As the most homologic homologue of silent information regulator 2 of yeast, Sirt1 gene is extensively expressed in mature tissues, and is rich in early embryo and reproductive cells. It is involved in the regulation of gene transcription, energy metabolism and cell aging. It promotes fat mobilization in adipocytes and glucose production in liver and regulates insulin secretion in islet beta cell. Furthermore, Sirt1 gene is an essential endogenous apoptosis inhibitor. In future, it may be used as new drug targets or applied in other disease management modalities.
Animals ; Humans ; Sirtuin 1 ; genetics ; metabolism ; physiology

Fatty Liver, Alcoholic ; etiology ; metabolism ; Humans ; Sirtuin 1 ; metabolism

As a kind of mental illness, depression produces great difficulties in clinical diagnosis and treatment, and has a high disability rate. It is urgent to clarify the mechanism of depression to find potential therapeutic targets and effective clinical treatment methods. As a deacetylase, silent mating type information regulator 2 homolog 1 (SIRT1) is involved in many biological processes such as cell aging, cancer, and cardiovascular disease. In recent years, more and more studies have found that SIRT1 gene plays an important role in the pathogenesis of depression, but the mechanism is still unclear. Therefore, this review mainly summarizes the relevant research progress on the role and mechanism of SIRT1 gene in the hippocampus, prefrontal cortex, amygdala, hypothalamic suprachiasmatic nucleus, and nucleus accumbens in depression, in order to provide new ideas for exploring the mechanism and prevention of depression.
Cellular Senescence ; Depression/genetics* ; Hippocampus/metabolism* ; Humans ; Nucleus Accumbens ; Sirtuin 1/metabolism*

Animals ; Cell Cycle Proteins/metabolism* ; Insulin Resistance/genetics* ; Liver/physiopathology* ; Mice ; Sirtuin 1/metabolism*

OBJECTIVETo investigate the role of the host-encoded silent information regulator 1 (SIRT1) on hepatocytes' lipid metabolism under conditions of hepatitis C virus (HCV) infection and assess its potential effects on virus replication in vitro.

METHODSThe Huh-7.5 human hepatocyte cell line was used as the control group and Huh-7.5 cells stably expressing the HCV replicon (Huh7.5-HCV) were used as the experimental group. Effects of interferon (IFN) treatment and activation of SIRT1 by resveratrol were also observed. The mRNA and protein expression levels of SIRT1 were detected by real time (q)PCR and western blotting. Effects on SIRT1 protein activity were tested by measuring the levels of reactive oxygen species (ROS) and the nicotinamide adenine dinucleotide (NAD+)/beta-nicotinamide adenine dinucleotide, reduced (NADH) by flow cytometry and chromatometry, and the levels of triacylglycerol (TG), total cholesterol (TC), and fatty acid beta oxidation rate by enzymatic analysis and liquid scintillation counting. Effects on mRNA expression of SIRT1 downstream lipid-metabolism genes were measured by qPCR.

RESULTSThe Huh7.5-HCV cells had a significantly higher level of ROS (3.8+/-0.5 vs. Huh-7.5: 1.0+/-0.2; t = 12.736, P less than 0.01) but significantly lower levels of NAD+/NADH (0.03+/-0.01 vs. 0.12+/-0.03; t = 6.971, P less than 0.01), SIRT1 activity (0.3+/-0.1 vs. 1.0+/-0.2, 0.9+/-0.2, F = 6.766, P less than 0.01), SIRT1 mRNA (0.4+/-0.1 vs. 1.0+/-0.3, 0.9+/-0.2, F = 5.864, P less than 0.01), and SIRT1 protein (0.3+/-0.1 vs. 0.8+/-0.2, 0.9+/-0.2, F = 5.419, P less than 0.01). The lower levels of SIRT1 in Huh7.5-HCV cells accompanied decreased phosphorylation of the forkhead box O1 (FoxO1), which not only up-regulated the downstream genes of SREBP-1c, FAS, ACC, SREBP-2, HMGR and HMGS (which increased fatty acid synthesis) but also down-regulated the downstream genes of PPAR and CPT1A genes (which decreased fatty acid beta oxidation). IFN treatment restored all of the aforementioned changes. Resveratrol-induced SIRT activation improved the perturbations in lipid metabolism pathways, as evidenced by an increase in fatty acid beta oxidation and a decrease in TG and TC synthesis, as well as inhibited HCV replication.

CONCLUSIONHCV may decrease the NAD+/NADH ratio in hepatocytes, leading to a down-regulation of SIRT1 activity and expression and perturbing the downstream expression profile of lipid metabolism-related factors, ultimately causing lipid metabolism disorders and establishing a permissive intracellular environment for HCV replication.

Cell Line ; Hepacivirus ; physiology ; Hepatocytes ; metabolism ; virology ; Humans ; Lipid Metabolism Disorders ; etiology ; metabolism ; Sirtuin 1 ; metabolism ; Triglycerides ; metabolism ; Virus Replication

The sirtuin proteins constitute class III histone deacetylases (HDACs). These evolutionarily conserved NAD(+)-dependent enzymes form an important component in a variety of cellular and biological processes with highly divergent as well as convergent roles in maintaining metabolic homeostasis, safeguarding genomic integrity, regulating cancer metabolism and also inflammatory responses. Amongst the seven known mammalian sirtuin proteins, SIRT1 has gained much attention due to its widely acknowledged roles in promoting longevity and ameliorating age-associated pathologies. The contributions of other sirtuins in the field of aging are also gradually emerging. Here, we summarize some of the recent discoveries in sirtuins biology which clearly implicate the functions of sirtuin proteins in the regulation of premature cellular senescence and accelerated aging. The roles of sirtuins in various cellular processes have been extrapolated to draw inter-linkage with anti-aging mechanisms. Also, the latest findings on sirtuins which might have potential effects in the process of aging have been reviewed.
Aging, Premature ; enzymology ; genetics ; Animals ; Humans ; Longevity ; genetics ; Sirtuin 1 ; genetics ; metabolism

Many studies have reported that the expression of silent information regulator 1 (Sirt1) is associated with the clinical features and prognosis of patients with gastric cancer, but the exact function remains controversial. We conducted this study to illustrate the clinical and prognostic value of Sirt1 in gastric cancer. The related publications before December 2015 were searched in the databases including Pubmed, Cochrane Library, Embase and China National Knowledge Infrastructure (CNKI). The studies were included and excluded according to the inclusion criteria and exclusion criteria. The 3- and 5-year overall survival (OS) and clinical features such as age, T stage, N stage and differentiation were analyzed by software RevMan 5.3. A total of 1650 patients in 7 studies were included according to the inclusion criteria and exclusion criteria. The high expression of Sirt1 was found in 58.4% cases by immunohistochemistry. High expression of Sirt1 was closely linked with the 3-year OS (OR=0.25, 95% CI: 0.16-0.39, P<0.00001, fixed), patient's age (≥60 years old vs. <60 years old; OR=1.43, 95% CI: 1.06-1.93, P=0.02, fixed), T stage (T3+T4 vs. T1+T2; OR=1.45, 95% CI: 1.08-1.94, P=0.01, fixed), N stage (N1+N2+N3 vs. N0; OR=3.47, 95% CI: 2.39-5.05, P<0.00001, fixed) and tumor differentiation (G1+G2 vs. G3; OR=0.50, 95% CI: 0.35-0.69, P<0.0001, fixed). Nevertheless, it seemed that high expression of Sirt1 was not associated with 5-year OS (OR=0.44, 95% CI: 0.15-1.28, P=0.13, random). It was suggested that the high expression of Sirt1 implies a poor prognosis of gastric cancer patients in a relatively short period (3 years), but not in a long time (≥5 years). The expression of Sirt1 is also linked with patients' age, T stage, N stage and tumor differentiation.
Biomarkers, Tumor ; genetics ; metabolism ; Carcinoma ; metabolism ; pathology ; Humans ; Middle Aged ; Sirtuin 1 ; genetics ; metabolism ; Stomach Neoplasms ; metabolism ; pathology ; Survival Analysis

OBJECTIVETo observe the effect of SIRT1 on intestinal barrier function of epithelial Caco-2 cells under hypoxia and investigate its mechanism.

METHODSCaco-2 cells were randomly divided into three groups: normoxia group (Nx), hypoxia group (Hx,1%O2 for 6 h) and hypoxia plus 40 μmol/L Resveratrol (agonist of SIRT1) group (Hx+Res). Transepithelial electrical resistance (TER) was determined. mRNA and protein expressions of SIRT1 and tight junctions (ZO-1, Occludin, Claudin-1) were examined by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting.

RESULTSBoth mRNA and protein expressions of SIRT1 were significantly reduced in Hx group as compared with Nx group (0.40±0.02 vs. 0.70±0.07, P=0.001; 0.37±0.03 vs. 0.76±0.03, P=0.001). The mRNA and protein expressions of SIRT1 were significantly increased in Hx+Res group as compared with Hx group(0.50±0.02 vs. 0.40±0.02, P=0.026; 0.54±0.02 vs. 0.37±0.03, P=0.011). The expression levels of ZO-1, Occludin and Claudin-1 in Hx group were lower than those in Nx group (P<0.05), however, pretreatment with Resveratrol could attenuate the decreased expression of above 3 molecules under hypoxia(P<0.05). TERs of Nx group, Hx group and Hx+Res group were (142±7) Ohm/cm(2), (94±3) Ohm/cm(2) and (119±7) Ohm/cm(2) respectively. Compare with the Nx group, the TER of Hx group was significantly decreased(P<0.05). TER of Hx+Res group was significantly increased compare with Hx group, but it was still significantly lower than that in Nx group(P<0.05).

CONCLUSIONSExpression of SIRT1 is significantly reduced under hypoxia. Activation of SIRT1 can maintain the epithelial barrier function through regulating the expression of tight junctions under hypoxia.

Caco-2 Cells ; Cell Hypoxia ; Claudin-1 ; metabolism ; Epithelial Cells ; metabolism ; Humans ; Intestinal Mucosa ; cytology ; Occludin ; metabolism ; Sirtuin 1 ; metabolism ; Zonula Occludens-1 Protein ; metabolism

AMP-Activated Protein Kinases ; metabolism ; Adiponectin ; metabolism ; Fatty Liver, Alcoholic ; pathology ; Humans ; Signal Transduction ; Sirtuin 1 ; metabolism

We demonstrated the effect of resveratrol on porcine primary preadipocytes apoptosis, to study the intracellular molecular mechanism. Porcine primary preadipocyte was treated with different concentration of resveratrol (0 micromol/L, 50 micromol/L, 100 micromol/L, 200 micromol/L, 400 micromol/L). We used optical microscope and fluorescence microscope to observe morphological changes during apoptosis after Hoechst 33258 Fluorescent dyes staining; and RT-PCR and Western blotting to measure the expression of apoptosis-associated gene sirt1, caspase-3, bcl-2, bax, p53, NF-kappaB. Primary preadipocyte apoptosis was apparent, accompanied by reduced cell volume, chromatin condensation, and nuclear shrinkage. Compared to the control and low concentration group, high dose group (200 micromol/L) significantly increased the ratio of primary preadipocyte apoptosis. The expression of sirt1, caspase-3, and bax was up-regulated markedly in response to resveratrol; in contrast, apoptotic inhibitor bcl-2, p53, NF-kappaB down-regulated. We further proved fact that resveratrol can specifically promote the activity of sirt1; moreover, activated sirt1 modulates the activity of caspase-3 and bcl-2 family, involving in transcriptional regulation of p53 and NF-kappaB through antagonizing factor-induced acetylation. Taken together, our data established resveratrol as new regulator in porcine primary preadipocyte apoptosis via activating the expression of sirt1, modulating activity of apoptotic-associated factor.
Adipocytes ; cytology ; Adipogenesis ; Animals ; Antioxidants ; pharmacology ; Apoptosis ; drug effects ; Caspase 3 ; metabolism ; Cells, Cultured ; Sirtuin 1 ; metabolism ; Stilbenes ; pharmacology ; Swine