The complement system activation-induced inflammation is a critical contributor to myocardial ischemia/reperfusion (I/R) injury. However, effective therapeutic targets and pharmacological interventions remain limited. In this study, we identified 13-methylpalmatine (13-Me-PLT), a natural isoquinoline alkaloid isolated from Coptidis chinensis , as a cardio-protective agent that improved cardiac function and reduced inflammation in a rat model of myocardial I/R injury. RNA sequencing (RNA-seq) analysis revealed significant up-regulation of neutrophil extracellular trap (NET) formation-related signaling pathway and C5ar1 gene in myocardial I/R, both of which were reversed by 13-Me-PLT treatment. Bioinformatics analysis, biophysical assays, and flow cytometry confirmed that 13-Me-PLT effectively inhibited C5a receptor 1 (C5aR1) on neutrophils. However, the role of the C5a-C5aR1 axis in NET formation during myocardial I/R injury has remained unclear. In this study, using a pharmacological inhibitor of C5aR1, we demonstrated that activation of the C5a-C5aR1 axis promoted myocardial I/R injury by inducing NET formation, and that 13-Me-PLT effectively inhibited both processes in a BM213 (C5aR1 agonist)-treated rat model. In vitro , 13-Me-PLT suppressed the expression of NET-associated proteins and alleviated fibrous NET structures in neutrophils, further supporting its cardio-protective effects. In conclusion, our findings revealed that C5a-C5aR1 axis activation exacerbated myocardial I/R injury in a NET-dependent manner. 13-Me-PLT exerted cardio-protective effects by potentially inhibiting C5a-C5aR1 axis-mediated NET formation, highlighting its potential as a therapeutic candidate for myocardial I/R injury.
Acute lung injury (ALI) is an acute respiratory-related progressive disorder, which lacks specific pharmacotherapy. Icariin (ICA) has been shown to be effective in treating ALI. However, the targets and pharmacological mechanisms underlying the effects of ICA in the treatment of ALI are relatively lacking. Based on network pharmacology and molecular docking analyses, the gene functions and potential target pathways of ICA in the treatment of ALI were determined. In addition, the underlying mechanisms of ICA were verified by immunohistochemistry, immunofluorescence, quantitative Real-time PCR, and Western blot in LPS-induced ALI mice. The biological processes targeted by ICA in the treatment of ALI included the pathological changes, inflammatory response, and cell signal transduction. Network pharmacology, molecular docking, and in vivo experimental results revealed that ICA inhibited the complement C5a-C5aR1 axis, TLR4 mediated NF-κB, MAPK, and JAK2-STAT3 signaling pathways related gene and protein expressions, and decreased inflammatory cytokine, chemokine, adhesion molecule expressions, and mitochondrial apoptosis in LPS-induced ALI.
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