Silent Information Regulator Protein Research Articles

SIRT1/FOXO1 Axis-Mediated Hippocampal Angiogenesis is Involved in the Antidepressant Effect of Chaihu Shugan San.

ObjectiveChaihu Shugan San (CSS) has a long history for treating major depressive disorder (MDD), which has been verified effectively and safely in clinical studies. Deficient angiogenesis plays important roles in MDD. However, the underlying mechanisms of CSS on angiogenesis remain poorly understood.MethodsNetwork pharmacology analysis was applied to explore the potential angiogenic targets and pathways between CSS and MDD. These targets would be validated in chronic unpredictable mild stress (CUMS)-induced depressive-like mice by Western blots, immunofluorescence, and immunohistochemistry. Then, the underlying molecular mechanisms were further investigated in brain microvascular endothelial cells (BMVECs) with CSS-containing serum by Western blots and immunofluorescence.ResultsNetwork pharmacology analysis showed that the antidepressant role of CSS was closely associated with Silent information regulator protein 1 (SIRT1)/Forkhead box O1 (FOXO1) axis-mediated angiogenesis. This prediction was confirmed in the following experiments. CSS induced angiogenesis, increased SIRT1 expression, and decreased FOXO1 expression in the hippocampus of CUMS mice. Five percent CSS-containing serum produced a significant increase in BMVECs proliferation, migration, and tube formation, but these effects were reduced by SIRT1 silencing. CSS serum could also promote FOXO1 translocation to the cytoplasm through SIRT1 signaling, which triggered FOXO1 protein degradation. What is more, CSS upregulated VEGFA and BDNF expressions not only in the hippocampus of depressive mice but also in BMVECs supernatants. Of note, these trophic factors play important roles in promoting neurogenesis.ConclusionThe study showed that CSS could promote angiogenesis and neurogenesis in the hippocampus of CUMS-induced mice. The underlying molecular mechanism involves the SIRT1/FOXO1 axis and subsequent regulation of VEGFA and BDNF. These findings provide novel insight into CSS drug development, and targeting the SIRT1/FOXO1 axis might be a promising strategy to treat MDD.

Correlation between the reduction in hippocampal SirT2 expression and depressive-like behaviors and neurological abnormalities in olfactory bulbectomized mice

Reduced activity of hippocampal silent information regulator protein 2 (SirT2) has been associated with the development of depression caused by disturbances in neuronal and synaptic plasticity. However, changes in the hippocampal SirTs in olfactory bulbectomized (OBX) mice, an animal model of depression, remain unknown. Therefore, this study examined depressive-like behaviors, hippocampal SirTs, synaptic plasticity-associated proteins, and cell proliferation in OBX mice. The OBX mice showed depressive-like behaviors; reduced SirT2, synaptophysin, and PSD95 levels; and reduced cell proliferation in the hippocampus. These data indicate that decreased hippocampal SirT2 may contribute to pathophysiological depression and strongly affect the psychological state.

Cyanidin-3-galactoside from Aronia melanocarpa ameliorates PM10 induced pulmonary injury by modulating M1/M2 macrophage polarization and NRF2/Sirt1 MAPK signaling

Abstract Aronia melanocarpa is rich in anthocyanins that exert many beneficial effects. We extracted cyanidin-3-galactoside (C3G), the most abundant anthocyanin in Aronia melanocarpa, and applied to PM10-exposed mice to investigate anti-inflammatory properties and underlying cellular mechanism. Administration of C3G ameliorated PM10-induced pulmonary inflammation by reducing recruitment of macrophages and pro-inflammatory cytokine mRNA levels in lung tissues. C3G also regulated M1 and M2 macrophage balance. An in vitro demonstrated that C3G decreased M1 macrophage markers, while increased M2 macrophage markers. The secretion of pro-inflammatory cytokines was reduced as well. Study of the cellular mechanism revealed that C3G inhibited mitogen-activated protein kinase and the translocation of nuclear factor-κB in to nuclei. C3G treatment also downregulated expression of reactive oxygen species, nuclear factor (erythroid-derived 2)-like 2, and silent information regulator protein 1 in macrophages. These findings highlight the potential use of C3G as a functional food to prevent the development of PM10-induced pulmonary injury.

Quercetin Improves Cardiomyocyte Vulnerability to Hypoxia by Regulating SIRT1/TMBIM6-Related Mitophagy and Endoplasmic Reticulum Stress.

Cardiomyocyte apoptosis is an important pathological mechanism underlying cardiovascular diseases and is commonly caused by hypoxia. Moreover, hypoxic injury occurs not only in common cardiovascular diseases but also following various treatments of heart-related conditions. One of the major mechanisms underlying hypoxic injury is oxidative stress. Quercetin has been shown to exert antioxidant stress and vascular protective effects, making it a promising candidate for treating cardiovascular diseases. Therefore, we examined the protective effect of quercetin on human cardiomyocytes subjected to hypoxia-induced oxidative stress damage and its underlying mechanism. Human cardiomyocytes were subjected to hypoxia/reoxygenation (H/R) in vitro with or without quercetin pretreatment; thereafter, flow cytometry, Cell Counting Kit-8 assay, laser scanning confocal microscopy, quantitative PCR, western blotting, and enzyme-linked immunosorbent assay were performed to analyze the effects of quercetin on cardiomyocytes. We found that H/R induced reactive oxygen species overproduction and endoplasmic reticulum stress, as well as inhibited the function of the mitochondria/endoplasmic reticulum and mitophagy, eventually leading to apoptosis and decreasing the viability of human cardiomyocytes. Quercetin pretreatment inhibited H/R-mediated overproduction of reactive oxygen species and damage caused by oxidative stress, increased mitophagy, regulated mRNA and protein expression of transmembrane BAX inhibitor-1 motif-containing 6 (TMBIM6), regulated endoplasmic reticulum stress, and improved the vulnerability of human cardiomyocytes to H/R. Furthermore, transfection with short interfering RNA against silent information regulator protein 1 (SIRT1) counteracted the protective effects of quercetin on cardiomyocytes. Thus, quercetin was predicted to regulate mitophagy and endoplasmic reticulum stress through SIRT1/TMBIM6 and inhibit H/R-induced oxidative stress damage. These findings may be useful for developing treatments for hypoxic injury-induced cardiovascular diseases and further highlight the potential of quercetin for regulating mitochondrial quality control and endoplasmic reticulum function.

Ameliorative Effect of Graviola (Annona muricata) on Mono Sodium Glutamate-Induced Hepatic Injury in Rats: Antioxidant, Apoptotic, Anti-inflammatory, Lipogenesis Markers, and Histopathological Studies.

Simple SummaryFood additives, especially monosodium glutamate (MSG), induces serious liver disorders. This study premeditated to investigate the effect of Graviola extract (GE) on hepatic and cellular alterations induced by MSG. Our result revealed that GE administration normalized the oxidative stress markers, as well as the proinflammatory cytokines, in addition to downregulation of the inducible nitric oxide synthase (iNOS) and FAS, hepatic fatty acid synthase, and led to the upregulation of the silent information regulator protein one (SIRT1) gene. This is the first report investigating the intracellular pathway and mechanism of Graviola extract’s action in alleviating the MSG supplementation injuries.Monosodium glutamate (MSG) is a widely used food additive, and there is a trepidation that MSG plays a critical role in multiple hepatic disorders. This study was planned to investigate Graviola extract (GE) effects on hepatic and cellular alterations induced by MSG. Fifty Wistar rats were randomly allocated into five groups: control (received normal saline), Graviola (received 200 mg/kg body weight), MSG (received 2.4 gm MSG/kg, 15% of Lethal dose (LD50) of MSG), Graviola + monosodium glutamate (MSG + GE; received GE, 200 mg/kg/day and MSG 2.4 gm/kg body weight (BW) for the next four weeks), and monosodium glutamate + Graviola (received MSG only (2.4 gm/kg BW) daily for four weeks, then concomitant with Graviola (200 mg/kg BW) daily for the next four weeks. MSG and GR were administered orally for eight weeks. Our results showed that MSG caused a significant increase in oxidative stress markers malondialdehyde (MDA), reactive oxygen species (ROS), nitric oxide (NO), hydrogen peroxide (H2O2), proinflammatory cytokines interleukin 6 (IL-6) level, a tumor protein (P53), hepatic cellular damage, as well as proapoptotic markers caspase-3, and B-cell lymphoma 2 (BCL-2)-like protein 4 (Bax). A significant decrease in superoxide dismutase (SOD), catalase (CAT), glutathione S transferase (GST), reduced glutathione (GSH), and an antiapoptotic agent B-cell lymphoma 2 (BCl-2) was observed. The detected MSG effects were normalized by Graviola administration, either a prophylactic or protecting dose. Besides, Graviola reduced the expression of inducible nitric oxide synthase (iNOS) and hepatic fatty acid synthase (FAS) and led to the upregulation of the silent information regulator protein one gene expression gene (SIRT1).In conclusion, the results suggest that Gaviola’s interrelated antiapoptotic, antioxidant, and anti-inflammatory properties are potential mechanisms to enhance hepatic deficits and protect the liver. Graviola can, therefore, be considered a promising hepatoprotective supplement. Additionally, further human clinical trials are also necessary to validate the present research.

The effect of high glucose on the biological characteristics of nucleus pulposus-derived mesenchymal stem cells.

Diabetes mellitus (DM) is a dependent risk factor in the progression of intervertebral disc degeneration (IVDD). High glucose supply has negative effects on nucleus pulpous (NP) cell and mesenchymal stem cell (MSC) biology. However, the effect of hyperglycaemia on the biological characterization of nucleus pulpous-derived mesenchymal stem cell (NPMSC) has not been investigated previously. Therefore, further exploration of the effects of DM-associated hyperglycaemia on NPMSC biology is important to better understand and develop endogenous repair strategies of DM patient-associated IVDD. Therefore, the cell biological characteristics were compared between NPMSC cultured in media with low glucose concentration (LG-NPMSC) and high glucose concentration (HG-NPMSC). The results demonstrated that HG-NPMSC showed significantly decreased cell proliferation, colony formation ability, migration and wound-healing capability compared with those of LG-NPMSC. HG-NPMSC also showed significantly decreased expressions of stemness genes and mRNA and protein expressions of silent information regulator protein 1 (SIRT1), SIRT6, hypoxia inducible factor-1α (HIF-1α) and glucose transporter 1 (GLUT-1), whereas increased cell apoptosis, cell senescence and caspase-3 expression. These results suggest that high glucose may decrease proliferation and stemness maintenance ability and increase apoptosis and senescence of NPMSC. SIGNIFICANCE OF THE STUDY: We found that high glucose concentration significantly decreased cell proliferation, colony formation ability, migration and wound-healing capability of nucleus pulposus-derived mesenchymal stem cells. Moreover, high glucose cultured nucleus pulposus-derived mesenchymal stem cells showed significantly decreased expression of stemness genes, related mRNA and protein, whereas increased cell apoptosis, cell senescence and expression of caspase-3. The present study indicated that better control of high concentration glucose in the early stage of diabetes mellitus should be recommended to prevent or limit intervertebral disc degeneration.

The effect of intervertebral disc degenerative change on biological characteristics of nucleus pulposus mesenchymal stem cell: an in vitro study in rats

ABSTRACTPurpose: To evaluate the change on biological characteristics of mesenchymal stem cell (MSC) derived from normal and degenerative intervertebral disc (IVD).Methods: MSC was isolated from normal and degenerative IVD rat model. Immunophenotype detected by flow cytometric analysis, expression of stemness genes determined by reverse‐transcription polymerase chain reaction (RT-PCR) and osteogenic, adipogenic and chondrogenic differentiation were compared between MSC derived from normal IVD (N-NPMSC) and degenerative IVD (D-NPMSC). The biological characteristics including cell proliferation, colony formation, apoptosis, caspase-3 activity and mRNA and protein expressions of hypoxia inducible factor-1α (HIF-1α), glucose transporter 1 (GLUT-1), vascular endothelial growth factor (VEGF), silent information regulator protein 1 (SIRT1) and silent information regulator protein 6 (SIRT6) were compared between N-NPMSC and D-NPMSC.Results: Both of N-NPMSC and D-NPMSC highly expressed CD105, CD90 and CD73, and lower expressed CD34 and CD45. There was no significant difference in cell morphology and multipotent differentiation ability between N-NPMSC and D-NPMSC. D-NPMSC showed significantly lower expressions of stemness genes, cell proliferation and colony formation ability. D-NPMSC also exhibited increased cell apoptosis rate and caspase-3 expression, and significantly lower expressions of HIF-1α, GLUT-1, VEGF, SIRT1 and SIRT6 in mRNA and protein levels compared with N-NPMSC.Conclusions: N-NPMSC showed significantly higher proliferation rate, better colony forming and stemness maintenance ability, whereas reduced cell apoptosis rate compared with D-NPMSC. HIF-1α-mediated signal pathway may be involved in the regulation of NPMSC proliferation. These findings indicated that degenerative change of IVD should be taken into account when selecting a source of NPMSC for clinical application.

SIRT1 Deletion Impairs Retinal Endothelial Cell Migration Through Downregulation of VEGF-A/VEGFR-2 and MMP14.

Silent information regulator protein 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent deacetylase that is abundantly expressed in vascular endothelial cells (VECs), and it has an essential role in angiogenesis. However, its contribution to retinal vascular development remains unclear. Here we characterize its involvement in regulating this process under both physiological and pathologic conditions. Endothelium-specific Sirt1 knockout mice were established using the Cre-lox system. VECs were isolated using magnetic beads and identified by immunostaining. Retinal whole-mount staining analyzed the retinal vascular patterns. SIRT1 was knocked down or overexpressed in human retinal microvascular endothelial cells (HRMECs) using small interfering RNA (siRNA) or lentivirus infection, respectively. Scratch assay, Transwell, and Matrigel angiogenesis assay evaluated cell migration and tube formation, respectively. Quantitative RT-PCR analyzed genes regulating VEC migration. Western blotting determined protein expression. Coimmunoprecipitation detected the interaction of hypoxia-inducible factor 1α (HIF-1α) and SIRT1 as well as acetylation status of HIF-1α. Specific deletion of Sirt1 in VECs dramatically delayed retinal vessel expansion and reduced vessel density. In the oxygen-induced retinopathy (OIR) mouse model, Sirt1 ablation markedly suppressed retinal revascularization and consequently increased retinal avascularity. SIRT1 downregulation in HRMECs inhibited cell migration and tube formation, while overexpression of SIRT1 had the opposite effects. Vascular endothelial growth factor-A (VEGF-A)/VEGF receptor-2 (VEGFR-2), and matrix metalloproteinases 14 (MMP14) expression significantly declined in Sirt1-null VECs, as well as SIRT1 siRNA-transfected HRMECs. SIRT1 downregulation upregulated the HIF-1α acetylation status. Conversely, SIRT1 overexpression decreased this response. SIRT1 contributes to both physiological and pathologic retinal angiogenesis through promoting retinal VEC migration. Its underlying molecular mechanism involves SIRT1-mediated deacetylation of HIF-1α and subsequent upregulation of VEGF-A/VEGFR-2 and MMP14 expression.

Protective effect of polysaccharide peptide on cerebral ischemia‑reperfusion injury in rats.

In the present study, the protective effects and regulatory mechanism of polysaccharide peptide (PSP) were investigated in rats with cerebral ischemia-reperfusion (IR) injury. Neuroblastoma N2a cells were divided into five groups: Negative control; IR injury; PSP low dose treatment; PSP middle dose treatment; and PSP high dose treatment. In vitro, the cell viability was detected by an MTT assay. ELISA was performed to determine the activity of lactate dehydrogenase (LDH) and caspase-3. A cerebral IR injury model in vivo was established, and hematoxylin and eosin (H&E) staining, western blotting, neurological deficit score and cerebral infarction were assessed. The cell viability was markedly improved following treatment with PSP and the activity of LDH and caspase-3 was decreased following PSP administration (P<0.05). The in vivo studies determined that the neurological deficit score and cerebral infarction volume were reduced with the concentration of PSP increasing between 150 and 250 mg/kg. The H&E staining indicated that PSP was able to protect the nerve cells against the cerebral IR injury. In addition, PSP upregulated the decreased silent information regulator protein 1, peroxisome proliferator-activated receptor γ coactivator-1α and apoptosis regulator B-cell lymphoma 2 expression induced by cerebral IR injury. The protein expression level of caspase-3 and apoptosis regulator apoptosis regulator Bcl-2-like protein 4 was downregulated following PSP administration. These results suggested that PSP may improve nerve cell viability, enhance the neuroprotective role in cerebral IR injury and provide a novel approach for the treatment of cerebral IR injury.

Comparison of biological characteristics of nucleus pulposus mesenchymal stem cells from non-degenerative and degenerative nucleus pulposus in rats

Objective To compare the biological characteristics of nucleus pulposus mesenchymal stem cells (NPMSCs) derived from non-degenerative and degenerative intervertebral disc (IVD). Methods NPMSCs were isolated from non-degenerative (N-NPMSCs) and degenerative IVD (D-NPMSCs). Flow cytometry was performed to detect the expressions of cell surface markers. The expression of the stemness genes was detected by reverse-transcription quantitative polymerase chain reaction (RT-PCR). The biological characteristics of NPMSCs, including cell colony formation, cell proliferation, cell apoptosis, cysteinyl aspartate-specific protease (Caspase)-3 activity, mRNA and protein expressions of hypoxia inducible factor-1α (HIF-1α), glucose transporter 1(GLUT-1), vascular endothelial growth factor (VEGF), silent information regulator protein 1 (SIRT1) and SIRT6 were compared. Results NPMSCs from both groups highly expressed CD105, CD90 and CD73 and low expressed CD45 and CD11b/c. D-NPMSCs showed lower expression of stemness genes [sex determination region related high mobility group box protein-2 (Sox-2): 1.52±0.21 vs. 3.41±0.94, Nanog: 2.15±0.16 vs. 4.72±1.12, octamer-binding transcription factor 4 (Oct-4): 1.73±0.11 vs. 3.22±1.03) (t=6.145, 6.556, 7.806, P=0.000, 0.000, 0.000). D-NPMSCs showed lower clonogenic [(23.5±10.1)% vs. (39.4±12.2)%, t=5.304, P=0.001] and proliferative activity, while increased rate of cell apoptosis (10.43% vs. 4.69%) (t=7.689, P=0.000) and Caspase-3 activity (0.77 vs. 0.72) (t=2.743, P=0.016). D-NPMSCs also showed lower expression of HIF-1α, GLUT-1, VEGF, SIRT1 and SIRT6 in the mRNA and protein levels (The results of each experiment were 0.35±0.23, 0.51±0.22; 0.94±0.14, 0.90±0.13; 0.02±0.01, 0.41±0.02; 0.04±0.02, 0.73±0.34 and 0.51±0.22, 0.84±0.05; respecticely) (The t value was 6.486, 5.015; 2.271, 2.572; 4.921, 6.275; 7.898, 6.754 and 7.016, 7.956; respectively; The P value was 0.000, 0.001; 0.044, 0.023; 0.001, 0.000; 0.000, 0.000 and 0.000, 0.000; respectively). Conclusion D-NPMSCs showed different biological behaviors including lower proliferative activity, lower expression of stemness gene and higher cell apoptosis rate. The HIF-1α-mediated pathway may be involved in the mechanism of cell proliferation. Key words: Nucleus pulposus mesenchymal stem cells; Intervertebral disc degeneration; Proliferation; Apoptosis; Hypoxia inducible factor-1α

(−)-Epicatechin and the colonic metabolite 3,4-dihydroxyphenylacetic acid protect renal proximal tubular cell against high glucose-induced oxidative stress by modulating NOX-4/SIRT-1 signalling

Oxidative stress plays a main role in the pathogenesis of the diabetic nephropathy. The present study investigated the effect of (−)-epicatechin (EC) and the colonic-derived flavonoid metabolites 2,3-dihydroxybenzoic acid, 3,4-dihydroxyphenylacetic acid (DHPAA), and 3-hydroxyphenylpropionic acid on the redox status in high-glucose-exposed renal proximal tubular NRK-52E cells. EC and DHPAA (10 µM) alleviated the redox imbalance induced in high-glucose-challenged cells, as both compounds reverted to control levels reactive oxygen species (ROS) values. EC and DHPAA pre-treatment prevented the decrease of antioxidant defences and silent information regulator protein-1 (SIRT-1), and the increase of phosphorylated mitogen-activated-protein-kinases and NADPH-oxidase-4 (NOX-4) values under high-glucose-conditions. The presence of selective NOX-4 and SIRT-1 inhibitors in EC- and DHPAA-pre-treated cells showed the involvement of both proteins in EC- and DHPAA-mediated protection. These findings suggest that EC and DHPAA protected NRK-52E cells against a high-glucose-challenge by improving the cellular redox status through multiple signalling pathways, playing NOX-4/SIRT-1 a relevant role.

Silent information regulator protein 6 and autophagy in age-related macular degeneration

Age-related macular degeneration is one of the major causes of blindness in the elderly. As an important pathway of cell metabolism, autophagy maintains intracellular homeostasis through the degradation and recycle of damaged organelles and macromolecules. Understanding its mechanism may promote discoveries to delay aging process, reduce the incidence of age-related diseases. In mammals, silent information regulator protein 6 (SIRT6) plays its deacetylase and ribonucleotransferase activity in multiple signaling pathways, including inhibition of cellular senescence, tumorigenesis, metabolic diseases, regulating cellular lifespan. It has a significant impact on the structure and function of tissues and organs. SIRT6 regulates intracellular autophagy mainly through the insulin-like growth factor-protein kinase B-mammalian target of rapamycin, reducing the accumulation of toxic metabolites and cellular senescence. The function of SIRT6 in age-related macular degeneration need to be combined with the genetic background, pathogenesis, clinical manifestations and other aspects of the disease, and it is expected to be further studied in subsequent studies. Key words: Sirtuins; Autophagy; Aging; Macular degeneration; Diabetic retinopathy

Expression of SIRT1 and P53 in Rat Lens Epithelial cells in Experimentally Induced DM

ABSTRACTPurpose: To determine the etiopathogenesis of diabetic cataract by studying changes in relative expressions of silent information regulator protein-1 (SIRT1) and P53 in rat lens epithelial cells (LECs) in experimentally induced diabetes mellitus (DM).Methods: Six-week-old male SD rats (n = 120) were randomly divided into experimental (n = 80 rats) and control (n = 40 rats) groups. DM was induced in the experimental group (diabetic model) by intraperitoneal (i.p.) injection of 60 mg/kg streptozotocin (STZ). Control group rats were injected similarly with phosphate-buffered saline (PBS). Four and eight weeks after successful induction of DM, relative expressions of SIRT1 and P53 in LECs were analyzed using quantitative real-time (qRT) fluorescence polymerase chain reaction (qRT-PCR) and Western blot analysis.Results: Expression of both SIRT1 and P53 was observed in LECs of control and experimental group rats at 4 and 8 weeks but was significantly greater in experimental compared with control group rats (p < 0.05).Conclusions: Expression of both SIRT1 and P53 increases in the early stages of diabetic cataract formation, indicating that they play potentially important roles in the pathogenesis of diabetic cataract.

TRPC5 channel modulates endothelial cells senescence

As a Ca2+-permeable cationic channel, canonical transient receptor potential 5 channel (TRPC5) has been known to be involved in various functions of cells. Although TRPC5 is abundantly expressed in vascular endothelium, it remains unknown whether TRPC5 plays a role in regulating endothelial senescence. In the present study, we investigated the involvement of TRPC5 in the senescence of mouse aortic endothelial cells (MAECs). Meanwhile, the regulatory role of TRPC5 in the endothelial dysfunction in aged mice was also studied. Results showed that the endothelium-dependent relaxations were significantly promoted but the endothelium-dependent contractions were markedly attenuated in aortic rings from aged mice with TRPC5 gene knocked out compared with those from aged C57BL/6J mice. Meanwhile, the nuclear telomerase activity and nitric oxide generation were notably enhanced but the reactive oxygen species production was significantly inhibited in aged mice or in hydrogen peroxide-induced senescent MAECs lacking the TRPC5 gene. In addition, by performing the senescence-associated β-galactosidase staining the oxidative stress-induced premature senescence was markedly depressed in MAECs with TRPC5 gene deficient. Expressions of endothelial nitric oxide synthase and silent information regulator protein 1 (SIRT1) were significantly up-regulated but those of P53 and P21 were markedly down-regulated both in aged mice and in hydrogen peroxide-treated MAECs in the absence of the TRPC5 gene. These results of our study uncover novel functions of TRPC5 in regulating vascular aging.

Hepatoprotective effect of grape seed oil against carbon tetrachloride induced oxidative stress in liver of γ-irradiated rat

Carbon tetrachloride (CCl4) and ionizing radiation are well known environmental pollutants that generate free radicals and induce oxidative stress. The liver is the primary and major target organ responsible for the metabolism of drugs, toxic chemicals and affected by irradiation. This study investigated the effect of grape seed oil (GSO) on acute liver injury induced by carbon tetrachloride (CCl4) in γ-irradiated rats (7Gy). CCl4-intoxicated rats exhibited an elevation of ALT, AST activities, IL-6 and TNF-α level in the serum. Further, the levels of MDA, NO, NF-κB and the gene expression of CYP2E1, iNOS and Caspase-3 were increased, and SOD, CAT, GSH-Px, GST activities and GSH content were decreased. Furthermore, silent information regulator protein 1 (SIRT1) gene expression was markedly down-regulated. Additionally, alterations of the trace elements; copper, manganese, zinc and DNA fragmentation was observed in the hepatic tissues of the intoxicated group. These effects were augmented in CCl4-intoxicated-γ-irradiated rats. However, the administration of GSO ameliorated these parameters. GSO exhibit protective effects on CCl4 induced acute liver injury in γ-irradiated rats that could be attributed to its potent antioxidant, anti-inflammatory and anti-apoptotic activities. The induction of the antioxidant enzymes activities, down-regulation of the CYP2E1, iNOS, Caspase-3 and NF-κB expression, up-regulation of the trace elements concentration levels and activation of SIRT1 gene expression are responsible for the improvement of the antioxidant and anti-inflammatory status in the hepatic tissues and could be claimed to be the hepatoprotective mechanism of GSO.

Non-alcoholic fatty liver disease in 2015.

There is worldwide epidemic of non-alcoholic fatty liver disease (NAFLD). NAFLD is a clinical entity related to metabolic syndrome. Majority of the patients are obese but the disease can affect non-obese individuals as well. Metabolic factors and genetics play important roles in the pathogenesis of this disorder. The spectrum of disorders included in NAFLD are benign macrovesicular hepatic steatosis, non-alcoholic steatohepatitis, hepatic fibrosis, cirrhosis of liver and hepatocellular carcinoma. Although the disease remains asymptomatic most of the time, it can slowly progress to end stage liver disease. It will be the most common indication of liver transplantation in the future. It is diagnosed by abnormal liver chemistry, imaging studies and liver biopsy. As there are risks of potential complications during liver biopsy, many patients do not opt for liver biopsy. There are some noninvasive scoring systems to find out whether patients have advanced hepatic fibrosis. At the present time, there are limited treatment options which include lifestyle modification to loose weight, vitamin E and thioglitazones. Different therapeutic agents are being investigated for optimal management of this entity. There are some studies done on incretin based therapies in patients with NAFLD. Other potential agents will be silent information regulator protein Sirtuin and antifibrotic monoclonal antibody Simtuzumab against lysyl oxidase like molecule 2. But they are still in the investigational phase.

Angiogenic Dysfunction in Bone Marrow-Derived Early Outgrowth Cells from Diabetic Animals Is Attenuated by SIRT1 Activation

Impaired endothelial repair is a key contributor to microvascular rarefaction and consequent end-organ dysfunction in diabetes. Recent studies suggest an important role for bone marrow-derived early outgrowth cells (EOCs) in mediating endothelial repair, but the function of these cells is impaired in diabetes, as in advanced age. We sought to determine whether diabetes-associated EOC dysfunction might be attenuated by pharmacological activation of silent information regulator protein 1 (SIRT1), a lysine deacetylase implicated in nutrient-dependent life span extension in mammals. Despite being cultured in normal (5.5 mM) glucose for 7 days, EOCs from diabetic rats expressed less SIRT1 mRNA, induced less endothelial tube formation in vitro and neovascularization in vivo, and secreted less of the proangiogenic ELR(+) CXC chemokines CXCL1, CXCL3, and CXCL5. Ex vivo SIRT1 activation restored EOC chemokine secretion and increased the in vitro and in vivo angiogenic activity of EOC conditioned medium derived from diabetic animals to levels similar to that derived from control animals. These findings suggest a pivotal role for SIRT1 in diabetes-induced EOC dysfunction and that its pharmacologic activation may provide a new strategy for the restoration of EOC-mediated repair mechanisms.

The protective role of silent information regulator protein 1 in myocardial ischemia/reperfusion injury

Background Silent information regulator protein 1 (Sirt1) is a NAD-depended class Ⅲ histone/nonhistone deaceytalase,which regulates various biological processes.Not only does Sirt1 play an important role in anti-aging,it also protects cardiomyocytes from ischemia and reperfusion (I/R) injury. Objective To review the mechanisms of Sirt1's protecting cardiomyocytes from myocardial I/R injury and several ways to activating sirt1. Content Sirt1 alleviates the I/R injury by increasing the generation of reactive oxygen species scavengers,inhibiting the apoptosis,promoting autophagic flux,attenuating the inflammatory reactions and promoting mitochondrial biogenesis.Activating Sirt1 is an important method in attenuating the I/R injury.Trend Sirt1 will be one of key targets in alleviating the I/R injury as the research about its protective mechanism is deepening. Key words: Silent information regulator protein 1 ; Ischemia/reperfusion injury ; Reactive oxygen species ; Apoptosis ; Autophagy ;

Potential roles of autophagy and silent information regulator protein family in myocardial ischemia/reperfusion injury

Background Autophagy is the endogenous,tightly regulated cellular process responsible for the degradation of damaged and dysfunctional cellular organelles and protein aggregates.There is a growing consensus that autophagy is upregulated in the setting of myocardial ischemia/reperfusion (I/R),but it has also been unclear whether autophagy is protective or detrimental in response to I/R.Silent information regulator protein (Sirt) family,which was considered as a longevity factor,may be involved in the regulation of autophagy in I/R.Objective To understand the relationship of Sirt family,autophagy and I/R.Content Thereview will discussthe basic process of autophagy,molecular machinery and signaling pathways of autophagy,the role of autophagy during I/R,and the relationship between Sirt family and autophagy.Trend In addition to understand the concept of autophagy deeply,the role of Sirt family in myocardial protection needs further exploration. Key words: Autophagy; Ischemia/reperfusion ; Cardiac myocyte s ; ATG genes; Silent information regulator protein family ; Longevity

Arabidopsis Putative Deacetylase AtSRT2 Regulates Basal Defense by Suppressing PAD4, EDS5 and SID2 Expression

The silent information regulator protein (Sir2) and its homologs are NAD+-dependent deacetylase enzymes that play important roles in a variety of physiological processes. However, the functions of the Sir2 family in plants are poorly understood. Here, we report that Arabidopsis AtSRT2, a homolog of yeast Sir2, negatively regulates plant basal defense against the pathogen Pseudomonas syringae pv. tomato DC3000 (PstDC3000). In response to PstDC3000 infection, the expression of AtSRT2 was down-regulated in a salicylic acid (SA)-independent manner. In addition, knock-out of AtSRT2 (srt2) enhanced resistance against PstDC3000 and increased expression of pathogenesis-related gene 1 (PR1). Conversely, overexpression of AtSRT2 resulted in hypersusceptibility to PstDC3000 and impaired PR1 induction. Consistent with this phenotype, expression of PAD4, EDS5 and SID2, three essential genes in the SA biosynthesis pathway, were increased in the srt2 mutant and decreased in AtSRT2-overexpressing plants. Taken together, these results demonstrate that AtSRT2 is a negative regulator of basal defense, possibly by suppressing SA biosynthesis.