Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

Fang, Jingqi; Yang, Jiping; Wu, Xun; Zhang, Gangming; Li, Tao; Xie, Wang; Zhang, Hong; Wang, Chih-chen; Liu, Guanghui; Wang, Lei

doi:10.1111/acel.12765

Cited by 130 publications

(110 citation statements)

References 50 publications

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“…GPx7 is responsible for direct elimination of the H 2 O 2 produced by Ero1α [30] . We have previously elucidated that GPx7 can be induced in human fibroblasts by NRF2, the master transcription factor responsible for cellular antioxidant response [32] . Here, we observed that the protein expression of NRF2 and GPx7 in HUVECs was elevated time-dependently after Hcy treatment ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Specifically, the Ero1α/GPx7/PDI triad couples H 2 O 2 elimination and disulfide generation to ensure efficient and safe oxidative protein folding [30] . Interestingly, deficiency of GPx7 is associated with increased carcinogenesis and shortened lifespan [31] , [32] . Nevertheless, whether GPx7 plays a role and the relationship between GPx7 and Ero1α in Hcy-induced ER oxidative stress are still open questions.…”

Section: Introductionmentioning

confidence: 99%

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Homocysteine causes vascular endothelial dysfunction by disrupting endoplasmic reticulum redox homeostasis

et al. 2019

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Endothelial dysfunction induced by hyperhomocysteinemia (HHcy) plays a critical role in vascular pathology. However, little is known about the role of endoplasmic reticulum (ER) redox homeostasis in HHcy-induced endothelial dysfunction. Here, we show that Hcy induces ER oxidoreductin-1α (Ero1α) expression with ER stress and inflammation in human umbilical vein endothelial cells and in the arteries of HHcy mice. Hcy upregulates Ero1α expression by promoting binding of hypoxia-inducible factor 1α to the ERO1A promoter. Notably, Hcy rather than other thiol agents markedly increases the GSH/GSSG ratio in the ER, therefore allosterically activating Ero1α to produce H2O2 and trigger ER oxidative stress. By contrast, the antioxidant pathway mediated by ER glutathione peroxidase 7 (GPx7) is downregulated in HHcy mice. Ero1α knockdown and GPx7 overexpression protect the endothelium from HHcy-induced ER oxidative stress and inflammation. Our work suggests that targeting ER redox homeostasis could be used as an intervention for HHcy-related vascular diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Homocysteine causes vascular endothelial dysfunction by disrupting endoplasmic reticulum redox homeostasis

et al. 2019

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“…We have recently established a platform of Werner syndrome (WS) and Hutchinson-Gilford progeria syndrome (HGPS) hMSCs for studying premature and physiological aging (Fang et al, 2018 ; Kubben et al, 2016 ; Li et al, 2016b ; Wu et al, 2018 ; Yang et al, 2017 ; Zhang et al, 2015 ). Here, we took advantage of this platform and screened for natural product compounds capable of alleviating premature senescence (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, in our study decreased ROS levels may also contribute to the restoration of heterochromatin architecture. In addition, we have recently demonstrated that, the premature aging phenotypes in HGPS hMSCs partially attributes to the repression of NRF2-mediated anti-oxidative response, whereas the reactivation of NRF2 reverses the nuclear defects in HGPS cells and restores their in vivo viability in mice (Fang et al, 2018 ; Kubben et al, 2016 ). Interestingly, Que is reported as an activator of NRF2-mediated anti-oxidative pathway (Bahar et al, 2017 ; Dai et al, 2018 ; Gao et al, 2018 ; Kim et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Chemical screen identifies a geroprotective role of quercetin in premature aging

et al. 2018

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Aging increases the risk of various diseases. The main goal of aging research is to find therapies that attenuate aging and alleviate aging-related diseases. In this study, we screened a natural product library for geroprotective compounds using Werner syndrome (WS) human mesenchymal stem cells (hMSCs), a premature aging model that we recently established. Ten candidate compounds were identified and quercetin was investigated in detail due to its leading effects. Mechanistic studies revealed that quercetin alleviated senescence via the enhancement of cell proliferation and restoration of heterochromatin architecture in WS hMSCs. RNA-sequencing analysis revealed the transcriptional commonalities and differences in the geroprotective effects by quercetin and Vitamin C. Besides WS hMSCs, quercetin also attenuated cellular senescence in Hutchinson-Gilford progeria syndrome (HGPS) and physiological-aging hMSCs. Taken together, our study identifies quercetin as a geroprotective agent against accelerated and natural aging in hMSCs, providing a potential therapeutic intervention for treating age-associated disorders.

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“…IgG-FITC, IgG-PE, and IgG-APC were used as isotype controls. The differentiation abilities of MSCs to adipocytes, osteoblasts and chondrocytes were assessed by oil red O, Von Kossa and Toluidine blue staining, respectively (Duan et al, 2015 ; Fang et al, 2018 ; Yang et al, 2017 ; Zhang et al, 2015 ).…”

Section: Methodsmentioning

confidence: 99%

CRISPR/Cas9-mediated gene knockout reveals a guardian role of NF-κB/RelA in maintaining the homeostasis of human vascular cells

et al. 2018

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Vascular cell functionality is critical to blood vessel homeostasis. Constitutive NF-κB activation in vascular cells results in chronic vascular inflammation, leading to various cardiovascular diseases. However, how NF-κB regulates human blood vessel homeostasis remains largely elusive. Here, using CRISPR/Cas9-mediated gene editing, we generated RelA knockout human embryonic stem cells (hESCs) and differentiated them into various vascular cell derivatives to study how NF-κB modulates human vascular cells under basal and inflammatory conditions. Multi-dimensional phenotypic assessments and transcriptomic analyses revealed that RelA deficiency affected vascular cells via modulating inflammation, survival, vasculogenesis, cell differentiation and extracellular matrix organization in a cell type-specific manner under basal condition, and that RelA protected vascular cells against apoptosis and modulated vascular inflammatory response upon tumor necrosis factor α (TNFα) stimulation. Lastly, further evaluation of gene expression patterns in IκBα knockout vascular cells demonstrated that IκBα acted largely independent of RelA signaling. Taken together, our data reveal a protective role of NF-κB/RelA in modulating human blood vessel homeostasis and map the human vascular transcriptomic landscapes for the discovery of novel therapeutic targets.Electronic supplementary materialThe online version of this article (10.1007/s13238-018-0560-5) contains supplementary material, which is available to authorized users.

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Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

Cited by 130 publications

References 50 publications

Homocysteine causes vascular endothelial dysfunction by disrupting endoplasmic reticulum redox homeostasis

Homocysteine causes vascular endothelial dysfunction by disrupting endoplasmic reticulum redox homeostasis

Chemical screen identifies a geroprotective role of quercetin in premature aging

CRISPR/Cas9-mediated gene knockout reveals a guardian role of NF-κB/RelA in maintaining the homeostasis of human vascular cells

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