• International journal of thyroidology
• /
• v.11 no.2
• /
• pp.143-151
• /
• 2018

Background and Objectives: Sirtuins (SIRTs) play important roles in cellular and organismal homeostasis. They have distinct gene expression patterns in various cancers; however, the relationship between SIRT expression and the progression of thyroid cancer is unclear. We investigated the expression of SIRTs in patients with papillary thyroid carcinoma (PTC) and their role as biomarkers for predicting the aggressiveness of this disease. Materials and Methods: We used immunohistochemical staining to evaluate the expression of SIRT1 and SIRT3 in tumor specimens from 270 patients with PTC. We also evaluated the potential association between SIRT expression and diverse clinicopathological features. Results: High SIRT1 expression was negatively correlated with lymphovascular invasion, central lymph node metastasis, and lateral lymph node metastasis. Multivariate analyses revealed that high SIRT1 expression was a negative independent risk factor for lateral lymph node metastasis. By contrast, high SIRT3 expression was positively correlated with locoregional recurrence. Interestingly, when patients were grouped by tumor SIRT expression patterns, the group with low SIRT1 expression and high SIRT3 expression was correlated with more aggressive cancer phenotypes including central lymph node metastasis and lateral lymph node metastasis. Conclusion: Our results suggest that SIRTs play dual roles in tumor progression, and the combination of decreased SIRT1 expression and increased SIRT3 expression is significantly associated with a poor prognosis in patients with PTC.

• Journal of Gastric Cancer
• /
• v.10 no.3
• /
• pp.91-98
• /
• 2010

Purpose: Silent mating-type information regulation 2 homologue 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent deacetylase. SIRT1 plays an important role in the regulation of cell death/survival and stress response in mammals. The aim of this study was to investigate whether the SIRT1 gene is involved in the development or progression of gastric cancers. Materials and Methods: SIRT1 and p53 genes in 86 gastric cancers were examined for genetic alterations by PCR-single strand conformation polymorphism sequencing, as well as SIRT1 protein expression in 170 gastric cancers by immunohistochemistry. Results: In the genetic analysis, we found SIRT1 and p53 mutations in two and 12 cases, respectively. Two missense mutations, c.599 C>T (T200I) and c.1258 G>A (E420K), were detected in the SIRT1 gene coding region. The SIRT1 and p53 mutation were found in mutually exclusive gastric cancers. The immunohistochemistry revealed that SIRT1 overexpression was found in 95 (55.9%) of 170 gastric cancers. Altered SIRT1 expression was not statistically associated with clinicopathological parameters, including tumor differentiation, location, lymph node metastasis, or p53 expression. Two cases with an SIRT1 mutation showed increased SIRT1 expression. Conclusions: These results suggest that genetic alterations and overexpression of the SIRT1 gene may contribute to gastric cancer development.

• Molecules and Cells
• /
• v.39 no.2
• /
• pp.87-95
• /
• 2016

Sirt1 is the most prominent and extensively studied member of sirtuins, the family of mammalian class III histone deacetylases heavily implicated in health span and longevity. Although primarily a nuclear protein, Sirt1's deacetylation of Peroxisome proliferator-activated receptor Gamma Coactivator-$1{\alpha}$ (PGC-$1{\alpha}$) has been extensively implicated in metabolic control and mitochondrial biogenesis, which was proposed to partially underlie Sirt1's role in caloric restriction and impacts on longevity. The notion of Sirt1's regulation of PGC-$1{\alpha}$ activity and its role in mitochondrial biogenesis has, however, been controversial. Interestingly, Sirt1 also appears to be important for the turnover of defective mitochondria by mitophagy. I discuss here evidences for Sirt1's regulation of mitochondrial biogenesis and turnover, in relation to PGC-$1{\alpha}$ deacetylation and various aspects of cellular physiology and disease.

• Reproductive and Developmental Biology
• /
• v.39 no.2
• /
• pp.43-47
• /
• 2015

Sirtuin proteins are evolutionary conserved Sir2-related $NAD^+$-dependent deacetylases and regulate many of cellular processes such as metabolism, inflammation, transcription, and aging. Sirtuin contains activity of either ADP-ribosyltransferase or deacetyltranfease and their activity is dependent on the localization in cells. However, the expression pattern of Sirtuins has not been well studied. To examine the expression levels of Sirtuins, RT-PCR was performed using total RNAs from various tissues including liver, small intestine, heart, brain, kidney, lung, spleen, stomach, uterus, ovary, and testis. Sirtuins were highly expressed in most of tissues including the testis. Immunostaining assay showed that Sirt1 and Sirt6 were mainly located in the nucleus of germ cells, spermatocytes, and spermatids in the seminiferous tubules, whereas Sirt2 and Sirt5 were exclusively present in the cytoplasm of germ cells and spermatocytes. Our results indicate that Sirtuins may function as regulators of spermatogenesis and their activities might be dependent on their location in the seminiferous tubules.

• Journal of Obesity & Metabolic Syndrome
• /
• v.27 no.4
• /
• pp.248-253
• /
• 2018

Background: Sirtuins mediate metabolic responses to nutrient availability and slow aging and accompanying decline in health. This study was designed to assess the expressions of sirtuin1 (SIRT1) and sirtuin3 (SIRT3) in the liver and hypothalamus after duodenal-jejunal bypass (DJB) surgery in rats. Methods: A total of 38 rats were randomly assigned to either sham group (n=8) or DJB group (n=30). DJB group was again divided into three groups according to the elapsed time after surgery (10 weeks, DJB10; 16 week, DJB16; 28 week, DJB28). The mRNA and protein expressions of SIRT1 and SIRT3 in the liver and hypothalamus were measured by reverse transcription polymerase chain reaction, Western blot, and immunohistochemistry analyses. $NAD^+/NADH$ ratio was also measured. Results: We found increased mRNA and protein expression levels of SIRT1 in the liver of DJB16 and DJB28 groups compared with those of sham group. The mRNA and protein expressions of SIRT3 in the liver of DJB group increased proportionally to the elapsed time after DJB surgery. The mRNA expression levels of SIRT1 in the hypothalamus increased in DJB16 and DJB28 groups and protein expression levels of SIRT1 in the hypothalamus increased in DJB10, DBJ16, and DJB28 groups compared with sham group. We observed that mRNA and protein levels of SIRT3 in the hypothalamus of DJB group were not changed. Conclusion: This study proves that DJB increases SIRT1 and SIRT3 expressions in the liver and SIRT1 expression in the hypothalamus. These results suggest the possibility of sirtuins being involved in bypass surgery-induced metabolic changes.

• Food Science of Animal Resources
• /
• v.40 no.1
• /
• pp.106-117
• /
• 2020

Cellular senescence is associated with age-related vascular disorders and has been implicated in vascular dysfunctions. Here, we show that duck oil-loaded nanoemulsion (DO-NE) attenuates premature senescence of vascular smooth muscle cells (VSMCs) triggered by angiotensin II (Ang II). Compared with control nanoemulsion (NE), DO-NE significantly inhibited the activity of senescence-associated β-galactosidase, which is a biomarker of cellular senescence, in Ang II-treated VSMCs. SIRT1 protein expression was dose- and time-dependently induced in VSMCs exposed to DO-NE, but not in those exposed to NE, and SIRT1 promoter activity was also elevated. Consistently, DO-NE also dose-dependently rescued Ang II-induced repression of SIRT1 expression, indicating that SIRT1 is linked to the anti-senescence action of DO-NE in VSMCs treated with Ang II. Furthermore, the SIRT1 agonist resveratrol potentiated the effects of DO-NE on VSMCs exposed to Ang II, whereas the SIRT1 inhibitor sirtinol elicited the opposite effect. These findings indicate that DO-NE inhibits senescence by upregulating SIRT1 and thereby impedes vascular aging triggered by Ang II.

• BMB Reports
• /
• v.52 no.4
• /
• pp.265-270
• /
• 2019

We investigated whether SIRT1 is associated with reactive oxygen species (ROS) accumulation during CK2 downregulation-mediated senescence. SIRT1 overexpression suppressed ROS accumulation, reduced transcription of FoxO3a target genes, and nuclear export and acetylation of FoxO3a, which were induced by CK2 downregulation in HCT116 and MCF-7 cells. Conversely, overexpression of a dominant-negative mutant SIRT1 (H363Y) counteracted decreased ROS levels, increased transcriptional activity of FoxO3a, and increased nuclear import and decreased acetylation of FoxO3a, which were induced by CK2 upregulation. CK2 downregulation destabilized SIRT1 protein via an ubiquitin-proteasome pathway in human cells, whereas CK2 overexpression reduced ubiquitination of SIRT1. Finally, the SIRT1 activator resveratrol attenuated the accumulation of ROS and lipofuscin as well as lifespan shortening, and reduced expression of the DAF-16 target gene sod-3, which were induced by CK2 downregulation in nematodes. Altogether, this study demonstrates that inactivation of the SIRT1-FoxO3a axis, at least in part, is involved in ROS generation during CK2 downregulation-mediated cellular senescence and nematode aging.

• BMB Reports
• /
• v.56 no.5
• /
• pp.314-319
• /
• 2023

Sepsis is a life-threatening multi-organ dysfunction with high mortality caused by the body's improper response to microbial infection. No new effective therapy has emerged that can adequately treat patients with sepsis. We previously demonstrated that interferon-β (IFN-β) protects against sepsis via sirtuin 1-(SIRT1)-mediated immunosuppression. Another study also reported its significant protective effect against acute respiratory distress syndrome, a complication of severe sepsis, in human patients. However, the IFN-β effect cannot solely be explained by SIRT1-mediated immunosuppression, since sepsis induces immunosuppression in patients. Here, we show that IFN-β, in combination with nicotinamide riboside (NR), alleviates sepsis by blocking endothelial damage via SIRT1 activation. IFN-β plus NR protected against cecal ligation puncture-(CLP)-induced sepsis in wild-type mice, but not in endothelial cell-specific Sirt1 knockout (EC-Sirt1 KO) mice. IFN-β upregulated SIRT1 protein expression in endothelial cells in a protein synthesis-independent manner. IFN-β plus NR reduced the CLP-induced increase in in vivo endothelial permeability in wild-type, but not EC-Sirt1 KO mice. IFN-β plus NR suppressed lipopolysaccharide-induced up-regulation of heparinase 1, but the effect was abolished by Sirt1 knockdown in endothelial cells. Our results suggest that IFN-β plus NR protects against endothelial damage during sepsis via activation of the SIRT1/heparinase 1 pathway.

• Development and Reproduction
• /
• v.23 no.4
• /
• pp.391-399
• /
• 2019

Nicotinamide is used to maturate pancreatic progenitors from embryonic stem cells (ESCs) into insulin-producing cells (IPCs). It has been known that nicotinamide inhibits the enzymatic activity of SIRT1, an NAD⁺-dependent deacetylase. Here we show that SIRT1 knockdown enhances the differentiation of human ESCs into IPCs. SIRT1 knockdown enhances the clustering size of IPCs and the expression of pancreatic genes including c-peptide, pancreas/duodenum homeobox protein 1 (PDX1), insulin, somatostatin, glucagon and Nkx6.1 in human ESC-derived IPCs. In addition, We found that IPCs differentiated from SIRT1 knockdowned human ESCs have more zinc compared to those from control human ESCs. Our data suggest that SIRT1 negatively regulates the differentiation of β cells from human ESCs.

• Journal of Life Science
• /
• v.26 no.7
• /
• pp.826-834
• /
• 2016

The present investigation was undertaken to examine the effectiveness of the combination treatment of an Hsp90 inhibitor and a SIRT1 inhibitor on suppressing the growth of chemo-resistant human cancer cells. We showed that inhibition of SIRT1 effectively potentiated the cytotoxicity of 17-allylamino-17-demethoxygeldanamycin (17-AAG) and reversed Hsp90 inhibitor resistance in multidrug-resistant (MDR) human ovarian HeyA8-MDR cells. Amurensin G, a potent natural SIRT1 inhibitor, enhanced Hsp90 inhibitor-mediated abrogation of the Hsp90 chaperone function and accelerated degradation of mutated p53 (mut p53), an Hsp90 client protein, by up-regulation of ubiquitin ligase CHIP. Knock-down of CHIP significantly attenuated amurensin G-induced mut p53 degradation. Down-regulation of mut p53 reduced the expression of heat shock factor1 (HSF1)/heat shock proteins (Hsps), a major cause of Hsp90 inhibitor resistance, which led to sensitization of the MDR cells to the Hsp90 inhibitor by the SIRT1 inhibitor. Amurensin G potentiated cytotoxicity of the Hsp90 inhibitor in HeyA8-MDR cells through suppression of 17-AAG-induced Hsp70 and Hsp27 induction via down-regulation of mut p53/HSF1, and it caused activation of PARP and inhibition of Bcl-2. Our data suggests that SIRT1 inhibitors could be used to sensitize MDR cells to Hsp90 inhibitors, possibly through suppression of the mut p53/HSF1-dependent pathway, and a novel mut p53-directed action of SIRT1 inhibition could effectively prevent mut p53 accumulation in MDR cells.