Search Results (959)

Introduction: Obstructive sleep apnea (OSA) is recognized as an independent risk factor for diabetes mellitus type 2 (T2DM) development, which is twice as common in patients with OSA compared to non-OSA patients. Objectives: This study aimed to investigate changes in oxygen metabolism and their role in T2DM development among OSA patients through epigenetic processes via miRNA-181a, miRNA-199a, and enzymatic processes via SIRT1 and HIF-1α. Methods: Based on polysomnography, apnea–hypopnea index and the presence of T2DM patients were divided into three groups: control group (n = 17), OSA group (n = 11), OSA&T2DM (n = 20) group. Total RNA was extracted from the buffy coat. Moreover, HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) was counted. Results: Morning miRNA-181a expression was significantly higher in the OSA&T2DM group than in the control group: 67.618 vs. 32.685 (p = 0.036). Evening miRNA-199a expression was significantly higher in the OSA group than in the control group: 5.043 vs. 2.081 (p = 0.042), while its morning expression was significantly higher in the OSA&T2DM group when compared to the control: 4.065 vs. 1.605 (p = 0.036). MiRNA-181a evening expression revealed a negative correlation with the SIRT1 evening and morning expressions (R = −0.367, p = 0.010 and R = −0.405, p = 0.004, respectively). Moreover, morning miRNA-181a was positively correlated with HOMA-IR (R = 0.321, p = 0.034). MiRNA-199a evening expression presented a moderate positive correlation with the SIRT1 morning expressions (R = 0.48, p < 0.001) and HOMA-IR (R = 0.35, p = 0.02). Conclusions: Patients suffering from OSA and T2DM had an increased expression of miRNA-181a. Moreover, a negative correlation between miRNA-181a and SIRT1 expression was observed, while a correlation between miRNA-181a and insulin resistance was positive. This phenomenon might suggest a possible epigenetic pathway for an increased incidence of T2DM in OSA patients however further research is needed. Full article

Background/Objectives: The antioxidant/antiapoptotic features of dapagliflozin (DPG) have mediated its beneficial actions against several experimental models. However, no studies have been conducted to determine whether DPG mitigates the renal injury triggered by cadmium (Cd). Herein, DPG was studied for its potential to attenuate kidney damage in Cd-intoxicated rats, as well as to unravel the mechanisms involving oxidative events, autophagy, and apoptosis. Methods: Histopathological analysis, immunohistochemical staining, and ELISA were conducted on kidney tissue samples. Results: Cd administration (5 mg/kg/day; p.o.) prompted significant renal damage, as evidenced by histopathological changes, elevated kidney injury molecule-1 (KIM-1) expression, and increased serum creatinine and urea. Interestingly, DPG (1 mg/kg/day; p.o.) significantly mitigated these harmful effects without affecting renal Cd metal accumulation. Mechanistically, DPG curbed Cd-induced renal pro-oxidant response and stimulated the antioxidant sirtuin 1 (SIRT1)/nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase 1 (HO-1) axis. Moreover, DPG restored autophagy by decreasing sequestosome-1/protein 62 (SQSTM-1/p62) accumulation and stimulating the AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) pathway. In tandem, DPG suppressed Cd-induced apoptosis by lowering renal Bcl-2 associated-x protein (Bax) and cytochrome C (Cyt C) levels and caspase 3 activity. Conclusions: These findings indicate that DPG attenuates Cd-induced nephrotoxicity by enhancing the SIRT1/Nrf2/HO-1 antioxidant pathway, promoting AMPK/mTOR-directed autophagy, and inhibiting apoptotic cell death. Full article

Background: Multiple myeloma, a malignancy of plasma cells, often involves the disruption of vitamin D metabolism. Vitamin D, acting through its receptor (VDR), affects transcription factors like FOXO and sirtuins, which regulate cellular processes. The impact of physical activity on these markers in multiple myeloma patients is unclear. Therefore, the objective of this study was to evaluate the effects of a 6-week training program on these parameters. Material and methods: The study was completed by 30 patients, including 16 in the Nordic walking training group (TG) and 14 in the control group (non-exercising, CG). All participants underwent a thorough medical interview before starting the project. Venous blood samples were collected from all participants four times—at baseline, after 3 weeks, after 6 weeks, and after 9 weeks (follow-up). The serum concentrations of sirtuin 1, sirtuin 3, Foxo3a, vitamin D receptor (VDR), 25(OH)D3, and 1,25(OH)2D were determined. Body composition, physical fitness, and physical activity level were assessed at baseline and after 6 weeks. Results: No statistically significant changes were observed in the serum levels of sirtuins, the FOXO3a protein, and 1,25(OH)2D. A statistically significant difference was observed in the levels of VDR for both time and group factors, but this was not confirmed in the post hoc test. Vitamin 25(OH)D3 level increased significantly in the study group with time. Conclusions: The applied 6-week Nordic walking training cycle positively affected the level of vitamin 25(OH)D3 but did not influence the rest of the biochemical parameters studied. The obtained results also indicate that the applied intervention is safe for patients and does not interfere with body composition. Full article

Gold kiwifruit is known for its high vitamin C content and various benefits. This study investigated the effects and molecular mechanisms of fermented gold kiwifruit (FGK) in a mouse model of high-fat diet (HFD)-induced obesity and hepatic steatosis. FGK powder was prepared using five strains of lactic acid bacteria: L. paracasei, Lc. lactis, L. acidophilus, L. casei, and L. helveticus. ICR mice were fed an HFD for 8 weeks to induce obesity and hepatic steatosis, and FGK supplementation was evaluated for its therapeutic potential. FGK administration significantly reduced serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol, triglyceride, and glucose compared to the HFD-only group. Histopathological analysis showed that FGK reduced lipid accumulation and hepatic lesions, as confirmed by hematoxylin and eosin (H&E) staining. Furthermore, administration of FGK activated the sirtuin 1(SIRT1)/adenosine monophosphate-activated protein kinase (AMPK) pathway and inhibited expression of the pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α in liver tissue. These findings suggest that FGK could reduce the severity of non-alcoholic fatty liver disease (NAFLD) by inhibiting fat synthesis, promoting fat breakdown, and suppressing inflammation in HFD-induced obese mice. Full article

Our preliminary data using bone marrow-derived macrophages (BMDMs) collected from ICR mice treated with anti-sirtuin (anti-SIRT) 1 antibody showed that Brucella uptake was significantly attenuated. We then further investigated the effect of an inhibitor of SIRT1/2, cambinol, in the progression of Brucella. The in vitro results using RAW264.7 cells revealed that cambinol treatment had no effect on adhesion, uptake, intracellular survival and nitric oxide (NO) production during B. abortus infection, nor did it directly affect bacterial growth for up to 72 h. Finally, intraperitoneal treatment of 8-week-old female ICR mice infected with Brucella showed no differences in the total average weights of spleens and livers; however, the treated mice displayed higher Brucella colony-forming units (CFUs) from the spleens. Furthermore, the interleukin (IL)-10 serum level was observed to be lower in treated mice at 7 d post-infection, and none of the cytokines tested showed a change at 14 d post-infection. The overall findings showed that cambinol treatment had no effect on the proliferation of Brucella in RAW264.7 macrophages but exacerbated the splenic proliferation of the bacteria in mice and displayed reduced anti-inflammatory cytokine IL-10 at the first week of infection, suggesting that cambinol as an inhibitory of SIRT1/2 could be beneficial in the context of Brucella dissemination in animal hosts and that exploration of activating SIRTs could be an alternative treatment against Brucella infection. Full article

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype characterised by the absence of targetable hormone receptors and increased metastatic rates. As nuclear softening strongly contributes to TNBC’s enhanced metastatic capacity, increasing the nuclear stiffness of TNBC cells may present a promising therapeutic avenue. Previous evidence has demonstrated the ability of Sirtuin 2 (SIRT2) inhibition to induce cytoskeletal reorganisation, a key factor in regulating nuclear mechanics. Thus, our study aimed to investigate the effect of SIRT2 inhibition on the nuclear mechanics and migratory behaviour of TNBC cells. To achieve this, SIRT2 was pharmacologically inhibited in MDA-MB-231 cells using AGK2, a SIRT2-specific inhibitor. Although SIRT2 inhibition had no effect on LINC complex composition, the AGK2-treated MDA-MB-231 cells displayed more prominent perinuclear organisations of acetylated α-tubulin, vimentin, and F-actin. Additionally, the nuclei of the AGK2-treated MDA-MB-231 cells exhibited greater resistance to collapse under osmotic shock. Scratch-wound assays also revealed that SIRT2 inhibition led to polarity defects in the MDA-MB-231 cells, while in vitro space-restrictive invasion assays highlighted their reduced migratory capacity upon AGK2 treatment. Taken together, our findings suggest that SIRT2 inhibition promotes a perinuclear cytoskeletal organisation in MDA-MB-231 cells, which enhances their nuclear rigidity and impedes their invasion through confined spaces in vitro. Full article

Pancreatic ductal adenocarcinoma (PDAC) stands as one of the most lethal cancers, marked by rapid progression, pronounced chemoresistance, and a complex network of genetic and epigenetic dysregulation. Within this challenging context, sirtuins, NAD⁺-dependent deacetylases, have emerged as pivotal modulators of key cellular processes that drive pancreatic cancer progression. Each sirtuin contributes uniquely to PDAC pathogenesis. SIRT1 influences apoptosis and chemoresistance through hypoxia, enhancing glycolytic metabolism and HIF-1α signaling, which sustain tumor survival against drugs like gemcitabine. SIRT2, conversely, disrupts cancer cell proliferation by inhibiting eIF5A, while SIRT3 exerts tumor-suppressive effects by regulating mitochondrial ROS and glycolysis. SIRT4 inhibits aerobic glycolysis, and its therapeutic upregulation has shown promise in curbing PDAC progression. Furthermore, SIRT5 modulates glutamine and glutathione metabolism, offering an avenue to disrupt PDAC’s metabolic dependencies. SIRT6 and SIRT7, through their roles in angiogenesis, EMT, and metastasis, represent additional targets, with modulators of SIRT6, such as JYQ-42, showing potential to reduce tumor invasiveness. This review aims to provide a comprehensive exploration of the emerging roles of sirtuins, a family of NAD⁺-dependent enzymes, as critical regulators within the oncogenic landscape of pancreatic cancer. This review meticulously explores the nuanced involvement of sirtuins in pancreatic cancer, elucidating their contributions to tumorigenesis and suppression through mechanisms such as metabolic reprogramming, the maintenance of genomic integrity and epigenetic modulation. Furthermore, it emphasizes the urgent need for the development of targeted therapeutic interventions aimed at precisely modulating sirtuin activity, thereby enhancing therapeutic efficacy and optimizing patient outcomes in the context of pancreatic malignancies. Full article

Endothelial–mesenchymal transition (EnMT) is the transversion of endothelial cells to mesenchymal cells under certain physiological or pathological conditions. When EnMT occurs in the corneal endothelium, corneal endothelial cells (CECs) lose their normal function and thus cannot maintain corneal clarity. Studies have shown that the mechanism of EnMT in CECs involves the transforming growth factor-β (TGF-β) signaling pathway, and one of the important inhibitors of the TGF-β/Smad2/3 pathway is sirtuin-1 (SIRT1). In this study, we used a rat model of corneal endothelium injury and TGF-β1-treated human CECs to induce EnMT, aiming to explore whether SIRT1 activation inhibits corneal EnMT in vivo and in vitro. SIRT1 was activated and suppressed using resveratrol (RSV) and EX527, respectively. The endothelial markers and mesenchymal markers were measured by immunofluorescence and Western blot assays. Co-immunoprecipitation was used to detect the interaction between SIRT1 and Smad2/3. The results showed that after mechanical injury, the group treated with RSV-activated SIRT1 regained corneal transparency and recovered from edema faster than the control group. Moreover, RSV-activated SIRT1 downregulated the expression levels of alpha smooth muscle actin (α-SMA), vimentin, and Snail and upregulated the expression levels of E-cadherin and Na⁺/K⁺-ATPase both in vivo and in vitro, but these effects were reversed when SIRT1 was inhibited by EX527. SIRT1 also upregulated the expression levels of TGF-β receptor 1 and phosphorylated Smad2/3. The interaction between SIRT1 and Smad2/3 in vitro was confirmed by co-immunoprecipitation. Overall, our results indicate that SIRT1 activation inhibits corneal EnMT via the TGF-β/Smad2/3 pathway, which may be a potential therapeutic target for corneal endothelium dysfunction. Full article

Quercetin is a natural flavonoid renowned for its potent antioxidant, anti-inflammatory, anti-diabetic, and antibacterial properties, making it a highly promising candidate for the treatment of various medical conditions. Our current study investigates the influence of quercetin on energy metabolism, fatty acid composition, oxidative stress gene expression, and sirtuin expression in early- and late-stage passages of stem cells derived from human exfoliated deciduous teeth (SHEDs). Mitochondrial respiration was analyzed by measuring oxygen consumption following a 24 h quercetin treatment, while fatty acid profiles were examined using gas chromatography–mass spectrometry (GC-MS). Additionally, quantitative PCR (qPCR) was used to assess the expression of oxidative stress genes and sirtuins. In younger SHEDs, quercetin enhances metabolic activity and mitochondrial respiration, although higher doses may decrease mitochondrial activity. Conversely, in older, senescent SHEDs, quercetin supports mitochondrial function at lower concentrations but appears to inhibit respiration at higher doses. These results suggest that quercetin may hold therapeutic potential for maintaining SHED viability and function, especially at lower doses in older cells. Further research is essential to fully elucidate a dose-dependent effect of quercetin and optimize its applications in regenerative medicine. Full article

Human immunodeficiency virus type-1 (HIV-1) associated comorbidities account for the majority of poor health outcomes in people living with HIV (PLWH) in the era of antiretroviral therapy. Lung-related comorbidities such as chronic obstructive pulmonary disease (COPD) and bacterial pneumonia are primarily responsible for increased morbidity and mortality in PLWH, even when compensated for smoking. Smokers and COPD patients demonstrate cilia shortening, attenuated ciliary beat frequency (CBF), dysfunctional ciliated cells along with goblet cell hyperplasia, and mucus hypersecretion. This is exacerbated by the fact that almost 60% of PLWH smoke tobacco, which can exacerbate inflammation and mucociliary clearance (MCC) dysfunction. This study shows that HIV Tat alters the microRNAome in airway epithelial cells and upregulates miR-34a-5p with consequent suppression of its target, Sirtuin 1 (SIRT1). SIRT1 is known to suppress Metalloproteinase 17 (ADAM17), a protease activating Notch signaling. HIV and cigarette smoke (CS) upregulate ADAM17. ADAM17 upregulation followed by SIRT1 suppression can lead to decreased ciliation, mucus hypersecretion, and attenuated MCC, a hallmark of chronic bronchitis in smokers and COPD. It is, therefore, essential to understand the pathophysiological mechanism resulting in acquired Notch dysregulation and its downstream impact on HIV-infected smokers. Full article

Sirtuins are a family of lysine deacetylases that regulate cellular homeostasis and energy sensing. Regeneration is the process that restores structural and functional homeostasis at the cellular, tissue, organ, and appendage levels. Several cellular processes, such as epithelial–mesenchymal transition (EMT), proliferation, migration, and differentiation, contribute to restoration after an injury. This review highlights the role of sirtuins in tissue, organ, and anatomical structure regeneration, showing how sirtuins modulate signalling pathways by deacetylating targets such as transcription factors. Furthermore, understanding the role of this protein family could help elucidate the molecular and cellular mechanisms underlying tissue regeneration, which may hold significant potential for fields such as regenerative medicine. The review compiles evidence suggesting that sirtuins are emerging factors in the regeneration of various organs (e.g., skin, liver, heart) and tissues (e.g., bone, muscle, cornea, spinal cord). Full article

Sirtuins (SIRTs), nicotine adenine dinucleotide (+)-dependent histone deacetylases, have emerged as critical regulators in many signalling pathways involved in a wide range of biological processes. Currently, seven mammalian SIRTs have been characterized and are found across a number of cellular compartments. There has been considerable interest in the role of SIRTs in the brain due to their role in a plethora of metabolic- and age-related diseases, including their involvement in learning and memory function in physiological and pathophysiological conditions. Although cognitive function declines over the course of healthy ageing, neurological disorders including Alzheimer’s disease (AD) can be associated with progressive cognitive impairments. This review aimed to report and integrate recent advances in the understanding of the role of SIRTs in cognitive function and dysfunction in the context of AD. We have also reviewed the use of selective and/or natural SIRT activators as potential therapeutic agents and/or adjuvants for AD. Full article

Actinic keratosis (AK) is a precursor to invasive squamous cell carcinoma, making early diagnosis and treatment essential to prevent progression. Among available therapeutic options, nicotinamide (NAM) has shown potential in reducing AK progression. NAM is a precursor of nicotinamide adenine dinucleotide (NAD⁺), which activates sirtuin (SIRT)1, a protein with anti-cancer properties. Although the role of SIRT1 in AK is still debated, no data currently exist on the systemic modulation of this protein in AK. Therefore, this study aims to evaluate whether NAM, by increasing serum NAD+ levels, may promote SIRT1 activation in peripheral blood mononuclear cells (PBMCs) in AK patients. Thirty patients were enrolled and treated with NAM for 24 months. Hematological, biochemical, and skin condition assessments were conducted, alongside the measurement of SIRT1 and NAD⁺ levels. A decrease in basophils, monocytes, total cholesterol, and blood glucose levels was observed in the study group, along with a reduction in AK lesions. Notably, NAM treatment significantly enhanced serum NAD⁺ levels, and nuclear SIRT1 activity in PBMCs. In conclusion, NAM administration significantly reduced AK progression in a NAD⁺/SIRT1-dependent manner, supporting its role as a chemopreventive agent in AK management. Full article

Lysine succinylation, and its reversal by sirtuin-5 (SIRT5), is known to modulate mitochondrial fatty acid β-oxidation (FAO). We recently showed that feeding mice dodecanedioic acid, a 12-carbon dicarboxylic acid (DC₁₂) that can be chain-shortened four rounds to succinyl-CoA, drives high-level protein hypersuccinylation in the peroxisome, particularly on peroxisomal FAO enzymes. However, the ability of SIRT5 to reverse DC₁₂-induced peroxisomal succinylation, or to regulate peroxisomal FAO in this context, remained unexplored. Here, we showed that feeding DC₁₂ strongly recruits SIRT5 into hepatic peroxisomes. Knocking out SIRT5 impaired peroxisomal FAO as evidenced by reduced ¹⁴C-DC₁₂ flux in liver homogenates and elevated levels of partially shortened DC₁₂ catabolites in urine. Further, mass spectrometry revealed a trend toward less peroxisomal protein succinylation in SIRT5 knockout liver. This is consistent with a reduced flux of DC₁₂ through the peroxisomal FAO pathway, thereby reducing the production of the succinyl-CoA that chemically reacts with lysine residues to produce protein succinylation. Mass spectrometry comparisons of site-level succinylation in wildtype and SIRT5 knockout liver did not reveal any clear pattern of SIRT5 target sites in the peroxisome after DC₁₂ feeding. However, SIRT5 co-immunoprecipitated with 15 peroxisomal proteins, including the key peroxisomal FAO enzymes acyl-CoA oxidase-1 and enoyl-CoA/3-hydroxyacyl-CoA dehydrogenase (EHHADH). In vitro, recombinant SIRT5 partially desuccinylated chemically modified recombinants ACOX1a, ACOX1b, and EHHADH. Desuccinylation by SIRT5 had no effect on enzyme activity for ACOX1a and EHHADH. For ACOX1b, SIRT5-mediated desuccinylation decreased activity by ~15%. Possible interpretations of these data are discussed. Full article

Depression is one of the most common neurological diseases, which imposes a substantial social and economic burden on modern society. The purpose of this study was to explore the mechanism of total ginsenoside ginseng root (TGGR) in the treatment of depression through a comprehensive strategy combining network pharmacology, transcriptomics, and in vivo experimental validation. The Traditional Chinese Medicine Systematic Pharmacology (TCMSP) database and literature were used to collect the main components and targets of TGGR. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were applied to explore the underlying mechanisms. In addition, the chronic unpredictable mild stress (CUMS)-induced C57BL/6 mouse model was used to evaluate the antidepressant activity of TGGR. The results showed that TGGR improved depression-like behavior in mice and increased the decrease in serum 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF) levels caused by CUMS. Combined network pharmacology and transcriptomic analysis showed that the AMP-activated kinase (AMPK) signaling pathway mainly enriched the core target. Immunohistochemistry, Western blotting, and reverse transcription quantitative polymerase chain reaction (RT-qPCR) were used to confirm whether TGGR exerts antidepressant effects by regulating this pathway. The results showed that TGGR has a regulatory impact on related proteins in the AMPK pathway, and the regulatory effect of TGGR on proteins was inhibited after the administration of related pathway inhibitors. In summary, total ginsenosides may regulate the AMPK signaling pathway and activate the sirtuin 1 (SIRT1) peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) pathway to have therapeutic effects on depression. Full article