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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. Male Sprague–Dawley rats with UFP‐MI were pre‐treated with SL intragastrically for 7 days. All the rats were then euthanized. Inflammatory cytokine detection and histopathological analysis were performed to assess the protective effects of SL. For the mechanism study, differentially expressed genes (DEGs) 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 (http://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. The results show that SL significantly suppressed inflammatory cell infiltration into myocardial tissue and exhibited significant anti‐inflammatory activity. Transcriptomic analysis revealed that the DEGs after SL treatment had significant anti‐inflammatory, immunomodulatory, and anti‐viral activities. Network pharmacology analysis illustrated that the targets of SL were mainly involved in regulation of the inflammatory response, apoptotic process, innate immune response, platelet activation, and coagulation process. 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 can suppress the secretion of the inflammatory cytokines Interleukin‐1 (IL‐1), Interleukin‐18(IL‐18) and Interleukin‐33(IL‐33) and suppress NLRP3 inflammasome activity. The results suggested that SL can directly inhibit the activation of NLRP3 inflammasomes and reduce the release of cytokines to protect against ultrafine particulate matter‐aggravated myocardial ischemic injury.

BackgroundCerebral malaria (CM) is a kind of serious neurological complication caused by the acute Plasmodium falciparum infection. About 300000 patients including children under 5 years old died from this disease every year. Even intravenous artesunate (Art) is employed as the most effictive drug in the treatment of CM, high incidence of death and neurological sequelae are still inevitable. Therefore, we assessed the combination of Art and tetramethylpyrazine (TMP), to treat experimental CM (ECM) in C57BL/6 mice infected with Plasmodium berghei ANKA (PbA). A non-biased whole brain quantitative proteomic analysis was also conducted to get some insight of the mechanism of the combinational treatment.ResultsTreatment of (ECM)-C57BL/6 mice with the combination of Art and TMP increased the survival, improved clinical signs and prevented neurological manifestations. These effects were related to reduction of parasitised red blood cells (pRBC) adhesion, sequestration, maintaining brain microvascular integrity, increasing nerve growth factor, neurotrophin levels, and alleviating hippocampal neuronal damage and astrocyte activation. The pharmacological effects of Art-TMP combination therapy were analyzed by ECM mice brain proteomic function enrichment. Based on an isobaric tag for relative and absolute quantitation (iTRAQ) fold-change of 1.2 (P-value < 0.05), 217 down-regulated and 177 up-regulated proteins were identified, presenting a significantly altered proteome profile of the combined Art and TMP group as compared to the group treated with Art or TMP alone. These results suggested that the Art-TMP combination could be used as a powerful solution for CM and its neurologic damage.ConclusionsAn effictive therapy for CM with low mortality rate and protect against ECM-induced neurocognitive impairment has been proposed through the combination of Art and TMP, which can provide an effective adjuvant treatment in the clinic. iTRAQ proteomics provide a resource for further mechanistic studies to examine the synergistic effects of Art and TMP and their potential to serve as an adjunctive treatment method and intervention targets.Author SummaryCerebral malaria (CM) is the most serious neurological complication caused by Plasmodium falciparum infection. Even after antimalarial treatment, severe neurological sequelae still exist. We used tetramethylpyrazine (TMP), the main ingredient of the traditional Chinese medicine Chuanxiong, and artesunate (Art) as a combination of drugs. We found that Art-TMP combination could improve the clinical symptoms of CM and protect the nervous system. At the same time, proteomics was used to analyze the protective mechanism of Art-TMP combination administration on ECM mice. This study suggests that the combination of Art and TMP may be used as an adjuvant therapy for clinical CM and iTRAQ proteomics provides resources for further study of Art-TMP combination and provides potential prognostic biomarkers for this therapeutic intervention.

Intravenous artesunate is effective against cerebral malaria (CM), but high mortality and neurological sequelae in survivors are inevitable. We investigated the effect of combined artesunate and tetramethylpyrazine using mouse models of experimental cerebral malaria (ECM). Artesunate + tetramethylpyrazine reduced microvascular blockage and improved neurological function, including the rapid murine coma and behavior scale (RMCBS), leading to improved survival and reduced pathology in ECM. This combination downregulated the expression of adhesion molecules and sequestration of parasitized red blood cells (pRBCs), increased cerebral blood flow, nerve growth factor (b-NGF), vascular endothelial growth factor A (VEGF-A), and neurotrophin (brain-derived neurotrophic factor (BDNF), neurotrophic factor-3 (NT-3)) levels, and alleviated hippocampal neuronal damage and astrocyte activation. Down-(n = 128) and upregulated (n = 64) proteins were identified in the artesunate group, while up-(n = 217) and downregulated (n = 177) proteins were identified in the artesunate + tetramethylpyrazine group, presenting a significantly altered proteome profile. KEGG analysis showed that 166 differentially expressed proteins were enriched in the Art group and 234, in the artesunate + tetramethylpyrazine group. The neuroprotective effects of artesunate + tetramethylpyrazine were mainly related to proteins involved in axon development and transportation between blood and brain. These results suggested that artesunate + tetramethylpyrazine could be a potential adjuvant therapy against CM, but this will have to be confirmed in future studies and trials.