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https://www.readbyqxmd.com/read/28547816/three-component-aminoalkylations-yielding-dihydronaphthoxazine-based-sirtuin-inhibitors-scaffold-modification-and-exploration-of-space-for-polar-side-chains
#1
Steffen Vojacek, Katja Beese, Zayan Alhalabi, Sören Swyter, Anja Bodtke, Carola Schulzke, Manfred Jung, Wolfgang Sippl, Andreas Link
Nonpolar derivatives of heterocyclic aromatic screening hits like the non-selective sirtuin inhibitor splitomicin tend to be poorly soluble in biological fluids. Unlike sp(3) -rich natural products, flat aromatic compounds are prone to stacking and often difficult to optimize into leads with activity in cellular systems. The aim of this work was to identify anchor points for the introduction of sp(3) -rich fragments with polar functional groups into the newly discovered active (IC50  = 5 μM) but nonpolar scaffold 1,2-dihydro-3H-naphth[1,2-e][1,3]oxazine-3-thione by a molecular modeling approach...
May 26, 2017: Archiv der Pharmazie
https://www.readbyqxmd.com/read/28526407/sirtuin-inhibition-leads-to-autophagy-and-apoptosis-in-porcine-preimplantation-blastocysts
#2
Min Gyeong Kim, Duk Hyoun Kim, Hye Ran Lee, Jun Sung Lee, Su Jin Jin, Hoon Taek Lee
Sirtuins are nicotinamide adenine dinucleotide dependent class III histone deacetylase proteins that play a crucial role in several cellular processes, including DNA repair, apoptosis, and lifespan. Previous studies have shown that sirtuin inhibition leads to embryonic developmental arrest and oxidative stress in porcine and murine. However, sirtuin-mediated mechanisms have not been examined in porcine preimplantation blastocysts. We therefore investigated the relationship between sirtuins and autophagy. Embryos were cultured with 100 μM sirtinol (SIRT1/2 inhibitor) in NCSU-23 media after in vitro fertilization...
May 16, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28524020/altered-gene-expression-of-epigenetic-modifying-enzymes-in-response-to-dietary-supplementation-with-linseed-oil
#3
Ran Li, Eveline M Ibeagha-Awemu
Recently we showed that 5% linseed oil (LSO) and 5% safflower oil (SFO) supplementation of cow's diets reduced milk fat yield by 30·38 and 32·42% respectively, accompanied by differential expression of genes and regulation by microRNAs (miRNA). This research communication addresses the hypothesis that epigenetic regulation could be involved in the observed milk fat reduction. Thus, this study investigated the gene expression pattern of major epigenetic modifying enzymes in response to dietary supplementation with LSO or SFO...
May 2017: Journal of Dairy Research
https://www.readbyqxmd.com/read/28514749/a-variant-in-sirt2-gene-3-utr-is-associated-with-susceptibility-to-colorectal-cancer
#4
Yong Yang, Jie Ding, Zhi-Gang Gao, Zhen-Jun Wang
SIRT2 is a member of sirtuin family and is associated with cell growth in various cancers. In this study, we searched for variants in functional region of SIRT2 gene and identify rs2015 and rs2241703 in the 3'UTR with minor allele frequency >0.05 in Chinese Han Beijing population from 1000 Genomes Project. We then genotyped these two variants in 842 colorectal cancer (CRC) patients and 1,718 healthy controls using Taqman genotyping assay. Association between variants and risk of CRC is calculated using logistic regression adjusted for sex and age...
April 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28506746/the-nad-dependent-deacetylase-bifidobacterium-longum-sir2-in-response-to-oxidative-stress-by-deacetylating-foxo3a-and-sigh-%C3%AF-h-in-bifidobacterium-longum-and-hek293t-cells-respectively
#5
Qing Guo, Shiyu Li, Yajie Xie, Qian Zhang, Mengge Liu, Zhenrui Xu, Hanxiao Sun, Yan Yang
Silent information regulator 2 (Sir2) enzymes which catalyze NAD+-dependent protein/histone deacetylation. The mammalian sirtuin family SIRT1, SIRT2, SIRT3 and SIRT6 can regulate oxidative stress. The probiotics (Bifidobacterium longum(B.longum) and Lactobacillus acidophilus(L. acidophilus)) have Sir2 gene family and have antioxidant activity in human body. it remains unknown whether probiotics Sir2 has a direct role in regulating oxidative stress. To this end, we knockout BL-sir2(sir2 B. longum) and LA-sir2(sir2 L...
May 12, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28503576/sirtuin-2-regulates-microvascular-inflammation-during-sepsis
#6
Nancy Buechler, Xianfeng Wang, Barbara K Yoza, Charles E McCall, Vidula Vachharajani
Objective. Sepsis and septic shock, the leading causes of death in noncoronary intensive care units, kill more than 200,000/year in the US alone. Circulating cell-endothelial cell interactions are the rate determining factor in sepsis inflammation. Sirtuin, a seven-member family of proteins (SIRT1-7), epigenetically controls inflammation. We have studied the roles of SIRTs 1, 3, and 6 in sepsis previously. In this project, we studied the role of SIRT2 on sepsis-related inflammation. Methods. Sepsis was induced in C57Bl/6 (WT), SIRT2 knockout (SIRT2KO), and SIRT2 overexpressing (SIRT2KI) mice by cecal ligation and puncture (CLP)...
2017: Journal of Immunology Research
https://www.readbyqxmd.com/read/28461331/sirtuin-2-mutations-in-human-cancers-impair-its-function-in-genome-maintenance
#7
PamelaSara E Head, Hui Zhang, Amanda J Bastien, Allyson E Koyen, Allison E Withers, Waaqo B Daddacha, Xiaodong Cheng, David S Yu
Sirtuin 2 (SIRT2) is a sirtuin family deacetylase, which maintains genome integrity and prevents tumorigenesis. While Sirt2 deficiency in mice leads to tumorigenesis, the functional significance of somatic SIRT2 mutations in human tumors is unclear. Using structural insight combined with bioinformatic and functional analyses, we show that naturally occurring cancer-associated SIRT2 mutations at evolutionarily conserved sites disrupt its deacetylation of DNA-damage response proteins by impairing SIRT2 catalytic activity or protein levels but not its localization or binding with substrate...
May 1, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28461090/nad-dependent-deacetylase-sirtuin-5-rescues-the-innate-inflammatory-response-of-endotoxin-tolerant-macrophages-by-promoting-acetylation-of-p65
#8
Kewei Qin, Chaofeng Han, Hua Zhang, Tianliang Li, Nan Li, Xuetao Cao
The induction and persistence of a hypo-inflammatory and immunosuppressive state in severe sepsis is commonly associated with increased risks of secondary infections and mortality. Toll-like receptor (TLR)-triggered inflammatory response of macrophages/monocytes plays an important role in determining the outcome of hyper-inflammation during the acute phase and the hypo-inflammation during immunosuppressive phase of sepsis. However, the mechanisms for controlling hypo-inflammatory response in endotoxin tolerant macrophages remain to be fully understood...
April 28, 2017: Journal of Autoimmunity
https://www.readbyqxmd.com/read/28446816/sirt2-and-glycolytic-enzyme-acetylation-in-pluripotent-stem-cells
#9
Tong Ming Liu, Ng Shyh-Chang
The metabolic transition from mitochondrial oxidative phosphorylation (OXPHOS) to glycolysis is critical for somatic reprogramming of induced pluripotent stem cells (iPSCs). SIRT2 has now been established as a previously unknown regulator of this metabolic transition during somatic reprogramming by controlling the acetylation status of glycolytic enzymes.
April 27, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28445509/functional-genetic-variants-within-the-sirt2-gene-promoter-in-acute-myocardial-infarction
#10
Wentao Yang, Feng Gao, Pei Zhang, Shuchao Pang, Yinghua Cui, Lixin Liu, Guanghe Wei, Bo Yan
Coronary artery disease (CAD), including acute myocardial infarction (AMI) is the complication of atherosclerosis. Recently, genome-wide association studies have identified a large number of CAD-related genetic variants. However, only 10% of CAD cases could be explained. Low frequent and rare genetic variants have been recently proposed to be main causes for CAD. SIRT2 is a member of sirtuin family, NAD(+)-dependent class III deacetylases. SIRT2 is involved in genomic stability, metabolism, inflammation, oxidative stress and autophagy, as well as in platelet function...
2017: PloS One
https://www.readbyqxmd.com/read/28436968/metabolic-control-of-primed-human-pluripotent-stem-cell-fate-and-function-by-the-mir-200c-sirt2-axis
#11
Young Cha, Min-Joon Han, Hyuk-Jin Cha, Janet Zoldan, Alison Burkart, Jin Hyuk Jung, Yongwoo Jang, Chun-Hyung Kim, Ho-Chang Jeong, Byung-Gyu Kim, Robert Langer, C Ronald Kahn, Leonard Guarente, Kwang-Soo Kim
A hallmark of cancer cells is the metabolic switch from oxidative phosphorylation (OXPHOS) to glycolysis, a phenomenon referred to as the 'Warburg effect', which is also observed in primed human pluripotent stem cells (hPSCs). Here, we report that downregulation of SIRT2 and upregulation of SIRT1 is a molecular signature of primed hPSCs and that SIRT2 critically regulates metabolic reprogramming during induced pluripotency by targeting glycolytic enzymes including aldolase, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate kinase, and enolase...
May 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28415012/discovery-of-2-4-6-dimethylpyrimidin-2-yl-thio-n-phenylacetamide-derivatives-as-new-potent-and-selective-human-sirtuin-2-inhibitors
#12
Lingling Yang, Xiaobo Ma, Chen Yuan, Yanying He, Ling Li, Sha Fang, Wei Xia, Tao He, Shan Qian, Zhihong Xu, Guobo Li, Zhouyu Wang
Human sirtuin 2 (SIRT2) plays pivotal roles in multiple biological processes such as cell cycle regulation, autophagy, immune and inflammatory responses. Dysregulation of SIRT2 was considered as a main aspect contributing to several human diseases, including cancer. Development of new potent and selective SIRT2 inhibitors is currently desirable, which may provide a new strategy for treatment of related diseases. Herein, a structure-based optimization approach led to new 2-((4,6-dimethylpyrimidin-2-yl)thio)-N-phenylacetamide derivatives as SIRT2 inhibitors...
July 7, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28400369/in-utero-particulate-matter-exposure-produces-heart-failure-electrical-remodeling-and-epigenetic-changes-at-adulthood
#13
Vineeta Tanwar, Matthew W Gorr, Markus Velten, Clayton M Eichenseer, Victor P Long, Ingrid M Bonilla, Vikram Shettigar, Mark T Ziolo, Jonathan P Davis, Stephen H Baine, Cynthia A Carnes, Loren E Wold
BACKGROUND: Particulate matter (PM; PM2.5 [PM with diameters of <2.5 μm]) exposure during development is strongly associated with adverse cardiovascular outcomes at adulthood. In the present study, we tested the hypothesis that in utero PM2.5 exposure alone could alter cardiac structure and function at adulthood. METHODS AND RESULTS: Female FVB mice were exposed either to filtered air or PM2.5 at an average concentration of 73.61 μg/m(3) for 6 h/day, 7 days/week throughout pregnancy...
April 11, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/28379698/chemically-induced-degradation-of-sirtuin-2-sirt2-by-a-proteolysis-targeting-chimera-protac-based-on-sirtuin-rearranging-ligands-sirreals
#14
Matthias Schiedel, Daniel Herp, Sören Hammelmann, Sören Swyter, Attila Lehotzky, Dina Robaa, Judit Oláh, Judit Ovádi, Wolfgang Sippl, Manfred Jung
Here we report the development of a proteolysis targeting chimera (PROTAC) based on the combination of the unique features of the sirtuin rearranging ligands (SirReals) as highly potent and isotype-selective Sirt2 inhibitors with thalidomide, a bona fide cereblon ligand. For the first time, we report the formation of a PROTAC by Cu(I)-catalyzed cycloaddition of a thalidomide-derived azide to an alkynylated inhibitor. This thalidomide-derived azide as well as the highly versatile linking strategy can be readily adapted to alkynylated ligands of other targets...
April 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28306500/catching-sirtuin-2-intermediates-one-structure-at-the-time
#15
Schuyler Lee, Zhongzhou Chen, Gongyi Zhang
Sirtuins are a large enzyme family involved in installing and removing post-translational modifications involving lysine side chains. These enzymes have been of intense research interest and we now understand many details of their mechanism, although later steps of the deacetylase activity have remained a mystery. In this issue of Cell Chemical Biology, Wang et al. (2017) capture a late intermediate of SIRT2 catalysis and describe its structure.
March 16, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28301150/discovery-of-new-sirt2-inhibitors-by-utilizing-a-consensus-docking-scoring-strategy-and-structure-activity-relationship-analysis
#16
Shenzhen Huang, Chunli Song, Xiang Wang, Guo Zhang, Yanlin Wang, Xiaojuan Jiang, Qizheng Sun, Luyi Huang, Rong Xiang, Yiguo Hu, Linli Li, Shengyong Yang
SIRT2, which is a NAD+ (nicotinamide adenine dinucleotide) dependent deacetylase, has been demonstrated to play an important role in the occurrence and development of a variety of diseases such as cancer, ischemia-reperfusion, and neurodegenerative diseases. Small molecule inhibitors of SIRT2 are thought to be potential interfering agents for relevant diseases. Discovery of SIRT2 inhibitors has attracted much attention recently. In this investigation, we adopted a consensus docking/scoring strategy to screen for novel SIRT2 inhibitors...
April 24, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28299833/unsupervised-pharmacophore-modeling-combined-with-qsar-analyses-revealed-novel-low-micromolar-sirt2-inhibitors
#17
Mohammad A Khanfar, Mutasem O Taha
Situin 2 (SIRT2) enzyme is a histone deacetylase that has important role in neuronal development. SIRT2 is clinically validated target for neurodegenerative diseases and some cancers. In this study, exhaustive unsupervised pharmacophore modeling was combined with quantitative structure-activity relationship (QSAR) analysis to explore the structural requirements for potent SIRT2 inhibitors using 146 known SIRT2 ligands. A computational workflow that combines genetic function algorithm with k-nearest neighbor or multiple linear regression was implemented to build self-consistent and predictive QSAR models based on combinations of pharmacophores and physicochemical descriptors...
March 15, 2017: Journal of Molecular Recognition: JMR
https://www.readbyqxmd.com/read/28292463/key-players-of-the-necroptosis-pathway-ripk1-and-sirt2-are-altered-in-placenta-from-preeclampsia-and-fetal-growth-restriction
#18
Natalie J Hannan, Sally Beard, Natalie K Binder, Kenji Onda, Tu'uhevaha J Kaitu'u-Lino, Qi Chen, Laura Tuohey, Manarangi De Silva, Stephen Tong
INTRODUCTION: Preeclampsia (PE) and fetal growth restriction (FGR) are among the leading causes of perinatal morbidity and mortality. Placental insufficiency is central to these conditions. The mechanisms underlying placental insufficiency are poorly understood. Apoptosis has long been considered the only form of regulated cell death, recent research has identified an alternate process of programmed cell death known as necroptosis [1]. Necroptosis is distinct from apoptosis, relying on the deacetylase sirtuin-2 [2], receptor interacting kinases RIPK1 and 3, and the pseudokinase MLKL [3]...
March 2017: Placenta
https://www.readbyqxmd.com/read/28292429/corrigendum-to-spop-promotes-sirt2-degradation-and-suppresses-non-small-cell-lung-cancer-cell-growth-biochem-biophys-res-commun-483-2017-880-884
#19
Jie Luo, Yu-Chen Bao, Xian-Xiu Ji, Bin Chen, Qin-Fang Deng, Song-Wen Zhou
No abstract text is available yet for this article.
April 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28287409/sirtuin-2-regulates-cellular-iron-homeostasis-via-deacetylation-of-transcription-factor-nrf2
#20
Xiaoyan Yang, Seong-Hoon Park, Hsiang-Chun Chang, Jason S Shapiro, Athanassios Vassilopoulos, Konrad T Sawicki, Chunlei Chen, Meng Shang, Paul W Burridge, Conrad L Epting, Lisa D Wilsbacher, Supak Jenkitkasemwong, Mitchell Knutson, David Gius, Hossein Ardehali
SIRT2 is a cytoplasmic sirtuin that plays a role in various cellular processes, including tumorigenesis, metabolism, and inflammation. Since these processes require iron, we hypothesized that SIRT2 directly regulates cellular iron homeostasis. Here, we have demonstrated that SIRT2 depletion results in a decrease in cellular iron levels both in vitro and in vivo. Mechanistically, we determined that SIRT2 maintains cellular iron levels by binding to and deacetylating nuclear factor erythroid-derived 2-related factor 2 (NRF2) on lysines 506 and 508, leading to a reduction in total and nuclear NRF2 levels...
April 3, 2017: Journal of Clinical Investigation
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