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https://www.readbyqxmd.com/read/28915567/melatonin-inhibits-sirt1-dependent-nampt-and-nfat5-signaling-in-chondrocytes-to-attenuate-osteoarthritis
#1
Jia Yi Guo, Feng Li, Yong Bing Wen, Hong Xun Cui, Ma Long Guo, Lin Zhang, Yun Fei Zhang, Yan Jin Guo, Yan Xing Guo
Osteoarthritis (OA) is a degenerative joint disease mainly characterized by cartilage degradation. Interleukin-1β (IL-1β) contributes to OA pathogenesis by enhancing oxidative stress and inflammation. Melatonin reportedly elicits potent protection against OA. However, the role of melatonin and underlying mechanism in IL-1β-stimulated chondrocytes remain largely unclear. In this study, we found that melatonin inhibited IL-1β-induced toxicity and sirtuin 1 (Sirt1) enhancement in human chondrocytes. Melatonin reduced the IL-1β-increased nicotinamide phosphoribosyltransferase (NAMPT) expression and the NAD(+) level in chondrocytes in a Sirt1-dependent manner...
August 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28904384/targeting-the-vulnerability-to-nad-depletion-in-b-cell-acute-lymphoblastic-leukemia
#2
S Takao, W Chien, V Madan, D-C Lin, L-W Ding, Q-Y Sun, A Mayakonda, M Sudo, L Xu, Y Chen, Y-Y Jiang, S Gery, M Lill, E Park, W Senapedis, E Baloglu, M Müschen, H P Koeffler
Although substantial progress has been made in the treatment of B-cell acute lymphoblastic leukemia (B-ALL), the prognosis of patients with either refractory or relapsed B-ALL remains dismal. Novel therapeutic strategies are needed to improve the outcome of these patients. KPT-9274 is a novel dual inhibitor of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT). PAK4 is a serine/threonine kinase, which regulates a variety of fundamental cellular processes. NAMPT is a rate-limiting enzyme in the salvage biosynthesis pathway of nicotinamide adenine dinucleotide (NAD), which plays a vital role in energy metabolism...
September 14, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28903011/inter-individual-responses-to-sprint-interval-training-a-pilot-study-investigating-interactions-with-the-sirtuin-system
#3
Stuart R Gray, Tom P Aird, Andrew J Farquharson, Graham W Horgan, Emily Fisher, John Wilson, Gareth E Hopkins, Bradley Anderson, Syed A Ahmad, Stuart R Davis, Janice E Drew
Sprint intensity interval training (SIT) is reported to improve blood glucose control and may be a useful public health tool. The sirtuins and associated genes are emerging as key players in blood glucose control. This study investigated the interplay between the sirtuin/NAD system and individual variation in insulin sensitivity responses after SIT in young healthy individuals. Before and after 4 weeks of SIT body mass and fat percentage were measured and oral glucose tolerance tests (OGTT) performed in 20 young healthy participants (7 females)...
September 13, 2017: Applied Physiology, Nutrition, and Metabolism, Physiologie Appliquée, Nutrition et Métabolisme
https://www.readbyqxmd.com/read/28899971/matrix-screen-identifies-synergistic-combination-of-parp-inhibitors-and-nicotinamide-phosphoribosyltransferase-nampt-inhibitors-in-ewing-sarcoma
#4
Christine M Heske, Mindy I Davis, Joshua T Baumgart, Kelli M Wilson, Michael V Gormally, Lu Chen, Xiaohu Zhang, Michele Ceribelli, Damien Duveau, Rajarshi Guha, Marc Ferrer, Fernanda I Arnaldez, Jiuping Jay Ji, Huong-Lan Tran, Yiping Zhang, Arnulfo Mendoza, Lee J Helman, Craig J Thomas
PURPOSE: While many cancers are showing remarkable responses to targeted therapies, pediatric sarcomas, including Ewing sarcoma, remain recalcitrant. To broaden the therapeutic landscape, we explored the in vitro response of Ewing sarcoma cell lines against a large collection of investigational and approved drugs to identify candidate combinations. EXPERIMENTAL DESIGN: Drugs displaying activity as single agents were evaluated in combinatorial (matrix) format to identify highly active, synergistic drug combinations, and combinations were subsequently validated in multiple cell lines using various agents from each class...
September 12, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28885834/small-molecule-inhibitors-simultaneously-targeting-cancer-metabolism-and-epigenetics-discovery-of-novel-nicotinamide-phosphoribosyltransferase-nampt-and-histone-deacetylase-hdac-dual-inhibitors
#5
Guoqiang Dong, Wei Chen, Xia Wang, Xinglin Yang, Tianying Xu, Pei Wang, Wannian Zhang, Yu Rao, Chao-Yu Miao, Chunquan Sheng
Cancer metabolism and epigenetics are among the most intensely pursued research areas in anticancer drug discovery. Here we report the first small molecules that simultaneously inhibit nicotinamide phosphoribosyltransferase (NAMPT) and histone deacetylase (HDAC), two important targets of cancer metabolism and epigenetics, respectively. Through iterative structure-based drug design, chemical synthesis and biological assays, a highly potent dual NAMPT and HDAC inhibitor was successfully identified. Compound 35 possessed excellent and balanced activities against both NAMPT (IC50 = 31 nM) and HDAC1 (IC50 = 55 nM)...
September 8, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28877980/nad-metabolism-fuels-human-and-mouse-intestinal-inflammation
#6
Romana R Gerner, Victoria Klepsch, Sophie Macheiner, Kathrin Arnhard, Timon E Adolph, Christoph Grander, Verena Wieser, Alexandra Pfister, Patrizia Moser, Natascha Hermann-Kleiter, Gottfried Baier, Herbert Oberacher, Herbert Tilg, Alexander R Moschen
OBJECTIVE: Nicotinamide phosphoribosyltransferase (NAMPT, also referred to as pre-B cell colony-enhancing factor or visfatin) is critically required for the maintenance of cellular nicotinamide adenine dinucleotide (NAD) supply catalysing the rate-limiting step of the NAD salvage pathway. NAMPT is strongly upregulated in inflammation including IBD and counteracts an increased cellular NAD turnover mediated by NAD-depleting enzymes. These constitute an important mechanistic link between inflammatory, metabolic and transcriptional pathways and NAD metabolism...
September 6, 2017: Gut
https://www.readbyqxmd.com/read/28870901/nicotinamide-phosphoribosyl-transferase-a-reliable-marker-of-progression-in-cervical-dysplasia
#7
Moiz Vora, Lubna A Alattia, Junaid Ansari, Menchu Ong, James Cotelingam, Domenico Coppola, Rodney Shackelford
BACKGROUND/AIM: Nicotinamide phosphoribosyl transferase (Nampt) catalyses the rate-limiting step of the mammalian nicotinamide adenine dinucleotide (NAD) salvage pathway. Nampt is highly expressed in several epithelial and mesenchymal neoplasms, where is promotes cell-cycle progression ans chemotherapy resistance. To our knowledge, alterations in Nampt expression have not been examined in cervical intraepithelial neoplasia (CIN) or squamous cell carcinoma (SCC). MATERIALS AND METHODS: We performed immunohistochemical analysis for Nampt using tissue microarrays on 14 samples of benign cervical squamous epithelium and 15 CIN I, 15 CIN II, and 13 samples of CIN III...
September 2017: Anticancer Research
https://www.readbyqxmd.com/read/28860121/nad-synthesis-pathway-interference-is-a-viable-therapeutic-strategy-for-chondrosarcoma
#8
Elisabeth Fp Peterse, Brendy van den Akker, Bertine Niessen, Jan Oosting, Johnny Suijker, Yvonne de Jong, Erik H Danen, Anne-Marie Cleton-Jansen, Judith V M G Bovee
Nicotinamide phosphoribosyltransferase (NAMPT) and nicotinic acid phosphoribosyltransferase (NAPRT) are rate-limiting enzymes in the nicotinamide adenine dinucleotide (NAD+) synthesis pathway. Chondrosarcoma is a malignant cartilage forming bone tumor, in which mutations altering isocitrate dehydrogenase-1 and -2 (IDH1 and IDH2) activity have been identified as potential driver mutations. Vulnerability for NAD+ depletion has been reported for IDH1/2 mutant cells. Here, the potency of NAMPT inhibitors as a treatment of chondrosarcoma was explored...
August 31, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28860003/sleep-restriction-induced-energy-methylation-and-lipogenesis-metabolic-switches-in-rat-liver
#9
Arjun Sengupta, Seth D Rhoades, Eun Ji Kim, Soumyashant Nayak, Gregory R Grant, Peter Meerlo, Aalim M Weljie
Sleep curtailment is ubiquitous in modern day society. Sleep debt is associated with maladaptive physiological changes that can lead to cardiometabolic and neuropsychiatric pathologies. Recent literature has shown the effects of sleep restriction (SR) on systemic metabolic profiles in biofluids, implying that tissue-specific metabolomes are impacted by SR. To test this hypothesis, we assessed hepatic metabolic profiles of rats after 5days of SR using UPLC-MS based metabolomics analysis and gene expression analysis...
August 28, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/28858298/crystal-structure-based-comparison-of-two-nampt-inhibitors
#10
Sai-Long Zhang, Tian-Ying Xu, Zhen-Lin Yang, Shuo Han, Qiang Zhao, Chao-Yu Miao
Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) is a novel strategy for cancer therapy, but only two inhibitors of NAMPT (FK866 and CHS828) have progressed into clinical trials. This study seeks to compare a novel potent NAMPT inhibitor, MS0, with a classical inhibitor FK866 in their biological activity and molecular binding mode, thereby contributing to future chemical optimization and a further understanding of the action mode of NAMPT inhibitors. The IC50 values of MS0 and FK866 in inhibition of recombinant human NAMPT activity were 9...
August 31, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28854367/deletion-of-nampt-in-projection-neurons-of-adult-mice-leads-to-motor-dysfunction-neurodegeneration-and-death
#11
Xiaowan Wang, Qiao Zhang, Ruisi Bao, Nannan Zhang, Yingzhen Wang, Luis Polo-Parada, Andrew Tarim, Aidan Alemifar, Xianlin Han, Heather M Wilkins, Russell H Swerdlow, Xinglong Wang, Shinghua Ding
Intracellular nicotinamide phosphoribosyltransferase (iNAMPT) is the rate-limiting enzyme of the mammalian NAD(+) biosynthesis salvage pathway. Using inducible and conditional knockout (cKO) mice, we show that Nampt gene deletion in adult projection neurons leads to a progressive loss of body weight, hypothermia, motor neuron (MN) degeneration, motor function deficits, paralysis, and death. Nampt deletion causes mitochondrial dysfunction, muscle fiber type conversion, and atrophy, as well as defective synaptic function at neuromuscular junctions (NMJs)...
August 29, 2017: Cell Reports
https://www.readbyqxmd.com/read/28845527/extracellular-nampt-visfatin-causes-p53-deacetylation-via-nad-production-and-sirt1-activation-in-breast-cancer-cells
#12
Kiarash Behrouzfar, Mohammad Alaee, Mitra Nourbakhsh, Zafar Gholinejad, Abolfazl Golestani
Visfatin, which is secreted as an adipokine and cytokine, has been implicated in cancer development and progression. In this study, we investigated the NAD-producing ability of visfatin and its relationship with SIRT1 (silent information regulator 2) and p53 to clarify the role of visfatin in breast cancer. MCF-7 breast cancer cells were cultured and treated with visfatin. SIRT1 activity was assessed by measuring fluorescence intensity from fluoro-substrate peptide. To investigate the effect of visfatin on p53 acetylation, SDS-PAGE followed by western blotting was performed using specific antibodies against p53 and its acetylated form...
August 2017: Cell Biochemistry and Function
https://www.readbyqxmd.com/read/28837586/nampt-serum-levels-are-selectively-elevated-in-acute-infectious-disease-and-in-acute-relapse-of-chronic-inflammatory-diseases-in-children
#13
Julia Gesing, Kathrin Scheuermann, Isabel Viola Wagner, Dennis Löffler, Daniela Friebe, Wieland Kiess, Volker Schuster, Antje Körner
Nicotinamide phosphoribosyl transferase (NAMPT) is an inflammatory adipocytokine shown to interact in immune modulation in chronic inflammatory diseases, acute respiratory distress syndrome, sepsis, cancer and obesity in adulthood. It is, however, not clear whether this association reflects a chronic elevation or acute inflammatory response. We analyzed NAMPT concentrations in distinct states of inflammation in 102 children and found consistently significantly increased NAMPT levels in subjects with acute infections...
2017: PloS One
https://www.readbyqxmd.com/read/28819322/nampt-enzyme-activity-regulates-catabolic-gene-expression-in-gingival-fibroblasts-during-periodontitis
#14
Ka Hyon Park, Duck-Kyu Kim, Yun Hyun Huh, Gyuseok Lee, Su-Hyeon Lee, Yunkyung Hong, Sun-Hun Kim, Min-Suk Kook, Jeong-Tae Koh, Jang-Soo Chun, Shee Eun Lee, Je-Hwang Ryu
Periodontal disease is one of the most prevalent chronic disorders worldwide. It is accompanied by inflammation of the gingiva and destruction of periodontal tissues, leading to alveolar bone loss. Here, we focused on the role of adipokines, which are locally expressed by periodontal tissues, in the regulation of catabolic gene expression leading to periodontal inflammation. The expression of the nicotinamide phosphoribosyltransferase (NAMPT) adipokine was dramatically increased in inflamed human and mouse gingival tissues...
August 18, 2017: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/28812414/adipokine-genes-and-radiographic-hand-osteoarthritis-in-finnish-women-a-cross-sectional-study
#15
S Hämäläinen, S Solovieva, T Vehmas, A Hirvonen, P Leino-Arjas
OBJECTIVES: Available evidence suggests that genetic factors and overweight play major roles in the aetiology of osteoarthritis (OA). We analysed the association of 18 single-nucleotide polymorphisms (SNPs) from nine adipokine and adipokine receptor genes (LEP, LEPR, ADIPOQ, RETN, NAMPT, SERPINA12, ITLN1, RARRES2, and APLN) with radiographic hand OA. METHOD: The study design was cross-sectional. Bilateral hand radiographs of 542 occupationally active Finnish female dentists and teachers aged 45-63 years were examined and classified for the presence of hand OA using reference images...
August 16, 2017: Scandinavian Journal of Rheumatology
https://www.readbyqxmd.com/read/28756747/nampt-mediated-nad-biosynthesis-as-the-internal-timing-mechanism-in-nad-world-time-is-running-in-its-own-way
#16
Borut Poljsak
The biological age of organisms differs from the chronological age and is determined by internal aging clock(s). How cells estimate time on a scale of 24 h is relatively well-studied; however, how biological time is measured by cells, tissues, organs or organisms in longer time periods (years and decades) is largely unknown. What is clear and widely agreed upon is that the link to age and age-related diseases is not chronological, as it does not depend on a fixed passage of time. Rather, this link depends on the biological age of an individual cell, tissue, organ or organism and not on time in a strictly chronological sense...
July 29, 2017: Rejuvenation Research
https://www.readbyqxmd.com/read/28756225/identification-of-novel-resistance-mechanisms-to-nampt-inhibition-via-the-de-novo-nad-biosynthesis-pathway-and-nampt-mutation
#17
Jun Guo, Lloyd T Lam, Kenton L Longenecker, Mai H Bui, Kenneth B Idler, Keith B Glaser, Julie L Wilsbacher, Chris Tse, William N Pappano, Tzu-Hsuan Huang
Cancer cells have an unusually high requirement for the central and intermediary metabolite nicotinamide adenine dinucleotide (NAD(+)), and NAD(+) depletion ultimately results in cell death. The rate limiting step within the NAD(+) salvage pathway required for converting nicotinamide to NAD(+) is catalyzed by nicotinamide phosphoribosyltransferase (NAMPT). Targeting NAMPT has been investigated as an anti-cancer strategy, and several highly selective small molecule inhibitors have been found to potently inhibit NAMPT in cancer cells, resulting in NAD(+) depletion and cytotoxicity...
September 23, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28752046/nicotinamide-riboside-kinases-display-redundancy-in-mediating-nicotinamide-mononucleotide-and-nicotinamide-riboside-metabolism-in-skeletal-muscle-cells
#18
Rachel S Fletcher, Joanna Ratajczak, Craig L Doig, Lucy A Oakey, Rebecca Callingham, Gabriella Da Silva Xavier, Antje Garten, Yasir S Elhassan, Philip Redpath, Marie E Migaud, Andrew Philp, Charles Brenner, Carles Canto, Gareth G Lavery
OBJECTIVE: Augmenting nicotinamide adenine dinucleotide (NAD(+)) availability may protect skeletal muscle from age-related metabolic decline. Dietary supplementation of NAD(+) precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) appear efficacious in elevating muscle NAD(+). Here we sought to identify the pathways skeletal muscle cells utilize to synthesize NAD(+) from NMN and NR and provide insight into mechanisms of muscle metabolic homeostasis. METHODS: We exploited expression profiling of muscle NAD(+) biosynthetic pathways, single and double nicotinamide riboside kinase 1/2 (NRK1/2) loss-of-function mice, and pharmacological inhibition of muscle NAD(+) recycling to evaluate NMN and NR utilization...
August 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28733523/preclinical-efficacy-of-the-novel-competitive-nampt-inhibitor-stf-118804-in-pancreatic-cancer
#19
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...
June 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28714034/inhibition-of-nampt-decreases-cell-growth-and-enhances-susceptibility-to-oxidative-stress
#20
Renhua Xu, Zhenwei Yuan, Lijuan Yang, Lele Li, Dan Li, Changjun Lv
Nicotinamide adenine dinucleotide (NAD) is an essential molecule for living organisms and plays a vital role in aging and age-associated diseases. In eukaryotic cells, cellular NAD is mainly generated by the scavenge pathway in which nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the formation of nicotinamide mononucleotide. Inhibition of NAMPT is a therapeutic strategy for cancer treatment. To explore the effects of NAMPT inhibition on cellular processes, cells were treated with 10 nM FK866, an NAMPT inhibitor, resulting in a decrease in the cellular NAD level, a lower growth rate, and enhanced susceptivity to oxidative stress as compared to the untreated cells...
July 6, 2017: Oncology Reports
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