Compound C Increases Sestrin2 Expression &lt;i&gt;via&lt;/i&gt; Mitochondria-Dependent ROS Production

Seo, Kyuhwa; Seo, Suho; Ki, Sung Hwan; Shin, Sook

doi:10.1248/bpb.b15-00938

Cited by 19 publications

(12 citation statements)

References 40 publications

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“…Conversely, genetic ablation of Sestrin2 augments mTOR activation and aggravates obesity-associated features such as glucose intolerance, insulin resistance, and hepatosteatosis in mice [23]. Consistent with the above findings, the inhibition of AMPK using compound C was shown to upregulate Sestrin2 via induction and accumulation of mitochondrial ROS [40]. …”

Section: Downstream Pathways and Mechanisms Modulated By Sestrinsmentioning

confidence: 75%

Sestrin2 as a Novel Biomarker and Therapeutic Target for Various Diseases

Pasha

Eid

et al. 2017

Oxidative Medicine and Cellular Longevity

124

130

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Sestrin2 (SESN2), a highly conserved stress-inducible metabolic protein, is known to repress reactive oxygen species (ROS) and provide cytoprotection against various noxious stimuli including genotoxic and oxidative stress, endoplasmic reticulum (ER) stress, and hypoxia. Studies demonstrate that the upregulation of Sestrin2 under conditions of oxidative stress augments autophagy-directed degradation of Kelch-like ECH-associated protein 1 (Keap1), which targets and breaks down nuclear erythroid-related factor 2 (Nrf2), a key regulator of various antioxidant genes. Moreover, ER stress and hypoxia are shown to induce Sestrins, which ultimately reduce cellular ROS levels. Sestrin2 also plays a pivotal role in metabolic regulation through activation of the key energy sensor AMP-dependent protein kinase (AMPK) and inhibition of mammalian target of rapamycin complex 1 (mTORC1). Other downstream effects of Sestrins include autophagy activation, antiapoptotic effects in normal cells, and proapoptotic effects in cancer cells. As perturbations in the aforementioned pathways are well documented in multiple diseases, Sestrin2 might serve as a potential therapeutic target for various diseases. Thus, the aim of this review is to discuss the upstream regulators and the downstream effectors of Sestrins and to highlight the significance of Sestrin2 as a biomarker and a therapeutic target in diseases such as metabolic disorders, cardiovascular and neurodegenerative diseases, and cancer.

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Section: Downstream Pathways and Mechanisms Modulated By Sestrinsmentioning

confidence: 75%

Sestrin2 as a Novel Biomarker and Therapeutic Target for Various Diseases

Pasha

Eid

et al. 2017

Oxidative Medicine and Cellular Longevity

124

130

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“…PPARGC1A and FOXO1 also induce SESN2 and TRIM63 expression, both of which are important players in controlling lipid metabolism by enhancing mitochondrial biogenesis and shuttling adenosine triphosphate to myofibrils in mice, respectively (Seo, Seo, Ki, & Shin, ; Willis et al., ). DKK2 , another target gene for PPARGC1A and FOXO1 , is associated with intramuscular fat content and backfat thickness in cattle (Zhan, Gao, Huangfu, Fu, & Zan, ).…”

Section: Discussionmentioning

confidence: 99%

Skeletal muscle and liver gene expression profiles in finishing steers supplemented with Amaize

Elolimy

Moisá

Brennan

et al. 2018

Animal Science Journal

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Our main objective was to evaluate the effects of feeding α-amylase (Amaize, Alltech Inc., Nicholasville, KY, USA) for 140 days on skeletal muscle and liver gene transcription in beef steers. Steers fed Amaize had lower average daily gain (p = .03) and gain:feed ratio (p = .05). No differences (p > .10) in serum metabolites or carcass traits were detected between the two groups but Amaize steers tended (p < .15) to have increased 12th rib fat depth. Microarray analysis of skeletal muscle revealed 21 differentially expressed genes (DEG), where 14 were up-regulated and seven were down-regulated in Amaize-fed steers. The bioinformatics analysis indicated that metabolic pathways involved in fat formation and deposition, stress response, and muscle function were activated, while myogenesis was inhibited in Amaize-fed steers. The quantitative PCR results for liver revealed a decrease (p < .01) in expression of fatty acid binding protein 1 (FABP1) and 3-hydroxybutyrate dehydrogenase 1 (BDH1) with Amaize. Because these genes are key for intracellular fatty acid transport, oxidation and ketone body production, data suggest a reduction in hepatic lipid catabolism. Future work to investigate potential positive effects of Amaize on cellular stress response, muscle function, and liver function in beef cattle appears warranted.

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“…Indeed, former studies of MI induced in rats showed that HIF-1α and -2α were upregulated in macrophages in infarcted tissue (27). Other mechanisms, such as mitochondria-dependent ROS production (28), Toll-like receptor-mediated AP-1, and Nrf2 signaling (29), have also been shown to induce Sestrin2 expression in macrophages or other cell types. Hence, our lab will test the involvement of these signal pathways in Sestrin2 expression in cardiac macrophages after MI.…”

Section: Discussionmentioning

confidence: 99%

Sestrin2 Suppresses Classically Activated Macrophages-Mediated Inflammatory Response in Myocardial Infarction through Inhibition of mTORC1 Signaling

et al. 2017

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Myocardial infarction (MI) triggers an intense inflammatory response that is essential for dead tissue clearance but also detrimental to cardiac repair. Macrophages are active and critical players in the inflammatory response after MI. Understanding the molecular mechanisms by which macrophage-mediated inflammatory response is regulated is important for designing new therapeutic interventions for MI. In the current study, we examined the role of Sestrin2, which is a stress-inducible protein that regulate metabolic homeostasis, in the regulation of inflammatory response of cardiac macrophages after MI. We found that cardiac macrophages upregulated Sestrin2 expression in a mouse MI model. Using a lentiviral transduction system to overexpress Sestrin2 in polarized M1 and M2 macrophages, we revealed that Sestrin2 predominantly functioned on M1 rather than M2 macrophages. Sestrin2 overexpression suppressed inflammatory response of M1 macrophages both in vitro and in vivo. Furthermore, in the mouse MI model with selective depletion of endogenous macrophages and adoptive transfer of exogenous Sestrin2-overexpressing macrophages, the anti-inflammatory and repair-promoting effect of Sestrin2-overexpressing macrophages was demonstrated. Furthermore, Sestrin2 significantly inhibited mTORC1 signaling in M1 macrophages. Taken together, our study indicates the importance of Sestrin2 for suppression of M1 macrophage-mediated cardiac inflammation after MI.

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Compound C Increases Sestrin2 Expression <i>via</i> Mitochondria-Dependent ROS Production

Cited by 19 publications

References 40 publications

Sestrin2 as a Novel Biomarker and Therapeutic Target for Various Diseases

Sestrin2 as a Novel Biomarker and Therapeutic Target for Various Diseases

Skeletal muscle and liver gene expression profiles in finishing steers supplemented with Amaize

Sestrin2 Suppresses Classically Activated Macrophages-Mediated Inflammatory Response in Myocardial Infarction through Inhibition of mTORC1 Signaling

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