Search Results (53)

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

Prostate cancer, accounting for 375,304 deaths in 2020, is the second most prevalent cancer in men worldwide. While many treatments exist for prostate cancer, novel therapeutic agents with higher efficacy are needed to target aggressive and hormone-resistant forms of prostate cancer, while sparing healthy cells. Plant-derived chemotherapy drugs such as docetaxel and paclitaxel have been established to treat cancers including prostate cancer. Carnosic acid (CA), a phenolic diterpene found in the herb rosemary (Rosmarinus officinalis) has been shown to have anticancer properties but its effects in prostate cancer and its mechanisms of action have not been examined. CA dose-dependently inhibited PC-3 and LNCaP prostate cancer cell survival and proliferation (IC₅₀: 64, 21 µM, respectively). Furthermore, CA decreased phosphorylation/activation of Akt, mTOR, and p70 S6K. A notable increase in phosphorylation/activation of AMP-activated kinase (AMPK), acetyl-CoA carboxylase (ACC) and its upstream regulator sestrin-2 was seen with CA treatment. Our data indicate that CA inhibits AKT-mTORC1-p70S6K and activates Sestrin-2-AMPK signaling leading to a decrease in survival and proliferation. The use of inhibitors and small RNA interference (siRNA) approaches should be employed, in future studies, to elucidate the mechanisms involved in carnosic acid’s inhibitory effects of prostate cancer. Full article

Non-small cell lung cancer (NSCLC) represents 80% of all lung cancer cases and is characterized by low survival rates due to chemotherapy and radiation resistance. Novel treatment strategies for NSCLC are urgently needed. Liver kinase B1 (LKB1), a tumor suppressor prevalently mutated in NSCLC, activates AMP-activated protein kinase (AMPK) which in turn inhibits mammalian target of rapamycin complex 1 (mTORC1) and activates unc-51 like autophagy activating kinase 1 (ULK1) to promote autophagy. Sestrin-2 is a stress-induced protein that enhances LKB1-dependent activation of AMPK, functioning as a tumor suppressor in NSCLC. In previous studies, rosemary (Rosmarinus officinalis) extract (RE) activated the AMPK pathway while inhibiting mTORC1 to suppress proliferation, survival, and migration, leading to the apoptosis of NSCLC cells. In the present study, we investigated the anticancer potential of carnosic acid (CA), a bioactive polyphenolic diterpene compound found in RE. The treatment of H1299 and H460 NSCLC cells with CA resulted in concentration and time-dependent inhibition of cell proliferation assessed with crystal violet staining and ³H-thymidine incorporation, and concentration-dependent inhibition of survival, assessed using a colony formation assay. Additionally, CA induced apoptosis of H1299 cells as indicated by decreased B-cell lymphoma 2 (Bcl-2) levels, increased cleaved caspase-3, -7, poly (ADP-ribose) polymerase (PARP), Bcl-2-associated X protein (BAX) levels, and increased nuclear condensation. These antiproliferative and proapoptotic effects coincided with the upregulation of sestrin-2 and the phosphorylation/activation of LKB1 and AMPK. Downstream of AMPK signaling, CA increased levels of autophagy marker light chain 3 (LC3), an established marker of autophagy; inhibiting autophagy with 3-methyladenine (3MA) blocked the antiproliferative effect of CA. Overall, these data indicate that CA can inhibit NSCLC cell viability and that the underlying mechanism of action of CA involves the induction of autophagy through a Sestrin-2/LKB1/AMPK signaling cascade. Future experiments will use siRNA and small molecule inhibitors to better elucidate the role of these signaling molecules in the mechanism of action of CA as well as tumor xenograft models to assess the anticancer properties of CA in vivo. Full article

Leucine (Leu), an essential amino acid, is known to stimulate protein synthesis in the skeletal muscle via mTOR complex 1 (mTORC1) activation. However, the intrinsic contribution of other amino acids to Leu-mediated activation of mTORC1 signaling remains unexplored. This study aimed to identify amino acids that can promote mTORC1 activity in combination with Leu and to assess the effectiveness of these combinations in vitro and in vivo. We found that tyrosine (Tyr) enhanced Leu-induced phosphorylation of S6 kinase (S6K), an indicator of mTORC1 activity, although it exerted no such effect individually. This booster effect was observed in C2C12 cells, isolated murine muscle, and the skeletal muscles of mice orally administered the amino acids. To explore the molecular mechanisms underlying this Tyr-mediated booster effect, the expression of the intracellular Leu sensors, Sestrin1 and 2, was suppressed, and the cells were treated with Leu and Tyr. This suppression enabled Tyr alone to induce S6K phosphorylation and enhanced the booster effect, suggesting that Tyr possibly contributes to mTORC1 activation when Sestrin-GAP activity toward Rags 2 (GATOR2) is dissociated through Sestrin knockdown or the binding of Sestrins to Leu. Collectively, these results indicate that Tyr is a key regulator of Leu-mediated protein synthesis. Full article

p53, a crucial tumor suppressor and transcription factor, plays a central role in the maintenance of genomic stability and the orchestration of cellular responses such as apoptosis, cell cycle arrest, and DNA repair in the face of various stresses. Sestrins, a group of evolutionarily conserved proteins, serve as pivotal mediators connecting p53 to kinase-regulated anti-stress responses, with Sestrin 2 being the most extensively studied member of this protein family. These responses involve the downregulation of cell proliferation, adaptation to shifts in nutrient availability, enhancement of antioxidant defenses, promotion of autophagy/mitophagy, and the clearing of misfolded proteins. Inhibition of the mTORC1 complex by Sestrins reduces cellular proliferation, while Sestrin-dependent activation of AMP-activated kinase (AMPK) and mTORC2 supports metabolic adaptation. Furthermore, Sestrin-induced AMPK and Unc-51-like protein kinase 1 (ULK1) activation regulates autophagy/mitophagy, facilitating the removal of damaged organelles. Moreover, AMPK and ULK1 are involved in adaptation to changing metabolic conditions. ULK1 stabilizes nuclear factor erythroid 2-related factor 2 (Nrf2), thereby activating antioxidative defenses. An understanding of the intricate network involving p53, Sestrins, and kinases holds significant potential for targeted therapeutic interventions, particularly in pathologies like cancer, where the regulatory pathways governed by p53 are often disrupted. Full article

Hypertension is a highly complex, intricate condition affecting millions of individuals across the globe. Nearly half of adults in the United States are diagnosed with hypertension, with incident rates projected to rise over the next decade. Hypertension is a precursor to many cardiovascular diseases including atherosclerosis, stroke, myocardial infarction, heart failure, and peripheral artery disease. This review describes the major processes contributing to the development of hypertension and how Sestrin2 (Sesn2), an antioxidative protein, could be a potential target in the treatment of hypertension. In hypertension, increased reactive oxygen species (ROS) production is a critical component in the etiology of the condition. The increased ROS in hypertension is derived from a variety of sources, all of which are covered in depth in this review. Increased ROS is generated from mitochondrial stress, endoplasmic reticulum (ER) stress, NADPH oxidase (NOX) overactivity, and the uncoupling of endothelial nitric oxidase synthase (eNOS). Sesn2, a highly conserved, stress-inducible protein, has the structural and functional characteristics to be a potential therapeutic target to alleviate the progression of hypertension. The structure, function, genetics, and characteristics of Sesn2 are presented in the review. The Nrf2/Sesn2, Sesn2/AMPK/mTOR, and Sesn2/Angiotensin II signaling pathways are described in detail in this review. Sesn2 can be utilized in a multitude of ways as a therapeutic modality in hypertension. This review explores potential Sesn2 inducers and activators and how Sesn2 can be incorporated into gene therapy for the treatment of hypertension. Full article

Pulmonary fibrosis (PF) is a life-threatening disorder that severely disrupts normal lung architecture and function, resulting in severe respiratory failure and death. It has no definite treatment. Empagliflozin (EMPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has protective potential in PF. However, the mechanisms underlying these effects require further elucidation. Therefore, this study aimed to evaluate the ameliorative effect of EMPA against bleomycin (BLM)-induced PF and the potential mechanisms. Twenty-four male Wister rats were randomly divided into four groups: control, BLM treated, EMPA treated, and EMPA+BLM treated. EMPA significantly improved the histopathological injuries illustrated by both hematoxylin and eosin and Masson’s trichrome-stained lung tissue sections, as confirmed by electron microscopic examination. It significantly reduced the lung index, hydroxyproline content, and transforming growth factor β1 levels in the BLM rat model. It had an anti-inflammatory effect, as evidenced by a decrease in the inflammatory cytokines’ tumor necrosis factor alpha and high mobility group box 1, inflammatory cell infiltration into the bronchoalveolar lavage fluid, and the CD68 immunoreaction. Furthermore, EMPA mitigated oxidative stress, DNA fragmentation, ferroptosis, and endoplasmic reticulum stress, as evidenced by the up-regulation of nuclear factor erythroid 2-related factor expression, heme oxygenase-1 activity, glutathione peroxidase 4 levels, and a decrease in C/EBP homologous protein levels. This protective potential could be explained on the basis of autophagy induction via up-regulating lung sestrin2 expression and the LC3 II immunoreaction observed in this study. Our findings indicated that EMPA protected against BLM-induced PF-associated cellular stress by enhancing autophagy and modulating sestrin2/adenosine monophosphate-activated protein kinase/nuclear factor erythroid 2-related factor 2/heme oxygenase 1 signaling. Full article