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https://www.readbyqxmd.com/read/28733523/preclinical-efficacy-of-the-novel-competitive-nampt-inhibitor-stf-118804-in-pancreatic-cancer
#1
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
#2
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
https://www.readbyqxmd.com/read/28714019/salidroside-protects-pc12-cells-from-a%C3%AE-1%C3%A2-40%C3%A2-induced-cytotoxicity-by-regulating-the-nicotinamide-phosphoribosyltransferase-signaling-pathway
#3
Xujiao Huang, Sanli Xing, Chuan Chen, Zhihua Yu, Jiulin Chen
Alzheimer's disease (AD) is the most common type of senile dementia, which often develops in elderly or presenile individuals. As one of the pathological features of AD, amyloid β‑protein (Aβ) causes energy dysmetabolism, thereby inducing cellular damage and apoptosis. Salidroside is the main active component of the traditional Chinese medicine Rhodiola. Previous studies have demonstrated that salidroside exerts a regulatory role in energy metabolism. However, the role and the mechanism of action of salidroside in AD remain unclear...
September 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28708087/resveratrol-induced-amp-activated-protein-kinase-activation-is-cell-type-dependent-lessons-from-basic-research-for-clinical-application
#4
Fan Lan, Karen A Weikel, Jose M Cacicedo, Yasuo Ido
Despite the promising effects of resveratrol, its efficacy in the clinic remains controversial. We were the first group to report that the SIRT1 activator resveratrol activates AMP-activated protein kinase (AMPK) (Diabetes 2005; 54: A383), and we think that the variability of this cascade may be responsible for the inconsistency of resveratrol's effects. Our current studies suggest that the effect of SIRT1 activators such as resveratrol may not be solely through activation of SIRT1, but also through an integrated effect of SIRT1-liver kinase B1 (LKB1)-AMPK...
July 14, 2017: Nutrients
https://www.readbyqxmd.com/read/28699485/change-in-serum-nampt-levels-and-its-significances-in-diabetic-nephropathy-patients
#5
Xiaoyu Ma, Li An, Qiuyue Wang
BACKGROUND: Nicotinamide phosphoribosyltransferase(Nampt) has a variety of biological effects, which can participate in the development of inflammatory diseases, metabolism diseases and chronic kidney disease, et al. However, he role of Nampt in T2DM and DN are still controversial. OBJECTIVE: To investigate changes in serum Nampt levels and its significance in diabetic nephropathy (DN). METHOD: A total of 321 type 2 diabetes (T2DM) were divided into normal albuminuria group (NA, n=110), microalbuminuria group (MA, n=106) and large amount of albuminuria group (LA, n=105)...
July 11, 2017: Endocrine, Metabolic & Immune Disorders Drug Targets
https://www.readbyqxmd.com/read/28698746/study-of-visfatin-level-in-type-1-diabetic-children-and-adolescents
#6
Mona H El Samahi, Nagwa Abdallah Ismail, Randa M Matter, Abeer Selim, Alshaymaa Ahmed Ibrahim, Walaa Nabih
BACKGROUND: Visfatin is an intracellular enzyme, known as nicotinamide phosphoribosyltransferase (Nampt) and pre-B-cell colony-enhancing factor (PBEF-1). It has insulin-mimetic effects and lowers plasma glucose levels. AIM: The aim of the work was to assess serum concentration of Visfatin in type 1 diabetic children and adolescents and study its relationships with duration of diabetes, body mass index (BMI), glycemic control, insulin dosage, lipid profile and microvascular complications...
June 15, 2017: Open Access Macedonian Journal of Medical Sciences
https://www.readbyqxmd.com/read/28690207/hypophosphatemia-after-hepatectomy-or-pancreatectomy-role-of-the-nicotinamide-phosphoribosyltransferase
#7
Jian Zheng, Ilya G Glezerman, Eran Sadot, Anjuli McNeil, Cristina Zarama, Mithat Gönen, John Creasy, Linda M Pak, Vinod P Balachandran, Michael I D'Angelica, Peter J Allen, Ronald P DeMatteo, T Peter Kingham, William R Jarnagin, Edgar A Jaimes
BACKGROUND: Postoperative hypophosphatemia is common and is associated with a lower risk of liver failure after hepatectomy but higher morbidity after pancreatectomy. Whether different physiologic mechanisms underlie the hypophosphatemia associated with these very different clinical outcomes is unclear. This study aims to evaluate the underlying mechanism in postoperative hypophosphatemia. STUDY DESIGNS: We prospectively enrolled 120 patients who underwent major hepatectomy (n=30), minor hepatectomy (n=30), pancreatectomy (n=30), and laparotomy without resection (control group, n=30)...
July 6, 2017: Journal of the American College of Surgeons
https://www.readbyqxmd.com/read/28685689/arylurea-derivatives-a-class-of-potential-cancer-targeting-agents
#8
Jia-Nian Chen, De-Wen Wu, Ting Li, Kang-Jian Yang, Li Cheng, Zu-Ping Zhou, Shi-Ming Pu, Wan-Hua Lin
Arylurea derivatives, an important class of small molecules, have received considerable attention in recent years due to their wide range of biological applications. Various molecular targeted agents with arylurea scaffold as potential enzyme/receptor inhibitors were constructed with the successful development of sorafenib and regorafenib. This review focuses on those arylureas possessing anti-cancer activities from 2010 to date. According to their different mechanisms of action, these arylureas are divided into the following six categories: (1) Ras/Raf/MEK/ERK signaling pathway inhibitors; (2) tumor angiogenesis inhibitors, their targets include vascular endothelial growth factor receptors (VEGFRs), fibroblast growth factor receptors (FGFRs), platelet-derived growth factor receptors (PDGFRs), epidermal growth factor receptors (EGFRs), insulin-like growth factor 1 receptor (IGF-1R), Fms-like tyrosine kinase 3 (FLT3), c-Kit, MET, and Smoothened (Smo); (3) PI3K/AKT/mTOR signaling pathway inhibitors; (4) cell cycle inhibitors, their targets include checkpoint kinases (Chks), cyclin-dependent kinases (CDKs), Aurora, SUMO activating enzyme 1 (SUMO E1), tubulin, and DNA; (5) tumor differentiation, migration, and invasion inhibitors, their targets include matrix metalloproteinases (MMPs), LIM kinase (Limk), nicotinamide phosphoribosyltransferase (Nampt), and histone deacetylase (HDAC); (6) arylureas from the rational modification of natural products...
July 7, 2017: Current Topics in Medicinal Chemistry
https://www.readbyqxmd.com/read/28668830/increased-nicotinamide-phosphoribosyltransferase-and-cystathionine-%C3%AE-synthase-in-renal-oncocytomas-renal-urothelial-carcinoma-and-renal-clear-cell-carcinoma
#9
Rodney E Shackelford, Jehan Abdulsattar, Eric X Wei, James Cotelingam, Domenico Coppola, Guillermo A Herrera
BACKGROUND: Renal oncocytomas (ROs), and clear cell (RCC) and urothelial carcinomas (UC), are common renal neoplasms. Nicotinamide phosphoribosyltransferase (Nampt) catalyzes the rate-limiting step of NAD(+) synthesis and its expression is increased in several tumors. Nampt concomitantly regulates hydrogen sulfide (H2S)-synthesizing enzyme levels, including cystathionine-β-synthase (CBS). MATERIALS AND METHODS: We used tissue microarrays to examine Nampt and the H2S-synthesizing enzyme CBS protein levels in benign kidney, RCC, UC and ROs...
July 2017: Anticancer Research
https://www.readbyqxmd.com/read/28666065/a-red-light-activated-ruthenium-caged-nampt-inhibitor-remains-phototoxic-in-hypoxic-cancer-cells
#10
Lucien N Lameijer, Daniël Ernst, Samantha L Hopkins, Michael S Meijer, Sven Hc Askes, Sylvia E Le Dévédec, Sylvestre Bonnet
Herein we describe two water-soluble ruthenium complexes [1]Cl2 and [2]Cl2 that, when irradiated with a low dose (21 J cm-2) of red light, release STF-31, a cytotoxic nicotinamide phosphoribosyltransferase (NAMPT) inhibitor, and this in an oxygen-independent manner. Using a specific NAMPT activity assay, up to an 18-fold increase in inhibition potency was measured upon red-light activation of [2]Cl2, while [1]Cl2 was thermally unstable. For the first time the dark and red light-induced cytotoxicity of these photocaged compounds could be tested under hypoxia (1% O2)...
June 30, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28656112/nicotinamide-administration-improves-remyelination-after-stroke
#11
Congxiao Wang, Yi Zhang, Jie Ding, Zhen Zhao, Cheng Qian, Ying Luan, Gao-Jun Teng
AIMS: Stroke is a leading cause of morbidity and mortality. This study aimed to determine whether nicotinamide administration could improve remyelination after stroke and reveal the underlying mechanism. METHODS: Adult male C57BL/6J mice were intraperitoneally (i.p.) administered with nicotinamide (200 mg/kg, daily) or saline after stroke induced by photothrombotic occlusion of the middle cerebral artery. FK866 (3 mg/kg, daily, bis in die), an inhibitor of NAMPT, and ANA-12 (0...
2017: Neural Plasticity
https://www.readbyqxmd.com/read/28641032/targeting-rho-gtpase-effector-p21-activated-kinase-4-pak4-suppresses-p-bad-microrna-drug-resistance-axis-leading-to-inhibition-of-pancreatic-ductal-adenocarcinoma-proliferation
#12
Ramzi M Mohammad, Yiwei Li, Irfana Muqbil, Amro Aboukameel, William Senapedis, Erkan Baloglu, Yosef Landesman, Philip A Philip, Asfar S Azmi
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and therapy resistant malignancy. Mutant K-Ras, found in >90% of refractory PDAC, acts as a molecular switch activating Rho GTPase signaling that in turn promotes a plethora of pro-survival molecules and oncogenic microRNAs. We investigated the impact of Rho GTPase effector protein p21 activated kinase 4 (PAK4) inhibition on pro-survival p-Bad and oncogenic miRNA signaling. We demonstrate that the dual NAMPT and PAK4 modulators (KPT-9274 and KPT-9307) inhibit PDAC cell proliferation through down-regulation of Bad phosphorylation and up-regulation tumor suppressive miRNAs (miR-145, let-7c, let-7d, miR-34c, miR320 and miR-100)...
June 22, 2017: Small GTPases
https://www.readbyqxmd.com/read/28637419/pharmacological-inhibitors-of-nad-biosynthesis-as-potential-anticancer-agents
#13
Stephanie Lucas, Claire Soave, Gazal Nabil, Zainab Ahmed, Guohua Chen, Hossny El-Banna, Q Ping Dou, Jian Wang
BACKGROUND: Alteration of cellular metabolism is a hallmark of cancer, which underlies exciting opportunities to develop effective, anti-cancer therapeutics by targeting through inhibition of cancer metabolism. Nicotinamide adenine dinucleotide (NAD+), an essential coenzyme of energy metabolism and a signaling molecule linking cellular energy status to a spectrum of molecular regulation, has been shown to be in high demand in a variety of cancer cells. Depletion of NAD+ by inhibition of its key biosynthetic enzymes has become an attractive strategy to target cancer...
June 19, 2017: Recent Patents on Anti-cancer Drug Discovery
https://www.readbyqxmd.com/read/28634829/potential-inhibitory-effect-of-indolizine-derivatives-on-the-two-enzymes-nicotinamide-phosphoribosyltransferase-and-beta-lactamase-a-molecular-dynamics-study
#14
Beata Szefler, Przemysław Czeleń
Nicotinamide phosphoribosyl-transferases (NAMPT) are enzymes that play a role in targeting cancer metabolism, while beta lactamases are involved in bacterial resistance to beta-lactam antibiotics. Many protein inhibitors exhibit such property which is often correlated with their cellular potency. In order to understand such a phenomenon, the present article conducts an analysis of the dynamic behavior of complexes formed by the inhibitors, that is indolizine derivatives, with the studied enzymes. Both docking and molecular dynamics led to identification of their interactions and showed the mechanism of inhibition of the two studied enzymes...
July 2017: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/28625978/the-alkylating-chemotherapeutic-temozolomide-induces-metabolic-stress-in-idh1-mutant-cancers-and-potentiates-nad-depletion-mediated-cytotoxicity
#15
Kensuke Tateishi, Fumi Higuchi, Julie Miller, Mara V A Koerner, Nina Lelic, Ganesh M Shankar, Shota Tanaka, David E Fisher, Tracy Batchelor, A John Iafrate, Hiroaki Wakimoto, Andrew S Chi, Daniel P Cahill
IDH1-mutant gliomas are dependent upon the canonical coenzyme nicotinamide adenine dinucleotide (NAD+) for survival. It is known that Poly(ADP-ribose) polymerase (PARP) activation consumes NAD+ during base excision repair (BER) of chemotherapy-induced DNA damage. We therefore hypothesized that a strategy combining NAD+ biosynthesis inhibitors with the alkylating chemotherapeutic agent temozolomide (TMZ) could potentiate NAD+ depletion-mediated cytotoxicity in mutant IDH1 cancer cells. To investigate the impact of TMZ on NAD+ metabolism, patient-derived xenografts and engineered mutant IDH1-expressing cell lines were exposed to TMZ, in vitro and in vivo, both alone and in combination with nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, which block NAD+ biosynthesis...
June 16, 2017: Cancer Research
https://www.readbyqxmd.com/read/28621682/melatonin-inhibits-sirt1-dependent-nampt-and-nfat5-signaling-in-chondrocytes-to-attenuate-osteoarthritis
#16
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...
June 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28610984/sar-and-characterization-of-non-substrate-isoindoline-urea-inhibitors-of-nicotinamide-phosphoribosyltransferase-nampt
#17
Michael L Curtin, H Robin Heyman, Richard F Clark, Bryan K Sorensen, George A Doherty, T Matthew Hansen, Robin R Frey, Kathy A Sarris, Ana L Aguirre, Anurupa Shrestha, Noah Tu, Kevin Woller, Marina A Pliushchev, Ramzi F Sweis, Min Cheng, Julie L Wilsbacher, Peter J Kovar, Jun Guo, Dong Cheng, Kenton L Longenecker, Diana Raich, Alla V Korepanova, Nirupama B Soni, Mikkel A Algire, Paul L Richardson, Violeta L Marin, Ilaria Badagnani, Anil Vasudevan, F Greg Buchanan, David Maag, Gary G Chiang, Chris Tse, Michael R Michaelides
Herein we disclose SAR studies that led to a series of isoindoline ureas which we recently reported were first-in-class, non-substrate nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. Modification of the isoindoline and/or the terminal functionality of screening hit 5 provided inhibitors such as 52 and 58 with nanomolar antiproliferative activity and preclinical pharmacokinetics properties which enabled potent antitumor activity when dosed orally in mouse xenograft models. X-ray crystal structures of two inhibitors bound in the NAMPT active-site are discussed...
August 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28546856/epigenetic-regulation-of-runx2-transcription-and-osteoblast-differentiation-by-nicotinamide-phosphoribosyltransferase
#18
Min Ling, Peixin Huang, Shamima Islam, Daniel P Heruth, Xuanan Li, Li Qin Zhang, Ding-You Li, Zhaohui Hu, Shui Qing Ye
BACKGROUND: Bone degenerative disorders like osteoporosis may be initiated by age-related shifts in anabolic and catabolic responses that control bone homeostasis. Although there are studies suggesting that metabolic changes occur with stem cell differentiation, the molecular mechanisms governing energy metabolism and epigenetic modification are not understood fully. Here we reported the key role of nicotinamide phosphoribosyltransferase (Nampt), which is the rate-limiting enzyme in the salvage pathway of NAD biosynthesis from nicotinamide, in the osteogenic differentiation of bone marrow stromal cells...
2017: Cell & Bioscience
https://www.readbyqxmd.com/read/28528966/nampt-inhibitor-protects-ischemic-neuronal-injury-in-rat-brain-via-anti-neuroinflammation
#19
Chen-Xiang Chen, Jing Huang, Ga-Qi Tu, Jia-Tong Lu, Xian Xie, Bing Zhao, Ming Wu, Qiao-Juan Shi, San-Hua Fang, Er-Qing Wei, Wei-Ping Zhang, Yun-Bi Lu
Nicotinamide phosphoribosyltransferase (NAMPT) is an important neuroprotective factor in cerebral ischemia, and it has been reported that NAMPT inhibitors can aggravate neuronal injury in the acute phase. However, because it is a cytokine, NAMPT participates in many inflammatory diseases in the peripheral system, and its inhibitors have therapeutic effects. Following cerebral ischemia, the peripheral and resident inflammatory and immune cells produce many pro-inflammatory mediators in the ischemic area, which induce neuroinflammation and impair the brain...
May 19, 2017: Neuroscience
https://www.readbyqxmd.com/read/28514875/identification-of-novel-nicotinamide-phosphoribosyltransferase-nampt-inhibitors-using-computational-approaches
#20
Manish Kesherwani, Sriram Raghavan, Krishnasamy Gunasekaran, Devadasan Velmurugan
Nicotinamide Phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in the biosynthesis of NAD. Cancer cells have elevated poly [ADP-Ribose] polymerase 1 (PARP) activity as well as the immense necessity of ATP: thereby consuming NAD at a higher rate than normal tissues. The perturbation of these intracellular processes is more sensitive and highly dependent on NAMPT to maintain the required NAD levels. Functional inhibition of NAMPT is, therefore, a promising drug target in therapeutic oncology. In this study, the importance of intermolecular contacts was realized based on contact occupancy and favorable energetic from molecular dynamic simulation to discern non-critical contacts of four different classes of potential NAMPT inhibitor bound complexes...
May 17, 2017: Journal of Biomolecular Structure & Dynamics
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