Identification of PIK3CG as a hub in septic myocardial injury using network pharmacology and weighted gene co-expression network analysis

Qiong Liu; Yushu Dong; Germaine Escames; Xue Wu; Jun Ren; Wenwen Yang; Shaofei Zhang; Yanli Zhu; Ye Tian; Darío Acuña-Castroviejo; Yang Yang

doi:10.1002/btm2.10384

Identification of PIK3CG as a hub in septic myocardial injury using network pharmacology and weighted gene co-expression network analysis

Bioeng Transl Med. 2022 Aug 3;8(1):e10384. doi: 10.1002/btm2.10384. eCollection 2023 Jan.

Authors

Qiong Liu^{1

2}, Yushu Dong³, Germaine Escames^{4

5

6}, Xue Wu^{1

2}, Jun Ren^{7

8

9}, Wenwen Yang^{1

2}, Shaofei Zhang^{1

2}, Yanli Zhu^{1

2}, Ye Tian^{1

2}, Darío Acuña-Castroviejo^{4

5

6}, Yang Yang^{1

2}

Affiliations

¹ Key Laboratory of Resource Biology and Biotechnology in Western China Ministry of Education, Faculty of life Science and Medicine, Northwest University Xi'an China.
² Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases Xi'an No. 3 Hospital, The Affiliated Hospital of Northwest University, Faculty of life Science and Medicine, Northwest University Xi'an China.
³ Institute of Neuroscience, General Hospital of Northern Theater Command Shenyang China.
⁴ Biomedical Research Center, Health Sciences Technology Park University of Granada Granada Spain.
⁵ Ibs. Granada, CIBERfes Granada Spain.
⁶ UGC of Clinical Laboratories Universitu San Cecilio's Hospital Granada Spain.
⁷ Department of Cardiology Zhongshan Hospital, Fudan University Shanghai China.
⁸ Shanghai Institute of Cardiovascular Diseases Shanghai China.
⁹ Department of Laboratory Medicine and Pathology University of Washington Seattle Washington USA.

Abstract

Sepsis causes multiple organ injuries, among which the heart is one most severely damaged organ. Melatonin (MEL) alleviates septic myocardial injury, although a systematic and comprehensive approach is still lacking to understand the precise protective machinery of MEL. This study aimed to examine the underlying mechanisms of MEL on improvement of septic myocardial injury at a systematic level. This study integrated three analytic modalities including database investigations, RNA-seq analysis, and weighted gene co-expression network analysis (WCGNA), in order to acquire a set of genes associated with the pathogenesis of sepsis. The Drugbank database was employed to predict genes that may serve as pharmacological targets for MEL-elicited benefits, if any. A pharmacological protein-protein interaction network was subsequently constructed, and 66 hub genes were captured which were enriched in a variety of immune response pathways. Notably, PIK3CG, one of the hub genes, displayed high topological characteristic values, strongly suggesting its promise as a novel target for MEL-evoked treatment of septic myocardial injury. Importantly, molecular docking simulation experiments as well as in vitro and in vivo studies supported an essential role for PIK3CG in MEL-elicited effect on septic myocardial injury. This study systematically clarified the mechanisms of MEL intervention in septic myocardial injury involved multiple targets and multiple pathways. Moreover, PIK3CG-governed signaling cascade plays an important role in the etiology of sepsis and septic myocardial injury. Findings from our study provide valuable information on novel intervention targets for the management of septic myocardial injury. More importantly, this study has indicated the utility of combining a series of techniques for disease target discovery and exploration of possible drug targets, which should shed some light on elucidation of experimental and clinical drug action mechanisms systematically.

Keywords: PIK3CG; melatonin; myocardial dysfunction; network pharmacology; sepsis.