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https://www.readbyqxmd.com/read/28205648/identification-of-a-novel-nampt-inhibitor-by-crispr-cas9-chemogenomic-profiling-in-mammalian-cells
#1
David Estoppey, Jeffrey W Hewett, Chantale T Guy, Edmund Harrington, Jason R Thomas, Markus Schirle, Rachel Cuttat, Annick Waldt, Bertran Gerrits, Zinger Yang, Sven Schuierer, Xuewen Pan, Kevin Xie, Walter Carbone, Judith Knehr, Alicia Lindeman, Carsten Russ, Elizabeth Frias, Gregory R Hoffman, Malini Varadarajan, Nadire Ramadan, John S Reece-Hoyes, Qiong Wang, Xin Chen, Gregory McAllister, Guglielmo Roma, Tewis Bouwmeester, Dominic Hoepfner
Chemogenomic profiling is a powerful and unbiased approach to elucidate pharmacological targets and the mechanism of bioactive compounds. Until recently, genome-wide, high-resolution experiments of this nature have been limited to fungal systems due to lack of mammalian genome-wide deletion collections. With the example of a novel nicotinamide phosphoribosyltransferase (NAMPT) inhibitor, we demonstrate that the CRISPR/Cas9 system enables the generation of transient homo- and heterozygous deletion libraries and allows for the identification of efficacy targets and pathways mediating hypersensitivity and resistance relevant to the compound mechanism of action...
February 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28202489/nicotinamide-phosphoribosyltransferase-promotes-pulmonary-vascular-remodeling-and-is-a-therapeutic-target-in-pulmonary-arterial-hypertension
#2
Jiwang Chen, Justin R Sysol, Sunit Singla, Shuangping Zhao, Aya Yamamura, Daniela Valdez-Jasso, Taimur Abbasi, Krystyna M Shioura, Sakshi Sahni, Vamsi Reddy, Arvind Sridhar, Hui Gao, Jaime Torres, Sara M Camp, Haiyang Tang, Shui Quing Ye, Suzy Comhair, Raed Dweik, Paul Hassoun, Jason X-J Yuan, Joe G N Garcia, Roberto F Machado
Background -Pulmonary arterial hypertension (PAH) is a severe and progressive disease, a hallmark of which is pulmonary vascular remodeling. Nicotinamide phosphoribosyltransferase (NAMPT), is a cytozyme which regulates intracellular NAD levels and cellular redox state, regulates histone deacetylases, promotes cell proliferation and inhibits apoptosis. We hypothesized that NAMPT promotes pulmonary vascular remodeling, and that inhibition of NAMPT could attenuate pulmonary hypertension. Methods -Plasma and mRNA and protein levels of NAMPT were measured in the lungs and isolated pulmonary artery endothelial cells (PAECs) from PAH patients, as well as in lungs of rodent models of pulmonary hypertension (PH)...
February 15, 2017: Circulation
https://www.readbyqxmd.com/read/28198380/a-novel-orally-bioavailable-compound-kpt-9274-inhibits-pak4-and-blocks-triple-negative-breast-cancer-tumor-growth
#3
Chetan Rane, William Senapedis, Erkan Baloglu, Yosef Landesman, Marsha Crochiere, Soumyasri Das-Gupta, Audrey Minden
Breast cancer is a heterogeneous disease consisting of several subtypes. Among these subtypes, triple negative breast cancer is particularly difficult to treat. This is due to a lack of understanding of the mechanisms behind the disease, and consequently a lack of druggable targets. PAK4 plays critical roles in cell survival, proliferation, and morphology. PAK4 protein levels are high in breast cancer cells and breast tumors, and the gene is often amplified in basal like breast cancers, which are frequently triple negative...
February 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28177124/acute-exercise-elicits-differential-expression-of-insulin-resistance-genes-in-the-skeletal-muscle-of-patients-with-polycystic-ovary-syndrome
#4
Wagner Silva Dantas, Igor Hisashi Murai, Luiz Augusto Perandini, Hatylas Azevedo, Carlos Alberto Moreira-Filho, Niels Olsen Saraiva Camara, Hamilton Roschel, Bruno Gualano
OBJECTIVE: This study aimed to explore the role of acute exercise on skeletal muscle gene expression related to insulin resistance in patients with polycystic ovary syndrome (PCOS) and controls. METHODS: Four obese women with PCOS and 4 body controls subjects (CTRL) participated in this study. After an overnight fast, the subjects underwent a single 40-minute bout of aerobic exercise. Muscle samples were obtained from vastus lateralis at baseline and 60 minutes after exercise...
February 8, 2017: Clinical Endocrinology
https://www.readbyqxmd.com/read/28168205/role-of-nampt-and-visceral-adiposity-in-esophagogastric-junction-adenocarcinoma
#5
Haijun Li, E Bai, Yong Zhang, Zhuoqi Jia, Shicai He, Junke Fu
Nampt including eNampt and iNampt may contribute to mediating obesity-associated cancers. This study investigated the role of Nampt in esophagogastric junction adenocarcinoma (EGA), a cancer strongly correlated with obesity. Visceral adiposity was defined by waist circumference or VFA. eNampt in sera were measured by enzyme-linked immunosorbent assay. iNampt expression in EGA was determined by PCR, western blot, and immunohistochemistry. Sera eNampt were significantly elevated in these overweight and obese patients, especially for viscerally obese patients, and positively correlated with BMI, waist circumference, VFA, and also primary tumor, regional lymph nodes, and TNM stage (P < 0...
2017: Journal of Immunology Research
https://www.readbyqxmd.com/read/28165872/nampt-is-an-essential-regulator-of-ra-mediated-periodontal-inflammation
#6
D Kim, G Lee, Y H Huh, S Y Lee, K H Park, S Kim, J Kim, J Koh, J Ryu
Recent studies have indicated a potential correlation between rheumatoid arthritis (RA) and periodontal inflammation. We undertook this study to verify whether RA mediates periodontitis-like phenotypes in experimental mouse models of RA and to explore the role of nicotinamide phosphoribosyltransferase (NAMPT) in periodontal inflammation during RA pathogenesis. Periodontal inflammation and alveolar bone loss have been reported in mice with collagen-induced arthritis (CIA) and in genetically modified tumor necrosis factor-α (TNF-α) transgenic (TG) mouse models...
February 1, 2017: Journal of Dental Research
https://www.readbyqxmd.com/read/28165742/identification-of-novel-triazole-based-nicotinamide-phosphoribosyltransferase-nampt-inhibitors-endowed-with-anti-proliferative-and-anti-inflammatory-activity
#7
Cristina Travelli, Silvio Aprile, Reza Rahimian, Ambra A Grolla, Federica Rogati, Mattia Bertolotti, Floriana Malagnino, Rosanna Di Paola, Daniela Impellizzeri, Roberta Fusco, Valentina Mercalli, Alberto Massarotti, Giorgio Stortini, Salvatore Terrazzino, Erika Del Grosso, Gohar Fakhfouri, Maria Pia Troiani, Maria Alessandra Alisi, Giorgio Grosa, Giovanni Sorba, Pier Luigi Canonico, Giuseppe Orsomando, Salvatore Cuzzocrea, Armando A Genazzani, Ubaldina Galli, Gian Cesare Tron
Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme involved in the recycling of nicotinamide to maintain adequate NAD levels inside the cells. It has been postulated to be a pharmacological target as it is over-expressed in cancer cells as well as in inflammatory diseases. We describe the synthesis and characterization of a novel class of one-digit nanomolar NAMPT inhibitors based on in vitro characterization. The most active compound tested, 30c, displayed activity in a xenograft and in allograft models, strengthening the potential of NAMPT inhibitors as anti-tumoural drugs...
February 6, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28163205/localization-pattern-of-visfatin-nampt-in-d-galactose-induced-aged-rat-testis
#8
Malsawmhriatzuala Jeremy, Guruswami Gurusubramanian, Vikas Kumar Roy
Aging is a complex irreversible process which leads to decline in body physiology including reproductive activity. Neurological and brain functions defects have been studied in the d-gal induced aging rodent model. However, there is dearth of literature on reproductive aging induced by d-gal treatment. Visfatin is an adipokine which regulates testicular steroidogenesis and its level increases under stress conditions to cope and extend longevity. To the best of our knowledge the expression and localization pattern of visfatin and histological evaluation of d-gal induced aged testis have not been investigated...
February 3, 2017: Annals of Anatomy, Anatomischer Anzeiger: Official Organ of the Anatomische Gesellschaft
https://www.readbyqxmd.com/read/28161061/protective-proteins-and-telomere-length-in-placentas-from-patients-with-pre-eclampsia-in-the-last-trimester-of-gestation
#9
Autumn J Broady, Matthew H Loichinger, Hyeong Jun Ahn, Philip M C Davy, Richard C Allsopp, Gillian D Bryant-Greenwood
INTRODUCTION: Visfatin/nicotinamide phosphoribosyltransferase (Nampt), an enzyme involved in energy metabolism and sirtuins, SIRT1 and SIRT3, which are NAD-dependent deacetylases, are critical for cellular function. All three either regulate or are regulated by intracellular NAD+ levels and therefore available cellular energy, important for placental cell survival and successful pregnancy. This study investigates whether these protective proteins are involved in the placental pathophysiology of pre-eclampsia (PE) and if they are associated with 8-oxo-deoxyguanosine (8OHdG), a marker of oxidative damage or with placental telomere length...
February 2017: Placenta
https://www.readbyqxmd.com/read/28160567/ews-fli1-confers-exquisite-sensitivity-to-nampt-inhibition-in-ewing-sarcoma-cells
#10
Cornelia N Mutz, Raphaela Schwentner, Dave N T Aryee, Eric D J Bouchard, Edgard M Mejia, Grant M Hatch, Maximilian O Kauer, Anna M Katschnig, Jozef Ban, Antje Garten, Javier Alonso, Versha Banerji, Heinrich Kovar
Ewing sarcoma (EwS) is the second most common bone cancer in children and adolescents with a high metastatic potential. EwS development is driven by a specific chromosomal translocation resulting in the generation of a chimeric EWS-ETS transcription factor, most frequently EWS-FLI1.Nicotinamide adenine dinucleotide (NAD) is a key metabolite of energy metabolism involved in cellular redox reactions, DNA repair, and in the maintenance of genomic stability. This study describes targeting nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of NAD synthesis, by FK866 in EwS cells...
February 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28159473/nicotinamide-phosphoribosyltransferase-nampt-may-serve-as-the-marker-for-osteoblast-differentiation-of-bone-marrow-derived-mesenchymal-stem-cells
#11
Xu He, Jiaxue He, Yingai Shi, Chenchen Pi, Yue Yang, Yanan Sun, Cao Ma, Lin Lin, Lihong Zhang, Yulin Li, Yan Li
Decreased bone volume and strength with aging and enhanced risk of fractures are in part due to reduced number of bone-forming mesenchymal stem cells (MSCs) and cellular dysfunction. In a previous study, we found that osteogenic differentiation of the multipotent and omnipotent preosteoblasts are accompanied by the alterations of intracellular NAD metabolism in which nicotinamide phosphoribosyltransferase (Nampt) plays a regulatory role. The increased Nampt during osteoblast differentiation, the enzyme catalyzing NAD resynthesis from nicotinamide was noted...
January 31, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28156058/aging-and-caloric-restriction-impact-adipose-tissue-adiponectin-and-circulating-lipids
#12
Karl N Miller, Maggie S Burhans, Josef P Clark, Porsha R Howell, Michael A Polewski, Tyler M DeMuth, Kevin W Eliceiri, Mary J Lindstrom, James M Ntambi, Rozalyn M Anderson
Adipose tissue expansion has been associated with system-wide metabolic dysfunction and increased vulnerability to diabetes, cancer, and cardiovascular disease. A reduction in adiposity is a hallmark of caloric restriction (CR), an intervention that extends longevity and delays the onset of these same age-related conditions. Despite these parallels, the role of adipose tissue in coordinating the metabolism of aging is poorly defined. Here, we show that adipose tissue metabolism and secretory profiles change with age and are responsive to CR...
February 3, 2017: Aging Cell
https://www.readbyqxmd.com/read/28131761/sirt3-mediates-decrease-of-oxidative-damage-and-prevention-of-ageing-in-porcine-fetal-fibroblasts
#13
Xiaoxian Xie, Liangliang Wang, Binggong Zhao, Yangyang Chen, Jiaqi Li
AIMS: Sirtuin 3 (SIRT3) is a mitochondria-specific protein required for the deacetylation of metabolic enzymes and the action of oxidative phosphorylation by acting as a nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase. SIRT3 increases oxidative stress resistance and prevents mitochondrial decay associated with ageing in response to caloric restriction. However, the effects of SIRT3 on oxidative damage and ageing are not well understood. We investigated the physiological functions of porcine SIRT3 on the damage and ageing in porcine fetal fibroblasts (PFFs)...
January 25, 2017: Life Sciences
https://www.readbyqxmd.com/read/28125705/nampt-expression-decreases-age-related-senescence-in-rat-bone-marrow-mesenchymal-stem-cells-by-targeting-sirt1
#14
Cao Ma, Chenchen Pi, Yue Yang, Lin Lin, Yingai Shi, Yan Li, Yulin Li, Xu He
Senescence restricts the development of applications involving mesenchymal stem cells (MSCs) in research fields, such as tissue engineering, and stem cell therapeutic strategies. Understanding the mechanisms underlying natural aging processes may contribute to the development of novel approaches to preventing age-related diseases or slowing individual aging processes. Nampt is a rate-limiting NAD biosynthetic enzyme that plays critical roles in energy metabolism, cell senescence and maintaining life spans. However, it remains unknown whether Nampt influences stem cell senescence...
2017: PloS One
https://www.readbyqxmd.com/read/28090296/endotoxin-and-mechanical-stress-induced-epigenetic-changes-in-the-regulation-of-the-nicotinamide-phosphoribosyltransferase-promoter
#15
Venkateswaran Ramamoorthi Elangovan, Sara M Camp, Gabriel T Kelly, Ankit A Desai, Djanybek Adyshev, Xiaoguang Sun, Stephen M Black, Ting Wang, Joe G N Garcia
Mechanical ventilation, a lifesaving intervention for patients with acute respiratory distress syndrome (ARDS), also unfortunately contributes to excessive mechanical stress and impaired lung physiological and structural integrity. We have elsewhere established the pivotal role of increased nicotinamide phosphoribosyltransferase (NAMPT) transcription and secretion as well as its direct binding to the toll-like receptor 4 (TLR4) in the progression of this devastating syndrome; however, regulation of this critical gene in ventilator-induced lung injury (VILI) is not well characterized...
December 2016: Pulmonary Circulation
https://www.readbyqxmd.com/read/28035412/nicotinamide-phosphoribosyltransferase-inhibits-receptor-activator-of-nuclear-factor-%C3%AE%C2%BAb-ligand-induced-osteoclast-differentiation-in%C3%A2-vitro
#16
Jong Min Baek, Sung-Jun Ahn, Yoon-Hee Cheon, Myeung Su Lee, Jaemin Oh, Ju-Young Kim
The adipokine nicotinamide phosphoribosyltransferase (Nampt), also known as pre-B-cell colony-enhancing factor or the insulin-mimetic hormone visfatin, has a crucial role in the conversion of nicotinamide to nicotinamide mononucleotide during biosynthesis of the coenzyme nicotinamide adenine dinucleotide. Previous reports have demonstrated the inhibitory effects of Nampt on osteoclast formation from human peripheral blood mononuclear cells and CD14+ monocytes. However, the effects of Nampt on bone marrow macrophage (BMM)‑derived osteoclastogenesis and its precise role in the process remain unclear...
February 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28032230/protective-effect-of-p7c3-on-retinal-ganglion-cells-from-optic-nerve-injury
#17
Hidehiro Oku, Seita Morishita, Taeko Horie, Yuko Nishikawa, Teruyo Kida, Masashi Mimura, Shota Kojima, Tsunehiko Ikeda
PURPOSE: To determine whether P7C3-A20, a proneurogenic neuroprotective agent, can protect the retinal ganglion cells (RGCs) of rats from optic nerve crushing. METHODS: The left optic nerve of 67 rats was crushed, and 5.0 mg/kg/day of P7C3-A20 (crush-P7C3) or its vehicle (crush-placebo) was injected intraperitoneally for 3 days from one day prior to the crushing. The protective effects were determined by the number of Tuj-1-stained RGCs and by the ratio of the mRNA levels of BAX/Bcl-2 on day 7...
December 28, 2016: Japanese Journal of Ophthalmology
https://www.readbyqxmd.com/read/27981536/nicotinamide-phosphoribosyltransferase-enhances-beta-cell-expansion-during-pregnancy
#18
J Feng, H-Y Li, X-L Wang, Y Huo, S-X Liu, L Li
OBJECTIVE: Many factors contribute to the development of gestational diabetes mellitus (GDM). Among these factors, nicotinamide phosphoribosyltransferase (NAMPT) plays a critical role. Previous studies have demonstrated the effects of NAMPT on insulin resistance during GDM, while the effects of NAMPT on beta cells remain unknown. Here we addressed this question. PATIENTS AND METHODS: Mouse islets were isolated and transduced with adeno-associated vectors carrying NAMPT...
December 2016: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/27966038/gm-csf-treatment-is-not-effective-in-congenital-neutropenia-patients-due-to-its-inability-to-activate-nampt-signaling
#19
Corinna Koch, Bardia Samareh, Tatsuya Morishima, Perihan Mir, Lothar Kanz, Cornelia Zeidler, Julia Skokowa, Karl Welte
Severe congenital neutropenia (CN) is a bone marrow failure syndrome characterized by an absolute neutrophil count (ANC) below 500 cells/μL and recurrent, life-threatening bacterial infections. Treatment with granulocyte colony-stimulating factor (G-CSF) increases the ANC in the majority of CN patients. In contrary, granulocyte-monocyte colony-stimulating factor (GM-CSF) fails to increase neutrophil numbers in CN patients in vitro and in vivo, suggesting specific defects in signaling pathways downstream of GM-CSF receptor...
March 2017: Annals of Hematology
https://www.readbyqxmd.com/read/27930300/an-nad-dependent-transcriptional-program-governs-self-renewal-and-radiation-resistance-in-glioblastoma
#20
Amit D Gujar, Son Le, Diane D Mao, David Y A Dadey, Alice Turski, Yo Sasaki, Diane Aum, Jingqin Luo, Sonika Dahiya, Liya Yuan, Keith M Rich, Jeffrey Milbrandt, Dennis E Hallahan, Hiroko Yano, David D Tran, Albert H Kim
Accumulating evidence suggests cancer cells exhibit a dependency on metabolic pathways regulated by nicotinamide adenine dinucleotide (NAD(+)). Nevertheless, how the regulation of this metabolic cofactor interfaces with signal transduction networks remains poorly understood in glioblastoma. Here, we report nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting step in NAD(+) synthesis, is highly expressed in glioblastoma tumors and patient-derived glioblastoma stem-like cells (GSCs). High NAMPT expression in tumors correlates with decreased patient survival...
December 20, 2016: Proceedings of the National Academy of Sciences of the United States of America
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