Metformin promotes PEN2 expression to attenuate microglia-mediated neurotoxicity induced by HIV-1 Tat.

IF 1.9 4区 医学 Q3 NEUROSCIENCES
Journal of NeuroVirology Pub Date : 2025-08-01 Epub Date: 2025-06-04 DOI:10.1007/s13365-025-01263-w
Ya Shen, Tianli Xu, Yezi Sun, Kelun Zhang, Xiaojun Cao, Limin Shen, Mengjie Tang
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Abstract

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.

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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。
二甲双胍是一种用于治疗2型糖尿病(T2DM)的一线药物,也能减少神经炎症,改善运动和认知结果。二甲双胍与早老素增强剂2 (PEN2)结合,进一步增强其治疗效果。hiv相关神经认知障碍(HANDs)的机制尚不清楚。HIV-1转录反式激活因子(Tat)参与HAND的神经毒性。我们发现,在HAND患者和tat感染的小胶质细胞中,PEN2的表达明显下降。二甲双胍(200µM)处理可显著降低tat诱导的细胞活力、氧化应激、促炎反应、过量谷氨酸和iNOS释放,并具有神经保护作用。随后,NF-κB活性增加,在治疗期间显著抑制。此外,小胶质细胞中PEN2的敲低显著逆转了二甲双胍对Tat的神经保护作用。我们的研究结果表明二甲双胍结合PEN2并调节HAND中小胶质细胞介导的HIV-1 Tat神经毒性。
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来源期刊
Journal of NeuroVirology
Journal of NeuroVirology 医学-病毒学
CiteScore
6.60
自引率
3.10%
发文量
77
审稿时长
6-12 weeks
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.
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