Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

Zamponi, Emiliano; Zamponi, Nahuel; Coşkun, Pınar; Quassollo, Gonzalo; Lorenzo, Alfredo; Cannas, Sergio A.; Pigino, Gustavo; Chialvo, Dante R.; Gardiner, Katheleen; Busciglio, Jorge; Helguera, Pablo

doi:10.1111/acel.12812

Cited by 52 publications

(56 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nrf‐2 induces transcription of various antioxidant enzymes such as glutathione S‐transferase, NAD(P)H:quinone oxidoreductase 1, catalase. Studies have been associated on the protective role of Nrf‐2 against oxidative damage in down syndrome, Amyloid beta formation . In this study we found that, DOX downregulated Nrf‐2 and its target gene expressions such as HO‐1 and NQO1 levels.…”

Section: Discussionmentioning

confidence: 50%

Genistein protects against doxorubicin‐induced cardiotoxicity through Nrf‐2/HO‐1 signaling in mice model

Bai

Wang

2019

Environmental Toxicology

View full text Add to dashboard Cite

Doxorubicin (DOX)-induced cardiomyopathy is a lethal disease. DOX-induced cardiotoxic effects are attributed towards increased redox status and apoptotic signaling. In this study, we show that genistein offers protection against DOX-induced cardio toxicity in the mice model. DOXmediated increase in serum cardiac troponin and redox markers (ROS, LPO, 4-hydroxynonenalprotein adducts [HNE] levels) was significantly reduced by genistein treatment. Significantly increased TNF-α, IL-6, IL-8 expressions during DOX-induced inflammatory responses were down regulated by genistein treatment. Further, we found that genistein regulated antioxidant response through increased Nrf-2, HO-1, NQO1 protein expressions. In addition, DOX downregulated survival proteins (p-Akt, Bcl-2) with concomitant upregulation in Erk (1/2), Bax and cleaved caspase-3 expressions. The apoptotic activation was significantly downregulated by genistein treatment through suppression of apoptosis. Altogether, these findings show that genistein protects against DOX-induced cardiotoxic effects through activation of Nrf-2/HO-1 signaling. K E Y W O R D S caspase, doxorubicin, genistein, inflammation, Nrf-2

show abstract

Section: Discussionmentioning

confidence: 50%

Genistein protects against doxorubicin‐induced cardiotoxicity through Nrf‐2/HO‐1 signaling in mice model

Bai

Wang

2019

Environmental Toxicology

View full text Add to dashboard Cite

show abstract

“…Pathways upregulated pathways in Sin3a-LOF AT2 cells compared to wildtype AT2 cells included oxidative phosphorylation, mitochondrial dysfunction, sirtuin signaling, EIF2 signaling, and mTOR signaling, which were all identified in our bulk AT2 cell RNA-seq analyses. In addition, our scRNA-Seq data revealed differential expression of several other genes and pathways linked to cellular senescence, including eIF4 and p70S6K (46), protein ubiquitination (56,57), PI3K/AKT signaling (21)(22)(23)(24), phagosome maturation (58,59), VEGF signaling (60), integrin signaling (61), NRF2mediated oxidative stress (62)(63)(64)(65), actin nucleation (66), and MAPK signaling (67-69) ( Fig 2H).…”

Section: And Supplementalmentioning

confidence: 90%

Senescence of alveolar stem cells drives progressive pulmonary fibrosis

Yao

Guan

Carraro

et al. 2019

Preprint

View full text Add to dashboard Cite

Tissue fibrosis is a common pathological outcome of chronic disease that markedly impairs organ function leading to morbidity and mortality. In the lung, idiopathic pulmonary fibrosis (IPF) is an insidious and fatal interstitial lung disease associated with declining pulmonary function. Here, we show that alveolar type 2 (AT2) stem cells isolated from IPF lung tissue exhibit characteristic transcriptomic features of cellular senescence. We used conditional loss of Sin3a in adult mouse AT2 cells to initiate a program of p53-dependent cellular senescence, AT2 cell depletion, and spontaneous, progressive pulmonary fibrosis. We establish that senescence rather than loss of epithelial stem cells serves as a proximal driver of Tgfb activation and progressive fibrosis and show that either genetic or pharmacologic interventions targeting p53 activation, senescence, or downstream Tgfb activation, block fibrogenesis.

show abstract

“…Short-term SOD2 depletion in mouse embryos increases mtROS; however, at the postnatal stage, it activates antioxidant defense by Nrf2 and remodels mitochondrial function in the liver [13]. In fibroblasts derived from Down syndrome patients, elevated mtROS production is counteracted by Nrf2, which is activated by PKCδ-mediated phosphorylation [14]. The expression of mitochondrially targeted catalase (mtCAT) alleviates oxidative stress and inhibits Nrf2 activation in fibroblasts from Down syndrome patients [14].…”

Section: Introductionmentioning

confidence: 99%

Regulation of Nrf2 by Mitochondrial Reactive Oxygen Species in Physiology and Pathology

et al. 2020

View full text Add to dashboard Cite

Reactive oxygen species (ROS) are byproducts of aerobic respiration and signaling molecules that control various cellular functions. Nrf2 governs the gene expression of endogenous antioxidant synthesis and ROS-eliminating enzymes in response to various electrophilic compounds that inactivate the negative regulator Keap1. Accumulating evidence has shown that mitochondrial ROS (mtROS) activate Nrf2, often mediated by certain protein kinases, and induce the expression of antioxidant genes and genes involved in mitochondrial quality/quantity control. Mild physiological stress, such as caloric restriction and exercise, elicits beneficial effects through a process known as “mitohormesis”. Exercise induces NOX4 expression in the heart, which activates Nrf2 and increases endurance capacity. Mice transiently depleted of SOD2 or overexpressing skeletal muscle-specific UCP1 exhibit Nrf2-mediated antioxidant gene expression and PGC1α-mediated mitochondrial biogenesis. ATF4 activation may induce a transcriptional program that enhances NADPH synthesis in the mitochondria and might cooperate with the Nrf2 antioxidant system. In response to severe oxidative stress, Nrf2 induces Klf9 expression, which represses mtROS-eliminating enzymes to enhance cell death. Nrf2 is inactivated in certain pathological conditions, such as diabetes, but Keap1 down-regulation or mtROS elimination rescues Nrf2 expression and improves the pathology. These reports aid us in understanding the roles of Nrf2 in pathophysiological alterations involving mtROS.

show abstract

Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells

Cited by 52 publications

References 57 publications

Genistein protects against doxorubicin‐induced cardiotoxicity through Nrf‐2/HO‐1 signaling in mice model

Genistein protects against doxorubicin‐induced cardiotoxicity through Nrf‐2/HO‐1 signaling in mice model

Senescence of alveolar stem cells drives progressive pulmonary fibrosis

Regulation of Nrf2 by Mitochondrial Reactive Oxygen Species in Physiology and Pathology

Contact Info

Product

Resources

About