Abstract
Snakebites are considered a neglected tropical disease in Brazil and 70% of cases of envenomation are attributed to the genus Bothrops. The efficient therapy to treat patients is administration of antivenom; however, the use of snake antivenom has some limitations. Thus, the search for new therapeutic alternatives using extract of plants to treat snakebites has become important to complement the conventional therapy. In this approach, we evaluated the anti-inflammatory ability of aqueous extract and fractions of Hancornia speciosa Gomes, Apocynaceae, rutin, and chlorogenic acid against B. jararaca snake venom-induced peritoneal leukocyte migration and myotoxicity in mice. In B. jararaca snake venom-induced peritoneal leukocyte migration, the mice were treated, by intravenous route, with 100 μl of aqueous extract (10, 15, or 20 mg/kg); snake antivenom, solvent fractions (F1, dichloromethane; F2, ethyl acetate; F3, n-butanol; at a dose of 20 mg/kg), and chlorogenic acid or rutin (1.5, 2, and 2.5 mg/kg). Simultaneously, the rodents received 100 μl the B. jararaca snake venom (0.3 mg/kg, i.p.). After 4 h, the aqueous extract, solvent fractions, and compounds showed reduction of leukocyte transmigration in peritoneal cavity. In B. jararaca snake venom-induced myotoxicity, the mice were treated with the same protocol and, simultaneously, received 50 μl of venom (0.6 mg/kg, intramuscular route). After 24 h, the treatment evidenced a reduction of influx of cells, an inhibitory edematogenic effect in gastrocnemius muscle. Moreover, the histological examination revealed that aqueous extract, solvent fractions, and rutin reduced inflammatory process through decreased leukocyte infiltration, formation of exudate and edema, and prevented the extravasation of erythrocytes to the muscular tissue. This is the first approach that evidences the inhibitory effect of the extract from H. speciosa fruits against inflammation induced by B. jararaca snake venom. Our results demonstrate that the active compounds from the extract, especially rutin and chlorogenic acid, may be responsible for the reported anti-inflammatory activity.
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References
Albuquerque PLMM, Paiva JHHGL, Martins AMC, Meneses GC, Silva Júnior GB, Buckley N, Daher EF (2020) Clinical assessment and pathophysiology of Bothrops venom-related acute kidney injury: a scoping review. J Venom Anim Toxins Incl Trop Dis 26:e201900. https://doi.org/10.1590/1678-9199-jvatitd-2019-0076
Almeida MT, Freitas-de-Sousa LA, Colombini M, Gimenes SNC, Kitano ES, Faquim-Mauro EL, Serrano SMT, Moura-da-Silva AM (2020) Inflammatory reaction induced by two metalloproteinases isolated from Bothrops atrox venom and by fragments generated from the hydrolysis of basement membrane components. Toxins 12:96. https://doi.org/10.3390/toxins12020096
Bitencourt MAO, Torres-Rêgo M, Lima MCJS, Furtado AA, Azevedo EP, Egito EST, Silva-Júnior AA, Zucolotto SM, Fernandes-Pedrosa MF (2019) Protective effect of aqueous extract, fractions and phenolic compounds of Hancornia speciosa fruits on the inflammatory damage in the lungs of mice induced by Tityus serrulatus envenomation. Toxicon 164:1–9. https://doi.org/10.1016/j.toxicon.2019.03.018
Choi SS, Park HR, Lee KA (2021) A comparative study of rutin and rutin glycoside: antioxidant activity, anti-inflammatory effect, effect on platelet aggregation and blood coagulation. Antioxidants 10:1696. https://doi.org/10.3390/antiox10111696
Cruz T, Gálvez J, Ocete MA, Crespo ME, Medina FLHS, Zarzuelo A (1998) Oral administration of rutoside can ameliorate inflammatory bowel disease in rats. Life Sci 62:687–695. https://doi.org/10.1016/S0024-3205(97)01164-8
Domitrovic R, Cvijanovic O, Susnic V, Katalinic N (2014) Renoprotective mechanisms of chlorogenic acid in cisplatin-induced kidney injury. Toxicology 324:98–107. https://doi.org/10.1016/j.tox.2014.07.004
Dorooshi G, Javid ZN, Meamar R, Farjzadegan Z, Nasri M, Eizadi-Mood N (2021) Evaluation of the effects of anti-inflammatory drugs on local and systemic manifestations of snakebite: a cross-sectional study. J Venom Res 11:21–25
Ferreira SS, Silva DP, Torres-Rêgo M, Silva-Júnior AA, Fernandes-Pedrosa MF (2021) The potential of phenolic acids in therapy against snakebites: a review. Toxicon 208:1–12. https://doi.org/10.1016/j.toxicon.2021.12.019
Fideles LS, Miranda JAL, Martins CS, Barbosa MLL, Pimenta HB, Pimentel PVS, Teixeira CS, Scafuri MAS, Façanha SO, Barreto JEF, Carvalho PMM, Scafuri AG, Araújo JL, Rocha JA, Vieira IGP, Ricardo NMPS, Silva Campelo M, Ribeiro MENP, Castro Brito GA, Cerqueira GS (2020) Role of rutin in 5-fluorouracil-induced intestinal mucositis: prevention of histological damage and reduction of inflammation and oxidative stress. Molecules 25:2786. https://doi.org/10.3390/molecules25122786
Furtado AA, Torres-Rêgo M, Lima MCJS, Bitencourt MAO, Estrela AB, Silva NS, Siqueira EMS, Tomaz JC, Lopes NP, Silva-Júnior AA, Zucolotto SM, Fernandes-Pedrosa MF (2016) Aqueous extract from Ipomoea asarifolia (Convolvulaceae) leaves and its phenolic compounds have anti-inflammatory activity in murine models of edema, peritonitis and air-pouch inflammation. J Ethnopharmacol 192:225–235. https://doi.org/10.1016/j.jep.2016.07.048
Geller FC, Teixeira MR, Pereira ABD, Dourado LPA, Souza DG, Braga FC, Simões CMO (2015) Evaluation of the wound healing properties of Hancornia speciosa leaves. Phyther Res 29:1887–1893. https://doi.org/10.1002/ptr.5438
Gutiérrez JM, Burnouf T, Harrison RA, Calvete JJ, Brown N, Jensen SD, Warrell DA, Williams DJ (2015) A call for incorporating social research in the global struggle against snakebite. PLoS Negl Trop Dis 9:e0003960. https://doi.org/10.1371/journal.pntd.0003960
Gutiérrez JM, Calvete JJ, Habib AG, Harrison RA, Williams DJ, Warrell DA (2017) Snakebite envenoming. Nat Rev Dis Prim 3:17063. https://doi.org/10.1038/nrdp.2017.63
Hirschmann GS, Arias AR (1990) A survey of medicinal plants of Minas Gerais, Brazil. J Ethnopharmacol 29:159–172. https://doi.org/10.1016/0378-8741(90)90052-U
Koch IAR, Simões AO, Kinoshita LS, Spina AP, Castello AC (2015) Apocynaceae in lista de espécies da flora do Brasil. Jadim Botânico do Rio de Janeiro. Available online: http://floradobrasil.jbrj.gov.br/jabot/floradobrasil/FB4861. Accessed 8 Apr 2019
Leonel TB, Gabrili JJM, Squaiella-Baptistão CC, Woodruff TM, Lambris JD, Tambourgi DV (2022) Bothrops jararaca snake venom inflammation induced in human whole blood: role of the complement system. Front Immunol 13:885223. https://doi.org/10.3389/fimmu.2022.885223
Luna KPO, Silva MB, Pereira VRA (2011) Clinical and immunological aspects of envenomations by Bothrops snakes. J Venom Anim Toxins Incl Trop Dis 17:130–141. https://doi.org/10.1590/S1678-91992011000200003
Magalhães A, Santos GB, Verdam MCS, Fraporti L, Malheiro A, Lima ES, Dos-Santos MC (2011) Inhibition of the inflammatory and coagulant action of Bothrops atrox venom by the plant species Marsypianthes chamaedrys. J Ethnopharmacol 134:82–88. https://doi.org/10.1016/j.jep.2010.11.062
Mamede CCN, Simamoto BBS, Pereira DFC, Costa JO, Ribeiro MSM, Oliveira F (2020) Edema, hyperalgesia and myonecrosis induced by Brazilian bothropic venoms: overview of the last decade. Toxicon 187:10–18. https://doi.org/10.1016/j.toxicon.2020.08.016
Marques SPD, Oliveira IR, Owen RW, Trevisan MTS (2015) Antioxidant capacity, angiotensin I converting enzyme (ACE) and acetylcholinesterase inhibition by extracts of the leaves and bark of Hancornia speciosa Gomes. Hum Journals 4:171–183
Ministério da Saúde (2019) Acidente por animais peçonhentos - notificações registradas no Sistema de Informação de Agravos de Notificação (SINAN) - SINAN NET, DATASUS. Tecnologia da Informação a Serviço do SUS, Ministério da Saúde, Secretaria de Vigilância Sanitária
Ministério da Saúde (2021) Sistema de Informação de Agravo de Notificação, Tipo Serpente segundo Ano acidente, http://tabnet.datasus.gov.br/cgi/tabcgi.exe?sinannet/cnv/animaisbr.def . Accessed date: 19Jul 2021.
Moreira V, Teixeira C, Silva HB, D’Império Lima MR, Dos-Santos MC (2016) The role of TLR2 in the acute inflammatory response induced by Bothrops atrox snake venom. Toxicon 118:121–128. https://doi.org/10.1016/j.toxicon.2016.04.042
Moreira V, Leiguez E, Janovits PM, Maia-Marques R, Fernandes CM, Teixeira C (2021) Inflammatory effects of Bothrops phospholipases A2: mechanisms involved in biosynthesis of lipid mediators and lipid accumulation. Toxins 13:868. https://doi.org/10.3390/toxins13120868
Moura VM, Sousa LAF, Dos-Santos MC, Raposo JDA, Lima AE, Oliveira RB, Silva MN, Mourão RHV (2015) Plants used to treat snakebites in Santarém, western Pará, Brazil: an assessment of their effectiveness in inhibiting hemorrhagic activity induced by Bothrops jararaca venom. J Ethnopharmacol 161:224–232. https://doi.org/10.1016/j.jep.2014.12.020
Moura VM, Souza LYA, Costa Guimarães N, Santos IGC, Almeida PDO, Oliveira RB, Mourão RHV, Dos-Santos MC (2017) The potential of aqueous extracts of Bellucia dichotoma Cogn. (Melastomataceae) to inhibit the biological activities of Bothrops atrox venom: a comparison of specimens collected in the states of Pará and Amazonas, Brazil. J Ethnopharmacol 196:168–177. https://doi.org/10.1016/j.jep.2016.12.031
Ontawong A, Duangjai A, Vaddhanaphuti CS, Amornlerdpison D, Pengnet S, Kamkaew N (2023) Chlorogenic acid rich in coffee pulp extract suppresses inflammatory status by inhibiting the p38, MAPK, and NF-κB pathways. Heliyon 9:e13917. https://doi.org/10.1016/j.heliyon.2023.e13917
Pereira LM, Messias EA, Sorroche BP, Oliveira AN, Arantes LMRB, Carvalho AC, Tanaka-Azevedo AM, Grego KF, Carvalho AL, Melendez ME (2020) In-depth transcriptome reveals the potential biotechnological application of Bothrops jararaca venom gland. J Venom Anim Toxins Incl Trop Dis 26. https://doi.org/10.1590/1678-9199-JVATITD-2019-0058
Pessini AC, Souza AM, Faccioli LH, Gregório ZMO, Arantes EC (2003) Time course of acute-phase response induced by Tityus serrulatus venom and TsTX-I in mice. Int Immunopharmacol 3:765–774. https://doi.org/10.1016/S1567-5769(03)00078-X
Pontes MCND, Torres-Rêgo M, Aquino AKS, Aquino NC, Teles YCF, Ximenes RM, Monteiro HSA, Silveira ER, Araújo RM (2021) Harpalyce brasiliana Benth: a prolific source of bioactive flavonoids with antiophidic potential. Phytochem Lett 41:158–167. https://doi.org/10.1016/j.phytol.2020.09.025
Rege MG, Ayanwuyi LO, Zezi AU, Odoma S (2021) Anti-nociceptive, anti-inflammatory and possible mechanism of anti-nociceptive action of methanol leaf extract of Nymphaea lotus Linn (Nymphaeceae). J Tradit Complement Med 11:123–129. https://doi.org/10.1016/j.jtcme.2020.02.010
Rengifo-Rios AM, Muñoz-Gómez LM, Cabezas-Fajardo FA, Guerrero-Vargas JA (2019) Edematic and coagulant effects caused by the venom of Bothrops rhombeatus neutralized by the ethanolic extract of Piper auritum. J Ethnopharmacol 242:112046. https://doi.org/10.1016/j.jep.2019.112046
Rocha Soares KS, Gláucia-Silva F, Daniele-Silva A, Torres-Rêgo M, Araújo NK, Menezes YAS, Damasceno IZ, Tambourgi DV, Silva-Júnior AA, Fernandes-Pedrosa MF (2018) Antivenom production against Bothrops jararaca and Bothrops erythromelas snake venoms using cross-linked chitosan nanoparticles as an immunoadjuvant. Toxins 10:158. https://doi.org/10.3390/toxins10040158
Sampaio TS (2008) Estudo fitoquímico de Hancornia speciosa Gomes: isolamento, determinação estrutural e atividade biológica. 190f. Dissertação (Mestrado em Química) - Universidade Federal de Sergipe, Sergipe, 2008.
Santana-Gálvez J, Cisneros-Zevallos L, Jacobo-Velázquez DA (2017) Chlorogenic acid: recent advances on its dual role as a food additive and a nutraceutical against metabolic syndrome. Molecules 22:7–9. https://doi.org/10.3390/molecules22030358
Santos Barreto GNL, Oliveira SS, Anjos IV, Chalkidis HM, Mourão RHV, Moura-da-Silva AM, Sano-Martins IS, Gonçalves LRC (2017) Experimental Bothrops atrox envenomation: efficacy of antivenom therapy and the combination of Bothrops antivenom with dexamethasone. PLoS Negl Trop Dis 11:e0005458. https://doi.org/10.1371/journal.pntd.0005458
Santos-Silva E, Torres-Rêgo M, Gláucia-Silva F, Feitosa RC, Lacerda AF, Rocha HAO, Fernandes-Pedrosa MF, Silva-Júnior AA (2022) Cationic PLGA nanoparticle formulations as biocompatible immunoadjuvant for serum production and immune response against Bothrops jararaca venom. Toxins 14:888. https://doi.org/10.3390/toxins14120888
Sarmento-Filha MJ, Torres-Rêgo M, Daniele-Silva A, Queiroz-Neto MF, Rocha HAO, Camara CA, Araújo RM, Silva-Júnior AA, Silva TMS, de Fernandes-Pedrosa MF (2022) Phytochemical analysis by UPLC-QTOF-MS/MS and evaluation of antioxidant and anti-inflammatory activities of the extract and fractions from flowers of Cochlospermum vitifolium. South African J Bot 148:293–306. https://doi.org/10.1016/j.sajb.2022.04.046
Silva HA, Ryan NM, Silva HJ (2016) Adverse reactions to snake antivenom, and their prevention and treatment. Br J Clin Pharmacol 81:446–452. https://doi.org/10.1111/bcp.12739
Silva DP, Ferreira SS, Torres-Rêgo M, Furtado AA, Yamashita FO, Diniz EAS, Vieira DS, Ururahy MAG, Silva-Júnior AA, Luna KPO, Fernandes-Pedrosa MF (2022) Antiophidic potential of chlorogenic acid and rosmarinic acid against Bothrops leucurus snake venom. Biomed Pharmacother 148:112766. https://doi.org/10.1016/j.biopha.2022.112766
Souza LBFC, Silva-Rocha WP, Ferreira MRA, Soares LAL, Svidzinski TIE, Milan EP, Pires RH, Almeida AMF, Mendes-Giannini MJS, Chaves GM (2018) Influence of Eugenia uniflora extract on adhesion to human buccal epithelial cells, biofilm formation, and cell surface hydrophobicity of Candida spp. from the oral cavity of kidney transplant recipients. Molecules 23:2418. https://doi.org/10.3390/molecules23102418
Teixeira CFP, Chaves F, Zamunér SR, Fernandes CM, Zuliani JP, Cruz-Hofling MA, Fernandes I, Gutiérrez JM (2005) Effects of neutrophil depletion in the local pathological alterations and muscle regeneration in mice injected with Bothrops jararaca snake venom. Int J Exp Pathol 86:107–115. https://doi.org/10.1111/j.0959-9673.2005.00419.x
Torres-Rêgo M, Furtado AA, Bitencourt MAO, Lima MCJS, Andrade RCLC, Azevedo EP, Soares TC, Tomaz JC, Lopes NP, Silva-Júnior AA, Zucolotto SM, Fernandes-Pedrosa MF (2016) Anti-inflammatory activity of aqueous extract and bioactive compounds identified from the fruits of Hancornia speciosa Gomes (Apocynaceae). BMC Complement Altern Med 16:275. https://doi.org/10.1186/s12906-016-1259-x
Torres-Rêgo M, Aquino-Vital AKS, Cavalcanti FF, Rocha EEA, Daniele-Silva A, Furtado AA, Silva DP, Ururahy MAG, Silveira ER, Fernandes-Pedrosa MF, Araújo RM (2022) Phytochemical analysis and preclinical toxicological, antioxidant, and anti-inflammatory evaluation of hydroethanol extract from the roots of Harpalyce brasiliana Benth (Leguminosae). J Ethnopharmacol 294:115364. https://doi.org/10.1016/j.jep.2022.115364
Vezza T, Rodríguez-Nogales A, Algieri F, Utrilla MP, Rodriguez-Cabezas ME, Galvez J (2016) Flavonoids in inflammatory bowel disease: a review. Nutrients 8:211. https://doi.org/10.3390/nu8040211
WHO (2021) Snakebite envenoming. In: https://www.who.int/news-room/fact-sheets/detail/snakebite-envenoming . (Accessed on 21 August 2023)
Yamashita FO, Torres-Rêgo M, Gomes JAS, Félix-Silva J, Passos JGR, Santis Ferreira L, Silva-Júnior AA, Zucolotto SM, Fernandes-Pedrosa MF (2020) Mangaba (Hancornia speciosa Gomes) fruit juice decreases acute pulmonary edema induced by Tityus serrulatus venom: potential application for auxiliary treatment of scorpion stings. Toxicon 179:42–52. https://doi.org/10.1016/j.toxicon.2020.02.025
Yun N, Kang J-W, Lee S-M (2012) Protective effects of chlorogenic acid against ischemia/reperfusion injury in rat liver: molecular evidence of its antioxidant and anti-inflammatory properties. J Nutr Biochem 23:1249–1255. https://doi.org/10.1016/j.jnutbio.2011.06.018
Zappi DC, Filardi FL, Ranzato Leitman P, Souza VC, Walter BMT, Pirani JR, Morim MP, Queiroz LP, Cavalcanti TB, Mansano VFM, Forzza RC, BFG (BFG) (2015) Growing knowledge: an overview of seed plant diversity in Brazil. Rodriguésia 66:1085–1113. https://doi.org/10.1590/2175-7860201566411
Zelanis A, Menezes MC, Kitano ES, Liberato T, Tashima AK, Pinto AFM, Sherman NE, Ho PL, Fox JW, Serrano SMT (2016) Proteomic identification of gender molecular markers in Bothrops jararaca venom. J Proteomics 139:26–37. https://doi.org/10.1016/j.jprot.2016.02.030
Zychar BC, Clissa PB, Carvalho E, Baldo C, Gonçalves LRC (2020) Leukocyte recruitment induced by snake venom metalloproteinases: role of the catalytic domain. Biochem Biophys Res Commun 521:402–407. https://doi.org/10.1016/j.bbrc.2019.10.144
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The work was financed by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil, and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil.
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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Finance Code 001, and Conselho Nacional de Desenvolvimento Científico e Tecnológico, grant number 437638/2018-9.
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MAOB: conceptualization, methodology, formal analysis, and investigation. MTR: formal analysis, investigation, and writing of original draft. ADS: investigation and writing of original draft. AAF: methodology, formal analysis, and investigation. MCJdSL: methodology and formal analysis. AAdSJ RMA, and SMZ: resources, writing, review and editing of final manuscript. MdFF-P: conceptualization, methodology, supervision, project administration, funding acquisition and writing, review and editing of final manuscript. All authors read and approved the final manuscript.
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Bitencourt, M.A.O., Torres-Rêgo, M., Daniele-Silva, A. et al. Aqueous Extract and Solvent Fractions of Hancornia speciosa Fruits, Rutin, and Chlorogenic Acid Attenuate the Edema, Inflammation, and Myonecrosis Caused by Bothrops jararaca Snake Venom in Mice. Rev. Bras. Farmacogn. 34, 585–594 (2024). https://doi.org/10.1007/s43450-023-00503-6
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DOI: https://doi.org/10.1007/s43450-023-00503-6