ENVIRONMENTAL POLLUTION
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2022
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IF 9.988
Ying Tu,Yongyong Yang,Yue Wang,Nana Wu,Junyan Tao,Guanghong Yang,Mingdan You
Neurodevelopmental exposure to chlorpyrifos (CPF) could increase risks for neurological disorders, such as autism spectrum disorder, cognitive impairment, or attention deficit hyperactivity disorder. The potential involvement of microglia reactive to inflammatory stimuli in these neurological disorders has been generally reported. However, the concrete effects and potential mechanisms of microglia dysfunction triggered by developmental CPF exposure remain unclear. Therefore, we established mouse and human embryonic microglial cells (HMC3 cell) models of developmental CPF exposure to evaluate the effects of developmental CPF exposure on neuroinflammation and underlying mechanisms. The results showed that developmental exposure to CPF enhanced the expression of Iba1 in hippocampus. CPF treatment increased inflammatory cytokines levels and TSPO expression in hippocampus and HMC3 cells. The levels of necroptosis and necroptosis-related signaling RIPK/MLKL were increased in hippocampus and HMC3 cells following CPF exposure. Furthermore, the expression of TLR4/TRIF signaling was increased in hippocampus and HMC3 cells subjected to CPF exposure. Notably, the increased levels of TLR4/TRIF signaling, RIPK/MLKL signaling, necroptosis and pro-inflammatory cytokines induced by CPF treatment were remarkably inhibited by TAK-242 (a specific TLR4 inhibitor). Additionally, the necroptosis and pro-inflammatory cytokines production induced by CPF treatment were significantly relieved by Nec-1 (a specific RIPK1 inhibitor). In general, the above results suggested that activated microglia in hippocampus subjected to developmental CPF exposure underwent RIPK1/MLKL-mediated necroptosis regulated by TLR4/TRIF signaling.
研究领域:
神经科学
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毒理学
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细胞生物学
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发育生物学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2026
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IF 5.7
Hui Zhang,Qimei Yun,Zezhou Xu,Yifan Wang,Xianzhi Zhou,Ling Deng,Binsheng He
Neuroinflammation plays an essential role in neurological dysfunction in cerebral ischemia and reperfusion injury. Understanding the molecular network associated with neuroinflammation will provide potential targets for the neuroprotective treatment of ischemic stroke. An ischemia/reperfusion (I/R) rat model was established by middle cerebral artery occlusion (MCAO) and verified by laser speckle imaging and neurological function scoring. The ipsilateral cortex was analyzed using transcriptomic sequencing. The resulting transcriptomic dataset was combined with the ischemic stroke-associated C0948008 dataset from DisGeNet to screen differentially expressed genes (DEGs). Protein‒protein interaction (PPI) analysis was performed on DEGs associated with the inflammatory response. The candidate genes were verified using Western blotting or ELISA. I/R rats were subsequently treated with the TLR4 inhibitor TAK-242 to investigate the role of the TLR4/SYK/NF-κB pathway in neuroinflammation during ischemic stroke. A total of 264 genes were identified, most of which were enriched in inflammatory response pathways. PPI analysis of the DEGs associated with the inflammatory response revealed a total of three mutually interacting gene clusters, with TLR4, SYK, and NF-κB serving as the hub genes. The expression of proteins in the TLR4/SYK/NF-κB pathway and inflammatory cytokines significantly upregulated the I/R rats, whereas the trends were dramatically reversed by TAK-242. In addition, TAK-242 efficiently decreased the infarct area, improved neurological function, alleviated poststroke cognitive impairment (PSCI), recovered neuronal viability, and inhibited the overactivation of microglia and astrocytes. These data suggest that the TLR4/SYK/NF-κB pathway plays an important role in neuroinflammation and provide potential targets for neuroprotective therapy for ischemic stroke.
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产品关联
DOI
PubMed
高影响因子
Small
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2024
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IF 13
Yu He,Ejun Peng,Xiaozhuo Ba,Jian Wu,Wen Deng,Qiu Huang,Yonghua Tong,Haojie Shang,Zichen Zhong,Xiao Liu,Yanlong Zhang,Tao Ye,Xiaoqi Yang,Kangyang Wang,Yabin Xie,Kehua Jiang,Ding Xia,Zhiqiang Chen,Kun Tang
Emerging studies have demonstrated that M1 macrophage polarization and oxidative stress play important roles in calcium oxalate (CaOx) induced kidney injury, which leads to increased crystals deposition. ROS scavenging nanozymes and kidney-targeted nanoparticles for antioxidant drugs delivery have emerged as an arisen methodology for kidney injury therapy. However, cell membrane biomimetic-modified nanozymes as anti-inflammatory drug delivery systems for the treatment of kidney injury is rarely reported. Herein, the ROS responsive red blood cell-membrane-coated resatorvid-loaded cerium oxide nanoparticles (RBCM@CeO 2 /TAK-242) are constructed to suppress CaOx induced kidney injury and crystals deposition. In vitro, RBCM@CeO 2 /TAK-242 shows effective internalization by renal tubular epithelial cells, along with demonstrated antioxidative, anti-inflammatory, and macrophage reprogramming effects. Glyoxalate(Gly)-induced renal CaOx crystals mouse model is established, RBCM@CeO 2 /TAK-242 shows excellent injured kidney targeting and biosafety, and could effectively suppress CaOx induced kidney injury and crystals deposition. RBCM@CeO 2 /TAK-242 has a dual protective effect by both inhibiting oxidative stress and modulating macrophage polarization in vivo. In addition, RNA seq analysis reveals that RBCM@CeO 2 /TAK-242 protects against CaOx induced kidney injury via suppressing the TLR4/NF-κB pathway. This study provides an innovative strategy for RBCM@CeO 2 /TAK-242 as injured kidney targeting and dual protective effects for the treatment of CaOx induced kidney injury and crystals deposition.
研究领域:
纳米技术
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药理学
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肾脏生理学
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炎症
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氧化应激
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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）