Abstract
Background: Air pollution is a growing public health burden associated with several negative health effects, especially cardiovascular disease. Shenlian extract (SL), a traditional Chinese medicine, has the effects of clearing heat-toxin and promoting blood circulation for removing blood stasis, and it has long been used to treat cardiovascular diseases and atherosclerosis. This study explored the underlying action mechanism of SL against ultrafine particle-induced myocardial ischemic injury (UFP-MI) through network pharmacology prediction and experimental verification. Methods: Male Sprague-Dawley rats with UFP-MI were pre-treated with SL intragastrically for 7 days, all the animals were randomly divided into five groups: Sham, Model (UFP+MI), SLL( 31.08mg/ kg×d) + UFP+ MI, SLM (62.16 mg/ kg×d) + UFP+MI, and SLH (124.32 mg/ kg×d) + UFP+ MI. SL or saline was administrated 7 days before UFP instillation (100 μg/kg), followed by 24 h of ischemia. Inflammatory cytokine detection and histopathological analysis were performed to assess the protective effects of SL. For the mechanism study, differentially expressed genes were identified in UFP-MI rats treated with SL through transcriptomic analysis. Subsequently, in combination with network pharmacology, potential pathways involved in the effects of SL treatment were identified using the Internet-based Computation Platform (www.tcmip.cn) and Cytoscape 3.6.0. Further validation experiments were performed to reveal the mechanism of the therapeutic effects of SL on UFP-MI.Results: In pharmacodynamics experiments, SL significantly suppressed inflammatory cell infiltration into myocardial tissue and exhibited significant anti -inflammatory activity. Transcriptomic analysis revealed that the differentially expressed genes after SL treatment had significant anti-inflammatory, immunomodulatory, and anti-viral activities. Network pharmacology analysis illustrated that the targets of SL participate in the inflammatory response, apoptotic process, innate immune response, platelet activation, and other processes. By combining transcriptomic and network pharmacology data, we found that SL may exert anti-inflammatory effects by acting on the NOD-like signaling pathway to regulate immune response activation and inhibit systemic inflammation. Verification experiments revealed that SL suppressed NLRP3 inflammasome active and inflammasomes are cytosolic protein complexes that stimulate the activation of Caspase-1, which in turn induces the secretion of the inflammatory cytokines Interleukin-1 (IL-1), Interleukin-18(IL-18) and Interleukin-33(IL-33) Conclusion: UFP can induce the activation of NLRP3 inflammasome, leading to the release of downstream the inflammatory cytokines, aggravate the pathological conditions of inflammatory infiltration, and further aggravate the myocardial ischemic injury. Experimental verification indicated that SL can directly inhibit the activation of NLRP3 inflammasomes in the NOD-like signaling pathway and reduce cytokines release. In conclusion, our results confirmed that SL may prevent UFP-MI by acting on the NOD-like signaling pathway.
Melatonin Attenuates Pyroptosis Upon Spinal Nerve Ligation in Rats via the NF-κB/NLRP3 Inflammasome Signaling Pathway