Role of CREB signaling in aging brain

Tang

Journal of Cardiovascular Pharmacology

et al. 2022

:Over the past decade, histone deacetylases (HDACs) has been proven to manipulate development and exacerbation of cardiovascular diseases, including myocardial ischemia/reperfusion injury, cardiac hypertrophy, ventricular remodeling, and myocardial fibrosis. Inhibition of HDACs, especially class-I HDACs, is potent to the protection of ischemic myocardium after ischemia/reperfusion (I/R). Herein, we examine whether mocetinostat (MGCD0103, MOCE), a class-I selective HDAC inhibitor in phase-II clinical trial, shows cardioprotection under I/R in vivo and in vitro, if so, reveal its potential pharmacological mechanism to provide an experimental and theoretical basis for mocetinostat usage in a clinical setting. Human cardiac myocytes (HCMs) were exposed to hypoxia and reoxygenation (H/R), with or without mocetinostat treatment. H/R reduced mitochondrial membrane potential and induced HCMs apoptosis. Mocetinostat pretreatment reversed these H/R-induced mitochondrial damage and cellular apoptosis and upregulated CREB, p-CREB, and PGC-1α in HCMs during H/R. Transfection with small interfering RNA against PGC-1α or CREB abolished the protective effects of mocetinostat on cardiomyocytes undergoing H/R. In vivo, mocetinostat was demonstrated to protect myocardial injury posed by myocardial I/R via the activation of CREB and upregulation of PGC-1α. Mocetinostat (MGCD0103) can protect myocardium from I/R injury through mitochondrial protection mediated by CREB/PGC-1α pathway. Therefore, activation of the CREB/PGC-1α signaling pathway via the inhibition of Class-I HDACs may be a promising new therapeutic strategy for alleviating myocardial reperfusion injury.

Section: Discussionmentioning

confidence: 99%

Isoform-Selective HDAC Inhibitor Mocetinostat (MGCD0103) Alleviates Myocardial Ischemia/Reperfusion Injury Via Mitochondrial Protection Through the HDACs/CREB/PGC-1α Signaling Pathway

Tang

Journal of Cardiovascular Pharmacology

et al. 2022

“…59 Nevertheless, alterations in CREB signaling can contribute to cognitive impairment 61 and may lead to increased incidence and progression of neurodegenerative diseases such as Huntington's, Alzheimer's, and Parkinson's disease. 62,63 Defects in Synaptic Plasticity May Reflect Altered Mitochondrial Function…”

Section: Activation Of Ltp Signalingmentioning

confidence: 99%

Low-Dose Ionizing Radiation Rapidly Affects Mitochondrial and Synaptic Signaling Pathways in Murine Hippocampus and Cortex

et al. 2015

The increased use of radiation-based medical imaging methods such as computer tomography is a matter of concern due to potential radiation-induced adverse effects. Efficient protection against such detrimental effects has not been possible due to inadequate understanding of radiation-induced alterations in signaling pathways. The aim of this study was to elucidate the molecular mechanisms behind learning and memory deficits after acute low and moderate doses of ionizing radiation. Female C57BL/6J mice were irradiated on postnatal day 10 (PND10) with gamma doses of 0.1 or 0.5 Gy. This was followed by evaluation of the cellular proteome, pathway-focused transcriptome, and neurological development/disease-focused miRNAome of hippocampus and cortex 24 h postirradiation. Our analysis showed that signaling pathways related to mitochondrial and synaptic functions were changed by acute irradiation. This may lead to reduced mitochondrial function paralleled by enhanced number of dendritic spines and neurite outgrowth due to elevated long-term potentiation, triggered by increased phosphorylated CREB. This was predominately observed in the cortex at 0.1 and 0.5 Gy and in the hippocampus only at 0.5 Gy. Moreover, a radiation-induced increase in the expression of several neural miRNAs associated with synaptic plasticity was found. The early changes in signaling pathways related to memory formation may be associated with the acute neurocognitive side effects in patients after brain radiotherapy but might also contribute to late radiation-induced cognitive injury.

“…CREB1, CAMP responsive element binding protein 1, is a protein that binds the cAMP response element and regulates transcription. Its expression and function can modulate oxidative stress-induced senescence in granulosa cells by reducing the mitochondrial function [ 85 ] and CREB signaling has been related to lung and brain aging [ 86 , 87 ]. Finally, EIF5A2 encoding for the Eukaryotic Initiation Factor 5A2, plays a key role in the regulation of protein translation, and it has been reported that, in transgenic mice, its overexpression enhances the aging process [ 88 ].…”

Section: Discussionmentioning

confidence: 99%

miRNome Profiling Detects miR-101-3p and miR-142-5p as Putative Blood Biomarkers of Frailty Syndrome

Carini

Mingardi

Bolzetta³

et al. 2022

Genes

Frailty is an aging-related pathology, defined as a state of increased vulnerability to stressors, leading to a limited capacity to meet homeostatic demands. Extracellular microRNAs (miRNAs) were proposed as potential biomarkers of various disease conditions, including age-related pathologies. The primary objective of this study was to identify blood miRNAs that could serve as potential biomarkers and candidate mechanisms of frailty. Using the Fried index, we enrolled 22 robust and 19 frail subjects. Blood and urine samples were analysed for several biochemical parameters. We observed that sTNF-R was robustly upregulated in the frail group, indicating the presence of an inflammatory state. Further, by RNA-seq, we profiled 2654 mature miRNAs in the whole blood of the two groups. Expression levels of selected differentially expressed miRNAs were validated by qPCR, and target prediction analyses were performed for the dysregulated miRNAs. We identified 2 miRNAs able to significantly differentiate frail patients from robust subjects. Both miR-101-3p and miR-142-5p were found to be downregulated in the frail vs. robust group. Finally, using bioinformatics targets prediction tools, we explored the potential molecular mechanisms and cellular pathways regulated by the two miRNAs and potentially involved in frailty.