RESUMO
The influence of long-term tacrolimus treatment on cognitive function remains to be elucidated. Using a murine model of chronic tacrolimus neurotoxicity, we evaluated the effects of tacrolimus on cognitive function, synaptic balance, its regulating protein (Klotho), and oxidative stress in the hippocampus. Compared to vehicle-treated mice, tacrolimus-treated mice showed significantly decreased hippocampal-dependent spatial learning and memory function. Furthermore, tacrolimus caused synaptic imbalance, as demonstrated by decreased excitatory synapses and increased inhibitory synapses, and downregulated Klotho in a dose-dependent manner; the downregulation of Klotho was localized to excitatory hippocampal synapses. Moreover, tacrolimus increased oxidative stress and was associated with activation of the PI3K/AKT pathway in the hippocampus. These results indicate that tacrolimus impairs cognitive function via synaptic imbalance, and that these processes are associated with Klotho downregulation at synapses through tacrolimus-induced oxidative stress in the hippocampus.
Assuntos
Transtornos Cognitivos/induzido quimicamente , Hipocampo/fisiopatologia , Imunossupressores/toxicidade , Proteínas Klotho/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Sinapses/efeitos dos fármacos , Tacrolimo/toxicidade , Animais , Transtornos Cognitivos/metabolismo , Dendritos/metabolismo , Regulação para Baixo/efeitos dos fármacos , Hipocampo/patologia , Imunossupressores/farmacologia , Proteínas Klotho/biossíntese , Proteínas Klotho/genética , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos BALB C , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Teste de Campo Aberto , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Distribuição Aleatória , Transdução de Sinais , Aprendizagem Espacial , Memória Espacial , Sinapses/fisiologia , Tacrolimo/farmacologiaRESUMO
Circular RNAs (circRNAs) are considered as a new regulatory factor in growth, metastasis and therapeutic resistance of human cancers. But the clinical significance and underlying mechanism of circular RNA ITCH (circ-ITCH) in gastric cancer (GC) remain unknown. In the present study, we found that circ-ITCH was down-regulated in GC cell lines, GC tissues and their serum-derived exosomes. The level of circ-ITCH was related to invasion depth. Functional assays showed that circ-ITCH overexpression inhibited the proliferation, migration, invasion and epithelial mesenchymal transition (EMT) of GC cells, whereas circ-ITCH knockdown appeared an opposite effect. Bioinformatic analysis and luciferase reporter assay confirmed that circ-ITCH acted as miR-199a-5p sponge and increased the level of Klotho. The expression level of miR-199-5p was up-regulated in GC tissues and negatively correlated with that of circ-ITCH. MiR-199a-5p mimics reversed the effects on inhibiting metastasis induced by circ-ITCH overexpression and decreased the level of Klotho in GC cells. Our findings indicate that circ-ITCH suppresses metastasis of GC by acting as the sponge of miR-199a-5p and increasing Klotho expression, which serves as a potential biomarker and targets for the diagnosis and therapy of GC.Abbreviations: CircRNAs: circular RNAs; GC: gastric cancer; circ-ITCH: circular RNA Itchy E3 ubiquitin protein ligase; ceRNA: competitive endogenous RNA; EMT: Epithelial-mesenchymal transition; siRNA: Small interfering RNA; TEM: transmission electron microscope; NTA: nanoparticle tracking analysis.