Exploring Pharmacological Mechanisms of Chaishi-Tuire Granules Antipyretic Effects based on Drug Target-disease Gene Interaction Network

Abstract

In recent years, acute infectious diseases, such as, COVID-19, SARS, avian influenza, are frequently in epidemic, and continually cause patients’ temperature rising even hyperpyrexia and seriously threaten the life of patients. The Chaishi-Tuire Granules (CTG)is used to treathyperpyrexia and infectious diseases. The purpose of this study is to investigate the potential pharmacological mechanisms of CTG action on hyperthermia. The drug target prediction tool is used in the TCM comprehensive pharmacology research platform(TCMIP, www.tcmip.cn), the target of active compound in CTG compound of Chinese herbal medicine was predicted. Then, the interaction network between CTG hypothesis targets and known heat-related genes was constructed, and the candidate targets of CTG therapy for heat-related genes were determined by the topology characteristics of the network. The gene ontology (GO) analysis and the enrichment analysis of Reactome pathway were carried out to study the specific functions and participating pathways of CTG acting on high-heat candidate targets, and further verification was conducted through animal experiments. CTG was composed of nine herbs, and 1721 related chemical components were retrieved in total. By constructing the known hyperthermally related gene network of CTG presumed targets, and calculating the topology characteristics of the network, we determined 72 candidate CTG targets related to the treatment of hyperpyretic, involving 93 active components in CTG. Functionally, these candidate CTG targets are significantly correlated with apoptosis, cytokine mediated signaling, DNA damage-induced protein phosphorylation, inflammation, and immune-related pathways. Furthermore, the antipyretic effects of CTG on rat hyperthermia and its regulatory effects on serum interleukin-1, interleukin-6, tumor necrosis factor, and hypothalamus cAMP were confirmed in vivo by lPS-induced rat hyperthermia model. CTG can play an antipyretic role by regulating its candidate targets, and its intrinsic mechanism is mainly through regulating inflammatory cytokines in hypothalamus and peripheral blood.