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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

{"title":"Therapeutic Targeting of Histone Deacetylation to Prevent Alzheimer's Disease.","authors":"Sophia Chacko, Warren Ladiges","doi":"","DOIUrl":"","url":null,"abstract":"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.","PeriodicalId":92999,"journal":{"name":"eMedical research","volume":"3 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9385167/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40426908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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

{"title":"Oxidized Glutathione Increases Delta-Subunit Expressing Epithelial Sodium Channel Activity in Xenopus laevis Oocytes.","authors":"Garett J Grant, Camila Coca, Xing-Ming Zhao, My N Helms","doi":"","DOIUrl":"","url":null,"abstract":"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.","PeriodicalId":92999,"journal":{"name":"eMedical research","volume":"2 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38152588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0