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https://www.readbyqxmd.com/read/29349500/exogenous-h2s-switches-cardiac-energy-substrate-metabolism-by-regulating-sirt3-expression-in-db-db-mice
#1
Yu Sun, Zhiliang Tian, Ning Liu, Linxue Zhang, Zhaopeng Gao, Xiaojiao Sun, Miao Yu, Jichao Wu, Fan Yang, Yajun Zhao, Huan Ren, He Chen, Dechao Zhao, Yan Wang, Shiyun Dong, Changqing Xu, Fanghao Lu, Weihua Zhang
Hydrogen sulfide (H2S) is involved in diverse physiological functions, such as anti-hypertension, anti-proliferation, regulating ATP synthesis, and reactive oxygen species production. Sirtuin 3 (SIRT3) is a NAD + -dependent deacetylase that regulates mitochondrial energy metabolism. The role of H2S in energy metabolism in diabetic cardiomyopathy (DCM) may be related to regulate SIRT3 expression; however, this role remains to be elucidated. We hypothesized that exogenous H2S could switch cardiac energy metabolic substrate preference by lysine acetylation through promoting the expression of SIRT3 in cardiac tissue of db/db mice...
January 19, 2018: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/29348808/dual-nampt-hdac-inhibitors-as-a-new-strategy-for-multitargeting-antitumor-drug-discovery
#2
Wei Chen, Guoqiang Dong, Ying Wu, Wannian Zhang, Chaoyu Miao, Chunquan Sheng
Novel dual nicotinamide phosphoribosyltransferase (NAMPT) and histone deacetylase (HDAC) inhibitors were designed by a pharmacophore fusion approach. The thiazolocarboxamide inhibitors were highly active for both targets. In particular, compound 7f (NAMPT IC50 = 15 nM, HDAC1 IC50 = 2 nM) showed potent in vivo antitumor efficacy in the HCT116 xenograft model. The study offers a new strategy for multitarget antitumor drug discovery by simultaneously acting on cancer metabolism and epigenetics.
January 11, 2018: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29337590/novel-mechanism-for-nicotinamide-phosphoribosyltransferase-inhibition-of-tnf-%C3%AE-mediated-apoptosis-in-human-lung-endothelial-cells
#3
Radu C Oita, Sara M Camp, Wenli Ma, Ermelinda Ceco, Mark Harbeck, Patrick Singleton, Joe Messana, Xiaoguang Sun, Ting Wang, Joe G N Garcia
Nicotinamide phosphoribosyltransferase (NAMPT) exists as both intracellular (iNAMPT) and extracellular (eNAMPT) proteins. eNAMPT is secreted into the blood and functions as a cytokine/enzyme (cytozyme) that activates NFκB signaling via ligation of the TLR4 receptor, further serving as a biomarker for inflammatory lung disorders such as the acute respiratory distress syndrome (ARDS). In contrast, iNAMPT is involved in nicotinamide mononucleotide (NMN) synthesis and has been implicated in the regulation of cellular apoptosis, although the exact mechanisms for this regulation are poorly understood...
January 16, 2018: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/29330025/the-role-of-extracellular-and-intracellular-nicotinamide-phosphoribosyl-transferase-in-cancer-diagnostic-and-therapeutic-perspectives-and-challenges
#4
REVIEW
Maria Dalamaga, Gerasimos Socrates Christodoulatos, Christos S Mantzoros
Nicotinamide phosphoribosyl-transferase (Nampt) or pre-B cell colony-enhancing factor or visfatin represents a pleiotropic molecule acting as an enzyme, a cytokine and a growth factor. Intracellular Nampt plays an important role in cellular bioenergetics and metabolism, particularly NAD biosynthesis. NAD biosynthesis is critical in DNA repair, oncogenic signal transduction, transcription, genomic integrity and apoptosis. Although its insulin-mimetic function remains a controversial issue, extracellular Nampt presents proliferative, anti-apoptotic, pro-inflammatory, pro-angiogenic and metastatic properties...
January 9, 2018: Metabolism: Clinical and Experimental
https://www.readbyqxmd.com/read/29295624/nad-deficiency-is-a-common-central-pathological-factor-of-a-number-of-diseases-and-aging-mechanisms-and-therapeutic-implications
#5
Mingchao Zhang, Weihai Ying
Increasing evidence has indicated critical roles of NAD+ in various biological functions. NAD+ deficiency has been found in models of a number of diseases such as cerebral ischemia, myocardial ischemia and diabetes, and in models of aging. Application of NAD+ or other approaches that can restore NAD+ levels are highly protective in these models of diseases and aging. NAD+ produces its beneficial effects by targeting at multiple pathological pathways, including attenuating mitochondrial alterations, DNA damage and oxidative stress by modulating such enzymes as sirtuins, glyceraldehyde-3-phosphate dehydrogenase and AP endonuclease...
January 2, 2018: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/29287958/fragment-based-discovery-of-a-potent-nampt-inhibitor
#6
Alla Korepanova, Kenton L Longenecker, Steve D Pratt, Sanjay C Panchal, Richard F Clark, Marc Lake, Sujatha M Gopalakrishnan, Diana Raich, Chaohong Sun, Andrew M Petros
NAMPT expression is elevated in many cancers, making this protein a potential target for anticancer therapy. We have carried out both NMR based and TR-FRET based fragment screens against human NAMPT and identified six novel binders with a range of potencies. Co-crystal structures were obtained for two of the fragments bound to NAMPT while for the other four fragments force-field driven docking was employed to generate a bound pose. Based on structural insights arising from comparison of the bound fragment poses to that of bound FK866 we were able to synthetically elaborate one of the fragments into a potent NAMPT inhibitor...
December 12, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29275937/structure-based-design-of-nicotinamide-phosphoribosyltransferase-nampt-inhibitors-from-a-phenotypic-screen
#7
Daniel S Palacios, Erik Meredith, Toshio Kawanami, Christopher Adams, Xin Chen, Veronique Darsigny, Erin Geno, Mark Palermo, Daniel Baird, Geoffrey Boynton, Scott A Busby, Elizabeth L George, Chantale Guy, Jeffrey Hewett, Laryssa Tierney, Sachin Thigale, Wilhelm Weihofen, Louis Wang, Nicole White, Ming Yin, Upendra A Argikar
Nicotinamide phosphoribosyltransferase is a key metabolic enzyme that is a potential target for oncology. Utilizing publicly available crystal structures of NAMPT and in silico docking of our internal compound library, a NAMPT inhibitor, 1, obtained from a phenotypic screening effort was replaced with a more synthetically tractable scaffold. This compound then provided an excellent foundation for further optimization using crystallography driven structure based drug design. From this approach, two key motifs were identified, the (S,S) cyclopropyl carboxamide and the (S)-1-N-phenylethylamide that endowed compounds with excellent cell based potency...
December 18, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29261224/mitochondrial-sirtuins-in-the-rat-adrenal-gland-location-within-the-glands-of-males-and-females-hormonal-and-developmental-regulation-of-gene-expressions
#8
Piotr Celichowski, Karol Jopek, Marta Szyszka, Marianna Tyczewska, Ludwik K Malendowicz, Marcin Rucinski
INTRODUCTION: Sirtuins are NAD dependent class III histone deacetylases. In adrenal cortex mitochondria are able to transform - via nicotinamide nucleotide transhydrogenase (NNT) - NAD into NADPH, which is required for steroidogenesis. These findings suggest that sirtuins expressed in mitochondria, Sirt3, Sirt4 and Sirt5, may be associated with adrenal steroidogenesis. Therefore, the purpose of this study was to characterize the expression of mitochondrial sirtuins (Sirt3-5) in individual compartments of rat adrenal cortex, their developmental regulation and to demonstrate whether their expression is dependent on adrenocorticotrophic hormone (ACTH) and Nampt (nicotinamide phosphoribosyltransferase also known as visfatin/PBEF), the rate-limiting enzyme in the regulation of mammalian NAD synthesis...
December 20, 2017: Folia Histochemica et Cytobiologica
https://www.readbyqxmd.com/read/29245920/nampt-overexpression-induces-cancer-stemness-and-defines-a-novel-tumor-signature-for-glioma-prognosis
#9
Antonio Lucena-Cacace, Daniel Otero-Albiol, Manuel P Jiménez-García, Javier Peinado-Serrano, Amancio Carnero
Gliomas are the most prevalent primary malignant brain tumors associated with poor prognosis. NAMPT, a rate-limiting enzyme that boosts the nicotinamide adenine dinucleotide (NAD) regeneration in the salvage pathway, is commonly expressed in these tumors. NAD metabolism is required to maintain tissue homeostasis. To maintain metabolism, cancer cells require a stable NAD regeneration circuit. However, high levels of NAD confer resistance to therapy to these tumors, usually treated with Temozolomide (TMZ). We report that NAMPT overexpression in glioma cell lines increases tumorigenic properties controlling stem cell pathways and enriching the cancer-initiating cell (CIC) population...
November 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/29217642/nicotinamide-riboside-preserves-cardiac-function-in-a-mouse-model-of-dilated-cardiomyopathy
#10
Nicolas Diguet, Samuel A J Trammell, Cynthia Tannous, Robin Deloux, Jérôme Piquereau, Nathalie Mougenot, Anne Gouge, Mélanie Gressette, Boris Manoury, Jocelyne Blanc, Marie Breton, Jean-François Decaux, Gareth Lavery, István Baczkó, Joffrey Zoll, Anne Garnier, Zhenlin Li, Charles Brenner, Mathias Mericskay
Background -Myocardial metabolic impairment is a major feature in chronic heart failure (HF). As the major coenzyme in fuel oxidation and oxidative phosphorylation and a substrate for enzymes signaling energy stress and oxidative stress response, NAD+ is emerging as a metabolic target in a number of diseases including HF. Little is known on mechanisms regulating homeostasis of NAD+ in the failing heart. Methods -To explore possible alterations of NAD+ homeostasis in the failing heart, we quantified expression of NAD+ biosynthetic enzymes in human failing heart and in the heart of a mouse model of dilated cardiomyopathy (DCM) triggered by SRF transcription factor depletion in the heart (SRFHKO) or of cardiac hypertrophy triggered by transverse aorta constriction (TAC)...
December 7, 2017: Circulation
https://www.readbyqxmd.com/read/29208611/perturbations-of-nad-salvage-systems-impact-mitochondrial-function-and-energy-homeostasis-in-mouse-myoblasts-and-intact-skeletal-muscle
#11
Marianne Agerholm, Morten Dall, Benjamin A H Jensen, Clara Prats, Søren Madsen, Astrid L Basse, Anne-Sofie Graae, Steve Risis, Julie Goldenbaum, Bjørn Quistorff, Steen Larsen, Sara G Vienberg, Jonas T Treebak
Nicotinamide adenine dinucleotide (NAD+) can be synthesized by nicotinamide phosphoribosyltransferase (NAMPT). We aimed to determine the role of NAMPT for maintaining NAD+ levels, mitochondrial function, and metabolic homeostasis in skeletal muscle cells. We generated stable Nampt knockdown (shNampt KD) C2C12 cells using a shRNA lentiviral approach. Moreover, we applied gene electrotransfer to express cre recombinase in tibialis anterior muscle of floxed Nampt mice. In shNampt KD C2C12 myoblasts, Nampt and NAD+ levels were reduced by 70% and 50%, respectively, and maximal respiratory capacity was reduced by 25%...
December 5, 2017: American Journal of Physiology. Endocrinology and Metabolism
https://www.readbyqxmd.com/read/29207896/rho-gtpase-effectors-and-nad-metabolism-in-cancer-immune-suppression
#12
Mahmoud Chaker, Audrey Minden, Suzie Chen, Robert H Weiss, Eduardo N Chini, Amit Mahipal, Asfar S Azmi
Sustained proliferative signaling and de-regulated cellular bioenergetics are two of the chief hallmarks of cancer. Alterations in the Ras pathway and its downstream effectors are among the major drivers for uncontrolled cell growth in many cancers. The GTPases are one of the signaling molecules that activate crucial signal transducing pathways downstream of Ras through several effector proteins. The GTPases (GTP bound) interact with several effectors and modulate a number of different biological pathways including those that regulate cytoskeleton, cellular motility, cytokinesis, proliferation, apoptosis, transcription and nuclear signaling...
December 6, 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/29203587/nampt-is-a-potent-oncogene-in-colon-cancer-progression-that-modulates-cancer-stem-cell-properties-and-resistance-to-therapy-through-sirt1-and-parp
#13
Amancio Carnero, Antonio Lucena-Cacace, Daniel Otero-Albiol, Manuel P Jimenez-Garcia, Sandra Muñoz-Galvan
PURPOSE: Colorectal cancer (CRC) is the second most common cancer in women and the third most common in men worldwide. However, despite current progress, many patients with advanced and metastatic tumors still die from the malignancy. Refractory disease often relies on nicotinamide adenine dinucleotide(NAD)-dependent mechanisms. NAD metabolism and a stable NAD regeneration circuit are required to maintain tissue homeostasis and metabolism. However, high levels of NAD confer therapy resistance to tumors...
December 4, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29197590/identification-and-expression-patterns-of-adipokine-genes-during-adipocyte-differentiation-in-the-tibetan-goat-capra-hircus
#14
Xueying Li, Yan Wang, Jiazhong Guo, Tao Zhong, Li Li, Hongping Zhang, Linjie Wang
Adipokines are secreted by adipose tissue and play an important role in the regulation of lipid metabolism. However, the information regarding adipokines in goats is limited. PPARγ is a key gene in adipocyte differentiation and activates adipokine genes. Rosiglitazone is a PPARγ agonist and can promote the expression of PPARγ to increase the expression of lipogenesis-related genes. Therefore, investigation of the relationship between rosiglitazone and adipokines will help us to better understand the function of PPARγ in lipid metabolism in Tibetan goats...
November 29, 2017: Gene
https://www.readbyqxmd.com/read/29185343/pyrroloquinoline-quinone-a-redox-active-o-quinone-stimulates-mitochondrial-biogenesis-by-activating-sirt1-pgc-1%C3%AE-signaling-pathway
#15
Kazuhiro Saihara, Ryosuke Kamikubo, Kazuto Ikemoto, Koji Uchida, Mitsugu Akagawa
Pyrroloquinoline quinone (PQQ), a redox-active o-quinone found in various foods and mammalian tissues, has received increasing attention in a number of health benefits due to its ability to enhance mitochondrial biogenesis. However, its underlying molecular mechanism remains incompletely understood. We have now established that the exposure of mouse NIH/3T3 fibroblasts to a physiologically relevant concentration of PQQ significantly stimulates the mitochondrial biogenesis. The exposure of NIH/3T3 cells to 10-100 nM PQQ for 48 h resulted in increased Mitotracker staining, the mitochondrial DNA content, and the mitochondrially-encoded cytochrome c oxidase subunit 1 (MTCO1) protein...
November 29, 2017: Biochemistry
https://www.readbyqxmd.com/read/29178516/nicotinamide-phosphoribosyltransferase-delays-cellular-senescence-by-upregulating-sirt1-activity-and-antioxidant-gene-expression-in-mouse-cells
#16
Fiqri D Khaidizar, Yasukazu Nakahata, Akira Kume, Kyosuke Sumizawa, Kenji Kohno, Takaaki Matsui, Yasumasa Bessho
Senescent cells accumulate in tissues of aged animals and deteriorate tissue functions. The elimination of senescent cells from aged mice not only attenuates progression of already established age-related disorders, but also extends median lifespan. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD+ salvage pathway, has shown a protective effect on cellular senescence of human primary cells. However, it still remains unclear how NAMPT has a protective impact on aging in vitro and in vivo...
November 27, 2017: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
https://www.readbyqxmd.com/read/29156703/preclinical-efficacy-of-the-novel-competitive-nampt-inhibitor-stf-118804-in-pancreatic-cancer
#17
Jair Machado Espindola-Netto, Claudia C S Chini, Mariana Tarragó, Enfeng Wang, Shamit Dutta, Krishnendu Pal, Debabrata Mukhopadhyay, Mauro Sola-Penna, Eduardo N Chini
NAD salvage is one of the pathways used to generate NAD in mammals. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in this pathway, uses nicotinamide (NAM) to generate nicotinamide mononucleotide (NMN). NMN is one of the main precursors of NAD synthesis in cells. Our previous study showed the importance of NAMPT in maintaining NAD levels in pancreatic ductal adenocarcinoma cells (PDAC), and that the NAMPT inhibitor FK866 decreased pancreatic cancer growth. We now tested the effect of STF-118804, a new highly specific NAMPT inhibitor, in models of pancreatic ductal adenocarcinoma...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29146412/skeletal-muscle-overexpression-of-nicotinamide-phosphoribosyl-transferase-in-mice-coupled-with-voluntary-exercise-augments-exercise-endurance
#18
Sheila R Costford, Bram Brouwers, Meghan E Hopf, Lauren M Sparks, Mauro Dispagna, Ana P Gomes, Heather H Cornnell, Chris Petucci, Peter Phelan, Hui Xie, Fanchao Yi, Glenn A Walter, Timothy F Osborne, David A Sinclair, Randall L Mynatt, Julio E Ayala, Stephen J Gardell, Steven R Smith
OBJECTIVE: Nicotinamide phosphoribosyl transferase (NAMPT) is the rate-limiting enzyme in the salvage pathway that produces nicotinamide adenine dinucleotide (NAD(+)), an essential co-substrate regulating a myriad of signaling pathways. We produced a mouse that overexpressed NAMPT in skeletal muscle (NamptTg) and hypothesized that NamptTg mice would have increased oxidative capacity, endurance performance, and mitochondrial gene expression, and would be rescued from metabolic abnormalities that developed with high fat diet (HFD) feeding...
November 6, 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/29132311/weighted-gene-co-expression-network-analysis-of-expression-data-of-monozygotic-twins-identifies-specific-modules-and-hub-genes-related-to-bmi
#19
Weijing Wang, Wenjie Jiang, Lin Hou, Haiping Duan, Yili Wu, Chunsheng Xu, Qihua Tan, Shuxia Li, Dongfeng Zhang
BACKGROUND: The therapeutic management of obesity is challenging, hence further elucidating the underlying mechanisms of obesity development and identifying new diagnostic biomarkers and therapeutic targets are urgent and necessary. Here, we performed differential gene expression analysis and weighted gene co-expression network analysis (WGCNA) to identify significant genes and specific modules related to BMI based on gene expression profile data of 7 discordant monozygotic twins. RESULTS: In the differential gene expression analysis, it appeared that 32 differentially expressed genes (DEGs) were with a trend of up-regulation in twins with higher BMI when compared to their siblings...
November 13, 2017: BMC Genomics
https://www.readbyqxmd.com/read/29125463/pharmacological-augmentation-of-nicotinamide-phosphoribosyltransferase-nampt-protects-against-paclitaxel-induced-peripheral-neuropathy
#20
Peter M LoCoco, April L Risinger, Hudson R Smith, Teresa S Chavera, Kelly A Berg, William P Clarke
Chemotherapy-induced peripheral neuropathy (CIPN) arises from collateral damage to peripheral afferent sensory neurons by anticancer pharmacotherapy, leading to debilitating neuropathic pain. No effective treatment for CIPN exists, short of dose-reduction which worsens cancer prognosis. Here we report that stimulation of nicotinamide phosphoribosyltransferase (NAMPT) produced robust neuroprotection in an aggressive CIPN model utilizing the frontline anticancer drug, paclitaxel (PTX). Daily treatment of rats with the first-in-class NAMPT stimulator, P7C3-A20, prevented behavioral and histologic indicators of peripheral neuropathy, stimulated tissue NAD recovery, improved general health, and abolished attrition produced by a near maximum-tolerated dose of PTX...
November 10, 2017: ELife
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