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Céline Ronin, David Mendes Costa, Joana Tavares, Joana Faria, Fabrice Ciesielski, Paola Ciapetti, Terry K Smith, Jane MacDougall, Anabela Cordeiro-da-Silva, Iain K Pemberton
The de novo crystal structure of the Leishmania infantum Silent Information Regulator 2 related protein 1 (LiSir2rp1) has been solved at 1.99Å in complex with an acetyl-lysine peptide substrate. The structure is broadly commensurate with Hst2/SIRT2 proteins of yeast and human origin, reproducing many of the structural features common to these sirtuin deacetylases, including the characteristic small zinc-binding domain, and the larger Rossmann-fold domain involved in NAD+-binding interactions. The two domains are linked via a cofactor binding loop ordered in open conformation...
2018: PloS One
Lisha Zhao, Xufeng Tao, Yan Qi, Lina Xu, Lianhong Yin, Jinyong Peng
Clinical application of doxorubicin (DOX) is limited because of its cardiotoxicity. Thus, exploration of effective lead compounds against DOX-induced cardiotoxicity is necessary. The aim of the present study was to investigate the effects and possible mechanisms of dioscin against DOX-induced cardiotoxicity. The in vitro model of DOX- treated H9C2 cells and the in vivo models of DOX-treated rats and mice were used in this study. The results showed that discoin markedly increased H9C2 cell viability, decreased the levels of CK, LDH, and improved histopathological and electrocardio- gram changes in rats and mice to protect DOX-induced cardiotoxicity...
March 6, 2018: Redox Biology
Bong-Geum Jang, Boyoung Choi, Suyeon Kim, Jae-Yong Lee, Min-Ju Kim
Neuroblastoma cell differentiation is a valuable model for studying therapeutic methods in neuroblastoma and the mechanisms of neuronal differentiation. Here, we used trichostatin A (TSA) and sirtinol, which are inhibitors of cHDACs and sirtuins, respectively, to show that classical histone deacetylases (cHDACs) and sirtuins (silent mating type information regulation 2 homolog; SIRTs) affect all-trans retinoic acid (ATRA)-induced differentiation of neuroblastoma cells. After first determining neurite elongation and expression levels of tyrosine hydroxylase and high size neurofilament as useful differentiation markers, we observed that TSA increased neuroblastoma cell differentiation, while sirtinol had the antagonistic effect of decreasing it...
March 7, 2018: Journal of Molecular Neuroscience: MN
Stéphane Fourcade, Tiago F Outeiro, Aurora Pujol
No abstract text is available yet for this article.
March 3, 2018: Aging
Mohsen Sarikhani, Sneha Mishra, Sangeeta Maity, Chaithanya Kotyada, Donald Wolfgeher, Mahesh P Gupta, Mahavir Singh, Nagalingam R Sundaresan
Glycogen synthase kinase 3 (GSK3) is a critical regulator of diverse cellular functions involved in the maintenance of structure and function. Enzymatic activity of GSK3 is inhibited by N-terminal serine phosphorylation. However, alternate post translational mechanism(s) responsible for GSK3 inactivation are not characterized. Here, we report that GSK3α and GSK3β are acetylated at Lys246 and Lys183 respectively. Molecular modeling and/or molecular dynamics simulations indicate that acetylation of GSK3 isoforms would hinder both the adenosine binding and prevent stable interactions of the negatively charged phosphates...
March 5, 2018: ELife
Diana Kalbas, Sandra Liebscher, Theresa Nowak, Marat Meleshin, Martin Pannek, Corinna Popp, Zayan Alhalabi, Frank Bordusa, Wolfgang Sippl, Clemens Steegborn, Mike Schutkowski
Sirtuins are protein deacylases regulating metabolism and stress responses and implicated in aging-related diseases. Modula-tors of the human sirtuins Sirt1-7 are sought as chemical tools and potential therapeutics, e.g., for cancer. Selective and po-tent inhibitors are available for Sirt2 but selective inhibitors for Sirt5 with Ki-values in the low nM range are lacking. We syn-thesized and screened 3-Arylthiosuccinylated- and 3-Benzylthiosuccinylated peptide derivatives yielding Sirt5 inhibitors with low nM Ki-values...
March 1, 2018: Journal of Medicinal Chemistry
Mohsen Sarikhani, Sneha Mishra, Perumal Arumugam Desingu, Chaithanya Kotyada, Donald Wolfgeher, Mahesh P Gupta, Mahavir Singh, Nagalingam R Sundaresan
c-Jun NH 2 -terminal kinases (JNKs) are responsive to stress stimuli and their activation regulate key cellular functions, including cell survival, growth, differentiation and aging. Previous studies demonstrate that activation of JNK requires dual phosphorylation by the mitogen-activated protein kinase kinases. However, other post-translational mechanisms involved in regulating the activity of JNK have been poorly understood. In this work, we studied the functional significance of reversible lysine acetylation in regulating the kinase activity of JNK...
February 15, 2018: Cell Death and Differentiation
Carla Tatone, Giovanna Di Emidio, Arcangelo Barbonetti, Gaspare Carta, Alberto M Luciano, Stefano Falone, Fernanda Amicarelli
BACKGROUND: Sirtuins (SIRT1-7) are a family of NAD+-dependent deacetylases that catalyze post-translational modifications of proteins. Together, they respond to metabolic challenges, inflammatory signals or hypoxic/oxidative stress, and are associated with aging and longevity. The role of Sirtuins in the regulation of fertility emerged in 2003 when a defective reproductive phenotype was observed in SIRT1-null mice. Although studies on Sirtuins in reproductive biology have been increasing in the last years, a recent comprehensive update on this issue is still lacking...
February 13, 2018: Human Reproduction Update
Mohsen Sarikhani, Sangeeta Maity, Sneha Mishra, Aditi Jain, Ankit K Tamta, Venkatraman Ravi, Kondapalli M Spurthi, Perumal A Desingu, Danish Khan, Shweta Kumar, Swathi Rao, Meena Inbaraj, Pandit A Shriniwas, Nagalingam Ravi Sundaresan
Heart failure is an aging-associated disease, which is the leading cause of death world-wide. Sirtuin family members have been largely studied in the context of aging and aging-associated diseases. Sirtuin 2 (SIRT2) is a cytoplasmic protein in the family of sirtuins that are NAD+-dependent class III histone deacetylases. In this work, we studied the role of SIRT2 in regulating NFAT transcription factor and the development of cardiac hypertrophy. Confocal microscopy analysis indicated that SIRT2 is localized in the cytoplasm of cardiomyocytes and SIRT2 levels are reduced during pathological hypertrophy of the heart...
February 13, 2018: Journal of Biological Chemistry
Robin E Bonomi, Maxwell Laws, Vadim Popov, Swatabdi Kamal, Shreya Potukutchi, Aleksandr Shavrin, Xin Lu, Nashaat Turkman, Ren-Shyan Liu, Thomas Mangner, Juri G Gelovani
PURPOSE: The purpose of this study was to develop a SIRT2-specific substrate-type radiotracer for non-invasive PET imaging of epigenetic regulatory processes mediated by SIRT2 in normal and disease tissues. PROCEDURES: A library of compounds containing tert-butyloxycarbonyl-lysine-aminomethylcoumarin backbone was derivatized with fluoroalkyl chains 3-16 carbons in length. SIRT2 most efficiently cleaved the myristoyl, followed by 12-fluorododecanoic and 10-fluorodecanoic groups (Kcat/Km 716...
February 8, 2018: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
Kana Tanabe, Jiaan Liu, Daiki Kato, Hitoshi Kurumizaka, Kenzo Yamatsugu, Motomu Kanai, Shigehiro A Kawashima
Chromatin structure and gene expression are dynamically regulated by posttranslational modifications of histones. Recent advance in mass spectrometry has identified novel types of lysine acylations, such as butyrylation and malonylation, whose functions and regulations are likely different from those of acetylation. Sirtuins, nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases, catalyze various deacylations. However, it is poorly understood how distinct sirtuins regulate the histone acylation states of nucleosomes that have many lysine residues...
February 8, 2018: Scientific Reports
Danhong Wu, Wenmei Lu, Zhenyu Wei, Ming Xu, Xueyuan Liu
Cerebral ischemic is the most common cause of stroke with high morbidity, disability and mortality. Sirtuin-2 (Sirt2), a vitally important NAD+-dependent deacetylase which has been widely researched in central nervous system diseases, has also been identified as a promising treatment target by using its specific inhibitors such as AK-7. In this study, we found that P38 was specifically activated after focal cerebral ischemia injury, and it was also significantly activated after AK-7 administration in a concentration-dependent manner in vitro and in vivo...
January 27, 2018: Neuroscience
Tingting Liu, Wentao Yang, Shuchao Pang, Shipeng Yu, Bo Yan
AIMS: Type 2 diabetes mellitus (T2D) is a common and complex metabolic diseases caused by interactions between environmental and genetic factors. Genome-wide association studies have identified more than 80 common genetic variants for T2D, which account for only ∼10% of the heritability of T2D cases. SIRT2, a member of NAD(+)-dependent class III deacetylases, is involved in genomic stability, metabolism, inflammation, oxidative stress and autophagy. In maintaining metabolic homeostasis, SIRT2 regulates adipocyte differentiation, fatty acid oxidation, gluconeogenesis, and insulin sensitivity...
January 31, 2018: Diabetes Research and Clinical Practice
Sheng-Tao Cheng, Ji-Hua Ren, Xue-Fei Cai, Hui Jiang, Juan Chen
Sirtuin 2 (SIRT2) is a class III histone deacetylase that has been implicated to promote HCC development. However, the functional role of SIRT2 in HBV is still unclear. In this study, we found that HBV could upregulate SIRT2 expression. Additionally, HBx could activate SIRT2 promoter to upregulate the mRNA and protein level of SIRT2. Furthermore, we found that SIRT2 could facilitate HBV transcription and replication. Finally, we demonstrated that upregulation of SIRT2 by HBx promoted hepatocarcinogenesis. In summary, our findings revealed a novel function of SIRT2 in HBV and HBV-mediated HCC...
January 20, 2018: Biochemical and Biophysical Research Communications
Seiran Zandi, Manouchehr A Hedayati, Ebrahim Mohammadi, Farshad Sheikhesmaeili
BACKGROUND: Helicobacter pylori Infection causes some clinical features of the human stomach such as gastritis, duodenal ulcer, and gastric cancer. It has been shown that Helicobacter pylori infection increases proinflammatory cytokine gene expressions in Gastric Epithelial Cells by activation of NF-kB signaling. Sirt1 and sirt2 as deacetylases play a certain role in the progress of inflammation in arthritis and lung infection by impacting the NF-kB. AIMS: Sirt1 and sirt2 gene expressions in Gastric Epithelial cells of gastritis patients were surveyed with and without Helicobacter pylori infection and rate of prevalence of cagA and hopQ genes in Helicobacter pylori strains were investigated...
January 17, 2018: Microbial Pathogenesis
Arzu Keskin-Aktan, Kazime Gonca Akbulut, Çiğdem Yazici-Mutlu, Gizem Sonugur, Müge Ocal, Hakan Akbulut
OBJECTIVE: Though the mechanisms are not clearly understood, melatonin and curcumin have been reported to have neuroprotective effects. However, the mechanisms of neuroprotective effects of melatonin and curcumin in the brain are not clearly understood. In the current study, we investigated the effects of melatonin and curcumin treatments on oxidative stress parameters, the expression of SIRT2, Bcl-2 and Bax in the hippocampus. METHODS: A total of twenty-four adult (13 months-old) male Wistar rats were divided into four groups: Control (1% ethanol:PBS), s...
January 8, 2018: Brain Research Bulletin
Lisha Zhao, Yan Qi, Lina Xu, Xufeng Tao, Xu Han, Lianhong Yin, Jinyong Peng
Clinical application of doxorubicin (DOX), an anthracycline antibiotic with potent anti- tumor effects, is limited because of its cardiotoxicity. However, its pathogenesis is still not entirely understood. The aim of this paper was to explore the mechanisms and new drug targets to treat DOX-induced cardiotoxicity. The in vitro model on H9C2 cells and the in vivo models on rats and mice were developed. The results showed that DOX markedly decreased H9C2 cell viability, increased the levels of CK, LDH, caused histopathological and ECG changes in rats and mice, and triggered myocardial oxidative damage via adjusting the levels of intracellular ROS, MDA, SOD, GSH and GSH-Px...
December 29, 2017: Redox Biology
David Siegel, Donna D Dehn, Samantha S Bokatzian, Kevin Quinn, Donald S Backos, Andrea Di Francesco, Michel Bernier, Nichole Reisdorph, Rafael de Cabo, David Ross
NQO1 is a FAD containing NAD(P)H-dependent oxidoreductase that catalyzes the reduction of quinones and related substrates. In cells, NQO1 participates in a number of binding interactions with other proteins and mRNA and these interactions may be influenced by the concentrations of reduced pyridine nucleotides. NAD(P)H can protect NQO1 from proteolytic digestion suggesting that binding of reduced pyridine nucleotides results in a change in NQO1 structure. We have used purified NQO1 to demonstrate the addition of NAD(P)H induces a change in the structure of NQO1; this results in the loss of immunoreactivity to antibodies that bind to the C-terminal domain and to helix 7 of the catalytic core domain...
2018: PloS One
Hitoshi Watanabe, Yuka Inaba, Kumi Kimura, Michihiro Matsumoto, Shuichi Kaneko, Masato Kasuga, Hiroshi Inoue
Impaired hepatic glucose uptake (HGU) causes postprandial hyperglycemia in type 2 diabetes. Here, we show that diminished hepatic Sirt2 activity impairs HGU in obese diabetic mice. Hepatic Sirt2 overexpression increases HGU in high-fat diet (HFD)-fed obese diabetic mice and mitigates their impaired glucose tolerance. Hepatic Sirt2 knockdown in non-diabetic mice reduces HGU and causes impaired glucose tolerance. Sirt2 promotes glucose-dependent HGU by deacetylating K126 of glucokinase regulatory protein (GKRP)...
January 2, 2018: Nature Communications
Hongdou Luo, Min Zhou, Kaibao Ji, Jiejie Zhuang, Wenjie Dang, Shiya Fu, Tao Sun, Xu Zhang
Sirtuins are a class of histone deacetylases (HDACs) that have been shown to regulate a range of pathophysiological processes such as cellular aging, inflammation, metabolism, and cell proliferation. There are seven mammalian Sirtuins (SIRT1-7) that play important roles in stress response, aging, and neurodegenerative diseases. However, the location and function of Sirtuins in neurons are not well defined. This study assessed the retinal expression of Sirtuins in mice, rats, and humans and measured the expression of Sirtuins in aged and injured retinas...
2017: Frontiers in Aging Neuroscience
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