SIRT1,HDAC

Intrahepatic cholestasis is a kind of clinical syndrome along with hepatotoxicity which caused by intrahepatic and systemic accumulations of bile acid. There are several crucial generating factors of the pathogenesis of cholestasis, such as inflammation, dysregulation of bile acid transporters and oxidative stress. SIRT1 is regarded as a class III histone deacetylase (HDAC). According to a set of researches, SIRT1 is one of the most important factors which can regulate the hepatic bile acid metabolism. SRT1720 is a kind of activator of SIRT1 which is 1000 times more potent than resveratrol, and this paper is aimed to study its protective influence on hepatotoxicity and cholestasis induced by alpha-naphthylisothiocyanate (ANIT) in mice...

A new series of N-aryl-N'-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)ureas bearing an alkoxycarbonylamino group at the 6-position were synthesized and examined as putative anticancer agents targeting sirtuins in glioma cells. On the basis of computational docking combined to in vitro sirtuin 1/2 inhibition assays, we selected compound 18 [R/S-N-3-cyanophenyl-N'-(6-tert-butoxycarbonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)urea] which displays a potent antiproliferative activity on various glioma cell types, assessed by quantitative videomicroscopy, eventually triggering senescence...

The persistence of latent HIV reservoirs presents a significant challenge to viral eradication. Effective latency reversing agents (LRAs) based on "shock and kill" strategy are urgently needed. The natural phytoalexin resveratrol has been demonstrated to enhance HIV gene expression, although its mechanism remains unclear. In this study, we demonstrated that resveratrol was able to reactivate latent HIV without global T cell activation in vitro. Mode of action studies showed resveratrol-mediated reactivation from latency did not involve the activation of silent mating type information regulation 2 homologue 1 (SIRT1), which belonged to class-3 histone deacetylase (HDAC)...

BACKGROUND: Previous studies have reported that ultraviolet B (UVB) inhibits DNA methyltransferase1 (DNMT1) activity in CD4+ T cells from systemic lupus erythematosus (SLE) patients. Silent mating type information regulation 2 homolog 1 (SIRT1) is a type of Class III histone deacetylases (HDACs), and has been reported to play roles in the pathogenesis of different autoimmune diseases and can modulate DNMT1 activity. Moreover, aryl hydrocarbon receptor (AhR) has been reported to link UVB with SLE...

Epigenetic modifications, including methylation or acetylation as well as post-transcriptional modifications, are mechanisms used by eukaryotic cells to increase the genome diversity in terms of differential gene expression and protein diversity. Among these modifying enzymes, sirtuins, a class III histone deacetylase (HDAC) enzymes, are of particular importance. Sirtuins regulate the cell cycle, DNA repair, cell survival, and apoptosis, thus having important roles in normal and cancer cells. Sirtuins can also regulate metabolic pathways by changing preference for glycolysis under aerobic conditions as well as glutaminolysis...

Reversible protein acetylation, one of the key types of post-translational modifications, is composed of histone acetylation and deacetylation, which is typically catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDACs) respectively. Herein, a label-free fluorescent method has been established for the homogeneous bioassay of HAT/HDAC activity and respective inhibitors. The proposed approach is primarily based on the electrostatic interaction between G-quadruplexes (G4s) and acetylation-related peptides, which results in marked change of fluorescent intensity of G4/Thioflavin T (ThT) complexes...

Since the first pan-HDAC inhibitor SAHA was approved by U.S. FDA 10 years ago, HDACs including SIRT1-7 have received significant attention due to the fact that aberrant histone deacetylase activtiy has been implicated in a variety of human diseases, such as cancers, virus infection, and neurodegenerative diseases. During the past years, a considerable achievement of development of isoform- or class-selective HDAC inhibitors has been made, yielding many drug candidates for further clinical studies, which represents a state-of-the-art technology in the drug discovery arena...

BACKGROUND: A role of proinflammation has been implicated in the pathogenesis of diabetes, but the up-stream regulatory signals and molecular signatures are poorly understood. While histone modifications such as changes in histone deacetylase (HDAC) are emerging as novel epigenetic biomarkers, there is lack of studies to demonstrate their clinical relevance in diabetes. Therefore, we investigated the extent of HDAC machinery and inflammatory signals in peripheral blood mononuclear cells (PBMCs) from patients with type 2 diabetes mellitus (T2DM) compared to control subjects...

Sirtuins (SIRT1-SIRT7) are unique histone deacetylases (HDACs) whose activity depends on NAD(+) levels and thus on the cellular metabolic status. SIRTs regulate energy metabolism and mitochondrial function. They orchestrate the stress response and damage repair. Through these functions sirtuins modulate the course of aging and affect neurodegenerative diseases. SIRTSs interact with multiple signaling proteins, transcription factors (TFs) and poly(ADP-ribose) polymerases (PARPs) another class of NAD(+)-dependent post-translational protein modifiers...

Enterovirus 71 (EV71) possesses a single-stranded positive RNA genome that contains a single open reading frame (ORF) flanked by a 5' untranslated region (5'UTR) and a polyadenylated 3'UTR. Here, we demonstrated that EV71 activates the production of silent mating type information regulation 2 homolog 1 (SIRT1), a histone deacetylase (HDAC). EV71 further stimulates SIRT1 sumoylation and deacetylase activity, and enhances SIRT1 translocation from the nucleus to the cytoplasm. More interestingly, activated SIRT1 subsequently binds with the EV71 3D(pol) protein (a viral RNA-dependent RNA polymerase, RdRp) to repress the acetylation and RdRp activity of 3D(pol), resulting in the attenuation of viral genome replication...

Sirtuins (SIRT1 to -7) are unique histone deacetylases (HDACs) whose activity depends on NAD+, thus making them capable of sensing the cellular metabolic status. Sirtuins orchestrate the stress response and damage repair, and are able to modulate the course of ageing and neurodegenerative diseases. Despite their classification as HDACs, sirtuins deacetylate a vast number of targets in many cellular compartments, and some display additional enzymatic activities including mono(ADP-ribosyl)ation. SIRTs interact with multiple signalling proteins, transcription factors and enzymes including p53, FOXOs (forkhead box subgroup O), PPARs (peroxisome proliferator-activated receptors), NF-B, and DNA-PK (DNA-dependent protein kinase)...

SIRT2 is a member of the human sirtuin family of proteins and possesses nicotinamide adenine dinucleotide (NAD)-dependent lysine deacetylase activity. SIRT2 has been involved in various cellular processes including gene transcription, genome constancy, and the cell cycle. In addition, SIRT2 is deeply implicated in diverse diseases including cancer. In this study, we identified a small molecule inhibitor of SIRT2 with a structure different from known SIRT2 inhibitors by screening from a chemical library. The hit compound showed a high selectivity toward SIRT2 as it only inhibited SIRT2, and not other sirtuins including SIRT1 and SIRT3 or zinc-dependent histone deacetylases (HDACs) including HDAC1 and HDAC6, in vitro...

Skeletal muscle dysfunction and atrophy are characteristic features accompanying chronic conditions. Epigenetic events regulate muscle mass and function maintenance. We hypothesized that the pattern of epigenetic events (muscle-enriched microRNAs and histone acetylation) and acetylation of transcription factors known to signal muscle wasting may differ between early- and late-time points in skeletal muscles of mice exposed to hindlimb immobilization (I) and recovery following I. Body and muscle weights, grip strength, muscle-enriched microRNAs, histone deacetylases (HDACs), acetylation of proteins, histones, and transcription factors (TF), myogenic TF factors, and muscle phenotype were assessed in gastrocnemius of mice exposed to periods (1, 2, 3, 7, 15, and 30 days, I groups) of hindlimb immobilization, and in those exposed to reloading for different periods of time (1, 3, 7, 15, and 30 days, R groups) following 7-day immobilization...

High prevalence of Kaposi's sarcoma (KS) is seen in diabetic patients. It is unknown if the physiological condition of diabetes contributes to KS development. We found elevated levels of viral lytic gene expression when Kaposi's sarcoma-associated herpesvirus (KSHV) infected cells were cultured in high glucose medium. To demonstrate the association between high glucose and KSHV replication, we xeno-grafted telomerase-immortalized human umbilical vein endothelial cells that are infected with KSHV (TIVE-KSHV) into hyperglycemic and normal nude mice...

Sirtuin1 (SIRT1) is a Class 3 nicotinamide adenine dinucleotide-dependent histone deacetylase (HDAC) that is thought to be implicated in the protection against autoimmune diseases. However, an association between SIRT1 and autoimmune thyroid disease (AITD) has not been reported. In this study, we selected four single nucleotide polymorphisms (SNPs) in the SIRT1 gene, rs12049646 T/C (termed SNP1), rs12778366 T/C (termed SNP2), rs3758391 T/C (termed SNP3), and rs4746720 T/C (termed SNP4). We genotyped each of these polymorphic sites in 185 patients with Graves' disease (GD), including 76 patients with intractable GD and 57 patients with GD in remission; 151 patients with Hashimoto's disease (HD), including 68 patients with severe HD and 54 patients with mild HD; and 96 healthy volunteers...

Silent information regulator type-1 (SIRT1) is the best-studied member of the Sirtuin (Sir2) family of nicotinamide dinucleotide (NAD)-dependent class III histone deacetylases (HDACs). Rrecently, it is suggested that SIRT1 may be involved in the development of malignant tumors including mouse lymphoma, but has not yet been explored in Angioimmunoblastic T-cell lymphoma (AITL). Therefore, we investigated the prevalence and the prognostic impact of SIRT1 expression in AITL. Immunohistochemical expression of SIRT1, p53 were evaluated by using a 2 mm core from 45 AITL patients...

Inhibition of histone deacetylases (HDACi) has emerged as a promising approach in the treatment of many types of cancer, including leukemias. Among the HDACs, Class III HDACs, also known as sirtuins (SIRTs), are unique in that their function is directly related to the cell's metabolic state through their dependency on the co-factor NAD(+). In this study, we examined the relation between SIRTs and the growth, survival, and differentiation of K562 erythroleukemia cells. Using a mass spectrometry approach we previously developed, we show that SIRT expression and deacetylase activity in these cells changes greatly with differentiation state (undifferentiated vs...

AMP-activated protein kinase (AMPK) and its yeast homolog, Snf1, are critical regulators in the maintenance of energy metabolic balance not only stimulating energy production but also inhibiting energy-consuming processes. The AMPK/Snf1 signaling controls energy metabolism by specific phosphorylation of many metabolic enzymes and transcription factors, enhancing or suppressing their functions. The AMPK/Snf1 complexes can be translocated from cytoplasm into nuclei where they are involved in the regulation of transcription...

Uveal melanoma (UM) is the most common intraocular malignancy in adults. Despite improvements in surgical, radiation and chemotherapy treatments, the overall survival of UM and prognosis remain poor. In the present study, we hypothesized that Sirtuin 1 and 2 (SIRT1/2), class III histone deacetylases (HDACs), were critical in controlling the destiny of bulk tumor cells and cancer stem cells (CSCs) of UM. We testified this hypothesis in four lines of UM cells (92.1, Mel 270, Omm 1 and Omm 2.3). Our results showed that inhibition of SIRT1/2 by Tenovin-6 induced apoptosis in UM cells by activating the expression of tumor suppressor genes such as p53 and elevating reactive oxygen species (ROS)...

Ultraviolet radiation (UVR) from sunlight is the primary effector of skin DNA damage. Chromatin remodeling and histone post-translational modification (PTM) are critical factors in repairing DNA damage and maintaining genomic integrity, however, the dynamic changes of histone marks in response to solar UVR are not well characterized. Here we report global changes in histone PTMs induced by solar simulated UVR (ssUVR). A decrease in lysine acetylation of histones H3 and H4, particularly at positions of H3 lysine 9, lysine 56, H4 lysine 5, and lysine 16, was found in human keratinocytes exposed to ssUVR...