{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T15:27:52Z","timestamp":1793114872632,"version":"4.5.0"},"reference-count":85,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T00:00:00Z","timestamp":1718582400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Saudi Cultural Bureau","award":["221708\/Z\/20\/Z"],"award-info":[{"award-number":["221708\/Z\/20\/Z"]}]},{"name":"Saudi Cultural Bureau","award":["223619\/Z\/21\/Z"],"award-info":[{"award-number":["223619\/Z\/21\/Z"]}]},{"name":"Saudi Cultural Bureau","award":["SBF008\\1127"],"award-info":[{"award-number":["SBF008\\1127"]}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust snakebite","doi-asserted-by":"publisher","award":["221708\/Z\/20\/Z"],"award-info":[{"award-number":["221708\/Z\/20\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust snakebite","doi-asserted-by":"publisher","award":["223619\/Z\/21\/Z"],"award-info":[{"award-number":["223619\/Z\/21\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust snakebite","doi-asserted-by":"publisher","award":["SBF008\\1127"],"award-info":[{"award-number":["SBF008\\1127"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"name":"AMS Springboard","award":["221708\/Z\/20\/Z"],"award-info":[{"award-number":["221708\/Z\/20\/Z"]}]},{"name":"AMS Springboard","award":["223619\/Z\/21\/Z"],"award-info":[{"award-number":["223619\/Z\/21\/Z"]}]},{"name":"AMS Springboard","award":["SBF008\\1127"],"award-info":[{"award-number":["SBF008\\1127"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Snakebite envenoming is a neglected tropical disease that causes &gt;100,000 deaths and &gt;400,000 cases of morbidity annually. Despite the use of mouse models, severe local envenoming, defined by morbidity-causing local tissue necrosis, remains poorly understood, and human-tissue responses are ill-defined. Here, for the first time, an ex vivo, non-perfused human skin model was used to investigate temporal histopathological and immunological changes following subcutaneous injections of venoms from medically important African vipers (Echis ocellatus and Bitis arietans) and cobras (Naja nigricollis and N. haje). Histological analysis of venom-injected ex vivo human skin biopsies revealed morphological changes in the epidermis (ballooning degeneration, erosion, and ulceration) comparable to clinical signs of local envenoming. Immunostaining of these biopsies confirmed cell apoptosis consistent with the onset of necrosis. RNA sequencing, multiplex bead arrays, and ELISAs demonstrated that venom-injected human skin biopsies exhibited higher rates of transcription and expression of chemokines (CXCL5, MIP1-ALPHA, RANTES, MCP-1, and MIG), cytokines (IL-1\u03b2, IL-1RA, G-CSF\/CSF-3, and GM-CSF), and growth factors (VEGF-A, FGF, and HGF) in comparison to non-injected biopsies. To investigate the efficacy of antivenom, SAIMR Echis monovalent or SAIMR polyvalent antivenom was injected one hour following E. ocellatus or N. nigricollis venom treatment, respectively, and although antivenom did not prevent venom-induced dermal tissue damage, it did reduce all pro-inflammatory chemokines, cytokines, and growth factors to normal levels after 48 h. This ex vivo skin model could be useful for studies evaluating the progression of local envenoming and the efficacy of snakebite treatments.<\/jats:p>","DOI":"10.3390\/toxins16060276","type":"journal-article","created":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T08:48:31Z","timestamp":1718614111000},"page":"276","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Investigating Snake-Venom-Induced Dermonecrosis and Inflammation Using an Ex Vivo Human Skin Model"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9983-0191","authenticated-orcid":false,"given":"Jaffer","family":"Alsolaiss","sequence":"first","affiliation":[{"name":"Centre for Snakebite Research and Interventions, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK"},{"name":"Abqaiq General Hospital, Rural Health Network, Eastern Health Cluster, Ministry of Health, Abqaiq 33241, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gail","family":"Leeming","sequence":"additional","affiliation":[{"name":"Department of Veterinary Anatomy, Physiology and Pathology, School of Veterinary Science, University of Liverpool, Liverpool L69 7ZX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael","family":"Da Silva","sequence":"additional","affiliation":[{"name":"Centre for Snakebite Research and Interventions, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nessrin","family":"Alomran","sequence":"additional","affiliation":[{"name":"Centre for Snakebite Research and Interventions, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK"},{"name":"Qatif Medical Fitness Center, Clinical Laboratory Department, Qatif Health Network, Eastern Health Cluster, Ministry of Health, Qatif 31911, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8035-4719","authenticated-orcid":false,"given":"Nicholas R.","family":"Casewell","sequence":"additional","affiliation":[{"name":"Centre for Snakebite Research and Interventions, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdulrazaq G.","family":"Habib","sequence":"additional","affiliation":[{"name":"African Snakebite Research Group (ASRG) Project, Bayero University, Kano 700251, Nigeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Harrison","sequence":"additional","affiliation":[{"name":"Centre for Snakebite Research and Interventions, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2211-3930","authenticated-orcid":false,"given":"Cassandra M.","family":"Modahl","sequence":"additional","affiliation":[{"name":"Centre for Snakebite Research and Interventions, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,17]]},"reference":[{"key":"ref_1","unstructured":"WHO (2022, July 19). Neglected Tropical Diseases. Available online: http:\/\/www.who.int\/neglected_diseases\/diseases\/en\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17063","DOI":"10.1038\/nrdp.2017.63","article-title":"Snakebite envenoming","volume":"3","author":"Calvete","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1016\/j.tips.2020.05.006","article-title":"Causes and consequences of snake venom variation","volume":"41","author":"Casewell","year":"2020","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_4","first-page":"1","article-title":"The Clinical Management of Snake Bites in the Southeast Asian Region","volume":"30","author":"Warrell","year":"1999","journal-title":"Southeast Asian J. Trop. Med. Public Helath"},{"key":"ref_5","unstructured":"WHO (2010). Guidelines for the Prevention and Clinical Management of Snakebite in Africa, WHO Regional Office for Africa."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"218","DOI":"10.3389\/fevo.2019.00218","article-title":"Multifunctional Toxins in Snake Venoms and Therapeutic Implications: From Pain to Hemorrhage and Necrosis","volume":"7","author":"Ferraz","year":"2019","journal-title":"Front. Ecol. Evo."},{"key":"ref_7","first-page":"1","article-title":"Necrosis, Haemorrhage and Complement Depletion Following Bites by the Spitting Cobra (Naja nigricollis)","volume":"45","author":"Warrell","year":"1976","journal-title":"QJM Int. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"222","DOI":"10.3109\/15563650.2015.1135337","article-title":"Coral snake bites (Micrurus spp.) in Brazil: A review of literature reports","volume":"54","author":"Bucaretchi","year":"2016","journal-title":"Clin. Toxicol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s40560-015-0081-8","article-title":"Venomous snake bites: Clinical diagnosis and treatment","volume":"3","author":"Hifumi","year":"2015","journal-title":"J. Intensive Care"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.sjpain.2015.07.005","article-title":"Complex regional pain syndrome following viper-bite","volume":"10","author":"Kleggetveit","year":"2016","journal-title":"Scand. J. Pain"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.toxicon.2016.03.006","article-title":"Comparative analysis of local effects caused by Bothrops alternatus and Bothrops moojeni snake venoms: Enzymatic contributions and inflammatory modulations","volume":"117","author":"Mamede","year":"2016","journal-title":"Toxicon"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2421","DOI":"10.1038\/jid.2008.118","article-title":"Skin Pathology Induced by Snake Venom Metalloproteinase: Acute Damage, Revascularization, and Re-epithelization in a Mouse Ear Model","volume":"128","author":"Escalante","year":"2008","journal-title":"J. Investig. Dermatol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Guti\u00e9rrez, J.M., Escalante, T., Hern\u00e1ndez, R., Gastaldello, S., Saravia-Otten, P., and Rucavado, A. (2018). Why is Skeletal Muscle Regeneration Impaired after Myonecrosis Induced by Viperid Snake Venoms?. Toxins, 10.","DOI":"10.3390\/toxins10050182"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Mora, J., Mora, R., Lomonte, B., and Guti\u00e9rrez, J.M. (2008). Effects of Bothrops asper snake venom on lymphatic vessels: Insights into a hidden aspect of envenomation. PLoS Negl. Trop. Dis., 2.","DOI":"10.1371\/journal.pntd.0000318"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1000181","DOI":"10.4172\/2161-0495.1000181","article-title":"Snake venom cytotoxins, phospholipase A2s, and Zn2+-dependent metalloproteinases: Mechanisms of action and pharmacological relevance","volume":"4","author":"Gasanov","year":"2014","journal-title":"J. Clin. Toxicol."},{"key":"ref_16","first-page":"1148","article-title":"Comparative study of structure and activity of cytotoxins from venom of the cobras Naja oxiana, Naja kaouthia, and Naja haje","volume":"69","author":"Feofanov","year":"2004","journal-title":"Biochemistry"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Bittenbinder, M.A., van Thiel, J., Cardoso, F.C., Casewell, N.R., Guti\u00e9rrez, J.-M., Kool, J., and Vonk, F.J. (2024). Tissue damaging toxins in snake venoms: Mechanisms of action, pathophysiology and treatment strategies. Commun. Biol., 7.","DOI":"10.1038\/s42003-024-06019-6"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.toxicon.2018.04.016","article-title":"Unresolved issues in the understanding of the pathogenesis of local tissue damage induced by snake venoms","volume":"148","author":"Rucavado","year":"2018","journal-title":"Toxicon"},{"key":"ref_19","first-page":"245","article-title":"Blister formation and skin damage induced by BaP1, a haemorrhagic metalloproteinase from the venom of the snake Bothrops asper","volume":"79","author":"Rucavado","year":"1998","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/0041-0101(94)00138-X","article-title":"Isolation and characterization of a metalloproteinase with weak hemorrhagic activity from the venom of the snake Bothrops asper (terciopelo)","volume":"33","author":"Romero","year":"1995","journal-title":"Toxicon"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1080\/09629350220131980","article-title":"Increments in cytokines and matrix metalloproteinases in skeletal muscle after injection of tissue-damaging toxins from the venom of the snake Bothrops asper","volume":"11","author":"Rucavado","year":"2002","journal-title":"Mediat. Inflamm."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1590\/S0074-02762005000900031","article-title":"Inflammatory effects of snake venom metalloproteinases","volume":"100","author":"Teixeira","year":"2005","journal-title":"Mem. Do Inst. Oswaldo Cruz"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5120","DOI":"10.1021\/pr900489m","article-title":"Wound exudate as a proteomic window to reveal different mechanisms of tissue damage by snake venom toxins","volume":"8","author":"Escalante","year":"2009","journal-title":"J. Proteome Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1016\/j.toxicon.2009.05.026","article-title":"Inflammation induced by Bothrops asper venom","volume":"54","author":"Teixeira","year":"2009","journal-title":"Toxicon"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1016\/j.toxicon.2003.11.006","article-title":"Inflammatory effects of snake venom myotoxic phospholipases A2","volume":"42","author":"Teixeira","year":"2003","journal-title":"Toxicon"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/j.molimm.2015.09.023","article-title":"Evaluation of the local inflammatory events induced by BpirMP, a metalloproteinase from Bothrops pirajai venom","volume":"68","author":"Bernardes","year":"2015","journal-title":"Mol. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1016\/S0041-0101(01)00131-3","article-title":"The effect of jararhagin, a metalloproteinase from Bothrops jararaca venom, on pro-inflammatory cytokines released by murine peritoneal adherent cells","volume":"39","author":"Clissa","year":"2001","journal-title":"Toxicon"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1080\/09629350020025728","article-title":"Bothrops asper snake venom and its metalloproteinase BaP\u20131 activate the complement system. Role in leucocyte recruitment","volume":"9","author":"Farsky","year":"2000","journal-title":"Mediat. Inflamm."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.toxicon.2009.07.025","article-title":"Contribution of metalloproteases, serine proteases and phospholipases A2 to the inflammatory reaction induced by Bothrops jararaca crude venom in mice","volume":"55","author":"Zychar","year":"2010","journal-title":"Toxicon"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Rucavado, A., Nicolau, C., Escalante, T., Kim, J., Herrera, C., Guti\u00e9rrez, J., and Fox, J. (2016). Viperid Envenomation Wound Exudate Contributes to Increased Vascular Permeability via a DAMPs\/TLR-4 Mediated Pathway. Toxins, 8.","DOI":"10.3390\/toxins8120349"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Almeida, M.T., Freitas-de-Sousa, L.A., Colombini, M., Gimenes, S.N.C., Kitano, E.S., Faquim-Mauro, E.L., Serrano, S.M.T., and Moura-da-Silva, A.M. (2020). Inflammatory Reaction Induced by Two Metalloproteinases Isolated from Bothrops atrox Venom and by Fragments Generated from the Hydrolysis of Basement Membrane Components. Toxins, 12.","DOI":"10.3390\/toxins12020096"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2000","DOI":"10.1002\/eji.1830260905","article-title":"Processing of pro-tumor necrosis factor-alpha by venom metalloproteinases: A hypothesis explaining local tissue damage following snake bite","volume":"26","author":"Laing","year":"1996","journal-title":"Eur. J. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3458","DOI":"10.1002\/eji.200324475","article-title":"Inflammatory pathogenesis of snake venom metalloproteinase-induced skin necrosis","volume":"33","author":"Laing","year":"2003","journal-title":"Eur. J. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Warrell, D.A. (2017). Clinical toxicology of snakebite in Africa and the Middle East\/Arabian Peninsula. Handbook of Clinical Toxicology of Animal Venoms and Poisons, CRC Press.","DOI":"10.1201\/9780203719442-26"},{"key":"ref_35","first-page":"949","article-title":"Development of simple standard assay procedures for the characterization of snake venoms","volume":"61","author":"Theakston","year":"1983","journal-title":"Bull. World Health Organ."},{"key":"ref_36","unstructured":"Russell, W.M.S., and Burch, R.L. (1959). The Principles of Humane Experimental Technique, Methuen."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Knudsen, C., Casewell, N.R., Lomonte, B., Guti\u00e9rrez, J.M., Vaiyapuri, S., and Laustsen, A.H. (2020). Novel Snakebite Therapeutics Must Be Tested in Appropriate Rescue Models to Robustly Assess Their Preclinical Efficacy. Toxins, 12.","DOI":"10.3390\/toxins12090528"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"830384","DOI":"10.3389\/fphar.2022.830384","article-title":"Rodent Lethality Models Are Problematic for Evaluating Antivenoms for Human Envenoming","volume":"13","author":"Silva","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"eaay8314","DOI":"10.1126\/scitranslmed.aay8314","article-title":"Preclinical validation of a repurposed metal chelator as an early-intervention therapeutic for hemotoxic snakebite","volume":"12","author":"Albulescu","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.toxicon.2019.06.216","article-title":"The neutralization efficacy of expired polyvalent antivenoms: An alternative option","volume":"168","author":"Migl","year":"2019","journal-title":"Toxicon"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"100118","DOI":"10.1016\/j.toxcx.2022.100118","article-title":"In vitro and in vivo preclinical venom inhibition assays identify metalloproteinase inhibiting drugs as potential future treatments for snakebite envenoming by Dispholidus typus","volume":"14","author":"Menzies","year":"2022","journal-title":"Toxicon X"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"7812","DOI":"10.1038\/s41467-023-43510-w","article-title":"Repurposed drugs and their combinations prevent morbidity-inducing dermonecrosis caused by diverse cytotoxic snake venoms","volume":"14","author":"Hall","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3184","DOI":"10.1038\/s41598-024-53366-9","article-title":"Differential effects of the venoms of Russell\u2019s viper and Indian cobra on human myoblasts","volume":"14","author":"Almeida","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"106955","DOI":"10.1016\/j.toxicon.2022.106955","article-title":"Proteomics and histological assessment of an organotypic model of human skin following exposure to Naja nigricollis venom","volume":"220","author":"Ahmadi","year":"2022","journal-title":"Toxicon"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1369\/jhc.2008.952044","article-title":"Assessment of apoptosis by immunohistochemistry to active caspase-3, active caspase-7, or cleaved PARP in monolayer cells and spheroid and subcutaneous xenografts of human carcinoma","volume":"57","author":"Bressenot","year":"2009","journal-title":"J. Histochem. Cytochem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"D733","DOI":"10.1093\/nar\/gkv1189","article-title":"Reference sequence (RefSeq) database at NCBI: Current status, taxonomic expansion, and functional annotation","volume":"44","author":"Wright","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.yexcr.2017.09.038","article-title":"The role of C1QBP in CSF-1-dependent PKC\u03b6 activation and macrophage migration","volume":"362","author":"Wang","year":"2018","journal-title":"Exp. Cell Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.diff.2017.09.004","article-title":"Human reconstructed skin xenografts on mice to model skin physiology","volume":"98","author":"Salgado","year":"2017","journal-title":"Differentiation"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.toxicon.2016.06.006","article-title":"Pathogenesis of dermonecrosis induced by venom of the spitting cobra, Naja nigricollis: An experimental study in mice","volume":"119","author":"Rivel","year":"2016","journal-title":"Toxicon"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1126\/science.abb9303","article-title":"Convergent evolution of pain-inducing defensive venom components in spitting cobras","volume":"371","author":"Kazandjian","year":"2021","journal-title":"Science"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.jprot.2013.11.012","article-title":"Proteomic analysis of Moroccan cobra Naja haje legionis venom using tandem mass spectrometry","volume":"96","author":"Malih","year":"2014","journal-title":"J. Proteom."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"giac121","DOI":"10.1093\/gigascience\/giac121","article-title":"High-throughput proteomics and in vitro functional characterization of the 26 medically most important elapids and vipers from sub-Saharan Africa","volume":"11","author":"Nguyen","year":"2022","journal-title":"GigaScience"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1016\/j.toxicon.2005.08.011","article-title":"Inflammation induced by Bothrops asper venom: Release of proinflammatory cytokines and eicosanoids, and role of adhesion molecules in leukocyte infiltration","volume":"46","author":"Zamuner","year":"2005","journal-title":"Toxicon"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1177\/0192623316675767","article-title":"Translating Mouse Models: Immune Variation and Efficacy Testing","volume":"45","author":"Sellers","year":"2016","journal-title":"Toxicol. Pathol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"746459","DOI":"10.1080\/0962935021000051548","article-title":"Cell adhesion molecules involved in the leukocyte recruitment induced by venom of the snake Bothrops jararaca","volume":"11","author":"Zamuner","year":"2002","journal-title":"Mediat. Inflamm."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1089\/107999003321455507","article-title":"The primary role in biologic activity of the neutrophil chemokines IL-8 and GRO-\u03b1 in cultured nasal epithelial cells","volume":"23","author":"Rudack","year":"2003","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1046\/j.1365-2222.2003.01609.x","article-title":"Expression of the neutrophil-activating CXC chemokine ENA-78\/CXCL5 by human eosinophils","volume":"33","author":"Persson","year":"2003","journal-title":"Clin. Exp. Allergy"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"90ra60","DOI":"10.1126\/scitranslmed.3002193","article-title":"CXCL5 mediates UVB irradiation\u2013induced pain","volume":"3","author":"Dawes","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.3389\/fimmu.2019.01137","article-title":"Complement System Inhibition Modulates the Pro-Inflammatory Effects of a Snake Venom Metalloproteinase","volume":"10","author":"Luchini","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3335","DOI":"10.1093\/brain\/awn243","article-title":"Granulocyte-colony stimulating factor improves outcome in a mouse model of amyotrophic lateral sclerosis","volume":"131","author":"Pitzer","year":"2008","journal-title":"Brain"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1016\/S0002-9440(10)65699-4","article-title":"Chemokines IL-8, GRO\u03b1, MCP-1, IP-10, and Mig are sequentially and differentially expressed during phase-specific infiltration of leukocyte subsets in human wound healing","volume":"153","author":"Engelhardt","year":"1998","journal-title":"Am. J. Pathol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/0167-5699(89)90085-6","article-title":"The cytokine network","volume":"10","author":"Balkwill","year":"1989","journal-title":"Immunol. Today"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s41232-019-0101-5","article-title":"The role of interleukin-1 in general pathology","volume":"39","author":"Kaneko","year":"2019","journal-title":"Inflamm. Regen."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.emc.2004.12.001","article-title":"The pathophysiology of acute pain","volume":"23","author":"Fink","year":"2005","journal-title":"Emerg. Med. Clin."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1006\/cyto.2000.0827","article-title":"Therapeutic relevance of altered cytokine expression","volume":"14","author":"Kulmatycki","year":"2001","journal-title":"Cytokine"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.toxicon.2004.10.005","article-title":"Role of TNF-\u03b1, IL-1\u03b2 and IL-6 in the local tissue damage induced by Bothrops asper snake venom: An experimental assessment in mice","volume":"45","author":"Chaves","year":"2005","journal-title":"Toxicon"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1007\/s00421-008-0946-9","article-title":"Administration of granulocyte colony-stimulating factor facilitates the regenerative process of injured mice skeletal muscle via the activation of Akt\/GSK3\u03b1\u03b2 signals","volume":"105","author":"Naito","year":"2009","journal-title":"Eur. J. Appl. Physiol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.3389\/fimmu.2019.01265","article-title":"Roles of GM-CSF in the Pathogenesis of Autoimmune Diseases: An Update","volume":"10","author":"Lotfi","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1084\/jem.175.6.1717","article-title":"Novel responses of human skin to intradermal recombinant granulocyte\/macrophage-colony-stimulating factor: Langerhans cell recruitment, keratinocyte growth, and enhanced wound healing","volume":"175","author":"Kaplan","year":"1992","journal-title":"J. Exp. Med."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Samy, R.P., Kandasamy, M., Gopalakrishnakone, P., Stiles, B.G., Rowan, E.G., Becker, D., Shanmugam, M.K., Sethi, G., and Chow, V.T.K. (2014). Wound healing activity and mechanisms of action of an antibacterial protein from the venom of the eastern diamondback rattlesnake (Crotalus adamanteus). PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0080199"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Megale, A.A.A., Portaro, F.C., and Da Silva, W.D. (2020). Bitis arietans Snake Venom Induces an Inflammatory Response Which Is Partially Dependent on Lipid Mediators. Toxins, 12.","DOI":"10.3390\/toxins12090594"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Coelho, K.F., Neves, J.C., Ibiapina, H.N., Magalh\u00e3es-Gama, F., Barbosa, F.B., Silva, F.S., Wellmann, I.A., Sachett, J.A., Tarrag\u00f4, A.M., and Ferreira, L.C. (2023). Exploring the Profile of Cell Populations and Soluble Immunological Mediators in Bothrops atrox Envenomations. Toxins, 15.","DOI":"10.3390\/toxins15030196"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1093\/cvr\/cvq049","article-title":"Extracellular matrix, inflammation, and the angiogenic response","volume":"86","author":"Arroyo","year":"2010","journal-title":"Cardiovasc. Res."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/S0300-9084(00)01163-9","article-title":"Snake venom metalloproteinases: Their role in the pathogenesis of local tissue damage","volume":"82","author":"Rucavado","year":"2000","journal-title":"Biochimie"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1126\/science.6823562","article-title":"Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid","volume":"219","author":"Senger","year":"1983","journal-title":"Science"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Ren, M., Gao, Y., Chen, Q., Zhao, H., Zhao, X., and Yue, W. (2020). The Overexpression of Keratin 23 Promotes Migration of Ovarian Cancer via Epithelial-Mesenchymal Transition. BioMed Res. Int., 2020.","DOI":"10.1155\/2020\/8218735"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Gimenes, S.N.C., Sachett, J.A.G., Colombini, M., Freitas-de-Sousa, L.A., Ibiapina, H.N.S., Costa, A.G., Santana, M.F., Park, J.J., Sherman, N.E., and Ferreira, L.C.L. (2021). Observation of Bothrops atrox Snake Envenoming Blister Formation from Five Patients: Pathophysiological Insights. Toxins, 13.","DOI":"10.3390\/toxins13110800"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1084\/jem.20070679","article-title":"RAGE signaling sustains inflammation and promotes tumor development","volume":"205","author":"Gebhardt","year":"2008","journal-title":"J. Exp. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1016\/j.immuni.2013.11.011","article-title":"S100A8-S100A9 Protein Complex Mediates Psoriasis by Regulating the Expression of Complement Factor C3","volume":"39","author":"Schonthaler","year":"2013","journal-title":"Immunity"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.toxicon.2009.08.010","article-title":"Preclinical assessment of the efficacy of a new antivenom (EchiTAb-Plus-ICP\u00ae) for the treatment of viper envenoming in sub-Saharan Africa","volume":"55","author":"Segura","year":"2010","journal-title":"Toxicon"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: A flexible trimmer for Illumina sequence data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: Ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2782","DOI":"10.1093\/bioinformatics\/bts515","article-title":"GFOLD: A generalized fold change for ranking differentially expressed genes from RNA-seq data","volume":"28","author":"Feng","year":"2012","journal-title":"Bioinformatics"},{"key":"ref_84","unstructured":"Oliveros, J.C., and Venny, C. (2022, March 10). An Interactive Tool for Comparing Lists with Venn Diagrams. Available online: https:\/\/bioinfogp.cnb.csic.es\/tools\/venny\/."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nprot.2008.211","article-title":"Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources","volume":"4","author":"Huang","year":"2009","journal-title":"Nat. Protoc."}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/16\/6\/276\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:00:00Z","timestamp":1760108400000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/16\/6\/276"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,17]]},"references-count":85,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["toxins16060276"],"URL":"https:\/\/doi.org\/10.3390\/toxins16060276","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,17]]}}}