Invasive inflammation and excessive scar formation are the main reasons for the difficulty in repairing nervous tissue after spinal cord injury.Microglia and astrocytes play key roles in the spinal cord injury micro-e...Invasive inflammation and excessive scar formation are the main reasons for the difficulty in repairing nervous tissue after spinal cord injury.Microglia and astrocytes play key roles in the spinal cord injury micro-environment and share a close interaction.However,the mechanisms involved remain unclear.In this study,we found that after spinal cord injury,resting microglia(M0)were polarized into pro-inflammatory phenotypes(MG1 and MG3),while resting astrocytes were polarized into reactive and scar-forming phenotypes.The expression of growth arrest-specific 6(Gas6)and its receptor Axl were significantly down-regulated in microglia and astrocytes after spinal cord injury.In vitro experiments showed that Gas6 had negative effects on the polarization of reactive astrocytes and pro-inflammatory microglia,and even inhibited the cross-regulation between them.We further demonstrated that Gas6 can inhibit the polarization of reactive astrocytes by suppressing the activation of the Yes-associated protein signaling pathway.This,in turn,inhibited the polarization of pro-inflammatory microglia by suppressing the activation of the nuclear factor-κB/p65 and Janus kinase/signal transducer and activator of transcription signaling pathways.In vivo experiments showed that Gas6 inhibited the polarization of pro-inflammatory microglia and reactive astrocytes in the injured spinal cord,thereby promoting tissue repair and motor function recovery.Overall,Gas6 may play a role in the treatment of spinal cord injury.It can inhibit the inflammatory pathway of microglia and polarization of astrocytes,attenuate the interaction between microglia and astrocytes in the inflammatory microenvironment,and thereby alleviate local inflammation and reduce scar formation in the spinal cord.展开更多
Ferroptosis of chondrocytes is a significant contributor to osteoarthritis(OA),for which there is still a lack of safe and effective therapeutic drugs targeting ferroptosis.Here,we screen for anti-ferroptotic drugs in...Ferroptosis of chondrocytes is a significant contributor to osteoarthritis(OA),for which there is still a lack of safe and effective therapeutic drugs targeting ferroptosis.Here,we screen for anti-ferroptotic drugs in Food and Drug Administration(FDA)-approved drug library via a high-throughput manner in chondrocytes.We identified a group of FDA-approved anti-ferroptotic drugs,among which vitamin K showed the most powerful protective effect.Further study demonstrated that vitamin K effectively inhibited ferroptosis and alleviated the extracellular matrix(ECM)degradation in chondrocytes.Intra-articular injection of vitamin K inhibited ferroptosis and alleviated OA phenotype in destabilization of the medial meniscus(DMM)mouse model.Mechanistically,transcriptome sequencing and knockdown experiments revealed that the anti-ferroptotic effects of vitamin K depended on growth arrest-specific 6(Gas6).Furthermore,exogenous expression of Gas6 was found to inhibit ferroptosis through the AXL receptor tyrosine kinase(AXL)/phosphatidylinositol 3-kinase(PI3K)/AKT serine/threonine kinase(AKT)axis.Together,we demonstrate that vitamin K inhibits ferroptosis and alleviates OA progression via enhancing Gas6 expression and its downstream pathway of AXL/PI3K/AKT axis,indicating vitamin K as well as Gas6 to serve as a potential therapeutic target for OA and other ferroptosis-related diseases.展开更多
目的:探讨系统性红斑狼疮患者血清β2-微球蛋白(β2-MG)、颗粒蛋白前体(PGRN)、生长停滞基因6(Gas6)水平与疾病严重程度和肾脏损害的关系。方法:选择2017年1月至2020年12月河北医科大学第二医院风湿免疫科收治的系统性红斑狼疮患者105例...目的:探讨系统性红斑狼疮患者血清β2-微球蛋白(β2-MG)、颗粒蛋白前体(PGRN)、生长停滞基因6(Gas6)水平与疾病严重程度和肾脏损害的关系。方法:选择2017年1月至2020年12月河北医科大学第二医院风湿免疫科收治的系统性红斑狼疮患者105例,根据系统性红斑狼疮疾病活动度指数(SLEDAI)将患者分为活动期组(SLEDAI≥5分)62例,缓解期组(SLEDAI≤4分)43例。另取同期于河北医科大学第二医院接受体检的健康志愿者60例作为对照组。比较各组血清β2-MG、PGRN、Gas6、红细胞沉降率(ESR)、C反应蛋白(CRP)、血清补体、抗dsDNA抗体、血尿素氮(BUN)、血肌酐(Scr),24 h尿蛋白(24h UTP),并分析其相关性。结果:活动期组β2-MG、PGRN、ESR、CRP、抗dsDNA抗体、BUN、Scr、24 h UTP水平高于缓解期组、对照组,Gas6、血清补体C3、C4水平低于缓解期组、对照组;缓解期组β2-MG、PGRN、ESR、CRP、抗dsDNA抗体、BUN、Scr、24 h UTP水平均高于对照组,Gas6、血清补体C3、C4水平低于对照组,活动期组SLEDAI评分高于缓解期组(P<0.05)。Pearson相关性分析可得:系统性红斑狼疮患者血清β2-MG、PGRN与SLEDAI、ESR、CRP、抗dsDNA、BUN、Scr、24h UTP呈正相关,与血清补体C3、补体C4呈负相关(均P<0.05),Gas6水平与SLEDAI、ESR、CRP、抗dsDNA、BUN、Scr、24h UTP呈负相关,与血清补体C3、补体C4呈正相关(均P<0.05)。结论:系统性红斑狼疮患者血清β2-MG、PGRN水平异常升高,Gas6水平异常降低,且和患者疾病活动程度及肾脏损害密切相关,检测其水平可能为系统性红斑狼疮疾病的评估提供参考。展开更多
基金supported by the National Natural Science Foundation of China, Nos.81971151 (to YW), 82102528 (to XL), 82102583 (to LW)the Natural Science Foundation of Guangdong Province, China, Nos.2020A1515010265 (to YW), 2020A1515110679 (to XL), and 2021A1515010358 (to XL)
文摘Invasive inflammation and excessive scar formation are the main reasons for the difficulty in repairing nervous tissue after spinal cord injury.Microglia and astrocytes play key roles in the spinal cord injury micro-environment and share a close interaction.However,the mechanisms involved remain unclear.In this study,we found that after spinal cord injury,resting microglia(M0)were polarized into pro-inflammatory phenotypes(MG1 and MG3),while resting astrocytes were polarized into reactive and scar-forming phenotypes.The expression of growth arrest-specific 6(Gas6)and its receptor Axl were significantly down-regulated in microglia and astrocytes after spinal cord injury.In vitro experiments showed that Gas6 had negative effects on the polarization of reactive astrocytes and pro-inflammatory microglia,and even inhibited the cross-regulation between them.We further demonstrated that Gas6 can inhibit the polarization of reactive astrocytes by suppressing the activation of the Yes-associated protein signaling pathway.This,in turn,inhibited the polarization of pro-inflammatory microglia by suppressing the activation of the nuclear factor-κB/p65 and Janus kinase/signal transducer and activator of transcription signaling pathways.In vivo experiments showed that Gas6 inhibited the polarization of pro-inflammatory microglia and reactive astrocytes in the injured spinal cord,thereby promoting tissue repair and motor function recovery.Overall,Gas6 may play a role in the treatment of spinal cord injury.It can inhibit the inflammatory pathway of microglia and polarization of astrocytes,attenuate the interaction between microglia and astrocytes in the inflammatory microenvironment,and thereby alleviate local inflammation and reduce scar formation in the spinal cord.
基金supported by grants from the Wenzhou Science and Technology Bureau Foundation,China(Grant No.:ZY2019014)“Pioneer”and“Leading Goose”R&D Program of Zhejiang,China(Grant No.:2022C03144)National Natural Science Foundation of China(Grant Nos.:82172494,and 82372461).
文摘Ferroptosis of chondrocytes is a significant contributor to osteoarthritis(OA),for which there is still a lack of safe and effective therapeutic drugs targeting ferroptosis.Here,we screen for anti-ferroptotic drugs in Food and Drug Administration(FDA)-approved drug library via a high-throughput manner in chondrocytes.We identified a group of FDA-approved anti-ferroptotic drugs,among which vitamin K showed the most powerful protective effect.Further study demonstrated that vitamin K effectively inhibited ferroptosis and alleviated the extracellular matrix(ECM)degradation in chondrocytes.Intra-articular injection of vitamin K inhibited ferroptosis and alleviated OA phenotype in destabilization of the medial meniscus(DMM)mouse model.Mechanistically,transcriptome sequencing and knockdown experiments revealed that the anti-ferroptotic effects of vitamin K depended on growth arrest-specific 6(Gas6).Furthermore,exogenous expression of Gas6 was found to inhibit ferroptosis through the AXL receptor tyrosine kinase(AXL)/phosphatidylinositol 3-kinase(PI3K)/AKT serine/threonine kinase(AKT)axis.Together,we demonstrate that vitamin K inhibits ferroptosis and alleviates OA progression via enhancing Gas6 expression and its downstream pathway of AXL/PI3K/AKT axis,indicating vitamin K as well as Gas6 to serve as a potential therapeutic target for OA and other ferroptosis-related diseases.
文摘目的:探讨系统性红斑狼疮患者血清β2-微球蛋白(β2-MG)、颗粒蛋白前体(PGRN)、生长停滞基因6(Gas6)水平与疾病严重程度和肾脏损害的关系。方法:选择2017年1月至2020年12月河北医科大学第二医院风湿免疫科收治的系统性红斑狼疮患者105例,根据系统性红斑狼疮疾病活动度指数(SLEDAI)将患者分为活动期组(SLEDAI≥5分)62例,缓解期组(SLEDAI≤4分)43例。另取同期于河北医科大学第二医院接受体检的健康志愿者60例作为对照组。比较各组血清β2-MG、PGRN、Gas6、红细胞沉降率(ESR)、C反应蛋白(CRP)、血清补体、抗dsDNA抗体、血尿素氮(BUN)、血肌酐(Scr),24 h尿蛋白(24h UTP),并分析其相关性。结果:活动期组β2-MG、PGRN、ESR、CRP、抗dsDNA抗体、BUN、Scr、24 h UTP水平高于缓解期组、对照组,Gas6、血清补体C3、C4水平低于缓解期组、对照组;缓解期组β2-MG、PGRN、ESR、CRP、抗dsDNA抗体、BUN、Scr、24 h UTP水平均高于对照组,Gas6、血清补体C3、C4水平低于对照组,活动期组SLEDAI评分高于缓解期组(P<0.05)。Pearson相关性分析可得:系统性红斑狼疮患者血清β2-MG、PGRN与SLEDAI、ESR、CRP、抗dsDNA、BUN、Scr、24h UTP呈正相关,与血清补体C3、补体C4呈负相关(均P<0.05),Gas6水平与SLEDAI、ESR、CRP、抗dsDNA、BUN、Scr、24h UTP呈负相关,与血清补体C3、补体C4呈正相关(均P<0.05)。结论:系统性红斑狼疮患者血清β2-MG、PGRN水平异常升高,Gas6水平异常降低,且和患者疾病活动程度及肾脏损害密切相关,检测其水平可能为系统性红斑狼疮疾病的评估提供参考。
