Dynamic changes in maternal‒zygotic transition (MZT) require complex regulation of zygote formation, maternal transcript decay, embryonic genome activation (EGA), and cell cycle progression. Although these changes are well described, some key regulatory factors are still elusive. Sirtuin-1 (SIRT1), an NAD+-dependent histone deacetylase, is a versatile driver of MZT via its epigenetic and nonepigenetic substrates. This study focused on the dynamics of SIRT1 in early embryos and its contribution to MZT. A conditional SIRT1-deficient knockout mouse model was used, accompanied by porcine and human embryos. Embryos across mammalian species showed the prominent localization of SIRT1 in the nucleus throughout early embryonic development. Accordingly, SIRT1 interacts with histone H4 on lysine K16 (H4K16) in both mouse and human blastocysts. While maternal SIRT1 is dispensable for MZT, at least one allele of embryonic Sirt1 is required for early embryonic development around the time of EGA. This role of SIRT1 is surprisingly mediated via a transcription-independent mode of action.
- MeSH
- blastocysta metabolismus MeSH
- embryo savčí metabolismus MeSH
- embryonální vývoj * genetika MeSH
- histony metabolismus MeSH
- lidé MeSH
- myši knockoutované * MeSH
- myši MeSH
- prasata MeSH
- sirtuin 1 * metabolismus genetika MeSH
- vývojová regulace genové exprese MeSH
- zvířata MeSH
- zygota * metabolismus MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Exercise can improve the cardiovascular health. However, the mechanism contributing to its beneficial effect on elderly patients with myocardial infarction is obscure. 20-month-old male Sprague-Dawley rats were used to establish myocardial infarction (MI) model by permanent ligation of the left anterior descending coronary artery (LAD) of the heart, followed by 4-week interval exercise training on a motor-driven rodent treadmill. The cardiac function, myocardial fibrosis, apoptosis, oxidative stress, and inflammatory responses were determined by using pressure transducer catheter, polygraph physiological data acquisition system, Masson's trichrome staining, and ELISA to evaluate the impact of post-MI exercise training on MI. Western blot were performed to detect the activation of AMPK/SIRT1/PGC-1alpha signaling in the hearts of aged rats. Exercise training significantly improved cardiac function and reduced the cardiac fibrosis. In infarcted heart, the apoptosis, oxidative stress, and inflammation were significantly reduced after 4-week exercise training. Mechanistically, AMPK/SIRT1/PGC-1alpha pathway was activated in the myocardial infarction area after exercise training, which might participate in the protection of cardiac function. Exercise training improves cardiac function in MI rats through reduction of apoptosis, oxidative stress, and inflammation, which may mediate by the activation of AMPK/SIRT1/PGC-1alpha signaling pathway.
- MeSH
- infarkt myokardu * metabolismus MeSH
- kondiční příprava zvířat * fyziologie MeSH
- krysa rodu rattus MeSH
- modely nemocí na zvířatech MeSH
- myokard metabolismus MeSH
- potkani Sprague-Dawley MeSH
- proteinkinasy aktivované AMP metabolismus MeSH
- sirtuin 1 metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Regular physical exercise is beneficial to the body. Acute exercise causes oxidant stress in many tissues including the liver by creating an unbalanced status between oxidant and antioxidant levels. Analgesic drugs are commonly consumed to reduce the pain after exercise. Acetaminophen (APAP), commonly used as an over-the-counter analgesic, can cause hepatotoxicity. The aim of this study was to investigate the effect and underlying mechanisms of APAP at subtoxic dose, which is given after the acute and exhaustive exercise on the rat livers. Male Wistar rats weighing 200-250 g were divided into 6 groups each consisting of 7 rats/group; Control, APAP (250 mg/kg, ip), Acute Exercise (AEx), Acute Exhaustive Exercise (AEEx), Acute Exercise and APAP (AEx+APAP) and Acute Exhaustive Exercise and APAP (AEEx+APAP) groups. Rats were exercised at moderate intensity or exhaustive on the treadmill and then received APAP. Tissue MDA levels were significantly increased in AEEx, AEx+APAP and AEEx+APAP groups compared with the control. There was no significant difference in GSH levels between groups. Tissue Sirtuin1 (Sirt1) levels of APAP, AEx and AEEx groups were significantly less than control. There was no significant difference between groups in VEGF levels. Liver damage score was significantly higher in all groups compared with control group. As a result, this study shows that subtoxic dose of APAP treatment alone or in combination with acute or exhaustive treadmill exercise can cause oxidative liver damage by affecting Sirt1 levels and without affecting VEGF levels.
- MeSH
- analgetika metabolismus MeSH
- játra metabolismus MeSH
- krysa rodu rattus MeSH
- lékové postižení jater * etiologie prevence a kontrola metabolismus MeSH
- oxidační stres MeSH
- oxidancia MeSH
- paracetamol * toxicita MeSH
- potkani Wistar MeSH
- sirtuin 1 metabolismus MeSH
- vaskulární endoteliální růstový faktor A metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Cancer cells have a special energy metabolism that enables them to multiply quickly. Under normal oxygen conditions, the Warburg effect is a distinguishing aspect of cancer metabolism in which anaerobic glycolysis is favored. Enhanced glycolysis also helps to produce nucleotides, amino acids, lipids, and folic acid, all of which are necessary for cancer cell division. In a variety of metabolic processes, including glycolysis, the co-enzyme nicotinamide adenine dinucleotide (NAD) mediates redox reactions. NAD levels that are higher promote glycolysis and supply energy to cancer cells. NAD metabolism, like energy metabolism, is linked in cancer genesis and could be a potential therapeutic target for cancer treatment. In this research, NAD-consuming enzymes, poly(ADP-ribose) polymerase (PARP) and SIRT1, have been investigated in breast cancer patients, in addition to detect the levels of serum malondialdehyde (MDA), superoxide dismutase (SOD) and vitamin K levels. Sixty participants were enrolled in this study, 30 women with breast cancer and 30 controls. Serum were analysed for determination of the levels of PARP1, SIRT1, MDA, SOD, and vitamin K. The results showed a drop in the expression levels of PARP and that was concomitant with the elevation in the expression levels of SIRT1 and MDA, in addition to the drop in SOD and vitamin K levels. These findings suggest that SIRT1 might be the most NAD-consuming enzyme in cancerous cells rather than PARP (the DNA repair enzyme), and this increase in MDA with the drop in SOD and vitamin K might be associated with the increase in cell proliferation and a decrease in apoptotic cell death. Finally, this study could be used as a treatment option for patients with breast cancer. could be used as a treatment option for patients with breast cancer.
- MeSH
- klinické laboratorní techniky metody MeSH
- lidé MeSH
- NAD metabolismus MeSH
- nádorové biomarkery analýza MeSH
- nádory prsu * diagnóza patologie MeSH
- poly-ADP-ribóza-polymeráza 1 analýza metabolismus MeSH
- sirtuin 1 analýza metabolismus MeSH
- superoxiddismutasa analýza metabolismus MeSH
- vitamin K analýza MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- klinická studie MeSH
Lysine deacetylases, like histone deacetylases (HDACs) and sirtuins (SIRTs), are involved in many regulatory processes such as control of metabolic pathways, DNA repair, and stress responses. Besides robust deacetylase activity, sirtuin isoforms SIRT2 and SIRT3 also show demyristoylase activity. Interestingly, most of the inhibitors described so far for SIRT2 are not active if myristoylated substrates are used. Activity assays with myristoylated substrates are either complex because of coupling to enzymatic reactions or time-consuming because of discontinuous assay formats. Here we describe sirtuin substrates enabling direct recording of fluorescence changes in a continuous format. Fluorescence of the fatty acylated substrate is different when compared to the deacylated peptide product. Additionally, the dynamic range of the assay could be improved by the addition of bovine serum albumin, which binds the fatty acylated substrate and quenches its fluorescence. The main advantage of the developed activity assay is the native myristoyl residue at the lysine side chain avoiding artifacts resulting from the modified fatty acyl residues used so far for direct fluorescence-based assays. Due to the extraordinary kinetic constants of the new substrates (KM values in the low nM range, specificity constants between 175,000 and 697,000 M-1s-1) it was possible to reliably determine the IC50 and Ki values for different inhibitors in the presence of only 50 pM of SIRT2 using different microtiter plate formats.
AIM: Currently available medicines have little to offer in terms of supporting the regeneration of injured hepatic cells. Previous experimental studies have shown that resveratrol and metformin, less specific activators of AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), can effectively attenuate acute liver injury. The aim of this experimental study was to elucidate whether modulation of AMPK and SIRT1 activity can modify drug/paracetamol (APAP)-induced hepatocyte damage in vitro. METHODS: Primary rat hepatocytes were pretreated with mutual combinations of specific synthetic activators and inhibitors of SIRT1 and AMPK and followed by a toxic dose of APAP. At the end of cultivation, medium samples were collected for biochemical analysis of alanine-aminotransferase and nitrite levels. Hepatocyte viability, thiobarbituric reactive substances, SIRT1 and AMPK activity and protein expression were also assessed. RESULTS: The harmful effect of APAP was associated with decreased AMPK and SIRT1 activity and protein expression alongside enhanced oxidative stress in hepatocytes. The addition of AMPK activator (AICAR) or SIRT1 activator (CAY10591) significantly attenuated the deleterious effects of AMPK inhibitor (Compound C) on the hepatotoxicity of APAP. Furthermore, CAY10591 but not AICAR markedly decreased the deleterious effect of APAP in combination with SIRT1 inhibitor (EX-527). CONCLUSION: Our findings demonstrate that decreased AMPK activity is associated with the hepatotoxic effect of APAP which can be significantly attenuated by the administration of a SIRT1 activator. These findings suggest that differentiated modulation of AMPK and SIRT1 activity could therefore provide an interesting and novel therapeutic opportunity in the future to combat hepatocyte injury.
- MeSH
- cyklopentany farmakologie MeSH
- hepatocyty * metabolismus MeSH
- krysa rodu rattus MeSH
- lékové postižení jater * etiologie genetika metabolismus patologie MeSH
- paracetamol toxicita MeSH
- proteinkinasy aktivované AMP * chemie metabolismus farmakologie MeSH
- sirtuin 1 * metabolismus farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The involvement of the mTOR system/enzyme sirtuin 1 (SIRT1) intracellular signaling system in the control of ovarian functions and its role in mediating hormonal action on the ovary has been proposed, but this hypothesis should be supported by a demonstrated influence of hormones on mTOR/SIRT1. Therefore, the aim of our in vitro experiments was to examine the effect of the known hormonal regulators of ovarian functions, such as follicle-stimulating hormone (FSH), oxytocin (OT) and insulin-like growth factor I (IGF-I), on mTOR/SIRT1. The accumulation of SIRT1 in porcine ovarian granulosa cells cultured with and without these hormones (at doses of 1, 10 or 100 ng.ml-1) was evaluated using immunocytochemistry. It was observed that the addition of FSH (at 10 ng.ml-1 but not at 1 or 100 ng/ml) and OT (at all tested doses) increased the expression of SIRT1 in ovarian cells. In addition, 100 ng.ml-1, but not at 1 or 10 ng.ml-1, of IGF-I decreased SIRT1 accumulation. Our observations are the first demonstration that hormones can directly regulate the ovarian mTOR/SIRT1 system and that this system could mediate the action of hormonal regulators on the ovary.
- MeSH
- apoptóza účinky léků MeSH
- folikulární buňky cytologie účinky léků metabolismus MeSH
- folikuly stimulující hormon farmakologie MeSH
- insulinu podobný růstový faktor I farmakologie MeSH
- kultivované buňky MeSH
- ovarium cytologie účinky léků metabolismus MeSH
- oxytocin farmakologie MeSH
- prasata MeSH
- proliferace buněk účinky léků MeSH
- sirtuin 1 biosyntéza genetika metabolismus MeSH
- uterotonika farmakologie MeSH
- zvířata MeSH
- Check Tag
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
This article is directed at highlighting the involvement of the endogenous stress sensor SIRT1 (silent information regulator T1) as a possible factor involved in hepatoprotection. The selective SIRT1 modulators whether activators (STACs) or inhibitors are being tried experimentally and clinically. We discuss the modulation of SIRT1 on cytoprotection or even cytotoxicity in the liver chemically injured by hepatotoxic agents in rats, to shed light on the crosstalk between SIRT1 and its modulators. A combination of D-galactosamine and lipopolysaccharide (D-GalN/LPS) downregulated SIRT1 expression, while SIRT1 activators, SRT1720, resveratrol, and quercetin, upregulated SIRT1 and alleviated D-GalN/LPS-induced acute hepatotoxicity. Liver injury markers exhibited an inverse relationship with SIRT1 expression. However, under subchronic hepatotoxicity, quercetin decreased the significant increase in SIRT1 expression to lower levels which are still higher than normal ones and mitigated the liver-damaging effects of carbon tetrachloride. Each of these STACs was hepatoprotective and returned the conventional antioxidant enzymes to the baseline. Polyphenols tend to fine-tune SIRT1 expression towards normal in the liver of intoxicated rats in both acute and subchronic studies. Together, all these events give an impression that the cytoprotective effects of SIRT1 are exhibited within a definite range of expression. The catalytic activity of SIRT1 is important in the hepatoprotective effects of polyphenols where SIRT1 inhibitors block and the allosteric SIRT1 activators mimic the hepatoprotective effects of polyphenols. Our findings indicate that the pharmacologic modulation of SIRT1 could represent both an important move in alleviating hepatic insults and a future major step in the treatment of xenobiotic-induced hepatotoxicity.
- MeSH
- lékové postižení jater farmakoterapie enzymologie MeSH
- lidé MeSH
- polyfenoly farmakologie MeSH
- sirtuin 1 antagonisté a inhibitory metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Hyperbaric oxygen preconditioning (HBO-PC) has been proposed as a safe and practical approach for neuroprotection in ischemic stroke. However, it is not known whether HPO-PC can improve cognitive deficits induced by cerebral ischemia, and the mechanistic basis for any beneficial effects remains unclear. We addressed this in the present study using rats subjected to middle cerebral artery occlusion (MCAO) as an ischemic stroke model following HBO-PC. Cognitive function and expression of phosphorylated neurofilament heavy polypeptide (pNF-H) and doublecortin (DCX) in the hippocampus were evaluated 14 days after reperfusion and after short interfering RNA-mediated knockdown of sirtuin1 (Sirt1). HBO-PC increased pNF-H and DCX expression and mitigated cognitive deficits in MCAO rats. However, these effects were abolished by Sirt1 knockdown. Our results suggest that HBO-PC can protect the brain from injury caused by ischemia-reperfusion and that Sirt1 is a potential molecular target for therapeutic approaches designed to minimize cognitive deficits caused by cerebral ischemia.
- MeSH
- časové faktory MeSH
- chování zvířat * MeSH
- fosforylace MeSH
- hipokampus enzymologie patofyziologie MeSH
- hyperbarická oxygenace * MeSH
- infarkt arteria cerebri media enzymologie patofyziologie psychologie terapie MeSH
- kognice * MeSH
- kognitivní poruchy enzymologie patofyziologie prevence a kontrola psychologie MeSH
- modely nemocí na zvířatech MeSH
- neurofilamentové proteiny metabolismus MeSH
- neuropeptidy metabolismus MeSH
- potkani Sprague-Dawley MeSH
- proteiny asociované s mikrotubuly metabolismus MeSH
- RNA interference MeSH
- sirtuin 1 genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The present study was designed to evaluate the therapeutic potential of quercetin in a sub-chronic model of hepatotoxicity. The roles of putative antioxidant enzymes, sirtuin 1 (SIRT1) and heme oxygenase 1 (HO-1), in hepatoprotection were also addressed. Sub-chronic liver injury was induced in rats by intraperitoneal administration of 0.5 ml/kg carbon tetrachloride (CTC), once every 3 days, for 2 weeks. Some CTC rats were concurrently treated with 100 mg/kg quercetin, intragastrically, once every day, for 2 weeks. The effects of these drugs in the liver were evaluated by biochemical, histological, immunohistochemical and molecular biological studies. CTC triggered oxidative damage to the liver as unanimously shown by altered biochemical parameters and liver morphology. Furthermore, CTC highly upregulated HO-1 and SIRT1 expression levels. Concomitant treatment of rats with quercetin downregulated SIRT1 expression and ameliorated the hepatotoxic effects of CTC. However, quercetin did not have any significant effect on HO-1 expression and bilirubin levels. Collectively, these results suggest that the antioxidant and cytoprotective effects of quercetin in CTC treated rats were SIRT1 mediated and less dependent on HO-1. Thus, pharmacologic modulation of SIRT1 could provide a logic therapeutic approach in sub-chronic hepatotoxicity.
- MeSH
- alanintransaminasa krev MeSH
- aspartátaminotransferasy krev MeSH
- bilirubin krev MeSH
- down regulace účinky léků MeSH
- hemoxygenasa-1 metabolismus MeSH
- imunohistochemie MeSH
- játra metabolismus patologie MeSH
- krysa rodu rattus MeSH
- ochranné látky farmakologie MeSH
- otrava chloridem uhličitým metabolismus patologie prevence a kontrola MeSH
- potkani Wistar MeSH
- quercetin farmakologie MeSH
- sirtuin 1 metabolismus MeSH
- upregulace účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
