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Rao S, Reghu N, Nair BG, Vanuopadath M. The Role of Snake Venom Proteins in Inducing Inflammation Post-Envenomation: An Overview on Mechanistic Insights and Treatment Strategies. Toxins (Basel) 2024; 16:519. [PMID: 39728777 PMCID: PMC11728808 DOI: 10.3390/toxins16120519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 10/23/2024] [Accepted: 11/05/2024] [Indexed: 12/28/2024] Open
Abstract
The intricate combination of organic and inorganic compounds found in snake venom includes proteins, peptides, lipids, carbohydrates, nucleotides, and metal ions. These components work together to immobilise and consume prey through processes such as paralysis and hypotension. Proteins, both enzymatic and non-enzymatic, form the primary components of the venom. Based on the effects they produce, venom can be classified as neurotoxic, hemotoxic, and cytotoxic. Studies have shown that, after envenomation, proteins in snake venom also contribute significantly to the induction of inflammatory responses which can either have systemic or localized consequences. This review delves into the mechanisms by which snake venom proteins trigger inflammatory responses, focusing on key families such as phospholipase A2, metalloproteinases, serine proteases, C-type lectins, cysteine-rich secretory proteins, and L-amino acid oxidase. In addition, the role of venom proteins in activating various inflammatory pathways, including the complement system, inflammasomes, and sterile inflammation are also summarized. The available therapeutic options are examined, with a focus on antivenom therapy and its side effects. In general, this review offers a comprehensive understanding of the inflammatory mechanisms that are triggered by snake venom proteins and the side effects of antivenom treatment. All these emphasize the need for effective strategies to mitigate these detrimental effects.
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Affiliation(s)
- Sudharshan Rao
- School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam 690 525, Kerala, India
- Systems Biology Ireland, University College Dublin, Belfield, D04 V1W8 Dublin, Ireland
| | - Nisha Reghu
- School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam 690 525, Kerala, India
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Resiere D, Kallel H, Florentin J, Houcke S, Mehdaoui H, Gutiérrez JM, Neviere R. Bothrops (Fer-de-lance) snakebites in the French departments of the Americas (Martinique and Guyana): Clinical and experimental studies and treatment by immunotherapy. PLoS Negl Trop Dis 2023; 17:e0011083. [PMID: 36854042 PMCID: PMC9974124 DOI: 10.1371/journal.pntd.0011083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/02/2023] Open
Abstract
Snakebite envenomation is a relevant medical hazard in French Guiana and Martinique, two French territories in the Americas. All snakebite envenomations in Martinique are inflicted by the endemic viperid species Bothrops lanceolatus, whereas Bothrops atrox is responsible for the majority of snakebites in French Guiana, although other venomous snake species also occur in this South American territory. This review summarizes some of the key aspects of the natural history of these species, as well as of their venom composition, the main clinical manifestations of envenomations, and their treatment by antivenoms. B. atrox venom induces the typical set of clinical manifestations characteristic of Bothrops sp. venoms, i.e., local tissue damage and systemic alterations associated with coagulopathies, hemorrhage, hemodynamic alterations, and acute kidney injury. In the case of B. lanceolatus venom, in addition to some typical features of bothropic envenomation, a unique and severe thrombotic effect occurs in some patients. The pathogenesis of this effect remains unknown but may be related to the action of venom components and inflammatory mediators on endothelial cells in the vasculature. A monospecific antivenom has been successfully used in Martinique to treat envenomations by B. lanceolatus. In the case of French Guiana, a polyvalent antivenom has been used for some years, but it is necessary to assess the preclinical and clinical efficacy against viperid venoms in this country of other antivenoms manufactured in the Americas.
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Affiliation(s)
- Dabor Resiere
- Cardiovascular Research Team EA7525, Université des Antilles, Fort de France, France
- Department of Critical Care Medicine, Toxicology and Emergency, CHU Martinique (University Hospital of Martinique), Fort-de-France, France
| | - Hatem Kallel
- Intensive Care Unit, Cayenne General Hospital, Cayenne, French Guiana, France
| | - Jonathan Florentin
- Cardiovascular Research Team EA7525, Université des Antilles, Fort de France, France
- Department of Critical Care Medicine, Toxicology and Emergency, CHU Martinique (University Hospital of Martinique), Fort-de-France, France
| | - Stephanie Houcke
- Intensive Care Unit, Cayenne General Hospital, Cayenne, French Guiana, France
| | - Hossein Mehdaoui
- Cardiovascular Research Team EA7525, Université des Antilles, Fort de France, France
- Department of Critical Care Medicine, Toxicology and Emergency, CHU Martinique (University Hospital of Martinique), Fort-de-France, France
| | - José María Gutiérrez
- Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica
| | - Remi Neviere
- Cardiovascular Research Team EA7525, Université des Antilles, Fort de France, France
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Light Emitting Diode Photobiomodulation Enhances Oxidative Redox Capacity in Murine Macrophages Stimulated with Bothrops jararacussu Venom and Isolated PLA2s. BIOMED RESEARCH INTERNATIONAL 2022; 2022:5266211. [PMID: 35872869 PMCID: PMC9307370 DOI: 10.1155/2022/5266211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 06/16/2022] [Indexed: 11/24/2022]
Abstract
Photobiomodulation therapy associated with conventional antivenom treatment has been shown to be effective in reducing the local effects caused by bothropic venoms in preclinical studies. In this study, we analyzed the influence of photobiomodulation using light emitting diode (LED) on the oxidative stress produced by murine macrophages stimulated with Bothrops jararacussu venom and it isolated toxins BthTX-I and BthTX-II. Under LED treatment, we evaluated the activity of the antioxidant enzymes catalase, superoxide dismutase, and peroxidase as well as the release of hydrogen peroxide and the enzyme lactate dehydrogenase. To investigate whether NADPH oxidase complex activation and mitochondrial pathways could contribute to hydrogen peroxide production by macrophages, we tested the effect of two selective inhibitors, apocynin and CCCP3, respectively. Our results showed that LED therapy was able to decrease the production of hydrogen peroxide and the liberation of lactate dehydrogenase, indicating less cell damage. In addition, the antioxidant enzymes catalase, superoxide dismutase, and peroxidase increased in response to LED treatment. The effect of LED treatment on macrophages was inhibited by CCCP3, but not by apocynin. These findings show that LED photobiomodulation treatment protects macrophages, at least in part, by reducing oxidative stress caused B. jararacussu venom and toxins.
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Dias ÊR, de Oliveira LA, Sales Lauria PS, Bordon KDCF, Rodrigues Domênico AM, da Silva Guerreiro ML, Wiezel GA, Cardoso IA, Rossini BC, Marino CL, Pimenta DC, Arantes EC, Casais-e-Silva LL, Branco A, dos Santos LD, Biondi I. Bothrops leucurus snake venom protein profile, isolation and biological characterization of its major toxin PLA2s-likeds. Toxicon 2022; 213:27-42. [DOI: 10.1016/j.toxicon.2022.04.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 04/02/2022] [Accepted: 04/04/2022] [Indexed: 12/17/2022]
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Moreira V, Leiguez E, Janovits PM, Maia-Marques R, Fernandes CM, Teixeira C. Inflammatory Effects of Bothrops Phospholipases A 2: Mechanisms Involved in Biosynthesis of Lipid Mediators and Lipid Accumulation. Toxins (Basel) 2021; 13:toxins13120868. [PMID: 34941706 PMCID: PMC8709003 DOI: 10.3390/toxins13120868] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 11/19/2021] [Accepted: 11/30/2021] [Indexed: 02/07/2023] Open
Abstract
Phospholipases A2s (PLA2s) constitute one of the major protein groups present in the venoms of viperid and crotalid snakes. Snake venom PLA2s (svPLA2s) exhibit a remarkable functional diversity, as they have been described to induce a myriad of toxic effects. Local inflammation is an important characteristic of snakebite envenomation inflicted by viperid and crotalid species and diverse svPLA2s have been studied for their proinflammatory properties. Moreover, based on their molecular, structural, and functional properties, the viperid svPLA2s are classified into the group IIA secreted PLA2s, which encompasses mammalian inflammatory sPLA2s. Thus, research on svPLA2s has attained paramount importance for better understanding the role of this class of enzymes in snake envenomation and the participation of GIIA sPLA2s in pathophysiological conditions and for the development of new therapeutic agents. In this review, we highlight studies that have identified the inflammatory activities of svPLA2s, in particular, those from Bothrops genus snakes, which are major medically important snakes in Latin America, and we describe recent advances in our collective understanding of the mechanisms underlying their inflammatory effects. We also discuss studies that dissect the action of these venom enzymes in inflammatory cells focusing on molecular mechanisms and signaling pathways involved in the biosynthesis of lipid mediators and lipid accumulation in immunocompetent cells.
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Affiliation(s)
- Vanessa Moreira
- Departamento de Farmacologia, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, Sao Paulo 04044-020, Brazil;
| | - Elbio Leiguez
- Laboratório de Farmacologia, Instituto Butantan, Sao Paulo 05503-900, Brazil; (E.L.); (P.M.J.); (R.M.-M.); (C.M.F.)
| | - Priscila Motta Janovits
- Laboratório de Farmacologia, Instituto Butantan, Sao Paulo 05503-900, Brazil; (E.L.); (P.M.J.); (R.M.-M.); (C.M.F.)
| | - Rodrigo Maia-Marques
- Laboratório de Farmacologia, Instituto Butantan, Sao Paulo 05503-900, Brazil; (E.L.); (P.M.J.); (R.M.-M.); (C.M.F.)
| | - Cristina Maria Fernandes
- Laboratório de Farmacologia, Instituto Butantan, Sao Paulo 05503-900, Brazil; (E.L.); (P.M.J.); (R.M.-M.); (C.M.F.)
| | - Catarina Teixeira
- Laboratório de Farmacologia, Instituto Butantan, Sao Paulo 05503-900, Brazil; (E.L.); (P.M.J.); (R.M.-M.); (C.M.F.)
- Correspondence:
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El-Benna J, Hurtado-Nedelec M, Gougerot-Pocidalo MA, Dang PMC. Effects of venoms on neutrophil respiratory burst: a major inflammatory function. J Venom Anim Toxins Incl Trop Dis 2021; 27:e20200179. [PMID: 34249119 PMCID: PMC8237995 DOI: 10.1590/1678-9199-jvatitd-2020-0179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 03/01/2021] [Indexed: 11/24/2022] Open
Abstract
Neutrophils play a pivotal role in innate immunity and in the inflammatory
response. Neutrophils are very motile cells that are rapidly recruited to the
inflammatory site as the body first line of defense. Their bactericidal activity
is due to the release into the phagocytic vacuole, called phagosome, of several
toxic molecules directed against microbes. Neutrophil stimulation induces
release of this arsenal into the phagosome and induces the assembly at the
membrane of subunits of the NAPDH oxidase, the enzyme responsible for the
production of superoxide anion that gives rise to other reactive oxygen species
(ROS), a process called respiratory burst. Altogether, they are responsible for
the bactericidal activity of the neutrophils. Excessive activation of
neutrophils can lead to extensive release of these toxic agents, inducing tissue
injury and the inflammatory reaction. Envenomation, caused by different animal
species (bees, wasps, scorpions, snakes etc.), is well known to induce a local
and acute inflammatory reaction, characterized by recruitment and activation of
leukocytes and the release of several inflammatory mediators, including
prostaglandins and cytokines. Venoms contain several molecules such as enzymes
(phospholipase A2, L-amino acid oxidase and proteases, among others) and
peptides (disintegrins, mastoporan, parabutoporin etc.). These molecules are
able to stimulate or inhibit ROS production by neutrophils. The present review
article gives a general overview of the main neutrophil functions focusing on
ROS production and summarizes how venoms and venom molecules can affect this
function.
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Affiliation(s)
- Jamel El-Benna
- Université de Paris, INSERM-U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation (CRI), Laboratoire d'Excellence Inflamex, Faculté de Médecine Xavier Bichat, Paris, France
| | - Margarita Hurtado-Nedelec
- Université de Paris, INSERM-U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation (CRI), Laboratoire d'Excellence Inflamex, Faculté de Médecine Xavier Bichat, Paris, France.,AP-HP, Centre Hospitalier Universitaire Xavier Bichat, UF Dysfonctionnements Immunitaires, Paris, France
| | - Marie-Anne Gougerot-Pocidalo
- Université de Paris, INSERM-U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation (CRI), Laboratoire d'Excellence Inflamex, Faculté de Médecine Xavier Bichat, Paris, France.,AP-HP, Centre Hospitalier Universitaire Xavier Bichat, UF Dysfonctionnements Immunitaires, Paris, France
| | - Pham My-Chan Dang
- Université de Paris, INSERM-U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation (CRI), Laboratoire d'Excellence Inflamex, Faculté de Médecine Xavier Bichat, Paris, France
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Ranéia E Silva PA, de Lima DS, Mesquita Luiz JP, Câmara NOS, Alves-Filho JCF, Pontillo A, Bortoluci KR, Faquim-Mauro EL. Inflammatory effect of Bothropstoxin-I from Bothrops jararacussu venom mediated by NLRP3 inflammasome involves ATP and P2X7 receptor. Clin Sci (Lond) 2021; 135:687-701. [PMID: 33620070 DOI: 10.1042/cs20201419] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 02/22/2021] [Accepted: 02/23/2021] [Indexed: 12/12/2022]
Abstract
Muscle tissue damage is one of the local effects described in bothropic envenomations. Bothropstoxin-I (BthTX-I), from Bothrops jararacussu venom, is a K49-phospholipase A2 (PLA2) that induces a massive muscle tissue injury, and, consequently, local inflammatory reaction. The NLRP3 inflammasome is a sensor that triggers inflammation by activating caspase 1 and releasing interleukin (IL)-1β and/or inducing pyroptotic cell death in response to tissue damage. We, therefore, aimed to address activation of NLRP3 inflammasome by BthTX-I-associated injury and the mechanism involved in this process. Intramuscular injection of BthTX-I results in infiltration of neutrophils and macrophages in gastrocnemius muscle, which is reduced in NLRP3- and Caspase-1-deficient mice. The in vitro IL-1β production induced by BthTX-I in peritoneal macrophages (PMs) requires caspase 1/11, ASC and NLRP3 and is dependent on adenosine 5'-triphosphate (ATP)-induced K+ efflux and P2X7 receptor (P2X7R). BthTX-I induces a dramatic release of ATP from C2C12 myotubes, therefore representing the major mechanism for P2X7R-dependent inflammasome activation in macrophages. A similar result was obtained when human monocyte-derived macrophages (HMDMs) were treated with BthTX-I. These findings demonstrated the inflammatory effect of BthTX-I on muscle tissue, pointing out a role for the ATP released by damaged cells for the NLRP3 activation on macrophages, contributing to the understanding of the microenvironment of the tissue damage of the Bothrops envenomation.
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Affiliation(s)
- Priscila Andrade Ranéia E Silva
- Laboratory of Immunopathology, Butantan Institute, São Paulo, Brazil
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, Sao Paulo, Brazil
| | - Dhêmerson Souza de Lima
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, Sao Paulo, Brazil
| | - João Paulo Mesquita Luiz
- Department of Pharmacology and Department of Immunology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | | | - José Carlos Farias Alves-Filho
- Department of Pharmacology and Department of Immunology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
| | - Alessandra Pontillo
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, Sao Paulo, Brazil
| | - Karina Ramalho Bortoluci
- Department of Biological Sciences and Center for Cellular and Molecular Therapy (CTC-Mol),Federal University of São Paulo, São Paulo, Brazil
| | - Eliana L Faquim-Mauro
- Laboratory of Immunopathology, Butantan Institute, São Paulo, Brazil
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, Sao Paulo, Brazil
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de Souza Barbosa Ê, Santos Ibiapina HN, Rocha da Silva S, Costa AG, Val FF, Mendonça-da-Silva I, Carlos de Lima Ferreira L, Sartim MA, Monteiro WM, Cardoso de Melo G, de Almeida Gonçalves Sachett J. Association of cfDNA levels and bothrops envenomation. Toxicon 2021; 192:66-73. [PMID: 33497746 DOI: 10.1016/j.toxicon.2021.01.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 12/21/2020] [Accepted: 01/20/2021] [Indexed: 01/05/2023]
Abstract
In the Amazon, around 90% of snakebites are caused by the Bothrops genus. Complications arising from Bothrops envenomations result from the inflammatory and coagulotoxic activities of the venom. The aim of this study was to investigate the potential of cell-free DNA (cfDNA) as a biomarker of severity in Bothrops snakebites. Patients were treated at the Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD), Manaus, in the Brazilian Amazon. cfDNA plasma levels were measured by amplifying the human telomerase reverse transcriptase (hTERT) sequence using quantitative RT-PCR. Median levels of cfDNA were compared between envenomed and healthy volunteers and among patients presenting different complications, such as renal failure, bleeding and infection. Of the 76 patients included, 82.9% were male, with a mean age of 32.8 years, and envenomations were mainly classified as severe (39.5%). ROC curve analysis showed a good accuracy of cfDNA levels (AUROC of 0.745) in envenomation diagnosis. A correlation analysis using laboratory variables showed positive correlation with lactate dehydrogenase (p = 0.033) and platelet count (p = 0.003). When cfDNA levels were compared with clinical complications, significant statistical differences were only found among individuals with mild and severe pain (p < 0.05). In summary, our results demonstrated that cfDNA levels are sufficiently accurate for discriminating between envenomed and non-envenomed patients, but are not able to distinguish different complications and the level of severity among envenomed patients. Thus, the role of cfDNA in the pathogenesis of the snakebite envenomations needs to be further investigated.
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Affiliation(s)
- Êndila de Souza Barbosa
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus, Brazil; Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus, Brazil
| | - Hiochelson Najibe Santos Ibiapina
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus, Brazil; Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus, Brazil
| | | | - Allyson Guimarães Costa
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus, Brazil; Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus, Brazil; Programa de Pós-Graduação em Imunologia Básica e Aplicada, Instituto de Ciências Biológicas, Universidade Federal do Amazonas (UFAM), Manaus, Brazil; Diretoria de Ensino e Pesquisa, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus, Brazil
| | - Fernando Fonseca Val
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus, Brazil; Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus, Brazil
| | - Iran Mendonça-da-Silva
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus, Brazil; Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus, Brazil
| | - Luiz Carlos de Lima Ferreira
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus, Brazil; Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus, Brazil; Faculdade de Medicina, Universidade Federal do Amazonas, Manaus, Brazil
| | - Marco Aurélio Sartim
- Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus, Brazil; Programa de Pós-Graduação em Imunologia Básica e Aplicada, Instituto de Ciências Biológicas, Universidade Federal do Amazonas (UFAM), Manaus, Brazil
| | - Wuelton Marcelo Monteiro
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus, Brazil; Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus, Brazil
| | - Gisely Cardoso de Melo
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus, Brazil; Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus, Brazil
| | - Jacqueline de Almeida Gonçalves Sachett
- Programa de Pós-Graduação em Medicina Tropical, Universidade do Estado do Amazonas (UEA), Manaus, Brazil; Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD), Manaus, Brazil; Diretoria de Ensino e Pesquisa, Fundação Alfredo da Matta, Manaus, Brazil.
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Polymorphonuclear neutrophil leukocytes in snakebite envenoming. Toxicon 2020; 187:188-197. [DOI: 10.1016/j.toxicon.2020.09.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 09/12/2020] [Accepted: 09/14/2020] [Indexed: 12/23/2022]
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