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1
Yasukawa, Hiro, and Kenji Yagita. "Silent information regulator 2 proteins encoded by Cryptosporidium parasites." Parasitology Research 107, no. 3 (June 19, 2010): 707–12. http://dx.doi.org/10.1007/s00436-010-1925-8.
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Ansari, A., and M. R. Gartenberg. "The yeast silent information regulator Sir4p anchors and partitions plasmids." Molecular and Cellular Biology 17, no. 12 (December 1997): 7061–68. http://dx.doi.org/10.1128/mcb.17.12.7061.
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Circular plasmids containing telomeric TG1-3 arrays or the HMR E silencer segregate efficiently between dividing cells of the yeast Saccharomyces cerevisiae. Subtelomeric X repeats augment the TG1-3 partitioning activity by a process that requires the SIR2, SIR3, and SIR4 genes, which are also required for silencer-based partitioning. Here we show that targeting Sir4p to DNA directly via fusion to the bacterial repressor LexA confers efficient mitotic segregation to otherwise unstable plasmids. The Sir4p partitioning activity resides within a 300-amino-acid region (residues 950 to 1262) which precedes the coiled-coil dimerization motif at the extreme carboxy end of the protein. Using a topology-based assay, we demonstrate that the partitioning domain also retards the axial rotation of LexA operators in vivo. The anchoring and partitioning properties of LexA-Sir4p chimeras persist despite the loss of the endogenous SIR genes, indicating that these functions are intrinsic to Sir4p and not to a complex of Sir factors. In contrast, inactivation of the Sir4p-interacting protein Rap1p reduces partitioning by a LexA-Sir4p fusion. The data are consistent with a model in which the partitioning and anchoring domain of Sir4p (PAD4 domain) attaches to a nuclear component that divides symmetrically between cells at mitosis; DNA linked to Sir4p by LexA serves as a reporter of protein movement in these experiments. We infer that the segregation behavior of telomere- and silencer-based plasmids is, in part, a consequence of these Sir4p-mediated interactions. The assays presented herein illustrate two novel approaches to monitor the intracellular dynamics of nuclear proteins.
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Horvath, Matej, Zorana Mihajlovic, Vera Slaninova, Raquel Perez-Gomez, Yuri Moshkin, and Alena Krejci. "The silent information regulator 1 (Sirt1) is a positive regulator of the Notch pathway in Drosophila." Biochemical Journal 473, no. 22 (November 10, 2016): 4129–43. http://dx.doi.org/10.1042/bcj20160563.
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The silent information regulator 1 (Sirt1) has been shown to have negative effects on the Notch pathway in several contexts. We bring evidence that Sirt1 has a positive effect on Notch activation in Drosophila, in the context of sensory organ precursor specification and during wing development. The phenotype of Sirt1 mutant resembles weak Notch loss-of-function phenotypes, and genetic interactions of Sirt1 with the components of the Notch pathway also suggest a positive role for Sirt1 in Notch signalling. Sirt1 is necessary for the efficient activation of enhancer of split [E(spl)] genes by Notch in S2N cells. Additionally, the Notch-dependent response of several E(spl) genes is sensitive to metabolic stress caused by 2-deoxy-d-glucose treatment, in a Sirt1-dependent manner. We found Sirt1 associated with several proteins involved in Notch repression as well as activation, including the cofactor exchange factor Ebi (TBL1), the RLAF/LAF histone chaperone complex and the Tip60 acetylation complex. Moreover, Sirt1 participates in the deacetylation of the CSL transcription factor Suppressor of Hairless. The role of Sirt1 in Notch signalling is, therefore, more complex than previously recognized, and its diverse effects may be explained by a plethora of Sirt1 substrates involved in the regulation of Notch signalling.
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Marmorstein, R. "Structure and chemistry of the Sir2 family of NAD+-dependent histone/protein deactylases." Biochemical Society Transactions 32, no. 6 (October 26, 2004): 904–9. http://dx.doi.org/10.1042/bst0320904.
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The yeast Sir2 (silent information regulator-2) protein functions as an NAD+-dependent histone deacetylase to silence gene expression from the mating-type locus, tolomeres and rDNA and also promotes longevity and genome stability in response to calorie restriction. Homologues of yeast Sir2 have been identified in the three domains of bacteria, archaea and eukaryotes; in mammalian cells, Sir2 proteins also deacetylate non-histone proteins such as the p53 tumour suppressor protein, α-tubulin and forkhead transcription factors to mediate diverse biological processes including metabolism, cell motility and cancer. We have determined the X-ray crystal structure of a Sir2 homologue from yeast Hst2 (yHst2), in various liganded forms, including the yHst2/acetyl-Lys-16 histone H4/NAD+ ternary complex; we have also performed related biochemical studies to address the conserved mode of catalysis by these enzymes as well as the distinguishing features that allow different members of the family to target their respective cognate substrates. These studies have implications for the structure-based design of Sir2-specific small molecule compounds, which might modulate Sir2 function for therapeutic application.
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Sherman, Joyce M., Elisa M. Stone, Lisa L. Freeman-Cook, Carrie B. Brachmann, Jef D. Boeke, and Lorraine Pillus. "The Conserved Core of a Human SIR2 Homologue Functions in Yeast Silencing." Molecular Biology of the Cell 10, no. 9 (September 1999): 3045–59. http://dx.doi.org/10.1091/mbc.10.9.3045.
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Silencing is a universal form of transcriptional regulation in which regions of the genome are reversibly inactivated by changes in chromatin structure. Sir2 (Silent Information Regulator) protein is unique among the silencing factors in Saccharomyces cerevisiae because it silences the rDNA as well as the silent mating-type loci and telomeres. Discovery of a gene family ofHomologues of Sir Two (HSTs) in organisms from bacteria to humans suggests that SIR2’s silencing mechanism might be conserved. The Sir2 and Hst proteins share a core domain, which includes two diagnostic sequence motifs of unknown function as well as four cysteines of a putative zinc finger. We demonstrate by mutational analyses that the conserved core and each of its motifs are essential for Sir2p silencing. Chimeras between Sir2p and a human Sir2 homologue (hSir2Ap) indicate that this human protein’s core can substitute for that of Sir2p, implicating the core as a silencing domain. Immunofluorescence studies reveal partially disrupted localization, accounting for the yeast–human chimeras’ ability to function at only a subset of Sir2p’s target loci. Together, these results support a model for the involvement of distinct Sir2p-containing complexes in HM/telomeric and rDNA silencing and that HST family members, including the widely expressed hSir2A, may perform evolutionarily conserved functions.
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Åström, Stefan U., and Jasper Rine. "Theme and Variation Among Silencing Proteins in Saccharomyces cerevisiae and Kluyveromyces lactis." Genetics 148, no. 3 (March 1, 1998): 1021–29. http://dx.doi.org/10.1093/genetics/148.3.1021.
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Abstract The cryptic mating type loci in Saccharomyces cerevisiae act as reservoirs of mating type information used in mating type switching in homothallic yeast strains. The transcriptional silencing of these loci depends on the formation of a repressive chromatin structure that is reminiscent of heterochromatin. Silent information regulator (Sir) proteins 2–4 are absolutely required for silencing. To learn more about silencing, we investigated mating type and Sir proteins in the yeast Kluyveromyces lactis, which contains cryptic copies of the mating type genes. A functional homolog of SIR4 from K. lactis complements the silencing defect of sir4 null mutations in S. cerevisiae. K. lactis sir2 and sir4 mutant strains showed partial derepression of the silent α1 gene, establishing that the silencing role of these proteins is conserved. K. lactis sir2 mutants are more sensitive than the wild type to ethidium bromide, and K. lactis sir4 mutants are more resistant phenotypes that are not observed for the corresponding mutants of S. cerevisiae. Finally, the deletion of sir4 in the two yeasts leads to opposite effects on telomere length. Thus, Sir proteins from K. lactis have roles in both silencing and telomere length maintenance, reflecting conserved functional themes. The various phenotypes of sir mutants in K. lactis and S. cerevisiae, however, revealed unanticipated variation between their precise roles.
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Pasupala, Nagesh, Sreesankar Easwaran, Abdul Hannan, David Shore, and Krishnaveni Mishra. "The SUMO E3 Ligase Siz2 Exerts a Locus-Dependent Effect on Gene Silencing in Saccharomyces cerevisiae." Eukaryotic Cell 11, no. 4 (February 17, 2012): 452–62. http://dx.doi.org/10.1128/ec.05243-11.
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ABSTRACT In the yeast Saccharomyces cerevisiae , the two silent mating-type loci and subtelomeric regions are subjected to a well-characterized form of gene silencing. Establishment of silencing involves the formation of a distinct chromatin state that is refractory to transcription. This structure is established by the action of silent information regulator proteins (Sir2, Sir3, and Sir4) that bind to nucleosomes and initiate the deacetylation of multiple lysine residues in histones H3 and H4. Sir2 protein is a conserved histone deacetylase that is critical for mating-type and telomeric silencing, as well as a Sir3/4-independent form of silencing observed within the ribosomal DNA (rDNA) repeat locus. We report here that sumoylation plays an important role in regulating gene silencing. We show that increased dosage of SIZ2 , a SUMO ( s mall u biquitin-related mo difier) ligase, is antagonistic to gene silencing and that this effect is enhanced by mutation of ESC1 , whose product is involved in tethering telomeres to the nuclear periphery. We present evidence indicating that an elevated SIZ2 dosage causes reduced binding of Sir2 protein to telomeres. These data support the idea that sumoylation of specific substrates at the nuclear periphery regulates the availability of Sir2 protein at telomeres.
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Cacicedo, José M., Marie-Soleil Gauthier, Nathan K. Lebrasseur, Ravi Jasuja, Neil B. Ruderman, and Yasuo Ido. "Acute exercise activates AMPK and eNOS in the mouse aorta." American Journal of Physiology-Heart and Circulatory Physiology 301, no. 4 (October 2011): H1255—H1265. http://dx.doi.org/10.1152/ajpheart.01279.2010.
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Exercise can prevent endothelial cell (EC) dysfunction and atherosclerosis even in the absence of improvements in plasma lipids. However, the mechanisms responsible for these effects are incompletely understood. In this study we examined in mice whether an acute bout of exercise activates enzymes that could prevent EC dysfunction, such as AMP-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS). We also examined whether exercise alters known regulators of these enzymes. C57BL/6 mice underwent a single bout of exhaustive treadmill exercise after which their aortas were analyzed for activation of AMPK, AMPK regulatory proteins, eNOS, and various enzymes that, like AMPK, activate eNOS. We found that such exercise acutely activates both AMPK and eNOS in the whole aorta and that the magnitude of these effects correlated with both the distance run and activation of the AMPK regulatory proteins silent information regulator-1 (SIRT1)-LKB1 and CaMKKβ. In contrast, Akt, PKA, PKG, and Src, other kinases known to activate eNOS, were unaffected. Immunohistochemical analysis revealed that AMPK and eNOS were both activated in the ECs of the aorta. This study provides the first evidence that an acute bout of exercise activates AMPK and eNOS in the endothelium of the aorta. The results also suggest that AMPK likely is the principal activator of eNOS in this setting and that its own activation may be mediated by both SIRT1-LKB1 and CaMKKβ.
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Colak, Yasar, Atakan Yesil, Hasan Huseyin Mutlu, Ozge Telci Caklili, Celal Ulasoglu, Ebubekir Senates, Mumtaz Takir, et al. "A Potential Treatment of Non-Alcoholic Fatty Liver Disease with SIRT1 Activators." Journal of Gastrointestinal and Liver Diseases 23, no. 3 (September 1, 2014): 311–19. http://dx.doi.org/10.15403/jgld.2014.1121.233.yck.
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Sirtuins (SIRTs) are members of the silent information regulator-2 family and act as nicotinamide adenine dinucleotide (NAD+)-dependent histone/protein deacetylases. The de-acetylation of proteins and histones results in an up- or down-regulation of gene transcription and protein function. In recent years, the regulatory action of the deacetylation activity of SIRT1 has been shown to have a positive impact on the pathophysiological mechanisms of nonalcoholic fatty liver disease (NAFLD). Among the effects of SIRT1 are: its healing activity on insulin sensitivity, thereby ameliorating glycemic regulation; its mimetic activity on calorie restriction; its antihyperlipidemic activity on lipid homeostasis via the liver, adipose tissues and skeletal muscles; its antiinflammatory activities; its protective effects against cardiovascular events and endothelial dysfunction; its positive influence on autophagy, apoptosis and cancer; and finally, its anti-aging activity. The current approach for the treatment of NAFLD involves the treatment of etiological factors and recommendation of life-style changes including more physical activity and a low-calorie diet. However, there are no specific medical treatments for NAFLD. The therapeutic potential of SIRT1 activity in the treatment of NAFLD discovered in humans has been presented in this article. In this review, the potential effects of SIRT1 activation on NAFLD-related pathophysiological mechanisms and on the treatment of NAFLD are discussed.
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Du, Yue-guang, Li-pei Wang, Jun-wen Qian, Ke-na Zhang, and Ke-fu Chai. "Panax notoginseng saponins protect kidney from diabetes by up-regulating silent information regulator 1 and activating antioxidant proteins in rats." Chinese Journal of Integrative Medicine 22, no. 12 (December 28, 2015): 910–17. http://dx.doi.org/10.1007/s11655-015-2446-1.
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You, Linya, Jianyun Nie, Wei-Jian Sun, Zhi-Qiang Zheng, and Xiang-Jiao Yang. "Lysine acetylation: enzymes, bromodomains and links to different diseases." Essays in Biochemistry 52 (May 25, 2012): 1–12. http://dx.doi.org/10.1042/bse0520001.
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Lysine acetylation refers to transfer of the acetyl moiety from acetyl-CoA to the ε-amino group of a lysine residue on a protein. This has recently emerged as a major covalent modification and interplays with other modifications, such as phosphorylation, methylation, ubiquitination (addition of a small protein called ubiquitin) and SUMOylation [addition of a ubiquitin-like protein known as SUMO (small ubiquitin-related modifier)], to form multisite modification programmes for cellular regulation in diverse organisms. This modification is post-translational (i.e. after synthesis of a protein) and reversible, with its level being dynamically balanced by two groups of enzymes known as lysine acetyltransferases and deacetylases. The acetyltransferases belong to three major families, whereas deacetylases have been divided into the classical and sirtuin [Sir-tu-in, for Sir2 (silent information regulator 2)-like protein; named after the yeast protein Sir2] families. In addition to these enzymes, proteins containing the bromodomain, a protein module named after the fly protein Brahma (God of creation in Hindu), are relevant to lysine acetylation biology due to their ability to recognize acetyl-lysine-containing peptides. Importantly, recent studies have made intimate links between these three different groups of proteins to different pathological conditions. In this chapter, we provide a brief overview of these proteins and emphasize their direct links to related human diseases.
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McBryant, Steven J., Christine Krause, Christopher L. Woodcock, and Jeffrey C. Hansen. "The Silent Information Regulator 3 Protein, SIR3p, Binds to Chromatin Fibers and Assembles a Hypercondensed Chromatin Architecture in the Presence of Salt." Molecular and Cellular Biology 28, no. 11 (March 24, 2008): 3563–72. http://dx.doi.org/10.1128/mcb.01389-07.
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ABSTRACT The telomeres and mating-type loci of budding yeast adopt a condensed, heterochromatin-like state through recruitment of the silent information regulator (SIR) proteins SIR2p, SIR3p, and SIR4p. In this study we characterize the chromatin binding determinants of recombinant SIR3p and identify how SIR3p mediates chromatin fiber condensation in vitro. Purified full-length SIR3p was incubated with naked DNA, nucleosome core particles, or defined nucleosomal arrays, and the resulting complexes were analyzed by electrophoretic shift assays, sedimentation velocity, and electron microscopy. SIR3p bound avidly to all three types of templates. SIR3p loading onto its nucleosomal sites in chromatin produced thickened condensed fibers that retained a beaded morphology. At higher SIR3p concentrations, individual nucleosomal arrays formed oligomeric suprastructures bridged by SIR3p oligomers. When condensed SIR3p-bound chromatin fibers were incubated in Mg2+, they folded and oligomerized even further to produce hypercondensed higher-order chromatin structures. Collectively, these results define how SIR3p may function as a chromatin architectural protein and provide new insight into the interplay between endogenous and protein-mediated chromatin fiber condensation pathways.
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Krey, Lea, Fred Lühder, Kathrin Kusch, Bozena Czech-Zechmeister, Birte Könnecke, Tiago Fleming Outeiro, and George Trendelenburg. "Knockout of Silent Information Regulator 2 (SIRT2) Preserves Neurological Function after Experimental Stroke in Mice." Journal of Cerebral Blood Flow & Metabolism 35, no. 12 (July 29, 2015): 2080–88. http://dx.doi.org/10.1038/jcbfm.2015.178.
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Sirtuin-2 (Sirt2) is a member of the NAD+-dependent protein deacetylase family. Various members of the sirtuin class have been found to be involved in processes related to longevity, regulation of inflammation, and neuroprotection. Induction of Sirt2 mRNA was found in the whole hemisphere after experimental stroke in a recent screening approach. Moreover, Sirt2 protein is highly expressed in myelin-rich brain regions after stroke. To examine the effects of Sirt2 on ischemic stroke, we induced transient focal cerebral ischemia in adult male Sirt2-knockout and wild-type mice. Two stroke models with different occlusion times were applied: a severe ischemia (45 minutes of middle cerebral artery occlusion (MCAO)) and a mild one (15 minutes of MCAO), which was used to focus on subcortical infarcts. Neurological deficit was determined at 48 hours after 45 minutes of MCAO, and up to 7 days after induction of 15 minutes of cerebral ischemia. In contrast to recent data on Sirt1, Sirt2−/− mice showed less neurological deficits in both models of experimental stroke, with the strongest manifestation after 48 hours of reperfusion. However, we did not observe a significant difference of stroke volumes or inflammatory cell count between Sirt2-deficient and wild-type mice. Thus we postulate that Sirt2 mediates myelin-dependent neuronal dysfunction during the early phase after ischemic stroke.
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Yu, Lei, Yingfeng Tu, Xueling Jia, Kun Fang, Li Liu, Lin Wan, Chuanying Xiang, et al. "Resveratrol Protects Against Pulmonary Arterial Hypertension in Rats via Activation of Silent Information Regulator 1." Cellular Physiology and Biochemistry 42, no. 1 (2017): 55–67. http://dx.doi.org/10.1159/000477115.
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Background/Objectives: The polyphenol resveratrol (Rev) has been found to exhibit various beneficial effects including prevention of pulmonary arterial hypertension (PAH). The present study was designed to investigate the action and potential mechanism of Rev on PAH, focusing on the role of SIRT1 (Silent Information Regulator 1) in apoptosis of pulmonary artery smooth muscle cells (PASMCs). Methods: PAH rats were established by exposure to hypoxia for 21 days. Rev and SRT1720 (a selective SIRT1 activator) were used to reverse PAH by gavaging rats. PASMCs were confronted with hypoxia for 24 h or 48 h and were then treated with Rev or SRT1720 in vitro. Western blot was performed to detect the protein expression of SIRT1. CCK-8 and scratch wound experiments were carried out to verify cell proliferation. In addition, the TUNEL positive assay and flow cytometry assay were used to measure PASMC apoptosis. Mitochondrial permeability transition (mPT) was identified by confocal microscopy. Right ventricular systolic pressure (RVSP) was determined with a Gould pressure transducer, and right ventricular hypertrophy (RVH) was determined by weighing the cardiac muscle. Results: We demonstrated that Rev could reverse the remodelling of the pulmonary vasculature, thus contributing to alleviating the severity of PAH. Down-regulation of SIRT1 was observed in PAH, but administration of Rev had no obvious effect on the protein expression of SIRT1. In addition, Rev could induce mitochondrial swelling and nuclear pyknosis, leading to small, dense, and dysmorphic mitochondria in rats exposed to hypoxia alone. Rev treatment inhibited PASMC proliferation in a dose-dependent manner in vitro. Incubation with SRT1720, a specific activator of SIRT1, significantly retarded PASMC proliferation and promoted PASMC apoptosis in vitro. The mechanism could be associated with inducing mPT damage in PASMCs. Rev and SRT1720 treatment mitigated RVSP and reduced RVH. Conclusion: Rev produced a beneficial effect partially by enhancing the activation of SIRT1, thus improving RVSP and reducing RVH. SIRT1 activation increased PASMC apoptosis by inducing mPT dysfunction, which might be a novel future strategy for the treatment of PAH.
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FESSEL, M. R., C. B. LIRA, S. GIORGIO, C. H. I. RAMOS, and M. I. N. CANO. "Sir2-Related Protein 1 fromLeishmania amazonensisis a glycosylated NAD+-dependent deacetylase." Parasitology 138, no. 10 (August 8, 2011): 1245–58. http://dx.doi.org/10.1017/s0031182011001077.
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SUMMARYSirtuin proteins form a family of NAD+-dependent protein deacetylases that are considered potential drug targets against parasites. Here, we present the first characterization of a sirtuin orthologue fromLeishmania amazonensis, an aetiological agent of American tegumentary leishmaniasis that has been the subject of many studies focused in the development of therapeutic approaches. The protein has high sequence identity with other Kinetoplastid Silent information regulator 2 Related Protein 1 (Sir2RP1) and was named LaSir2RP1. The gene exists as a single copy, encoding a monomeric protein (LaSir2RP1) of approximately 41 kDa that has NAD+-dependent deacetylase activity. LaSir2RP1 was immunodetected in total protein extracts, in cytoplasmic granules, and in the secreted material of both promastigotes and lesion-derived amastigotes. Analysis of both lectin‑affinity purified promastigote and amastigote extracts revealed the presence of a major enriched protein of approximately 66 kDa that was recognized by an anti-LaSir2RP1 serum, suggesting that a parasite sirtuin could be glycosylatedin vivo.
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Tatone, Carla, Giovanna Di Emidio, Maurizio Vitti, Michela Di Carlo, Silvano Santini, Anna Maria D’Alessandro, Stefano Falone, and Fernanda Amicarelli. "Sirtuin Functions in Female Fertility: Possible Role in Oxidative Stress and Aging." Oxidative Medicine and Cellular Longevity 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/659687.
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In search for strategies aimed at preventing oxidative threat to female fertility, a possible role of sirtuins has emerged. Sirtuins (silent information regulator 2 (Sir2) proteins), NAD+dependent enzymes with deacetylase and/or mono-ADP-ribosyltransferase activity, are emerging as key antiaging molecules and regulators in many diseases. Recently, a crucial role for SIRT1 and SIRT3, the main components of sirtuin family, as sensors and guardians of the redox state in oocytes, granulosa cells, and early embryos has emerged. In this context, the aim of the present review is to summarize current knowledge from research papers on the role of sirtuins in female fertility with particular emphasis on the impairment of SIRT1 signalling with oocyte aging. On this basis, the authors wish to build up a framework to promote research on the possible role of sirtuins as targets for future strategies for female fertility preservation.
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Michan, Shaday, and David Sinclair. "Sirtuins in mammals: insights into their biological function." Biochemical Journal 404, no. 1 (April 26, 2007): 1–13. http://dx.doi.org/10.1042/bj20070140.
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Sirtuins are a conserved family of proteins found in all domains of life. The first known sirtuin, Sir2 (silent information regulator 2) of Saccharomyces cerevisiae, from which the family derives its name, regulates ribosomal DNA recombination, gene silencing, DNA repair, chromosomal stability and longevity. Sir2 homologues also modulate lifespan in worms and flies, and may underlie the beneficial effects of caloric restriction, the only regimen that slows aging and extends lifespan of most classes of organism, including mammals. Sirtuins have gained considerable attention for their impact on mammalian physiology, since they may provide novel targets for treating diseases associated with aging and perhaps extend human lifespan. In this review we describe our current understanding of the biological function of the seven mammalian sirtuins, SIRT1–7, and we will also discuss their potential as mediators of caloric restriction and as pharmacological targets to delay and treat human age-related diseases.
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Bupp, Jennifer M., Adriana E. Martin, Elizabeth S. Stensrud, and Sue L. Jaspersen. "Telomere anchoring at the nuclear periphery requires the budding yeast Sad1-UNC-84 domain protein Mps3." Journal of Cell Biology 179, no. 5 (November 26, 2007): 845–54. http://dx.doi.org/10.1083/jcb.200706040.
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Positioning of telomeres at the nuclear periphery can have dramatic effects on gene expression by establishment of heritable, transcriptionally repressive subdomains. However, little is known about the integral membrane proteins that mediate telomere tethering at the nuclear envelope. Here, we find a previously unrecognized function for the Saccharomyces cerevisiae Sad1-UNC-84 domain protein Mps3 in regulating telomere positioning in mitotic cells. Our data demonstrate that the nucleoplasmic N-terminal acidic domain of Mps3 is not essential for viability. However, this acidic domain is necessary and sufficient for telomere tethering during S phase and the silencing of reporter constructs integrated at telomeres. We show that this is caused by the role of the Mps3 acidic domain in binding and localization of the silent information regulator protein Sir4 to the nuclear periphery. Thus, Mps3 functions as an integral membrane anchor for telomeres and is a novel nuclear receptor for the Sir4 pathway of telomere tethering and gene inactivation.
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Smith, Jeffrey S., Carrie Baker Brachmann, Lorraine Pillus, and Jef D. Boeke. "Distribution of a Limited Sir2 Protein Pool Regulates the Strength of Yeast rDNA Silencing and Is Modulated by Sir4p." Genetics 149, no. 3 (July 1, 1998): 1205–19. http://dx.doi.org/10.1093/genetics/149.3.1205.
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Abstract Transcriptional silencing in Saccharomyces cerevisiae occurs at the silent mating-type loci HML and HMR, at telomeres, and at the ribosomal DNA (rDNA) locus RDN1. Silencing in the rDNA occurs by a novel mechanism that depends on a single Silent Information Regulator (SIR) gene, SIR2. SIR4, essential for other silenced loci, paradoxically inhibits rDNA silencing. In this study, we elucidate a regulatory mechanism for rDNA silencing based on the finding that rDNA silencing strength directly correlates with cellular Sir2 protein levels. The endogenous level of Sir2p was shown to be limiting for rDNA silencing. Furthermore, small changes in Sir2p levels altered rDNA silencing strength. In rDNA silencing phenotypes, sir2 mutations were shown to be epistatic to sir4 mutations, indicating that SIR4 inhibition of rDNA silencing is mediated through SIR2. Furthermore, rDNA silencing is insensitive to SIR3 overexpression, but is severely reduced by overexpression of full-length Sir4p or a fragment of Sir4p that interacts with Sir2p. This negative effect of SIR4 overexpression was overridden by co-overexpression of SIR2, suggesting that SIR4 directly inhibits the rDNA silencing function of SIR2. Finally, genetic manipulations of SIR4 previously shown to promote extended life span also resulted in enhanced rDNA silencing. We propose a simple model in which telomeres act as regulators of rDNA silencing by competing for limiting amounts of Sir2 protein.
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Yang, Se-Ran, Jessica Wright, Mark Bauter, Kathryn Seweryniak, Aruna Kode, and Irfan Rahman. "Sirtuin regulates cigarette smoke-induced proinflammatory mediator release via RelA/p65 NF-κB in macrophages in vitro and in rat lungs in vivo: implications for chronic inflammation and aging." American Journal of Physiology-Lung Cellular and Molecular Physiology 292, no. 2 (February 2007): L567—L576. http://dx.doi.org/10.1152/ajplung.00308.2006.
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The silent information regulator 2 (Sir2) family of proteins (sirtuins or SIRTs), which belong to class III histone/protein deacetylases, have been implicated in calorie restriction, aging, and inflammation. We hypothesized that cigarette smoke-mediated proinflammatory cytokine release is regulated by SIRT1 by its interaction with NF-κB in a monocyte-macrophage cell line (MonoMac6) and in inflammatory cells of rat lungs. Cigarette smoke extract (CSE) exposure to MonoMac6 cells caused dose- and time-dependent decreases in SIRT1 activity and levels, which was concomitant to increased NF-κB-dependent proinflammatory mediator release. Similar decrements in SIRT1 were also observed in inflammatory cells in the lungs of rats exposed to cigarette smoke as well as with increased levels of several NF-κB-dependent proinflammatory mediators in bronchoalveolar lavage fluid and in lungs. Sirtinol, an inhibitor of SIRT1, augmented, whereas resveratrol, an activator of SIRT1, inhibited CSE-mediated proinflammatory cytokine release. CSE-mediated inhibition of SIRT1 was associated with increased NF-κB levels. Furthermore, we showed that SIRT1 interacts with the RelA/p65 subunit of NF-κB, which was disrupted by cigarette smoke, leading to increased acetylation RelA/p65 in MonoMac6 cells. Thus our data show that SIRT1 regulates cigarette smoke-mediated proinflammatory mediator release via NF-κB, implicating a role of SIRT1 in sustained inflammation and aging of the lungs.
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Tang, Yinhe, Naijing Ma, Hao Luo, Shizuan Chen, and Fuxiang Yu. "Downregulated long non-coding RNA LINC01093 in liver fibrosis promotes hepatocyte apoptosis via increasing ubiquitination of SIRT1." Journal of Biochemistry 167, no. 5 (February 11, 2020): 525–34. http://dx.doi.org/10.1093/jb/mvaa013.
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Abstract The apoptosis of hepatocytes contributes to the activation of hepatic stellate cells (HSCs), thus promoting the accumulation of extracellular matrix proteins and aggravating liver fibrosis. Silent information regulator 1 (SIRT1) is an anti-fibrotic protein whose downregulation induces hepatocyte apoptosis. This study aims to identify whether SIRT1 is regulated by long non-coding RNA LINC01093 and explore its underlying mechanisms. Liver fibrosis was induced in mice using CCl4, and the differential expressions of several fibrosis-related long noncoding RNAs were detected in liver tissues. The effect of LINC01093 on cell apoptosis and viability of hepatocytes were investigated after LINC01093 overexpression or knockdown using flow cytometry and MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. The anti-fibrotic effect of LINC01093 overexpression was observed in vivo. LncRNA LINC01093 is downregulated in CCl4-induced liver tissues and TGF-β1-stimulated hepatocytes. Downregulated LINC01093 promoted cell apoptosis and inhibited cell viability of hepatocytes. The co-culture between LINC01093-knockdown hepatocytes and HSCs increased the expressions of pro-fibrotic proteins. Downregulated LINC01093 promoted hepatocyte apoptosis via promoting degradation and ubiquitination of SIRT1 under TGF-β1 stimulation. The injection of LINC01093-overexpressing vectors alleviated liver fibrosis in vivo. In liver fibrosis, the downregulated LINC01093 promoted hepatocyte apoptosis, which is mediated by increasing the degradation and ubiquitination of SIRT1.
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Ravindra, Anish, Kerstin Weiss, and Robert T. Simpson. "High-Resolution Structural Analysis of Chromatin at Specific Loci: Saccharomyces cerevisiae Silent Mating-Type Locus HMRa." Molecular and Cellular Biology 19, no. 12 (December 1, 1999): 7944–50. http://dx.doi.org/10.1128/mcb.19.12.7944.
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ABSTRACT Genetic and biochemical evidence implicates chromatin structure in the silencing of the two quiescent mating-type loci near the telomeres of chromosome III in yeast. With high-resolution micrococcal nuclease mapping, we show that the HMRa locus has 12 precisely positioned nucleosomes spanning the distance between the E and I silencer elements. The nucleosomes are arranged in pairs with very short linkers; the pairs are separated from one another by longer linkers of ∼20 bp. Both the basic amino-terminal region of histone H4 and the silent information regulator protein Sir3p are necessary for the organized repressive chromatin structure of the silent locus. Compared to HMRa, only small differences in the availability of the TATA box are present for the promoter in the cassette at the active MATa locus. Features of the chromatin structure of this silent locus compared to the previously studied HMLα locus suggest differences in the mechanisms of silencing and may relate to donor selection during mating-type interconversion.
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Chen, Sifan, Jinghua Li, Zili Zhang, Wenxue Li, Yanshuang Sun, Quanxin Zhang, Xiang Feng, and Wei Zhu. "Effects of resveratrol on the amelioration of insulin resistance in KKAy mice." Canadian Journal of Physiology and Pharmacology 90, no. 2 (February 2012): 237–42. http://dx.doi.org/10.1139/y11-123.
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Resveratrol (Res) has attracted great interest regarding its effects related to metabolic syndrome, especially for lipid metabolic disorder or insulin resistance; however, the underlying mechanisms remain elusive. To explore the effects of Res on insulin sensitivity and the underlying mechanism, insulin-resistant KKAy mice were treated with 2 and 4 g/kg diets of Res for 12 weeks. After the treatment, blood glucose, serum insulin, glucose tolerance, and insulin tolerance, as well as other indices such as adiponectin mRNA in epididymal adipose tissues, silent information regulator 1 (Sirt1), AMP-activated protein kinase (AMPK), insulin receptor substrate 1 (IRS1), and phosphorylated protein kinase B (PKB/AKT) proteins in liver and soleus muscles, were investigated. The results indicate that Res intervention reduces blood glucose and serum insulin levels, improves insulin and glucose tolerance, increases serum adiponectin and adiponectin mRNA levels in epididymal adipose tissues, and more importantly, elevates Sirt1, p-AMPK, p-IRS1, and p-AKT levels in liver and soleus muscles. In conclusion, Res could improve insulin sensitivity and ameliorate insulin resistance in KKAy mice, which may be associated with the upregulation of Sirt1 protein in liver and soleus muscles and consequent AMPK activation, as well as insulin-signaling related proteins.
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Schwer, Björn, Brian J. North, Roy A. Frye, Melanie Ott, and Eric Verdin. "The human silent information regulator (Sir)2 homologue hSIRT3 is a mitochondrial nicotinamide adenine dinucleotide–dependent deacetylase." Journal of Cell Biology 158, no. 4 (August 19, 2002): 647–57. http://dx.doi.org/10.1083/jcb.200205057.
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The yeast silent information regulator (Sir)2 protein links cellular metabolism and transcriptional silencing through its nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase activity. We report that mitochondria from mammalian cells contain intrinsic NAD-dependent deacetylase activity. This activity is inhibited by the NAD hydrolysis product nicotinamide, but not by trichostatin A, consistent with a class III deacetylase. We identify this deacetylase as the nuclear-encoded human Sir2 homologue hSIRT3, and show that hSIRT3 is located within the mitochondrial matrix. Mitochondrial import of hSIRT3 is dependent on an NH2-terminal amphipathic α-helix rich in basic residues. hSIRT3 is proteolytically processed in the mitochondrial matrix to a 28-kD product. This processing can be reconstituted in vitro with recombinant mitochondrial matrix processing peptidase (MPP) and is inhibited by mutation of arginines 99 and 100. The unprocessed form of hSIRT3 is enzymatically inactive and becomes fully activated in vitro after cleavage by MPP. These observations demonstrate the existence of a latent class III deacetylase that becomes catalytically activated upon import into the human mitochondria.
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Moretti, Paolo, and David Shore. "Multiple Interactions in Sir Protein Recruitment by Rap1p at Silencers and Telomeres in Yeast." Molecular and Cellular Biology 21, no. 23 (December 1, 2001): 8082–94. http://dx.doi.org/10.1128/mcb.21.23.8082-8094.2001.
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ABSTRACT Initiation of transcriptional silencing at mating type loci and telomeres in Saccharomyces cerevisiaerequires the recruitment of a Sir2/3/4 (silent information regulator) protein complex to the chromosome, which occurs at least in part through its association with the silencer- and telomere-binding protein Rap1p. Sir3p and Sir4p are structural components of silent chromatin that can self-associate, interact with each other, and bind to the amino-terminal tails of histones H3 and H4. We have identified a small region of Sir3p between amino acids 455 and 481 that is necessary and sufficient for association with the carboxyl terminus of Rap1p but not required for Sir complex formation or histone binding.SIR3 mutations that delete this region cause a silencing defect at HMR and telomeres. However, this impairment of repression is considerably less than that displayed by Rap1p carboxy-terminal truncations that are defective in Sir3p binding. This difference may be explained by the ability of the Rap1p carboxyl terminus to interact independently with Sir4p, which we demonstrate by in vitro binding and two-hybrid assays. Significantly, the Rap1p-Sir4p two-hybrid interaction does not require Sir3p and is abolished by mutation of the carboxyl terminus of Rap1p. We propose that both Sir3p and Sir4p can directly and independently bind to Rap1p at mating type silencers and telomeres and suggest that Rap1p-mediated recruitment of Sir proteins operates through multiple cooperative interactions, at least some of which are redundant. The physical separation of the Rap1p interaction region of Sir3p from parts of the protein required for Sir complex formation and histone binding raises the possibility that Rap1p can participate directly in the maintenance of silent chromatin through the stabilization of Sir complex-nucleosome interactions.
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Balaiya, Sankarathi, Khaled K. Abu-Amero, Altaf A. Kondkar, and Kakarla V. Chalam. "Sirtuins Expression and Their Role in Retinal Diseases." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–11. http://dx.doi.org/10.1155/2017/3187594.
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Sirtuins have received considerable attention since the discovery that silent information regulator 2 (Sir2) extends the lifespan of yeast. Sir2, a nicotinamide adenine dinucleotide- (NAD-) dependent histone deacetylase, serves as both a transcriptional effector and energy sensor. Oxidative stress and apoptosis are implicated in the pathogenesis of neurodegenerative eye diseases. Sirtuins confer protection against oxidative stress and retinal degeneration. In mammals, the sirtuin (SIRT) family consists of seven proteins (SIRT1–SIRT7). These vary in tissue specificity, subcellular localization, and enzymatic activity and targets. In this review, we present the current knowledge of the sirtuin family and discuss their structure, cellular location, and biological function with a primary focus on their role in different neuroophthalmic diseases including glaucoma, optic neuritis, and age-related macular degeneration. The potential role of certain therapeutic targets is also described.
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Bose, Melissa E., Kristopher H. McConnell, Kelly A. Gardner-Aukema, Ulrika Müller, Michael Weinreich, James L. Keck, and Catherine A. Fox. "The Origin Recognition Complex and Sir4 Protein Recruit Sir1p to Yeast Silent Chromatin through Independent Interactions Requiring a Common Sir1p Domain." Molecular and Cellular Biology 24, no. 2 (January 15, 2004): 774–86. http://dx.doi.org/10.1128/mcb.24.2.774-786.2004.
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ABSTRACT Sir1p is one of four SIR (silent information regulator) proteins required for silencing the cryptic mating-type locus HMR a in the budding yeast Saccharomyces cerevisiae. A Sir1p interaction with Orc1p, the largest subunit of the origin recognition complex (ORC), is critical for Sir1p's ability to bind HMR a and function in the formation of silent chromatin. Here we show that a discrete domain within Sir1p, the ORC interaction region (OIR), was necessary and sufficient for a Sir1p-ORC interaction. The OIR contains the originally defined silencer recognition-defective region as well as additional amino acids. In addition, a Sir1p-Sir4p interaction required a larger region of Sir1p that included the OIR. Amino acid substitutions causing defects in either a Sir1p-Orc1p or a Sir1p-Sir4p interaction reduced HMR a silencing and Sir1p binding to HMR a in chromatin. These data support a model in which Sir1p's association with HMR a is mediated by separable Sir1p-ORC and Sir1p-Sir4p interactions requiring a common Sir1p domain, and they indicate that a Sir1p-ORC interaction is restricted to silencers, at least in part, through interactions with Sir4p.
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Zhang, Jiandi. "Resveratrol inhibits insulin responses in a SirT1-independent pathway." Biochemical Journal 397, no. 3 (July 13, 2006): 519–27. http://dx.doi.org/10.1042/bj20050977.
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Resveratrol mimics calorie restriction to extend lifespan of Caenorhabditis elegans, yeast and Drosophila, possibly through activation of Sir2 (silent information regulator 2), a NAD+-dependent histone deacetylase. In the present study, resveratrol is shown to inhibit the insulin signalling pathway in several cell lines and rat primary hepatocytes in addition to its broad-spectrum inhibition of several signalling pathways. Resveratrol effectively inhibits insulin-induced Akt and MAPK (mitogen-activated protein kinase) activation mainly through disruption of the interactions between insulin receptor substrates and its downstream binding proteins including p85 regulatory subunit of phosphoinositide 3-kinase and Grb2 (growth factor receptor-bound protein 2). The inhibitory effect of resveratrol on insulin signalling is also demonstrated at mRNA level, where resveratrol reverses insulin effects on phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, fatty acid synthase and glucokinase. In addition, RNA interference experiment shows that the inhibitory effect of resveratrol on insulin signalling pathway is not weakened in cells with reduced expression of SirT1, the mammalian counterpart of Sir2. These observations raise the possibility that resveratrol may additionally modulate lifespan through inhibition of insulin signalling pathway, independently of its activation of SirT1 histone deacetylase. Furthermore, the present study may help to explain a wide range of biological effects of resveratrol, and provides further insight into the molecular basis of calorie restriction.
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Maiese, Kenneth. "FoxO Proteins in the Nervous System." Analytical Cellular Pathology 2015 (2015): 1–15. http://dx.doi.org/10.1155/2015/569392.
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Acute as well as chronic disorders of the nervous system lead to significant morbidity and mortality for millions of individuals globally. Given the ability to govern stem cell proliferation and differentiated cell survival, mammalian forkhead transcription factors of the forkhead box class O (FoxO) are increasingly being identified as potential targets for disorders of the nervous system, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and auditory neuronal disease. FoxO proteins are present throughout the body, but they are selectively expressed in the nervous system and have diverse biological functions. The forkhead O class transcription factors interface with an array of signal transduction pathways that include protein kinase B (Akt), serum- and glucocorticoid-inducible protein kinase (SgK), IκB kinase (IKK), silent mating type information regulation 2 homolog 1 (S. cerevisiae) (SIRT1), growth factors, and Wnt signaling that can determine the activity and integrity of FoxO proteins. Ultimately, there exists a complex interplay between FoxO proteins and their signal transduction pathways that can significantly impact programmed cell death pathways of apoptosis and autophagy as well as the development of clinical strategies for the treatment of neurodegenerative disorders.
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Dong, Yi-jun, Nian Liu, Zhi Xiao, Tao Sun, Shu-hui Wu, Wei-xia Sun, Zhong-gao Xu, and Hang Yuan. "Renal Protective Effect of Sirtuin 1." Journal of Diabetes Research 2014 (2014): 1–8. http://dx.doi.org/10.1155/2014/843786.
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Silent information regulator 2 (Sir2) is a nicotinamide adenine dinucleotide- (NAD+-) dependent deacetylase. The homology of SIRT1 and Sir2 has been extensively studied. SIRT1 deacetylates target proteins using the coenzyme NAD+and is therefore linked to cellular energy metabolism and the redox state through multiple signalling and survival pathways. During the past decade, investigators have reported that SIRT1 activity is essential in cancer, neurodegenerative diseases, diabetes, cardiovascular disease, and other age-related diseases. In the kidneys, SIRT1 may inhibit renal cell apoptosis, inflammation, and fibrosis. Therefore its activation may also become a new therapeutic target in the patients with chronic kidney disease including diabetic nephropathy. In this paper, we would like to review the protective functions of sirtuins and the role of SIRT1 in the onset of kidney disease based on previous studies, including diabetic nephropathy, acute renal injury, chronic kidney disease as well as lupus nephritis.
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Cao, Kun, Yang-Ting Dong, Jie Xiang, Yi Xu, Wei Hong, Hui Song, and Zhi-Zhong Guan. "Reduced expression of SIRT1 and SOD-1 and the correlation between these levels in various regions of the brains of patients with Alzheimer's disease." Journal of Clinical Pathology 71, no. 12 (September 5, 2018): 1090–99. http://dx.doi.org/10.1136/jclinpath-2018-205320.
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AimsThis study was designed to explore the expression and distribution of silent information regulator 1 (SIRT1) and superoxide dismutase 1 (SOD-1) in various regions of the brains of patients with Alzheimer's disease (AD), as well as to assess potential correlations between the levels of these proteins and also between these proteins and the Braak stage of AD.MethodsIn the temporal and frontal cortices, hippocampus and cerebellum of 10 patients with AD and 10 age-matched control subjects, expression of SIRT1 and SOD-1, together with histopathology, were assessed by immunohistochemical and immunofluorescent stainings. Relationships between variables were examined with the Pearson correlation test.ResultsThe numbers of both SIRT1-positive and SOD-1-positive neurons and integrated optical density of immunohistochemical staining for these proteins in the temporal and frontal cortices, and hippocampus of patients with AD were significantly decreased than those in corresponding controls. In the case of the cerebellum, very weak expression of SIRT1 and obvious expression of SOD-1 were observed in granule cells, with no significant difference between AD and the control group. Interestingly, the protein levels between SIRT1 and SOD-1, as well as the level of SIRT1 or SOD-1 and Braak stage, were significantly correlated in neurons in all regions of the AD brains investigated except for the cerebellum.ConclusionsThese findings indicate that the reduced level of SIRT1 in the brains of patients with AD may be related to the decline in SOD-1 and neuropathological changes of this disorder.
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Wang, Shichun, Qianqian Tang, Fuchao Ge, and Qing Guo. "Typhae pollen polysaccharides protect hypoxia-induced PC12 cell injury via regulation of miR-34a/SIRT1." International Journal of Immunopathology and Pharmacology 34 (January 2020): 205873842091000. http://dx.doi.org/10.1177/2058738420910005.
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This current research was performed to investigate the role of typhae pollen polysaccharides (TPP) in hypoxia-treated PC12 cell which was an in vitro cell model of cerebral ischemia. Hypoxia-treated cells were treated with TPP for 12 h. Cell viability and apoptosis were detected by 3-(4,5-dimethylthiazol-2-yl)-2 5-diphenyl-2H-tetrazolium bromide (MTT) assay and flow cytometry, respectively. Cell apoptotic proteins and PI3K/AKT and Ras/Raf/MEK/ERK signal pathway–associated proteins were also examined by western blot. Furthermore, abnormal expression of miR-34a and silent information regulator 1 (SIRT1) was achieved by transfection. Besides, the expression of miR-34a and SIRT1 was examined by quantitative real-time polymerase chain reaction (qRT-PCR). The expression of SIRT1 was detected by qRT-PCR and western blot. The relationship between miR-34a and SIRT1 was verified by luciferase assay. We found that TPP enhanced cell viability and inhibited apoptosis in hypoxia-treated PC12 cells. Moreover, TPP increased the accumulated levels of Bcl-2 while decreased expression of Bax, cleaved Caspase-3, and cleaved PARP. TPP downregulated miR-34a expression while induced by hypoxia. Further results showed that miR-34a overexpression reversed the results led by TPP in cell viability, apoptosis, and its related proteins. In addition, SIRT1 was upregulated by TPP and was verified to be a target of miR-34a. Silence of SIRT1 led to the opposite results led by TPP. In the end, TPP activated PI3K/AKT and Ras/Raf/MEK/ERK signal pathways. In conclusion, TPP plays important roles in regulating cell viability and apoptosis in hypoxia-treated PC12 cells via modulating miR-34a/SIRT1, as well as activating PI3K/AKT and Ras/Raf/MEK/ERK signal pathways.
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Isobe, W., S. Murakami, T. Saito, S. Kumagai, and M. Sakita. "Effect of aerobic exercise on muscle structure and expression of proteins promoting hypertrophy and metabolism in aged rats." Comparative Exercise Physiology 16, no. 5 (October 20, 2020): 377–85. http://dx.doi.org/10.3920/cep190077.
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Aging and physical inactivity lead to histochemical changes in muscles. The expression of many muscle proteins, including brain-derived neurotrophic factor (BDNF), silent information regulator of transcription 1 (SIRT1), and peroxisome proliferator-activated receptor γγ coactivator-1α (PGC-1a), declines with age. However, the effect of aerobic exercise on muscle structure and the expression profile of these proteins in elderly rats is unknown. Here, we investigated whether short-term aerobic exercise improves muscle structure and increases BDNF, SIRT1, and PGC-1a levels in aged rats. Ten male Wistar rats (95-week-old) were assigned to sedentary (SED) or exercise (Ex) groups. The Ex group performed running on a treadmill for 1 h, 6 times per week, for 2 weeks. The extensor digitorum longus muscles were removed to examine the muscle fibre type composition, cross-sectional area, and capillary-to-fibre (C/F) ratio. BDNF, SIRT1, and PGC-1a levels were evaluated by western blotting. Relative to the SED group, the Ex group showed increased proportion of Type I fibres (P<0.05), cross-sectional area of all muscle fibre types (P<0.05), succinate dehydrogenase activity (P<0.001), C/F ratio (P<0.05), and expression of BDNF, SIRT1, and PGC-1a (P<0.05).Thus, 2 weeks of aerobic exercise is sufficient to improve muscle histology and hypertrophic marker protein expression, indicating that it could prevent skeletal muscle atrophy in elderly rats.
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Horio, Yoshiyuki, Takashi Hayashi, Atsushi Kuno, and Risa Kunimoto. "Cellular and molecular effects of sirtuins in health and disease." Clinical Science 121, no. 5 (May 20, 2011): 191–203. http://dx.doi.org/10.1042/cs20100587.
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Sirtuins are NAD+-dependent protein deacetylases that are broadly conserved from bacteria to humans. Because sirtuins extend the lifespan of yeast, worms and flies, much attention has been paid to their mammalian homologues. Recent studies have revealed diverse physiological functions of sirtuins that are essentially similar to those of their yeast homologue, Sir2 (silent information regulator 2). Sirtuins are implicated in the pathology of many diseases, for which sirtuin activators such as resveratrol have great promise as potential treatments. In the present review, we describe the functions of sirtuins in cell survival, inflammation, energy metabolism, cancer and differentiation, and their impact on diseases. We also discuss the organ-specific functions of sirtuins, focusing on the brain and blood vessels.
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U.Åström, Stefan, Andreas Kegel, Jimmy O. O. Sjöstrand, and Jasper Rine. "Kluyveromyces lactis Sir2p Regulates Cation Sensitivity and Maintains a Specialized Chromatin Structure at the Cryptic α-Locus." Genetics 156, no. 1 (September 1, 2000): 81–91. http://dx.doi.org/10.1093/genetics/156.1.81.
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Abstract In Saccharomyces cerevisiae, transcriptional silencing of the cryptic mating type loci requires the formation of a heterochromatin-like structure, which is dependent on silent information regulator (Sir) proteins and DNA sequences, called silencers. To learn more about silencing, we characterized the mating type loci from the yeast Kluyveromyces lactis. The K. lactis MAT, HMRa, and HMLα loci shared flanking DNA sequences on both sides of the loci presumably acting as recombinational targets during mating type switching. HMRa contained two genes, the a1 gene similar to the Saccharomyces a1 gene and the a2 gene similar to mating type genes from other yeasts. K. lactis HMLα contained three genes, the α1 and α2 genes, which were similar to their Saccharomyces counterparts, and a novel third gene, α3. A dam-methylase assay showed Sir-dependent, but transcription-independent changes of the chromatin structure of the HMLα locus. The HMLα3 gene did not appear to be part of the silent domain because α3p was expressed from both MATα3 and HMLα3 and sir mutations failed to change the chromatin structure of the HMLα3 gene. Furthermore, a 102-bp silencer element was isolated from the HMLα flanking DNA. HMLα was also flanked by an autonomously replicating sequence (ARS) activity, but the ARS activity did not appear to be required for silencer function. K. lactis sir2 strains grown in the presence of ethidium bromide (EtBr) accumulated the drug, which interfered with the essential mitochondrial genome. Mutations that bypassed the requirement for the mitochondrial genome also bypassed the EtBr sensitivity of sir2 strains. Sir2p localized to the nucleus, indicating that the role of Sir2p to hinder EtBr accumulation was an indirect regulatory effect. Sir2p was also required for growth in the presence of high concentrations of Ni2+ and Cu2+.
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Stone, Elisa M., Cheryl Reifsnyder, Mitch McVey, Brandy Gazo, and Lorraine Pillus. "Two Classes of sir3 Mutants Enhance the sir1 Mutant Mating Defect and Abolish Telomeric Silencing in Saccharomyces cerevisiae." Genetics 155, no. 2 (June 1, 2000): 509–22. http://dx.doi.org/10.1093/genetics/155.2.509.
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Abstract Silent information regulators, or Sir proteins, play distinct roles in chromatin-mediated transcriptional control at the silent mating-type loci, telomeres, and within the rDNA repeats of Saccharomyces cerevisiae. An unusual collection of sir3 mutant alleles was identified in a genetic screen for enhancers of the sir1 mutant mating-defective phenotype. These sir3-eso mutants, like the sir1 mutant, exhibit little or no mating defects alone, but the sir1 sir3-eso double mutants are essentially nonmating. All of the sir3-eso mutants are defective in telomeric silencing. In some mutants, this phenotype is suppressed by tethering Sir1p to telomeres; other mutants are dominant for mating and telomeric silencing defects. Additionally, several sir3-eso mutants are nonmating in combination with the nat1 N-terminal acetyltransferase mutant. The temperature-sensitive allele sir3-8 has an eso phenotype at permissive temperature, yet acts as a null allele at restrictive temperature due to loss of sir3-8 protein. Sequence analysis showed that eight of the nine sir3-eso alleles have mutations within the N-terminal region that is highly similar to the DNA replication initiation protein Orc1p. Together, these data reveal modular domains for Sir3p and further define its function in silencing chromatin.
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Gurd, Brendon J., Christopher G. R. Perry, George J. F. Heigenhauser, Lawrence L. Spriet, and Arend Bonen. "High-intensity interval training increases SIRT1 activity in human skeletal muscle." Applied Physiology, Nutrition, and Metabolism 35, no. 3 (June 2010): 350–57. http://dx.doi.org/10.1139/h10-030.
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The effects of training on silent mating-type information regulator 2 homolog 1 (SIRT1) activity and protein in relationship to peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and mitochondrial content were determined in human skeletal muscle. Six weeks of high-intensity interval training (∼1 h of 10 × 4 min intervals at 90% peak oxygen consumption separated by 2 min rest, 3 days per week) increased maximal activities of mitochondrial enzymes in skeletal muscle by 28% to 36% (citrate synthase, β-hydroxyacyl-coenzyme A dehydrogenase, and cytochrome c oxidase subunit IV) and PGC-1α protein (16%) when measured 4 days after training. Interestingly, total muscle SIRT1 activity (31%) and activity per SIRT1 protein (58%) increased despite decreased SIRT1 protein (20%). The present data demonstrate that exercise-induced mitochondrial biogenesis is accompanied by elevated SIRT1 activity in human skeletal muscle.
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Wang, Yali, Dongjun Lv, Wenwen Liu, Siyue Li, Jing Chen, Yun Shen, Fen Wang, Li-Fang Hu, and Chun-Feng Liu. "Disruption of the Circadian Clock Alters Antioxidative Defense via the SIRT1-BMAL1 Pathway in 6-OHDA-Induced Models of Parkinson’s Disease." Oxidative Medicine and Cellular Longevity 2018 (2018): 1–11. http://dx.doi.org/10.1155/2018/4854732.
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Parkinson’s disease (PD) is the second most common neurodegenerative disease and is known to involve circadian dysfunction and oxidative stress. Although antioxidative defense is regulated by the molecular circadian clock, few studies have examined their function in PD and their regulation by silent information regulator 1 (SIRT1). We hypothesize that reduced antioxidative activity in models of PD results from dysfunction of the molecular circadian clock via the SIRT1 pathway. We treated rats and SH-SY5Y cells with 6-hydroxydopamine (6-OHDA) and measured the expression of core circadian clock and associated nuclear receptor genes using real-time quantitative PCR as well as levels of SIRT1, brain and muscle Arnt-like protein 1 (BMAL1), and acetylated BMAL1 using Western blotting. We found that 6-OHDA treatment altered the expression patterns of clock and antioxidative molecules in vivo and in vitro. We also detected an increased ratio of acetylated BMAL1:BMAL1 and a decreased level of SIRT1. Furthermore, resveratrol, an activator of SIRT1, decreased the acetylation of BMAL1 and inhibited its binding with CRY1, thereby reversing the impaired antioxidative activity induced by 6-OHDA. These results suggest that a dysfunctional circadian clock contributes to an abnormal antioxidative response in PD via a SIRT1-dependent BMAL1 pathway.
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Kitada, Munehiro, Shinji Kume, Ai Takeda-Watanabe, Keizo Kanasaki, and Daisuke Koya. "Sirtuins and renal diseases: relationship with aging and diabetic nephropathy." Clinical Science 124, no. 3 (October 5, 2012): 153–64. http://dx.doi.org/10.1042/cs20120190.
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Sirtuins are members of the Sir2 (silent information regulator 2) family, a group of class III deacetylases. Mammals have seven different sirtuins, SIRT1–SIRT7. Among them, SIRT1, SIRT3 and SIRT6 are induced by calorie restriction conditions and are considered anti-aging molecules. SIRT1 has been the most extensively studied. SIRT1 deacetylates target proteins using the coenzyme NAD+ and is therefore linked to cellular energy metabolism and the redox state through multiple signalling and survival pathways. SIRT1 deficiency under various stress conditions, such as metabolic or oxidative stress or hypoxia, is implicated in the pathophysiologies of age-related diseases including diabetes, cardiovascular diseases, neurodegenerative disorders and renal diseases. In the kidneys, SIRT1 may inhibit renal cell apoptosis, inflammation and fibrosis, and may regulate lipid metabolism, autophagy, blood pressure and sodium balance. Therefore the activation of SIRT1 in the kidney may be a new therapeutic target to increase resistance to many causal factors in the development of renal diseases, including diabetic nephropathy. In addition, SIRT3 and SIRT6 are implicated in age-related disorders or longevity. In the present review, we discuss the protective functions of sirtuins and the association of sirtuins with the pathophysiology of renal diseases, including diabetic nephropathy.
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Casey, Laurieann, Erin E. Patterson, Ulrika Müller, and Catherine A. Fox. "Conversion of a Replication Origin to a Silencer through a Pathway Shared by a Forkhead Transcription Factor and an S Phase Cyclin." Molecular Biology of the Cell 19, no. 2 (February 2008): 608–22. http://dx.doi.org/10.1091/mbc.e07-04-0323.
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Silencing of the mating-type locus HMR in Saccharomyces cerevisiae requires DNA elements called silencers. To establish HMR silencing, the origin recognition complex binds the HMR-E silencer and recruits the silent information regulator (Sir)1 protein. Sir1 in turn helps establish silencing by stabilizing binding of the other Sir proteins, Sir2–4. However, silencing is semistable even in sir1Δ cells, indicating that SIR1-independent establishment mechanisms exist. Furthermore, the requirement for SIR1 in silencing a sensitized version of HMR can be bypassed by high-copy expression of FKH1 (FKH1hc), a conserved forkhead transcription factor, or by deletion of the S phase cyclin CLB5 (clb5Δ). FKH1hc caused only a modest increase in Fkh1 levels but effectively reestablished Sir2–4 chromatin at HMR as determined by Sir3-directed chromatin immunoprecipitation. In addition, FKH1hc prolonged the cell cycle in a manner distinct from deletion of its close paralogue FKH2, and it created a cell cycle phenotype more reminiscent to that caused by a clb5Δ. Unexpectedly, and in contrast to SIR1, both FKH1hc and clb5Δ established silencing at HMR using the replication origins, ARS1 or ARSH4, as complete substitutes for HMR-E (HMRΔE::ARS). HMRΔE::ARS1 was a robust origin in CLB5 cells. However, initiation by HMRΔE::ARS1 was reduced by clb5Δ or FKH1hc, whereas ARS1 at its native locus was unaffected. The CLB5-sensitivity of HMRΔE::ARS1 did not result from formation of Sir2–4 chromatin because sir2Δ did not rescue origin firing in clb5Δ cells. These and other data supported a model in which FKH1 and CLB5 modulated Sir2–4 chromatin and late-origin firing through opposing regulation of a common pathway.
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Cockell, M., F. Palladino, T. Laroche, G. Kyrion, C. Liu, A. J. Lustig, and S. M. Gasser. "The carboxy termini of Sir4 and Rap1 affect Sir3 localization: evidence for a multicomponent complex required for yeast telomeric silencing." Journal of Cell Biology 129, no. 4 (May 15, 1995): 909–24. http://dx.doi.org/10.1083/jcb.129.4.909.
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The Silent Information Regulatory proteins, Sir3 and Sir4, and the telomeric repeat-binding protein RAP1 are required for the chromatin-mediated gene repression observed at yeast telomeric regions. All three proteins are localized by immunofluorescence staining to foci near the nuclear periphery suggesting a relationship between subnuclear localization and silencing. We present several lines of immunological and biochemical evidence that Sir3, Sir4, and RAP1 interact in intact yeast cells. First, immunolocalization of Sir3 to foci at the yeast nuclear periphery is lost in rap1 mutants carrying deletions for either the terminal 28 or 165 amino acids of RAP1. Second, the perinuclear localization of both Sir3 and RAP1 is disrupted by overproduction of the COOH terminus of Sir4. Third, overproduction of the Sir4 COOH terminus alters the solubility properties of both Sir3 and full-length Sir4. Finally, we demonstrate that RAP1 and Sir4 coprecipitate in immune complexes using either anti-RAP1 or anti-Sir4 antibodies. We propose that the integrity of a tertiary complex between Sir4, Sir3, and RAP1 is involved in both the maintenance of telomeric repression and the clustering of telomeres in foci near the nuclear periphery.
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Chi, M. H., and D. Shore. "SUM1-1, a dominant suppressor of SIR mutations in Saccharomyces cerevisiae, increases transcriptional silencing at telomeres and HM mating-type loci and decreases chromosome stability." Molecular and Cellular Biology 16, no. 8 (August 1996): 4281–94. http://dx.doi.org/10.1128/mcb.16.8.4281.
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Transcriptional silencing in the yeast Saccharomyces cerevisiae occurs at HML and HMR mating-type loci and telomeres and requires the products of the silent information regulator (SIR) genes. Recent evidence suggests that the silencer- and telomere-binding protein Rap1p initiates silencing by recruiting a complex of Sir proteins to the chromosome, where they act in some way to modify chromatin structure or accessibility. A single allele of the SUM1gene (SUM1-1) which restores silencing at HM loci in strains mutant for any of the four SIR genes was identified a number of years ago. However, conflicting genetic results and the lack of other alleles of SUM1 made it difficult to surmise the wild-type function of SUM1 or the manner in which the SUM1-1 mutation restores silencing in sir mutant strains. Here we report the cloning and characterization of the SUM1 gene and the SUM1-1 mutant allele. Our results indicate that SUM1-1 is an unusual altered-function mutation that can bypass the need for SIR function in HM silencing and increase repression at telomeres. A sum1 deletion mutation has only minor effects on silencing in SIR strains and does not restore silencing in sir mutants. In addition to its effect on transcriptional silencing, the SUM1-1 mutation (but not a sum1 deletion) increases the rate of chromosome loss and cell death. We suggest several speculative models for the action of SUM1-1 in silencing based on these and other data.
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Mahlknecht, Ulrich R., and Susanne F. Voelter-Mahlknecht. "Characterization of the NAD-Dependent Human Histone Deacetylases Gene Sirtuin 1 and Its Implications on Aging and the Development of Malignant Disease." Blood 108, no. 11 (November 16, 2006): 4299. http://dx.doi.org/10.1182/blood.v108.11.4299.4299.
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Abstract A dysregulation of the tightly controlled equilibrium of acetylation and deacetylation plays a causative role in the generation as well as in the suppression of cancer. Histone acetylation modifiers are therefore gaining increasing attention as potential targets in the treatment of cancer. Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, which belongs to the silent information regulator 2 (Sir2) family of sirtuin histone deacetylases (HDACs). The yeast Sir2 protein and its mammalian derivatives play a central role in epigenetic gene silencing, DNA repair and recombination, cell-cycle, microtubule organization, and in the regulation of aging. We have isolated and characterized the human Sirt1 genomic sequence and identified a number of SIRT1 protein interaction partners, which will be important for the further understanding its physiological role. The Sirt1 gene spans a region of 33,660 bp and is located on chromosome 10q21.3. The protein is localized in the nucleus, and interacts with and deacetylates a growing number of proteins, such as p53, the Forkhead transcription factor FOXO3A, PML, BCL6, TAFI68, HES1, and CTIP2. SIRT1 has been shown to be essential for embryonic development, muscle differentiation and is an important mediator of organismal longevity through a number of different mechanisms such as the induction of cell cycle arrest, resistance to oxidative stress and the inhibition of apoptosis. Some histone deacetylase genes have been shown to be rearranged in the context of chromosomal translocations in human acute leukemias and solid tumors, where fusions of regulatory and coding regions of a variety of transcription factor genes result in completely new gene products, which may interfere with regulatory cascades that control cell growth and differentiation. On the other hand, some histone acetylation modifying enzymes have been located within chromosomal regions that are particularly prone to chromosomal breaks. In these cases gains and losses of chromosomal material may affect the availability of functionally active HATs and HDACs, which in turn disturbs the tightly controlled equilibrium of histone acetylation. A deletion of Sirt1 would therefore most probably shift the steady state toward acetylation at the level of specific genes targeted by SIRT1 and either upregulate or downregulate transcriptional events. Such dysregulation might represent a critical event in the multistep pathway leading to full cellular transformation and the development of malignancy.
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Broderick, Tom L., Suhail Rasool, Rongzi Li, Yuxian Zhang, Miranda Anderson, Layla Al-Nakkash, Jeffrey H. Plochocki, Thangiah Geetha, and Jeganathan Ramesh Babu. "Neuroprotective Effects of Chronic Resveratrol Treatment and Exercise Training in the 3xTg-AD Mouse Model of Alzheimer’s Disease." International Journal of Molecular Sciences 21, no. 19 (October 4, 2020): 7337. http://dx.doi.org/10.3390/ijms21197337.
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To date, there is no cure or effective treatment for Alzheimer’s disease (AD), a chronic neurodegenerative condition that affects memory, language, and behavior. AD is characterized by neuroinflammation, accumulation of brain amyloid-beta (Aβ) oligomers and neurofibrillary tangles, increased neuronal apoptosis, and loss of synaptic function. Promoting regular exercise and a diet containing polyphenols are effective non-pharmacological approaches that prevent the progression of neurodegenerative diseases. In this study, we measured various conformational toxic species of Aβ and markers of inflammation, apoptosis, endolysosomal degradation, and neuroprotection after 5 months of exercise training (ET), resveratrol (Resv) treatment, or combination treatment in the 3xTg-AD mouse model of AD. Our main results indicate that Resv decreased neuroinflammation and accumulation of Aβ oligomers, increased levels of neurotrophins, synaptic markers, silent information regulator, and decreased markers of apoptosis, autophagy, endolysosomal degradation and ubiquitination in the brains of 3xTg-AD mice. ET improved some markers related to neuroprotection, but when combined with Resv treatment, the benefits achieved were as effective as Resv treatment alone. Our results show that the neuroprotective effects of Resv, ET or Resv and ET are associated with reduced toxicity of Aβ oligomers, suppression of neuronal autophagy, decreased apoptosis, and upregulation of key growth-related proteins.
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Li, Ling, Lei Zhao, Wuliya Yi-Ming, Yong-Sheng Yu, Chun-Yan Xia, Jun-Li Duan, and Ding-Feng Su. "Sirt1 hyperexpression in SHR heart related to left ventricular hypertrophy." Canadian Journal of Physiology and Pharmacology 87, no. 1 (January 2009): 56–62. http://dx.doi.org/10.1139/y08-099.
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Sirt1 is a human homologue of the silent information regulator factor 2 (Sir2) and has an NAD+-dependent histone deacetylase activity. This protein is reported to have a pathogenetic role in muscle differentiation, diabetic nephropathy, and heart failure. In this study, we investigated the expression of sirt1 in spontaneously hypertensive rat (SHR) to obtain insight into the function of sirt1 in hypertensive cardiovascular hypertrophy. The gene and protein expression of sirt1 was increased in the heart in SHR compared with normotensive WKY rats. Sirt1 mRNA was not different in the aorta between SHR and WKY rats. Sirt1 mRNA expression in heart and aorta was not related to hemodynamic parameters in SHR. Hypertensive left ventricular hypertrophy was significantly and positively related to the expression of heart tissue sirt1 mRNA in SHR. Aortic hypertrophy, however, was not related to sirt1 mRNA in the aorta. The increased sirt1 protein expression was accompanied by severe cardiac hypertrophy in older SHR. These results suggest that the increase of sirt1 gene and protein expression in the heart was associated with cardiac hypertrophy.
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Lin, Yanfei, Yujuan Sun, Yufang Weng, Akira Matsuura, Lan Xiang, and Jianhua Qi. "Parishin fromGastrodia elataExtends the Lifespan of Yeast via Regulation of Sir2/Uth1/TOR Signaling Pathway." Oxidative Medicine and Cellular Longevity 2016 (2016): 1–11. http://dx.doi.org/10.1155/2016/4074690.
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Parishin is a phenolic glucoside isolated fromGastrodia elata, which is an important traditional Chinese medicine; this glucoside significantly extended the replicative lifespan of K6001 yeast at 3, 10, and 30 μM. To clarify its mechanism of action, assessment of oxidative stress resistance, superoxide dismutase (SOD) activity, malondialdehyde (MDA), and reactive oxygen species (ROS) assays, replicative lifespans ofsod1,sod2,uth1, andskn7yeast mutants, and real-time quantitative PCR (RT-PCR) analysis were conducted. The significant increase of cell survival rate in oxidative stress condition was observed in parishin-treated groups. Silent information regulator 2 (Sir2) gene expression and SOD activity were significantly increased after treating parishin in normal condition. Meanwhile, the levels of ROS and MDA in yeast were significantly decreased. The replicative lifespans ofsod1,sod2,uth1,andskn7mutants of K6001 yeast were not affected by parishin. We also found that parishin could decrease the gene expression ofTORC1, ribosomal protein S26A (RPS26A), and ribosomal protein L9A (RPL9A) in the target of rapamycin (TOR) signaling pathway. Gene expression levels ofRPS26AandRPL9Ainuth1, as well as inuth1,sir2double mutants, were significantly lower than those of the control group. Besides,TORC1gene expression inuth1mutant of K6001 yeast was inhibited significantly. These results suggested that parishin exhibited antiaging effects via regulation of Sir2/Uth1/TOR signaling pathway.
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Koka, Saisudha, Hema S. Aluri, Lei Xi, Edward J. Lesnefsky, and Rakesh C. Kukreja. "Chronic inhibition of phosphodiesterase 5 with tadalafil attenuates mitochondrial dysfunction in type 2 diabetic hearts: potential role of NO/SIRT1/PGC-1α signaling." American Journal of Physiology-Heart and Circulatory Physiology 306, no. 11 (June 1, 2014): H1558—H1568. http://dx.doi.org/10.1152/ajpheart.00865.2013.
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Enhanced nitric oxide (NO) production is known to activate silent information regulator 1 (SIRT1), which is a histone deacetylase that regulates PGC-1α, a regulator of mitochondrial biogenesis and coactivator of transcription factors impacting energy homeostasis. Since phosphodiesterase-5 inhibitors potentiate NO signaling, we hypothesized that chronic treatment with phosphodiesterase-5 inhibitor tadalafil would activate SIRT1-PGC-1α signaling and protect against metabolic stress-induced mitochondrial dysfunction in diabetic hearts. Diabetic db/db mice ( n = 32/group; 40 wk old) were randomized to receive DMSO (10%, 0.2 ml ip) or tadalafil (1 mg/kg ip in 10% DMSO) for 8 wk. Wild-type C57BL mice served as nondiabetic controls. The hearts were excised and homogenized to study SIRT1 activity and downstream protein targets. Mitochondrial function was determined by measuring oxidative phosphorylation (OXPHOS), and reactive oxygen species generation was studied in isolated mitochondria. Tadalafil-treated diabetic mice demonstrated significantly improved left ventricular function, which is associated with increased cardiac SIRT1 activity. Tadalafil also enhanced plasma NO oxidation levels, myocardial SIRT1, PGC-1α expression, and phosphorylation of eNOS, Akt, and AMPK in the diabetic hearts. OXPHOS with the complex I substrate glutamate was decreased by 50% in diabetic hearts compared with the nondiabetic controls. Tadalafil protected OXPHOS with an improved glutamate state 3 respiration rates. The increased reactive oxygen species production from complex I was significantly decreased by tadalafil treatment. In conclusion, chronic treatment with tadalafil activates NO-induced SIRT1-PGC-1α signaling and attenuates mitochondrial dysfunction in type 2 diabetic hearts.
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Zhang, Lingyu, Fengna Li, Qiuping Guo, Yehui Duan, Wenlong Wang, Yinzhao Zhong, Yuhuan Yang, and Yulong Yin. "Leucine Supplementation: A Novel Strategy for Modulating Lipid Metabolism and Energy Homeostasis." Nutrients 12, no. 5 (May 2, 2020): 1299. http://dx.doi.org/10.3390/nu12051299.
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Lipid metabolism is an important and complex biochemical process involved in the storage of energy and maintenance of normal biological functions. Leucine, a branched amino acid, has anti-obesity effects on glucose tolerance, lipid metabolism, and insulin sensitivity. Leucine also modulates mitochondrial dysfunction, representing a new strategy to target aging, neurodegenerative disease, obesity, diabetes, and cardiovascular disease. Although various studies have been carried out, much uncertainty still exists and further studies are required to fully elucidate the relationship between leucine and lipid metabolism. This review offers an up-to-date report on leucine, as key roles in both lipid metabolism and energy homeostasis in vivo and in vitro by acceleration of fatty acid oxidation, lipolysis, activation of the adenosine 5′-monophosphate-activated protein kinase (AMPK)–silent information regulator of transcription 1 (SIRT1)–proliferator-activated receptor γ coactivator-1α (PGC-1α) pathway, synthesis, and/or secretion of adipokines and stability of the gut microbiota.
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Strum, Jay C., Jennifer H. Johnson, James Ward, Hongbo Xie, John Feild, Austin Hester, Alexander Alford, and K. Michelle Waters. "MicroRNA 132 Regulates Nutritional Stress-Induced Chemokine Production through Repression of SirT1." Molecular Endocrinology 23, no. 11 (November 1, 2009): 1876–84. http://dx.doi.org/10.1210/me.2009-0117.
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Abstract Human adipose tissue secretes a number of proinflammatory mediators that may contribute to the pathophysiology of obesity-related disorders. Understanding the regulatory pathways that control their production is paramount to developing effective therapeutics to treat these diseases. Using primary human adipose-derived stem cells as a source of preadipocytes and in vitro differentiated adipocytes, we found IL-8 and monocyte chemoattractant protein-1 (MCP-1) are constitutively secreted by both cell types and induced in response to serum deprivation. MicroRNA profiling revealed the rapid induction of microRNA 132 (miR-132) in these cells when switched to serum-free medium. Furthermore, miR-132 overexpression was sufficient to induce nuclear factor-κB translocation, acetylation of p65, and production of IL-8 and MCP-1. Inhibitors of miR-132 decreased acetylated p65 and partially inhibited the production of IL-8 and MCP-1 induced by serum deprivation. MiR-132 was shown to inhibit silent information regulator 1 (SirT1) expression through a miR-132 binding site in the 3′-untranslated region of SirT1. Thus, in response to nutritional availability, induction of miR-132 decreases SirT1-mediated deacetylation of p65 leading to activation of nuclear factor-κB and transcription of IL-8 and MCP-1 in primary human preadipocytes and in vitro differentiated adipocytes.
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Gotta, Monica, Francesca Palladino, and Susan M. Gasser. "Functional Characterization of the N Terminus of Sir3p." Molecular and Cellular Biology 18, no. 10 (October 1, 1998): 6110–20. http://dx.doi.org/10.1128/mcb.18.10.6110.
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ABSTRACT Silent information regulator 3 is an essential component of theSaccharomyces cerevisiae silencing complex that functions at telomeres and the silent mating-type loci, HMR andHML. We show that expression of the N- and C-terminal-encoding halves of SIR3 in transpartially complements the mating defect of the sir3 null allele, suggesting that the two domains have distinct functions. We present here a functional characterization of these domains. The N-terminal domain (Sir3N) increases both the frequency and extent of telomere-proximal silencing when expressed ectopically inSIR + yeast strains, although we are unable to detect interaction between this domain and any known components of the silencing machinery. In contrast to its effect at telomeres, Sir3N overexpression derepresses transcription of reporter genes inserted in the ribosomal DNA (rDNA) array. Immunolocalization of Sir3N-GFP and Sir2p suggests that Sir3N directly antagonizes nucleolar Sir2p, releasing an rDNA-bound population of Sir2p so that it can enhance repression at telomeres. Overexpression of the C-terminal domain of either Sir3p or Sir4p has a dominant-negative effect on telomeric silencing. In strains overexpressing the C-terminal domain of Sir4p, elevated expression of either full-length Sir3p or Sir3N restores repression and the punctate pattern of Sir3p and Rap1p immunostaining. The similarity of Sir3N and Sir3p overexpression phenotypes suggests that Sir3N acts as an allosteric effector of Sir3p, either enhancing its interactions with other silencing components or liberating the full-length protein from nonfunctional complexes.