Research Paper|Volume 16, Issue 8|pp 6921—6936

Compound sophora decoction alleviates ulcerative colitis by regulating macrophage polarization through cGAS inhibition: network pharmacology and experimental validation

Fei Gao¹, Shuangjiao Deng¹, Yujin Liu¹, Pengcheng Wu², Lifen Huang³, Feng Zhu¹, Chunzhu Wei¹, Yuyi Yuan¹, Yang Gui¹, Yushi Tian¹, Heng Fan¹, Hui Wu¹

¹Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
²Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
³Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China

* Equal contribution

Received: November 24, 2023Accepted: March 18, 2024Published: April 10, 2024

https://doi.org/10.18632/aging.205734

Copyright: © 2024 Gao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Introduction: Ulcerative colitis (UC) is a refractory disease with complex pathogenesis, and its pathogenesis is not clear. The present study aimed to investigate the potential target and related mechanism of Compound Sophora Decoction (CSD) in treating UC.

Methods: A network pharmacology approach predicted the components and targets of CSD to treat UC, and cell and animal experiments confirmed the findings of the approach and a new target for CSD treatment of UC.

Results: A total of 155 potential targets were identified for CSD treatment of UC, with some related to macrophage polarization, such as nitric oxide synthase (NOS2), also known as inducible nitric oxide synthase (iNOS). GO and KEGG enrichment analysis indicated that oxidative stress response and multiple inflammatory signaling pathways such as TNF-α may play a significant role. In vitro experiments revealed that Interferon-stimulated DNA (ISD) interference can cause polarization imbalances in Raw 264.7 and bone marrow-derived macrophages (BMDMs). Flow cytometry demonstrated that polarization of macrophages in the intestine, spleen, and lymph nodes in vivo was also unbalanced after dextran sulfate sodium (DSS) modeling with pathological intestinal injury. Both in vitro and in vivo studies indicated that after inducing inflammation, the levels of macrophage polarization-related markers (iNOS and Arg1) and inflammation-related factors (CCL17, IL10, TNF-α, and CXCL10) changed, accompanied by increased expression of cGAS. However, CSD treatment based on inflammation can inhibit the expression of cGAS protein and mRNA, lower the level of inflammatory factors, promote the expression of anti-inflammatory factors, and regulate macrophage polarization.

Conclusion: We concluded that CSD alleviated DSS-induced UC by inhibiting cGAS, thus regulating macrophage polarization.