School of Life Science, Beijing University of Chinese Medicine, Beijing, China.
School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China.
Phytomedicine. 2023 Jun;114:154786. doi: 10.1016/j.phymed.2023.154786. Epub 2023 Mar 26.
The transcription factor NRF2 is a master redox switch that regulates the cellular antioxidant response. However, recent advances have revealed new roles for NRF2, including the regulation of antiviral responses to various viruses, suggesting that pharmacological NRF2-activating agents may be a promising therapeutic drug for viral diseases. Isoliquiritigenin (ISL), a chalcone isolated from liquorice (Glycyrrhizae Radix) root, is reported to be a natural NRF2 agonist and has has antiviral activities against HCV (hepatitis C virus) and IAV (influenza A virus). However, the spectrum of antiviral activity and associated mechanism of ISL against other viruses are not well defined.
This study investigated the antiviral activity and underlying mechanism of ISL against vesicular stomatitis virus (VSV), influenza A virus (H1N1), encephalomyocarditis virus (EMCV), herpes simplex virus type 1 (HSV-1).
We evaluated the antiviral activity of ISL against VSV, H1N1, EMCV, and HSV-1 using flow cytometry and qRT-PCR analysis. RNA sequencing and bioinformatic analysis were performed to investigate the potential antiviral mechanism of ISL. NRF2 knockout cells were used to investigate whether NRF2 is required for the antiviral activity of ISL. The anti-apoptosis and anti-inflammatory activities of ISL were further measured by counting cell death ratio and assessing proinflammatory cytokines expression in virus-infected cells, respectively. In addition, we evaluated the antiviral effect of ISL in vivo by measuring the survival rate, body weights, histological analysis, viral load, and cytokine expression in VSV-infected mouse model.
Our data demonstrated that ISL effectively suppressed VSV, H1N1, HSV-1, and EMCV replication in vitro. The antiviral activity of ISL could be partially impaired in NRF2-deficient cells. Virus-induced cell death and proinflammatory cytokines were repressed by ISL. Finally, we showed that ISL treatment protected mice against VSV infection by reducing viral titers and suppressing the expression of inflammatory cytokines in vivo.
These findings suggest that ISL has antiviral and anti-inflammatory effects in virus infections, which are associated with its ability to activate NRF2 signaling, thus indicating that ISL has the potential to serve as an NRF2 agonist in the treatment of viral diseases.
转录因子 NRF2 是一种调节细胞抗氧化反应的主要氧化还原开关。然而，最近的进展揭示了 NRF2 的新作用，包括对各种病毒的抗病毒反应的调节，这表明药理学 NRF2 激活剂可能是治疗病毒疾病的有前途的药物。异甘草素（ISL）是从甘草（甘草根）根中分离出来的查尔酮，据报道它是一种天然的 NRF2 激动剂，具有抗 HCV（丙型肝炎病毒）和 IAV（甲型流感病毒）的抗病毒活性。然而，ISL 对其他病毒的抗病毒活性谱及其相关机制尚不清楚。
本研究探讨了 ISL 对水疱性口炎病毒（VSV）、甲型流感病毒（H1N1）、心肌炎病毒（EMCV）、单纯疱疹病毒 1 型（HSV-1）的抗病毒活性及其潜在机制。
我们通过流式细胞术和 qRT-PCR 分析评估了 ISL 对 VSV、H1N1、EMCV 和 HSV-1 的抗病毒活性。进行 RNA 测序和生物信息学分析以研究 ISL 的潜在抗病毒机制。使用 NRF2 敲除细胞来研究 NRF2 是否是 ISL 抗病毒活性所必需的。通过计数病毒感染细胞中的细胞死亡比例和评估促炎细胞因子的表达，进一步测量 ISL 的抗凋亡和抗炎活性。此外，我们通过测量 VSV 感染小鼠模型中的存活率、体重、组织学分析、病毒载量和细胞因子表达，评估了 ISL 的体内抗病毒作用。
我们的数据表明，ISL 可有效抑制体外 VSV、H1N1、HSV-1 和 EMCV 的复制。在 NRF2 缺陷细胞中，ISL 的抗病毒活性可部分受损。ISL 抑制病毒诱导的细胞死亡和促炎细胞因子的表达。最后，我们表明 ISL 通过降低病毒滴度和抑制体内炎症细胞因子的表达来治疗 VSV 感染的小鼠。
这些发现表明，ISL 在病毒感染中具有抗病毒和抗炎作用，这与其激活 NRF2 信号的能力有关，因此表明 ISL 有可能作为治疗病毒疾病的 NRF2 激动剂。
