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Results: 1 to 10 of 11

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Discovery of gene-gene interactions across multiple independent data sets of late onset Alzheimer disease from the Alzheimer Disease Genetics Consortium.
Hohman TJ, Bush WS, Jiang L, Brown-Gentry KD, Torstenson ES, Dudek SM, Mukherjee S, Naj A, Kunkle BW, Ritchie MD, Martin ER, Schellenberg GD, Mayeux R, Farrer LA, Pericak-Vance MA, Haines JL, Thornton-Wells TA, Alzheimer's Disease Genetics Consortium
(2016) Neurobiol Aging 38: 141-150
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, Alzheimer Disease, Cadherins, Calcium Channels, L-Type, Datasets as Topic, Disease Progression, Epistasis, Genetic, Female, Genetic Association Studies, Humans, Male, Models, Genetic, Phosphatidylethanolamine Binding Protein, Polymorphism, Single Nucleotide, Receptors, Adrenergic, alpha-1, Receptors, N-Methyl-D-Aspartate, Risk, Ryanodine Receptor Calcium Release Channel, Saposins, Sirtuin 1
Show Abstract · Added April 10, 2018
Late-onset Alzheimer disease (AD) has a complex genetic etiology, involving locus heterogeneity, polygenic inheritance, and gene-gene interactions; however, the investigation of interactions in recent genome-wide association studies has been limited. We used a biological knowledge-driven approach to evaluate gene-gene interactions for consistency across 13 data sets from the Alzheimer Disease Genetics Consortium. Fifteen single nucleotide polymorphism (SNP)-SNP pairs within 3 gene-gene combinations were identified: SIRT1 × ABCB1, PSAP × PEBP4, and GRIN2B × ADRA1A. In addition, we extend a previously identified interaction from an endophenotype analysis between RYR3 × CACNA1C. Finally, post hoc gene expression analyses of the implicated SNPs further implicate SIRT1 and ABCB1, and implicate CDH23 which was most recently identified as an AD risk locus in an epigenetic analysis of AD. The observed interactions in this article highlight ways in which genotypic variation related to disease may depend on the genetic context in which it occurs. Further, our results highlight the utility of evaluating genetic interactions to explain additional variance in AD risk and identify novel molecular mechanisms of AD pathogenesis.
Copyright © 2016 Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
20 MeSH Terms
Inhibition of miR-29 has a significant lipid-lowering benefit through suppression of lipogenic programs in liver.
Kurtz CL, Fannin EE, Toth CL, Pearson DS, Vickers KC, Sethupathy P
(2015) Sci Rep 5: 12911
MeSH Terms: Animals, Cholesterol, Dyslipidemias, Female, Lipogenesis, Liver, Mice, MicroRNAs, Receptors, Aryl Hydrocarbon, Sirtuin 1
Show Abstract · Added April 25, 2016
MicroRNAs (miRNAs) are important regulators and potential therapeutic targets of metabolic disease. In this study we show by in vivo administration of locked nucleic acid (LNA) inhibitors that suppression of endogenous miR-29 lowers plasma cholesterol levels by ~40%, commensurate with the effect of statins, and reduces fatty acid content in the liver by ~20%. Whole transcriptome sequencing of the liver reveals 883 genes dysregulated (612 down, 271 up) by inhibition of miR-29. The set of 612 down-regulated genes are most significantly over-represented in lipid synthesis pathways. Among the up-regulated genes are the anti-lipogenic deacetylase sirtuin 1 (Sirt1) and the anti-lipogenic transcription factor aryl hydrocarbon receptor (Ahr), the latter of which we demonstrate is a direct target of miR-29. In vitro radiolabeled acetate incorporation assays confirm that pharmacologic inhibition of miR-29 significantly reduces de novo cholesterol and fatty acid synthesis. Our findings indicate that miR-29 controls hepatic lipogenic programs, likely in part through regulation of Ahr and Sirt1, and therefore may represent a candidate therapeutic target for metabolic disorders such as dyslipidemia.
0 Communities
1 Members
0 Resources
10 MeSH Terms
Controlling COR competence: BCL-6 regulates neurogenesis and tumor suppression.
Chiang C, Ihrie RA
(2014) Cancer Cell 26: 773-774
MeSH Terms: Animals, DNA-Binding Proteins, Humans, Medulloblastoma, Neurogenesis, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-6, Repressor Proteins, Signal Transduction, Sirtuin 1
Show Abstract · Added January 26, 2015
In this issue of Cancer Cell, Tiberi and colleagues describe a tumor-suppressor role for BCL6. In the cerebellum, BCL6 is required for the transition from proliferative precursor cell to a more differentiated immature neuron through repressing the expression of Hedgehog effectors, thus controlling a pathway that is aberrantly activated in medulloblastoma.
Copyright © 2014 Elsevier Inc. All rights reserved.
1 Communities
2 Members
0 Resources
10 MeSH Terms
Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging.
Gomes AP, Price NL, Ling AJ, Moslehi JJ, Montgomery MK, Rajman L, White JP, Teodoro JS, Wrann CD, Hubbard BP, Mercken EM, Palmeira CM, de Cabo R, Rolo AP, Turner N, Bell EL, Sinclair DA
(2013) Cell 155: 1624-38
MeSH Terms: AMP-Activated Protein Kinases, Aging, Animals, Cell Nucleus, Hypoxia-Inducible Factor 1, alpha Subunit, Mice, Mitochondria, Muscle, Skeletal, NAD, Oxidative Phosphorylation, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Reactive Oxygen Species, Sirtuin 1, Transcription Factors
Show Abstract · Added March 4, 2015
Ever since eukaryotes subsumed the bacterial ancestor of mitochondria, the nuclear and mitochondrial genomes have had to closely coordinate their activities, as each encode different subunits of the oxidative phosphorylation (OXPHOS) system. Mitochondrial dysfunction is a hallmark of aging, but its causes are debated. We show that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits. We trace the cause to an alternate PGC-1α/β-independent pathway of nuclear-mitochondrial communication that is induced by a decline in nuclear NAD(+) and the accumulation of HIF-1α under normoxic conditions, with parallels to Warburg reprogramming. Deleting SIRT1 accelerates this process, whereas raising NAD(+) levels in old mice restores mitochondrial function to that of a young mouse in a SIRT1-dependent manner. Thus, a pseudohypoxic state that disrupts PGC-1α/β-independent nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age, a process that is apparently reversible.
Copyright © 2013 Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
14 MeSH Terms
Silent information regulator (Sir)T1 inhibits NF-κB signaling to maintain normal skeletal remodeling.
Edwards JR, Perrien DS, Fleming N, Nyman JS, Ono K, Connelly L, Moore MM, Lwin ST, Yull FE, Mundy GR, Elefteriou F
(2013) J Bone Miner Res 28: 960-9
MeSH Terms: Acetylation, Aging, Animals, Bone Remodeling, Bone and Bones, Gene Deletion, Gene Knockdown Techniques, I-kappa B Proteins, Mice, NF-KappaB Inhibitor alpha, NF-kappa B, Organ Size, Organ Specificity, Osteoblasts, Osteoclasts, Signal Transduction, Sirtuin 1
Show Abstract · Added November 14, 2013
Silent information regulator T1 (SirT1) is linked to longevity and negatively controls NF-κB signaling, a crucial mediator of survival and regulator of both osteoclasts and osteoblasts. Here we show that NF-κB repression by SirT1 in both osteoclasts and osteoblasts is necessary for proper bone remodeling and may contribute to the mechanisms linking aging and bone loss. Osteoclast- or osteoblast-specific SirT1 deletion using the Sirt(flox/flox) mice crossed to lysozyme M-cre and the 2.3 kb col1a1-cre transgenic mice, respectively, resulted in decreased bone mass caused by increased resorption and reduced bone formation. In osteoclasts, lack of SirT1 promoted osteoclastogenesis in vitro and activated NF-κB by increasing acetylation of Lysine 310. Importantly, this increase in osteoclastogenesis was blocked by pharmacological inhibition of NF-κB. In osteoblasts, decreased SirT1 reduced osteoblast differentiation, which could also be rescued by inhibition of NF-κB. In further support of the critical role of NF-κB signaling in bone remodeling, elevated NF-κB activity in IκBα(+/-) mice uncoupled bone resorption and formation, leading to reduced bone mass. These findings support the notion that SirT1 is a genetic determinant of bone mass, acting in a cell-autonomous manner in both osteoblasts and osteoclasts, through control of NF-κB and bone cell differentiation.
Copyright © 2013 American Society for Bone and Mineral Research.
2 Communities
6 Members
0 Resources
17 MeSH Terms
Age-related susceptibility to apoptosis in human retinal pigment epithelial cells is triggered by disruption of p53-Mdm2 association.
Bhattacharya S, Chaum E, Johnson DA, Johnson LR
(2012) Invest Ophthalmol Vis Sci 53: 8350-66
MeSH Terms: Acetylation, Adult, Aged, Aged, 80 and over, Aging, Apoptosis, Apoptosis Regulatory Proteins, Benzamides, Blotting, Western, Caspase 3, Cell Proliferation, Cells, Cultured, DNA Fragmentation, Disease Susceptibility, Enzyme-Linked Immunosorbent Assay, Fluorescent Antibody Technique, Indirect, Humans, Imidazoles, In Situ Nick-End Labeling, Middle Aged, Naphthols, Phosphorylation, Piperazines, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-mdm2, RNA, Small Interfering, Retinal Pigment Epithelium, Sirtuin 1, Sirtuin 2, Tumor Suppressor Protein p53
Show Abstract · Added June 11, 2018
PURPOSE - Relatively little is known about the contribution of p53/Mdm2 pathway in apoptosis of retinal pigment epithelial (RPE) cells or its possible link to dysfunction of aging RPE or to related blinding disorders such as age-related macular degeneration (AMD).
METHODS - Age-associated changes in p53 activation were evaluated in primary RPE cultures from human donor eyes of various ages. Apoptosis was evaluated by activation of caspases and DNA fragmentation. Gene-specific small interfering RNA was used to knock down expression of p53.
RESULTS - We observed that the basal rate of p53-dependent apoptosis increased in an age-dependent manner in human RPE. The age-dependent increase in apoptosis was linked to alterations in several aspects of the p53 pathway. p53 phosphorylation Ser15 was increased through the stimulation of ATM-Ser1981. p53 acetylation Lys379 was increased through the inhibition of SIRT1/2. These two posttranslational modifications of p53 blocked the sequestration of p53 by Mdm2, thus resulting in an increase in free p53 and of p53 stimulation of apoptosis through increased expression of PUMA (p53 upregulated modulator of apoptosis) and activation of caspase-3. Aged RPE also had reduced expression of antiapoptotic Bcl-2, which contributed to the increase in apoptosis. Of particular interest in these studies was that pharmacologic treatments to block p53 phosphorylation, acetylation, or expression were able to protect RPE cells from apoptosis.
CONCLUSIONS - Our studies suggest that aging in the RPE leads to alterations of specific checkpoints in the apoptotic pathway, which may represent important molecular targets for the treatment of RPE-related aging disorders such as AMD.
0 Communities
1 Members
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MeSH Terms
SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function.
Price NL, Gomes AP, Ling AJ, Duarte FV, Martin-Montalvo A, North BJ, Agarwal B, Ye L, Ramadori G, Teodoro JS, Hubbard BP, Varela AT, Davis JG, Varamini B, Hafner A, Moaddel R, Rolo AP, Coppari R, Palmeira CM, de Cabo R, Baur JA, Sinclair DA
(2012) Cell Metab 15: 675-90
MeSH Terms: Animals, Cells, Cultured, Enzyme Activation, Hepatocytes, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Muscle, Skeletal, NAD, Protein Kinases, Resveratrol, Signal Transduction, Sirtuin 1, Stilbenes
Show Abstract · Added April 25, 2013
Resveratrol induces mitochondrial biogenesis and protects against metabolic decline, but whether SIRT1 mediates these benefits is the subject of debate. To circumvent the developmental defects of germline SIRT1 knockouts, we have developed an inducible system that permits whole-body deletion of SIRT1 in adult mice. Mice treated with a moderate dose of resveratrol showed increased mitochondrial biogenesis and function, AMPK activation, and increased NAD(+) levels in skeletal muscle, whereas SIRT1 knockouts displayed none of these benefits. A mouse overexpressing SIRT1 mimicked these effects. A high dose of resveratrol activated AMPK in a SIRT1-independent manner, demonstrating that resveratrol dosage is a critical factor. Importantly, at both doses of resveratrol no improvements in mitochondrial function were observed in animals lacking SIRT1. Together these data indicate that SIRT1 plays an essential role in the ability of moderate doses of resveratrol to stimulate AMPK and improve mitochondrial function both in vitro and in vivo.
Copyright © 2012 Elsevier Inc. All rights reserved.
0 Communities
0 Members
1 Resources
15 MeSH Terms
Berberine protects against high fat diet-induced dysfunction in muscle mitochondria by inducing SIRT1-dependent mitochondrial biogenesis.
Gomes AP, Duarte FV, Nunes P, Hubbard BP, Teodoro JS, Varela AT, Jones JG, Sinclair DA, Palmeira CM, Rolo AP
(2012) Biochim Biophys Acta 1822: 185-95
MeSH Terms: AMP-Activated Protein Kinases, Animals, Berberine, Cell Line, Diet, High-Fat, Glucose, Hormones, Hyperglycemia, Insulin Resistance, Male, Mice, Mitochondria, Mitochondria, Muscle, Muscle, Skeletal, Myoblasts, NAD, Obesity, Organelle Biogenesis, Phosphorylation, Rats, Rats, Sprague-Dawley, Sirtuin 1
Show Abstract · Added April 25, 2013
Berberine (BBR) has recently been shown to improve insulin sensitivity in rodent models of insulin resistance. Although this effect was explained partly through an observed activation of AMP-activated protein kinase (AMPK), the upstream and downstream mediators of this phenotype were not explored. Here, we show that BBR supplementation reverts mitochondrial dysfunction induced by High Fat Diet (HFD) and hyperglycemia in skeletal muscle, in part due to an increase in mitochondrial biogenesis. Furthermore, we observe that the prevention of mitochondrial dysfunction by BBR, the increase in mitochondrial biogenesis, as well as BBR-induced AMPK activation, are blocked in cells in which SIRT1 has been knocked-down. Taken together, these data reveal an important role for SIRT1 and mitochondrial biogenesis in the preventive effects of BBR on diet-induced insulin resistance.
Copyright © 2011 Elsevier B.V. All rights reserved.
0 Communities
0 Members
1 Resources
22 MeSH Terms
SIRT1 and SIRT3 deacetylate homologous substrates: AceCS1,2 and HMGCS1,2.
Hirschey MD, Shimazu T, Capra JA, Pollard KS, Verdin E
(2011) Aging (Albany NY) 3: 635-42
MeSH Terms: Acetate-CoA Ligase, Acetylation, Animals, Evolution, Molecular, Humans, Hydroxymethylglutaryl-CoA Synthase, Isoenzymes, Phylogeny, Sirtuin 1, Sirtuin 3
Show Abstract · Added April 18, 2017
SIRT1 and SIRT3 are NAD+-dependent protein deacetylases that are evolutionarily conserved across mammals. These proteins are located in the cytoplasm/nucleus and mitochondria, respectively. Previous reports demonstrated that human SIRT1 deacetylates Acetyl-CoA Synthase 1 (AceCS1) in the cytoplasm, whereas SIRT3 deacetylates the homologous Acetyl-CoA Synthase 2 (AceCS2) in the mitochondria. We recently showed that 3-hydroxy-3-methylglutaryl CoA synthase 2 (HMGCS2) is deacetylated by SIRT3 in mitochondria, and we demonstrate here that SIRT1 deacetylates the homologous 3-hydroxy-3-methylglutaryl CoA synthase 1 (HMGCS1) in the cytoplasm. This novel pattern of substrate homology between cytoplasmic SIRT1 and mitochondrial SIRT3 suggests that considering evolutionary relationships between the sirtuins and their substrates may help to identify and understand the functions and interactions of this gene family. In this perspective, we take a first step by characterizing the evolutionary history of the sirtuins and these substrate families.
0 Communities
1 Members
0 Resources
10 MeSH Terms
Sirt1 activation protects the mouse renal medulla from oxidative injury.
He W, Wang Y, Zhang MZ, You L, Davis LS, Fan H, Yang HC, Fogo AB, Zent R, Harris RC, Breyer MD, Hao CM
(2010) J Clin Invest 120: 1056-68
MeSH Terms: Animals, Apoptosis, Cells, Cultured, Cyclooxygenase 2, Fibrosis, Heterocyclic Compounds, 4 or More Rings, Kidney Medulla, Male, Mice, Mice, Inbred C57BL, Oxidative Stress, Resveratrol, Sirtuin 1, Stilbenes, Ureteral Obstruction
Show Abstract · Added December 10, 2013
Sirtuin 1 (Sirt1) is a NAD+-dependent deacetylase that exerts many of the pleiotropic effects of oxidative metabolism. Due to local hypoxia and hypertonicity, the renal medulla is subject to extreme oxidative stress. Here, we set out to investigate the role of Sirt1 in the kidney. Our initial analysis indicated that it was abundantly expressed in mouse renal medullary interstitial cells in vivo. Knocking down Sirt1 expression in primary mouse renal medullary interstitial cells substantially reduced cellular resistance to oxidative stress, while pharmacologic Sirt1 activation using either resveratrol or SRT2183 improved cell survival in response to oxidative stress. The unilateral ureteral obstruction (UUO) model of kidney injury induced markedly more renal apoptosis and fibrosis in Sirt1+/- mice than in wild-type controls, while pharmacologic Sirt1 activation substantially attenuated apoptosis and fibrosis in wild-type mice. Moreover, Sirt1 deficiency attenuated oxidative stress-induced COX2 expression in cultured mouse renal medullary interstitial cells, and Sirt1+/- mice displayed reduced UUO-induced COX2 expression in vivo. Conversely, Sirt1 activation increased renal medullary interstitial cell COX2 expression both in vitro and in vivo. Furthermore, exogenous PGE2 markedly reduced apoptosis in Sirt1-deficient renal medullary interstitial cells following oxidative stress. Taken together, these results identify Sirt1 as an important protective factor for mouse renal medullary interstitial cells following oxidative stress and suggest that the protective function of Sirt1 is partly attributable to its regulation of COX2 induction. We therefore suggest that Sirt1 provides a potential therapeutic target to minimize renal medullary cell damage following oxidative stress.
1 Communities
4 Members
0 Resources
15 MeSH Terms