{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T15:22:57Z","timestamp":1788535377744,"version":"build-2803163510"},"reference-count":33,"publisher":"American Chemical Society (ACS)","issue":"9","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo-FAPESP","award":["2022\/10722-2, 2023\/01651-7, 2013\/07467-1"],"award-info":[{"award-number":["2022\/10722-2, 2023\/01651-7, 2013\/07467-1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>In Brazil, approximately 25,000 snakebites occur annually, with Bothrops atrox responsible for most cases. Local morbidity is high, driven primarily by snake venom metalloproteases (SVMPs). The major SVMPs in B. atrox venom, Atroxlysin-Ia (ATXL) and Batroxrhagin (BATX), efficiently hydrolyze extracellular matrix proteins, inducing rapid hemorrhage and dermonecrosis. Thus, we characterized the composition of the exudate produced after SVMPs injection into the mice gastrocnemius muscle using proteomics. Muscle damage was evaluated by histological analysis. The composition of the exudate was analyzed by mass spectrometry. The SVMPs induced disorganization of muscle fibers and inflammatory cell migration. However, ATXL-induced a significantly higher neutrophil influx compared to BATX, likely triggered by an increase in CXCL16, suggesting a superior inflammatory capacity. In summary, despite being metalloproteases, these toxins exhibit distinct pathological profiles: ATXL is predominantly inflammatory, while BATX is more hemorrhagic. Interestingly, while endogenous serine proteinase levels were similar in both exudates, BATX showed significantly higher levels of proteinase inhibitors. Furthermore, identification of peptide bond cleavage sites revealed a pattern consistent with trypsin-like serine proteinases. These findings suggest that SVMPs not only damage tissue directly but also associate with the activation of host endogenous proteinases, which may contribute to the complex pathology of B. atrox envenomation, although direct causation remains to be established.<\/jats:p>","DOI":"10.1021\/acs.jproteome.6c00380","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T23:21:06Z","timestamp":1788218466000},"page":"4811-4822","source":"Crossref","is-referenced-by-count":0,"title":["Upregulation\nof Endogenous Serine Proteinases by SVMPs\nContributes to Muscle Damage Induced by\n                    <i>Bothrops atrox<\/i>\n                    Venom"],"prefix":"10.1021","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6017-6671","authenticated-orcid":true,"given":"Alison Felipe Alencar","family":"Chaves","sequence":"first","affiliation":[{"name":"Instituto Butantan , , , ,","place":["Sa\u0303o Paulo, SP, Brazil, 05503-000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilly Campos","family":"Tioyama","sequence":"additional","affiliation":[{"name":"Instituto Butantan , , , ,","place":["Sa\u0303o Paulo, SP, Brazil, 05503-000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mo\u0302nica","family":"Colombini","sequence":"additional","affiliation":[{"name":"Instituto Butantan , , , ,","place":["Sa\u0303o Paulo, SP, Brazil, 05503-000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah N. C.","family":"Gimenes","sequence":"additional","affiliation":[{"name":"Instituto Butantan , , , ,","place":["Sa\u0303o Paulo, SP, Brazil, 05503-000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella Mitie de","family":"Camargo","sequence":"additional","affiliation":[{"name":"Instituto Butantan , , , ,","place":["Sa\u0303o Paulo, SP, Brazil, 05503-000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karina Maria Pereira","family":"Silva","sequence":"additional","affiliation":[{"name":"Instituto Butantan , , , ,","place":["Sa\u0303o Paulo, SP, Brazil, 05503-000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni Perez Machado da","family":"Silveira","sequence":"additional","affiliation":[{"name":"Instituto Butantan , , , ,","place":["Sa\u0303o Paulo, SP, Brazil, 05503-000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Savio Stefanini","family":"Sant\u2019Anna","sequence":"additional","affiliation":[{"name":"Instituto Butantan , , , ,","place":["Sa\u0303o Paulo, SP, Brazil, 05503-000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliana Lima","family":"Faquim-Mauro","sequence":"additional","affiliation":[{"name":"Instituto Butantan , , , ,","place":["Sa\u0303o Paulo, SP, Brazil, 05503-000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Solange M. T.","family":"Serrano","sequence":"additional","affiliation":[{"name":"Instituto Butantan , , , ,","place":["Sa\u0303o Paulo, SP, Brazil, 05503-000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana M.","family":"Moura-da-Silva","sequence":"additional","affiliation":[{"name":"Instituto Butantan , , , ,","place":["Sa\u0303o Paulo, SP, Brazil, 05503-000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana A.","family":"Freitas-de-Sousa","sequence":"additional","affiliation":[{"name":"Instituto Butantan , , , ,","place":["Sa\u0303o Paulo, SP, Brazil, 05503-000"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"2026090409134467000_cit1","unstructured":"Ministry of Health (Brazil).\n          . Epidemiological Bulletin: Snakebite Accidents in Brazil, 2023 Secretariat\nof Health Surveillance and Environment Brasi\u0301lia2024https:\/\/www.saude.gov.br\/svs. (accessed April 6, 2026)."},{"key":"2026090409134467000_cit2","first-page":"101","article-title":"When and where\nto find a pitviper: activity patterns\nand habitat use of the lancehead, Bothrops atrox, in central Amazonia,\nBrazil","volume":"8","author":"Oliveira","year":"2001","journal-title":"Herpetol. Nat. Hist."},{"key":"2026090409134467000_cit3","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1016\/j.toxicon.2020.09.007","article-title":"Venomous snakes and people in a floodplain\nforest in the Western Brazilian Amazon: potential risks for snakebites","volume":"187","author":"da Silva","year":"2020","journal-title":"Toxicon"},{"issue":"7","key":"2026090409134467000_cit4","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0132237","article-title":"Older age and time to\nmedical assistance are\nassociated with severity and mortality of snakebites in the Brazilian\nAmazon: a case-control study","volume":"10","author":"Feitosa","year":"2015","journal-title":"PLoS One"},{"key":"2026090409134467000_cit5","first-page":"419","article-title":"Production\nof Antivenoms and Perspectives of Modernization by Molecular Biology\nTechniques","volume-title":"Animais Pec\u0327onhentos\nno Brasil","author":"Cardoso","year":"2009","edition":"2"},{"key":"2026090409134467000_cit6","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/S0041-0101(02)00287-8","article-title":"Epidemiology of\nsnakebite in central region of Brazil","volume":"41","author":"da Silva","year":"2003","journal-title":"Toxicon"},{"issue":"1","key":"2026090409134467000_cit7","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/S0035-9203(03)00005-1","article-title":"Clinical trial of two antivenoms for the treatment\nof Bothrops and Lachesis bites in\nthe northeastern Amazon region of Brazil","volume":"98","author":"de Oliveira Pardal","year":"2004","journal-title":"Trans.\nR. Soc. Trop. Med. Hyg."},{"key":"2026090409134467000_cit8","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.jprot.2009.07.013","article-title":"Snake venomics and antivenomics of Bothrops atrox venoms from Colombia and the Amazon regions\nof Brazil, Peru and Ecuador suggest geographic variation of venom\nphenotype by a trend towards paedomorphism","volume":"73","author":"Nu\u0301n\u0303ez","year":"2009","journal-title":"J. Proteomics"},{"key":"2026090409134467000_cit9","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1016\/j.jprot.2011.01.003","article-title":"Snake\npopulation venomics and antivenomics of Bothrops atrox: paedomorphism along its transamazonian dispersal\nand implications of geographic venom variability on snakebite management","volume":"74","author":"Calvete","year":"2011","journal-title":"J. Proteomics"},{"issue":"9","key":"2026090409134467000_cit10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0002442","article-title":"Comparison of phylogeny,\nvenom composition and neutralization by antivenom in diverse species\nof Bothrops complex","volume":"7","author":"Sousa","year":"2013","journal-title":"PLoS Neglected\nTrop. Dis."},{"key":"2026090409134467000_cit11","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.biochi.2015.08.006","article-title":"Comparison\nof venoms from wild and long-term captive Bothrops atrox snakes and characterization of Batroxrhagin, the predominant class\nPIII metalloproteinase","volume":"118","author":"Freitas-de-Sousa","year":"2015","journal-title":"Biochimie"},{"issue":"8","key":"2026090409134467000_cit12","doi-asserted-by":"publisher","DOI":"10.3390\/toxins9080239","article-title":"Insights\ninto mechanisms involved in hemorrhage and dermonecrosis induced by\nAtroxlysin-Ia, a PI-class snake venom metalloproteinase","volume":"9","author":"Freitas-de-Sousa","year":"2017","journal-title":"Toxins"},{"key":"2026090409134467000_cit13","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxcx.2020.100037","article-title":"Bothrops atrox, the most important\nsnake involved in human envenomings in the Amazon: how venomics contributes\nto the knowledge of snake biology and clinical toxinology","volume":"6","author":"Monteiro","year":"2020","journal-title":"Toxicon: X"},{"issue":"6","key":"2026090409134467000_cit14","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0008299","article-title":"The relationship between\nclinics and the venom of the causative Amazon pit viper (Bothrops atrox)","volume":"14","author":"Moura-da-Silva","year":"2020","journal-title":"PLoS Neglected Trop. Dis."},{"issue":"2","key":"2026090409134467000_cit15","doi-asserted-by":"publisher","DOI":"10.3390\/toxins12020096","article-title":"Inflammatory\nreaction induced by two metalloproteases isolated from Bothrops atrox venom and by fragments generated from basement membrane\nhydrolysis","volume":"12","author":"Almeida","year":"2020","journal-title":"Toxins"},{"key":"2026090409134467000_cit16","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.63","article-title":"Snakebite envenoming","volume":"3","author":"Gutie\u0301rrez","year":"2017","journal-title":"Nat. Rev.\nDis. Primers"},{"issue":"11","key":"2026090409134467000_cit17","doi-asserted-by":"publisher","DOI":"10.3390\/toxins13110800","article-title":"Observation\nof Bothrops atrox snake envenoming blister formation\nfrom five\npatients: pathophysiological insights","volume":"13","author":"Gimenes","year":"2021","journal-title":"Toxins"},{"issue":"2","key":"2026090409134467000_cit18","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1080\/09629350220131980","article-title":"Increments in cytokines and matrix\nmetalloproteinases in skeletal muscle after injection of tissue-damaging\ntoxins from Bothrops asper venom","volume":"11","author":"Rucavado","year":"2002","journal-title":"Mediators Inflammation"},{"issue":"9","key":"2026090409134467000_cit19","doi-asserted-by":"publisher","first-page":"1103","DOI":"10.1007\/s00726-023-03299-w","article-title":"Mouse skin peptidomic analysis of\nhemorrhage induced by a snake venom metalloprotease","volume":"55","author":"Asega","year":"2023","journal-title":"Amino Acids"},{"issue":"8","key":"2026090409134467000_cit20","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcpro.2025.101023","article-title":"Signatures of\nsystemic effects of a snake venom and antivenom: multiomics profiling\nof kidney pathology","volume":"24","author":"Chaves","year":"2025","journal-title":"Mol. Cell. Proteomics"},{"issue":"11","key":"2026090409134467000_cit21","doi-asserted-by":"publisher","first-page":"5120","DOI":"10.1021\/pr900489m","article-title":"Wound exudate as a proteomic window to reveal mechanisms\nof tissue damage by snake venom toxins","volume":"8","author":"Escalante","year":"2009","journal-title":"J. Proteome\nRes."},{"issue":"11","key":"2026090409134467000_cit22","doi-asserted-by":"publisher","DOI":"10.3390\/toxins8120349","article-title":"Viperid envenomation wound exudate\ncontributes to increased vascular permeability via a DAMPs\/TLR4-mediated\npathway","volume":"8","author":"Rucavado","year":"2016","journal-title":"Toxins"},{"key":"2026090409134467000_cit23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.toxicon.2016.04.048","article-title":"Characterising\nthe Enzymatic Profile\nof Crude Tentacle Extracts from the South Atlantic Jellyfish Olindias\nsambaquiensis (Cnidaria: Hydrozoa)","volume":"119","author":"Knittel","year":"2016","journal-title":"Toxicon"},{"key":"2026090409134467000_cit24","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adf9717","article-title":"A simple, time- and cost-effective,\nhigh-throughput depletion strategy for deep plasma proteomics","volume":"9","author":"Viode","year":"2023","journal-title":"Sci. Adv."},{"issue":"2","key":"2026090409134467000_cit25","doi-asserted-by":"publisher","DOI":"10.3390\/toxins16020083","article-title":"Venom composition of neglected bothropoid snakes\nfrom the Amazon rainforest: ecological and toxinological implications","volume":"16","author":"Freitas-de-Sousa","year":"2024","journal-title":"Toxins"},{"issue":"1","key":"2026090409134467000_cit26","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0007041","article-title":"Mechanisms underpinning permanent muscle damage induced\nby snake venom metalloprotease","volume":"13","author":"Williams","year":"2019","journal-title":"PLoS Neglected\nTrop. Dis."},{"issue":"5","key":"2026090409134467000_cit27","doi-asserted-by":"publisher","DOI":"10.4110\/in.2019.19.e34","article-title":"Neutrophilic granule\nprotein is a novel murine LPS antagonist","volume":"19","author":"Hong","year":"2019","journal-title":"Immune\nNetwork"},{"key":"2026090409134467000_cit28","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.jprot.2018.03.032","article-title":"Molecular\nmechanisms underlying intraspecific variation in snake venom","volume":"181","author":"Amazonas","year":"2018","journal-title":"J. Proteomics"},{"issue":"3","key":"2026090409134467000_cit29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0000727","article-title":"Mechanisms\nof vascular damage by hemorrhagic snake venom metalloproteinases:\ntissue distribution and in situ hydrolysis","volume":"4","author":"Baldo","year":"2010","journal-title":"PLoS Neglected Trop. Dis."},{"issue":"4","key":"2026090409134467000_cit30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0003731","article-title":"Tissue localization and extracellular\nmatrix degradation by PI, PII and PIII snake venom metalloproteinases:\nclues on the mechanisms of venom-induced hemorrhage","volume":"9","author":"Herrera","year":"2015","journal-title":"PLoS Neglected Trop. Dis."},{"key":"2026090409134467000_cit31","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-023-01524-9","article-title":"The role of CXCL family\nmembers in different diseases","volume":"9","author":"Zhou","year":"2023","journal-title":"Cell Death Discovery"},{"issue":"6","key":"2026090409134467000_cit32","doi-asserted-by":"publisher","first-page":"2518","DOI":"10.2353\/ajpath.2009.090275","article-title":"Chemokine CXCL16 regulates neutrophil\nand macrophage\ninfiltration into injured muscle, promoting muscle regeneration","volume":"175","author":"Zhang","year":"2009","journal-title":"Am. J. Pathol."},{"issue":"D1","key":"2026090409134467000_cit33","doi-asserted-by":"publisher","first-page":"D442","DOI":"10.1093\/nar\/gky1106","article-title":"The PRIDE database and\nrelated tools and resources in 2019: improving support for quantification\ndata","volume":"47","author":"Perez-Riverol","year":"2019","journal-title":"Nucleic Acids Res."}],"container-title":["Journal of Proteome Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jproteome.6c00380","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jprobs\/article-pdf\/25\/9\/4811\/67405881\/acs.jproteome.6c00380.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jprobs\/article-pdf\/25\/9\/4811\/67405881\/acs.jproteome.6c00380.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T14:53:34Z","timestamp":1788533614000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jprobs\/article\/25\/9\/4811\/5328894\/Upregulation-of-Endogenous-Serine-Proteinases-by"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,25]]},"references-count":33,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,8,25]]},"published-print":{"date-parts":[[2026,9,4]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jproteome.6c00380","relation":{},"ISSN":["1535-3893","1535-3907"],"issn-type":[{"value":"1535-3893","type":"print"},{"value":"1535-3907","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,25]]}}}