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Abstract Background Diabetic kidney disease (DKD) is one of the most serious microvascular complications of diabetes mellitus (DM) and the leading cause of chronic kidney disease (CKD) worldwide. Since obesity and type 2 DM (T2DM) are considered as inflammatory conditions, thus reducing their accompanied systemic inflammation may lessen their complications. Sestrin 2 belongs to a group of stress induced proteins which are produced in response to oxidative stress, inflammation and DNA damage. Betatrophin; a hormone that stimulates the growth, proliferation and mass expansion of pancreatic beta-cells and improves glucose tolerance. The objective of the study was to evaluate levels of serum Sestrin 2 and betatrophin in patients with different stages of diabetic nephropathy (DN)) and compare results with healthy control. Methods This cross sectional study was carried out on 60 patients above 18 years old, recruited from Tanta University hospitals out patients clinics and 20 apparently healthy individuals of matched sex and age as a control group. Participants were divided into two groups: group I: 20 normal subjects as control group and group II: 60 patients with type 2 DM,. further subdivided in to three equal groups: group 1IIA(20 patients) with normo-albuminuria (ACR 300 mg/g). They were subjected to detailed history taking, careful clinical examination and laboratory investigations including blood urea, serum creatinine, estimated glomerular filtration rate (eGFR), urinary albumin creatinine ratio, and specific laboratory tests for Sestrin 2 and Betatrophin by using ELISA technique. Results Serum Sestrin 2 significantly decreased, while serum betatrophin level significantly increased in macroalbuminuric group compared to control and other 2 diabetic groups (P value 98.25 ng/ml with sensitivity 98%, specificity 82%. Serum betatrophin positively correlated with age, fasting, 2 h postprandial, BMI, triglyceride, total cholesterol, serum creatinine, blood urea, UACR, and negatively correlated with eGFR and serum albumin. Serum Sestrin 2 positively correlated with serum albumin. BMI, serum urea, UACR and serum albumin. Serum betatrophin are found to be risk factors or predictors for diabetic nephropathy. Conclusions Patients with DN, particularly the macroalbuminuria group, had a significant increase in betatrophin levels and a significant decrease in serum Sestrin 2 level. The function of Sestrin 2 is compromised in DN, and restoring it can reverse a series of molecular alterations with subsequent improvement of the renal functions, albuminuria and structural damage.

Background: Diabetic kidney disease (DKD) is one of the most serious microvascular complications of diabetes mellitus (DM) and the leading cause of chronic kidney disease (CKD) worldwide. Since obesity and type 2 DM (T2DM) are considered as inflammatory conditions, thus reducing their accompanied systemic inflammation may lessen their complications. Sestrin 2 belongs to a group of stress induced proteins which are produced in response to oxidative stress, inflammation and DNA damage. Betatrophin; a hormone that stimulates the growth, proliferation and mass expansion of pancreatic beta-cells and improves glucose tolerance. The objective of the study was to evaluate levels of serum Sestrin 2 and betatrophin in patients with different stages of diabetic nephropathy (DN)) and compare results with healthy control. Methods: This cross sectional study was carried out on 60 patients above 18 years old, recruited from Tanta University hospitals out patients clinics and 20 apparently healthy individuals of matched sex and age as a control group. Participants were divided into two groups: group I: 20 normal subjects as control group and group II: 60 patients with type 2 DM,. further subdivided in to three equal groups: group 1IIA(20 patients) with normo-albuminuria (ACR < 30 mg/g), group IIB (20 patients) with micro albuminuria (ACR = 30 to 300 mg/g) and group IIC (20 patients) with macro albuminuria (ACR > 300 mg/g). They were subjected to detailed history taking, careful clinical examination and laboratory investigations including blood urea, serum creatinine, estimated glomerular filtration rate (eGFR), urinary albumin creatinine ratio, and specific laboratory tests for Sestrin 2 and Betatrophin by using ELISA technique. Results: Serum Sestrin 2 significantly decreased, while serum betatrophin level significantly increased in macroalbuminuric group compared to control and other 2 diabetic groups (P value < 0.05). The cut off value of serum sestrin 2 was 0.98 ng/ml with sensitivity 99%, specificity 66% while the cut off value of serum betatrophin was > 98.25 ng/ml with sensitivity 98%, specificity 82%. Serum betatrophin positively correlated with age, fasting, 2 h postprandial, BMI, triglyceride, total cholesterol, serum creatinine, blood urea, UACR, and negatively correlated with eGFR and serum albumin. Serum Sestrin 2 positively correlated with serum albumin. BMI, serum urea, UACR and serum albumin. Serum betatrophin are found to be risk factors or predictors for diabetic nephropathy. Conclusions: Patients with DN, particularly the macroalbuminuria group, had a significant increase in betatrophin levels and a significant decrease in serum Sestrin 2 level. The function of Sestrin 2 is compromised in DN, and restoring it can reverse a series of molecular alterations with subsequent improvement of the renal functions, albuminuria and structural damage. [ABSTRACT FROM AUTHOR]

Background/Objectives: This study investigates the correlation between the serum levels of Sestrin 2 and the presence of endometrial polyps or uterine leiomyomas, aiming to enhance the understanding of the pathophysiology underlying these gynecological conditions and evaluate the potential of Sestrin 2 as an early diagnostic biomarker. Methods: In a prospective case-control format, patients with preliminary diagnoses of endometrial polyps or uterine leiomyomas confirmed by histopathological analysis following surgery were included. This study analyzed serum Sestrin 2 levels across different patient groups, revealing significant variations that underscore the diagnostic value of Sestrin 2. Results: Elevated serum Sestrin 2 levels were observed in patients with endometrial polyps and uterine leiomyomas compared to the control group, suggesting its utility as a novel marker for early detection. Conclusions: The study indicates the promising role of serum Sestrin 2 levels as a valuable biomarker for early diagnosis of endometrial polyps and uterine leiomyomas, advocating for further research into its diagnostic and therapeutic potential. [ABSTRACT FROM AUTHOR]

AIM: To investigate the function of sestrin 2 （Sesn2） in macrophages and its impact on macrophage polarization and inflammatory response. METHODS: Knockdown of Sesn2 in RAW264. 7 mouse macrophages was established using siRNA, and an in vitro inflammation model was created by treating RAW264. 7 cells with lipopolysaccharide （LPS）. The mRNA levels of interleukin-1β （IL-1β）, IL-6, tumor necrosis factor-α （TNF-α）, CD86 and inducible nitric oxide synthase（ iNOS） in RAW264. 7 cells were detected by RT-qPCR. The concentrations of IL-1β, IL-6 and TNF-α in the culture medium were measured by ELISA. The percentage of M1-type macrophages marked by CD86 was determined by flow cytometry. The protein levels of mammalian target of rapamycin （mTOR）, p70 ribosomal protein S6 kinase （p70S6K） and eukaryotic translation initiation factor 4E binding protein 1 （4EBP1） were analyzed by Western blot. RESULTS: In the LPS-induced in vitro inflammation model, the expression levels of Sesn2, inflammatory factors （IL-1β, IL-6 and TNF-α）, and M1 macrophage markers （CD86 and iNOS） in RAW264. 7 cells were significantly increased, along with elevated protein expression of mTOR, p70S6K and 4EBP1. Silencing of Sesn2 with siRNA further enhanced these effects. However, if rapamycin was added before LPS in the experiment, these changes could be mitigated. CONCLUSION: Sesn2 can regulate M1 macrophage polarization through mTOR/p70S6K/4EBP1 signaling pathway and affect the expression of pro-inflammatory factors. [ABSTRACT FROM AUTHOR]

Aims: Obese patients are highly sensitive to adriamycin (ADR)-induced cardiotoxicity. However, the potential mechanism of superimposed toxicity remains to be elucidated. Sestrin 2 (SESN2), a potential antioxidant, could attenuate stress-induced cardiomyopathy; therefore, this study aims to explore whether SESN2 enhances cardiac resistance to ADR-induced oxidative damage in high-fat diet (HFD)–induced obese mice. Results: The results revealed that obesity decreased SESN2 expression in ADR-exposed heart. And, HFD mice may predispose to ADR-induced cardiotoxicity, which was probably associated with inhibiting protein kinase B (AKT), glycogen synthase kinase-3 beta (GSK-3β) phosphorylation and subsequently blocking nuclear localization of nuclear factor erythroid-2 related factor 2 (NRF2), ultimately resulting in cardiac oxidative damage. However, these destructive cascades and cardiac oxidative damage effects induced by HFD/sodium palmitate combined with ADR were blocked by overexpression of SESN2. Moreover, the antioxidant effect of SESN2 could be largely abolished by sh-Nrf2 or wortmannin. And sulforaphane, an NRF2 agonist, could remarkably reverse cardiac pathological and functional abnormalities caused by ADR in obese mice. Innovation and Conclusion: This study demonstrated that SESN2 might be a promising therapeutic target for improving anthracycline-related cardiotoxicity in obesity by upregulating activity of NRF2 via AKT/GSK-3β/Src family tyrosine kinase signaling pathway. Antioxid. Redox Signal. 40, 598–615. [ABSTRACT FROM AUTHOR]

Background/aim: This study was designed to evaluate the relationship of two new biomarkers [tribbles homolog 3 (TRB3) and sestrin 2 levels], which were previously associated with obesity, with metabolic parameters in obese and nonobese women with polycystic ovary syndrome (PCOS). Materials and methods: This cross-sectional case control study was conducted between September 2017 and August 2019 in the gynecology department of a tertiary referral hospital. The values of the plasma sestrin 2, TRB3, insulin, fasting plasma glucose, lipid profile, and homeostasis model assessment of insulin resistance (HOMA-IR) were compared in 90 obese women with PCOS (BMI > 30), 90 women with nonobese PCOS (BMI < 30), and 90 control patients (BMI < 30). Results: The mean age of the study group consisting of all PCOS patients (26.11 ± 4.64 years) and the mean age of the control group (26.3 ± 4.4 years) were statistically similar (p = 0.239). The serum sestrin 2 values of the obese PCOS group were found to be statistically significantly lower than the control and non-obese PCOS groups (p = 0.001, p = 0.0001), while the sestrin 2 values of the nonobese PCOS group were found to be statistically significantly lower than the control group (p = 0.0001). The TRB3 values of the control group were found to be statistically significantly lower than the obese and nonobese PCOS groups (p = 0.0001), while the TRB3 values of the nonobese PCOS group were found to be statistically significantly lower than the obese PCOS group (p = 0.0001). A negative correlation was observed between the sestrin 2 level and BMI (r = -0.272 p = 0.0001), insulin (r = -0.261 p = 0.0001), and HOMA-IR levels (r = -0.250 p = 0.0001). A positive correlation was observed between the TRB3 values and TG (r = 0.248 p = 0.0001), and LDL-C values (r = 0.235 p = 0.0001). Conclusion: According to the findings in this study, low sestrin 2 and high TRB3 levels may be related to impaired metabolic status in the obese PCOS group. Thus, it may be promising for the development of treatment of PCOS and associated metabolic disorder in the future. [ABSTRACT FROM AUTHOR]

Aims: Noise damage to auditory hair cells is associated with oxidative stress and mitochondrial dysfunction. This study aimed to investigate the possible effect of sestrin 2 (SESN2), an endogenous antioxidant protein, on noise-induced hearing loss (NIHL) and the underlying mechanisms. Results: We identified SESN2 as a protective factor against oxidative stress in NIHL through activation of Parkin-mediated mitophagy. Consistently, SESN2 expression was increased and mitophagy was induced during the early stage after a temporary threshold shift due to noise exposure or hydrogen peroxide(H2O2) stimulation; conversely, SESN2 deficiency blocked mitophagy and exacerbated acoustic trauma. Mechanistically, SESN2 interacted with Unc-51-like protein kinase 1(ULK1), promoting ULK1 protein-level stabilization by interfering with its proteasomal degradation. This stabilization is essential for mitophagy initiation, since restoring ULK1 expression in SESN2-silenced cells rescued mitophagy defects. Innovation and Conclusion: Our results provide novel insights regarding SESN2 as a therapeutic target against noise-induced cochlear injury, possibly through improved mitophagy. Antioxid. Redox Signal. 38, 115–136. [ABSTRACT FROM AUTHOR]

[Display omitted] • Gallic acid and treadmill training reduces liver fat in supplemented mice. • Gallic acid associated with aerobic training in animals improves insulin sensitivity. • Molecular docking analyses of the Wdr 24 complex and GATOR2 with a binding energy of −5.5 kcal/mol. Obesity and overweight are multifactorial diseases affecting more than one-third of the world's population. Physical inactivity contributes to a positive energy balance and the onset of obesity. Exercise combined with a balanced diet is an effective non-pharmacological strategy to improve obesity-related disorders. Gallic acid (GA), is a natural endogenous polyphenol found in a variety of fruits, vegetables, and wines, with beneficial effects on energetic homeostasis. The present study aims to investigate the effects of exercise training on obese mice supplemented with GA. Animal experimentation was performed with male Swiss mice divided into five groups: ST (standard control), HFD (obese control), HFD + GA (GA supplement), HFD + Trained (training), and HFD + GA + Trained (GA and training). The groups are treated for eight weeks with 200 mg/kg/body weight of the feed compound and, if applicable, physical training. The main findings of the present study show that GA supplementation improves liver fat, body weight, adiposity, and plasma insulin levels. In addition, animals treated with the GA and a physical training program demonstrate reduced levels of anxiety. Gene expression analyses show that Sesn2 is activated via PGC-1α independent of the GATOR2 protein, which is activated by GA in the context of physical activity. These data are corroborated by molecular docking analysis, demonstrating the interaction of GA with GATOR2. The present study contributes to understanding the metabolic effects of GA and physical training and demonstrates a new hepatic mechanism of action via Sestrin 2 and PGC-1α. [ABSTRACT FROM AUTHOR]

Abstract Sestrin 2, a highly conserved stress-induced protein, participates in the pathological processes of metabolic and age-related diseases. This p53-inducible protein also regulates cell growth and metabolism, which is closely related to malignant tumorigenesis. Sestrin 2 was reported to regulate various cellular processes, such as tumor cell proliferation, invasion and metastasis, apoptosis, anoikis resistance, and drug resistance. Although sestrin 2 is associated with colorectal, lung, liver, and other cancers, sestrin 2 expression varies among different types of cancer, and the effects and mechanisms of action of this protein are also different. Sestrin 2 was considered a tumor suppressor gene in most studies, whereas conflicting reports considered sestrin 2 an oncogene. Thus, this review aims to examine the literature regarding sestrin 2 in various cancers, summarize its roles in suppression and tumorigenesis, discuss potential mechanisms in the regulation of cancer, and provide a basis for follow-up research and potential cancer treatment development.

Placenta accreta spectrum (PAS) is an important disease group with risks such as maternal bleeding, hysterectomy, and death, which expresses the pathological adhesion of the placenta to the uterine myometrium, including placenta accreta, increta, and percreta, with an increased incidence with an increase in cesarean section rates. In this study, we aimed to investigate the Nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-related protein 1 (Keap1) pathway in these patients. Serum Sestrin 2, Nrf2, Keap1, glycogen synthase kinase 3β (GSK-3β), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activities and malondialdehyde-modified low-density lipoprotein (MDA-LDL) levels were performed by the Enzyme-Linked Immunosorbent Assay (ELISA) method. In the findings obtained, Nrf2, Keap1, GSK-3ß, MDA-LDL levels, SOD and GSH-Px activities were statistically significantly different in the patient group compared to the control group. While MDA-LDL values were found to be high in the patient group, Nrf2, Keap1, GSK-3ß levels, SOD and GSH-Px activities were significantly lower, except for Sestrin 2 values. In addition, when grouped according to the degree of invasion, Nrf2 levels were found to be lower and Keap1 levels higher. As a result, it was determined that the Nrf2-Keap1 pathway was disrupted in PAS patients, and the oxidant/antioxidant balance was impaired in the oxidant direction. The results show that Nrf2 and Keap1 parameters can be useful in determining the degree of placental invasion., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Abstract Aim The present work investigated serum levels of miR-29a, miR-122 and sestrin2 in obese children with/without type-2-diabetes mellitus (T2DM), and their correlations with inflammatory, metabolic and anthropometric parameters. Methods The study included 298 children, divided into: G1 (control, n = 136), G2 (obese without diabetes, n = 90) and G3 (obese with T2DM, n = 72). Metabolic and anthropometric parameters, miR-29a, miR-122 relative expressions, and sestrin2, high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) levels were measured by their specific methods. The data was processed and analyzed by SPSS V.26 using the corresponding tests. After testing the variables’ normality, Kruskal–Wallis one-way-ANOVA, Spearman correlations coefficient were used. Results Significant higher serum miR-29a, miR-122, IL-6, hsCRP and TNF-α and lower sestrin2 levels were found in G2 and G3 than G1 and in G3 than G2 (p= > 0.001 for all). Especially in G3, miR-29a and miR-122 levels correlated positively while sestrin2 levels correlated negatively with waist circumference and BMI percentiles, serum levels of LDL-cholesterol, triacylglycerol, total cholesterol, HbA1c%, glucose, insulin, c-peptide, homeostatic model assessment-insulin resistance (HOMA-IR), IL-6, hsCRP and TNF-α. Conclusion The change in the serum miR-29a, miR-122 and sestrin2 levels in obese children with/without T2DM may suggest a possible role of these biomarkers in the pathogenesis of childhood obesity and their accompanied complications e.g. inflammations and T2DM. Also, further studies are required to test drugs that antagonize the action miR-29a and miR-122 or upregulate sestrin2 in the management of these cases.

• Sestrin 2-Sqstm1-driven autophagic Keap1 degradation may alleviate pulmonary fibrosis. • Tan-IIA triggers non-canonical Nrf2 activation through the sestrin 2-Sqstm1 axis. • Tan IIA inhibits myofibroblast activation by sestrin 2-Sqstm1 axis-mediated autophagy. Activation of myofibroblasts, linked to oxidative stress, emerges as a pivotal role in the progression of pulmonary fibrosis (PF). Our prior research has underscored the therapeutic promise of tanshinone IIA (Tan-IIA) in mitigating PF by enhancing nuclear factor-erythroid 2-related factor 2 (Nrf2) activity. Nevertheless, the molecular basis through which Tan-IIA influences Nrf2 activity has yet to be fully elucidated. The influence of Tan-IIA on PF was assessed in vivo and in vitro models. Inhibitors, overexpression plasmids, and small interfering RNA (siRNA) were utilized to probe its underlying mechanism of action in vitro. We demonstrate that Tan-IIA effectively activates the kelch-like ECH-associated protein 1 (Keap1)-Nrf2 antioxidant pathway, which in turn inhibits myofibroblast activation and ameliorates PF. Notably, the stability and nucleo-cytoplasmic shuttling of Nrf2 is shown to be dependent on augmented autophagic flux, which is in alignment with the observation that Tan-IIA induces autophagy. Inhibition of autophagy, conversely, fosters the activation of extracellular matrix (ECM)-producing myofibroblasts. Further, Tan-IIA initiates an autophagy program through the sestrin 2 (Sesn2)-sequestosome 1 (Sqstm1) signaling axis, crucial for protecting Nrf2 from Keap1-mediated degradation. Meanwhile, these findings were corroborated in a murine model of PF. Collectively, we observed for the first time that the Sqstm1-Sesn2 axis-mediated autophagic degradation of Keap1 effectively prevents myofibroblast activation and reduces the synthesis of ECM. This autophagy‐dependent degradation of Keap1 can be initiated by the Tan-IIA treatment, which solidifies its potential as an Nrf2-modulating agent for PF treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Sestrin 2, a highly conserved stress-induced protein, participates in the pathological processes of metabolic and age-related diseases. This p53-inducible protein also regulates cell growth and metabolism, which is closely related to malignant tumorigenesis. Sestrin 2 was reported to regulate various cellular processes, such as tumor cell proliferation, invasion and metastasis, apoptosis, anoikis resistance, and drug resistance. Although sestrin 2 is associated with colorectal, lung, liver, and other cancers, sestrin 2 expression varies among different types of cancer, and the effects and mechanisms of action of this protein are also different. Sestrin 2 was considered a tumor suppressor gene in most studies, whereas conflicting reports considered sestrin 2 an oncogene. Thus, this review aims to examine the literature regarding sestrin 2 in various cancers, summarize its roles in suppression and tumorigenesis, discuss potential mechanisms in the regulation of cancer, and provide a basis for follow-up research and potential cancer treatment development. [ABSTRACT FROM AUTHOR]

Objective To investigate the role and underlying mechanism of Sestrin2 in hypoxia/reoxygenation injury of rat cardiomyocytes. Methods H9C2 cardiomyocytes were cultured in vitro and inflicted to establish hypoxia/reoxygenation injury (H/R) model. Thus, the cells were divided into control group, hypoxia 4-hour group (H4h group), and hypoxia 4-hour + reoxygenation 2- and 4-hour groups (H4hR2h and H4hR4h groups). Cell survival rate was measured by cell counting kit-8 (CCK8) assay; Annexin V/7AAD staining with flow cytometry was used to detect cell apoptosis. Micro-enzymatic method was used to detect the content of myocardial injury marker, lactate dehydrogenase (LDH). Then H9C2 cardiomyocytes were divided into normal control group, hypoxia 4-hour+si-NC group (negative control), hypoxia 4-hour+Sestrin2 siRNA group, hypoxia/reoxygenation 4 hour+si-NC group and hypoxia/reoxygenation 4 h+Sestrin2 siRNA group. Recombinant siRNA for Sestrin2 silencing and negative control (si-NC) were constructed and transfected into H9C2 cardiomyocytes with liposomes. The expression of Sestrin2, Nrf2 and HO-1 proteins was detected by Western blotting. Flow cytometry was used to measure the cell apoptosis. Results The cell viability of cardiomyocytes was significantly lower (P < 0.05), and the apoptosis (P < 0.05) as well as LDH level (P < 0.01) was obviously increased in the H4hR4h group than the control group. The expression of Sestrin2 protein was increased in both hypoxia and reoxygenation groups when compared with the control group (P < 0.01), with the level in the H/R groups higher than that in the H groups (P < 0.01). Transfected of Sestrin2 siRNA significantly knocked down the protein expression (P < 0.05), enhanced the cell apoptosis (P < 0.05), and decreased the expression levels of Nrf2 (P < 0.01) and HO-1 (P < 0.05). Conclusion Sestrin2 exerts protective effect on oxidative damage in H9C2 cardiomyocytes induced by H/R injury, which might be due to its activating Nrf2/HO-1 related signaling pathway.

This study explored whether sufentanil, a lipophilic opioid, can protect against myocardial ischemia-reperfusion (I/R) injury via regulating Sestrin 2 (Sesn2) expression. The expression of Sesn2 was measured in the blood of patients with myocardial I/R after sufentanil administration. H9c2 cells were applied to establish I/R injury by oxygen-glucose deprivation and reoxygenation (OGD/R). After treatment with 5, 10 and 20 μmol/L sufentanil, the expression of Sesn2 was examined. Then, shRNA-Sesn2 was transfected into H9c2 cells. The concentrations of creatine kinase (CK), CK isoenzymes (CK-MB), cardiac troponin I (cTnI), inflammation-related factors and oxidative-related factors were sequentially determined by kits. Western blotting was exploited to determine the expression of AMP-activated protein kinase (AMPK) pathway proteins. The results revealed that the expression of Sesn2 was increased in patients after administration with sufentanil. OGD/R intervention upregulated the expression of Sesn2, which continued to increase in a dose-dependent manner following treatment with sufentanil. Moreover, sufentanil attenuated the concentrations of CK, CK-MB and cTnl induced by OGD/R in H9c2 cells. This effect was reversed after Sesn2 silencing. Meanwhile, the levels of inflammatory factors and oxidative stress were notably decreased when cells were treated with sufentanil, and these inhibitory effects were alleviated after transfection with shRNA-Sesn2. Furthermore, sufentanil enhanced the phosphorylation of AMPK and its downstream acetyl CoA carboxylase (ACC), whereas Sesn2 silencing inhibited the expression of the above proteins. These findings demonstrated that sufentanil could attenuate inflammation and oxidative stress in myocardial I/R injury via upregulating Sesn2 expression and activating the AMPK pathway.

Aim: The present work investigated serum levels of miR-29a, miR-122 and sestrin2 in obese children with/without type-2-diabetes mellitus (T2DM), and their correlations with inflammatory, metabolic and anthropometric parameters. Methods: The study included 298 children, divided into: G1 (control, n = 136), G2 (obese without diabetes, n = 90) and G3 (obese with T2DM, n = 72). Metabolic and anthropometric parameters, miR-29a, miR-122 relative expressions, and sestrin2, high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) levels were measured by their specific methods. The data was processed and analyzed by SPSS V.26 using the corresponding tests. After testing the variables' normality, Kruskal–Wallis one-way-ANOVA, Spearman correlations coefficient were used. Results: Significant higher serum miR-29a, miR-122, IL-6, hsCRP and TNF-α and lower sestrin2 levels were found in G2 and G3 than G1 and in G3 than G2 (p= > 0.001 for all). Especially in G3, miR-29a and miR-122 levels correlated positively while sestrin2 levels correlated negatively with waist circumference and BMI percentiles, serum levels of LDL-cholesterol, triacylglycerol, total cholesterol, HbA1c%, glucose, insulin, c-peptide, homeostatic model assessment-insulin resistance (HOMA-IR), IL-6, hsCRP and TNF-α. Conclusion: The change in the serum miR-29a, miR-122 and sestrin2 levels in obese children with/without T2DM may suggest a possible role of these biomarkers in the pathogenesis of childhood obesity and their accompanied complications e.g. inflammations and T2DM. Also, further studies are required to test drugs that antagonize the action miR-29a and miR-122 or upregulate sestrin2 in the management of these cases. [ABSTRACT FROM AUTHOR]

Objective: To investigate sestrin 2 (SESN2) levels in preeclampsia (PE) cases and uncomplicated pregnancies. Methods: Cross-sectional study including 26 pregnant women with PE, 24 with severe-PE, and 30 randomly selected healthy pregnant women. Results: The mean arterial pressure, severe proteinuria, number of HELLP syndrome cases, and serum SESN2 levels in the severe PE group were significantly higher than those in the other groups (p

Background/Aims: Sestrin 2 is associated with the pathophysiology of several diseases. The aim of this study was to investigate the effects and potential mechanisms of Sestrin 2 in rat hepatic stellate cells (HSCs) during liver fibrogenesis. Methods: In this study, Sestrin 2 protein expression was detected in rat HSC-T6 cells challenged with transforming growth factor-β (TGF-β) and in mice treated with carbon tetrachloride (CCl4), a well-known model of hepatic fibrosis. Next, HSC-T6 cells and fibrotic mice were transfected with lentivirus. The mRNA expression levels of markers of liver fibrosis [alpha-smooth muscle actin (α-SMA) and collagen 1A1 (Col1A1)] were analyzed by quantitative reverse transcription–polymerase chain reaction (RT-PCR). Cell death and proliferation were evaluated by the MTT assay, and biochemical markers of liver damage in serum [alanine transaminase (ALT) and aspartate transaminase (AST)] were also measured using a biochemical analyzer. Histopathological examination was used to evaluate the degree of liver fibrosis, and protein expression [phospho-adenosine monophosphate-activated protein kinase (p-AMPK), AMPK, phospho-mammalian target of rapamycin (p-mTOR), and mTOR] was determined by western blotting. Results: We found that Sestrin 2 was elevated in both the HSC-T6 cell and hepatic fibrosis models. In vitro, overexpression of Sestrin 2 attenuated the mRNA levels of α-SMA and Col1A1, suppressed α-SMA protein expression, and modulated HSC-T6 cell proliferation. In vivo, overexpression of Sestrin 2 reduced the ALT and AST levels as well as the α-SMA and Col1A1 protein expression in the CCl4 model of liver fibrosis. Moreover, the degree of liver fibrosis was ameliorated. Interestingly, overexpression of Sestrin 2 increased p-AMPK but decreased p-mTOR protein expression. Conclusion: Our findings indicate that Sestrin 2 may attenuate the activation of HSCs and ameliorate liver fibrosis, most likely via upregulation of AMPK phosphorylation and suppression of the mTOR signaling pathway.

Liver regeneration is a remarkably complex phenomenon conserved across all vertebrates, enabling the restoration of lost liver mass in a matter of days. Unfortunately, extensive damage to the liver may compromise this process, often leading to the death of affected individuals. Ischemia/reperfusion injury (IRI) is a common source of damage preceding regeneration, often present during liver transplantation, resection, trauma, or hemorrhagic shock. Increased oxidative stress and mitochondrial dysfunction are key hallmarks of IRI, which can jeopardize the liver's ability to regenerate. Therefore, a better understanding of both liver regeneration and IRI is of important clinical significance. In the current review, we discuss the potential role of sestrin 2 (SESN2), a novel anti-aging protein, in liver regeneration and ischemia/reperfusion preceding regeneration. We highlight its beneficial role in protecting cells from mitochondrial dysfunction and oxidative stress as key aspects of its involvement in liver regeneration. Additionally, we describe how its ability to promote the expression of Nrf2 bears significant importance in this context. Finally, we focus on a potential novel link between SESN2, mitohormesis and ischemic preconditioning, which could explain some of the protective effects of preconditioning. Image 1 • Liver regeneration is often compromised by ischemia/reperfusion Injury. • Sestrin 2 protects tissues from ischemia/reperfusion injury. • Sestrin 2 enhances mitochondrial health and decreases oxidative stress. • Sestrin 2 may improve the post clinical outcome of the ALPPS procedure. [ABSTRACT FROM AUTHOR]

Physiological reactive oxygen species (ROS) play an important role in cellular signal transduction. However, excessive ROS is an important pathological mechanism in most cardiovascular diseases (CVDs), such as myocardial aging, cardiomyopathy, ischemia/reperfusion injury (e.g., myocardial infarction) and heart failure. Programmed cell death, hypertrophy and fibrosis may be due to oxidative stress. Sestrin 2 (Sesn2), a stress-inducible protein associated with various stress conditions, is a potential antioxidant. Sesn2 can suppress the process of heart damage caused by oxidative stress, promote cell survival and play a key role in a variety of CVDs. This review discusses the effect of Sesn2 on the redox signal, mainly via participation in the signaling pathway of nuclear factor erythroid 2-related factor 2, activation of adenosine monophosphate-activated protein kinase and inhibition of mammalian target of rapamycin complex 1. It also discusses the effect of Sesn2's antioxidant activity on different CVDs. We speculate that Sesn2 plays an important role in CVDs by stimulating the process of antioxidation and promoting the adaptation of cells to stress conditions and/or the environment, opening a new avenue for related therapeutic strategies. Image 1 • The stress-inducible Sestrin 2 protein acts as an antioxidant. • Oxidative stress is a critical pathological mechanism of most cardiovascular diseases. • Sestrin 2 is cardioprotective by reducing oxidative stress. • Sestrin2 may be a target to treat cardiovascular diseases secondary to oxidative stress. [ABSTRACT FROM AUTHOR]

This study explored whether sufentanil, a lipophilic opioid, can protect against myocardial ischemia-reperfusion (I/R) injury via regulating Sestrin 2 (Sesn2) expression. The expression of Sesn2 was measured in the blood of patients with myocardial I/R after sufentanil administration. H9c2 cells were applied to establish I/R injury by oxygen-glucose deprivation and reoxygenation (OGD/R). After treatment with 5, 10 and 20 μmol/L sufentanil, the expression of Sesn2 was examined. Then, shRNA-Sesn2 was transfected into H9c2 cells. The concentrations of creatine kinase (CK), CK isoenzymes (CK-MB), cardiac troponin I (cTnI), inflammation-related factors and oxidative-related factors were sequentially determined by kits. Western blotting was exploited to determine the expression of AMP-activated protein kinase (AMPK) pathway proteins. The results revealed that the expression of Sesn2 was increased in patients after administration with sufentanil. OGD/R intervention upregulated the expression of Sesn2, which continued to increase in a dose-dependent manner following treatment with sufentanil. Moreover, sufentanil attenuated the concentrations of CK, CK-MB and cTnl induced by OGD/R in H9c2 cells. This effect was reversed after Sesn2 silencing. Meanwhile, the levels of inflammatory factors and oxidative stress were notably decreased when cells were treated with sufentanil, and these inhibitory effects were alleviated after transfection with shRNA-Sesn2. Furthermore, sufentanil enhanced the phosphorylation of AMPK and its downstream acetyl CoA carboxylase (ACC), whereas Sesn2 silencing inhibited the expression of the above proteins. These findings demonstrated that sufentanil could attenuate inflammation and oxidative stress in myocardial I/R injury via upregulating Sesn2 expression and activating the AMPK pathway. [ABSTRACT FROM AUTHOR]

Background: Kidney stone disease is one of the most common disorders of urinary tract, manifesting with high clinical and genetic heterogeneity in population. Sestrin 2 is involved in many essential processes, especially oxidative and genotoxic stress. Regarding the importance of oxidative stress pathway deregulation in systemic diseases such as kidney disorders, this study was conducted to investigate the association between rs7526084 3′ downstream polymorphism of the sestrin 2 gene and risk of kidney stone in south Iranian patients. Materials and Methods: In this case-control study, 150 patients with kidney stone disease and 180 age- and gender-matched healthy individuals were participated from March to December 2015. Genotyping of the rs7526084 polymorphism was performed using the T-ARMS PCR method. Results: Frequency of the G allele was higher in controls than in cases, and a reduced risk of the disease was shown in the presence of this allele (OR: 0.66, 95%CI: 0.48-0.91, P=0.01). Also, the risk of the disease was reduced in the presence of heterozygote CG (OR: 0.49, 95%CI: 0.30-0.80, P=0.004) and homozygote GG (OR: 0.47, 95%CI: 0.23-0.96, P=0.04) genotypes. Under the dominant genetic model for the G allele (GG+GC vs. CC), this allele significantly reduced the risk of the disease (OR: 0.49, 95%CI: 0.31- 0.78, P= 0.002). Conclusion: Reduced risk of kidney stone in the presence of the G allele of the sestrin 2 gene polymorphism might provide the evidence in favor of the involvement of the oxidative stress pathway in the pathogenesis of kidney stone disease.

Proper regulation of mTORC1 and mTORC2 upon nutrient starvation is critical for cancer cell survival. Upregulation of Sestrin2 in response to glutamine deprivation rescues cell death by suppressing mTORC1. However, the contribution of mTORC2 to Sestrin2-mediated mTORC1 suppression remains unclear. Here, we report that both Sestrin2 and mTORC2 are upregulated in glutamine-depleted lung cancer cells. Moreover, glutamine depletion caused Sestrin2 to associate with mTORC2, which was required for the increase in Sestrin2 protein stability and the reduction in mTORC1 activity. Ultimately, differential regulation of mTORC1 and 2 by Sestrin2 reprogramed lipid metabolism and enabled glutamine-depleted lung cancer cells to survive by maintaining energy and redox balance. Importantly, combined inhibition of glutamine utilization and Sestrin2 induced lung cancer cell death both in vitro and in vivo. This study shows that differential Sestrin2-mediated regulation of mTORC1 and mTORC2 is necessary for the survival of glutamine-depleted lung cancer cells.

Objective: We aimed to explore the effect and potential mechanism of Sestrin 2 (SESN2) in human lens epithelial cells (HLECs)., Methods: To mimic the oxidative stress environment, SAR01/04 cells were treated with 200 μM hydrogen peroxide (H 2 O 2 ) for 24 h. Cell viability and apoptosis were checked by cell counting kit-8 and flow cytometry. Western blot was taken to check the protein changes of SESN2, B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X (Bax), mechanistic target of rapamycin (mTOR), phosphorylated (p)-mTOR, ribosomal protein S6 kinase B1 (p70S6K), p-p70S6K, and nuclear factor erythroid 2-related factor 2 (Nrf2). Superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and reactive oxygen species (ROS) were detected via the corresponding reagent kit. The levels of interleukin (IL)-1β, IL-18, and tumor necrosis factor (TNF)-α were measured using enzyme-linked immunosorbent assay., Results: SESN2 was down-regulated in cataract lens tissue and up-regulated in SAR01/04 cells treated with H 2 O 2 . Under treatment of H 2 O 2 , up-regulation of SESN2 improved cell viability, enhanced the activity of SOD and CAT, inhibited cell apoptosis, and reduced the levels of MDA, ROS, IL-1β, IL-18, and TNF-α, while down-regulation of SESN2 caused the contrary effects. Further bioinformatics analysis suggested that SESN2 regulated the mTOR signaling pathway. Treatment of H 2 O 2 inhibited p-mTOR and p-p70S6K protein expression, while overexpression of SESN2 increased p-mTOR and p-p70S6K protein expression in the H 2 O 2 group and down-regulation of SESN2 further decreased p-mTOR and p-p70S6K protein expression in the H 2 O 2 group. Additionally, H 2 O 2 increased Nrf2 protein expression, and overexpression of SESN2 further increased Nrf2 protein expression in the H 2 O 2 group. Importantly, rapamycin (an inhibitor of mTOR signaling pathway) and knockdown of Nrf2 reversed the promotive effects of SESN2 on cell viability and the inhibitive effects of SESN2 on cell apoptosis, oxidative stress, and inflammatory reaction., Conclusion: SESN2 protected HLECs damage induced by H 2 O 2 , which was related to the activation of mTOR/Nrf2 pathway., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Rosemary extract (RE) is an approved food preservative in the European Union and contains dietary phytochemicals that are beneficial for gastrointestinal health. This study investigated the effects of RE on dextran sodium sulfate (DSS)-induced colitis and also determined the pharmacokinetics of dietary phytochemicals administered to mice via oral gavage. Individual components of rosemary extract were separated and identified by LC–MS/MS. The pharmacokinetics of two major diterpenes from RE, carnosic acid (CA) and carnosol (CL), administered to mice via oral gavage were determined. Then, the effect of RE pre-treatment on the disease activity index (DAI) of DSS-induced colitis in mice was investigated. The study determined that 100 mg/kg RE significantly improved DAI in DSS-induced colitis compared to negative control. Sestrin 2 protein expression, which increased with DSS exposure, was reduced with RE treatment. Intestinal barrier integrity was also shown to improve via fluorescein isothiocyanate (FITC)–dextran administration and Western blot of zonula occludens-1 (ZO-1), a tight junction protein. Rosemary extract was able to improve the DAI of DSS-induced colitis in mice at a daily dose of 100 mg/kg and showed improvement in the intestinal barrier integrity. This study suggests that RE can be an effective preventative agent against IBD.

Aims: Hepatic fibrosis results from chronic liver injury and inflammatory responses. Sestrin 2 (Sesn2), an evolutionarily conserved antioxidant enzyme, reduces the severities of acute hepatitis and metabolic liver diseases. However, the role of Sesn2 in the pathogenesis of liver fibrosis remains obscure. Here, we used cultured hepatic stellate cells (HSCs) and chronic carbon tetrachloride (CCl4) and bile duct ligation (BDL) murine models to investigate the effects of Sesn2 on fibrogenesis. Results: Sesn2 protein and mRNA levels were upregulated in activated primary HSCs, and by increasing transcription, transforming growth factor-β (TGF-β) also increased Sesn2 expression in HSCs. Furthermore, Smad activation was primarily initiated by TGF-β signaling, and Smad3 activation increased Sesn2 luciferase activity. In silico analysis of the 5′ upstream region of the Sesn2 gene revealed a putative Smad-binding element (SBE), and its deletion demonstrated that the SBE between −964 and −956 bp within human Sesn2 promoter was critically required for TGF-β-mediated response. Moreover, ectopic expression of Sesn2 reduced gene expressions associated with HSC activation, and this was accompanied by marked decreases in SBE luciferase activity and Smad phosphorylation. Infection of recombinant adenovirus Sesn2 reduced hepatic injury severity, as evidenced by reductions in CCl4- or BDL-induced alanine aminotransferase and aspartate aminotransferase, and inhibited collagen accumulation. Furthermore, HSC-specific lentiviral delivery of Sesn2 prevented CCl4-induced liver fibrosis. Finally, Sesn2 expression was downregulated in the livers of patients with liver cirrhosis and in mouse models of hepatic fibrosis. Innovation and Conclusion: Our findings suggest that Sesn2 has the potential to inhibit HSC activation and hepatic fibrosis. [ABSTRACT FROM AUTHOR]

Oxidative stress is widely involved in pathophysiological processes of cardiac remodeling. Molecules associated with antioxidant functions may be ideal targets for reversing cardiac remodeling. Sestrin2 is the important component of endogenous antioxidant defense, while there is little information on the pathophysiological roles of it in cardiac remodeling. The aim of this study was to investigate whether Sestrin2 is closely involved in cardiac remodeling, and whether the protective effect of pentamethylquercetin (PMQ) on cardiac remodeling is related to upregulation of the Sestrin2 endogenous antioxidant system. We generated a transverse aorta constriction (TAC)-induced pressure-overload cardiac-remodeling model in mice, and also established an isoproterenol (ISO)-induced neonatal rat cardiomyocyte (NRCM) hypertrophy model. The data showed Sestrin2 expression was downregulated significantly, and Nrf2 and HO-1 expression was also reduced in myocardial tissue or NRCM of model group, whereas keap1 expression was upregulated. PMQ significantly ameliorated cardiac remodeling and rectified the abnormal expression of Sestrin2/Nrf2/keap1. Sestrin2 small interfering RNA (SiRNA) reduced the protective effect of PMQ on NRCMs, as well as abolished its regulating effect on the Nrf2/keap1 pathway. In conclusion, Sestrin2 may be an important target in the anti-myocardial remodeling of PMQ. • Sestrin2 is an important endogenous defense factor against cardiac remodeling. • Sestrin2 can regulate Nrf2/keap1 endogenous antioxidant system in cardiac remodeling. • The protective effect of PMQ on cardiac remodeling is Sestrin2 dependent. [ABSTRACT FROM AUTHOR]

Objective: To investigate sestrin 2 (SESN2) levels in preeclampsia (PE) cases and uncomplicated pregnancies.Methods: Cross-sectional study including 26 pregnant women with PE, 24 with severe-PE, and 30 randomly selected healthy pregnant women.Results: The mean arterial pressure, severe proteinuria, number of HELLP syndrome cases, and serum SESN2 levels in the severe PE group were significantly higher than those in the other groups (p < 0.001, p < 0.001, p = 0.006, and p = 0.004, respectively). Negative correlation was found between the birth interval (r = -.262, p = 0.019) and the SESN2 level.Conclusion: SESN2 seems to play a role in the pathophysiology of PE, especially in severe PE cases. [ABSTRACT FROM AUTHOR]

Background/Aims: Sestrin 2 is associated with the pathophysiology of several diseases. The aim of this study was to investigate the effects and potential mechanisms of Sestrin 2 in rat hepatic stellate cells (HSCs) during liver fibrogenesis. Methods: In this study, Sestrin 2 protein expression was detected in rat HSC-T6 cells challenged with transforming growth factor-β (TGF-β) and in mice treated with carbon tetrachloride (CCl4), a well-known model of hepatic fibrosis. Next, HSC-T6 cells and fibrotic mice were transfected with lentivirus. The mRNA expression levels of markers of liver fibrosis [alpha-smooth muscle actin (α-SMA) and collagen 1A1 (Col1A1)] were analyzed by quantitative reverse transcription–polymerase chain reaction (RT-PCR). Cell death and proliferation were evaluated by the MTT assay, and biochemical markers of liver damage in serum [alanine transaminase (ALT) and aspartate transaminase (AST)] were also measured using a biochemical analyzer. Histopathological examination was used to evaluate the degree of liver fibrosis, and protein expression [phospho-adenosine monophosphate-activated protein kinase (p-AMPK), AMPK, phospho-mammalian target of rapamycin (p-mTOR), and mTOR] was determined by western blotting. Results: We found that Sestrin 2 was elevated in both the HSC-T6 cell and hepatic fibrosis models. In vitro, overexpression of Sestrin 2 attenuated the mRNA levels of α-SMA and Col1A1, suppressed α-SMA protein expression, and modulated HSC-T6 cell proliferation. In vivo, overexpression of Sestrin 2 reduced the ALT and AST levels as well as the α-SMA and Col1A1 protein expression in the CCl4 model of liver fibrosis. Moreover, the degree of liver fibrosis was ameliorated. Interestingly, overexpression of Sestrin 2 increased p-AMPK but decreased p-mTOR protein expression. Conclusion: Our findings indicate that Sestrin 2 may attenuate the activation of HSCs and ameliorate liver fibrosis, most likely via upregulation of AMPK phosphorylation and suppression of the mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

[Display omitted] • SESN2 binds leucine in the C-terminal domain where the charged residues Glu451 and Arg390 anchor the ligand. • SESN2 binds to the gallic acid compound with a binding energy of −7.1 kcal/mol. • Interactions were observed between residues Thr377, Thr374 and Thr386 of SESN2 and GA. Sestrins (SESNs) are a family of evolutionarily conserved proteins among mammals. They have several body homeostatic functions such as antioxidant, metabolic, and anti-aging, and are required to regenerate hyperoxidized forms of peroxiredoxins and reactive oxygen species. Sestrin 2 has been studied as a therapeutic agent in obesity treatment. Gallic acid (GA) is a triphenolic compound with beneficial biological activities including anti-inflammatory, antidiabetic, antihypertensive, and antioxidant effects. Recent studies demonstrated the GA's ability to reduce body weight gain and improve glycemic parameters. In this sense, the present study aims to investigate the GA activating potential of Sestrin using the molecular docking method. The 3D structure of gallic acid was retrieved from the NCBI PubChem database and the chemical structure of the Sestrin2 protein from the RCSB Protein Data Bank (5DJ4). The docking calculus was performed via UCSF Chimera and AutoDock Vinaprograms. The results showed that amino acids Arg390, Glu451, Trp444, Thr386, Arg448, Thr374, Tyr375, Asn376, Thr377, Leu389, His454, Ser450, His86, and Val455 are very important for GA stabilization, resembling the interactions that permit Leucine to activate SESN2. In this context, the obesity therapeutic property of GA can be understood from a Sestrin activating process through amino acid metabolism. [ABSTRACT FROM AUTHOR]

Abstract Background To date, there still is a lack of specific acute pancreatitis markers and specifically an early marker that can reliably predict disease severity. The inflammatory response in acute pancreatitis is mediated in part through oxidative stress and calcineurin-NFAT (Nuclear Factor of Activated T-cells) signaling, which is inducing its own negative regulator, regulator of calcineurin 1 (RCAN1). Caerulein induction is a commonly used in vivo model of experimental acute pancreatitis. Caerulein induces CN-NFAT signaling, reactive oxygen species and inflammation. Methods To screen for potential markers of acute pancreatitis, we used the caerulein model of experimental acute pancreatitis (AP) in C57Bl/6 J mice. Pancreata from treated and control mice were used for expression profiling. Promising gene candidates were validated in cell culture experiments using primary murine acinar cells and rat AR42J cells. These candidates were then further tested for their usefulness as biomarkers in mouse and human plasma. Results We identified a number of novel genes, including Regulator of calcineurin 1 (Rcan1) and Sestrin 2 (Sesn2) and demonstrated that they are induced by oxidative stress, by stimulation with H 2 O 2 and by inhibiting caerulein stimulated expression with the antioxidant N-acetylcysteine. We found Rcan1 protein to be significantly elevated in AP-induced mouse plasma as well as in plasma from AP patients. Conclusion We demonstrated that Rcan1 is regulated by oxidative stress and identified RCAN1 as a potential diagnostic marker of AP. [ABSTRACT FROM AUTHOR]

Aims Sestrins, a class of stress-related proteins, is involved in the control of aging-induced organic dysfunctions and metabolic control. However, the factors that modulate the levels of Sestrins are poorly studied. Here, we evaluated the effects of acute and chronic aerobic exercise on Sestrin 1 (Sesn1) and Sesn2 protein contents in the skeletal muscle of mice. Main methods Male C57BL/6 J mice performed an acute or chronic (4 weeks) exercise protocols on a treadmill running at 60% of the peak workload. Then, the quadriceps muscle was removed and analyzed by Western blot. Bioinformatics analysis was also performed to evaluate Sesn1 and Sesn2 mRNA in the skeletal muscle and phenotypic pattern in a large panel of isogenic strains of BXD mice. Key findings While acute aerobic exercise increased Sesn1 accumulation and induced a discrete augment of Sesn2 protein content and AMPK threonine phosphorylation, chronic exercise reduced the basal levels of Sesn1 and Sesn2 as well as of AMPK threonine phosphorylation in the quadriceps muscles of C57BL/6 J mice. In accordance with these experimental approaches, transcriptomic analysis revealed that Sesn1 and Sesn2 mRNA levels in the skeletal muscle were inversely correlated with the locomotor activity in several strains of BXD mice. Significance Our data suggest that physical exercise has role on Sestrin1 and Sestrin2 expression on skeletal muscle, providing new insights into the mechanism by which physical exercise affects stress-related proteins in skeletal muscles. [ABSTRACT FROM AUTHOR]

Sestrins and autophagy deficiencies are associated with several aging-related organic dysfunctions and metabolic disorders. Here we evaluate the effects of acute exercise on Sestrin 2 (Sesn2) protein content and autophagy markers in the skeletal muscle of experimental models of aging. Twenty-four months-old C57BL/6 J male mice were submitted to a single bout of swimming exercise and the gastrocnemius muscle was evaluated by Western blot. Transcriptomic and phenotypic analysis were also performed by using strains of genetically-diverse BXD mice. The bioinformatics analysis showed a negative correlation between Sesn2 mRNA levels in the skeletal muscle and body weight gain, plasma triglycerides and fasting glucose and positive correlation with several autophagic markers in the muscle of BXD mice. Consistent with these findings, low levels of Sesn2 protein content were observed in the gastrocnemius muscle of C57BL/6 J old mice when compared to young group. Interestingly, the acute aerobic exercise induced Sesn2 accumulation and modulated several markers of autophagy in the gastrocnemius muscle old mice, including unc-51-like kinase-1 (Ulk1) phosphorylation and the protein levels of Atg5, Atg7, p62 and LC3-II. Finally, exercise increased insulin sensitivity in old animals, as demonstrated by kITT. Taken together, these findings demonstrated the acutely, aerobic physical exercise recovers Sestrin 2 protein content and induces autophagy in the skeletal muscle of old mice, contributing with the improvement of insulin sensitivity an aging animal model. [ABSTRACT FROM AUTHOR]

Cardiac hypertrophy is an adaptive response triggered by many physiological and pathological conditions and will lead to heart failure eventually. Sestrin 2, which is a stress-responsive protein, was reported to protect heart from ischemia reperfusion injury. However, the role of Sestrin 2 in cardiac hypertrophy remains unknown. In our present study, we aimed to explore the effects of Sestrin 2 on cardiomyocyte hypertrophy. We found that knockdown of Sestrin 2 protein aggravated cardiomyocyte hypertrophy induced by phenylephrine (PE), featured by increased hypertrophic marker ANP and cell surface area. During this process, ERK1/2 cascade was further activated, while p38, JNK1/2, and mTOR signaling pathways were not affected by downregulation of Sestrin 2. Moreover, overexpression of Sestrin 2 protein protected cardiomyocytes from PE-induced hypertrophy and ERK1/2 cascade was suppressed correspondingly. Importantly, pharmacological inhibition of ERK1/2 eliminated the exacerbated hypertrophic phenotype due to Sestrin 2 protein knockdown. In conclusion, we discovered that Sestrin 2 protected against cardiomyocyte hypertrophy induced by PE via inhibiting ERK1/2 signaling. [ABSTRACT FROM AUTHOR]

Summary Proper regulation of mTORC1 and mTORC2 upon nutrient starvation is critical for cancer cell survival. Upregulation of Sestrin2 in response to glutamine deprivation rescues cell death by suppressing mTORC1. However, the contribution of mTORC2 to Sestrin2-mediated mTORC1 suppression remains unclear. Here, we report that both Sestrin2 and mTORC2 are upregulated in glutamine-depleted lung cancer cells. Moreover, glutamine depletion caused Sestrin2 to associate with mTORC2, which was required for the increase in Sestrin2 protein stability and the reduction in mTORC1 activity. Ultimately, differential regulation of mTORC1 and 2 by Sestrin2 reprogramed lipid metabolism and enabled glutamine-depleted lung cancer cells to survive by maintaining energy and redox balance. Importantly, combined inhibition of glutamine utilization and Sestrin2 induced lung cancer cell death both in vitro and in vivo. This study shows that differential Sestrin2-mediated regulation of mTORC1 and mTORC2 is necessary for the survival of glutamine-depleted lung cancer cells. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a devastating disease that is highly modulated by dietary nutrients. Mechanistic target of rapamycin complex 1 (mTORC1) contributes to tumor growth and limits therapy responses. Growth factor signaling is a major mechanism of mTORC1 activation. However, compensatory pathways exist to sustain mTORC1 activity after therapies that target oncogenic growth factor signaling. Amino acids potently activate mTORC1 via amino acid–sensing GTPase activity towards Rags (GATOR). The role of amino acid–sensing pathways in CRC is unclear. Human colon cancer cell lines, preclinical intestinal epithelial–specific GATOR1 and GATOR2 knockout mice subjected to colitis-induced or sporadic colon tumor models, small interfering RNA screening targeting regulators of mTORC1, and tissues of patients with CRC were used to assess the role of amino acid sensing in CRC. We identified loss-of-function mutations of the GATOR1 complex in CRC and showed that altered expression of amino acid–sensing pathways predicted poor patient outcomes. We showed that dysregulated amino acid–sensing induced mTORC1 activation drives colon tumorigenesis in multiple mouse models. We found amino acid–sensing pathways to be essential in the cellular reprogramming of chemoresistance, and chemotherapeutic-resistant patients with colon cancer exhibited de-regulated amino acid sensing. Limiting amino acids in in vitro and in vivo models (low-protein diet) reverted drug resistance, revealing a metabolic vulnerability. Our findings suggest a critical role for amino acid–sensing pathways in driving CRC and highlight the translational implications of dietary protein intervention in CRC. [Display omitted] [ABSTRACT FROM AUTHOR]

Background and Aim: The hippocampus has a key role in memory and learning, which means that this brain structure has high-energy demand. Accordingly, mitochondrial dysfunction in the hippocampus has deleterious effects on brain function. MitoQ is an antioxidant that accumulates selectively in mitochondria at high concentration. In this study, the effect of MitoQ alone and in combination with endurance training (ET) was investigated on spatial memory (distance, time, and number of passes in the target quarter), antioxidant status (superoxide dismutase [SOD] and glutathione peroxidase [GPx]), and neurogenic factor levels (vascular endothelial growth factor [VEGF] and brain-derived neurotrophic factor [BDNF]) in male Wistar rats., Methods: Rats were assigned to a control (CTL) group, ET group, ET+MitoQ group, and a MitoQ group. Rats were trained on a treadmill for 8 weeks, 5 days/week, and 50 min/day. MitoQ (250 μM daily) was administered through drinking water for 8 weeks. Spatial memory (Morris water maze test), gene expression (real-time PCR), protein expression (Western blotting), and antioxidants (ELISA method) were determined., Results: Distance and number of passes in the target quarter in the ET, MitoQ, and ET+MitoQ groups were higher than in the CTL group ( P =0.001). MitoQ+ET had more impact on the abovementioned indices than MitoQ or ET alone. Simultaneous use of MitoQ and ET significantly increased gene and protein expression of VEGF ( P =0.0001) and gene expression of BDNF ( P =0.004) and Sestrin 2 ( SESN2 ) ( P =0.0001) in hippocampal tissue. The expression of VEGF ( P =0.007) and SESN2 ( P =0.001) was higher in the MitoQ group compared to the CTL group. Tissue GPx levels were increased following all three interventions ( P ≤0.013) compared to the CTL group while SOD levels remained unchanged in all groups., Conclusions: The combination of ET and MitoQ has additive effects on spatial memory in rats by modulating parameters that are involved in hippocampal neurogenesis. In addition, MitoQ may have positive effects on the antioxidant defense by improving GPx activity., Relevance for Patients: Considering the positive effects of MitoQ on improving the memory and the antioxidant defense, it seems that it can play a positive role in improving the diseases associated with memory loss in the long term, and ET along with this supplement can increase the possible positive effects., Competing Interests: All the authors declare that they have no conflicts of interest., (Copyright: © 2022 Author(s).)

Sestrin 2, initially identified as a p53 target protein, accumulates in cells exposed to stress and inhibits mammalian target of rapamycin (mTOR) signaling. In normal rat kidneys, sestrin 2 was selectively expressed in parietal epithelial cells (PECs), identified by the marker protein gene product 9.5. In adriamycin nephropathy, sestrin 2 expression decreased in PECs on day 14, together with increased expression of phosphorylated S6 ribosomal protein (P-S6RP), a downstream target of mTOR. Sestrin 2 expression was markedly decreased on day 42, coinciding with glomerulosclerosis and severe periglomerular fibrosis. In puromycin aminonucleoside nephropathy, decreased sestrin 2 expression, increased P-S6RP expression, and periglomerular fibrosis were observed on day 9, when massive proteinuria developed. These changes were transient and nearly normalized by day 28. In crescentic glomerulonephritis, sestrin 2 expression was not detected in cellular crescents, whereas P-S6RP increased. In conditionally immortalized cultured PECs, the forced downregulation of sestrin 2 by short hairpin RNA resulted in increased expression of P-S6RP and increased apoptosis. These data suggest that sestrin 2 is involved in PEC homeostasis by regulating the activity of mTOR. In addition, sestrin 2 could be a novel marker of PECs, and decreased expression of sestrin 2 might be a marker of PEC injury. [ABSTRACT FROM AUTHOR]

Abstract: JNK signaling functions to induce defense mechanisms that protect organisms against a variety of different situations. The sestrin 2 gene, a p53-regulated member of the sestrins family, which lead to AMPK-dependent inhibition of TOR signaling, emerges as a novel player in autophagy induction. However, the relationship between JNK pathway, autophagy induction and sestrin 2 expression remains elusive. In the present study, we identify JNK as a regulator of autophagy in nasopharyngeal carcinoma cell lines CNE1 and CNE2 exposed to excisanin A or serum deprivation and demonstrate that activation of JNK can cause upregulation of sestrin 2 expression, which could be blocked by specific siRNAs directed against JNK1/2 or c-Jun. Chromatin immunoprecipitation and luciferase reporter analysis revealed that c-Jun was transcriptionally involved in the regulation of sestrin 2. Furthermore, knockdown of sestrin 2 by siRNAs similarly inhibited autophagy induction. Moreover, silencing the expression of autophagy related gene ATG5 or sestrin 2 significantly decreases cell death induced by excisanin A. Our results therefore identify JNK as a novel mediator of sestrin 2 expression, which plays a key role in autophagy induction following anticancer therapies in cancers. [Copyright &y& Elsevier]

Abstract: Sestrin 2 (SESN2) is a stress-inducible protein required for maintaining redox homeostasis. However, its mode of action remains to be clarified. In this study, we found that SESN2 is induced in human glioblastoma U87 cells following ionizing radiation (IR). SESN2 silencing not only results in increased oxidative stress but also sensitizes U87 cells to IR. Intriguingly, we found SESN2 silencing significantly increases the expression of platelet-derived growth factor receptor β (PDGFRβ). Using a double knockdown technique, we showed that inhibition of PDGFRβ accumulation in SESN2-silencing cells protects the cells from the deleterious effects induced by SESN2 silencing. Taken together, we revealed that PDGFRβ accumulation is associated with increased oxidative stress and cellular damage in SESN2 silenced human glioblastoma U87 cells. [Copyright &y& Elsevier]