Efecto de las proteínas del látex de Plumeria pudica sobre la mucositis intestinal causada por 5-fluorouracilo en ratones

Autores/as

DOI:

https://doi.org/10.33448/rsd-v14i2.48239

Palabras clave:

Citotoxicidad; Efecto protector; Estrés oxidativo; Inflamación.

Resumen

Plumeria pudica produce un látex rico en proteínas (PLPp) con propiedades antiinflamatorias, antinociceptivas y antidiarreicas, además de reducir la periodontitis y actuar como protector en la colitis ulcerosa. El presente estudio tuvo como objetivo evaluar los efectos de las proteínas del látex sobre la mucositis intestinal inducida por 5-fluorouracilo, con el fin de contribuir con información significativa para la solución de este problema y, de ser posible, convertirse en una herramienta terapéutica para la mucositis intestinal. Para este propósito, los ratones Balb/c hembra se dividieron en tres grupos: solución salina, 5-FU y PLPp + 5-FU. La mucositis se indujo con tres dosis de 5-FU, mientras que PLPp se administró una hora antes de cada aplicación de quimioterapia, durante tres días. Se recogió el intestino delgado para análisis histopatológicos, morfométricos, de estrés oxidativo (MDA, GSH y SOD) e inflamatorios (MPO y NO3/NO2). Se evaluó la citotoxicidad in vitro de PLPp solo y en combinación con 5-FU. PLPp redujo los niveles de MPO y NO3/NO2, demostrando una acción antiinflamatoria, aunque no revirtió los cambios histopatológicos. Además, PLPp no mostró citotoxicidad en las células HCT 116 analizadas y su asociación con 5-FU no redujo la IC50 del fármaco de quimioterapia. Se concluyó que PLPp protege la mucosa intestinal contra el estrés oxidativo y la inflamación inducida por 5-FU, aunque su actividad proteolítica puede comprometer la eficacia farmacológica.

Citas

Alencar, N. M. N., da Silveira Bitencourt, F., de Figueiredo, I. S. T., Luz, P. B., Lima‐Júnior, R. C. P., Aragão, K. S., ... & Ramos, M. V. (2017). Side‐effects of Irinotecan (CPT‐11), the clinically used drug for colon cancer therapy, are eliminated in experimental animals treated with latex proteins from Calotropis procera (Apocynaceae). Phytotherapy Research, 31(2), 312-320. Doi: https://doi.org/10.1002/ptr.5752

Araújo, L. C. R., Lins, M. A., de Lima, G. R., Moreschi, A. R. C., Lima, E. S., Hanan, S. A., ... & Bandeira, M. F. C. L. (2020). Atividade do o? leo de copai? ba sobre radicais livres formados durante a resposta inflamato? ria. Brazilian Journal of Development, 6(7), 53538-53553.

Arends, J. (2018). How to feed patients with gastrointestinal mucositis. Current Opinion in Supportive and Palliative Care, 12(2), 168-173.

Baek, J., & Lee, M. G. (2016). Oxidative stress and antioxidant strategies in dermatology. Redox Report, 21(4), 164-169.

Bansal, A., & Simon, M. C. (2018). Glutathione metabolism in cancer progression and treatment resistance. Journal of Cell Biology, 217(7), 2291-2298.

Bradley, P. P., Priebat, D. A., Christensen, R. D., & Rothstein, G. (1982). Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. Journal of investigative dermatology, 78(3), 206-209.

Bunel, V., Ouedraogo, M., Nguyen, A. T., Stévigny, C., & Duez, P. (2014). Methods applied to the in vitro primary toxicology testing of natural products: state of the art, strengths, and limits. Planta medica, 80(14), 1210-1226.

Carneiro-Filho, B. A., Oriá, R. B., Rea, K. W., Brito, G. A., Fujii, J., Obrig, T., ... & Guerrant, R. L. (2004). Alanyl-glutamine hastens morphologic recovery from 5-fluorouracil–induced mucositis in mice. Nutrition, 20(10), 934-941.

Chelakkot, C., Ghim, J., & Ryu, S. H. (2018). Mechanisms regulating intestinal barrier integrity and its pathological implications. Experimental & molecular medicine, 50(8), 1-9.

Das, K., Samanta, L., & Chainy, G. B. N. (2000). A modified spectrophotometric assay of superoxide dismutase using nitrite formation by superoxide radicals. Indian Journal of Biochemistry & Biophysics, 37(3), 201-204.

Dussourd, D. E. (2017). Behavioral sabotage of plant defenses by insect folivores. Annual review of entomology, 62(1), 15-34.

Eduardo, F. D. P., Bezinelli, L. M., Gobbi, M. F., Pereira, A. Z., Vogel, C., Hamerschlak, N., & Corrêa, L. (2018). Impact of oral and gastrointestinal mucositis on body weight alterations during hematopoietic stem cell transplantation. Nutrition and cancer, 70(2), 241-248.

Elad, S., Cheng, K. K. F., Lalla, R. V., Yarom, N., Hong, C., Logan, R. M., ... & Zur, E. (2020). MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer, 126(19), 4423-4431.

Escalante, J., McQuade, R. M., Stojanovska, V., & Nurgali, K. (2017). Impact of chemotherapy on gastrointestinal functions and the enteric nervous system. Maturitas, 105, 23-29.

Fernandes, H. B., Machado, D. L., Dias, J. M., Brito, T. V., Batista, J. A., Silva, R. O., ... & Oliveira, J. S. (2015). Laticifer proteins from Plumeria pudica inhibit the inflammatory and nociceptive responses by decreasing the action of inflammatory mediators and pro-inflammatory cytokines. Revista Brasileira de Farmacognosia, 25, 269-277.

Focaccetti, C., Bruno, A., Magnani, E., Bartolini, D., Principi, E., Dallaglio, K., ... & Albini, A. (2015). Effects of 5-fluorouracil on morphology, cell cycle, proliferation, apoptosis, autophagy and ROS production in endothelial cells and cardiomyocytes. PloS one, 10(2), e0115686.

Gai, Y. P., Zhao, Y. N., Zhao, H. N., Yuan, C. Z., Yuan, S. S., Li, S., ... & Ji, X. L. (2017). The latex protein MLX56 from mulberry (Morus multicaulis) protects plants against insect pests and pathogens. Frontiers in Plant Science, 8, 1475.

Galdino, F. M. P., Andrade, M. E. R., de Barros, P. A. V., de Vasconcelos Generoso, S., Alvarez-Leite, J. I., de Almeida-Leite, C. M., ... & Cardoso, V. N. (2018). Pretreatment and treatment with fructo-oligosaccharides attenuate intestinal mucositis induced by 5-FU in mice. Journal of Functional Foods, 49, 485-492.

Germolec, D. R., Shipkowski, K. A., Frawley, R. P., & Evans, E. (2018). Markers of inflammation. Immunotoxicity testing: Methods and protocols, 57-79.

Green, L. C., Wagner, D. A., Glogowski, J., Skipper, P. L., Wishnok, J. S., & Tannenbaum, S. R. (1982). Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids. Analytical biochemistry, 126(1), 131-138.

Huang, P., Sun, M., & Zeng, J. (2020). Low-molecular compounds of latex-bearing plants and their biosynthesis. Advances in botanical research, 93, 99-118.

Jesus, L. C. L. de. (2018). Efeito terapêutico do leite fermentado por Lactobacillus delbrueckii subsp. lactis CIDCA 133 em modelo de mucosite intestinal induzido pelo antineoplásico 5-Fluorouracil [Dissertação de Mestrado, Universidade Federal de Minas Gerais].

Jones, R., & Ocen, J. (2020). Cytotoxic chemotherapy: clinical aspects. Medicine, 48(2), 97-102.

Keefe, D. M. K., Brealey, J., Goland, G. J., & Cummins, A. (2000). Chemotherapy for cancer causes apoptosis that precedes hypoplasia in crypts of the small intestine in humans. Gut, 47(5), 632-637.

Król, M., & Kepinska, M. (2020). Human nitric oxide synthase—Its functions, polymorphisms, and inhibitors in the context of inflammation, diabetes and cardiovascular diseases. International journal of molecular sciences, 22(1), 56.

Lee, C. S., Ryan, E. J., & Doherty, G. A. (2014). Gastro-intestinal toxicity of chemotherapeutics in colorectal cancer: the role of inflammation. World journal of gastroenterology: WJG, 20(14), 3751.

Lee, J. M., Chun, H. J., Choi, H. S., Kim, E. S., Seo, Y. S., Jeen, Y. T., ... & Sul, D. (2017). Selenium administration attenuates 5-flurouracil-induced intestinal mucositis. Nutrition and cancer, 69(4), 616-622.

Li, H. L., Lu, L., Wang, X. S., Qin, L. Y., Wang, P., Qiu, S. P., ... & Wu, X. J. (2017). Alteration of gut microbiota and inflammatory cytokine/chemokine profiles in 5-fluorouracil induced intestinal mucositis. Frontiers in cellular and infection microbiology, 7, 455.

Li, X., Cao, X., Ying, Z., Yang, G., Hoogendijk, E. O., & Liu, Z. (2022). Plasma superoxide dismutase activity in relation to disability in activities of daily living and objective physical functioning among Chinese older adults. Maturitas, 161, 12-17.

Lima, R. C. S., Silva, M. C. C., Aguiar, C. C. T., Chaves, E. M. C., Dias, K. C. F., Macedo, D. S., ... & Vasconcelos, S. M. M. (2012). Anticonvulsant action of Calotropis procera latex proteins. Epilepsy & Behavior, 23(2), 123-126.

Liu, T., Sun, L., Zhang, Y., Wang, Y., & Zheng, J. (2022). Imbalanced GSH/ROS and sequential cell death. Journal of Biochemical and Molecular Toxicology, 36(1), e22942.

Luz, P. B. (2012). Fração proteica isolada do látex de Calotropis procera (AIT.) R.Br reduz hipernocicepção inflamatória mecânica em camundongos: mecanismos e mediadores envolvidos [Dissertação de Mestrado, Universidade Federal do Ceará]. Universidade Federal do Ceará.

MacPherson, B. R., & Pfeiffer, C. J. (1978). Experimental production of diffuse colitis in rats. Digestion, 17(2), 135-150.

Marciano, J. S. P. (2017). Identificação de proteínas presentes no soro do látex da Himatanthus sucuuba (Apocynaceae) [Tese de Doutorado, Universidade de Ribeirão Preto]. Universidade de Ribeirão Preto.

Mosmann, T. (1983). Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. Journal of immunological methods, 65(1-2), 55-63.

Odenwald, M. A., & Turner, J. R. (2017). The intestinal epithelial barrier: a therapeutic target?. Nature reviews Gastroenterology & hepatology, 14(1), 9-21.

Oliveira, J. S., Bezerra, D. P., de Freitas, C. D. T., Marinho Filho, J. D. B., de Moraes, M. O., Pessoa, C., ... & Ramos, M. V. (2007). In vitro cytotoxicity against different human cancer cell lines of laticifer proteins of Calotropis procera (Ait.) R. Br. Toxicology in vitro, 21(8), 1563-1573.

Oliveira, J. S., Costa-Lotufo, L. V., Bezerra, D. P., Alencar, N. M., Marinho-Filho, J. D. B., Figueiredo, I. S. T., ... & Ramos, M. V. (2010). In vivo growth inhibition of sarcoma 180 by latex proteins from Calotropis procera. Naunyn-Schmiedeberg's archives of pharmacology, 382, 139-149.

Oliveira, L. E., Moita, L. A., Souza, B. S., Oliveira, N. M., Sales, A. C., Barbosa, M. S., ... & Oliveira, J. S. (2021). Latex proteins from Plumeria pudica reduce ligature‐induced periodontitis in rats. Oral Diseases, 28(3), 786-795.

Oliveira, M. M. B., Araújo, A. A., Ribeiro, S. B., de Sales Mota, P. C. M., Marques, V. B., da Silva Martins Rebouças, C., ... & de Medeiros, C. A. C. X. (2021). Losartan improves intestinal mucositis induced by 5-fluorouracil in mice. Scientific reports, 11(1), 23241.

Pisoschi, A. M., & Pop, A. (2015). The role of antioxidants in the chemistry of oxidative stress: A review. European journal of medicinal chemistry, 97, 55-74.

Quaresma, M., Damasceno, S., Monteiro, C., Lima, F., Mendes, T., Lima, M., ... & Soares, P. (2020). Probiotic mixture containing Lactobacillus spp. and Bifidobacterium spp. attenuates 5-fluorouracil-induced intestinal mucositis in mice. Nutrition and Cancer, 72(8), 1355-1365.

Ramos, M. V., Demarco, D., da Costa Souza, I. C., & de Freitas, C. D. T. (2019). Laticifers, latex, and their role in plant defense. Trends in plant science, 24(6), 553-567.

Ramos, M. V., Freitas, A. P. F., Leitão, R. F., Costa, D. V., Cerqueira, G. S., Martins, D. S., ... & Brito, G. A. C. (2020). Anti-inflammatory latex proteins of the medicinal plant Calotropis procera: a promising alternative for oral mucositis treatment. Inflammation Research, 69, 951-966.

Rangel, G. F. P. (2019). Efeito de proteases isoladas da fração LPII do látex de Calotropis procera na prevenção da mucosite intestinal induzida por irinotecano em camundongos [Dissertação de Mestrado, Universidade Federal do Ceará]. Universidade Federal do Ceará.

Rtibi, K., Selmi, S., Grami, D., Amri, M., Sebai, H., & Marzouki, L. (2018). Contribution of oxidative stress in acute intestinal mucositis induced by 5 fluorouracil (5-FU) and its pro-drug capecitabine in rats. Toxicology mechanisms and methods, 28(4), 262-267.

Santana, L. D. A. B., Aragão, D. P., Araújo, T. D. S. L., de Sousa, N. A., de Souza, L. K. M., Oliveira, L. E. S., ... & Oliveira, J. S. (2018). Antidiarrheal effects of water-soluble proteins from Plumeria pudica latex in mice. Biomedicine & Pharmacotherapy, 97, 1147-1154.

Sedlak, J., & Lindsay, R. H. (1968). Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Analytical biochemistry, 25, 192-205.

Sies, H. (2015). Oxidative stress: a concept in redox biology and medicine. Redox biology, 4, 180-183.

Soares, P. M., Lima, S. R., Matos, S. G., Andrade, M. M., Patrocínio, M. C., de Freitas, C. D., ... & Vasconcelos, S. M. (2005). Antinociceptive activity of Calotropis procera latex in mice. Journal of ethnopharmacology, 99(1), 125-129.

Soares, P. M., Mota, J. M. S., Souza, E. P., Justino, P. F., Franco, A. X., Cunha, F. Q., ... & Souza, M. H. (2013). Inflammatory intestinal damage induced by 5-fluorouracil requires IL-4. Cytokine, 61(1), 46-49.

Sonis, S. T. (2004). The pathobiology of mucositis. Nature Reviews Cancer, 4(4), 277-284.

Souza, B. S., de Moraes Oliveira, N. V., Moita, L. A., Oliveira, L. E. S., de Brito, F. C., da Silva, F. R. P., ... & Oliveira, J. S. (2021). Acute and Subchronic Toxicity Assessment of Proteins from Plumeria pudica Latex in Mice. Research, Society and Development, 10(6), e58610616174-e58610616174.

Vellosa, J. C. R., Biavatti, M., Françóia, P. C. O., de Mello, B. J., de Almeida, A. C., & Bueno, G. E. (2021). Estresse oxidativo: uma introdução ao estado da arte. Brazilian Journal of Development, 7(1), 10152-10168.

Warowicka, A., Nawrot, R., & Goździcka-Józefiak, A. (2020). Pharmacologically active compounds from latex-bearing plants. In Advances in botanical research (Vol. 93, pp. 119-151). Academic Press.

Xiang, D. C., Yang, J. Y., Xu, Y. J., Zhang, S., Li, M., Zhu, C., ... & Liu, D. (2020). Protective effect of Andrographolide on 5-Fu induced intestinal mucositis by regulating p38 MAPK signaling pathway. Life sciences, 252, 117612.

Zhao, H., Zhang, R., Yan, X., & Fan, K. (2021). Superoxide dismutase nanozymes: an emerging star for anti-oxidation. Journal of Materials Chemistry B, 9(35), 6939-6957.

Publicado

20/02/2025

Cómo citar

ANDRADE, G. L. de; SOUZA, B. da S.; SALES, A. C. S.; SILVA, F. D. S. da; SOUZA, T. F. de; OLIVEIRA, A. P. de; MEDEIROS, J. V. R.; SOUZA, L. P. de; BARRETO, A. F. dos S.; ARAÚJO, A. J.; MARINHO FILHO, J. D. B.; SOUZA, J. M. T.; OLIVEIRA, J. S. de. Efecto de las proteínas del látex de Plumeria pudica sobre la mucositis intestinal causada por 5-fluorouracilo en ratones. Research, Society and Development, [S. l.], v. 14, n. 2, p. e6914248239, 2025. DOI: 10.33448/rsd-v14i2.48239. Disponível em: https://rsdjournal.org/index.php/rsd/article/view/48239. Acesso em: 2 abr. 2025.

Número

Sección

Ciencias de la salud