槲皮素通过中断SIRT3/ROS/NF-κB/SPI1反馈环路改善小胶质细胞介导的HIV-1 Tat神经毒性
Quercetin Interrupts the SIRT3/ROS/NF-κB/SPI1 Feedback Loop to Ameliorate Microglia-Mediated HIV-1 Tat Neurotoxicity.
摘要(中文译文)
槲皮素是一种黄酮类化合物，已被认为与多种神经系统疾病有关。然而，槲皮素在HIV相关神经认知障碍（HAND）中的功能作用及机制仍不清楚。HIV-1编码的反式激活因子（Tat）是HAND进展的主要致病因子。在中枢神经系统中，小胶质细胞介导的Tat神经毒性主要包括炎症反应、一氧化氮（NO）和过量谷氨酸。在本研究中，我们证明Tat激活的NF-κB p65直接诱导IL-6和TNF-α的释放以及NO的产生，而Tat通过NF-κB/SPI1通路促进谷氨酸释放。相反，槲皮素可上调SIRT3表达以减少活性氧（ROS）生成，从而抑制NF-κB/SPI1通路并减轻小胶质细胞介导的Tat神经毒性。此外，我们还观察到槲皮素以SIRT3/ROS/NF-κB依赖性方式减轻小胶质细胞来源条件培养基诱导的神经元凋亡。进一步发现，Tat通过NF-κB/SPI1通路下调SIRT3表达，而槲皮素在小胶质细胞中可逆转这一效应。因此，我们的数据表明槲皮素通过打断SIRT3/ROS/NF-κB/SPI1反馈环路来减弱小胶质细胞介导的Tat神经毒性。最后，在小鼠模型中，我们重现了给予槲皮素可显著改善Tat诱导的体内神经病变和认知衰退。综上所述，我们的研究揭示了槲皮素在改善小胶质细胞介导的Tat神经毒性中的神经保护作用，并凸显其作为治疗HAND潜在药物的价值。
Abstract
Quercetin, a kind of flavonoids, has been implicated in multiple neurological diseases. Nevertheless, the functional roles and mechanisms of quercetin in HIV-associated neurocognitive disorders (HAND) remain unclear. HIV-1-encoded transactivator of transcription (Tat) is the major pathogenic factor for the progression of HAND. In the central nervous system, microglia-mediated Tat neurotoxicity is mainly comprised of inflammatory response, nitric oxide (NO) and excessive glutamate. In this study, we demonstrated that Tat-activated NF-κB p65 directly induce the release of IL-6 and TNF-α as well as NO production, while Tat promoted glutamate release via NF-κB/SPI1 pathway. Conversely, quercetin could upregulate SIRT3 expression to reduce reactive oxygen species (ROS) generation, thereby inhibiting NF-κB/SPI1 pathway and mitigating microglia-mediated Tat neurotoxicity. In addition, we also observed that quercetin alleviated neuronal apoptosis induced by the microglia-derived conditioned media in a SIRT3/ROS/NF-κB-dependent manner. Furthermore, Tat was found to downregulate SIRT3 expression via NF-κB/SPI1 pathway, which was reversed by quercetin in microglia. Thus, our data establish that quercetin disrupts the SIRT3/ROS/NF-κB/SPI1 feedback loop to attenuate microglia-mediated Tat neurotoxicity. Finally, in murine models, we recapitulated that administration of quercetin remarkably ameliorated Tat‑induced neuropathy and cognitive decline in vivo. Taken together, our study uncovers the neuroprotective roles of quercetin in the amelioration of microglia-mediated Tat neurotoxicity and highlights its potential as a therapeutic agent for the treatment of HAND.
如何引用
AMA
Lin Gao, Duo Cao, Wenhua Tao, Dongmei Zhang. Quercetin Interrupts the SIRT3/ROS/NF-κB/SPI1 Feedback Loop to Ameliorate Microglia-Mediated HIV-1 Tat Neurotoxicity.. Journal of medical virology. 2026; doi:10.1002/jmv.70906.
APA
Lin Gao, Duo Cao, Wenhua Tao, Dongmei Zhang (2026). Quercetin Interrupts the SIRT3/ROS/NF-κB/SPI1 Feedback Loop to Ameliorate Microglia-Mediated HIV-1 Tat Neurotoxicity.. Journal of medical virology. https://doi.org/10.1002/jmv.70906
GB/T 7714
Lin Gao, Duo Cao, Wenhua Tao, Dongmei Zhang. Quercetin Interrupts the SIRT3/ROS/NF-κB/SPI1 Feedback Loop to Ameliorate Microglia-Mediated HIV-1 Tat Neurotoxicity.[J]. Journal of medical virology, 2026 doi:10.1002/jmv.70906.
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