no effective therapy for liver fibrosis; thus, treatments are urgently needed. Therefore, in the present study, mice infected with Schistosoma japonicum were treated with JQ-1, a small-molecule bromodomain inhibitor with reliable anti-tumor and anti-inflammatory activities. The fibrotic area of the liver measured by computer-assisted morphometric analysis and the expression levels of the cytoskeletal protein alpha smooth muscle actin (α-SMA) and of collagen assessed by quantitative PCR, Western blot and immunohistochemistry were significantly decreased in the liver following JQ-1 treatment compared with vehicle-treated controls. Total RNA was extracted from the liver of JQ-1–treated Schistosoma-infected mice for RNA-sequencing analysis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that JQ-1 affected biological processes and the expression of cellular components known to play key roles in the transdifferentiation of HSCs to myofibroblasts. In vitro treatment with JQ-1 of JS-1 cells, a mouse HSC line, indicated that JQ-1 significantly inhibited JS-1 proliferation but had no effect on JS-1 activity, senescence, or apoptosis. Western blot results showed that JQ-1 inhibited the expression levels of phosphorylated JAK2 and phosphorylated STAT3 without altering expression levels of these non-phosphorylated proteins. Taken together, these findings suggested that JQ-1 treatment ameliorated S. japonicum egg–induced liver fibrosis, at least in part, by suppressing HSC activation and proliferation through the inhibition of JAK2/STAT3 signaling. These results lay a foundation for the development of novel approaches to treat and control liver fibrosis caused by S. japonicum.Han DingXuhan YangJiaming TianXinran WangYongsheng JiSaeed El-AshramCuiping RenJijia ShenMiao LiuElsevierarticleSchistosoma japonicumFibrosisJQ-1JAK2/STAT3Therapeutics. PharmacologyRM1-950ENBiomedicine & Pharmacotherapy, Vol 144, Iss , Pp 112281- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Schistosoma japonicum Fibrosis JQ-1 JAK2/STAT3 Therapeutics. Pharmacology RM1-950
spellingShingle	Schistosoma japonicum Fibrosis JQ-1 JAK2/STAT3 Therapeutics. Pharmacology RM1-950 Han Ding Xuhan Yang Jiaming Tian Xinran Wang Yongsheng Ji Saeed El-Ashram Cuiping Ren Jijia Shen Miao Liu JQ-1 ameliorates schistosomiasis liver fibrosis by suppressing JAK2 and STAT3 activation
description	Schistosomiasis is a serious parasitic infection caused by Schistosoma. The parasite deposits eggs in the host liver, causing inflammation that activates hepatic stellate cells (HSCs), which leads to liver fibrosis. Currently, there is no effective therapy for liver fibrosis; thus, treatments are urgently needed. Therefore, in the present study, mice infected with Schistosoma japonicum were treated with JQ-1, a small-molecule bromodomain inhibitor with reliable anti-tumor and anti-inflammatory activities. The fibrotic area of the liver measured by computer-assisted morphometric analysis and the expression levels of the cytoskeletal protein alpha smooth muscle actin (α-SMA) and of collagen assessed by quantitative PCR, Western blot and immunohistochemistry were significantly decreased in the liver following JQ-1 treatment compared with vehicle-treated controls. Total RNA was extracted from the liver of JQ-1–treated Schistosoma-infected mice for RNA-sequencing analysis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that JQ-1 affected biological processes and the expression of cellular components known to play key roles in the transdifferentiation of HSCs to myofibroblasts. In vitro treatment with JQ-1 of JS-1 cells, a mouse HSC line, indicated that JQ-1 significantly inhibited JS-1 proliferation but had no effect on JS-1 activity, senescence, or apoptosis. Western blot results showed that JQ-1 inhibited the expression levels of phosphorylated JAK2 and phosphorylated STAT3 without altering expression levels of these non-phosphorylated proteins. Taken together, these findings suggested that JQ-1 treatment ameliorated S. japonicum egg–induced liver fibrosis, at least in part, by suppressing HSC activation and proliferation through the inhibition of JAK2/STAT3 signaling. These results lay a foundation for the development of novel approaches to treat and control liver fibrosis caused by S. japonicum.
format	article
author	Han Ding Xuhan Yang Jiaming Tian Xinran Wang Yongsheng Ji Saeed El-Ashram Cuiping Ren Jijia Shen Miao Liu
author_facet	Han Ding Xuhan Yang Jiaming Tian Xinran Wang Yongsheng Ji Saeed El-Ashram Cuiping Ren Jijia Shen Miao Liu
author_sort	Han Ding
title	JQ-1 ameliorates schistosomiasis liver fibrosis by suppressing JAK2 and STAT3 activation
title_short	JQ-1 ameliorates schistosomiasis liver fibrosis by suppressing JAK2 and STAT3 activation
title_full	JQ-1 ameliorates schistosomiasis liver fibrosis by suppressing JAK2 and STAT3 activation
title_fullStr	JQ-1 ameliorates schistosomiasis liver fibrosis by suppressing JAK2 and STAT3 activation
title_full_unstemmed	JQ-1 ameliorates schistosomiasis liver fibrosis by suppressing JAK2 and STAT3 activation
title_sort	jq-1 ameliorates schistosomiasis liver fibrosis by suppressing jak2 and stat3 activation
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/a0e897dc1eb44c03aaff0e59bc579fb1
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JQ-1 ameliorates schistosomiasis liver fibrosis by suppressing JAK2 and STAT3 activation

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