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.

• Klíčová slova
• bovine serum albumin effect, continuous activity assay, fluorescence quenching, histone deacetylases, myristoylated substrates, sirtuin inhibitors, sirtuins,
• MeSH
• barvicí látky MeSH
• lysin MeSH
• peptidy MeSH
• sirtuin 1 metabolismus   MeSH
• sirtuin 2 metabolismus   MeSH
• sirtuin 3 * metabolismus   MeSH
• sirtuiny * metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• barvicí látky MeSH
• lysin MeSH
• peptidy MeSH
• sirtuin 1 MeSH
• sirtuin 2 MeSH
• sirtuin 3 * MeSH
• sirtuiny * MeSH

Histone deacylase 11 and human sirtuins are able to remove fatty acid-derived acyl moieties from the ε-amino group of lysine residues. Specific substrates are needed for investigating the biological functions of these enzymes. Additionally, appropriate screening systems are required for identification of modulators of enzymatic activities of HDAC11 and sirtuins. We designed and synthesized a set of activity probes by incorporation of a thioamide quencher unit into the fatty acid-derived acyl chain and a fluorophore in the peptide sequence. Systematic variation of both fluorophore and quencher position resulted "super-substrates" with catalytic constants of up to 15,000,000 M-1s-1 for human sirtuin 2 (Sirt2) enabling measurements using enzyme concentrations down to 100 pM in microtiter plate-based screening formats. It could be demonstrated that the stalled intermediate formed by the reaction of Sirt2-bound thiomyristoylated peptide and NAD+ has IC50 values below 200 pM.

• Klíčová slova
• HDAC11 assay, Histone deacetylase (HDAC) inhibitor, Microtiter plate-based screening, Photoinduced electron transfer quenching, Sirtuin assay, Thioamide,
• MeSH
• fluorescenční barviva chemie   farmakologie   MeSH
• fotochemické procesy MeSH
• histondeacetylasy chemie   genetika   metabolismus   MeSH
• lidé MeSH
• molekulární struktura MeSH
• pozitronová emisní tomografie * MeSH
• sirtuiny antagonisté a inhibitory   chemie   metabolismus   MeSH
• thioamidy chemie   farmakologie   MeSH
• transport elektronů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fluorescenční barviva MeSH
• histondeacetylasy MeSH
• sirtuiny MeSH
• thioamidy MeSH

Class IV sirtuin (SIRT6 and SIRT7) played essential roles in biometabolism processes via deacetylating specific transcription factors. The present study was conducted to search for mutations in SIRT6/7 and determine their associations with growth traits in black Tibetan sheep. Via DNA sequencing methods, three single-nucleotide polymorphisms (SNPs) were identified in 427 ewes, including a mutation (g.3724C > T) in the intron 1 of SIRT6 and two mutations (g.3668G > T and g.4223C > G) in SIRT7 intron 6 and 8, respectively. Based on the χ2 test, both g.3724C > T and g.4223C > G loci fitted with Hardy-Weinberg equilibrium (p > 0.05). Compared with animals with genotype TT, the CC genotype at g.3724C > T locus (SIRT6) exhibited the highest mean for body weight (p < 0.05) and heart girth (p < 0.05). At g.3668G > T locus (SIRT7), individuals carrying the GG genotype tended to have heavier body weight than those of TT genotype (p < 0.05). With the exception of body weight, body measurement traits not affected by combinative genotype (p > 0.05). Our results could be used as genetic markers for marker-assisted selection and maybe guide sheep breeding in economic traits.

• Klíčová slova
• Black Tibetan sheep, SIRT6, SIRT7, combined genotype, growth traits,
• MeSH
• fenotyp MeSH
• genotyp MeSH
• jednonukleotidový polymorfismus MeSH
• ovce * genetika   růst a vývoj   MeSH
• sirtuiny * genetika   MeSH
• tělesná hmotnost genetika   MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Tibet MeSH
• Názvy látek
• SIRT6 protein, human MeSH Prohlížeč
• sirtuiny * MeSH

A vast collection of data obtained during the last decade supports the view on sirtuins as sensors of actual cellular metabolic state being involved in cell cycle progression, apoptosis/survival decision making, longevity, inflammation etc. Moreover, sirtuins themselves can control metabolism through their ability to consume NAD(+). In turn, cellular NAD parameters may affect the generation of ATP, a main cellular currency of energy. Therefore, sirtuins became recognized as critical affectors of cellular metabolism which participate in fat mobilization, gluconeogenesis, caloric restriction etc. Cellular senescence is viewed as a mechanism to restrict excessive cell growth when it is unnecessary or harmful. It is therefore necessary to understand the mechanism of senescence to design new approaches to combat cancer. Growth in turn depends on metabolism as it requires energy. Therefore, in this review, we address the connection of sirtuins to senescence through their participation in the regulation of metabolic and biochemical parameters and related signaling.

• MeSH
• antiflogistika nesteroidní farmakologie   MeSH
• lidé MeSH
• NAD metabolismus   MeSH
• resveratrol MeSH
• signální transdukce * MeSH
• sirtuiny účinky léků   metabolismus   MeSH
• stárnutí * účinky léků   MeSH
• stilbeny farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• antiflogistika nesteroidní MeSH
• NAD MeSH
• resveratrol MeSH
• sirtuiny MeSH
• stilbeny MeSH

Sirtuin activating compounds (STACs) attenuate various type of liver insults through mechanisms which are not fully understood. In the present study, we investigated the ameliorative potential of quercetin (natural polyphenol) and SRT1720 (synthetic SIRT1 activator) against D-galactosamine/lipopolysaccharide-induced hepatotoxicity (an experimental model of acute liver failure). Moreover, we compared and contrasted the roles of stress responsive enzymes, sirtuin 1 (SIRT1) and heme oxygenase 1 (HO-1) in hepatoprotection/ hepatotoxicity. Liver injury was induced in male Wistar rats by intraperitoneal injection of D-galactosamine (400 mg/kg) and lipopolysaccharide (10 microg/kg). Some animals were pretreated with quercetin (50 mg/kg i.p.) or SRT1720 (5 mg/kg i.p.). Twenty-four hours later, the effects of these treatments were evaluated by biochemical studies and Western blot. D-GalN/LPS treatment upregulated HO-1 expression, downregulated SIRT1 expression, decreased AST: ALT ratio and markedly increased bilirubin, catalase and conjugated diene levels. Pretreatment of D-GalN/LPS rats with either quercetin or SRT1720 returned SIRT1 expression, HO-1 expression and all the aforementioned markers towards normal. Collectively, these findings suggest that elevated HO-1 and low SIRT1 expressions are involved in the pathogenesis of D-GalN/LPS-induced hepatotoxicity. Drugs that downregulate HO-1 and/or upregulate SIRT1 seem to have antihepatotoxic effects and need further exploration.

• MeSH
• galaktosamin toxicita   MeSH
• hemová oxygenasa (decyklizující) antagonisté a inhibitory   metabolismus   MeSH
• heterocyklické sloučeniny tetra- a více cyklické farmakologie   terapeutické užití   MeSH
• krysa rodu Rattus MeSH
• lékové postižení jater farmakoterapie   metabolismus   MeSH
• lipopolysacharidy toxicita   MeSH
• náhodné rozdělení MeSH
• potkani Wistar MeSH
• sirtuin 1 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• galaktosamin MeSH
• hemová oxygenasa (decyklizující) MeSH
• heterocyklické sloučeniny tetra- a více cyklické MeSH
• Hmox1 protein, rat MeSH Prohlížeč
• lipopolysacharidy MeSH
• Sirt1 protein, rat MeSH Prohlížeč
• sirtuin 1 MeSH
• SRT1720 MeSH Prohlížeč

BACKGROUND AND PURPOSE: N-methyl-d-aspartate receptor (NMDAR) and leucine-rich glioma-inactivated protein 1 (LGI1) encephalitis are important types of autoimmune encephalitis (AE) with significant morbidity. In this study, we used a proteomic approach in search of novel clinically relevant biomarkers in these types of encephalitides. METHODS: Swedish and Czech tertiary neuroimmunology centers collaborated in this retrospective exploratory study. Fifty-eight cerebrospinal fluid (CSF) samples of 28 patients with AE (14 definite NMDAR, 14 with definite LGI1 encephalitis) and 30 controls were included. CSF samples were analyzed using proximity extension assay technology (Olink Target 96 Inflammation panel). For each CSF sample, 92 proteins were measured. Clinical variables were retrospectively collected, and correlations with protein levels were statistically analyzed. RESULTS: Patients and controls differed significantly in the following 18 biomarkers: TNFRSF9, TNFRSF12, TNFRSF14, TNFβ, TNFα, IL7, IL10, IL12B, IFNγ, CD5, CD6, CASP8, MMP1, CXCL8, CXCL10, CXCL11, IL20RA, and sirtuin 2 (SIRT2). In LGI1 encephalitis, no clinically useful association was found between biomarkers and clinical variables. In the NMDAR encephalitis group, SIRT2, TNFβ, and CD5 were significantly associated with ovarian teratoma. For SIRT2, this was true even for the first patients' CSF sample (SIRT2 without vs. with tumor, mean ± SD = 2.2 ± 0.29 vs. 2.88 ± 0.48; p = 0.007, 95% confidence interval = -1.15 to -0.22; r statistic in point-biserial correlation (rpb) = 0.66, p = 0.011). SIRT2 was positively correlated with age (rpb = 0.39, p = 0.018) and total hospital days (r = 0.55, p = <0.001). CONCLUSIONS: SIRT2 should be investigated as a biomarker of paraneoplastic etiology in NMDAR encephalitis.

• Klíčová slova
• anti-N-methyl-d-aspartate receptor encephalitis, encephalitis, limbic encephalitis, paraneoplastic syndromes, sirtuin 2,
• MeSH
• autoprotilátky MeSH
• biologické markery mozkomíšní mok   MeSH
• encefalitida s protilátkami proti NMDA receptorům * mozkomíšní mok   MeSH
• encefalitida MeSH
• Hashimotova nemoc MeSH
• lidé MeSH
• novorozenec MeSH
• proteomika MeSH
• retrospektivní studie MeSH
• sirtuin 2 MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• autoprotilátky MeSH
• biologické markery MeSH
• SIRT2 protein, human MeSH Prohlížeč
• sirtuin 2 MeSH

D-Galactosamine/Lipopolysaccharide (D-GalN/LPS) is a well known model of hepatotoxicity that closely resembles acute liver failure (ALF) seen clinically. The role of sirtuin 1 in this model has not yet been documented. However, there have been a number of studies about the cytoprotective effects of resveratrol, a SIRT1 activator, in the liver. This study was aimed at elucidating the roles of SIRT1 protein expression or catalytic activity in D-GalN/LPS model of hepatotoxicity. ALF was induced in male Wistar rats by intraperitoneal injection of D-GalN and LPS. Some groups of animals were pretreated with resveratrol and/or EX-527 (SIRT1 inhibitor). The effects of these treatments were evaluated by biochemical and Western blot studies. D-GalN/LPS treatment was able to induce hepatotoxicity and significantly increase all markers of liver damage and lipid peroxidation. A dramatic decrease of SIRT1 levels in response to D-GalN/LPS treatment was also documented. Resveratrol pretreatment attenuated D-GalN/LPS-induced hepatotoxicity. EX-527 blocked the cytoprotective effects of resveratrol. However, both resveratrol and EX-527 pretreatments did not exhibit any significant effect on SIRT1 protein expression. Collectively, these results suggest that downregulation of SIRT1 expression is involved in the cytotoxic effects of D-GalN/LPS model and SIRT1 activity contributes to the cytoprotective effects of resveratrol in the liver.

• MeSH
• antioxidancia farmakologie   MeSH
• cytoprotekce MeSH
• down regulace MeSH
• galaktosamin * MeSH
• inhibitory enzymů farmakologie   MeSH
• játra účinky léků   enzymologie   patologie   MeSH
• karbazoly farmakologie   MeSH
• lékové postižení jater enzymologie   etiologie   patologie   prevence a kontrola   MeSH
• lipopolysacharidy * MeSH
• modely nemocí na zvířatech MeSH
• peroxidace lipidů účinky léků   MeSH
• potkani Wistar MeSH
• resveratrol MeSH
• sirtuin 1 antagonisté a inhibitory   metabolismus   MeSH
• stilbeny farmakologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide MeSH Prohlížeč
• antioxidancia MeSH
• galaktosamin * MeSH
• inhibitory enzymů MeSH
• karbazoly MeSH
• lipopolysacharidy * MeSH
• resveratrol MeSH
• Sirt1 protein, rat MeSH Prohlížeč
• sirtuin 1 MeSH
• stilbeny MeSH

Sirtuin 1 (SIRT1) is involved in important biological processes such as energy metabolism and regulatory functions of the cell cycle, apoptosis, and inflammation. Our previous studies have shown hepatoprotective effect of polyphenolic compound resveratrol, which is also an activator of SIRT1. Therefore, the aim of our present study was to clarify the role of SIRT1 in process of hepatoprotection in animal model of drug-induced liver damage. Male Wistar rats were used for both in vivo and in vitro studies. Hepatotoxicity was induced by single dose of acetaminophen (APAP). Some rats and hepatocytes were treated by resveratrol or synthetic selective activator of sirtuin 1 (CAY10591). The degree of hepatotoxicity, the activity and expression of the SIRT1 were determined by biochemical, histological and molecular-biological assessments of gained samples (plasma, liver tissue, culture media and hepatocytes). Resveratrol and CAY attenuated APAP-induced hepatotoxicity in vivo and in vitro. Moreover, both drugs enhanced APAP-reduced SIRT1 activity. Our results show that modulation of the SIRT1 activity plays a role in hepatoprotection. Synthetic activators of SIRT1 would help in understanding the role of SIRT1 and are therefore a major boost towards the search for specific treatment of liver disease.

• MeSH
• hepatocyty účinky léků   metabolismus   MeSH
• krysa rodu Rattus MeSH
• kultivované buňky MeSH
• lékové postižení jater farmakoterapie   metabolismus   MeSH
• modely nemocí na zvířatech * MeSH
• paracetamol toxicita   MeSH
• potkani Wistar MeSH
• resveratrol MeSH
• sirtuin 1 fyziologie   MeSH
• stilbeny farmakologie   terapeutické užití   MeSH
• viabilita buněk účinky léků   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• paracetamol MeSH
• resveratrol MeSH
• sirtuin 1 MeSH
• stilbeny MeSH

Aging is a natural process of gradual decrease in physical and mental capacity. Biological age (accumulation of changes and damage) and chronological age (years lived) may differ. Biological age reflects the risk of various types of disease and death from any cause. We selected potential biomarkers of aging - telomerase, AGEs, GDF11 and 15 (growth differentiation factor 11/15), sirtuin 1, NAD+ (nicotinamide adenine dinucleotide), inflammasome NLRP3, DNA/RNA damage, and klotho to investigate changes in their levels depending on age and sex. We included 169 healthy volunteers and divided them into groups according to age (under 35; 35-50; over 50) and sex (male, female; male and female under 35; 35-50, over 50). Markers were analyzed using commercial ELISA kits. We found differences in values depending on age and gender. GDF15 increased with age (under 30 and 35-50 p < 0.002; 35-50 and over 50; p < 0.001; under 35 and over 50; p < 0.001) as well as GDF11 (35-50 and over 50; p < 0.03; under 35 and over 50; p < 0.02), AGEs (under 30 and 35-50; p < 0.005), NLRP3 (under 35 over 50; p < 0.03), sirtuin 1 (35-50 and over 50; p < 0.0001; under 35 and over 50; p < 0.004). AGEs and GDF11 differed between males and females. Correlations were identified between individual markers, markers and age, and markers and sex. Markers that reflect the progression of biological aging vary with age (GDF15, GDF11, AGEs, NLRP3, sirtuin) and sex (AGEs, GDF11). Their levels could be used in clinical practice, determining biological age, risk of age-related diseases and death of all-causes, and initiating or contraindicating a therapy in the elderly based on the patient's health status.

• Klíčová slova
• AGEs, Aging, DNA/RNA damage, GDF15, NLRP3, Sirtuin 1,
• MeSH
• biologické markery MeSH
• DNA MeSH
• kostní morfogenetické proteiny MeSH
• lidé MeSH
• NAD * MeSH
• produkty pokročilé glykace MeSH
• protein NLRP3 MeSH
• růstové diferenciační faktory metabolismus   MeSH
• senioři MeSH
• sirtuin 1 MeSH
• stárnutí genetika   MeSH
• telomerasa * MeSH
• zdravotní stav MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• biologické markery MeSH
• DNA MeSH
• GDF11 protein, human MeSH Prohlížeč
• kostní morfogenetické proteiny MeSH
• NAD * MeSH
• produkty pokročilé glykace MeSH
• protein NLRP3 MeSH
• růstové diferenciační faktory MeSH
• sirtuin 1 MeSH
• telomerasa * MeSH

Sirtuins, named after their homology to the Saccharomyces cerevisiae Silent Information Regulator Two, constitute a family of highly conserved nicotinamide adenine dinucleotide-dependent enzymes that deacetylate histones and residues of acetylated lysine. The main aim of this article is to put forward the pharmacological importance of major sirtuin 1 activators of natural or synthetic origin tested in last years in cases of oxidative tissue damage. The related bioactivity of these activators as "leading" compounds in the search for new drugs and remedies is also described. With the recent development of our knowledge on the cross talks between sirtuin 1 and its modulators (e.g. resveratrol), pharmacological and clinical research on this topic is getting a new horizon.

• MeSH
• antioxidancia farmakologie   fyziologie   MeSH
• lidé MeSH
• oxidační stres fyziologie   MeSH
• sirtuin 1 fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antioxidancia MeSH
• sirtuin 1 MeSH