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首页> 外文期刊>The Biochemical Journal >The anti-neurodegenerative agent clioquinol regulates the transcriptionTI The anti-neurodegenerative agent clioquinol regulates the transcription factor FOXO1a
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The anti-neurodegenerative agent clioquinol regulates the transcriptionTI The anti-neurodegenerative agent clioquinol regulates the transcription factor FOXO1a

机译：抗神经变性剂氯喹醇调节转录TI抗神经变性剂氯喹醇调节转录因子FOXO1a

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Many diseases of aging including AD (Alzheimer's disease) and T2D (Type 2 diabetes) are strongly associated with common risk factors, suggesting that there may be shared aging mechanisms underlying these diseases, with the scope to identify common cellular targets for therapy. In the present study we have examined the insulin-like signalling properties of an experimental AD 8-hydroxyquinoline drug known as CQ (clioquinol). The IIS [insulin/IGF-1 (insulin-like growth factor-1) signalling] kinase Akt/PKB (protein kinase B) inhibits the transcription factor FOXO1a (forkhead box O1a) by phosphorylating it on residues that trigger its exit from the nucleus. In HEK (human embryonic kidney)-293 cells, we found that CQ treatment induces similar responses. A key transcriptional response to US is the inhibition of hepatic gluconeogenic gene expression, and, in rat liver cells, CQ represses expression of the key gluconeogenic regulatory enzymes PEPCK (phosphoenolpyruvate carboxykinase) and G6Pase (glucose-6-phosphatase). The effects on FOXO1. a and gluconeogenic gene expression require the presence of Zn2+ ions, reminiscent of much earlier studies examining diabetogenic properties of 8-hydroxyquinolines. Comparative investigation of the signalling properties of a panel of these compounds demonstrates that CQ alone exhibits FOXO1a regulation without diabetogenicity. Our results suggest that Zn2+-dependent regulation of FOXOs and gluconeogenesis may contribute to the therapeutic properties of this drug. Further investigation of this signalling response might illuminate novel pharmacological strategies for the treatment of age-related diseases.
机译：包括AD（阿尔茨海默氏病）和T2D（2型糖尿病）在内的许多衰老疾病与常见危险因素密切相关，这表明这些疾病可能存在共同的衰老机制，并具有确定治疗通用细胞靶标的范围。在本研究中，我们已经研究了称为CQ（氯喹诺醇）的实验性AD 8-羟基喹啉药物的类胰岛素信号传导特性。 IIS [胰岛素/ IGF-1（胰岛素样生长因子-1）信号转导]激酶Akt / PKB（蛋白激酶B）通过将转录因子FOXO1a（叉头盒O1a）磷酸化而触发其从核中退出的残基来抑制转录因子。在HEK（人类胚胎肾脏）-293细胞中，我们发现CQ治疗诱导相似的反应。对US的关键转录反应是抑制肝糖异生基因的表达，在大鼠肝细胞中，CQ抑制关键糖异生调节酶PEPCK（磷酸烯醇丙酮酸羧激酶）和G6Pase（葡萄糖6磷酸酶）的表达。对FOXO1的影响。 α和糖异生基因的表达需要存在Zn2 +离子，这让人想起了早期的研究，研究了8-羟基喹啉的致糖尿病特性。一组这些化合物的信号传递特性的比较研究表明，仅CQ即可表现出FOXO1a调控，而无致糖尿病性。我们的结果表明，依赖Zn2 +的FOXO和糖异生的调控可能有助于该药物的治疗特性。对该信号应答的进一步研究可能会为治疗与年龄有关的疾病阐明新的药理策略。

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