{"title":"二甲双胍促进PEN2表达以减轻HIV-1 Tat诱导的小胶质细胞介导的神经毒性。","authors":"Ya Shen, Tianli Xu, Yezi Sun, Kelun Zhang, Xiaojun Cao, Limin Shen, Mengjie Tang","doi":"10.1007/s13365-025-01263-w","DOIUrl":null,"url":null,"abstract":"<p><p>Metformin, a first-line drug used to treat type 2 diabetes mellitus (T2DM), also reduces neuroinflammation and improves motor and cognitive outcomes. Metformin binds to presenilin enhancer 2 (PEN2) and further enhances its therapeutic benefits. The mechanisms of HIV-associated neurocognitive disorders (HANDs) remain unclear. HIV-1 trans-activator of transcription (Tat) contributes to neurotoxicity in HAND. We revealed that PEN2 expression decreased markedly in HAND patients and Tat-infected microglia. Metformin (200 µM) treatment significantly reduced Tat-induced decreases in cell viability, oxidative stress, the proinflammatory response and excessive glutamate and iNOS release and had neuroprotective effects. Tat subsequently increased NF-κB activity, which was prominently suppressed during treatment. In addition, PEN2 knockdown in microglia dramatically reversed the neuroprotective effect of metformin against Tat. Our findings indicate that metformin binds PEN2 and modulates microglia-mediated HIV-1 Tat neurotoxicity in HAND.</p>","PeriodicalId":16665,"journal":{"name":"Journal of NeuroVirology","volume":" ","pages":"376-388"},"PeriodicalIF":1.9000,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12446413/pdf/","citationCount":"0","resultStr":"{\"title\":\"Metformin promotes PEN2 expression to attenuate microglia-mediated neurotoxicity induced by HIV-1 Tat.\",\"authors\":\"Ya Shen, Tianli Xu, Yezi Sun, Kelun Zhang, Xiaojun Cao, Limin Shen, Mengjie Tang\",\"doi\":\"10.1007/s13365-025-01263-w\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Metformin, a first-line drug used to treat type 2 diabetes mellitus (T2DM), also reduces neuroinflammation and improves motor and cognitive outcomes. Metformin binds to presenilin enhancer 2 (PEN2) and further enhances its therapeutic benefits. The mechanisms of HIV-associated neurocognitive disorders (HANDs) remain unclear. HIV-1 trans-activator of transcription (Tat) contributes to neurotoxicity in HAND. We revealed that PEN2 expression decreased markedly in HAND patients and Tat-infected microglia. Metformin (200 µM) treatment significantly reduced Tat-induced decreases in cell viability, oxidative stress, the proinflammatory response and excessive glutamate and iNOS release and had neuroprotective effects. Tat subsequently increased NF-κB activity, which was prominently suppressed during treatment. In addition, PEN2 knockdown in microglia dramatically reversed the neuroprotective effect of metformin against Tat. Our findings indicate that metformin binds PEN2 and modulates microglia-mediated HIV-1 Tat neurotoxicity in HAND.</p>\",\"PeriodicalId\":16665,\"journal\":{\"name\":\"Journal of NeuroVirology\",\"volume\":\" \",\"pages\":\"376-388\"},\"PeriodicalIF\":1.9000,\"publicationDate\":\"2025-08-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12446413/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of NeuroVirology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s13365-025-01263-w\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/6/4 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of NeuroVirology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s13365-025-01263-w","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/6/4 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Metformin promotes PEN2 expression to attenuate microglia-mediated neurotoxicity induced by HIV-1 Tat.
Metformin, a first-line drug used to treat type 2 diabetes mellitus (T2DM), also reduces neuroinflammation and improves motor and cognitive outcomes. Metformin binds to presenilin enhancer 2 (PEN2) and further enhances its therapeutic benefits. The mechanisms of HIV-associated neurocognitive disorders (HANDs) remain unclear. HIV-1 trans-activator of transcription (Tat) contributes to neurotoxicity in HAND. We revealed that PEN2 expression decreased markedly in HAND patients and Tat-infected microglia. Metformin (200 µM) treatment significantly reduced Tat-induced decreases in cell viability, oxidative stress, the proinflammatory response and excessive glutamate and iNOS release and had neuroprotective effects. Tat subsequently increased NF-κB activity, which was prominently suppressed during treatment. In addition, PEN2 knockdown in microglia dramatically reversed the neuroprotective effect of metformin against Tat. Our findings indicate that metformin binds PEN2 and modulates microglia-mediated HIV-1 Tat neurotoxicity in HAND.
期刊介绍:
The Journal of NeuroVirology (JNV) provides a unique platform for the publication of high-quality basic science and clinical studies on the molecular biology and pathogenesis of viral infections of the nervous system, and for reporting on the development of novel therapeutic strategies using neurotropic viral vectors. The Journal also emphasizes publication of non-viral infections that affect the central nervous system. The Journal publishes original research articles, reviews, case reports, coverage of various scientific meetings, along with supplements and special issues on selected subjects.
The Journal is currently accepting submissions of original work from the following basic and clinical research areas: Aging & Neurodegeneration, Apoptosis, CNS Signal Transduction, Emerging CNS Infections, Molecular Virology, Neural-Immune Interaction, Novel Diagnostics, Novel Therapeutics, Stem Cell Biology, Transmissable Encephalopathies/Prion, Vaccine Development, Viral Genomics, Viral Neurooncology, Viral Neurochemistry, Viral Neuroimmunology, Viral Neuropharmacology.