{"title":"七氟醚通过调节PER2甲基化，阻断AKT通路抑制的小胶质细胞NLRP3炎性囊泡，诱导认知功能障碍。","authors":"Shuangjiang Li, Bin Wang","doi":"10.1080/08923973.2025.2496666","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>The anesthetic sevoflurane can cause cognitive dysfunction and may be involved in mediating DeoxyriboNucleic Acid (DNA) methylation. In this study, we dig into the mechanism of sevoflurane inducing cognitive dysfunction <i>via</i> DNA methylation pathway.</p><p><strong>Methods: </strong><i>In vivo</i> and <i>in vitro</i> experiments were performed in sevoflurane-induced rat models and microglia. <i>In vivo</i> experiments included Morris water maze, Western blot, methylation analysis and immunofluorescence, while <i>in vitro</i> experiments consisted of quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. MK2206 was used as a protein kinase B (AKT) inhibitor.</p><p><strong>Results: </strong>Sevoflurane induced cognitive dysfunction in rats, promoted levels of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), Interleukin (IL)-18, IL-1β, and ionized calcium-binding adapter molecule 1 (Iba-1) proteins, and inhibited Period2 (PER2) expression by enhancing methylation modification. PER2 was found to be located in microglia. Sevoflurane activated DNA methyltransferases (DNMTs) expression and suppressed PER2 <i>in vitro</i>. PER2 overexpression reduced NLRP3 inflammasomes-related protein expressions and restored AKT activation in sevoflurane-treated cells. Furthermore, MK2206 reversed the inhibitory effect of PER2 overexpression on cellular inflammation and AKT pathway activation.</p><p><strong>Conclusion: </strong>Sevoflurane affects AKT pathway-suppressed NLRP3 inflammasomes in microglia by modulating PER2 methylation, thereby contributing to cognitive dysfunction.</p>","PeriodicalId":13420,"journal":{"name":"Immunopharmacology and Immunotoxicology","volume":" ","pages":"1-9"},"PeriodicalIF":2.9000,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Sevoflurane induces cognitive dysfunction by modulating PER2 methylation to block AKT pathway-suppressed NLRP3 inflammatory vesicle in microglia.\",\"authors\":\"Shuangjiang Li, Bin Wang\",\"doi\":\"10.1080/08923973.2025.2496666\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>The anesthetic sevoflurane can cause cognitive dysfunction and may be involved in mediating DeoxyriboNucleic Acid (DNA) methylation. In this study, we dig into the mechanism of sevoflurane inducing cognitive dysfunction <i>via</i> DNA methylation pathway.</p><p><strong>Methods: </strong><i>In vivo</i> and <i>in vitro</i> experiments were performed in sevoflurane-induced rat models and microglia. <i>In vivo</i> experiments included Morris water maze, Western blot, methylation analysis and immunofluorescence, while <i>in vitro</i> experiments consisted of quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. MK2206 was used as a protein kinase B (AKT) inhibitor.</p><p><strong>Results: </strong>Sevoflurane induced cognitive dysfunction in rats, promoted levels of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), Interleukin (IL)-18, IL-1β, and ionized calcium-binding adapter molecule 1 (Iba-1) proteins, and inhibited Period2 (PER2) expression by enhancing methylation modification. PER2 was found to be located in microglia. Sevoflurane activated DNA methyltransferases (DNMTs) expression and suppressed PER2 <i>in vitro</i>. PER2 overexpression reduced NLRP3 inflammasomes-related protein expressions and restored AKT activation in sevoflurane-treated cells. Furthermore, MK2206 reversed the inhibitory effect of PER2 overexpression on cellular inflammation and AKT pathway activation.</p><p><strong>Conclusion: </strong>Sevoflurane affects AKT pathway-suppressed NLRP3 inflammasomes in microglia by modulating PER2 methylation, thereby contributing to cognitive dysfunction.</p>\",\"PeriodicalId\":13420,\"journal\":{\"name\":\"Immunopharmacology and Immunotoxicology\",\"volume\":\" \",\"pages\":\"1-9\"},\"PeriodicalIF\":2.9000,\"publicationDate\":\"2025-05-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Immunopharmacology and Immunotoxicology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/08923973.2025.2496666\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Immunopharmacology and Immunotoxicology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/08923973.2025.2496666","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
Sevoflurane induces cognitive dysfunction by modulating PER2 methylation to block AKT pathway-suppressed NLRP3 inflammatory vesicle in microglia.
Background: The anesthetic sevoflurane can cause cognitive dysfunction and may be involved in mediating DeoxyriboNucleic Acid (DNA) methylation. In this study, we dig into the mechanism of sevoflurane inducing cognitive dysfunction via DNA methylation pathway.
Methods: In vivo and in vitro experiments were performed in sevoflurane-induced rat models and microglia. In vivo experiments included Morris water maze, Western blot, methylation analysis and immunofluorescence, while in vitro experiments consisted of quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. MK2206 was used as a protein kinase B (AKT) inhibitor.
Results: Sevoflurane induced cognitive dysfunction in rats, promoted levels of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), Interleukin (IL)-18, IL-1β, and ionized calcium-binding adapter molecule 1 (Iba-1) proteins, and inhibited Period2 (PER2) expression by enhancing methylation modification. PER2 was found to be located in microglia. Sevoflurane activated DNA methyltransferases (DNMTs) expression and suppressed PER2 in vitro. PER2 overexpression reduced NLRP3 inflammasomes-related protein expressions and restored AKT activation in sevoflurane-treated cells. Furthermore, MK2206 reversed the inhibitory effect of PER2 overexpression on cellular inflammation and AKT pathway activation.
Conclusion: Sevoflurane affects AKT pathway-suppressed NLRP3 inflammasomes in microglia by modulating PER2 methylation, thereby contributing to cognitive dysfunction.
期刊介绍：
The journal Immunopharmacology and Immunotoxicology is devoted to pre-clinical and clinical drug discovery and development targeting the immune system. Research related to the immunoregulatory effects of various compounds, including small-molecule drugs and biologics, on immunocompetent cells and immune responses, as well as the immunotoxicity exerted by xenobiotics and drugs. Only research that describe the mechanisms of specific compounds (not extracts) is of interest to the journal.
The journal will prioritise preclinical and clinical studies on immunotherapy of disorders such as chronic inflammation, allergy, autoimmunity, cancer etc. The effects of small-drugs, vaccines and biologics against central immunological targets as well as cell-based therapy, including dendritic cell therapy, T cell adoptive transfer and stem cell therapy, are topics of particular interest. Publications pointing towards potential new drug targets within the immune system or novel technology for immunopharmacological drug development are also welcome.
With an immunoscience focus on drug development, immunotherapy and toxicology, the journal will cover areas such as infection, allergy, inflammation, tumor immunology, degenerative disorders, immunodeficiencies, neurology, atherosclerosis and more.
Immunopharmacology and Immunotoxicology will accept original manuscripts, brief communications, commentaries, mini-reviews, reviews, clinical trials and clinical cases, on the condition that the results reported are based on original, clinical, or basic research that has not been published elsewhere in any journal in any language (except in abstract form relating to paper communicated to scientific meetings and symposiums).
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