{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:15:02Z","timestamp":1787030102274,"version":"build-2736575974"},"reference-count":42,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T00:00:00Z","timestamp":1697500800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"S\u00e3o Paulo Research Foundation","doi-asserted-by":"publisher","award":["2017\/11161\u20136"],"award-info":[{"award-number":["2017\/11161\u20136"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"S\u00e3o Paulo Research Foundation","doi-asserted-by":"publisher","award":["Finance Code 001"],"award-info":[{"award-number":["Finance Code 001"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"S\u00e3o Paulo Research Foundation","doi-asserted-by":"publisher","award":["301685\/2017\u20137"],"award-info":[{"award-number":["301685\/2017\u20137"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"S\u00e3o Paulo Research Foundation","doi-asserted-by":"publisher","award":["312491-2021-2"],"award-info":[{"award-number":["312491-2021-2"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior\u2014Brasil (CAPES)","award":["2017\/11161\u20136"],"award-info":[{"award-number":["2017\/11161\u20136"]}]},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior\u2014Brasil (CAPES)","award":["Finance Code 001"],"award-info":[{"award-number":["Finance Code 001"]}]},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior\u2014Brasil (CAPES)","award":["301685\/2017\u20137"],"award-info":[{"award-number":["301685\/2017\u20137"]}]},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior\u2014Brasil (CAPES)","award":["312491-2021-2"],"award-info":[{"award-number":["312491-2021-2"]}]},{"name":"National Council for Scientific and Technological Development-CNPQ","award":["2017\/11161\u20136"],"award-info":[{"award-number":["2017\/11161\u20136"]}]},{"name":"National Council for Scientific and Technological Development-CNPQ","award":["Finance Code 001"],"award-info":[{"award-number":["Finance Code 001"]}]},{"name":"National Council for Scientific and Technological Development-CNPQ","award":["301685\/2017\u20137"],"award-info":[{"award-number":["301685\/2017\u20137"]}]},{"name":"National Council for Scientific and Technological Development-CNPQ","award":["312491-2021-2"],"award-info":[{"award-number":["312491-2021-2"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Macrophage plasticity is a fundamental feature of the immune response since it favors the rapid and adequate change of the functional phenotype in response to the pathogen or the microenvironment. Several studies have shown that Crotoxin (CTX), the major toxin of the Crotalus durissus terrificus snake venom, has a long-lasting antitumor effect both in experimental models and in clinical trials. In this study, we show the CTX effect on the phenotypic reprogramming of macrophages in the mesenchymal tumor microenvironment or those obtained from the peritoneal cavity of healthy animals. CTX (0.9 or 5 \u03bcg\/animal subcutaneously) administered concomitantly with intraperitoneal inoculation of tumor cells (1 \u00d7 107\/0.5 mL, injected intraperitoneally) of Ehrlich Ascitic Tumor (EAT) modulated the macrophages phenotype (M1), accompanied by increased NO\u2022 production by cells from ascites, and was evaluated after 13 days. On the other hand, in healthy animals, the phenotypic profile of macrophages was modulated in a dose-dependent way at 0.9 \u03bcg\/animal: M1 and at 5.0 \u03bcg\/animal: M2; this was accompanied by increased NO\u2022 production by peritoneal macrophages only for the dose of 0.9 \u03bcg\/animal of CTX. This study shows that a single administration of CTX interferes with the phenotypic reprogramming of macrophages, as well as with the secretory state of cells from ascites, influencing events involved with mesenchymal tumor progression. These findings may favor the selection of new therapeutic targets to correct compromised immunity in different systems.<\/jats:p>","DOI":"10.3390\/toxins15100616","type":"journal-article","created":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T08:25:09Z","timestamp":1697531109000},"page":"616","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Crotoxin Modulates Macrophage Phenotypic Reprogramming"],"prefix":"10.3390","volume":"15","author":[{"given":"Camila Lima","family":"Neves","sequence":"first","affiliation":[{"name":"Laboratory of Pathophysiology, Butantan Institute, S\u00e3o Paulo 05503-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiano Marcello Vaz","family":"Barbosa","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Federal University of S\u00e3o Paulo, S\u00e3o Paulo 04044-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priscila Andrade","family":"Ran\u00e9ia-Silva","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, University of Ribeir\u00e3o Preto, Campus Guaruj\u00e1, S\u00e3o Paulo 11440-003, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliana L.","family":"Faquim-Mauro","sequence":"additional","affiliation":[{"name":"Laboratory of Immunopathology, Butantan Institute, S\u00e3o Paulo 05503-900, Brazil"},{"name":"Department of Immunology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-220, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra Coccuzzo","family":"Sampaio","sequence":"additional","affiliation":[{"name":"Laboratory of Pathophysiology, Butantan Institute, S\u00e3o Paulo 05503-900, Brazil"},{"name":"Department of Pharmacology, Institute of Biomedical Sciences, University of S\u00e3o Paulo, S\u00e3o Paulo 05508-220, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/s10555-006-9001-7","article-title":"Role of Tumor-Associated Macrophages in Tumor Progression and Invasion","volume":"25","author":"Mantovani","year":"2006","journal-title":"Cancer Metastasis Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"642","DOI":"10.4049\/jimmunol.1000413","article-title":"Tumor-Conditioned Macrophages Secrete Migration-Stimulating Factor: A New Marker for M2-Polarization, Influencing Tumor Cell Motility","volume":"185","author":"Solinas","year":"2010","journal-title":"J. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1111\/j.1365-2249.2011.04515.x","article-title":"Immunology in the Clinic Review Series; Focus on Cancer: Tumour-Associated Macrophages: Undisputed Stars of the Inflammatory Tumour Microenvironment","volume":"167","author":"Allavena","year":"2012","journal-title":"Clin. Exp. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1016\/j.ejca.2006.01.003","article-title":"Tumour-Associated Macrophages Are a Distinct M2 Polarised Population Promoting Tumour Progression: Potential Targets of Anti-Cancer Therapy","volume":"42","author":"Sica","year":"2006","journal-title":"Eur. J. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.semcancer.2008.03.004","article-title":"Macrophage Polarization in Tumour Progression","volume":"18","author":"Sica","year":"2008","journal-title":"Semin. Cancer Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/0167-5699(92)90008-U","article-title":"The Origin and Function of Tumor-Associated Macrophages","volume":"13","author":"Mantovani","year":"1992","journal-title":"Immunol. Today"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1674","DOI":"10.4049\/jimmunol.153.4.1674","article-title":"Tumor-Induced Regulation of Suppressor Macrophage Nitric Oxide and TNF-Alpha Production. Role of Tumor-Derived IL-10, TGF-Beta, and Prostaglandin E2","volume":"153","author":"Alleva","year":"1994","journal-title":"J. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1023\/A:1009685206353","article-title":"Cytokine-Induced Production of NO by Macrophages Induces Apoptosis and Immunological Rejection of AK-5 Histiocytic Tumor","volume":"3","author":"Bhaumik","year":"1998","journal-title":"Apoptosis"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2128","DOI":"10.1111\/j.1349-7006.2010.01652.x","article-title":"Involvement of M2-Polarized Macrophages in the Ascites from Advanced Epithelial Ovarian Carcinoma in Tumor Progression via Stat3 Activation","volume":"101","author":"Takaishi","year":"2010","journal-title":"Cancer Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2972","DOI":"10.2353\/ajpath.2010.090879","article-title":"Tumor Progression Stage and Anatomical Site Regulate Tumor-Associated Macrophage and Bone Marrow-Derived Monocyte Polarization","volume":"176","author":"Redente","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Na, Y.R., Yoon, Y.N., Son, D.I., and Seok, S.H. (2013). Cyclooxygenase-2 Inhibition Blocks M2 Macrophage Differentiation and Suppresses Metastasis in Murine Breast Cancer Model. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0063451"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1111\/cas.12452","article-title":"Antitumor Effect of Nuclear Factor-\u039aB Decoy Transfer by Mannose-Modified Bubble Lipoplex into Macrophages in Mouse Malignant Ascites","volume":"105","author":"Kono","year":"2014","journal-title":"Cancer Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/nrclinonc.2016.217","article-title":"Tumour-Associated Macrophages as Treatment Targets in Oncology","volume":"14","author":"Mantovani","year":"2017","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_14","first-page":"505","article-title":"Estudos Qu\u00edmicos Sobre Os Venenos Of\u00eddicos. 4\u2014Purifica\u00e7\u00e3o e Cristaliza\u00e7\u00e3o Do Veneno Da Cobra Cascavel","volume":"12","author":"Slotta","year":"1938","journal-title":"Mem. Inst. Butantan"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/0003-9861(56)90397-6","article-title":"Fractionation and Composition of Crotoxin","volume":"60","author":"Singer","year":"1956","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_16","first-page":"394","article-title":"Neurotoxins from South American Rattlesnake","volume":"71","author":"Brazil","year":"1972","journal-title":"J. Formos. Med. Assoc."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/0041-0101(84)90141-7","article-title":"Cellular and Mitochondrial Changes Induced in the Structure of Murine Skeletal Muscle by Crotoxin, a Neurotoxic Phospholipase A2 Complex","volume":"22","author":"Gopalakrishnakone","year":"1984","journal-title":"Toxicon"},{"key":"ref_18","unstructured":"Stocker, K. (1990). Medical Use of Snake Venom Proteins, CRC Press."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/j.toxicon.2010.01.011","article-title":"Crotoxin: Novel Activities for a Classic \u03b2-Neurotoxin","volume":"55","author":"Sampaio","year":"2010","journal-title":"Toxicon"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.jmb.2011.07.027","article-title":"Crystal Structure of Crotoxin Reveals Key Residues Involved in the Stability and Toxicity of This Potent Heterodimeric \u03b2-Neurotoxin","volume":"412","author":"Faure","year":"2011","journal-title":"J. Mol. Biol."},{"key":"ref_21","first-page":"1033","article-title":"Phase I and Pharmacokinetics Study of Crotoxin (Cytotoxic PLA2, NSC-624244) in Patients with Advanced Cancer","volume":"8","author":"Cura","year":"2002","journal-title":"Clin. Cancer Res."},{"key":"ref_22","unstructured":"Reid, P.F. (2013). Crotoxin Administration for Cancer Treatment and Pain Relief. (8921305B2), U.S. Patent."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.toxicon.2022.07.011","article-title":"Crotoxin modulates metabolism and secretory activity of peritoneal macrophages from Walker 256 tumor-bearing rats","volume":"15","author":"Faiad","year":"2022","journal-title":"Toxicon"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1080\/09629350124986","article-title":"Role of Crotoxin, a Phospholipase A2 Isolated from Crotalus Durissus Terrificus Snake Venom, on Inflammatory and Immune Reactions","volume":"10","author":"Cardoso","year":"2001","journal-title":"Mediat. Inflamm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1016\/j.toxicon.2009.12.011","article-title":"Crotoxin Is Responsible for the Long-Lasting Anti-Inflammatory Effect of Crotalus Durissus Terrificus Snake Venom: Involvement of Formyl Peptide Receptors","volume":"55","author":"Nunes","year":"2010","journal-title":"Toxicon"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.vascn.2014.09.001","article-title":"Characterization of the Inflammatory Response during Ehrlich Ascitic Tumor Development","volume":"71","author":"Fernandes","year":"2015","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"ref_27","first-page":"171","article-title":"Tumor Transplantation","volume":"Volume II","author":"Gay","year":"1965","journal-title":"Methods of Animal Experimentation"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1016\/j.intimp.2005.07.002","article-title":"Angiogenic and Proliferative Effects of the Cytokine VEGF in Ehrlich Ascites Tumor Cells Is Inhibited by Glycyrrhiza Glabra","volume":"6","author":"Sheela","year":"2006","journal-title":"Int. Immunopharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10147-012-0396-6","article-title":"Malignant Ascites: Pathophysiology and Treatment","volume":"18","author":"Cavazzoni","year":"2013","journal-title":"Int. J. Clin. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4281","DOI":"10.1038\/s41598-019-40903-0","article-title":"Crotoxin Promotes Macrophage Reprogramming towards an Antiangiogenic Phenotype","volume":"9","author":"Bretones","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1080\/0962935029000041","article-title":"Cytokine Profile of Ehrlich Ascites Tumor Treated with Bothrops Jararaca Venom","volume":"11","author":"Vilela","year":"2002","journal-title":"Mediat. Inflamm."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2457532","DOI":"10.1155\/2016\/2457532","article-title":"Walker 256 Tumor Growth Suppression by Crotoxin Involves Formyl Peptide Receptors and Lipoxin A4","volume":"2016","author":"Brigatte","year":"2016","journal-title":"Mediat. Inflamm."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1002\/ijc.30424","article-title":"Lipoxin A4 Selectively Programs the Profile of M2 Tumor-Associated Macrophages Which Favour Control of Tumor Progression","volume":"140","author":"Morandi","year":"2017","journal-title":"Int. J. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1084\/jem.20021183","article-title":"Parasite-Induced Lipoxin A 4 Is an Endogenous Regulator of IL-12 Production and Immunopathology in Toxoplasma Gondii Infection","volume":"196","author":"Aliberti","year":"2002","journal-title":"J. Exp. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"91","DOI":"10.2174\/187152806776383125","article-title":"Lipoxin and Synthetic Lipoxin Analogs: An Overview of Anti-Inflammatory Functions and New Concepts in Immunomodulation","volume":"5","author":"Parkinson","year":"2006","journal-title":"Inflamm. Allergy Drug Targets"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.toxicon.2013.08.057","article-title":"Involvement of formyl peptide receptors in the stimulatory effect of crotoxin on macrophages co-cultivated with tumour cells","volume":"74","author":"Costa","year":"2013","journal-title":"Toxicon"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"S24","DOI":"10.1016\/j.toxicon.2019.06.106","article-title":"Crotoxin modulates the phenotypic reprogramming of quiescent macrophages or stimulated by tumor microenvironment","volume":"168","author":"Neves","year":"2019","journal-title":"Toxicon"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/j.toxicon.2004.07.004","article-title":"Immunosuppresive Role of Principal Toxin (Crotoxin) of Crotalus Durissus Terrificus Venom","volume":"44","author":"Lima","year":"2004","journal-title":"Toxicon"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/0003-2697(76)90527-3","article-title":"A Rapid and Sensitive Method for the Quantitation of Microgram Quantities of Protein Utilizing the Principle of Protein-Dye Binding","volume":"72","author":"Bradford","year":"1976","journal-title":"Anal. Biochem."},{"key":"ref_40","first-page":"734","article-title":"Kinetic Peculiarities of the Development of Ehrlich Ascites Tumor in Linear and Non-Linear Mice","volume":"5","author":"Ostrovskaia","year":"1966","journal-title":"Izv. Akad. Nauk. SSSR Seriia Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.toxicon.2017.07.002","article-title":"Crotoxin, a Rattlesnake Toxin, down-Modulates Functions of Bone Marrow Neutrophils and Impairs the Syk-GTPase Pathway","volume":"136","author":"Lima","year":"2017","journal-title":"Toxicon"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2407","DOI":"10.4049\/jimmunol.141.7.2407","article-title":"Release of Reactive Nitrogen Intermediates and Reactive Oxygen Intermediates from Mouse Peritoneal Macrophages","volume":"141","author":"Ding","year":"1988","journal-title":"J. Immunol."}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/15\/10\/616\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:08:12Z","timestamp":1760130492000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/15\/10\/616"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,17]]},"references-count":42,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["toxins15100616"],"URL":"https:\/\/doi.org\/10.3390\/toxins15100616","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,17]]}}}