文献类型：期刊文献

英文题名：Potential molecular mechanism of atmospheric particulate matter aggravating inflammatory injury in ischemic stroke; [大气颗粒物加重缺血性卒中炎症损伤的潜在分子机制研究]

作者：Li B.; Xiong B.; Yi L.

第一作者：Li B.

机构：[1]College of Integrated Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, 730000, China;[2]First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou, 730000, China

第一机构：甘肃中医药大学

通信机构：[1]College of Integrated Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou, 730000, China|[10735]甘肃中医药大学;

年份：2026

卷号：25

期号：3

起止页码：251

外文期刊名：Chinese Journal of Neuromedicine

收录：Scopus(收录号：2-s2.0-105040336667)

语种：英文

外文关键词：Atmospheric particulate matter; Ischemic stroke; Myeloid differentiation factor 88; Network toxicology; Neuroinflammation; Nuclear factor-κB; Toll-like receptor 4; Toll样受体4

摘要：Objective To investigate the potential molecular mechanism of atmospheric particulate matter exacerbating inflammatory injury in ischemic stroke. Methods (1) Network toxicology: based on databases including PubChem, STITCH, OMIM, STRING, and DAVID, the cerebral toxicity of components of SRM 1648a (a standard reference material of urban atmospheric particulate matter) was verified, potential target genes were collected, and common targets associated with ischemic stroke were screened. A protein-protein interaction network was constructed, followed by Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. (2) Animal experiments: a total of 72 rats were randomly divided into a sham-operated group, a model group, a low-dose exposure group, a medium-dose exposure group, a high-dose exposure group, and a Toll-like receptor 4 (TLR4) inhibitor group (n=12 per group). Models of focal cerebral ischemia were induced by middle cerebral artery occlusion for 1 h followed by 24 h of reperfusion in the latter five groups. Rats in the latter four groups received intranasal administration of 1.25, 12.50, 125.00, or 12.50 mg/mL SRM 1648a every other day for 4 consecutive weeks before modeling. Rats in the TLR4 inhibitor group were intraperitoneally injected with 1% TAK-242 solution (1.5 mg/kg) 1 h before each exposure, while rats in the sham-operated and model groups received sterile normal saline intranasally simultaneously. At 24 h after reperfusion, neurological deficits were evaluated using the Bederson grading scale; infarct volume was assessed by TTC staining, neuronal injury by Nissl staining, and apoptosis by TUNEL staining. TLR4 expression was detected by immunohistochemistry; numbers of glial fibrillary acidic protein (GFAP)+, ionized calcium-binding adaptor molecule 1 (Iba1)+, TLR4+/Iba1+, TLR4+/GFAP+, C3d+/GFAP+, and S100 calcium-binding protein A10 (S100A10)+/GFAP+ cells were detected by immunofluorescence staining. Brain water content was determined by dry-wet weight method. Levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) were measured by ELISA; protein expressions of TLR4, myeloid differentiation factor 88 (MyD88), vascular endothelial-cadherin, AQP4, claudin-1, and nuclear factor-κB (NF-κB) were determined by Western blotting; mRNA expressions of TLR4, MyD88, and NF-κB were detected by quantitative real-time PCR. Results (1) Network toxicology results: among 53 components in 3 categories of SRM 1648a, 51 showed cerebral toxicity, corresponding to 374 potential target genes; a total of 145 potential targets underlying SRM 1648a-induced ischemic stroke were screened, and 33 core targets were finally identified. GO and KEGG enrichment analyses suggested that SRM 1648a may exacerbate post-ischemic inflammatory injury by regulating nitric oxide biosynthesis in cerebrovascular endothelial cells and neuronal apoptosis, and activating the signaling pathways of receptor for advanced glycation end products and Toll-like receptor. (2) Animal experiment results: compared with the model group, the low-, medium-, and high-dose exposure groups exhibited significantly higher Bederson score, larger infarct volume, higher brain water content, higher/lower expressions of blood-brain barrier-related proteins (vascular endothelial-cadherin, AQP4, and claudin-1), higher apoptotic rate, elevated proinflammatory factor (IL-1β, IL-6, and TNF-α) levels, enhanced glial activation and proinflammatory phenotypes (increased numbers of GFAP+, Iba1+, C3d+/GFAP+, TLR4+/GFAP+, and TLR4+/Iba1+ cells, and decreased number of S100A10+/GFAP+ cells), and upregulated mRNA and protein expressions of TLR4/MyD88/NF-κB (TLR4 protein: 1.189±0.002, 1.944±0.013, 2.251±0.001 and 3.282±0.011; MyD88 protein: 1.170±0.066, 1.843±0.057, 2.046±0.033 and 2.941±0.129; NF-κB protein: 1.122±0.040, 1.657±0.070, 1.705±0.016 and 2.515±0.048 in the model, low-, medium-, and high-dose groups, respectively, with significant differences all P<0.05). These indicators were significantly improved in the TLR4 inhibitor group compared with the medium- and high-dose exposure groups (all P<0.05). Conclusion Atmospheric particulate matter can aggravate cerebral inflammatory injury in rats with ischemic stroke, and its mechanism is related to the activation of the TLR4/MyD88/NF-κB pathway; TAK-242 can block this pathway and alleviate brain injury. 2026, Chinese Medical Association