Silent Information Regulator 2 Homolog 1 Research Articles

Resveratrol promotes hUC-MSCs engraftment and neural repair in a mouse model of Alzheimer’s disease

Mesenchymal stem cell transplantation is a promising therapeutic approach for Alzheimer’s disease (AD). However, poor engraftment and limited survival rates are major obstacles for its clinical application. Resveratrol, an activator of silent information regulator 2, homolog 1 (SIRT1), regulates cell destiny and is beneficial for neurodegenerative disorders. The present study is designed to explore whether resveratrol regulates the fate of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and whether hUC-MSCs combined with resveratrol would be efficacious in the treatment of neurodegeneration in a mouse model of AD through SIRT1 signaling. Herein, we report that resveratrol facilitates hUC-MSCs engraftment in the hippocampus of AD mice and resveratrol enhances the therapeutic effects of hUC-MSCs in this model as demonstrated by improved learning and memory in the Morris water maze, enhanced neurogenesis and alleviated neural apoptosis in the hippocampus of the AD mice. Moreover, hUC-MSCs and resveratrol jointly regulate expression of hippocampal SIRT1, PCNA, p53, ac-p53, p21, and p16. These data strongly suggests that hUC-MSCs transplantation combined with resveratrol may be an effective therapy for AD.

SIRT1 promotes tumor-like invasion of fibroblast-like synoviocytes in rheumatoid arthritis via targeting TIMP1.

Suppression of tissue inhibitor of matrix metalloproteinase (TIMP) is associated with the tumor-like invasion of fibroblast-like synoviocytes (FLSs) that occurs during rheumatoid arthritis-related cartilage destruction. Silent information regulator 2 homolog1 (SIRT1), a histone deacetylase, is widely involved in transcriptional regulation, genomic stability, metabolism and DNA repair. Recent studies suggest that SIRT1 may also impact inflammatory response and the proliferation of FLSs in rheumatoid arthritis (RA). However, it is unknown whether SIRT1 has a role in the tumor-like invasion of FLSs in rheumatoid arthritis. Herein we report that SIRT1 contributes to FLS invasion and cartilage destruction via a TIMP1-dependent mechanism. Elevated SIRT1 in RA synovia suppresses TIMP1 expression via deacetylation of TIMP1-associated histones, thereby disrupting the binding of the transcription factor specificity protein 1 (Sp1) to the TIMP1 promoter. In rats with collagen-induced arthritis, depletion of SIRT1 remarkably promoted TIMP1 expression in synovial tissues and ameliorated cartilage destruction. These results describe a new role for SIRT1 and demonstrate its potential value as a therapeutic target for rheumatoid arthritis.

SIRT1 gene polymorphisms and its protein level in colorectal cancer

Colorectal cancer (CRC) is a major cause of mortality and morbidity, and accounts for over 9% of cancer incidence worldwide. Nuclear localized silent information regulator 2 homolog 1 (SIRT1) gene exerts its effects via modulation of histone and non-histone targets. SIRT1 gene functions in the cell via histone deacetylase (HDAC) and/or adenosine diphosphate ribosyl transferase (ADPRT) enzymatic activity. The aim of this work is to study the relationship between SIRT1 polymorphism and its protein level in colorectal cancer patients in comparison to control cases. This study includes two group, thirty healthy subjects (control group) and one hundred CRC patients. SIRT-1 serum level was measured in both the groups by ELISA and gene polymorphisms of rs12778366, rs375891 and rs3740051were detected by real time PCR. For CRC patients clinical data was collected including tumor size, tumor grade, tumor site, obesity. CRC patients showed a significant increase in the mean level of serum SIRT-1 compared to control group (P<0.001). Mean serum level of SIRT-1 showed a significant increase in patients with tumor size ≥5cm compared to the size <5cm (P<0.05). In CRC patients, the percentage of T allele of rs12778366 was significantly lower than controls, CC genotype and C allele C of rs375891 were significantly higher than control group. In CRC patients, the CC genotype of rs12778366, was 75% in the rectosigmoid colon and 25% in cecum & ascending colon. According to tumor size, the percentage of CC genotype was 87.5% in tumor size ≥5cm. ConclusionSerum level of SIRT-1 and T allele, C allele of rs12778366 and rs375891 respectively can be used as diagnostic markers for CRC patients.

The effect of lead exposure on expression of SIRT1 in the rat hippocampus.

Based on how the silent information regulator 2 homolog 1 (SIRT1) regulates the cyclic AMP response element binding protein (CREB), which is the molecular switch of long-term memory that maintains cognitive function, it is postulated that the impact of lead (Pb) on SIRT1 is one of the mechanisms leading to Pb-induced cognitive and learning deficits. Hence, the purpose of this study was to investigate the effect of Pb exposure on the expression of SIRT1, and the reversion effect of resveratrol, which is an activator of SIRT1. We examined the effects of maternal rat ingestion of Pb in drinking water during gestation and lactation on the expression of SIRT1 and CREB in the hippocampus of their offspring at postnatal week 3 (PNW3) and 52 (PNW52), and then reexamined these effects in offspring after intragastric administration of resveratrol for 4 weeks. Pb exposure decreased SIRT1 and CREB phosphorylation in a dose-dependent manner in the rat hippocampus at both PNW3 and 52, and resveratrol reversed those losses. These results indicated that SIRT1 might be a novel target to prevent Pb neurotoxicity.

SIRT1 attenuates severe ischemic damage by preserving cerebral blood flow.

Silent information regulator 2 homolog 1 (SIRT1) is a protein deacetylase that has been reported to suppress neurodegenerative and cardiovascular pathologies in model organisms. We have recently reported that SIRT1 overexpression preserves cerebral blood flow (CBF) after bilateral common carotid artery stenosis (∼50% stenosis) by the deacetylation of endothelial nitric oxide synthase. This study was designed to determine whether cerebral SIRT1 expression would be effective in a more severe model of cerebral ischemia caused by bilateral common carotid artery occlusion (BCAO) in vivo. Sirt1-overexpressing (Sirt1-Tg) mice (n=13) and their wild-type littermates (n=17) were subjected to BCAO for 10 min using microaneurysm clips. Temporal CBF changes were measured by laser speckle flowmetry before and 5, 10 min, and 2 h after BCAO. Histological evaluation of hippocampal changes was performed 7 days after BCAO. Histological findings were significantly less severe in Sirt1-Tg mice than in wild-type mice; wild-type mice showed strokes in the hippocampus, whereas Sirt1-Tg mice had minimal hippocampal damage 7 days after BCAO. Consistent with this observation, wild-type mice showed a severe reduction in CBF to ∼20-25% of the baseline level during BCAO, whereas Sirt1-Tg littermates showed significantly preserved CBF up to 45-50% of the baseline level. Our study provides evidence for the promising role of SIRT1 in protecting against cerebral global ischemia by preserving CBF and restoring the cerebrovascular reserve.

Silent information regulator 2 homolog 1 counters cerebral hypoperfusion injury by deacetylating endothelial nitric oxide synthase.

Silent information regulator 2 homolog 1 (SIRT1) is a protein deacetylase that has been reported to suppress neurodegenerative and cardiovascular diseases in model organisms. We hypothesized that neurovascular protection is one of the diverse actions of SIRT1. This study was designed to determine whether SIRT1 protects against the consequences of cerebral hypoperfusion in vivo. Sirt1-overexpressing (Sirt1-Tg) mice driven by a prion promoter and their wild-type littermates were subjected to bilateral common carotid artery stenosis using external microcoils. Using Sirt1-Tg mice, we assessed the effect of SIRT1 on cerebral blood flow, cerebral angioarchitecture, histological and ultrastructural changes, and spatial working memory at several time points. We also evaluated the effects of preadministration of SIRT1 inhibitors or endothelial nitric oxide synthase inhibitors on cerebral blood flow after bilateral common carotid artery stenosis in Sirt1-Tg mice. Levels of acetylated and nonacetylated endothelial nitric oxide synthase were measured semiquantitatively with immunoblotting. Cerebral hypoperfusion induced by bilateral common carotid artery stenosis caused memory impairment and histological changes in wild-type littermates. However, these phenotypes were rescued in Sirt1-Tg mice, where cerebral blood flow was maintained even poststenosis. Electron microscopic analyses showed irregularities in the vascular endothelia, such as tight junction openings in wild-type mice, which were absent in Sirt1-Tg littermates. Brain endothelial nitric oxide synthase was acetylated after cerebral hypoperfusion in wild-type littermates but remained unacetylated in Sirt1-Tg mice. Moreover, treatment with SIRT1 inhibitors and endothelial nitric oxide synthase inhibitors abolished the vasculoprotective effects of SIRT1. Our results indicate that neurovascular endothelial SIRT1 potentiation upregulates the nitric oxide system and counters cerebral hypoperfusion injury. This novel cerebral blood flow-preserving mechanism offers potential molecular targets for future therapeutic intervention.