Search Results (59)

Sestrins are an evolutionarily conserved family of stress-responsive proteins that regulate cellular metabolism, redox balance, and survival. Their expression is induced by diverse cellular stresses through activation of transcription factors such as p53, NRF2, and FOXO. Through antioxidant activity and modulation of mTORC1 and mTORC2 signalling, Sestrins limit the accumulation of reactive oxygen species, regulate metabolic pathways, and promote autophagy. In this review, we analyse published studies reporting SESN1, SESN2, and SESN3 expression in human tissues, circulation, and experimental disease models. The available evidence indicates that Sestrin levels are dynamically regulated across multiple pathologies, including metabolic, ageing, cardiovascular, inflammatory, neurodegenerative, and degenerative disorders. Notably, changes in tissue Sestrin expression are often mirrored in circulation. These observations suggest that Sestrins may serve as informative biomarkers of cellular stress and disease states, and that monitoring their expression in tissues or blood could provide insight into disease progression and therapeutic response. Full article

Background/Objectives: Endometriosis is a chronic inflammatory disease characterized by ectopic endometrial tissue growth and is strongly associated with oxidative stress; however, systemic biomarkers reflecting this stress response remain limited. Advanced glycation end products (AGEs) promote oxidative and inflammatory signaling, while sestrin 2 (SESN2) is a stress-inducible protein involved in cellular redox homeostasis. This prospective case–control study aimed to evaluate serum AGEs and SESN2 levels in women with ovarian endometrioma and to assess their diagnostic performance. Methods: A total of 80 reproductive-aged women were enrolled, including 37 patients with ultrasonographically confirmed ovarian endometrioma and 43 healthy controls. Serum AGEs and SESN2 concentrations were measured using enzyme-linked immunosorbent assay. Results: Both biomarkers were significantly elevated in patients compared with controls (AGEs: 110.11 ± 33.35 vs. 91.70 ± 41.82 ng/mL, p = 0.007; SESN2: 9.32 ± 2.59 vs. 5.57 ± 1.52 ng/mL, p < 0.001). Receiver operating characteristic analysis demonstrated modest discriminatory ability for AGEs (AUC = 0.656), whereas SESN2 showed high diagnostic accuracy (AUC = 0.893), with 87.39% sensitivity and 86.05% specificity at an optimal cut-off value. Neither AGEs nor SESN2 levels were associated with lesion size, laterality, or pain symptoms. Conclusions: These findings provide the first evidence that circulating AGEs and SESN2 are elevated in ovarian endometrioma, supporting the role of systemic oxidative stress and stress-response pathways in endometriosis. SESN2, in particular, emerges as a promising biomarker candidate for disease presence, warranting further validation in larger and more diverse endometriosis cohorts. Full article

Oral squamous cell carcinoma (OSCC) is a prevalent malignancy with a poor prognosis. Sestrin2 (Sesn2), a stress-inducible protein, has been implicated in various cancers, but its precise role and mechanism in OSCC remain unclear. This study investigated the molecular mechanisms of Sesn2 in OSCC. Sesn2 expression was analyzed using data from TCGA and immunohistochemical results from the HPA. Functional assays, including CCK-8, flow cytometry for cell cycle, wound healing, and Transwell assays, were performed following Sesn2 knockdown with siRNA in OSCC cell lines (CAL-27 and SAS). Underlying mechanisms were investigated by Western blotting and ELISA for MMP-2 and MMP-9 levels. Sesn2 was significantly upregulated in OSCC tissues compared to normal controls. Its knockdown markedly suppressed cell proliferation, induced G1 phase cell cycle arrest, and impaired migratory and invasive capabilities. This reduction in invasion was further confirmed by decreased levels of MMP-2 and MMP-9 upon Sesn2 knockdown. Furthermore, Sesn2 silencing induced apoptosis via Caspase-3 activation with divergent BAX/BCL-2 modulation; SAS cells exhibited elevated BAX and reduced BCL-2, whereas these proteins remained unchanged in CAL-27 cells. Mechanistically, we found that Sesn2 depletion downregulated the PI3K/AKT/mTOR pathway and reduced the phosphorylation of AKT and p38 MAPK. Our findings demonstrate that Sesn2 functions as an oncogene in OSCC, promoting tumor progression by modulating the PI3K/AKT/mTOR and MAPK signaling pathways, suggesting its potential as a therapeutic target for OSCC. Full article

Sestrin2 (SESN2) is a highly conserved stress-inducible protein that serves as a central hub for integrating cellular responses to nutrient availability, oxidative stress, and endoplasmic reticulum (ER) stress. A key function of SESN2 is its role as a direct sensor for the branched-chain amino acid (BCAA) leucine, which modulates the activity of the mechanistic target of rapamycin complex 1 (mTORC1), a master regulator of cell growth and metabolism. While the functional link between leucine and SESN2 is well-established, the precise molecular determinants that confer its high specificity for leucine over other BCAAs, such as isoleucine and valine, remain poorly understood. This study employs an integrated computational approach, spanning atomic interactions to global protein dynamics, combining molecular docking, extensive all-atom molecular dynamics (MD) simulations, and binding free energy calculations, to elucidate the structural and dynamic basis of BCAA-SESN2 recognition. Our thermodynamic analysis reveals a distinct binding affinity hierarchy (Leucine > Isoleucine > Valine), which is primarily driven by superior van der Waals interactions and the shape complementarity of leucine’s isobutyl side chain within the protein’s hydrophobic pocket. Critically, a quantitative analysis of the conformational ensemble reveals that leucine induces a dramatic collapse of the protein’s structural heterogeneity. This “conformational locking” mechanism funnels the flexible, high-entropy unbound protein—which samples 35 distinct conformations—into a sharply restricted ensemble of just 9 stable states. This four-fold reduction in conformational freedom is accompanied by a kinetic trapping effect, which significantly lowers the rate of transitions between states. This process of conformational selection stabilizes a well-defined, signaling-competent structure, providing a comprehensive, atom-to-global-scale model of SESN2’s function. In the context of these findings, this work provides a critical framework for understanding SESN2’s complex role in disease and offers a clear rationale for the design of next-generation allosteric therapeutics. Full article

Diabetes mellitus is prevalent worldwide, with vascular complications responsible for over 70% of deaths associated with the condition. Methylglyoxal (MGO), a by-product of glycolysis, is a significant modulator of vascular dysfunction in diabetes. Sestrin2 (SESN2) has been recognized as a vital regulator of cellular homeostasis and stress responses. Although SESN2’s role in cellular defense is gaining recognition, its precise function in endothelial cells under diabetic-like conditions remains poorly understood. This study examines the role of SESN2 in preserving endothelial cell angiogenic function under MGO-induced stress. The study reveals that SESN2 is a vital regulator of multiple protective pathways, as demonstrated by both loss-of-function and gain-of-function approaches in EA.hy926 endothelial cells. Our data showed that SESN2 overexpression significantly maintained tubular network formation, proliferation, and invasive capacity under MGO stress, whereas SESN2 silencing exacerbated MGO-induced impairment of angiogenic capacity. SESN2 was identified as orchestrating NRF2/HO-1 antioxidant pathway activation while simultaneously enhancing VEGF-C expression, offering a dual strategy for cellular protection and angiogenesis. Moreover, SESN2 facilitated a regulated equilibrium of the AKT/mTOR signaling pathway, ensuring synchronized activation during stress conditions. SESN2 also regulated stress-activated MAPK pathways, diminishing P38 and ERK1/2 activation upon MGO exposure. This study highlights SESN2 as a pivotal regulator of endothelial cell homeostasis and angiogenic activity under MGO-induced stress, indicating its potential as a therapeutic target for addressing diabetic vascular complications and improving patient outcomes. Full article

Background and Objectives: The mechanisms underlying pneumonia-associated complications are not yet fully understood. Emerging evidence indicates that Sestrin2 (SESN2), a component of the antioxidant defense system, may play a significant clinical role in various diseases. However, the relationship between Sestrin2 expression and pneumonia in pediatric patients is unclear. Materials and Methods: In this study, the relationship between Sestrin2 expression and pneumonia was investigated in children hospitalized for pneumonia between 1 January and 1 April 2024. Results: The study involved 39 patients with a median age of 48 months (range: 12–84) diagnosed with pneumonia and treated at our hospital’s pediatric wards, as well as 37 healthy controls with a median age of 86 months (range: 48–132). In the patient group, the level of reactive oxygen species (ROS) was higher than that in the control group, but the difference was non-significant (394.35 [322.61–586.14] vs. 380.99 [320.03–410.54], p = 0.057). Conversely, the SESN2 level was significantly lower in the patient group than in the control group (2.89 [1.94–4.1] vs. 3.58 [2.94–4.38], p = 0.039). Correlation analysis indicated a strong positive correlation between SESN2 and ROS in the patient group (r = 0.743, p = 0.001), along with a moderate negative correlation between SESN2 and age (r = −0.467, p = 0.003). Conclusions: The decreased SESN2 levels, as observed in the patient group, may contribute to the clinical manifestations of the disease. Mitigating oxidative stress, blocking the elevated ROS levels, and increasing SESN2 levels may be an important step in reducing pneumonia-related complications. For this purpose, SESN2 can be used as a clinical biomarker and prognostic factor in pediatric pneumonia. Full article

The yellowtail kingfish (Seriola aureovittata), a commercially important marine species, encounters significant survival challenges under low-temperature conditions during winter aquaculture. To elucidate its molecular adaptation mechanisms, this study employed RNA-Seq to analyze transcriptional responses in juvenile muscle tissues under acute cold stress (10 °C) at 0, 6, 12, and 24 h. Differential gene expression analysis revealed time-dependent patterns, with 269, 863, and 984 differentially expressed genes (DEGs) identified at 6, 12, and 24 h, respectively. Key pathways were identified, including lipid metabolism, carbohydrate metabolism, and stress response. Sestrin3 upregulation implicated AMPK-mediated energy homeostasis in cold adaptation. These findings provide novel insights into the molecular strategies underlying cold adaptation in yellowtail kingfish, offering potential targets for breeding cold-resistant strains and improving aquaculture resilience. Full article

Sestrins (SESN1-3) are a family of stress-responsive proteins that regulate cellular metabolism and redox balance, both of which are frequently disrupted in cancer. As direct targets of stress-responsive transcription factors, including tumour suppressor p53, Sestrins function as leucine-dependent inhibitors of mTORC1 and potent antioxidants. Their downregulation is widely observed across multiple cancers and is associated with increased tumour growth and poor prognosis. Despite their consistent tumour-suppressive effects through mTORC1 inhibition and promotion of p53-dependent apoptosis, Sestrins exhibit a limited role in tumour initiation, which appears to be context-dependent. Their antioxidant activity reduces oxidative damage, thereby protecting against genomic instability and other cancer-promoting events. However, in certain contexts, Sestrins may promote tumour survival and progression by stimulating pro-survival pathways, such as AKT signalling through mTORC2 activation. This review examines the molecular mechanisms underlying these dual functions, with a particular focus on mTOR signalling and oxidative stress. We also discuss Sestrin expression patterns and functional outcomes in various cancer types, including lung, liver, colon, skin, prostate, and follicular lymphomas, highlighting their potential as diagnostic markers and therapeutic targets. Full article

Although the strong causal association between PM_2.5 and cardiovascular disease has been extensively studied, the latent molecular mechanisms have not been entirely explained. The objective of this research was to assess the cardiotoxicity of Traffic-related PM_2.5 (TRPM_2.5), water-soluble components (WSC), and water-insoluble components (WIC) in human cardiomyocytes (AC16) and to investigate the underlying molecular mechanisms. Endoplasmic reticulum stress (ERS), autophagy, and apoptosis were activated 24 h after exposure to total-TRPM_2.5, WSC, or WIC. WIC was predominantly related to cardiotoxicity compared to WSC. Sestrin2 is an upstream molecule in several signaling pathways, including those involved in autophagy and apoptosis. In this study, we found that the knockdown of Protein Kinase RNA-like Endoplasmic Reticulum Kinase (PERK) suppressed the expression of PERK, Sestrin2, Caspase-12, Caspase-3, LC3, and p62 in TRPM_2.5-treated AC16 cells. These results indicate that ERS participates in the activation of autophagy and apoptosis through the PERK/Sestrin2 pathway. We found that inhibiting autophagy with 3-methyladenine (3-MA) decreased the expression of autophagy-related factors and aggravated apoptosis. These observations suggest that protective autophagy was initiated. Finally, our findings provide valuable insights into the molecular mechanism by which ERS might regulate autophagy through the PERK/Sestrin2 signaling pathway, and protective autophagy may be activated to relieve TRPM_2.5 and component-mediated apoptosis in AC16 cells. Full article

Aging is associated with the accumulation of cellular damage due to oxidative stress and chronic low-grade inflammation, collectively referred to as “inflammaging”. This contributes to the functional decline in various tissues, including the brain and skeletal system, which closely interplay. Mesenchymal stem cells (MSCs), known for their regenerative potential and ability to modulate inflammation, offer a promising therapeutic approach to counteract aging-related declines. In this study, we investigated the effects of homotaurine (a small molecule with neuroprotective properties) on MSCs and its effects on osteogenesis. We found that homotaurine treatment significantly reduced reactive oxygen species (ROS) levels, improved MSC viability, and modulated key stress response pathways, including the sestrin 1 and p21 proteins. Furthermore, homotaurine promoted osteogenesis and angiogenesis in zebrafish models by enhancing the expression of critical osteogenesis-associated genes, such as those coding for β-catenin and Runt-related transcription factor 2 (Runx2), and increasing the levels of the kinase insert domain receptor-like angiogenesis marker in aged zebrafish. In Parkinson’s disease models using patient-specific midbrain organoids with the leucine-rich repeat kinase 2 G2019S mutation, homotaurine treatment enhanced β-catenin expression and reduced ROS levels, highlighting its potential to counteract the oxidative stress and dysfunctional signaling pathways associated with neurodegeneration. Our findings suggest that homotaurine not only offers neuroprotective benefits but also holds promise as a dual-target therapeutic strategy for enhancing both neuronal and bone homeostasis in aging and neurodegenerative diseases. Full article

Cardiac ischemia–reperfusion injury (IRI) occurs when blood flow is restored to the myocardium after a period of ischemia, leading to oxidative stress and subsequent myocardial cell damage, primarily due to the accumulation of reactive oxygen species (ROS). In our previous research, we identified that miR-25 is significantly overexpressed in pressure overload-induced heart failure, and its inhibition improves cardiac function by restoring the expression of SERCA2a, a key protein involved in calcium regulation. In this study, we aimed to investigate the role of miR-25 in the context of ischemia–reperfusion injury. We found that miR-25 was markedly upregulated under hypoxic conditions in both in vitro and in vivo models. Through in silico analysis, we identified Sestrin3 (SESN3), an antioxidant protein known for its protective effects against oxidative stress, as a novel target of miR-25. Based on these findings, we hypothesized that inhibiting miR-25 would restore Sestrin3 expression, thereby reducing ROS-induced myocardial cell damage and improving cardiac function. To test this hypothesis, we employed two model systems: a hypoxia/reoxygenation (H/R) stress model using H9c2 myoblasts and a surgically induced ischemia–reperfusion injury mouse model. Our results demonstrated that the use of miR-25 inhibitors significantly improved cardiac function and reduced myocardial damage in both models through the restoration of SESN3 expression. In conclusion, our findings suggest that targeting miR-25 may serve as a novel therapeutic modality to alleviate oxidative damage in the heart. Full article

Sestrin2 (SESN2) is a stress-inducible protein known for its cytoprotective functions, but its role in diabetic vascular complications remains unclear. This study investigated the impact of SESN2 on methylglyoxal (MGO)-induced endothelial–mesenchymal transition (EndMT). Human endothelial cells were transfected with SESN2 siRNA duplexes to silence SESN2 expression, followed by MGO treatment. SESN2 knockdown significantly exacerbated MGO-induced oxidative stress, as evidenced by the reduced expression of antioxidant markers. Furthermore, SESN2 silencing enhanced the inflammatory response to MGO, demonstrated by the increased levels of pro-inflammatory cytokines. Notably, SESN2 deficiency promoted EndMT, a key process in diabetes-induced cardiovascular complications, as shown by the increased expression of mesenchymal markers and the decreased expression of endothelial markers. These findings suggest that SESN2 plays a critical protective role in endothelial cells against MGO-induced damage. The study provides novel insights into the molecular mechanisms underlying diabetic cardiovascular complications and identifies SESN2 as a potential therapeutic target for preventing endothelial dysfunction in diabetes. Our results indicate that SESN2 downregulation may contribute to the pathogenesis of diabetic vascular complications by promoting EndMT, increased oxidative stress, and inflammation. Full article

Sestrins are a conserved family of stress-responsive proteins that play a crucial role in cellular metabolism, stress response, and ageing. Vertebrates have three Sestrin genes (SESN1, SESN2, and SESN3), while invertebrates encode only one. Initially identified as antioxidant proteins that regulate cell viability, Sestrins are now recognised as crucial inhibitors of the mechanistic target of rapamycin complex 1 kinase (mTORC1), a central regulator of anabolism, cell growth, and autophagy. Sestrins suppress mTORC1 through an inhibitory interaction with the GATOR2 protein complex, which, in concert with GATOR1, signals to inhibit the lysosomal docking of mTORC1. A leucine-binding pocket (LBP) is found in most vertebrate Sestrins, and when bound with leucine, Sestrins do not bind GATOR2, prompting mTORC1 activation. This review examines the evolutionary conservation of Sestrins and their functional motifs, focusing on their origins and development. We highlight that the most conserved regions of Sestrins are those involved in GATOR2 binding, and while analogues of Sestrins exist in prokaryotes, the unique feature of eukaryotic Sestrins is their structural presentation of GATOR2-binding motifs. Full article

Tanshinone IIA (T2A) is a bioactive compound that provides promise in the treatment of glioblastoma multiforme (GBM), with a range of molecular mechanisms including the inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) and the induction of autophagy. Recently, T2A has been demonstrated to function through sestrin 2 (SESN) to inhibit mTORC1 activity, but its possible impact on autophagy through this pathway has not been investigated. Here, the model system Dictyostelium discoideum and GBM cell lines were employed to investigate the cellular role of T2A in regulating SESN to inhibit mTORC1 and activate autophagy through a GATOR2 component MIOS. In D. discoideum, T2A treatment induced autophagy and inhibited mTORC1 activity, with both effects lost upon the ablation of SESN (sesn^-) or MIOS (mios^-). We further investigated the targeting of MIOS to reproduce this effect of T2A, where computational analysis identified 25 novel compounds predicted to strongly bind the human MIOS protein, with one compound (MIOS inhibitor 3; Mi3) reducing cell proliferation in two GBM cells. Furthermore, Mi3 specificity was demonstrated through the loss of potency in the D. discoideum mios^- cells regarding cell proliferation and the induction of autophagy. In GBM cells, Mi3 treatment also reduced mTORC1 activity and induced autophagy. Thus, a potential T2A mimetic showing the inhibition of mTORC1 and induction of autophagy in GBM cells was identified. Full article

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. Full article