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Increased von Willebrand factor (vWF) plasma levels, stemming from activated platelets and endothelium injury during sepsis, can bind to integrin \u03b1v\u03b23, exacerbating endothelial permeability. Hence, targeting this pathway presents a potential therapeutic avenue for sepsis. Recently, we identified isaridin E (ISE), a marine-derived fungal cyclohexadepsipeptide, as a promising antiplatelet and antithrombotic agent with a low bleeding risk. ISE\u2019s influence on septic mortality and sepsis-induced lung injury in a mouse model of sepsis, induced by caecal ligation and puncture, is investigated in this study. ISE dose-dependently improved survival rates, mitigating lung injury, thrombocytopenia, pulmonary endothelial permeability, and vascular inflammation in the mouse model. ISE markedly curtailed vWF release from activated platelets in septic mice by suppressing vesicle-associated membrane protein 8 and soluble N-ethylmaleide-sensitive factor attachment protein 23 overexpression. Moreover, ISE inhibited healthy human platelet adhesion to cultured lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs), thereby significantly decreasing vWF secretion and endothelial hyperpermeability. Using cilengitide, a selective integrin \u03b1v\u03b23 inhibitor, it was found that ISE can improve endothelial hyperpermeability by inhibiting vWF binding to \u03b1v\u03b23. Activation of the integrin \u03b1v\u03b23-FAK\/Src pathway likely underlies vWF-induced endothelial dysfunction in sepsis. In conclusion, ISE protects against sepsis by inhibiting endothelial hyperpermeability and platelet-endothelium interactions.<\/jats:p>","DOI":"10.3390\/md22060283","type":"journal-article","created":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T06:29:43Z","timestamp":1718605783000},"page":"283","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Isaridin E Protects against Sepsis by Inhibiting Von Willebrand Factor-Induced Endothelial Hyperpermeability and Platelet\u2013Endothelium Interaction"],"prefix":"10.3390","volume":"22","author":[{"given":"Yao-Sheng","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Liang","family":"Chen","sequence":"additional","affiliation":[{"name":"Scientific Research Center, the Medical Interdisciplinary Science Research Center of Western Guangdong, College of Women and Children, the Second Affiliated Hospital of Guangdong Medical University, Zhanjiang 524023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Wei","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Hong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao-Lin","family":"Zheng","sequence":"additional","affiliation":[{"name":"Division of Biosciences, University College London, London WC1E 6BT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ni","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, The Second Clinical College, Guangzhou Medical University, Guangzhou 510261, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Yan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sen-Hua","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Marine Sciences, Sun Yat-sen University, Guangzhou 510006, China"},{"name":"Southern Marine Sciences and Engineering Guangdong Laboratory (Zhuhai), Zhuhai 519000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3036-3879","authenticated-orcid":false,"given":"Ming-Hua","family":"Jiang","sequence":"additional","affiliation":[{"name":"School of Marine Sciences, Sun Yat-sen University, Guangzhou 510006, China"},{"name":"Southern Marine Sciences and Engineering Guangdong Laboratory (Zhuhai), Zhuhai 519000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen-Chen","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Chen","family":"Mi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao-Hui","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Zhe","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-Jun","family":"Liu","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Clinical Research Center of Critical Care Medicine, Guangzhou 510080, China"},{"name":"Department of Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, 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