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地西泮在表观遗传学中的作用:从分子水平到临床意义。

The Role of Diazepam in Epigenetics: From the Molecular Level to Clinical Implications.

出版信息

Adv Mind Body Med. 2021;35(1):25-33.

PMID:33513583
Abstract

There is growing evidence linking epigenetic mutations to neurologic disorders such as epilepsy. The effect of the medications primarily used to treat neurologic disorders has recently been studied, including research on epilepsy and the epigenetic process. The impact of the widely used medication diazepam on epigenomics, microRNA levels, the ensuing genetic exposure and potential clinical effects was reviewed. The action of diazepam, particularly in altering the synthesis of enzyme 5' adenosine monophosphate activated protein kinase (AMPK) was found to affect many enzymes, which changes or modifies the epigenetics. Epigenetic enzymes such as histone acetyltransferases (HATs), class II histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) are mainly activated by AMPKs, including the phosphorylate substrates, which often lead to their inhibition, although HAT1 activity may be improved. It has been reported that diazepam can reduce histone methyltransferase expression exposure, may increase class III histone deacetylases activity and may decrease the effect of DNA methyltransferases inhibitors. Diazepam has been found to contribute to mutations of the epigenome and genetic expression, and may protect against neurologic disorders, aging, dementia and several brain diseases. It has also been found that microRNA expression can be influenced by diazepam treatment and may have neurologic effects. Although the reported effects of diazepam on epigenetic enzymes of are equally effective in both amplifying and reducing acetylation of histone, histone and DNA methylation and gene expression, the effect of diazepam on the epigenome, genetic expression, and subsequent effects in all healthy diazepam users is unclear.

摘要

越来越多的证据将表观遗传突变与癫痫等神经紊乱联系起来。最近研究了主要用于治疗神经紊乱的药物的效果,包括对癫痫和表观遗传过程的研究。综述了广泛使用的药物地西泮对表观基因组学、microRNA 水平、随后的遗传暴露和潜在临床影响的影响。地西泮的作用,特别是改变酶 5' 腺苷单磷酸激活蛋白激酶(AMPK)的合成,被发现会影响许多酶,从而改变或修饰表观遗传。表观遗传酶,如组蛋白乙酰转移酶(HATs)、II 类组蛋白去乙酰化酶(HDACs)和 DNA 甲基转移酶(DNMTs),主要被 AMPKs 激活,包括磷酸化底物,这通常导致它们被抑制,尽管 HAT1 活性可能会提高。据报道,地西泮可以降低组蛋白甲基转移酶表达的暴露,可以增加 III 类组蛋白去乙酰化酶的活性,并降低 DNA 甲基转移酶抑制剂的效果。地西泮被发现会导致表观基因组和基因表达的突变,并可能预防神经紊乱、衰老、痴呆和几种脑部疾病。还发现地西泮治疗可以影响 microRNA 表达,并可能具有神经作用。尽管报道的地西泮对表观遗传酶的作用同样有效,可以增强和减少组蛋白、组蛋白和 DNA 甲基化以及基因表达的乙酰化,但地西泮对所有健康地西泮使用者的表观基因组、基因表达和随后的影响尚不清楚。

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