Aggravation of Myocardial Ischemia upon Particulate Matter Exposure in Atherosclerosis Animal Model

The health problems caused by air pollution (especially particulate pollution) are getting more and more attention, especially among cardiovascular ...

China Academy of Chinese Medical Sciences

China Academy Of Chinese Medical Sciences

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- ( = 128) and upregulated ( = 64) proteins were identified in the artesunate group, while up- ( = 217) and downregulated ( = 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.

Synergistic Effect of Combined Artesunate and Tetramethylpyrazine in Experimental Cerebral Malaria.

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 (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.

Shenlian extract protects against ultrafine particulate matter-aggravated myocardial ischemic injury by inhibiting inflammation response via the activation of NLRP3 inflammasomes.

 Ultrafine particulate matter (UFPM) induces oxidative stress (OS) and is considered to be a risk factor of myocardial ischemia (MI). Shengmai formula (SMF) is a traditional Chinese medicine with antioxidant properties and has been used to treat cardiovascular diseases for a long time. The aim of this study was to explore the protective role of SMF and the mechanism by which it prevents myocardial injury in UFPM-exposed rats with MI.  An MI rat model was established. Animals were randomly divided into five groups: sham, UFPM + MI, SMF (1.08 mg/kg⋅d) + UFPM + MI, SMF (2.16 mg/kg⋅d) + UFPM + MI, and SMF (4.32 mg/kg⋅d) + UFPM + MI. SMF or saline was administrated 7 days before UFPM instillation (100 μg/kg), followed by 24 h of ischemia. Physiological and biochemical parameters were measured, and histopathological examinations were conducted to evaluate myocardial damage. We also explored the potential mechanism of the protective role of SMF using a system pharmacology approach and an  myoblast cell model with small molecule inhibitors.  UFPM produced myocardial injuries on myocardial infarct size; serum levels of LDH, CK-MB, and cardiac troponin; and OS responses in the rats with MI. Pretreatment with SMF significantly attenuated these damages  reversing the biomarkers. SMF also improved histopathology induced by UFPM and significantly altered the PI3K/AKT/MAPK and OS signaling pathways. The expression patterns of , , and  in the UFPM model group were reversed in the SMF-treated group. In  studies, SMF attenuated UFPM-induced reactive oxygen species production, mitochondrial damage, and OS responses. The PI3K/AKT/p38 MAPK/Nrf2 pathway was significantly changed in the SMF group compared with that in the UFPM group, whereas opposite results were obtained for pathway inhibition.  These findings indicate that SMF prevents OS responses and exerts beneficial effects against myocardial injury induced by UFPM + MI in rats. Furthermore, the PI3K/AKT/p38 MAPK/Nrf2 signaling pathway might be involved in the protective effects of SMF.

The Protective Effects of Shengmai Formula Against Myocardial Injury Induced by Ultrafine Particulate Matter Exposure and Myocardial Ischemia are Mediated by the PI3K/AKT/p38 MAPK/Nrf2 Pathway.

Cerebral malaria (CM) is caused by , resulting in severe sequelae; one of its pathogenic factors is the low bioavailability of nitric oxide (NO). Our previous study suggested that the combination of artesunate (AS) and tetramethylpyrazine (TMP) exerts an adjuvant therapeutic effect on the symptoms of experimental CM (ECM) and that NO regulation plays an important role. In the present study, we further verified the effects of AS+TMP on cerebral blood flow (CBF) and detected NO-related indicators. We focused on the role of NO through -nitrosoproteome based on previous proteomics data and explored the mechanism of AS+TMP for improving pathological ECM symptoms. We observed that AS+TMP reduces adhesion, increases CBF, and regulates NO synthase (NOS) activity, thereby regulating the level of -nitrosothiols, such as metabolism-related or neuro-associated receptors, for improving ECM symptoms. These results demonstrated that AS+TMP could be an effective strategy in adjuvant therapy of CM.

Lina Chen

China Academy of Chinese Medical Sciences

Aggravation of Myocardial Ischemia upon Particulate Matter Exposure in Atherosclerosis Animal Model