{"title":"PCSK9通过上调cGAS-STING信号加重七氟醚诱导的神经炎症反应和细胞凋亡。","authors":"Tao Su, Yuting Si","doi":"10.1016/j.tice.2025.102739","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Postoperative cognitive dysfunction (POCD) is a postoperative complication that can be induced by anaesthesia. PCSK9 has been shown to have a role in neuronal development and apoptosis. However, PCSK9 has not been studied in sevoflurane-induced POCD-related disorders.</p><p><strong>Objective: </strong>To explore whether PCSK9 can exacerbate sevoflurane-induced neuroinflammatory response and apoptosis by up-regulating cGAS-STING signalling.</p><p><strong>Methods: </strong>A POCD model was constructed by stimulating BV2 microglia with Sevoflurane. CCK8 was used to detect the cell viability, and immunofluorescence was used to observe the expression of microglial activation markers (Iba-1, CD11b) and BDNF to determine the activation of BV2 microglia. Cell proliferation was measured by EDU staining, and apoptosis was analyzed by flow cytometry and western blot. The levels of inflammatory cytokines, ROS, MDA, SOD and CAT were respectively detected by ELISA, DCFH-DA staining, and kits to determine the neuroinflammation and oxidative stress of cells. Mitochondrial ROS, mitochondrial membrane potential, mtDNA and ATP levels were measured to evaluate cellular mitochondrial function.</p><p><strong>Results: </strong>Transfection of si-PCSK9 inhibited Sevoflurane-induced microglial activation and restored cellular viability, promoted cell proliferation, inhibited apoptosis and neuroinflammation, decreased ROS and MDA levels in the cells while up-regulating the levels of SOD and CAT, thus inhibiting oxidative stress, restored the mitochondrial membrane potential to normal and decreased mitochondrial ROS and mtDNA levels and increased ATP production, thereby alleviating mitochondrial dysfunction. Moreover, PCSK9 depletion also down-regulated the expression of cGAS and STING to inactivate cGAS-STING signaling. However, cGAS overexpression partially reversed the effects of si-PCSK9.</p><p><strong>Conclusion: </strong>PCSK9 exacerbates sevoflurane-induced neuroinflammatory response and apoptosis by upregulating cGAS-STING signaling.</p>","PeriodicalId":23201,"journal":{"name":"Tissue & cell","volume":"93 ","pages":"102739"},"PeriodicalIF":2.7000,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"PCSK9 exacerbates sevoflurane-induced neuroinflammatory response and apoptosis by up-regulating cGAS-STING signal.\",\"authors\":\"Tao Su, Yuting Si\",\"doi\":\"10.1016/j.tice.2025.102739\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Postoperative cognitive dysfunction (POCD) is a postoperative complication that can be induced by anaesthesia. PCSK9 has been shown to have a role in neuronal development and apoptosis. However, PCSK9 has not been studied in sevoflurane-induced POCD-related disorders.</p><p><strong>Objective: </strong>To explore whether PCSK9 can exacerbate sevoflurane-induced neuroinflammatory response and apoptosis by up-regulating cGAS-STING signalling.</p><p><strong>Methods: </strong>A POCD model was constructed by stimulating BV2 microglia with Sevoflurane. CCK8 was used to detect the cell viability, and immunofluorescence was used to observe the expression of microglial activation markers (Iba-1, CD11b) and BDNF to determine the activation of BV2 microglia. Cell proliferation was measured by EDU staining, and apoptosis was analyzed by flow cytometry and western blot. The levels of inflammatory cytokines, ROS, MDA, SOD and CAT were respectively detected by ELISA, DCFH-DA staining, and kits to determine the neuroinflammation and oxidative stress of cells. Mitochondrial ROS, mitochondrial membrane potential, mtDNA and ATP levels were measured to evaluate cellular mitochondrial function.</p><p><strong>Results: </strong>Transfection of si-PCSK9 inhibited Sevoflurane-induced microglial activation and restored cellular viability, promoted cell proliferation, inhibited apoptosis and neuroinflammation, decreased ROS and MDA levels in the cells while up-regulating the levels of SOD and CAT, thus inhibiting oxidative stress, restored the mitochondrial membrane potential to normal and decreased mitochondrial ROS and mtDNA levels and increased ATP production, thereby alleviating mitochondrial dysfunction. Moreover, PCSK9 depletion also down-regulated the expression of cGAS and STING to inactivate cGAS-STING signaling. However, cGAS overexpression partially reversed the effects of si-PCSK9.</p><p><strong>Conclusion: </strong>PCSK9 exacerbates sevoflurane-induced neuroinflammatory response and apoptosis by upregulating cGAS-STING signaling.</p>\",\"PeriodicalId\":23201,\"journal\":{\"name\":\"Tissue & cell\",\"volume\":\"93 \",\"pages\":\"102739\"},\"PeriodicalIF\":2.7000,\"publicationDate\":\"2025-01-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Tissue & cell\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1016/j.tice.2025.102739\",\"RegionNum\":4,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ANATOMY & MORPHOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Tissue & cell","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.tice.2025.102739","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ANATOMY & MORPHOLOGY","Score":null,"Total":0}
PCSK9 exacerbates sevoflurane-induced neuroinflammatory response and apoptosis by up-regulating cGAS-STING signal.
Background: Postoperative cognitive dysfunction (POCD) is a postoperative complication that can be induced by anaesthesia. PCSK9 has been shown to have a role in neuronal development and apoptosis. However, PCSK9 has not been studied in sevoflurane-induced POCD-related disorders.
Objective: To explore whether PCSK9 can exacerbate sevoflurane-induced neuroinflammatory response and apoptosis by up-regulating cGAS-STING signalling.
Methods: A POCD model was constructed by stimulating BV2 microglia with Sevoflurane. CCK8 was used to detect the cell viability, and immunofluorescence was used to observe the expression of microglial activation markers (Iba-1, CD11b) and BDNF to determine the activation of BV2 microglia. Cell proliferation was measured by EDU staining, and apoptosis was analyzed by flow cytometry and western blot. The levels of inflammatory cytokines, ROS, MDA, SOD and CAT were respectively detected by ELISA, DCFH-DA staining, and kits to determine the neuroinflammation and oxidative stress of cells. Mitochondrial ROS, mitochondrial membrane potential, mtDNA and ATP levels were measured to evaluate cellular mitochondrial function.
Results: Transfection of si-PCSK9 inhibited Sevoflurane-induced microglial activation and restored cellular viability, promoted cell proliferation, inhibited apoptosis and neuroinflammation, decreased ROS and MDA levels in the cells while up-regulating the levels of SOD and CAT, thus inhibiting oxidative stress, restored the mitochondrial membrane potential to normal and decreased mitochondrial ROS and mtDNA levels and increased ATP production, thereby alleviating mitochondrial dysfunction. Moreover, PCSK9 depletion also down-regulated the expression of cGAS and STING to inactivate cGAS-STING signaling. However, cGAS overexpression partially reversed the effects of si-PCSK9.
Conclusion: PCSK9 exacerbates sevoflurane-induced neuroinflammatory response and apoptosis by upregulating cGAS-STING signaling.
期刊介绍：
Tissue and Cell is devoted to original research on the organization of cells, subcellular and extracellular components at all levels, including the grouping and interrelations of cells in tissues and organs. The journal encourages submission of ultrastructural studies that provide novel insights into structure, function and physiology of cells and tissues, in health and disease. Bioengineering and stem cells studies focused on the description of morphological and/or histological data are also welcomed.
Studies investigating the effect of compounds and/or substances on structure of cells and tissues are generally outside the scope of this journal. For consideration, studies should contain a clear rationale on the use of (a) given substance(s), have a compelling morphological and structural focus and present novel incremental findings from previous literature.
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