Dexamethasone improves redox state in ataxia telangiectasia cells by promoting an NRF2‐mediated antioxidant response

Abstract

Ataxia telangiectasia (A-T) is a rare incurable neurodegenerative disease caused by biallelic mutations in the gene for ataxia-telangiectasia mutated (ATM). The lack of a functional ATM kinase leads to a pleiotropic phenotype, and oxidative stress is considered to have a crucial role in the complex physiopathology. Recently, steroids have been shown to reduce the neurological symptoms of the disease, although the molecular mechanism of this effect is largely unknown. In the present study, we have demonstrated that dexamethasone treatment of A-T lymphoblastoid cells increases the content of two of the most abundant antioxidants [glutathione (GSH) and NADPH] by up to 30%. Dexamethasone promoted the nuclear accumulation of the transcription factor nuclear factor (erythroid-derived 2)-like 2 to drive expression of antioxidant pathways involved in GSH synthesis and NADPH production. The latter effect was via glucose 6-phosphate dehydrogenase activation, as confirmed by increased enzyme activity and enhancement of the pentose phosphate pathway rate. This evidence indicates that glucocorticoids are able to potentiate antioxidant defenses to counteract oxidative stress in ataxia telangiectasia, and also reveals an unexpected role for dexamethasone in redox homeostasis and cellular antioxidant activity

Disrupting G6PD-mediated Redox homeostasis enhances chemosensitivity in colorectal cancer

“…Responding to ROS, NRF2 plays a vital role in transcriptionally regulating the expression of antioxidants genes including G6PD. 17 , 18 Immunoblotting analysis indicated that oxaliplatin treatment induced NFR2 activation and G6PD expression in CRC cells ( Figure 3b ). Also, RNAi depletion of NRF2 decreased G6PD mRNA and protein levels in these oxaliplatin-treated CRC cells ( Figures 3b and c ).…”

Zinc and Oxidative Stress: Current Mechanisms

“…In contrast, zinc supplementation exerts a protective role against damage to the vascular system. The mechanisms by which zinc protects the blood vessels include the regulation of Nrf2, a transcription factor important for the expression of genes encoding antioxidant enzymes and for the induction and expression of metallothionein [32,33,34]. …”

DDIT4 gene expression is switched on by a new HDAC4 function in ataxia telangiectasia

“…[21][22][23][24][25][26][27] Li et al reported the role of ATM in balancing HDAC4 function in AT neurons. [21][22][23][24][25][26][27] Li et al reported the role of ATM in balancing HDAC4 function in AT neurons.…”