{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T14:32:19Z","timestamp":1772807539141,"version":"3.50.1"},"reference-count":40,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2019,12,3]],"date-time":"2019-12-03T00:00:00Z","timestamp":1575331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Curine is a bisbenzylisoquinoline alkaloid (BBA) with anti-allergic, analgesic, and anti-inflammatory properties. Previous studies have demonstrated that this alkaloid is orally active at non-toxic doses. However, the mechanisms underlying its anti-inflammatory effects remain to be elucidated. This work aimed to investigate the effects of curine on macrophage activation and neutrophil recruitment. Using a murine model of lipopolysaccharide (LPS)-induced pleurisy, we demonstrated that curine significantly inhibited the recruitment of neutrophils in association with the inhibition of cytokines tumor necrosis factor (TNF-\u03b1), interleukin (IL)-1\u03b2, IL-6, monocyte chemotactic protein (CCL2\/MCP-1) as well as leukotriene B4 in the pleural lavage of mice. Curine treatment reduced cytokine levels and the expression of iNOS in in vitro cultures of macrophages stimulated with LPS. Treatment with a calcium channel blocker resulted in comparable inhibition of TNF-\u03b1 and IL-1\u03b2 production, as well as iNOS expression by macrophages, suggesting that the anti-inflammatory effects of curine may be related to the inhibition of calcium-dependent mechanisms involved in macrophage activation. In conclusion, curine presented anti-inflammatory effects that are associated with inhibition of macrophage activation and neutrophil recruitment by inhibiting the production of inflammatory cytokines, LTB4 and nitric oxide (NO), and possibly by negatively modulating Ca2+ influx.<\/jats:p>","DOI":"10.3390\/toxins11120705","type":"journal-article","created":{"date-parts":[[2019,12,4]],"date-time":"2019-12-04T04:30:35Z","timestamp":1575433835000},"page":"705","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Curine Inhibits Macrophage Activation and Neutrophil Recruitment in a Mouse Model of Lipopolysaccharide-Induced Inflammation"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3126-6509","authenticated-orcid":false,"given":"Jaime","family":"Ribeiro-Filho","sequence":"first","affiliation":[{"name":"Laborat\u00f3rio de Investiga\u00e7\u00e3o em Gen\u00e9tica e Hematologia Translacional, Instituto Gon\u00e7alo Moniz, FIOCRUZ, Salvador 40296-710, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fagner","family":"Carvalho Leite","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunofarmacologia, Departamento de Fisiologia e Patologia, UFPB, Jo\u00e3o Pessoa 58051-900, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Surrage Calheiros","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunofarmacologia, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro 21040-360, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan","family":"de Brito Carneiro","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunofarmacologia, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro 21040-360, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juliana","family":"Alves Azeredo","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunofarmacologia, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro 21040-360, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edson","family":"Fernandes de Assis","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunofarmacologia, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro 21040-360, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Celidarque","family":"da Silva Dias","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Fitoqu\u00edmica, Departamento de Ci\u00eancias Farmac\u00eauticas, UFPB, Jo\u00e3o Pessoa 58051-900, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M\u00e1rcia","family":"Regina Piuvezam","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunofarmacologia, Departamento de Fisiologia e Patologia, UFPB, Jo\u00e3o Pessoa 58051-900, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patr\u00edcia","family":"T. Bozza","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunofarmacologia, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro 21040-360, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.immuni.2010.11.011","article-title":"Neutrophils, from marrow to microbes","volume":"33","author":"Borregaard","year":"2010","journal-title":"Immunity"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1074\/jbc.274.1.264","article-title":"p38 Mitogen-activated Protein Kinase Regulates Cyclooxygenase-2 mRNA Stability and Transcription in Lipopolysaccharide-treated Human Monocytes","volume":"274","author":"Dean","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_3","first-page":"184.6","article-title":"Production of TLRs triggered pro-inflammatory cytokines through calcium dependent and independent pathways in HaCaT cells","volume":"31","author":"Kim","year":"2017","journal-title":"FASEB J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1007\/s00441-017-2753-2","article-title":"Partners in crime: neutrophils and monocytes\/macrophages in inflammation and disease","volume":"371","author":"Kumar","year":"2018","journal-title":"Cell Tissue Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1038\/s41467-019-09046-8","article-title":"Neutrophils promote the development of reparative macrophages mediated by ROS to orchestrate liver repair","volume":"10","author":"Yang","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1055\/s-2002-35662","article-title":"Mechanisms involved in the vasodilator effect of curine in rat resistance arteries","volume":"68","author":"Dias","year":"2002","journal-title":"Planta Med."},{"key":"ref_7","unstructured":"Correa, P.M. (1984). Dicion\u00e1rio Das Plantas \u00dateis do Brasil e das Ex\u00f3ticas Cultivadas."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"8515","DOI":"10.3390\/molecules16108515","article-title":"Anti-inflammatory activity of alkaloids: An update from 2000 to 2010","volume":"16","author":"Souto","year":"2011","journal-title":"Molecules"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1211\/0022357021779032","article-title":"Mechanism of the vasodilator effect of 12-O-methylcurine in rat aortic rings","volume":"54","author":"Guedes","year":"2002","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.ejphar.2011.07.044","article-title":"Curine, abisbenzylisoquinoline alkaloid, blocks L-type Ca2+ channels and decreases intracellular Ca2+ transients in A7r5 cells","volume":"669","author":"Medeiros","year":"2011","journal-title":"Eur. J. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.taap.2013.08.015","article-title":"Curine inibits eosinophil activation and airway hyper-responsiveness in a mouse model of allergic asthma","volume":"273","author":"Calheiros","year":"2013","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1016\/j.jep.2014.06.041","article-title":"Curine inhibits mast cell-dependent responses in mice","volume":"155","author":"Leite","year":"2014","journal-title":"J. Ethnopharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1055\/s-0034-1382997","article-title":"Curine, an Alkaloid Isolated from Chondrodendron platyphyllum Inhibits Prostaglandin E2 in Experimental Models of Inflammation and Pain","volume":"80","author":"Leite","year":"2014","journal-title":"Planta Med."},{"key":"ref_14","first-page":"342","article-title":"Arginase modulates nitric oxide production in activated macrophages","volume":"274","author":"Chang","year":"1998","journal-title":"Am. J. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1590\/S0102-695X2006000100020","article-title":"Anti-inflammatory activity of alkaloids: A twenty-century review","volume":"16","author":"Piuvezam","year":"2006","journal-title":"Braz. J. Pharmacogn."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4695","DOI":"10.3390\/molecules20034695","article-title":"Anti-allergic properties of curine, a bisbenzylisoquinoline alkaloid","volume":"20","author":"Piuvezam","year":"2015","journal-title":"Molecules"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1590\/S0102-311X2000000100018","article-title":"Assist\u00eancia farmac\u00eautica na aten\u00e7\u00e3o b\u00e1sica de sa\u00fade: A experi\u00eancia de tr\u00eas estados brasileiros","volume":"16","author":"Cosendey","year":"2000","journal-title":"Cad. Sa\u00fade P\u00fablica"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/1-4020-5688-5_1","article-title":"Anti-inflammatory drugs in the 21st century","volume":"42","author":"Rainsford","year":"2007","journal-title":"Sub-Cel. Biochem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/intimm\/dxh186","article-title":"Toll-like receptors in innate immunity","volume":"17","author":"Takeda","year":"2005","journal-title":"Int. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1146\/annurev-immunol-020711-074942","article-title":"Neutrophil Function: From Mechanisms to Disease","volume":"30","author":"Amulic","year":"2012","journal-title":"Ann. Rev. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"33123","DOI":"10.1038\/srep33123","article-title":"Chemokine CXCL1 mediated neutrophil recruitment: Role of glycosaminoglycan interactions","volume":"6","author":"Sawant","year":"2010","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1182\/blood.V58.3.658.658","article-title":"Leukotriene B4 is a potent and stereospecific stimulator of neutrophil chemotaxis and adherence","volume":"58","author":"Palmblad","year":"1981","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1016\/j.devcel.2012.02.003","article-title":"LTB4 is a signal-relay molecule during neutrophil chemotaxis","volume":"22","author":"Afonso","year":"2012","journal-title":"Dev. Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6562","DOI":"10.4049\/jimmunol.1002400","article-title":"Leukotriene B4 mediates neutrophil migration induced by heme","volume":"186","author":"Monteiro","year":"2011","journal-title":"J. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.4049\/jimmunol.145.6.1727","article-title":"IFN-gamma enhances endothelial activation induced by tumor necrosis factor but not IL-1","volume":"145","author":"Doukas","year":"1990","journal-title":"J. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.4049\/jimmunol.154.4.1870","article-title":"Regulation of the production of the RANTES chemokine by endothelial cells. Synergistic induction by IFN-gamma plus TNF-alpha and inhibition by IL-4 and IL-13","volume":"154","author":"Devergne","year":"1995","journal-title":"J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1301\/nr.2007.dec.S140-S146","article-title":"Inflammatory Mechanisms: The Molecular Basis of Inflammation and Disease","volume":"65","author":"Libby","year":"2007","journal-title":"Nutr. Rev."},{"key":"ref_28","first-page":"281","article-title":"Macrophages in inflammation and Allergy","volume":"4","author":"Fujiwara","year":"2005","journal-title":"Curr. Drug Targets"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/j.it.2009.06.006","article-title":"Neutrophil granule proteins tune monocytic cell function","volume":"30","author":"Soehnlein","year":"2009","journal-title":"Trends Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.niox.2010.01.001","article-title":"Nitric oxide donors release extracellular traps from human neutrophils by augmenting free radical generation","volume":"22","author":"Patel","year":"2010","journal-title":"Nitric Oxide"},{"key":"ref_31","first-page":"109","article-title":"Nitric oxide: Physiology, pathophysiology, and pharmacology","volume":"43","author":"Moncada","year":"1991","journal-title":"Pharmacol. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.celrep.2019.03.011","article-title":"Intercellular Calcium Signaling Induced by ATP Potentiates Macrophage Phagocytosis","volume":"27","author":"Zumerle","year":"2019","journal-title":"Cell Rep."},{"key":"ref_33","first-page":"1","article-title":"Purinergic and calcium signaling in macrophage function and plasticity","volume":"5","author":"Desai","year":"2010","journal-title":"Front. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1111\/j.1476-5381.1992.tb14503.x","article-title":"The pivotal role of tumour necrosis factor alpha in the development of inflammatory hyperalgesia","volume":"107","author":"Cunha","year":"1992","journal-title":"Br. J. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1038\/334698a0","article-title":"Interleukin-1\u03b2 as a potent hyperalgesic agent antagonized by a tripeptide analogue","volume":"334","author":"Ferreira","year":"1988","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.niox.2011.06.004","article-title":"Pain and analgesia: The dual effect of nitric oxide in the nociceptive system","volume":"25","author":"Cury","year":"2011","journal-title":"Nitric Oxide"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1055\/s-2000-8610","article-title":"Spectral characterisation and antiplasmodial activity of bisbenzylisoquinolines from Isolona ghesquiereina","volume":"66","author":"Mambu","year":"2000","journal-title":"Planta Med."},{"key":"ref_38","unstructured":"Brasil. Conselho Nacional de Controle de Experimenta\u00e7\u00e3o animal (CONCEA) (2019, October 15). Procedimentos\u2013Roedores E Lagomorfos Mantidos Em Instala\u00e7\u00f5es de Institui\u00e7\u00f5es de Ensino Ou Pesquisa Cient\u00edfica. Resolu\u00e7\u00e3o Normativa N\u00b0 33, de 18 de Novembro de 2016, Available online: http:\/\/www.in.gov.br\/materia\/-\/asset_publisher\/Kujrw0TZC2Mb\/content\/id\/22073702\/do1-2016-11-21-resolucao-normativa-n-33-de-18-de-novembro-de-2016-22073453."},{"key":"ref_39","first-page":"7","article-title":"Rodent gavage technique concerns: Avoiding excess mortality","volume":"40","author":"McIntyre","year":"2001","journal-title":"Contemp. Top. Lab. Anim. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/PL00000249","article-title":"Mechanisms of allergen- and LPS-induced bone marrow eosinophil mobilization and eosinophil accumulation into the pleural cavity: A role for CD11b\/CD18 complex","volume":"50","author":"Laranjeira","year":"2001","journal-title":"Inflamm. Res."}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/11\/12\/705\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:39:45Z","timestamp":1760189985000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/11\/12\/705"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,3]]},"references-count":40,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["toxins11120705"],"URL":"https:\/\/doi.org\/10.3390\/toxins11120705","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,3]]}}}