Sestrin2 in hypoxia and hypoxia-related diseases

Che, Xiaojing; Chai, Jiagui; Yan, Fang; Zhang, Xifeng; Zu, Anju; Li, Lin; Sun, Shibo; Ye, Weimin

doi:10.1080/13510002.2021.1948774

Cited by 16 publications

(9 citation statements)

References 76 publications

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“…Sestrin2 has a dual function, which can directly reduce oxidative stress by restoring peroxiredoxin peroxide and indirectly reduce oxidative stress by regulating mTOR to enhance autophagy activity (Chen et al 2021a ). Sestrin2 plays a key role in various cell signal transduction processes, and its dysregulation has been linked to various diseases (Che et al 2021 ). For example, calycosin has an inhibitory effect on papillary thyroid cancer by promoting apoptosis and autophagy through the Sestrin2/AMPK/mTOR pathway (Qu et al 2022 ), and studies have shown that Sestrin2 is involved in the regulation of ferroptosis.…”

Section: Introductionmentioning

confidence: 99%

Sestrin2 ameliorates diabetic retinopathy by regulating autophagy and ferroptosis

Xi,

Chen,

et al. 2024

J Mol Histol

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Diabetic retinopathy (DR) is a serious microvascular complication of diabetes. The aim of this study was to explore the effect of Sestrin2 on DR through the regulation of autophagy and ferroptosis levels and its mechanism. In vitro and in vivo DR models were established by high glucose (HG) and streptozotocin (STZ) induction of ARPE-19 human retinal pigment epithelial cells and C57BL/6 mice, respectively. In this study, we demonstrated that after HG treatment, the activity of ARPE-19 cells was decreased, the apoptosis rate was increased, endoplasmic reticulum (ER) stress was activated, autophagy levels were decreased, and ferroptosis levels were increased. Overexpression of Sestrin2 enhanced cell viability, reduced apoptosis and ferroptosis, and enhanced autophagy. However, the effect of overexpression of Sestrin2 was attenuated after the addition of the STAT3 phosphorylation activator Colivelin TFA (C-TFA), the mTOR pathway activator MHY1485 or the autophagy inhibitor 3-methyladenine (3-MA). In addition, the effect of Sestrin2 knockdown on cells was opposite to the effect of overexpression of Sestrin2, while the effect of Sestrin2 knockdown was attenuated after treatment with the ER stress inhibitor 4-phenylbutyric acid (4-PBA). Animal experiments also confirmed the results of cell experiments and attenuated the effects of overexpression of Sestrin2 after injection of the ferroptosis activators erastin or 3-MA. Our study revealed that Sestrin2 inhibits ferroptosis by inhibiting STAT3 phosphorylation and ER stress and promoting autophagy levels, thereby alleviating DR.

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Section: Introductionmentioning

confidence: 99%

Sestrin2 ameliorates diabetic retinopathy by regulating autophagy and ferroptosis

Xi,

Chen,

et al. 2024

J Mol Histol

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“…As a sensitive stress receptor, Sestrin2 is activated in stress conditions. A variety of adverse stresses could promote Sestrin2 expression, such as oxidative stress, ER stress, hypoxia, energetic stress, and age-and obesity-associated metabolic pathological conditions (7)(8)(9)(10). Up-regulated Sestrin2 exerts pleiotropic biological effects in diverse physiological and pathological states, through attenuating oxidative stress, and modulating a series of cellular events such as autophagy, ER stress, mitochondrial biogenesis, protein synthesis, cell energy homeostasis and apoptosis, while many of these responsive pathways are interconnected (5,(11)(12)(13)(14).…”

Section: Sestrinpathways and Modulating Mechanismsmentioning

confidence: 99%

Sestrin2 in diabetes and diabetic complications

Zhang,

Luo,

et al. 2023

Front. Endocrinol.

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Diabetes is a global health problem which is accompanied with multi-systemic complications. It is of great significance to elucidate the pathogenesis and to identify novel therapies of diabetes and diabetic complications. Sestrin2, a stress-inducible protein, is primarily involved in cellular responses to various stresses. It plays critical roles in regulating a series of cellular events, such as oxidative stress, mitochondrial function and endoplasmic reticulum stress. Researches investigating the correlations between Sestrin2, diabetes and diabetic complications are increasing in recent years. This review incorporates recent findings, demonstrates the diverse functions and regulating mechanisms of Sestrin2, and discusses the potential roles of Sestrin2 in the pathogenesis of diabetes and diabetic complications, hoping to highlight a promising therapeutic direction.

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“…4 Sestrin2 plays a key role in various cell signal transduction processes, and its dysregulation is associated with various diseases. 5 Pasha M et al have found that the up-regulation of Sestrin2 under oxidative stress enhances the autophagy-directed degradation of Keap1, which targets and degrades nuclear factor erythroid-2-related factor 2 (Nrf2). 6 Nrf2 is a pleiotropic protein that regulates the cellular defense against toxic and oxidative insults.…”

Section: Introductionmentioning

confidence: 99%

Tricin attenuates diabetic retinopathy by inhibiting oxidative stress and angiogenesis through regulating Sestrin2/Nrf2 signaling

Yang

2023

Hum Exp Toxicol

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To explore the potential function of tricin in diabetic retinopathy (DR) and investigate whether Sestrin2 is closely involved in DR. A single intraperitoneal injection of streptozotocin-induced diabetes model in Sprague-Dawley rats and a high glucose-induced retinal epithelial cell model in ARPE-19 cells were established. The retinas were removed and examined by hematoxylin-eosin (HE) staining and dihydroethidium (DHE) staining. The proliferation ability and reactive oxygen species (ROS) level of ARPE-19 cells were detected by 5-ethynyl-2′-deoxyuridine (EdU) and flow cytometry. Then, the content of superoxide dismutase (SOD), malonaldehyde (MDA), and glutathione peroxidase (GSH-Px) in serum or cell supernatant was tested using enzyme linked immunosorbent assay (ELISA). In addition, the expression of Sestrin2, nuclear factor erythroid-2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), platelet endothelial cell adhesion molecule-1 (CD31), and vascular endothelial growth factor receptor 2 (VEGFR2) in retina tissue or ARPE-19 cells were validated through western blot and immunofluorescence assays. With the increase of MDA and ROS concentration, Sestrin2 expression was downregulated significantly, and Nrf2 and HO-1 expression was also reduced in retina tissue or ARPE-19 cells of model group, whereas CD31 and VEGFR2 expression was upregulated. However, tricin ameliorated the oxidative stress and angiogenesis and rectified the abnormal expression of Sestrin2/Nrf2 in diabetic retinopathy. Further mechanistic studies showed that silence Sestrin2 reduced the protective effect of tricin on ARPE-19 cells, as well as abolished its regulating effect on the Nrf2 pathway. These results suggested that tricin inhibits oxidative stress and angiogenesis in retinal epithelial cells of DR rats via reinforcing Sestrin2/Nrf2 signaling.

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Sestrin2 in hypoxia and hypoxia-related diseases

Cited by 16 publications

References 76 publications

Sestrin2 ameliorates diabetic retinopathy by regulating autophagy and ferroptosis

Sestrin2 ameliorates diabetic retinopathy by regulating autophagy and ferroptosis

Sestrin2 in diabetes and diabetic complications

Tricin attenuates diabetic retinopathy by inhibiting oxidative stress and angiogenesis through regulating Sestrin2/Nrf2 signaling

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