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Therapeutic Targeting of Histone Deacetylation to Prevent Alzheimer's Disease. 靶向组蛋白去乙酰化预防阿尔茨海默病。

eMedical research

Pub Date : 2021-01-01 Epub Date: 2021-04-26

Sophia Chacko, Warren Ladiges

Efforts to find disease-modifying treatments for Alzheimer's disease (AD) have been largely unsuccessful. The relative lack of progress and the age-related incidence of AD suggest that modulation of aging per se may be a useful alternative treatment approach. Therapeutics aimed at preventing or reversing aging should be effective in preventing or reversing dementia and the pathology associated with progressive AD. Epigenetic dysregulation of neuronal gene expression occurs with age, propagating deficits in cellular homeostasis. Regulators of epigenetic processes, such as histone deacetylases (HDACs), are well documented and may represent promising therapeutic targets. HDAC activity becomes dysregulated with age and in AD. An intriguing concept is that HDAC inhibition effectively forestalls AD pathology measured more broadly, addressing the notion that rectifying homeostatic gene expression may be the critical step in ameliorating AD pathogenesis at the earliest stage of disease initiation. HDAC inhibitors target several pathways associated with aging and AD neuropathology including loss of synaptic function, mitochondrial dysfunction, increased oxidative stress, and decreased autophagy activity. Since transcriptional levels of numerous genes are shown to decrease with increasing age, a recovery of their transcriptional activity through HDAC inhibition could prevent or delay age-associated declines in neurological function and provide pathways for treating AD.

寻找治疗阿尔茨海默病(AD)的治疗方法的努力在很大程度上是不成功的。相对缺乏进展和与年龄相关的AD发病率表明，调节衰老本身可能是一种有用的替代治疗方法。旨在预防或逆转衰老的治疗方法应该有效地预防或逆转痴呆和与进行性阿尔茨海默病相关的病理。神经元基因表达的表观遗传失调随着年龄的增长而发生，细胞内稳态的繁殖缺陷。表观遗传过程的调节因子，如组蛋白去乙酰化酶(hdac)，已被充分记录，并可能代表有希望的治疗靶点。HDAC活性随着年龄和AD的增长而失调。一个有趣的概念是，HDAC抑制有效地预防了更广泛的AD病理测量，解决了在疾病初始阶段纠正稳态基因表达可能是改善AD发病机制的关键步骤的概念。HDAC抑制剂靶向与衰老和AD神经病理相关的几种途径，包括突触功能丧失、线粒体功能障碍、氧化应激增加和自噬活性降低。由于许多基因的转录水平显示随着年龄的增长而下降，通过抑制HDAC恢复其转录活性可以预防或延缓与年龄相关的神经功能下降，并为治疗AD提供途径。

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引用次数: 0

Oxidized Glutathione Increases Delta-Subunit Expressing Epithelial Sodium Channel Activity in Xenopus laevis Oocytes. 氧化谷胱甘肽增加非洲爪蟾卵母细胞表达上皮钠通道的δ亚基活性。

eMedical research

Pub Date : 2020-01-01 Epub Date: 2020-05-25

Garett J Grant, Camila Coca, Xing-Ming Zhao, My N Helms

Epithelial sodium channels (ENaC) are heterotrimeric structures, made up of α, β, and γ subunits, and play an important role in maintaining fluid homeostasis. When δ-ENaC subunits are expressed in place of (or in addition to) the α-ENaC subunit alongside β- and γ- subunits, fundamental changes in the biophysical properties of ENaC can be observed. Using human ENaC cRNA constructs and the Xenopas laevis oocyte expression system, we show that oxidized glutathione (GSSG) differently effects αβγ-ENaC and αβγ-ENaC current. GSSG (400 μM) significantly decreased normalized whole cell current in oocytes expressing αβγ-ENaC, and conversely increased whole cell current in δ1βγ-ENaC and δ2βγ-ENaC expressing oocytes. GSSG treatment increased current in oocytes expressing all four subunits. Western blot and PCR analysis show that human small airway epithelial cells (hSAEC) express canonical αβγ-subunits alongside δ-ENaC subunits. Differences in single channel responses to GSSG in hSAECs indicate that airway epithelia redox sensitivity may depend on whether δ- or α- subunits assemble in the membrane. In silico analysis predict that six Cys amino acids in the δ-ENaC extracellular loop, and a single Cys in the N-terminal domain, are susceptible to post-translational modification by GSSG. Additional studies are needed to better understand the molecular regulation and pathophysiological roles of oxidized glutathione and δ-ENaC in lung disorders.

上皮钠通道(ENaC)是由α、β和γ亚基组成的异三聚体结构，在维持体液稳态中起重要作用。当δ-ENaC亚基与β-和γ-亚基一起代替(或补充)α-ENaC亚基时，可以观察到ENaC生物物理性质的根本变化。利用人ENaC cRNA构建和非洲色狼卵母细胞表达系统，我们发现氧化谷胱甘肽(GSSG)对αβγ-ENaC和αβγ-ENaC电流的影响不同。GSSG (400 μM)显著降低表达αβγ-ENaC的卵母细胞的归一化全细胞电流，相反地增加表达δ1βγ-ENaC和δ2βγ-ENaC的卵母细胞的归一化全细胞电流。GSSG处理增加了表达所有四个亚基的卵母细胞的电流。Western blot和PCR分析表明，人小气道上皮细胞(hSAEC)在δ-ENaC亚基的同时表达典型αβγ-亚基。hsaec对GSSG单通道反应的差异表明，气道上皮氧化还原敏感性可能取决于膜中是否聚集了δ或α-亚基。计算机分析预测，δ-ENaC胞外环中的6个Cys氨基酸和n端结构域的1个Cys易受GSSG翻译后修饰的影响。氧化谷胱甘肽和δ-ENaC在肺部疾病中的分子调控和病理生理作用有待进一步研究。

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