The Nrf2-Keap1-ARE pathway is the principal regulator of antioxidant and phase II detoxification genes. Its activation increases the expression of antioxidant and cytoprotective proteins, protecting cells against infections. Nrf2 modulates virus-induced oxidative stress, ROS generation, and disease pathogenesis, which are vital in the viral life cycle. During respiratory viral infections, such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an inflammatory process, and oxidative stress of the epithelium lining cells activate the transcription factor Nrf2, which protects cells from oxidative stress and inflammation. Nrf2 reduces angiotensin-converting enzyme 2 (ACE2) receptors expression in respiratory epithelial cells. SARS-CoV2 has a high affinity for ACE2 that works as receptors for coronavirus surface spike glycoprotein, facilitating viral entry. Disease severity may also be modulated by pre-existing conditions, such as impaired immune response, obesity, and age, where decreased level of Nrf2 is a common feature. Consequently, Nrf2 activators may increase Nrf2 levels and enhance antiviral mediators’ expression, which could initiate an “antiviral state”, priming cells against viral infection. Therefore, this hypothesis paper describes the use of flavonoid supplements combined with vitamin D3 to activate Nrf2, which may be a potential target to prevent and/or decrease SARS-CoV-2 infection severity, reducing oxidative stress and inflammation, enhancing innate immunity, and downregulating ACE2 receptors.

中文翻译：

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类黄酮激活转录因子 Nrf2 作为预防和调节 SARS-CoV-2 感染严重程度的假设方法。

Nrf2-Keap1-ARE 途径是抗氧化和 II 期解毒基因的主要调节因子。它的激活增加了抗氧化剂和细胞保护蛋白的表达，保护细胞免受感染。Nrf2 调节病毒诱导的氧化应激、ROS 生成和疾病发病机制，这在病毒生命周期中至关重要。在呼吸道病毒感染期间，例如严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2)，炎症过程和上皮细胞的氧化应激会激活转录因子 Nrf2，从而保护细胞免受氧化应激和炎症的影响。Nrf2 降低呼吸道上皮细胞中血管紧张素转换酶 2 (ACE2) 受体的表达。SARS-CoV2 与 ACE2 具有高亲和力，ACE2 作为冠状病毒表面刺突糖蛋白的受体，促进病毒进入。疾病的严重程度也可能受到现有条件的调节，例如免疫反应受损、肥胖和年龄，其中 Nrf2 水平降低是一个常见特征。因此，Nrf2 激活剂可能会增加 Nrf2 水平并增强抗病毒介质的表达，从而启动“抗病毒状态”，启动细胞抵抗病毒感染。因此，这篇假设论文描述了使用类黄酮补充剂与维生素 D3 结合来激活 Nrf2，这可能是预防和/或减轻 SARS-CoV-2 感染严重程度、减少氧化应激和炎症、增强先天免疫和下调 ACE2 受体。