Search Results (242)

Skeletal muscle atrophy is a critical health issue affecting the quality of life of elderly individuals and patients with chronic diseases. These conditions induce dysregulation of glucocorticoid (GC) secretion. GCs play a critical role in maintaining homeostasis in the stress response and glucose metabolism. However, prolonged exposure to GC is directly linked to muscle atrophy, which is characterized by a reduction in muscle size and weight, particularly affecting fast-twitch muscle fibers. The GC-activated glucocorticoid receptor (GR) decreases protein synthesis and facilitates protein breakdown. Numerous antagonists have been developed to mitigate GC-induced muscle atrophy, including 11β-HSD1 inhibitors and myostatin and activin receptor blockers. However, the clinical trial results have fallen short of the expected efficacy. Recently, several emerging pathways and targets have been identified. For instance, GC-induced sirtuin 6 isoform (SIRT6) expression suppresses AKT/mTORC1 signaling. Lysine-specific demethylase 1 (LSD1) cooperates with the GR for the transcription of atrogenes. The kynurenine pathway and indoleamine 2,3-dioxygenase 1 (IDO-1) also play crucial roles in protein synthesis and energy production in skeletal muscle. Therefore, a deeper understanding of the complexities of GR transactivation and transrepression will provide new strategies for the discovery of novel drugs to overcome the detrimental effects of GCs on muscle tissues. Full article

Saffron (Crocus sativus L.) contains bioactive compounds with potential health benefits, including modulation of protein function and gene expression. However, their ability to tune the epigenetic machine remains poorly understood. This study employs molecular docking (AutoDock Vina 1.4), dynamics simulations, and MM/PBSA calculations to investigate the interactions between four saffron-derived molecules—crocetin, beta-D-glucosyl trans-crocetin, picrocrocin and safranal—and four epigenetic enzymes—DNMT1, DNMT3a, HDAC2, and SIRT1. Our in silico screening identifies beta-D-glucosyl trans-crocetin, one of the saffron’s crocins, as a potential DNMT1 inhibitor. Along with crocetin, it also shows the ability to inhibit HDAC2 and activate SIRT1. Picrocrocin displays a resveratrol-like ability to activate SIRT1. None of the saffron-derived compounds effectively bind or inhibit DNMT3a. Among the tested molecules, safranal shows no interaction with the selected epigenetic targets. These findings highlight saffron’s nutriepigenomic potential and emphasize the need for functional validation within relevant in vitro and in vivo experimental methodologies. Full article

Background/Objectives: Hutchinson–Gilford progeria syndrome (HGPS) is a rare and fatal genetic disease caused by a silent mutation in the LMNA gene, leading to the production of progerin, a defective prelamin A variant. Progerin accumulation disrupts nuclear integrity, alters chromatin organization, and drives systemic cellular dysfunction. While autophagy and inflammation are key dysregulated pathways in HGPS, the role of microRNAs (miRNAs) in these processes remains poorly understood. Methods: We performed an extensive literature review to identify miRNAs involved in autophagy and inflammation. Through stem-loop RT-qPCR in aging HGPS and control fibroblast strains, we identified significant miRNAs and focused on the most prominent one, miR-181a-5p, for in-depth analysis. We validated our in vitro findings with miRNA expression studies in skin biopsies from an HGPS mouse model and conducted functional assays in human fibroblasts, including immunofluorescence staining, β-Galactosidase assay, qPCR, and Western blot analysis. Transfection studies were performed using an miR-181a-5p mimic and its inhibitor. Results: We identified miR-181a-5p as a critical regulator of premature senescence in HGPS. miR-181a-5p was significantly upregulated in HGPS fibroblasts and an HGPS mouse model, correlating with Sirtuin 1 (SIRT1) suppression and induction of senescence. Additionally, we demonstrated that TGFβ1 induced miR-181a-5p expression, linking inflammation to miRNA-mediated senescence. Inhibiting miR-181a-5p restored SIRT1 levels, increased proliferation, and alleviated senescence in HGPS fibroblasts, supporting its functional relevance in disease progression. Conclusions: These findings highlight the important role of miR-181a-5p in premature aging and suggest its potential as a therapeutic target for modulating senescence in progeroid syndromes. Full article

Sirtuins (SIRTs), a family of NAD+-dependent enzymes, play crucial roles in epigenetic regulation, metabolism, DNA repair, and stress response, making them relevant to glioma biology. This review systematically summarizes the molecular mechanisms and context-specific functions of SIRT1–SIRT7 in central nervous system tumors, with particular focus on gliomas. SIRT1, SIRT3, SIRT5, and SIRT7 are often overexpressed and promote glioma cell proliferation, stemness, therapy resistance, and metabolic adaptation. Conversely, SIRT2, SIRT4, and SIRT6 generally exhibit tumor-suppressive functions by inducing apoptosis, inhibiting invasion, and counteracting oncogenic signaling. Preclinical studies have identified several sirtuin modulators—both inhibitors and activators—that alter tumor growth, sensitize cells to temozolomide, and regulate pathways such as JAK2/STAT3, NF-κB, and mitochondrial metabolism. Emerging evidence positions sirtuins as promising targets for glioma therapy. Future studies should evaluate sirtuin modulators in clinical trials and explore their potential for patient stratification and combined treatment strategies. Full article

Hypertension and diabetes mellitus are key contributors to kidney damage, with the renal tubule playing a central role in the progression of kidney disease. MicroRNAs have important regulatory roles in renal injury and are among the most abundant cargos within extracellular vesicles (EVs), emerging as novel kidney disease biomarkers and therapeutic tools. Previously, we identified miR-200a-3p and its target SIRT1 as having a potential role in kidney injury. We aimed to evaluate miR-200a-3p levels in EVs from patient’s urine and delve into its function in causing tubular injury. We quantified miR-200a-3p urinary EV levels in hypertensive patients with and without diabetes (n = 69), 42 of which were with increased urinary albumin excretion (UAE). We analysed miR-200a-3p levels in EVs and cellular pellets, as well as their targets at mRNA and protein levels in renal tubule cells (RPTECs) subjected to high glucose and Angiotensin II treatments, and observed their influence on apoptosis, RPTEC markers and tubular injury markers. We conducted microRNA mimic and inhibitor transfections in treated RPTECs. Our findings revealed elevated miR-200a-3p levels in increased UAE patient urinary EVs, effectively discriminating UAE (AUC of 0.75, p = 0.003). In vitro, miR-200a-3p and renal injury markers increased, while RPTEC markers, SIRT1, and apoptosis decreased under treatments. Experiments using miR-200a-3p mimics and inhibitors revealed a significant impact on SIRT1 and decrease in tubular damage through miR-200a-3p inhibition. Increased levels of miR-200a-3p emerge as a potential disease marker, and its inhibition provides a therapeutic target aimed at reducing renal tubular damage linked to hypertension and diabetes. Full article

Background. Metabolic dysfunction-associated steatotic liver disease (MASLD) affects more than 30% of the world population. Progression to its inflammatory state, MASH, is associated with increasing liver fibrosis, leading to end-stage liver disease (ESLD) and hepatocellular carcinoma (HCC). SW033291, an inhibitor of 15-PGDH (the PGE2 degradation enzyme), has been shown to increase in vivo regeneration of liver parenchyma, ameliorating oxidative stress and inflammation. We hypothesized that SW033291 abrogates MASH progression by inducing a paucity of the initial apoptotic switch and restoring physiological collagen’s microenvironment. Methods. The expression levels of the cell metabolic proteins FOXO1, mTOR, and SIRT7 were determined in a diet-induced MASH-mouse model at 16, 20, and 24 weeks. Non-targeted metabolomics in mouse plasma were measured by LC-MS/MS. Liver morphology and apoptotic activity were quantified by the NAS score and TUNEL assay, respectively. Statistical analyses between groups (NMC, HFD, and SW033291) were determined by ANOVA, t-test/Tukey’s post hoc test using GraphPad Prism. Metabolomics data were analyzed using R-lab. Results. The treated group showed significant decreases in total body fat, cellular oxidative stress, and inflammation and an increase in total lean mass with improved insulin resistance and favorable modulation of metabolic protein expressions (p < 0.05). SW033291 significantly decreased GS:SG, citric acid, and corticosterone, NAS scores (9.4 ± 0.2 vs. 6.2 ± 0.1, p < 0.05), liver fibrosis scores (1.3 ± 0.5 vs. 0.25 ± 0.1, p < 0.05), and apoptotic activity (43.9 ± 4.6 vs. 0.38 ± 0.1%, p < 0.05) compared with controls at 24W. Conclusions. The inhibition of 15-PGDH appears to normalize the metabolic and morphological disturbances during MASH progression with a paucity of the initial apoptotic switch, restoring normal collagen architecture. SW033291 warrants further investigation for its translation. Full article

This study investigates the role of melatonin in alleviating the oxidative stress and apoptosis of TM3 Leydig cells induced by 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), the primary active metabolite of Bisphenol A, and clarifies its potential mechanisms involving the SIRT1/PGC-1α pathway. We found that melatonin effectively mitigated MBP-induced cytotoxicity in TM3 cells (p < 0.05). The testosterone levels and steroid hormone synthesis proteins were significantly restored by melatonin. Furthermore, there was a significant reduction in apoptosis after melatonin treatment both in MBP-treated TM3 cells and Bisphenol A-treated testicular interstitial tissues (p < 0.05), along with a significant decrease in the pro-apoptotic markers Bax and cleaved caspase 3, and a significant increase in the anti-apoptotic Bcl-2 level and the Bcl-2/Bax ratio in TM3 cells (p < 0.05). Additionally, the mitochondrial membrane potential improved significantly, ROS and MDA levels were down-regulated, and ATP production was elevated following melatonin treatment in TM3 cells. Mechanistically, melatonin promoted PGC-1α expression and activated the SIRT1 signaling pathway in MBP-treated TM3 cells and Bisphenol A-treated testicular interstitial tissues. This leads to increased expression of NRF2 and its downstream antioxidant genes, mitochondrial respiratory chain complex-related genes, mitochondrial biogenesis genes, and mitochondrial fusion genes while significantly reducing mitochondrial fission genes (p < 0.05). The PGC-1α inhibitor SR-18292 reversed these protective effects, confirming the critical role of this pathway. Conclusively, melatonin exerts a protective effect against MBP-induced oxidative stress and apoptosis in TM3 cells through the SIRT1/PGC-1α pathway, indicating its potential as a therapeutic agent for improving male reproductive health compromised by environmental toxins. Full article

Background and Objectives: Methotrexate (MTX) is a widely utilised pharmaceutical agent in the treatment of various malignancies and inflammatory diseases. However, its clinical utility is often constrained by its potential for hepatotoxicity. Although pyridostigmine is a well-established reversible acetylcholinesterase inhibitor, its potential therapeutic role in preventing hepatic injury remains incompletely defined. The present study aimed to investigate whether pyridostigmine provides protective effects against MTX-triggered liver damage in a rat model. Methods: Thirty-six female Wistar albino rats randomly assigned to three groups: control (n = 12), MTX + saline (n = 12), and MTX + pyridostigmine (n = 12). Hepatotoxicity was induced by a single-dose MTX injection (20 mg/kg), followed by daily oral administration of either pyridostigmine (5 mg/kg) or saline for ten consecutive days. Hepatic function markers, oxidative stress parameters, fibrosis-associated mediators, and histopathological changes were assessed. Results: Pyridostigmine significantly attenuated MTX-induced elevations in plasma alanine aminotransferase (p < 0.05) and cytokeratin-18 levels (p < 0.001), and reduced liver and plasma malondialdehyde (MDA) levels (p < 0.05). Additionally, pyridostigmine treatment resulted in reduced levels of transforming growth factor-beta (p < 0.05), bone morphogenetic protein-9 (p < 0.001), and endoglin levels (p < 0.05), as well as increased sirtuin 1 level (p < 0.05). Histopathological examination revealed that pyridostigmine treatment significantly reduced MTX-induced hepatocyte necrosis, fibrosis, and cellular infiltration. Conclusions: Pyridostigmine exerted hepatoprotective effects against MTX-induced liver injury by attenuating oxidative stress, restoring SIRT1 expression, and suppressing pro-fibrotic signaling. These findings indicate that pyridostigmine may hold therapeutic potential for the prevention of MTX-associated hepatotoxicity. Full article

Background/Objectives: Cellular aging represents a crucial element in the progression of musculoskeletal diseases, contributing to muscle atrophy, functional decline, and alterations in bone turnover, which promote fragility fractures. However, knowledge about expression patterns of factors potentially involved in aging and senescence at the tissue level remains limited. Our pilot study aimed to characterize the expression profile of cell cycle regulators, factors released by aged cells, and sirtuin 1 (SIRT1) in the muscle tissue of 26 elderly patients undergoing hip arthroplasty, including 13 with low-energy fracture and 13 with osteoarthritis (OA). Methods: The mRNA expression levels of cyclin-dependent kinase inhibitor 1A (CDKN1A), cyclin-dependent kinase inhibitor 1B (CDKN1B), cyclin-dependent kinase inhibitor 2A (CDKN2A), p53, tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), interleukin-15 (IL-15), chemokine (C-C motif) ligand 2 (CCL2), chemokine (C-C motif) ligand 3 (CCL3), growth differentiation factor 15 (GDF15), and SIRT1 were evaluated in muscle tissue by qRT-PCR. In addition, immunohistochemistry and Western blotting analysis were conducted to measure the protein levels of SIRT1. Results: A marked muscle atrophy was observed in fractured patients compared to the OA group, in association with an up-regulation of cell cycle regulators and factors released by the aged cells. The expression of matrix metallopeptidase 3 (MMP3), plasminogen activator inhibitor 1 (PAI-1), and fas cell surface death receptor (FAS) was also investigated, although no significant differences were observed between the two experimental groups. Notably, SIRT1 expression was significantly higher in OA patients, confirming its role in maintaining muscle health during aging. Conclusions: Further studies will be needed to clarify the role of SIRT1 in the senescence characteristic of age-related musculoskeletal disorders, counteracting the muscle atrophy that predisposes to fragility fractures. Full article

Background: Sepsis-induced acute lung injury (SALI) is a critical clinical challenge with high mortality. Metabolic dysregulation drives SALI pathogenesis, disrupting lung function and energy metabolism. Despite proven benefits, metabolic restoration is underused in sepsis. This study explores chiglitazar’s role in balancing metabolism to protect against SALI. Methods: The protective effects of chiglitazar in CLP rats were demonstrated by the survival curve, histological analysis, and immunohistochemical analysis in the lung tissue. Metabolomic and lipidomic analyses of lung tissue samples using gas chromatography–mass spectrometry (GC-MS) and liquid chromatography–mass spectrometry (LC-MS) were performed to evaluate metabolic shifts induced by CLP surgery and chiglitazar pretreatment. The mRNA and protein levels of the underlying targets directing nicotinamide adenine dinucleotide (NAD+) and triglyceride synthesis were analyzed by qPCR and Western blotting. To validate the mechanism by which chiglitazar protected against SALI, the SIRT1 inhibitor EX-527 was applied to human normal lung epithelial (BEAS-2B) cells and another batch of rats to observe its reverse effect against chiglitazar’s action. Results: Chiglitazar pretreatment significantly restored NAD+ and improved dysregulated lipid metabolism by enhancing the synthesis of triglycerides (TGs) and suppressing accumulated fatty acids (FAs). The metabolic modulation mediated by chiglitazar was associated with the upregulations of the SIRT1/PGC-1α/PPARα/GPAT3 axis. Co-treatment with EX-527 in LPS-stimulated BEAS-2B cells and CLP rats inhibited the effects of chiglitazar on the aforementioned signaling pathways and worsened the protective effects of chiglitazar on lung injury, respectively. Conclusions: Chiglitazar alleviates SALI by restoring NAD+ and TG synthesis, highlighting the balancing of metabolism as a promising therapeutic strategy in the management of SALI. Full article

Background/Objectives: Exercise training (ET) can improve wound healing and prevent the recurrence of skin lesions. Aerobic ET stimulates the NAD+-dependent deacetylase sirtuin 1 (SIRT1). The beneficial effects of ET and SIRT1 activation in wound healing have been characterized when considered separately. This study aimed to investigate the potential role of SIRT1 as a mediator of the effects of sera isolated from athletes who regularly participate in aerobic ET (middle-distance running, MDR) on cells primarily involved in wound healing. Methods: Human keratinocytes, fibroblasts and endothelial cells were conditioned with sera from middle-distance runners and age-matched sedentary subjects (sed). Cell motility, angiogenesis and the expression of key biomarkers of cell activation were evaluated in the presence or absence of the selective SIRT1 inhibitor EX-527. Results: Higher SIRT1 activity was detected in all of the cell lines conditioned with the MDR group sera compared with that in the cells in the sed group sera. The involvement of SIRT1 was demonstrated by EX-527’s selective inhibition. Alongside the increase in SIRT1 activity, a marked increase in migration, invasion and angiogenesis was observed. The levels of E-cadherin decreased while those of integrin β1 and vinculin increased in the keratinocytes and fibroblasts conditioned with the MDR group sera compared to these values with the sed group sera, respectively. Increased levels of differentiation markers, such as involucrin in the keratinocytes, FAP1α in the fibroblasts and CD31 in the endothelial cells, were observed with the MDR group sera compared to these values using the sed group sera. Conclusions: The ex vivo/in vitro approach used here links aerobic ET-induced SIRT1 activity to proper tissue regeneration. Full article

Empagliflozin (EMPA)—a sodium-glucose cotransporter type 2 inhibitor—reduces endoplasmic reticulum (ER) stress, oxidative stress, and inflammation during metabolic dysfunction-associated steatotic liver disease (MASLD) progression. However, the direct effects of EMPA on hepatic lipid metabolism and oxidative stress are unclear. Through the current study, we seek to explore the effects of EMPA on oxidative stress and related mechanisms in MASLD. To this end, MASLD was induced in C57BL/6J mice using a high-fat diet (HFD); nuclear respiratory factor 1 (NRF1) was downregulated via viral transduction (AAV8-shNrf1). Glucose homeostasis and liver histology were assessed, and oxidative stress and inflammation were measured. HFD-fed mice-derived liver tissue samples exhibited more lipid droplets, higher triglyceride levels, and elevated oxidative and ER stress than chow diet (CD)-fed mice. EMPA attenuated HFD-induced liver oxidative and ER stress. Additionally, the HFD significantly decreased NRF1 and Sirtuin (SIRT)7 expression compared with CD, which was rescued by EMPA treatment. However, these results did not affect insulin resistance or lipid synthesis-related changes upon EMPA treatment in the Nrf1-knockdown mice. Furthermore, EMPA alleviated HFD-induced hepatic steatosis and oxidative stress; however, these effects were lost in Nrf1-knockdown mice. Collectively, the results of this study suggest that EMPA ameliorates MASLD by reducing steatosis and attenuating oxidative stress via NRF1. Full article

Sirtuins are involved in cellular processes in multiple ways. Therefore, the development of potent and selective Sirt2 inhibitors provides an important contribution to understanding physiological and pathophysiological mechanisms, particularly for the research and treatment of cancer and neurodegenerative diseases. Based on established SirReal-type lead inhibitors, further selective Sirt2 inhibitors were synthesized in a docking-guided rigidization approach, and the knowledge regarding requirements and properties of the Sirt2-binding pocket was expanded by means of a comprehensive SAR study. Naphthalene derivative FM69 emerged from the screening as the most potent rigidized inhibitor, which, with an IC₅₀ value of 0.15 µM against Sirt2, represents a promising foundation for the further development of novel potent and selective Sirt2 inhibitors based on the presented rigidization strategy. Full article

Silent Information Regulator 5 (SIRT5) has been established as a crucial regulator of cellular alanylation modification. Furthermore, accumulating evidence suggests that SIRT5 plays a significant regulatory role in key metabolic pathways, including glycolysis, the tricarboxylic acid (TCA) cycle, and fatty acid oxidation, all of which are closely associated with cellular lipid metabolism. Despite these advancements, the specific role of SIRT5 in regulating intramuscular fat (IMF) deposition in goats, as well as the underlying molecular mechanisms, remains largely unexplored. In this study, we cloned the complete coding sequence of the goat SIRT5 gene and, through amino acid sequence alignment, demonstrated its closest phylogenetic relationship with sheep. Additionally, we characterized the higher expression of SIRT5 during the differentiation of goat intramuscular precursor adipocytes. The silencing of SIRT5 by siRNA-mediated knockdown significantly upregulated the expression of lipogenesis-related genes and enhanced lipid deposition in goat intramuscular preadipocytes. Concurrently, SIRT5 deficiency led to the inhibition of cell proliferation and a marked reduction in apoptosis. Interestingly, although overexpression of SIRT5 promoted cell proliferation, it did not significantly alter lipid deposition in goat intramuscular precursor adipocytes. RNA sequencing (RNA-seq) analysis identified a total of 106 differentially expressed genes (DEGs) following SIRT5 silencing in goat preadipocytes, predominantly involved in the Focal adhesion, HIF-1, PI3K-Akt, and MAPK signaling pathways by KEGG pathway enrichment analysis. Notably, we successfully reversed the phenotypic effects observed in SIRT5 knockdown goat precursor adipocytes by inhibiting the PI3K-Akt and MAPK signaling pathways using the AKT inhibitor LY294002 and the p38 MAPK pathway inhibitor PD169316, respectively. In conclusion, our findings demonstrated that SIRT5 may modulate intramuscular fat deposition in goats through PI3k-Akt and MAPK signaling pathways. These results expand the gene regulatory network associated with IMF formation and provide a theoretical foundation for improving meat quality by targeting IMF deposition. Full article

Empagliflozin (EMPA), a sodium-glucose co-transporter 2 (SGLT2) inhibitor, prevents endothelial dysfunction, but its effects on vascular tone in hypertension remain unclear. This study investigated whether EMPA modulates vasomotor tone via sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK) pathways in spontaneously hypertensive rats (SHR) and controls (Wistar Kyoto rats, WKY). Functional (wire myography, organ bath) and biochemical (Western blot) studies were conducted on the third-order of the superior mesenteric arteries (sMAs) and/or aortas. EMPA induced concentration-dependent relaxation of preconstricted sMAs in both groups. In SHR, EMPA enhanced acetylcholine (Ach)-induced relaxation in sMAs and aortas and reduced constriction induced by phenylephrine (Phe) and U46619 in sMAs. The SIRT1 inhibitor (EX527) abolished EMPA’s effects on Ach-mediated relaxation and U46619-induced vasoconstriction, while AMPK inhibition reduced Ach-mediated relaxation and Phe-induced vasoconstriction. SHR showed increased SGLT2 and SIRT1 expression and decreased pAMPK/AMPK levels in sMAs. In conclusion, EMPA might exert vasoprotective effects in hypertension by enhancing endothelium-dependent relaxation and reducing constriction via AMPK/SIRT1 pathways. These properties could improve vascular health in patients with hypertension and related conditions. Further studies are needed to explore new indications for SGLT2 inhibitors. Full article