Li Xingyan, Yang Yejing, Sun Guili, Dai Wanwu, Jie Xuri, Du Yongjun, Huang Runjie, Zhang Jiaming
Department of Bone and Joint Surgery, The Third Affiliated Hospital of Guangxi Medical University, Nanning, China.
Department of Nutriology, The Third Affiliated Hospital of Guangxi Medical University, Nanning, China.
Bone Joint Res. 2020 Aug 2;9(8):501-514. doi: 10.1302/2046-3758.98.BJR-2019-0301.R1. eCollection 2020 Aug.
Rheumatoid arthritis (RA) is a systematic autoimmune disorder, characterized by synovial inflammation, bone and cartilage destruction, and disease involvement in multiple organs. Although numerous drugs are employed in RA treatment, some respond little and suffer from severe side effects. This study aimed to screen the candidate therapeutic targets and promising drugs in a novel method.
We developed a module-based and cumulatively scoring approach that is a deeper-layer application of weighted gene co-expression network (WGCNA) and connectivity map (CMap) based on the high-throughput datasets.
Four noteworthy RA-related modules were identified, revealing the immune- and infection-related biological processes and pathways involved in RA. , , , , , , , , , , , , , , , , , and were recognized as the key hub genes with high connectivity in gene regulation networks and gene pathway networks. Moreover, the long noncoding RNAs (lncRNAs) in the RA-related modules, such as and , were identified as the indispensable interactors with the hub genes. Finally, candidate drugs were screened by developing a cumulatively scoring approach based on the selected modules. Niclosamide and the other compounds of T-type calcium channel blocker, IKK inhibitor, and PKC activator, HIF activator, and proteasome inhibitor, which harbour the similar gene signature with niclosamide, were promising drugs with high specificity and broad coverage for the RA-related modules.
This study provides not only the promising targets and drugs for RA but also a novel methodological insight into the target and drug screening.Cite this article: 2020;9(8):501-514.
类风湿关节炎（RA）是一种系统性自身免疫性疾病，其特征为滑膜炎症、骨与软骨破坏以及多器官受累。尽管有多种药物用于RA治疗，但部分患者疗效欠佳且伴有严重副作用。本研究旨在用一种新方法筛选候选治疗靶点和有前景的药物。
我们开发了一种基于模块且累积评分的方法，这是基于高通量数据集对加权基因共表达网络（WGCNA）和连接图谱（CMap）的更深层次应用。
识别出四个值得关注的与RA相关的模块，揭示了参与RA的免疫和感染相关生物学过程及通路。 、 、 、 、 、 、 、 、 、 、 、 、 、 、 被认定为在基因调控网络和基因通路网络中具有高连接性的关键枢纽基因。此外，RA相关模块中的长链非编码RNA（lncRNA），如 和 ，被确定为与枢纽基因不可或缺的相互作用分子。最后，通过基于所选模块开发累积评分方法筛选候选药物。氯硝柳胺以及T型钙通道阻滞剂、IKK抑制剂、PKC激活剂、HIF激活剂和蛋白酶体抑制剂的其他化合物，它们具有与氯硝柳胺相似的基因特征，是对RA相关模块具有高特异性和广泛覆盖性的有前景药物。
本研究不仅为RA提供了有前景的靶点和药物，还为靶点和药物筛选提供了一种新的方法学见解。引用本文： 2020；9(8)：501 - 514。
