Efeito de inibição da proteína galectina-3 na toxicidade cardiorrenal induzida pela cisplatina em ratos
Data
2023
Autores
Belote, Nycole Morelli [UNIFESP]
Orientadores
Gil, Cristiane Damas [UNIFESP]
Tipo
Trabalho de conclusão de curso de graduação
Título da Revista
ISSN da Revista
Título de Volume
Resumo
A inflamação e estresse oxidativo são mecanismos muito comuns na citotoxicidade provocada pela cisplatina. Neste contexto, destacamos a galectina-3 (Gal-3), uma proteína ligante de β-galactosídeos que regula os processos inflamatórios e oxidativos, mas seu papel em modelos de toxicidade não está bem determinado. Sendo assim, o objetivo deste estudo foi avaliar o efeito da inibição farmacológica da Gal-3 na toxicidade cardíaca e renal induzida pela cisplatina. Para tanto, Ratos Wistar machos foram divididos em 4 grupos (n = 6/grupo): SHAM e CIS, que receberam respectivamente salina estéril ou cisplatina (10 mg/kg/dia) via intraperitoneal (i.p.) por 3 dias e PEC e PEC+CIS, que receberam pectina cítrica modificada (inibidor da Gal-3) via oral (100 mg/kg/dia) por 7 dias, seguida por salina estéril ou cisplatina i.p. por 3 dias (CEUA nº 5338060422). Observamos que a administração de cisplatina produziu perda de peso significante dos animais no 3º dia, enquanto nos outros grupos não ocorreram alterações significantes. A resposta sistêmica foi associada com um aumento significante no perfil de neutrófilos circulantes e das citocinas IL-6 e IL-10. Além disso, no grupo PEC+CIS as citocinas IL-1β e TNF-α aumentaram significantemente em relação aos grupos SHAM e PEC. O tratamento com a PEC não alterou os níveis da proteína Gal-3 no sangue e coração, mas foi eficaz na redução nos rins do grupo PEC em relação ao grupo SHAM. As análises histológicas não mostraram alterações nos cardiomiócitos entre as diferentes condições experimentais, porém um dano tubular renal caracterizado pela degeneração das células epiteliais foi evidenciado nos rins dos grupos tratados com cisplatina. As alterações na homeostase redox mostram ter um papel inicial no dano em ambos os tecidos neste modelo experimental, evidenciadas principalmente no grupo PEC+CIS pelo aumento da peroxidação lipídica em ambos os órgãos, perda da integridade dos complexos da cadeia fosforilativa mitocondrial e resposta da atividade da catalase no coração. Em conclusão, o tecido cardíaco se mostrou mais resistente à toxicidade e ao tratamento com a pectina cítrica modificada, enquanto os rins sofreram intensos danos morfológicos e depleção dos níveis de Gal-3. Nesse sentido, mais investigações são necessárias para determinar as funções da Gal-3 a curto e a longo prazo, uma vez que ela pode exercer tanto papéis benéficos quanto maléficos nos tecidos.
Cisplatin is an antineoplasic agent related to cardiac toxicity. Inflammation and oxidative stress are very common mechanisms in the cytotoxicity caused by cisplatin. In this context, we highlight galectin-3 (Gal-3), a β-galactoside-binding protein that regulates inflammatory and oxidative processes, and an important biomarker of cardiac fibrosis. Therefore, this study aimed to evaluate the effect of pharmacological inhibition of Gal-3 with modified citrus pectin (MCP) on the heart in a model of cisplatin-induced acute toxicity. For that, Male Wistar rats were divided into 4 groups (n=6/group): SHAM – received sterile saline intraperitoneally (i.p) for 3 days; CIS – received cisplatin i.p (10mg/kg/day) for 3 days; MCP – received MCP orally (100 mg/kg/day) for 7 days, followed by sterile saline i.p for 3 days; MCP+CIS – received MCP orally for 7 days followed by cisplatin for another 3 days. After 6 hours of the last dose of cisplatin or vehicle, blood, heart and kidneys were collected (CEUA nº 5338060422). We observe that cisplatin administration produced a marked weight loss in the animals on the 3rd day, while in the other groups there were no significant changes. The systemic response was associated with a significant increase in the profile of circulating neutrophils and the cytokines IL-6 and IL-10. Furthermore, in the MCP+CIS group, the cytokines IL-1β and TNF-α increased significantly in relation to the SHAM and MCP groups. MCP treatment did not alter Gal-3 protein levels in the blood and heart, but it was effective in reducing kidneys in the MCP group compared to the SHAM group. Histological analyzes did not show changes in cardiomyocytes between the different experimental conditions, but renal tubular damage characterized by degeneration of epithelial cells was evidenced in the kidneys. Changes in redox homeostasis are shown to have an initial role in the damage in both tissues of this experimental model, evidenced mainly in the MCP+CIS group by increased lipid peroxidation, loss of integrity of mitochondrial phosphorylative chain complexes and catalase activity. Still, treatment with MCP did not change the levels of Gal-3 protein in the blood and heart, but it was effective in reducing the levels in the kidneys of the MCP group in relation to the SHAM group. In conclusion, cardiac tissue was more resistant to toxicity and treatment with modified citrus pectin, while kidneys suffered intense morphological damage and depletion of Gal-3 levels. In this context, further investigations are needed to determine the acute and chronic functions of Gal-3, since it can exert both beneficial and harmful roles in tissues.
Cisplatin is an antineoplasic agent related to cardiac toxicity. Inflammation and oxidative stress are very common mechanisms in the cytotoxicity caused by cisplatin. In this context, we highlight galectin-3 (Gal-3), a β-galactoside-binding protein that regulates inflammatory and oxidative processes, and an important biomarker of cardiac fibrosis. Therefore, this study aimed to evaluate the effect of pharmacological inhibition of Gal-3 with modified citrus pectin (MCP) on the heart in a model of cisplatin-induced acute toxicity. For that, Male Wistar rats were divided into 4 groups (n=6/group): SHAM – received sterile saline intraperitoneally (i.p) for 3 days; CIS – received cisplatin i.p (10mg/kg/day) for 3 days; MCP – received MCP orally (100 mg/kg/day) for 7 days, followed by sterile saline i.p for 3 days; MCP+CIS – received MCP orally for 7 days followed by cisplatin for another 3 days. After 6 hours of the last dose of cisplatin or vehicle, blood, heart and kidneys were collected (CEUA nº 5338060422). We observe that cisplatin administration produced a marked weight loss in the animals on the 3rd day, while in the other groups there were no significant changes. The systemic response was associated with a significant increase in the profile of circulating neutrophils and the cytokines IL-6 and IL-10. Furthermore, in the MCP+CIS group, the cytokines IL-1β and TNF-α increased significantly in relation to the SHAM and MCP groups. MCP treatment did not alter Gal-3 protein levels in the blood and heart, but it was effective in reducing kidneys in the MCP group compared to the SHAM group. Histological analyzes did not show changes in cardiomyocytes between the different experimental conditions, but renal tubular damage characterized by degeneration of epithelial cells was evidenced in the kidneys. Changes in redox homeostasis are shown to have an initial role in the damage in both tissues of this experimental model, evidenced mainly in the MCP+CIS group by increased lipid peroxidation, loss of integrity of mitochondrial phosphorylative chain complexes and catalase activity. Still, treatment with MCP did not change the levels of Gal-3 protein in the blood and heart, but it was effective in reducing the levels in the kidneys of the MCP group in relation to the SHAM group. In conclusion, cardiac tissue was more resistant to toxicity and treatment with modified citrus pectin, while kidneys suffered intense morphological damage and depletion of Gal-3 levels. In this context, further investigations are needed to determine the acute and chronic functions of Gal-3, since it can exert both beneficial and harmful roles in tissues.