• The Korean Journal of Physiology and Pharmacology
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• 제19권5호
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• pp.451-460
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• 2015

Sirtuin 1 (SIRT1) is a mammalian $NAD^+$-dependent protein deacetylase that regulates cellular metabolism and inflammatory response. The organ-specific deletion of SIRT1 induces local inflammation and insulin resistance in dietary and genetic obesity. Macrophage-mediated inflammation contributes to insulin resistance and metabolic syndrome, however, the macrophage-specific SIRT1 function in the context of obesity is largely unknown. C57/BL6 wild type (WT) or myeloid-specific SIRT1 knockout (KO) mice were fed a high-fat diet (HFD) or normal diet (ND) for 12 weeks. Metabolic parameters and markers of hepatic steatosis and inflammation in liver were compared in WT and KO mice. SIRT1 deletion enhanced HFD-induced changes on body and liver weight gain, and increased glucose and insulin resistance. In liver, SIRT1 deletion increased the acetylation, and enhanced HFD-induced nuclear translocation of nuclear factor kappa B (NF-${\kappa}B$), hepatic inflammation and macrophage infiltration. HFD-fed KO mice showed severe hepatic steatosis by activating lipogenic pathway through sterol regulatory element-binding protein 1 (SREBP-1), and hepatic fibrogenesis, as indicated by induction of connective tissue growth factor (CTGF), alpha-smooth muscle actin (${\alpha}$-SMA), and collagen secretion. Myeloid-specific deletion of SIRT1 stimulates obesity-induced inflammation and increases the risk of hepatic fibrosis. Targeted induction of macrophage SIRT1 may be a good therapy for alleviating inflammation-associated metabolic syndrome.

• Biomolecules & Therapeutics
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• 제25권5호
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• pp.511-518
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• 2017

Ultraviolet (UV) irradiation is a relevant environment factor to induce cellular senescence and photoaging. Both autophagy- and silent information regulator T1 (SIRT1)-dependent pathways are critical cellular processes of not only maintaining normal cellular functions, but also protecting cellular senescence in skin exposed to UV irradiation. In the present studies, we investigated whether modulation of autophagy induction using a novel synthetic SIRT1 activator, heptasodium hexacarboxymethyl dipeptide-12 (named as Aquatide), suppresses the UVB irradiation-induced skin aging. Treatment with Aquatide directly activates SIRT1 and stimulates autophagy induction in cultured human dermal fibroblasts. Next, we found that Aquatide-mediated activation of SIRT1 increases autophagy induction via deacetylation of forkhead box class O (FOXO) 1. Finally, UVB irradiation-induced cellular senescence measured by $SA-{\beta}-gal$ staining was significantly decreased in cells treated with Aquatide in parallel to occurring SIRT1 activation-dependent autophagy. Together, Aquatide modulates autophagy through SIRT1 activation, contributing to suppression of skin aging caused by UV irradiation.

• The Korean Journal of Physiology and Pharmacology
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• 제27권6호
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• pp.533-540
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• 2023

Sweroside is a natural monoterpene derived from Swertia pseudochinensis Hara. Recently, studies have shown that sweroside exhibits a variety of biological activities, such as anti-inflammatory, antioxidant, and hypoglycemic effects. However, its role and mechanisms in high glucose (HG)-induced renal injury remain unclear. Herein, we established a renal injury model in vitro by inducing human renal tubular epithelial cell (HK-2 cells) injury by HG. Then, the effects of sweroside on HK-2 cell activity, inflammation, reactive oxygen species (ROS) production, and epithelial mesenchymal transition (EMT) were observed. As a result, sweroside treatment ameliorated the viability, inhibited the secretion of inflammatory cytokines (TNF-α, IL-1β, and VCAM-1), reduced the generation of ROS, and inhibited EMT in HK-2 cells. Moreover, the protein expression of SIRT1 was increased and the acetylation of p65 NF-kB was decreased in HK-2 cells with sweroside treatment. More importantly, EX527, an inhibitor of SIRT1, that inactivated SIRT1, abolished the improvement effects of sweroside on HK-2 cells. Our findings suggested that sweroside may mitigate HG-caused injury in HK-2 cells by promoting SIRT1-mediated deacetylation of p65 NF-kB.

• Molecules and Cells
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• 제28권2호
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• pp.87-92
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• 2009

Human SIRT3 gene contains an intronic VNTR enhancer. A T > C transition occurring in the second repeat of each VNTR allele implies the presence/absence of a putative GATA binding motif. A partially overlapping AP-1 site, not affected by the transition, was also identified. Aims of the present study were: 1) to verify if GATA and AP-1 sites could bind GATA2 and c-Jun/c-Fos factors, respectively; 2) to investigate whether such sites modulate the enhancer activity of the SIRT3-VNTR alleles. DAPA assay proved that GATA2 and c-Jun/c-Fos factors are able to bind the corresponding sites. Moreover, co-transfection experiments showed that the over-expression of GATA2 and c-Jun/c-Fos factors boosts the VNTR enhancer activity in an allelic-specific way. Furthermore, we established that GATA2 and c-Jun/c-Fos act additively in modulating the SIRT3-VNTR enhancer function. Therefore, GATA2 and AP-1 are functional sites and the T > C transition of the second VNTR repeat affects their activity.

• BMB Reports
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• 제56권12호
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• pp.651-656
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• 2023

Senescence, a cellular process through which damaged or dysfunctional cells suppress the cell cycle, contributes to aging or age-related functional decline. Cell metabolism has been closely correlated with aging processes, and it has been widely recognized that metabolic changes underlie the cellular alterations that occur with aging. Here, we report that fatty acid oxidation (FAO) serves as a critical regulator of cellular senescence and uncover the underlying mechanism by which FAO inhibition induces senescence. Pharmacological or genetic ablation of FAO results in a p53-dependent induction of cellular senescence in human fibroblasts, whereas enhancing FAO suppresses replicative senescence. We found that FAO inhibition promotes cellular senescence through acetyl-CoA, independent of energy depletion. Mechanistically, increased formation of autophagosomes following FAO inhibition leads to a reduction in SIRT1 protein levels, thereby contributing to senescence induction. Finally, we found that inhibition of autophagy or enforced expression of SIRT1 can rescue the induction of senescence as a result of FAO inhibition. Collectively, our study reveals a distinctive role for the FAO-autophagy-SIRT1 axis in the regulation of cellular senescence.

• Journal of Microbiology and Biotechnology
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• 제33권4호
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• pp.441-448
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• 2023

Brucellosis is a contagious zoonotic disease that infects millions of people annually with hundreds of millions more being exposed. It is caused by Brucella, a highly infectious bacterial species capable of infecting humans with an estimated dose of 10-100 organisms. Sirtuin 1 (SIRT1) has been reported to contribute to prevention of viral diseases as well as a chronic infection caused by Mycobacterium bovis. Here, we investigated the role of SIRT1 in the establishment of Brucella abortus infection in both in vitro and in vivo systems using the reported SIRT1 activators resveratrol (RES), piceatannol (PIC), and ginsenoside Rg3 (Rg3). In RAW264.7 cells, SIRT1 activators did not alter the adherence of Brucella or Salmonella Typhimurium. However, reduced uptake of Brucella was observed in cells treated with PIC and Rg3, and survival of Brucella within the cells was only observed to decrease in cells that were treated with Rg3, while PIC treatment reduced the intracellular survival of Salmonella. SIRT1 treatment in mice via oral route resulted in augmented Brucella resistance for PIC and Rg3, but not RES. PIC treatment favors Th2 immune response despite reduced serum pro-inflammatory cytokine production, while Rg3-treated mice displayed high IL-12 and IFN-γ serum production. Overall, our findings encourage further investigation into the complete mechanisms of action of the different SIRT1 activators used as well as their potential benefit as an effective alternative approach against intracellular and extracellular pathogens.

• 대한임상검사과학회지
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• 제47권3호
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• pp.112-116
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• 2015

산화질소(Nitric Oxide, NO)는 생리학적, 병리학적으로 주요한 역할을 하고 있는 것으로 알려져 있다. 본 실험에서는 NO donor인 sodium nitroprusside (SNP)가 HaCaT 세포에서 apoptosis를 유도한다는 것을 DAPI염색과 PARP, caspase-3 단백질 절단을 western blot으로 확인하였다. SNP는 ER stress와 관련 있는 Bip, CHOP 유전자 발현에는 영향이 없었다. 최근 NAD+ 의존 deacetylase인 sirt1이 세포의 생존 및 사멸에 매우 중요한 단백질이라는 보고가 있다. 본 실험에서 SNP는 HaCaT 세포의 sirt1 유전자 발현을 감소시켰으며 이는 apoptosis와 관련이 있을 수 있다.

• BMB Reports
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• 제52권3호
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• pp.190-195
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• 2019

Acetaminophen (APAP) overdose can cause hepatotoxicity by inducing mitochondrial damage and subsequent necrosis in hepatocytes. Sirtuin2 (Sirt2) is an $NAD^+$-dependent deacetylase that regulates several biological processes, including hepatic gluconeogenesis, as well as inflammatory pathways. We show that APAP decreases the expression of Sirt2. Moreover, the ablation of Sirt2 attenuates APAP-induced liver injuries, such as oxidative stress and mitochondrial damage in hepatocytes. We found that Sirt2 deficiency alleviates the APAP-mediated endoplasmic reticulum (ER) stress and phosphorylation of the p70 ribosomal S6 kinase 1 (S6K1). Moreover, Sirt2 interacts with and deacetylates S6K1, followed by S6K1 phosphorylation induction. This study elucidates the molecular mechanisms underlying the protective role of Sirt2 inactivation in APAP-induced liver injuries.

• Journal of the Korean Wood Science and Technology
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• 제33권5호통권133호
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• pp.29-37
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• 2005

A previous study verified that the SIRT (simultaneous iterative reconstruction technique) method is more efficient than the back-projection method as a CT algorithm for wood. However, it was expected that the determination of the initial model function of the SIRT method would influence the quality of CT image. Therefore, in this study, we intended to develop a technique that could be used to determine an adequate initial model function. For this purpose, we proposed several techniques, and for each technique we examined the effects of the initial model function on the average errors and the CT image at each iteration. Through this study, it was shown that the average error was decreased and the image quality was improved using the proposed techniques. This tendency was most pronounced when the back-projection method was used to determine the initial model function. From the results of this study, we drew the following conclusions: 1) The initial model function of the SIRT method should be determined with careful attention, and 2) the back-projection method efficiently determines the initial model function of the SIRT method.

• Restorative Dentistry and Endodontics
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• 제40권3호
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• pp.223-228
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• 2015

Objectives: The aim of this study was to investigate the expression of 7 different sirtuin genes (SIRT1-SIRT7) in human dental pulp cells (HDPCs), and to determine the role of SIRTs in the odontoblastic differentiation potential of HDPCs. Materials and Methods: HDPCs were isolated from freshly extracted third molar teeth of healthy patients and cultulred in odontoblastic differentiation inducing media. Osteocalcin (OCN) and dentin sialophosphoprotein (DSPP) expression was analyzed to evaluate the odontoblastic differentiation of HDPCs by reverse transcription-polymerase chain reaction (RT-PCR), while alizarin red staining was used for the mineralization assay. To investigate the expression of SIRTs during odontoblastic differentiation of HDPCs, real time PCR was also performed with RT-PCR. Results: During the culture of HDPCs in the differentiation inducing media, OCN, and DSPP mRNA expressions were increased. Mineralized nodule formation was also increased in the 14 days culture. All seven SIRT genes were expressed during the odontogenic induction period. SIRT4 expression was increased in a time-dependent manner. Conclusions: Our study identified the expression of seven different SIRT genes in HDPCs, and revealed that SIRT4 could exert an influence on the odontoblast differentiation process. Further studies are needed to determine the effects of other SIRTs on the odontogenic potential of HDPCs.