Mining host candidate regulators of schistosomiasis-induced liver fibrosis in response to artesunate therapy through transcriptomics approach

Yajie Yuan; Xinyue Lv; Yahan Wu; Youhong Weng; Fangwei Dai; Haojie Ding; Riping Chen; Bin Zheng; Wenxia Zhao; Qunbo Tong; Jianzu Ding; Di Lou; Yunru Lai; Xiaofeng Chu; Longyou Zhao; Shaohong Lu; Qingming Kong

doi:10.1371/journal.pntd.0011626

Mining host candidate regulators of schistosomiasis-induced liver fibrosis in response to artesunate therapy through transcriptomics approach

PLoS Negl Trop Dis. 2023 Sep 29;17(9):e0011626. doi: 10.1371/journal.pntd.0011626. eCollection 2023 Sep.

Authors

Yajie Yuan^{1

2}, Xinyue Lv¹, Yahan Wu¹, Youhong Weng¹, Fangwei Dai³, Haojie Ding⁴, Riping Chen⁵, Bin Zheng⁴, Wenxia Zhao⁵, Qunbo Tong⁴, Jianzu Ding⁴, Di Lou⁴, Yunru Lai⁶, Xiaofeng Chu³, Longyou Zhao⁶, Shaohong Lu⁴, Qingming Kong^{1

4}

Affiliations

¹ Key Laboratory of Biomarkers and In Vitro Diagnosis Translation of Zhejiang province, School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, China.
² Department of Pathogen Biology, School of Basic Medicine, Nanjing Medical University, Nanjing, China.
³ Zhejiang Key Laboratory of Experimental Animal and Safety Evaluation, Hangzhou Medical College, Zhejiang Academy of Medical Sciences, Hangzhou, China.
⁴ School of Basic Medicine and Forensics, Key Laboratory of Bio-tech Vaccine of Zhejiang Province, Engineering Research Center of Novel Vaccine of Zhejiang Province, Hangzhou Medical College, Hangzhou, China.
⁵ School of Public Health, Hangzhou Medical College, Zhejiang Academy of Medical Sciences, Hangzhou, China.
⁶ Department of Laboratory Medicine, Lishui Second People's Hospital Affiliated to Wenzhou Medical University, Lishui, China.

Abstract

Background: Artesunate (ART) has been reported to have an antifibrotic effect in various organs. The underlying mechanism has not been systematically elucidated. We aimed to clarify the effect of ART on liver fibrosis induced by Schistosoma japonicum (S. japonicum) in an experimentally infected rodent model and the potential underlying mechanisms.

Methods: The effect of ART on hepatic stellate cells (HSCs) was assessed using CCK-8 and Annexin V-FITC/PI staining assays. The experimental model of liver fibrosis was established in the Mongolian gerbil model infected with S. japonicum cercariae and then treated with 20 mg/kg or 40 mg/kg ART. The hydroxyproline (Hyp) content, malondialdehyde (MDA) content, superoxide dismutase (SOD) and glutathione peroxidase (GPX) activities in liver tissue were measured and histopathological changes of liver tissues were observed. Whole-transcriptome RNA sequencing (RNA-seq) of the liver tissues was performed. Differentially expressed genes (DEGs) were identified using bioinformatic analysis and verified by quantitative PCR (qPCR) and western blot assay.

Results: ART significantly inhibited the proliferation and induce the apoptosis of HSCs in a dose-dependent manner. In vivo, Hyp content decreased significantly in the ART-H group compared to the model (MOD) group and GPX activity was significantly higher in the ART-H group than in the MOD group. Besides, ART treatment significantly reduced collagen production (p <0.05). A total of 158 DEGs and 44 differentially expressed miRNAs related to ART-induced anti-schistosomiasis liver fibrosis were identified. The qPCR and western blot results of selected DEGs were consistent with the sequencing results. These DEGs were implicated in key pathways such as immune and inflammatory response, integrin-mediated signaling and toll-like receptor signaling pathways.

Conclusion: ART is effective against liver fibrosis using Mongolian gerbil model induced by S. japonicum infection. We identified host candidate regulators of schistosomiasis-induced liver fibrosis in response to ART through transcriptomics approach.

Copyright: © 2023 Yuan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Grants and funding

This study was supported by the National Natural Science Foundation of China (Grant No. 31501050 to QMK), Zhejiang Provincial Program for the Cultivation of High-Level Innovative Health Talents (Grant No. WJW2021002 to QMK), Basic Public Welfare Research Project of Zhejiang Province (Grant No. LGF22H180015 to FWD), Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (Grant No. 2020KY530 to FWD),The S&T Major Project of Lishui (Grant No. 2023GYX03 to LYZ), Zhejiang Medical and Health Science and Technology Plan (Grant No. WKJ-ZJ-2203 to SHL), and the Central Leading Local Science and Technology Development Fund Project (Grant No. 2023ZY1019 to SHL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.