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Hemostasis-inflammation interaction during envenomation by Bothrops jararaca snakes: pathogenesis of thrombocytopenia, and therapeutic anti-ophidian mechanisms of quercetin-3-rutinoside (rutin)

Grant number: 19/07618-6
Support Opportunities:Regular Research Grants
Duration: July 01, 2020 - June 30, 2022
Field of knowledge:Biological Sciences - Pharmacology - Toxicology
Principal Investigator:Marcelo Larami Santoro
Grantee:Marcelo Larami Santoro
Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Associated researchers:Aparecida Sadae Tanaka ; Francisco Rafael Martins Laurindo ; Maria Elisa Peichoto ; Vânia Gomes de Moura Mattaraia

Abstract

Bothrops jararaca snake venom (BjV) remarkably alters Hemostasis and Inflammation, but few studies have examined the interaction between these processes during envenomation, whose understanding is essential to improve the treatment of patients. Various toxins from BjV showing either pro- or anti-hemostatic activities induce bleeding in bitten patients, associated with the presence of thrombocytopenia and coagulopathy. However, it is not known which one induces thrombocytopenia in vivo. Linked to hemostatic changes, proinflammatory toxins promote cell stimulation, and the release of cytokines and reactive species. Since Bothrops envenomation has a complex pathophysiology, and an effective treatment is lacking to prevent secondary complications not treated by specific antivenom therapy - e.g. local inflammatory changes, renal lesions, microangiopathic anemia and hemorrhagic strokes -, it is essential that new ancillary therapeutic compounds be sought to restrain the development of such manifestations induced by BjV. In previous studies from our group, rutin (quercetin-3-rutinoside) - a cheap and commercially available flavonoid that has well-established antioxidant, anti-inflammatory and pro-hemostatic activities - has proven to be efficacious in combating the hemostatic disorders occurring during envenomation. Thus, this proposal aims to: (1) isolate and characterize BjV toxins that induce thrombocytopenia during envenomation, and to investigate their mechanisms of action, particularly in microcirculation; (2) to investigate in conventional and genetically-modified animal models (a) the pathogenesis of BjV-induced changes in the inflammation-coagulation interface, and (b) the therapeutic activity and mechanism of action of rutin. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
LOTTO, NICHOLAS P.; MODESTO, JEANNE C. DE ALBUQUERQUE; SANT'ANNA, SAVIO S.; GREGO, KATHLEEN F.; GUARNIERI, MIRIAM C.; LIRA-DA-SILVA, REJANE M.; SANTORO, MARCELO L.; OGUIURA, NANCY. The absence of thrombin-like activity in Bothrops erythromelas venom is due to the deletion of the snake venom thrombin-like enzyme gene. PLoS One, v. 16, n. 4, . (19/07618-6, 15/00003-5)
THOMAZINI, CAMILA MARTOS; SACHETTO, ANA TERESA AZEVEDO; DE ALBUQUERQUE, CYNTHIA ZACCANINI; DE MOURA MATTARAIA, VANIA GOMES; DE OLIVEIRA, ANA KARINA; SERRANO, SOLANGE MARIA DE TOLEDO; LEBRUN, IVO; BARBARO, KATIA CRISTINA; SANTORO, MARCELO LARAMI. Involvement of von Willebrand factor and botrocetin in the thrombocytopenia induced by Bothrops jararaca snake venom. PLoS Neglected Tropical Diseases, v. 15, n. 9, . (13/07467-1, 18/26015-8, 13/20239-8, 19/07618-6, 13/25177-0)
MALAQUE, CEILA M. S.; NOVAES, CHRISTINA T. G.; PIORELLI, ROBERTA O.; RISK, JOSE Y.; MURAD, JEFFERSON C.; LARA, AMANDA N.; VIRGULINO, CRISTIANA C.; MIYAJI, KARINA T.; SANTORO, MARCELO L.. Impact of antivenom administration on the evolution of cutaneous lesions in loxoscelism: A prospective observational study. PLoS Neglected Tropical Diseases, v. 16, n. 10, p. 17-pg., . (19/07618-6)

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