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This study investigates the anti-inflammatory activity of caulerpin, a bisindolic alkaloid isolated from Caulerpa racemosa. In vitro assays demonstrated that caulerpin significantly reduced nitric oxide, TNF-\u03b1, IL-6, and IL-12 levels in macrophages stimulated with LPS + IFN-\u03b3, without affecting cell viability. In silico toxicity predictions using Protox 3.0 reinforce a favorable safety profile of caulerpin. Molecular docking and molecular dynamics simulations revealed its high-affinity binding to the glucocorticoid receptor ligand-binding domain (GR-LBD), suggesting a mechanism of action similar to dexamethasone. The involvement of the glucocorticoid receptor was confirmed by the partial reversal of caulerpin\u2019s effects upon RU486 treatment. In vivo, caulerpin exhibited a favorable safety profile, with no signs of acute toxicity at an oral dose of 100 mg\/kg. Moreover, in a mouse model of endotoxic shock, caulerpin administration significantly improved survival rates in a dose-dependent manner, providing complete protection at 4 mg\/kg. These findings highlight caulerpin as a promising candidate for the development of novel anti-inflammatory therapies. Further studies are warranted to explore its pharmacokinetics, optimize its structure, and evaluate its efficacy in chronic inflammatory diseases.<\/jats:p>","DOI":"10.3390\/md23060232","type":"journal-article","created":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T04:46:38Z","timestamp":1748493998000},"page":"232","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The Alkaloid Caulerpin Exhibits Potent and Selective Anti-Inflammatory Activity Through Interaction with the Glucocorticoid Receptor"],"prefix":"10.3390","volume":"23","author":[{"given":"J\u00f4natas Sousa Pires","family":"dos Santos","sequence":"first","affiliation":[{"name":"Department of Life Sciences, State University of Bahia (UNEB), Salvador 40020-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dahara Keyse Carvalho","family":"Silva","sequence":"additional","affiliation":[{"name":"Gon\u00e7alo Moniz Institute, Oswaldo Cruz Foundation, FIOCRUZ, Salvador 40296-710, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"da Silva Oliveira","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, State University of Bahia (UNEB), Salvador 40020-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5074-4016","authenticated-orcid":false,"given":"Sergio Santos Silva","family":"Junior","sequence":"additional","affiliation":[{"name":"Gon\u00e7alo Moniz Institute, Oswaldo Cruz Foundation, FIOCRUZ, Salvador 40296-710, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edivaldo","family":"dos Santos Rodrigues","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Modeling and Computational Structural Biology, Walter Mors Natural Products Research Institute, Health Sciences Center, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro 21941-599, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia Valeria Campos","family":"de Souza","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Modeling and Computational Structural Biology, Walter Mors Natural Products Research Institute, Health Sciences Center, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro 21941-599, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina Teixeira","family":"Martinez","sequence":"additional","affiliation":[{"name":"Institute of Innovation in Advanced Health Systems (ISI SAS), University SENAI\/CIMATEC, Salvador 41650-010, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7407-158X","authenticated-orcid":false,"given":"Osvaldo Andrade","family":"Santos-Filho","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Modeling and Computational Structural Biology, Walter Mors Natural Products Research Institute, Health Sciences Center, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro 21941-599, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7578-3615","authenticated-orcid":false,"given":"C\u00e1ssio Santana","family":"Meira","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, State University of Bahia (UNEB), Salvador 40020-000, Brazil"},{"name":"Gon\u00e7alo Moniz Institute, Oswaldo Cruz Foundation, FIOCRUZ, Salvador 40296-710, Brazil"},{"name":"Institute of Innovation in Advanced Health Systems (ISI SAS), University SENAI\/CIMATEC, Salvador 41650-010, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milena Botelho Pereira","family":"Soares","sequence":"additional","affiliation":[{"name":"Gon\u00e7alo Moniz Institute, Oswaldo Cruz Foundation, FIOCRUZ, Salvador 40296-710, Brazil"},{"name":"Institute of Innovation in Advanced Health Systems (ISI SAS), University SENAI\/CIMATEC, Salvador 41650-010, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"121","DOI":"10.4103\/aam.aam_56_18","article-title":"Inflammation and cancer","volume":"18","author":"Singh","year":"2019","journal-title":"Ann. 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