Academy of Chinese Medical Science, Henan University of Chinese Medicine, Zhengzhou, China.
Department of Microbiology & Immunology, New York Medical College, Valhalla, NY, USA.
FASEB J. 2021 Apr;35(4):e21360. doi: 10.1096/fj.202001792R.
The novel coronavirus disease, COVID-19, has grown into a global pandemic and a major public health threat since its breakout in December 2019. To date, no specific therapeutic drug or vaccine for treating COVID-19 and SARS has been FDA approved. Previous studies suggest that berberine, an isoquinoline alkaloid, has shown various biological activities that may help against COVID-19 and SARS, including antiviral, anti-allergy and inflammation, hepatoprotection against drug- and infection-induced liver injury, as well as reducing oxidative stress. In particular, berberine has a wide range of antiviral activities such as anti-influenza, anti-hepatitis C, anti-cytomegalovirus, and anti-alphavirus. As an ingredient recommended in guidelines issued by the China National Health Commission for COVID-19 to be combined with other therapy, berberine is a promising orally administered therapeutic candidate against SARS-CoV and SARS-CoV-2. The current study comprehensively evaluates the potential therapeutic mechanisms of berberine in preventing and treating COVID-19 and SARS using computational modeling, including target mining, gene ontology enrichment, pathway analyses, protein-protein interaction analysis, and in silico molecular docking. An orally available immunotherapeutic-berberine nanomedicine, named NIT-X, has been developed by our group and has shown significantly increased oral bioavailability of berberine, increased IFN-γ production by CD8+ T cells, and inhibition of mast cell histamine release in vivo, suggesting a protective immune response. We further validated the inhibition of replication of SARS-CoV-2 in lung epithelial cells line in vitro (Calu3 cells) by berberine. Moreover, the expression of targets including ACE2, TMPRSS2, IL-1α, IL-8, IL-6, and CCL-2 in SARS-CoV-2 infected Calu3 cells were significantly suppressed by NIT-X. By supporting protective immunity while inhibiting pro-inflammatory cytokines; inhibiting viral infection and replication; inducing apoptosis; and protecting against tissue damage, berberine is a promising candidate in preventing and treating COVID-19 and SARS. Given the high oral bioavailability and safety of berberine nanomedicine, the current study may lead to the development of berberine as an orally, active therapeutic against COVID-19 and SARS.
新型冠状病毒病（COVID-19）自 2019 年 12 月爆发以来，已成为全球性大流行和主要的公共卫生威胁。迄今为止，美国食品药品监督管理局（FDA）尚未批准用于治疗 COVID-19 和 SARS 的特定治疗药物或疫苗。先前的研究表明，小檗碱作为一种异喹啉生物碱，具有多种可能有助于对抗 COVID-19 和 SARS 的生物学活性，包括抗病毒、抗过敏和炎症、保护肝脏免受药物和感染引起的肝损伤，以及减轻氧化应激。特别是，小檗碱具有广泛的抗病毒活性，如抗流感、抗丙型肝炎、抗巨细胞病毒和抗甲病毒。作为中国国家卫生健康委员会发布的 COVID-19 指南中建议与其他疗法联合使用的成分之一，小檗碱是一种很有前途的针对 SARS-CoV 和 SARS-CoV-2 的口服治疗候选药物。本研究通过计算建模，包括靶点挖掘、基因本体富集分析、通路分析、蛋白质-蛋白质相互作用分析和计算机分子对接，全面评估了小檗碱预防和治疗 COVID-19 和 SARS 的潜在治疗机制。我们的研究小组已经开发了一种口服免疫治疗小檗碱纳米药物，命名为 NIT-X，它显著提高了小檗碱的口服生物利用度，增加了 CD8+T 细胞产生的 IFN-γ，并抑制了体内肥大细胞组胺释放，提示具有保护免疫反应。我们进一步验证了小檗碱在体外（Calu3 细胞）抑制 SARS-CoV-2 复制的作用。此外，NIT-X 还显著抑制了 SARS-CoV-2 感染的 Calu3 细胞中 ACE2、TMPRSS2、IL-1α、IL-8、IL-6 和 CCL-2 等靶基因的表达。通过支持保护性免疫，同时抑制促炎细胞因子；抑制病毒感染和复制；诱导细胞凋亡；和保护组织免受损伤，小檗碱是预防和治疗 COVID-19 和 SARS 的有希望的候选药物。鉴于小檗碱纳米药物具有较高的口服生物利用度和安全性，本研究可能促使将小檗碱开发为治疗 COVID-19 和 SARS 的口服活性治疗药物。
