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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/28733231/tussilagonone-induced-nrf2-pathway-activation-protects-hepg2-cells-from-oxidative-injury
#2
Kyung-Mi Lee, Tae Yeon Kwon, Unwoo Kang, Eun Kyoung Seo, Ji Ho Yun, Chu Won Nho, Yeong Shik Kim
Tussilagonone is a compound derived from the medicinal plant Tussilago farfara L., which is used as a traditional medicine for respiratory diseases, including asthma and pneumonia. Recent reports suggest that tussilagonone exhibits anti-inflammatory effects; however, the scope of protective functions has not been elucidated yet. In this study, we demonstrate that tussilagonone enhances cellular detoxification by increasing quinone reductase activity in Hepa1c1c7 cells. In addition, tussilagonone decreased tert-butyl hydroperoxide(t-BHP)-induced ROS production and cell death, suggesting that it also acts as a potent antioxidant...
July 18, 2017: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/28731346/kinetics-of-light-induced-intramolecular-energy-transfer-in-different-conformational-states-of-nadh
#3
Zsuzsanna Heiner, Thomas Roland, Jérémie Léonard, Stefan Haacke, Géza I Groma
When bound to a protein, the coenzyme NAD+/NADH typically exists in an extended conformation, while in aqueous solutions it can be characterized by an equilibrium of folded and unfolded structures. It was recognized long ago that in the folded conformation light absorption at the adenine ring initiates an effective energy transfer (ET) towards the nicotinamide group, but the mechanism of this process is still unexplored. Here we apply ultrafast transient absorption measurements on NADH combined with compartmental model analysis for following the kinetics of the ET...
July 21, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28728845/crystal-structure-of-cis-dihydrodiol-naphthalene-dehydrogenase-nahb-from-pseudomonas-sp-mc1-insights-into-the-early-binding-process-of-the-substrate
#4
Ae Kyung Park, Hyun Kim, Il-Sup Kim, Soo Jung Roh, Seung Chul Shin, Jun Hyuck Lee, Hyun Park, Han-Woo Kim
The bacterial strain Pseudomonas sp. MC1 harbors an 81-kb metabolic plasmid, which encodes enzymes involved in the conversion of naphthalene to salicylate. Of these, the enzyme NahB (cis-dihydrodiol naphthalene dehydrogenase), which catalyzes the second reaction of this pathway, binds to various substrates such as cis-1,2-dihydro-1,2-dihydroxy-naphthalene (1,2-DDN), cis-2,3-dihydro-2,3-dihydroxybiphenyl (2,3-DDB), and 3,4-dihydro-3,4-dihydroxy-2,2',5,5'-tetrachlorobiphenyl (3,4-DD-2,2',5-5-TCB). However, the mechanism underlying its broad substrate specificity is unclear owing to the lack of structural information...
July 17, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28724915/quinolinate-phosphoribosyltransferase-is-an-antiviral-host-factor-against-hepatitis-c-virus-infection
#5
Zhilong Wang, Yanhang Gao, Chao Zhang, Haiming Hu, Dongwei Guo, Yi Xu, Qiuping Xu, Weihong Zhang, Sisi Deng, Pingyun Lv, Yan Yang, Yanhua Ding, Qingquan Li, Changjiang Weng, Xinwen Chen, Sitang Gong, Hairong Chen, Junqi Niu, Hong Tang
HCV infection can decrease NAD(+)/NADH ratio, which could convert lipid metabolism to favor HCV replication. In hepatocytes, quinolinate phosphoribosyl transferase (QPRT) catabolizes quinolinic acid (QA) to nicotinic acid mononucleotide (NAMN) for de novo NAD synthesis. However, whether and how HCV modulates QPRT hence the lipogenesis is unknown. In this work, we found QPRT was reduced significantly in livers of patients or humanized C/O(Tg) mice with persistent HCV infection. Mechanistic studies indicated that HCV NS3/4A promoted proteasomal degradation of QPRT through Smurf2, an E3 ubiquitin-protein ligase, in Huh7...
July 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28724806/nicotinamide-mononucleotide-requires-sirt3-to-improve-cardiac-function-and-bioenergetics-in-a-friedreich-s-ataxia-cardiomyopathy-model
#6
Angelical S Martin, Dennis M Abraham, Kathleen A Hershberger, Dhaval P Bhatt, Lan Mao, Huaxia Cui, Juan Liu, Xiaojing Liu, Michael J Muehlbauer, Paul A Grimsrud, Jason W Locasale, R Mark Payne, Matthew D Hirschey
Increasing NAD+ levels by supplementing with the precursor nicotinamide mononucleotide (NMN) improves cardiac function in multiple mouse models of disease. While NMN influences several aspects of mitochondrial metabolism, the molecular mechanisms by which increased NAD+ enhances cardiac function are poorly understood. A putative mechanism of NAD+ therapeutic action exists via activation of the mitochondrial NAD+-dependent protein deacetylase sirtuin 3 (SIRT3). We assessed the therapeutic efficacy of NMN and the role of SIRT3 in the Friedreich's ataxia cardiomyopathy mouse model (FXN-KO)...
July 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28724407/characterization-of-the-cytochrome-p450-monooxygenase-genes-p450ome-from-the-carotenogenic-yeast-xanthophyllomyces-dendrorhous
#7
Pamela Córdova, Ana-María Gonzalez, David R Nelson, María-Soledad Gutiérrez, Marcelo Baeza, Víctor Cifuentes, Jennifer Alcaíno
BACKGROUND: The cytochromes P450 (P450s) are a large superfamily of heme-containing monooxygenases involved in the oxidative metabolism of an enormous diversity of substrates. These enzymes require electrons for their activity, and the electrons are supplied by NAD(P)H through a P450 electron donor system, which is generally a cytochrome P450 reductase (CPR). The yeast Xanthophyllomyces dendrorhous has evolved an exclusive P450-CPR system that specializes in the synthesis of astaxanthin, a carotenoid with commercial potential...
July 19, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28722682/activation-of-the-nrf2-are-signaling-pathway-by-probucol-contributes-to-inhibiting-inflammation-and-neuronal-apoptosis-after-spinal-cord-injury
#8
Zipeng Zhou, Chang Liu, Shurui Chen, Haosen Zhao, Kang Zhou, Wei Wang, Yajiang Yuan, Zhuo Li, Yue Guo, Zhaoliang Shen, Xifan Mei
The nuclear erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway plays an essential role in the cellular antioxidant and anti-inflammatory responses. Spinal cord injury (SCI) results in a massive release of inflammatory factors and free radicals, which seriously compromise nerve recovery and axon regeneration. In this study, we examined the efficacy of probucol on anti-inflammatory responses and functional recovery after SCI by activating the Nrf2/ARE signaling pathway. We also investigated the mechanism by which inflammation is inhibited in this process...
July 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28722654/a-lectin-receptor-kinase-as-a-potential-sensor-for-extracellular-nicotinamide-adenine-dinucleotide-in-arabidopsis-thaliana
#9
Chenggang Wang, Mingqi Zhou, Xudong Zhang, Jin Yao, Yanping Zhang, Zhonglin Mou
Nicotinamide adenine dinucleotide (NAD(+)) participates in intracellular and extracellular signaling events unrelated to metabolism. In animals, purinergic receptors are required for extracellular NAD(+) (eNAD(+)) to evoke biological responses, indicating that eNAD(+) may be sensed by cell-surface receptors. However, the identity of eNAD(+)-binding receptors still remains elusive. Here, we identify a lectin receptor kinase (LecRK), LecRK-I.8, as a potential eNAD(+) receptor in Arabidopsis. The extracellular lectin domain of LecRK-I...
July 19, 2017: ELife
https://www.readbyqxmd.com/read/28721437/erk1-is-dispensable-for-mouse-pancreatic-beta-cell-function-but-is-necessary-for-glucose-induced-full-activation-of-msk1-and-creb
#10
Michele Leduc, Joy Richard, Safia Costes, Dany Muller, Annie Varrault, Vincent Compan, Julia Mathieu, Jean-François Tanti, Gilles Pagès, Jacques Pouyssegur, Gyslaine Bertrand, Stéphane Dalle, Magalie A Ravier
AIMS/HYPOTHESIS: Insufficient insulin secretion from pancreatic beta cells, which is associated with a decrease in beta cell mass, is a characteristic of type 2 diabetes. Extracellular signal-related kinase 1 and 2 (ERK1/2) inhibition in beta cells has been reported to affect insulin secretion, gene transcription and survival, although whether ERK1 and ERK2 play distinct roles is unknown. The aim of this study was to assess the individual roles of ERK1 and ERK2 in beta cells using ERK1 (also known as Mapk3)-knockout mice (Erk1 (-/-) mice) and pharmacological approaches...
July 18, 2017: Diabetologia
https://www.readbyqxmd.com/read/28720729/inhibition-of-inflammasome-dependent-interleukin-1%C3%AE-production-by-streptococcal-nad-glycohydrolase-evidence-for-extracellular-activity
#11
Dóra Hancz, Elsa Westerlund, Benedicte Bastiat-Sempe, Onkar Sharma, Christine Valfridsson, Lena Meyer, John F Love, Maghnus O'Seaghdha, Michael R Wessels, Jenny J Persson
Group A Streptococcus (GAS) is a common human pathogen and the etiologic agent of a large number of diseases ranging from mild, self-limiting infections to invasive life-threatening conditions. Two prominent virulence factors of this bacterium are the genetically and functionally linked pore-forming toxin streptolysin O (SLO) and its cotoxin NAD(+)-glycohydrolase (NADase). Overexpression of these toxins has been linked to increased bacterial virulence and is correlated with invasive GAS disease. NADase can be translocated into host cells by a SLO-dependent mechanism, and cytosolic NADase has been assigned multiple properties such as protection of intracellularly located GAS bacteria and induction of host cell death through energy depletion...
July 18, 2017: MBio
https://www.readbyqxmd.com/read/28719017/contrasting-sirtuin-and-parp-activity-of-selected-2-4-6-trisubstituted-benzimidazoles
#12
Keng Yoon Yeong, Soo Choon Tan, Chun-Wai Mai, Chee-Onn Leong, Felicia Fei-Lei Chung, Yean Kee Lee, Chin Fei Chee, Noorsaadah Abdul Rahman
Both sirtuin and poly(ADP-ribose)polymerase (PARP) family of enzymes utilize NAD+ as co-substrate. Inhibitors of sirtuins and PARPs are important tools in drug discovery as they are reported to be linked to multiple diseases such as cancer. New potent sirtuin inhibitors (2,4,6-trisubstituted benzimidazole) were discovered from reported PARP inhibitor scaffold. Interestingly, the synthesized compounds have contrasting sirtuin and PARP-1 inhibitory activity. We showed that modification on benzimidazoles may alter their selectivity towards sirtuin or PARP-1 enzymes...
July 18, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28718934/nad-a-key-metabolic-regulator-with-great-therapeutic-potential
#13
REVIEW
Ghazal Sultani, Azrah F Samsudeen, Brenna Osborne, Nigel Turner
Nicotinamide adenine dinucleotide (NAD(+) ) is a ubiquitous metabolite that serves an essential role in the catabolism of nutrients. Recently there has been a surge of interest in NAD(+) biology, with the recognition that NAD(+) influences many biological processes beyond metabolism, including transcription, signalling and cell survival. There are a multitude of pathways involved in the synthesis and breakdown of NAD(+) , and alterations in NAD(+) homeostasis have emerged as a common feature of a range of disease states...
July 18, 2017: Journal of Neuroendocrinology
https://www.readbyqxmd.com/read/28716423/nadk2-positively-modulates-abscisic-acid-induced-stomatal-closure-by-affecting-accumulation-of-h2o2-ca-2-and-nitric-oxide-in-arabidopsis-guard-cells
#14
Lirong Sun, Yaping Li, Wenwen Miao, Tingting Piao, Yang Hao, Fu-Shun Hao
NAD kinase2 (NADK2) plays key roles in chloroplastic NADP biosynthesis, stress adaptation and modulation of cellular metabolisms in Arabidopsis. However, it is unknown whether and how NADK2 affects abscisic acid (ABA)-mediated stomatal movement. Here, we detected that null mutant nadk2 was more sensitive to drought stress than WT, and NADK2 gene was active in guard cells. Furthermore, NADK2 mutation impaired ABA-induced stomatal closure and ABA inhibition of light-promoted stomatal opening. NADK2 disruption also impaired ABA-stimulated accumulation of H2O2, Ca(2+) and nitric oxide (NO) in guard cells, but did not affect the stomatal closure evoked by exogenous H2O2, Ca(2+) or NO...
September 2017: Plant Science: An International Journal of Experimental Plant Biology
https://www.readbyqxmd.com/read/28715469/cofactor-engineering-improved-calb-production-in-pichia-pastoris-through-heterologous-expression-of-nadh-oxidase-and-adenylate-kinase
#15
Charumathi Jayachandran, Balakumaran Palanisamy Athiyaman, Meenakshisundaram Sankaranarayanan
The cofactor engineering strategy can relieve the metabolic stress induced by expression of recombinant protein in cellular metabolism related to cofactor and energy reactions. To study the effect of cofactor regeneration on recombinant protein expression, NADH oxidase (noxE) was engineered in P. pastoris expressing lipase B (GSCALB). Expression of noxE in P. pastoris (GSCALBNOX) increased NAD+ levels by 85% with a concomitant reduction in NADH/NAD+ ratio of 67% compared to GSCALB. The change in the redox level positively influenced the methanol uptake rate and made 34% augment in CALB activity...
2017: PloS One
https://www.readbyqxmd.com/read/28714938/taxifolin-activates-the-nrf2-anti-oxidative-stress-pathway-in-mouse-skin-epidermal-jb6-p-cells-through-epigenetic-modifications
#16
Haixue Kuang, Zhenqiu Tang, Chengyue Zhang, Zhibin Wang, Wenji Li, Chunjuan Yang, Qiuhong Wang, Bingyou Yang, Ah-Ng Kong
Nuclear factor erythroid-2 related factor 2 (Nrf2) is a vital transcription factor that regulates the anti-oxidative defense system. Previous reports suggested that the expression of the Nrf2 gene can be regulated by epigenetic modifications. The potential epigenetic effect of taxifolin (TAX), a potent cancer chemopreventive agent, in skin cancer chemoprotection is unknown. In this study, we investigated how Nrf2 is epigenetically regulated by TAX in JB6 P+ cells. TAX was found to inhibit the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced colony formation of JB6 P+ cells...
July 17, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28714034/inhibition-of-nampt-decreases-cell-growth-and-enhances-susceptibility-to-oxidative-stress
#17
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
#18
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...
July 5, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28713490/picroside-ii-shows-protective-functions-for-severe-acute-pancreatitis-in-rats-by-preventing-nf-%C3%AE%C2%BAb-dependent-autophagy
#19
Xuehua Piao, Baohai Liu, Lianyi Guo, Fanji Meng, Leming Gao
Picroside II, from the herb Picrorhiza scrophulariiflora Pennell, has antioxidant and anti-inflammatory activities. However, its function on severe acute pancreatitis (SAP) and molecular mechanism remains unknown. The effects of picroside II on the SAP induced by cerulean were investigated. SAP rats were treated with picroside II (25 mg/kg). The severity of SAP was evaluated by using biochemical and histological analyses. Pancreatic cancer cell PANC-1 was transfected with ptfLC3 (an indicator of autophagic activity), pcDNA3...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28712849/structure-function-and-mechanism-of-proline-utilization-a-puta
#20
REVIEW
Li-Kai Liu, Donald F Becker, John J Tanner
Proline has important roles in multiple biological processes such as cellular bioenergetics, cell growth, oxidative and osmotic stress response, protein folding and stability, and redox signaling. The proline catabolic pathway, which forms glutamate, enables organisms to utilize proline as a carbon, nitrogen, and energy source. FAD-dependent proline dehydrogenase (PRODH) and NAD(+)-dependent glutamate semialdehyde dehydrogenase (GSALDH) convert proline to glutamate in two sequential oxidative steps. Depletion of PRODH and GSALDH in humans leads to hyperprolinemia, which is associated with mental disorders such as schizophrenia...
July 13, 2017: Archives of Biochemistry and Biophysics
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