{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T03:48:32Z","timestamp":1771645712719,"version":"3.50.1"},"reference-count":28,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2023,11,27]],"date-time":"2023-11-27T00:00:00Z","timestamp":1701043200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Treatment of cutaneous leishmaniasis depends on drugs that potentially cause serious side effects and resistance. Thus, topical therapies are attractive alternatives to the drugs currently used. 3\u03b2, 6\u03b2, 16\u03b2-trihydroxylup-20 (29)-ene is a lupane triterpene isolated from<jats:italic>Combretum leprosum<\/jats:italic>Mart. leaves (CLF-1), with reports of<jats:italic>in vitro<\/jats:italic>antileishmanial effect against<jats:italic>L<\/jats:italic>.<jats:italic>amazonensis<\/jats:italic>and to promote lesion healing in animal model. Herein, we evaluated the<jats:italic>in vitro<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>antileishmanial and healing effects of CLF-1 against<jats:italic>L<\/jats:italic>.<jats:italic>braziliensis<\/jats:italic>. CLF-1 treatment showed low toxicity in macrophages and significantly reduced parasite load<jats:italic>in vitro<\/jats:italic>. CLF-1 induced higher IL-12 and TNF-\u03b1 production and more discrete IL-4 and IL-10 production. For<jats:italic>in vivo<\/jats:italic>evaluation, a CLF-1 cream formulation was prepared to treat hamsters infected with<jats:italic>L<\/jats:italic>.<jats:italic>braziliensis<\/jats:italic>. CLF-1 treatment was able to reduce parasite load of the infected skin and lymph node more efficiently than the conventional treatment. Histopathological analysis indicated a strong inflammatory response accompanied by an important healing response. Data from this study indicate that topical CLF-1 treatment was effective and non-toxic in<jats:italic>L<\/jats:italic>.<jats:italic>braziliensis<\/jats:italic>infected hamsters suggesting its potential for further development as a future therapeutic intervention.<\/jats:p>","DOI":"10.1371\/journal.pone.0287665","type":"journal-article","created":{"date-parts":[[2023,11,27]],"date-time":"2023-11-27T19:18:58Z","timestamp":1701112738000},"page":"e0287665","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Leishmanicidal and healing effects of 3\u03b2,6\u03b2,16\u03b2-trihydroxy lup-20 (29)-ene isolated from Combretum leprosum on Leishmania braziliensis infection in vitro and in vivo"],"prefix":"10.1371","volume":"18","author":[{"given":"Aline","family":"Sombra Santos","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naya L\u00facia","family":"de Castro Rodrigues","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francisco Rafael","family":"Marciano Fonseca","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathalia","family":"Braga Fay\u00e3o Oliveira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9803-9525","authenticated-orcid":true,"given":"Bianca","family":"Oliveira Loucard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fab\u00edola","family":"Fernandes Heredia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa Neuma","family":"Albuquerque Gomes Nogueira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ticiana","family":"Monteiro Abreu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5527-164X","authenticated-orcid":true,"given":"H\u00e9lcio","family":"Silva dos Santos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edson","family":"Holanda Teixeira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luzia Kalyne","family":"Almeida Moreira Leal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Regis Bernardo","family":"Brandim Gomes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clarissa","family":"Romero Teixeira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Jania","family":"Teixeira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,11,27]]},"reference":[{"key":"pone.0287665.ref001","doi-asserted-by":"crossref","first-page":"e3283","DOI":"10.1371\/journal.pntd.0003283","article-title":"Forecasting temporal dynamics of cutaneous leishmaniasis in northeast Brazil","volume":"8","author":"JA Lewnard","year":"2014","journal-title":"PLos Neglected Trop Diseas"},{"key":"pone.0287665.ref002","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/clinids\/22.1.1","article-title":"Clinical spectrum of Leishmaniasis","volume":"22","author":"RD Pearson","year":"1996","journal-title":"Clin Infect Dis"},{"key":"pone.0287665.ref003","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1080\/00034983.1988.11812290","article-title":"Grimaldi Jr.G, Alencar JE. Epidemiological studies on American leishmaniasis in Cear\u00e1 state, Brazil. A. of","volume":"82","author":"IAB Vasconcelos","year":"1988","journal-title":"Trop. Med. & Parasitol"},{"key":"pone.0287665.ref004","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1016\/j.jaad.2014.08.051","article-title":"Clinical and mucocutaneous leishmaniasis: Clinical perspectives","volume":"73","author":"MZ Handler","year":"2015","journal-title":"J.Am.Dermatol"},{"key":"pone.0287665.ref005","doi-asserted-by":"crossref","first-page":"e1947","DOI":"10.1371\/journal.pntd.0001947","article-title":"IFN-\u03b3 production to Leishmania antigen supplements the Leishmania skin test in identifying exposure to L. braziliensis infection","volume":"6","author":"D Schnorr","year":"2012","journal-title":"Plos Neglect Diseas"},{"key":"pone.0287665.ref006","doi-asserted-by":"crossref","first-page":"6734","DOI":"10.1128\/IAI.70.12.6734-6740.2002","article-title":"Up-regulation of Th1-type responses in mucosal leishmaniasis patients","volume":"70","author":"O Bacellar","year":"2002","journal-title":"Infect and Immun"},{"key":"pone.0287665.ref007","doi-asserted-by":"crossref","first-page":"6139","DOI":"10.4049\/jimmunol.180.9.6139","article-title":"Immunological and genetic evidence for a crucial role of IL-10 in cutaneous lesions in humans infected with Leishmania braziliensis","volume":"180","author":"A Salhi","year":"2008","journal-title":"J of Immunol"},{"key":"pone.0287665.ref008","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1038\/nri933","article-title":"The immunology of susceptibility and resistance to Leishmania major in mice","volume":"2","author":"D Sacks","year":"2002","journal-title":"Nature Reviews Immunol"},{"key":"pone.0287665.ref009","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1111\/j.1365-2249.2007.03436.x","article-title":"Can interferon-\u03b3 and interleukin-10 balance be associated with severity of human Leishmania (Viannia) braziliensis infection?","volume":"149","author":"A Gomes-Silva","year":"2007","journal-title":"Clin. And Experim. Immunol"},{"key":"pone.0287665.ref010","doi-asserted-by":"crossref","first-page":"319","DOI":"10.2174\/1381612023396258","article-title":"Chemotherapy of leishmaniasis","volume":"8","author":"SL Croft","year":"2002","journal-title":"Curr.Pharm.Des"},{"key":"pone.0287665.ref011","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s40249-016-0112-2","article-title":"Current challenges in treatment options for visceral leishmaniasis in India: a public health perspective","volume":"8","author":"OP Singh","year":"2016","journal-title":"Infect. Dis. Pov"},{"key":"pone.0287665.ref012","first-page":"98","article-title":"Recent developments and prospects in the treatment of visceral leishmaniasis","volume":"3","author":"S Sundar","year":"2016","journal-title":"Therap. Advances in Infect. Dis"},{"key":"pone.0287665.ref013","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1111\/j.1469-0691.2011.03630.x","article-title":"Leishmaniasis chemotherapy\u2013challenges and opportunities","volume":"17","author":"SLL Croft","year":"2011","journal-title":"Clinical Microbiol. and Infect"},{"key":"pone.0287665.ref014","first-page":"58","volume":"22","author":"PM Cheuka","year":"2016","journal-title":"The role of natural products in drug discovery and development against neglected tropical diseases"},{"key":"pone.0287665.ref015","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1590\/S0103-50532011000500017","article-title":"Activity of the lupane isolated from Combretum leprosum against Leishmania amazonensis promastigotes","volume":"22","author":"CBG Teles","year":"2011","journal-title":"J of Brazil. Chem, Soc"},{"key":"pone.0287665.ref016","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1186\/s12906-015-0681-9","article-title":"A lupane-triterpene isolated from Combretum leprosum Mart. fruit extracts that interferes with the intracellular development of Leishmania (L.) amazonensis in vitro","volume":"15","author":"CBG Teles","year":"2015","journal-title":"BMC Complem. and Altern. Med"},{"key":"pone.0287665.ref017","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.jep.2015.05.037","article-title":"Effect of the triterpene 3\u03b2, 6\u03b2, 16\u03b2-trihydroxydroxylup-20(29)-ene isolated from leaves of Combretum leprosum Mart. on cutaneous wounds in mice","volume":"171","author":"LG Nascimento-Neto","year":"2015","journal-title":"J. of Ethnopharmacology"},{"key":"pone.0287665.ref018","first-page":"729358","article-title":"Antimicrobial effect of the triterpene 3\u03b2, 6\u03b2, 16\u03b2-trihydroxylp-20(29)-ene on planktonic cells and biofilms from gram positive and gram negative bacteria","volume":"2014","author":"FFV Evaristo","year":"2014","journal-title":"Biomed Res. Intern"},{"key":"pone.0287665.ref019","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1007\/s12639-021-01455-1","article-title":"Anti-Leishmania infantum in vitro effect of n-cyclohexyl-1,2,4-xadiazole and its ADME\/TOX parameters","volume":"46","author":"CVG Pinheiro","year":"2021","journal-title":"J. Parasit. Dis"},{"key":"pone.0287665.ref020","doi-asserted-by":"crossref","first-page":"5827","DOI":"10.1128\/IAI.73.9.5827-5834.2005","article-title":"Toward a novel experimental model of infection to study American cutaneous leishmaniasis caused by Leishmania braziliensis","volume":"73","author":"TR De Moura","year":"2005","journal-title":"Infect. Immun"},{"key":"pone.0287665.ref021","doi-asserted-by":"crossref","first-page":"2108","DOI":"10.4049\/jimmunol.135.3.2108","article-title":"Therapeutic effect of anti-L3T4 monoclonal antibody GK 1.5 on cutaneous leishmaniasis in genetically\u2013susceptible BALB\/c mice","volume":"135","author":"RG Titus","year":"1985","journal-title":"The J. of Immuno"},{"key":"pone.0287665.ref022","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/0022-1759(84)90430-7","article-title":"Limiting dilution assays for the determination of immunocompetent cell frequencies III. Validity tests for the single-hit Poisson model","volume":"72","author":"C. Taswell","year":"1984","journal-title":"J. Immunol. Meth"},{"key":"pone.0287665.ref023","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1086\/507710","article-title":"American tegumentary leishmaniasis: is antimonial treatment outcome related to parasite drug susceptibility?","volume":"194","author":"V Yardley","year":"2006","journal-title":"The J. of Infect. Dis"},{"key":"pone.0287665.ref024","first-page":"68","article-title":"In vitro sensitivity of Leishmania (Viannia) braziliensis and Leishmania (Leishmania) amazonensis Brazilian isolates to meglumine antimoniate and amphotericin B","volume":"15","author":"RC Zauli-Nascimento","year":"2010","journal-title":"Trop. Med. and Intern. Health"},{"key":"pone.0287665.ref025","doi-asserted-by":"crossref","first-page":"776","DOI":"10.3390\/ph15070776","article-title":"Therapeutic efficacy of Arnica in hamsters with Cutaneous Leishmaniasis caused by Leishmania braziliensis and L. tropica","volume":"15","author":"SM Robledo","year":"2022","journal-title":"Pharmaceuticals"},{"key":"pone.0287665.ref026","doi-asserted-by":"crossref","first-page":"e180535","DOI":"10.1590\/0074-02760180535","article-title":"Therapeutic response and safety of the topical, sequential use of antiseptic, keratolytic, and pentamidine creams (3-PACK) on Leishmania (Viannia) braziliensis-infected mice","volume":"114","author":"BY Mu\u00f1oz","year":"2019","journal-title":"Mem. Inst Oswaldo Cruz"},{"key":"pone.0287665.ref027","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1093\/jac\/dkz049","article-title":"Anti-leishmanial activity of a topical miltefosine gel in experimental models of New World cutaneous leishmamiasis","volume":"74","author":"LF Neira","year":"2019","journal-title":"J Antimicrob Chemother"},{"key":"pone.0287665.ref028","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1590\/S0100-879X1998000100020","article-title":"Cytokine profile and pathology in human leishmaniasis","volume":"31","author":"A. Ribeiro-de-Jesus","year":"1998","journal-title":"Braz J Med Biol Res"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0287665","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,26]],"date-time":"2023-12-26T20:55:51Z","timestamp":1703624151000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0287665"}},"subtitle":[],"editor":[{"given":"Manas Ranjan","family":"Dikhit","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2023,11,27]]},"references-count":28,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,11,27]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0287665","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,27]]}}}