Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy.
University of Naples Federico II, Department of Pharmacy, Naples, Italy.
Biochem Pharmacol. 2021 Jun;188:114564. doi: 10.1016/j.bcp.2021.114564. Epub 2021 Apr 17.
The severe acute respiratory syndrome (SARS)-CoV-2 is the pathogenetic agent of Corona Virus Induced Disease (COVID)19. The virus enters the human cells after binding to the angiotensin converting enzyme (ACE)2 receptor in target tissues. ACE2 expression is induced in response to inflammation. The colon expression of ACE2 is upregulated in patients with inflammatory bowel disease (IBD), highlighting a potential risk of intestinal inflammation in promoting viral entry in the human body. Because mechanisms that regulate ACE2 expression in the intestine are poorly understood and there is a need of anti-SARS-CoV-2 therapies, we have settled to investigate whether natural flavonoids might regulate the expression of Ace2 in intestinal models of inflammation. The results of these studies demonstrated that pelargonidin activates the Aryl hydrocarbon Receptor (AHR) in vitro and reverses intestinal inflammation caused by chronic exposure to high fat diet or to the intestinal braking-barrier agent TNBS in a AhR-dependent manner. In these two models, development of colon inflammation associated with upregulation of Ace2 mRNA expression. Colon levels of Ace2 mRNA were directly correlated with Tnf-α mRNA levels. Molecular docking studies suggested that pelargonidin binds a fatty acid binding pocket on the receptor binding domain of SARS-CoV-2 Spike protein. In vitro studies demonstrated that pelargonidin significantly reduces the binding of SARS-CoV-2 Spike protein to ACE2 and reduces the SARS-CoV-2 replication in a concentration-dependent manner. In summary, we have provided evidence that a natural flavonoid might hold potential in reducing intestinal inflammation and ACE2 induction in the inflamed colon in a AhR-dependent manner.
严重急性呼吸系统综合症（SARS）-冠状病毒 2 是导致 2019 年冠状病毒疾病（COVID）的病原体。该病毒在与靶组织中的血管紧张素转化酶（ACE）2 受体结合后进入人体细胞。ACE2 的表达是在炎症反应的刺激下诱导产生的。炎症性肠病（IBD）患者的结肠 ACE2 表达上调，突出了肠道炎症促进病毒进入人体的潜在风险。由于调节肠道中 ACE2 表达的机制尚不清楚，且需要 SARS-CoV-2 的治疗方法，我们决定研究天然类黄酮是否可能调节肠道炎症模型中 Ace2 的表达。这些研究的结果表明，锦葵素在体外激活芳香烃受体（AHR），并以 AHR 依赖的方式逆转慢性高脂肪饮食或肠道制动-屏障剂 TNBS 引起的肠道炎症。在这两种模型中，结肠炎症的发展与 Ace2 mRNA 表达的上调有关。结肠 Ace2 mRNA 水平与 Tnf-α mRNA 水平直接相关。分子对接研究表明，锦葵素结合 SARS-CoV-2 刺突蛋白受体结合域上的一个脂肪酸结合口袋。体外研究表明，锦葵素可显著降低 SARS-CoV-2 刺突蛋白与 ACE2 的结合，并以浓度依赖的方式降低 SARS-CoV-2 的复制。总之，我们提供的证据表明，天然类黄酮可能以 AHR 依赖的方式具有减少肠道炎症和炎症结肠中 Ace2 诱导的潜力。
