Si-Ying Xiang1, Jing Zhao1, Ying Lu1, Ru-Meng Chen1, Yan Wang1, Yi Chen2, Bin Long1, Li-Ping Zhu1, Pei-Fen Yao1, Yi-Feng Xu3, Jian-Hua Chen4. 1. Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, PR China. 2. Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, PR China. 3. Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, PR China. Electronic address: hyyyyb@gmail.com. 4. Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, PR China. Electronic address: chenjhv@hotmail.com.
Abstract
BACKGROUND: The metabolic syndrome (MetS) is a common side effect of second-generation antipsychotic drugs (SGAs), leading to poor prognosis in patients with mental illness. The traditional Chinese herbal formula Ling-Gui-Zhu-Gan decoction (LGZGD) is a clinically validated remedy for SGAs-induced MetS, but its underlying mechanism remains unclear. METHODS: A network pharmacology-based analysis was performed to explore predicted plasma-absorbed components, putative therapeutic targets, and main pathways involved in LGZGD bioactivity. We constructed a target interaction network between the predicted targets of LGZGD and the known targets of MetS, after which we extracted major hubs using topological analysis. Thereafter, the maximum value of "edge betweenness" of all interactions was defined as a bottleneck, which suggested its importance in connecting all targets in the network. Finally, a pathway enrichment analysis of major hubs was used to reveal the biological functions of LGZGD. RESULTS: This approach identified 120 compounds and 361 candidate targets of LGZGD. According to the data generated in this study, the interaction between JUN and APOA1 plays a vital role in the treatment of SGAs-induced MetS using LGZGD. Interestingly, JUN was a putative target of LGZGD and APOA1 is one of the known targets of both MetS and SGAs (olanzapine and clozapine). LGZGD was significantly associated with several pathways including PI3K-Akt signaling, insulin resistance, and MAPK signaling pathway. CONCLUSIONS: LGZGD might inhibit JUN and thereby increases the expression of APOA1 to maintain metabolic homeostasis via some vital pathways.
BACKGROUND: The metabolic syndrome (MetS) is a common side effect of second-generation antipsychotic drugs (SGAs), leading to poor prognosis in patients with mental illness. The traditional Chinese herbal formula Ling-Gui-Zhu-Gan decoction (LGZGD) is a clinically validated remedy for SGAs-induced MetS, but its underlying mechanism remains unclear. METHODS: A network pharmacology-based analysis was performed to explore predicted plasma-absorbed components, putative therapeutic targets, and main pathways involved in LGZGD bioactivity. We constructed a target interaction network between the predicted targets of LGZGD and the known targets of MetS, after which we extracted major hubs using topological analysis. Thereafter, the maximum value of "edge betweenness" of all interactions was defined as a bottleneck, which suggested its importance in connecting all targets in the network. Finally, a pathway enrichment analysis of major hubs was used to reveal the biological functions of LGZGD. RESULTS: This approach identified 120 compounds and 361 candidate targets of LGZGD. According to the data generated in this study, the interaction between JUN and APOA1 plays a vital role in the treatment of SGAs-induced MetS using LGZGD. Interestingly, JUN was a putative target of LGZGD and APOA1 is one of the known targets of both MetS and SGAs (olanzapine and clozapine). LGZGD was significantly associated with several pathways including PI3K-Akt signaling, insulin resistance, and MAPK signaling pathway. CONCLUSIONS: LGZGD might inhibit JUN and thereby increases the expression of APOA1 to maintain metabolic homeostasis via some vital pathways.