Efeito da inibição da proteína galectina-3 na toxicidade hepática induzida pela cisplatina em ratos
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2023-04-19
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Universidade Estadual Paulista (Unesp)
Resumo
A galectina-3 (Gal-3) é uma lectina de ligação a β-galactosídeo, que atua como um mediador pleiotrópico com inúmeras funções exercidas intra e extracelularmente, entre outras funções, como aquelas relacionadas à resposta inflamatória, tumorigênese e imunidade inata e adquirida. Diferentes modelos experimentais de hepatotoxicidade mostram um papel essencial da Gal-3 no estresse oxidativo, lesão e fibrose hepática, e nesse sentido, compostos capazes de inibir a expressão de Gal-3 têm sido utilizados como uma possível ferramenta no tratamento de doenças inflamatórias. Assim, avaliamos o efeito da inibição da Gal-3 pela pectina cítrica modificada (MCP) em modelo experimental de toxicidade hepática induzida pela cisplatina. Ratos machos Wistar foram distribuídos em quatro grupos experimentais com n = 6 animais/grupo. Os animais foram tratados via oral (gavagem) com salina (grupos SHAM e CIS) ou MCP (100 mg/kg/dia) (grupos MCP e MCP+CIS) por 7 dias. Após este período, os animais receberam por injeção intraperitoneal cisplatina (10 mg/kg/dia) ou salina por 3 dias. Após 6 horas da última dose de cisplatina, os animais foram eutanasiados para coleta de sangue e fígado. Os animais dos grupos CIS e MCP+CIS apresentaram perda de peso significativa, efeito corroborado pela redução acentuada no armazenamento de glicogênio nos hepatócitos, em comparação com os grupos SHAM e MCP. A cisplatina também produziu um aumento acentuado no influxo de leucócitos no fígado, degeneração hepática com aumento de corpos apoptóticos, níveis de ROS e ativação de STAT3 nos hepatócitos. Sistemicamente, os grupos CIS e MCP+CIS apresentaram aumento nos níveis plasmáticos de IL-6, IL-10, e biomarcadores de toxicidade hepática (ARG1, GSTα, SDH). Os níveis reduzidos de Gal-3 no fígado do grupo MCP+CIS foram associados ao aumento dos níveis de MDA e da expressão do complexo respiratório mitocondrial I. Além disso, o grupo MCP+CIS apresentou níveis plasmáticos aumentados de IL-1β, TNF-α e GOT1. A terapia com MCP antagonizou eficientemente a Gal-9 no fígado, mas não a Gal-1, que apresentou níveis aumentados. Em conclusão, a redução dos níveis endógenos de Gal-3 nos hepatócitos favorece o processo de morte celular e aumento do estresse oxidativo no modelo agudo de toxicidade induzida pela cisplatina.
Galectin-3 (Gal-3) is a β-galactoside-binding lectin, which acts as a pleiotropic mediator with numerous functions exerted intra and extracellularly, among other functions such as those related to the inflammatory response, tumorigenesis, and innate and acquired immunity. Different experimental models of hepatotoxicity show an essential role for Gal-3 in oxidative stress, injury, and liver fibrosis, and in this sense, compounds capable of inhibiting Gal-3 expression have been used as a possible tool in the treatment of inflammatory diseases. Thus, we evaluated the effect of Gal-3 inhibition by modified citrus pectin (MCP) in an experimental model of cisplatin-induced liver toxicity. Male Wistar rats were distributed into four experimental groups with n = 6 animals/group. The animals were treated orally (gavage) with saline (SHAM and CIS groups) or MCP (100 mg/kg/day) (MCP and MCP+CIS groups) for 7 days. After this period, the animals received cisplatin (10 mg/kg/day) or saline by intraperitoneal injection for 3 days. Six hours after the last cisplatin dose, the animals were euthanized for blood and liver collection. Animals in the CIS and MCP+CIS groups showed significant weight loss, an effect corroborated by the marked reduction in glycogen storage in hepatocytes, compared to the SHAM and MCP groups. Cisplatin also produced a marked increase in the influx of leukocytes into the liver, hepatic degeneration with an increase in apoptotic bodies, ROS levels and STAT3 activation in hepatocytes. Systemically, the CIS and MCP+CIS groups showed increased plasma levels of IL-6, IL-10, and liver toxicity biomarkers (ARG1, GSTα, SDH). Reduced levels of Gal-3 in the liver of the MCP+CIS group were associated with increased levels of MDA and expression of the mitochondrial respiratory complex I. In addition, the MCP+CIS group showed increased plasma levels of IL-1β, TNF- α and GOT1. MCP therapy efficiently antagonized Gal-9 in the liver, but not Gal-1, which showed increased levels. In conclusion, the reduction of endogenous Gal-3 levels in hepatocytes favors the process of cell death and increased oxidative stress in the acute model of cisplatin-induced toxicity.
Galectin-3 (Gal-3) is a β-galactoside-binding lectin, which acts as a pleiotropic mediator with numerous functions exerted intra and extracellularly, among other functions such as those related to the inflammatory response, tumorigenesis, and innate and acquired immunity. Different experimental models of hepatotoxicity show an essential role for Gal-3 in oxidative stress, injury, and liver fibrosis, and in this sense, compounds capable of inhibiting Gal-3 expression have been used as a possible tool in the treatment of inflammatory diseases. Thus, we evaluated the effect of Gal-3 inhibition by modified citrus pectin (MCP) in an experimental model of cisplatin-induced liver toxicity. Male Wistar rats were distributed into four experimental groups with n = 6 animals/group. The animals were treated orally (gavage) with saline (SHAM and CIS groups) or MCP (100 mg/kg/day) (MCP and MCP+CIS groups) for 7 days. After this period, the animals received cisplatin (10 mg/kg/day) or saline by intraperitoneal injection for 3 days. Six hours after the last cisplatin dose, the animals were euthanized for blood and liver collection. Animals in the CIS and MCP+CIS groups showed significant weight loss, an effect corroborated by the marked reduction in glycogen storage in hepatocytes, compared to the SHAM and MCP groups. Cisplatin also produced a marked increase in the influx of leukocytes into the liver, hepatic degeneration with an increase in apoptotic bodies, ROS levels and STAT3 activation in hepatocytes. Systemically, the CIS and MCP+CIS groups showed increased plasma levels of IL-6, IL-10, and liver toxicity biomarkers (ARG1, GSTα, SDH). Reduced levels of Gal-3 in the liver of the MCP+CIS group were associated with increased levels of MDA and expression of the mitochondrial respiratory complex I. In addition, the MCP+CIS group showed increased plasma levels of IL-1β, TNF- α and GOT1. MCP therapy efficiently antagonized Gal-9 in the liver, but not Gal-1, which showed increased levels. In conclusion, the reduction of endogenous Gal-3 levels in hepatocytes favors the process of cell death and increased oxidative stress in the acute model of cisplatin-induced toxicity.
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Citocinas, Hepatotoxicidade, Inflamação, Peroxidação lipídica, Mitocôndrias, Pectina cítrica modificada, Espécies reativas de oxigênio, Cytokines, Hepatotoxicity, Inflammation, Lipid peroxidation, Mitochondria, Modified citrus pectin, Reactive oxygen species