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In an effort to develop novel anti-coronavirus therapeutics and achieve prophylactics, we used gene set enrichment analysis (GSEA) for drug screening and identified that Astragalus polysaccharide (PG2), a mixture of polysaccharides purified from Astragalus membranaceus, could effectively reverse COVID-19 signature genes. Further biological assays revealed that PG2 could prevent the fusion of BHK21-expressing wild-type (WT) viral spike (S) protein and Calu-3-expressing ACE2. Additionally, it specifically prevents the binding of recombinant viral S of WT, alpha, and beta strains to ACE2 receptor in our non-cell-based system. In addition, PG2 enhances let-7a, miR-146a, and miR-148b expression levels in the lung epithelial cells. These findings speculate that PG2 has the potential to reduce viral replication in lung and cytokine storm via these PG2-induced miRNAs. Furthermore, macrophage activation is one of the primary issues leading to the complicated condition of COVID-19 patients, and our results revealed that PG2 could regulate the activation of macrophages by promoting the polarization of THP-1-derived macrophages into an anti-inflammatory phenotype. In this study, PG2 stimulated M2 macrophage activation and increased the expression levels of anti-inflammatory cytokines IL-10 and IL-1RN. Additionally, PG2 was recently used to treat patients with severe COVID-19 symptoms by reducing the neutrophil-to-lymphocyte ratio (NLR). Therefore, our data suggest that PG2, a repurposed drug, possesses the potential to prevent WT SARS-CoV-2 S-mediated syncytia formation with the host cells; it also inhibits the binding of S proteins of WT, alpha, and beta strains to the recombinant ACE2 and halts severe COVID-19 development by regulating the polarization of macrophages to M2 cells.<\/jats:p>","DOI":"10.3390\/v15030641","type":"journal-article","created":{"date-parts":[[2023,2,28]],"date-time":"2023-02-28T03:29:46Z","timestamp":1677554986000},"page":"641","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Repurposing Astragalus Polysaccharide PG2 for Inhibiting ACE2 and SARS-CoV-2 Spike Syncytial Formation and Anti-Inflammatory Effects"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5236-4231","authenticated-orcid":false,"given":"Chia-Yin","family":"Lee","sequence":"first","affiliation":[{"name":"Taiwan National Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei 112304, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anh Thuc","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Taiwan National Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei 112304, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4557-1988","authenticated-orcid":false,"given":"Ly Hien","family":"Doan","sequence":"additional","affiliation":[{"name":"Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6291-4436","authenticated-orcid":false,"given":"Li-Wei","family":"Chu","sequence":"additional","affiliation":[{"name":"Department and Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Hung","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery, Far Eastern Memorial Hospital, New Taipei City 220216, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5297-6836","authenticated-orcid":false,"given":"Hui-Kang","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Basic Chinese Medicine, National Research Institute of Chinese Medicine (NRICM), Ministry of Health and Welfare, Taipei 112304, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I-Lin","family":"Lee","sequence":"additional","affiliation":[{"name":"PhytoHeath Corporation, Taipei 105403, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teng-Hsu","family":"Wang","sequence":"additional","affiliation":[{"name":"PhytoHeath Corporation, Taipei 105403, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Mei","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Life Science, College of Science and Engineering, Fu Jen Catholic University, New Taipei City 242062, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Ming","family":"Tsao","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Medicine, School of Medicine, Chung Shan Medical University Hospital, Chung Shan Medical University, Taichung 402306, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsiu-Jung","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City 220216, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2604-9913","authenticated-orcid":false,"given":"Yueh-Hsin","family":"Ping","sequence":"additional","affiliation":[{"name":"Department and Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi-Ying F.","family":"Huang","sequence":"additional","affiliation":[{"name":"Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1080\/22221751.2020.1719902","article-title":"Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan","volume":"9","author":"Chan","year":"2020","journal-title":"Emerg. 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