Search Results (60)

Superoxide dismutase-rich Tetraselmis chuii (T. chuii) is derived from marine microalgae and has been reported to increase gene expression of nuclear factor erythroid 2-related factor 2 (NRF2) and related antioxidant enzymes in myoblast tissue culture models. Human research has indicated that T. chuii supplementation can improve recovery from exercise-induced muscle damage, but its effects on endurance exercise performance and the molecular bases that may underlie any ergogenic effects are unclear. Healthy participants underwent 14 days of supplementation with 25 mg·day⁻¹T. chuii and placebo in a randomized, double-blind, crossover experimental design. Prior to and following each supplementation period, participants completed a high-intensity cycling test to assess time to exhaustion and peak oxygen uptake (${\dot{\mathrm{V}}\mathrm{O}}_{2\mathrm{peak}}$). A resting skeletal muscle biopsy was collected after both supplementation periods to assess gene expression changes. Compared to pre-supplementation values, ${\dot{\mathrm{V}}\mathrm{O}}_{2\mathrm{peak}}$ was increased following T. chuii (p = 0.013) but not placebo (p = 0.66). Fold-change in glutathione peroxidase 7 [(GPX7) 1.26 ± 1.37], glutathione-disulfide reductase [(GSR) 1.22 ± 1.41], glutathione S-transferase Mu 3 [(GSTM3) 1.34 ± 1.49], peroxiredoxin 6 [(PRDX6) 1.36 ± 1.57], extracellular signal-regulated kinase 3 [(ERK3) 1.92 ± 2.42], NRF2 (1.62 ± 2.16), p38 alpha [(p38a) 1.33 ± 1.58] and sirtuin 1 [(SIRT1) 1.73 ± 2.25] gene expression were higher after T. chuii compared to placebo supplementation (p < 0.05). Short-term T. chuii supplementation increased ${\dot{\mathrm{V}}\mathrm{O}}_{2\mathrm{peak}}$ and skeletal muscle gene expression of key enzymatic antioxidants (GPX7, GSR, GSTM3, and PRDX6), signalling kinases (ERK3 and p38a), post-translational regulators (SIRT1), and transcription factors (NRF2) that may protect against cellular stress insults. Full article

Osteoporosis is a prevalent metabolic bone disorder characterized by decreased bone mineral density and increased fracture risk, particularly among aging populations. While conventional pharmacological treatments exist, they often have adverse effects, necessitating the search for alternative therapies. Resveratrol, a naturally occurring polyphenol, has gained significant attention for its potential osteoprotective properties through various molecular mechanisms. This systematic review aims to comprehensively analyze the molecular pathways through which resveratrol protects against osteoporosis. Using an advanced search strategy in the Scopus, PubMed, and Web of Science databases, we identified 513 potentially relevant articles. After title and abstract screening, followed by full-text review, 28 studies met the inclusion criteria. The selected studies comprised 14 in vitro studies, 8 mixed in vitro and in vivo studies, 6 in vivo studies, and 1 cross-sectional study in postmenopausal women. Our findings indicate that resveratrol exerts its osteoprotective effects by enhancing osteoblast differentiation through the activation of the Phosphoinositide 3-Kinase/Protein Kinase B (PI3K/Akt), Sirtuin 1 (SIRT1), AMP-Activated Protein Kinase (AMPK), and GATA Binding Protein 1 (GATA-1) pathways while simultaneously inhibiting osteoclastogenesis by suppressing Mitogen-Activated Protein Kinase (MAPK) and TNF Receptor-Associated Factor 6/Transforming Growth Factor-β-Activated Kinase 1 (TRAF6/TAK1). Additionally, resveratrol mitigates oxidative stress and inflammation-induced bone loss by activating the Hippo Signaling Pathway/Yes-Associated Protein (Hippo/YAP) and Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) pathways and suppressing Reactive Oxygen Species/Hypoxia-Inducible Factor-1 Alpha (ROS/HIF-1α) and NADPH Oxidase 4/Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (Nox4/NF-κB). Despite promising preclinical findings, the low bioavailability of resveratrol remains a significant challenge, highlighting the need for novel delivery strategies to improve its therapeutic potential. This review provides critical insights into the molecular mechanisms of resveratrol in bone health, supporting its potential as a natural alternative for osteoporosis prevention and treatment. Further clinical studies are required to validate its efficacy and establish optimal dosing strategies. 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

Hepatocellular carcinoma (HCC) is a formidable challenge to global human health, while recent years have witnessed the important role of NAD+ in tumorigenesis and progression. However, the expression pattern and prognostic value of NAD+ in HCC still remain elusive. Gene expression files and corresponding clinical pathological files associated with HCC were obtained from the Cancer Genome Atlas (TCGA) database, and genes associated with NAD+ were retrieved from the GSEA and differentially analyzed in tumor and normal tissues. A consensus clustering analysis was conducted by breaking down TCGA patients into four distinct groups, while Kaplan–Meier curves were generated to investigate the disparity in clinical pathology and endurance between clusters. A prognostic model based on NAD+-associated genes was established and assessed by combining LASSO-Cox regression, uni- and multi-variate Cox regression, and ROC curve analyses. Investigations were conducted to determine the expression of distinct mRNAs and proteins in both HCC and non-tumor tissues. A novel two-gene signature including poly (ADP-Ribose) polymerase 2 (PARP2) and sirtuin 6 (SIRT6) was obtained through LASSO-Cox regression and was identified to have favorable prognostic performance in HCC patients from TCGA. Analyses of both single and multiple variables showed that the prognostic model was a distinct prognostic factor in the endurance of liver cancer patients in both the training and trial groups. The nomogram also exhibited clinical significance in the prognosis of HCC patients. Immunohistochemistry, qRT-PCR, and Western blotting revealed that HCC samples exhibited higher PARP2 and SIRT6 expression levels than those of normal controls. This study identified a robust prognostic model comprising two NAD+-associated genes using bioinformatic methods, which is accurate in predicting the survival outcome of HCC patients. This model might benefit the early diagnosis of HCC and further facilitate the management of individualized medical service and clinical decision-making. Full article

Background/Objectives: People living with HIV (PLWH) treated with combined antiretroviral therapy (cART) show a greater predisposition to metabolic and inflammatory disturbances compared to the general population. This study aimed to assess the effect of five years of cART use on the level of selected parameters related to carbohydrate and lipid metabolism and inflammation in PLWH compared to the uninfected. Methods: The levels of sirtuins (-1, -3, -6); irisin (IRS); myostatin (MSTN); peptide YY (PYY); glucagon-like peptide-1 (GLP-1); dipeptidyl peptidase IV (DPP-4); fetuin-A (FETU-A); pentraxin 3 (PTX3); chemokine stromal cell-derived factor 1 (SDF-1); regulated on activation, normal T cell expressed and presumably secreted (RANTES); and interleukins (-4, -7, -15) in the plasma of PLWH and a control group were evaluated by immunoassay methods. The results obtained after five years of antiretroviral therapy were compared with the levels obtained before and one year after cART. Results: Analysis of the parameters after five years of cART showed significantly higher levels in PLWH compared to the control group for SIRT-6, IRS, and IL-4 and significantly lower levels for RANTES and IL-7. There were significantly higher levels of SIRT-6, PYY, GLP-1, and PTX3 obtained after five years of cART compared to the results before therapy and after one year of cART. Conclusions: The results indicated changes occur in the expression of selected parameters during cART use in PLWH. Further research on the clinical usefulness of selected parameters and obtaining new information on the development of HIV-related comorbidities needs to be conducted. Full article

Anoikis, a form of apoptosis resulting from the loss of cell–extracellular matrix interaction, is a significant barrier to cancer cell metastasis. However, the epigenetic regulation of this process remains to be explored. Here, we demonstrate that the histone deacetylase sirtuin 6 (SIRT6) plays a pivotal role in conferring anoikis resistance to colorectal cancer (CRC) cells. The protein level of SIRT6 is negatively correlated with anoikis in CRC cells. The overexpression of SIRT6 decreases while the knockdown of SIRT6 increases detachment-induced anoikis. Mechanistically, SIRT6 inhibits the transcription of N-myc downstream-regulated gene 1 (NDRG1), a negative regulator of the AKT signaling pathway. We observed the up-regulation of SIRT6 in advanced-stage CRC samples. Together, our findings unveil a novel epigenetic program regulating the anoikis of CRC cells. Full article

Small-molecule positive allosteric modulator 1 (SPAM1), which targets pituitary adenylate cyclase-activating polypeptide receptor 1 (PAC1-R), has been found to have a neuroprotective effect, and the underlying mechanism was explored in this study. First, using a D-galactose (D-gal)-induced aging mouse model, we confirmed that SPAM1 improves the structure of the hippocampal dentate gyrus and restores the number of neurons. Compared with D-gal model mice, SPAM1-treated mice showed up-regulated expression of Sirtuin 6 (SIRT6) and Lamin B1 and down-regulated expression of YinYang 1 (YY1) and p16. A similar tendency was observed in senescent RGC-5 cells induced by long-term culture, indicating that SPAM1 exhibits significant in vitro and in vivo anti-senescence activity in neurons. Then, using whole-transcriptome sequencing and proteomic analysis, we further explored the mechanism behind SPAM1’s neuroprotective effects and found that SPAM is involved in the longevity-regulating pathway. Finally, the up-regulation of neurofilament light and medium polypeptides indicated by the proteomics results was further confirmed by Western blotting. These results help to lay a pharmacological network foundation for the use of SPAM1 as a potent anti-aging therapeutic drug to combat neurodegeneration with anti-senescence, neuroprotective, and nerve regeneration activity. Full article

Amyotrophic Lateral Sclerosis (ALS) is a progressive disease with prevalent mitochondrial dysfunctions affecting both upper and lower motor neurons in the motor cortex, brainstem, and spinal cord. Despite mitochondria having their own genome (mtDNA), in humans, most mitochondrial genes are encoded by the nuclear genome (nDNA). Our study aimed to simultaneously screen for nDNA and mtDNA genomes to assess for specific variant enrichment in ALS compared to control tissues. Here, we analysed whole exome (WES) and whole genome (WGS) sequencing data from spinal cord tissues, respectively, of 6 and 12 human donors. A total of 31,257 and 301,241 variants in nuclear-encoded mitochondrial genes were identified from WES and WGS, respectively, while mtDNA reads accounted for 73 and 332 variants. Despite technical differences, both datasets consistently revealed a specific enrichment of variants in the mitochondrial Control Region (CR) and in several of these genes directly associated with mitochondrial dynamics or with Sirtuin pathway genes within ALS tissues. Overall, our data support the hypothesis of a variant burden in specific genes, highlighting potential actionable targets for therapeutic interventions in ALS. Full article

Physiology disorders of the liver, as it is an important tissue in lipid metabolism, can cause fatty liver disease. The mechanism might be regulated by 17 circadian clock genes and 18 fat metabolism genes, together with a high-fat diet (HFD). Due to their rich nutritional and medicinal value, Chinese soft-shelled turtles (Trionyx sinensis) are very popular among the Chinese people. In the study, we aimed to investigate the influence of an HFD on the daily expression of both the core clock genes and the lipid metabolism genes in the liver tissue of the turtles. The two diets were formulated with 7.98% lipid (the CON group) and 13.86% lipid (the HFD group) to feed 180 juvenile turtles, which were randomly divided into two groups with three replicates per group and 30 turtles in each replicate for six weeks, and the diet experiment was administrated with a photophase regimen of a 24 h light/dark (12L:12D) cycle. At the end of the experiment, the liver tissue samples were collected from nine turtles per group every 3 h (zeitgeber time: ZT 0, 3, 6, 9, 12, 15, 18, 21 and 24) for 24 h to investigate the daily expression and correlation analysis of these genes. The results showed that 11 core clock genes [i.e., circadian locomotor output cycles kaput (Clock), brain and muscle arnt-like protein 1 and 2 (Bmal1/2), timeless (Tim), cryptochrome 1 (Cry2), period2 (Per2), nuclear factor IL-3 gene (Nfil3), nuclear receptor subfamily 1, treatment D, member 1 and 2 (Nr1d1/2) and retinoic acid related orphan receptor α/β/γ β and γ (Rorβ/γ)] exhibited circadian oscillation, but 6 genes did not, including neuronal PAS domain protein 2 (Npas2), Per1, Cry1, basic helix-loop-helix family, member E40 (Bhlhe40), Rorα and D-binding protein (Dbp), and 16 lipid metabolism genes including fatty acid synthase (Fas), diacylglycerol acyltransferase 1 (Dgat1), 3-hydroxy-3-methylglutaryl-CoA reductase (Hmgcr), Low-density lipoprotein receptor-related protein 1-like (Ldlr1), Lipin 1 (Lipin1), Carnitine palmitoyltransferase 1A (Cpt1a), Peroxisome proliferator activation receptor α, β and γ (Pparα/β/γ), Sirtuin 1 (Sirt1), Apoa (Apoa1), Apolipoprotein B (Apob), Pyruvate Dehydrogenase kinase 4 (Pdk4), Acyl-CoA synthase long-chain1 (Acsl1), Liver X receptors α (Lxrα) and Retinoid X receptor, α (Rxra) also demonstrated circadian oscillations, but 2 genes did not, Scd and Acaca, in the liver tissues of the CON group. However, in the HFD group, the circadian rhythms’ expressional patterns were disrupted for the eight core clock genes, Clock, Cry2, Per2, Nfil3, Nr1d1/2 and Rorβ/γ, and the peak expression of Bmal1/2 and Tim showed delayed or advanced phases. Furthermore, four genes (Cry1, Per1, Dbp and Rorα) displayed no diurnal rhythm in the CON group; instead, significant circadian rhythms appeared in the HFD group. Meanwhile, the HFD disrupted the circadian rhythm expressions of seven fat metabolism genes (Fas, Cpt1a, Sirt1, Apoa1, Apob, Pdk4 and Acsl1). Meanwhile, the other nine genes in the HFD group also showed advanced or delayed expression peaks compared to the CON group. Most importantly of all, there were remarkably positive or negative correlations between the core clock genes and the lipid metabolism genes, and their correlation relationships were altered by the HFD. To sum up, circadian rhythm alterations of the core clock genes and the lipid metabolism genes were induced by the high-fat diet (HFD) in the liver tissues of T. sinensis. This result provides experimental and theoretical data for the mass breeding and production of T. sinensis in our country. Full article

SIRT6 is a nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylase, predominantly located in the nucleus, that is involved in the processes of histone modification, DNA repair, cell cycle regulation, and apoptosis. Disturbances in SIRT6 expression levels have been observed in the development and progression of various types of cancer. Therefore, it is important to better understand the role of SIRT6 in biochemical pathways and assign it specific biological functions. This review aims to summarize the role of SIRT6 in carcinogenesis and tumor development. A better understanding of the factors influencing SIRT6 expression and its biological role in carcinogenesis may help to develop novel anti-cancer therapeutic strategies. Moreover, we discuss the anti-cancer effects and mechanism of action of small molecule SIRT6 modulators (both activators and inhibitors) in different types of cancer. Full article

Breast cancer (BC) is a heterogeneous condition and comprises molecularly distinct subtypes. An imbalance in the levels of epigenetic histone deacetylases (HDACs), modulating estrogen accumulation, especially 17β-estradiol (E2), promotes breast tumorigenesis. In the present study, analyses of The Cancer Genome Atlas (TCGA) pan-cancer normalized RNA-Seq datasets revealed the dysregulation of 16 epigenetic enzymes (among a total of 18 members) in luminal BC subtypes, in comparison to their non-cancerous counterparts. Explicitly, genomic profiling of these epigenetic enzymes displayed increases in HDAC1, 2, 8, 10, 11, and Sirtuins (SIRTs) 6 and 7, and decreases in HDAC4–7, –9, and SIRT1–4 levels, respectively, in TCGA breast tumors. Kaplan–Meier plot analyses showed that these HDACs, with the exception of HDAC2 and SIRT2, were not correlated with the overall survival of BC patients. Additionally, disruption of the epigenetic signaling in TCGA BC subtypes, as assessed using both heatmaps and boxplots, was associated with the genomic expression of factors that are instrumental for cholesterol trafficking/utilization for accelerating estrogen/E2 levels, in which steroidogenic acute regulatory protein (STAR) mediates the rate-limiting step in steroid biosynthesis. TCGA breast samples showed diverse expression patterns of a variety of key steroidogenic markers and hormone receptors, including LIPE, CYP27A1, STAR, STARD3, CYP11A1, CYP19A1, ER, PGR, and ERBB2. Moreover, regulation of STAR-governed steroidogenic machinery was found to be influenced by various transcription factors, i.e., CREB1, CREM, SF1, NR4A1, CEBPB, SREBF1, SREBF2, SP1, FOS, JUN, NR0B1, and YY1. Along these lines, ingenuity pathway analysis (IPA) recognized a number of new targets and downstream effectors influencing BCs. Of note, genomic, epigenomic, transcriptional, and hormonal anomalies observed in human primary breast tumors were qualitatively similar in pertinent BC cell lines. These findings identify the functional correlation between dysregulated epigenetic enzymes and estrogen/E2 accumulation in human breast tumors, providing the molecular insights into more targeted therapeutic approaches involving the inhibition of HDACs for combating this life-threatening disease. Full article

The kidney plays a crucial role in glucose homeostasis by regulating glucose transport. We aimed to investigate the impact of alterations in glucose transport on glucose metabolism during ageing. Adult male Sprague Dawley rats were divided into five groups: 3-month, 6-month, and 12-month control groups, and 6- and 12-month groups receiving the hydrogen sulfide donor molecule GYY4137. The study found that, as age increased, daily urinary uric acid and protein levels increased in the 12-month group. Blood sugar level and HOMA-IR index increased in the 12-month group, and were partially improved by GYY4137. The kidney tissue showed mild glomerulosclerosis in the 12-month group, which was diminished by GYY4137. Gene expression analysis showed decreased sirtuin and increased p21 expression in the aging groups. Increased SGLT1 and SGLT2 expression was observed in the 12-month group, which was reversed by GYY4137. Both GLUT1 and GLUT2 expression was increased in the 6- and 12-month groups, and reversed by GYY4137 in the 12-month group. The study concluded that aging was associated with increased blood sugar levels and the HOMA-IR index, and the abundance of renal glucose transporters increased as aging progressed. GYY4137 effectively reversed aging-related alterations in glucose homeostasis and renal epithelial transporters. Full article

Aging is an independent risk factor for recurrent tearing after surgical repair of rotator cuff ruptures around the tendon-to-bone area. However, aging signature factors and related mechanisms involved in the healing of the rotator cuff are still unknown. We hypothesized that differences in proteins involved in the rotator cuff according to age may affect tendon-to-bone healing. The proteome analysis performed to identify the signature aging proteins of the rotator cuff confirmed the sirtuin signal as an age-specific protein. In particular, the expression of SIRT6 was markedly down-regulated with age. Ingenuity pathway analysis of omics data from age-dependent rat rotator cuffs and linear regression from human rotator cuffs showed SIRT6 to be closely related to the Wnt/β-catenin signal. We confirmed that overexpression of SIRT6 in the rotator cuff and primary tenocyte regulated canonical Wnt signaling by inhibiting the transcriptional expression of sclerostin, a Wnt antagonist. Finally, SIRT6 overexpression promoted tendon-to-bone healing after tenotomy with reconstruction in elderly rats. This approach is considered an effective treatment method for recovery from recurrent rotator cuff tears, which frequently occur in the elderly. Full article

Histone deacetylase Sirtuin 6 (SIRT6) regulates many biological processes. SIRT6 is known to regulate hepatic lipid metabolism and inhibit the development of nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the role of hepatocyte SIRT6 in the development of atherosclerosis and further characterize the mechanism underlying SIRT6’s effect on NAFLD. Ldlr^−/− mice overexpressing or lacking hepatocyte SIRT6 were fed a Western diet for 16 weeks. The role of hepatic SIRT6 in the development of nonalcoholic steatohepatitis (NASH), atherosclerosis, and obesity was investigated. We also investigated whether p53 participates in the pathogenesis of NAFLD in mice overexpressing hepatic SIRT6. Our data show that loss of hepatocyte SIRT6 aggravated the development of NAFLD, atherosclerosis, and obesity in Ldlr^−/− mice, whereas adeno-associated virus (AAV)-mediated overexpression of human SIRT6 in the liver had opposite effects. Mechanistically, hepatocyte SIRT6 likely inhibited the development of NAFLD by inhibiting lipogenesis, lipid droplet formation, and p53 signaling. Hepatocyte SIRT6 also likely inhibited the development of atherosclerosis by inhibiting intestinal lipid absorption and hepatic VLDL secretion. Hepatic SIRT6 also increased energy expenditure. In conclusion, our data indicate that hepatocyte SIRT6 protects against atherosclerosis, NAFLD, and obesity by regulating lipid metabolism in the liver and intestine. Full article

Sirtuins, in mammals, are a group of seven enzymes (SIRT1–SIRT7) involved in the post-translational modification of proteins—they are considered longevity proteins. SIRT6, classified as class IV, is located on the cell nucleus; however, its action is also connected with other regions, e.g., mitochondria and cytoplasm. It affects many molecular pathways involved in aging: telomere maintenance, DNA repair, inflammatory processes or glycolysis. A literature search for keywords or phrases was carried out in PubMed and further searches were carried out on the ClinicalTrials.gov website. The role of SIRT6 in both premature and chronological aging has been pointed out. SIRT6 is involved in the regulation of homeostasis—an increase in the protein’s activity has been noted in calorie-restriction diets and with significant weight loss, among others. Expression of this protein is also elevated in people who regularly exercise. SIRT6 has been shown to have different effects on inflammation, depending on the cells involved. The protein is considered a factor in phenotypic attachment and the migratory responses of macrophages, thus accelerating the process of wound healing. Furthermore, exogenous substances will affect the expression level of SIRT6: resveratrol, sirtinol, flavonoids, cyanidin, quercetin and others. This study discusses the importance of the role of SIRT6 in aging, metabolic activity, inflammation, the wound healing process and physical activity. Full article