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Xiangying Guan, Alok Upadhyay, Sudipto Munshi, Raj Chakrabarti
Across all families of enzymes, only a dozen or so distinct classes of non-natural small molecule activators have been characterized, with only four known modes of activation among them. All of these modes of activation rely on naturally evolved binding sites that trigger global conformational changes. Among the enzymes that are of greatest interest for small molecule activation are the seven sirtuin enzymes, nicotinamide adenine dinucleotide (NAD+)-dependent protein deacylases that play a central role in the regulation of healthspan and lifespan in organisms ranging from yeast to mammals...
2018: PloS One
Julia J Mack, M Luisa Iruela-Arispe
PURPOSE OF REVIEW: The formation of a hierarchical vascular network is a complex process that requires precise temporal and spatial integration of several signaling pathways. Amongst those, Notch has emerged as a key regulator of multiple steps that expand from endothelial sprouting to arterial specification and remains relevant in the adult. This review aims to summarize major concepts and rising hypotheses on the role of Notch signaling in the endothelium. RECENT FINDINGS: A wealth of new information has helped to clarify how Notch signaling cooperates with other pathways to orchestrate vascular morphogenesis, branching, and function...
March 14, 2018: Current Opinion in Hematology
Nadia Sawicka-Gutaj, Mirosław Andrusiewicz, Agata Czarnywojtek, Joanna Waligórska-Stachura, Maciej Biczysko, Jerzy Skrobisz, Jerzy Sowiński, Marek Ruchała
Purpose: Our aim was to analyze NAMPT expression in thyroid tissue derived from patients with Graves' disease with (GD) and without (GO) orbitopathy, patients with toxic nodular goiters (TNG) and thyroid cancers (TC), and healthy controls. Methods: 153 thyroid tissue samples of consecutive patients who underwent thyroidectomy were collected. Previous therapy with steroids was an exclusion criterion. We collected clinicopathological data of all subjects and we assessed NAMPT expression using qPCR...
2018: BioMed Research International
Xin Zhao, Jinyu Liu, Shijun Yang, Dandan Song, Chen Wang, Chen Chen, Xiaoya Li, Qiuting Wang, Shasha Ge, Runmei Yang, Xiuhua Liu, Yulin Lin, Dayong Cai
ETHNOPHARMACOLOGICAL RELEVANCE: Vascular dementia (VaD) is the common cognitive disorder derived mainly from lacunar stroke (LS). The oxidative stress induced neurovascular coupling (NVC) dysfunction involves in the pathogenesis of VaD. Currently, there is no specific drug for VaD. Ling-Yang-Gou-Teng -Decoction (LG), a well-known traditional Chinese formula, has been used for preventing VaD in clinic. AIM OF THE STUDY: In this study, we aimed to investigate the underlying mechanism of LG on VaD in rats...
March 12, 2018: Journal of Ethnopharmacology
Megerditch Kiledjian
A hallmark of eukaryotic mRNAs has long been the 5'-end m7 G cap. This paradigm was recently amended by recent reports that Saccharomyces cerevisiae and mammalian cells also contain mRNAs carrying a novel nicotinamide adenine dinucleotide (NAD+ ) cap at their 5'-end. The presence of an NAD+ cap on mRNA uncovers a previously unknown mechanism for controlling gene expression through nucleotide metabolite-directed mRNA turnover. In contrast to the m7 G cap that stabilizes mRNA, the NAD+ cap targets RNA for rapid decay in mammalian cells through the DXO non-canonical decapping enzyme which removes intact NAD+ from RNA in a process termed 'deNADding'...
March 12, 2018: Trends in Cell Biology
Shubhankar Suman, Santosh Kumar, Albert J Jr Fornace, Kamal Datta
Carbon irradiation due to its higher biological effectiveness relative to photon radiation is a concern for toxicity to proliferative normal gastrointestinal (GI) tissue after radiotherapy and long-duration space missions such as mission to Mars. Although radiation-induced oxidative stress is linked to chronic diseases such as cancer, effects of carbon irradiation on normal GI tissue have not been fully understood. This study assessed and compared chronic oxidative stress in mouse intestine and colon after different doses of carbon and γ radiation, which are qualitatively different...
March 16, 2018: Free Radical Research
Karamat Mohammad, Paméla Dakik, Younes Medkour, Mélissa McAuley, Darya Mitrofanova, Vladimir I Titorenko
The concentrations of some key metabolic intermediates play essential roles in regulating the longevity of the chronologically aging yeast Saccharomyces cerevisiae . These key metabolites are detected by certain ligand-specific protein sensors that respond to concentration changes of the key metabolites by altering the efficiencies of longevity-defining cellular processes. The concentrations of the key metabolites that affect yeast chronological aging are controlled spatially and temporally. Here, we analyze mechanisms through which the spatiotemporal dynamics of changes in the concentrations of the key metabolites influence yeast chronological lifespan...
March 15, 2018: International Journal of Molecular Sciences
Natthakan Thongon, Chiara Zucal, Vito Giuseppe D'Agostino, Toma Tebaldi, Silvia Ravera, Federica Zamporlini, Francesco Piacente, Ruxanda Moschoi, Nadia Raffaelli, Alessandro Quattrone, Alessio Nencioni, Jean-Francois Peyron, Alessandro Provenzani
Background: Inhibitors of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD+ biosynthesis from nicotinamide, exhibit anticancer effects in preclinical models. However, continuous exposure to NAMPT inhibitors, such as FK866, can induce acquired resistance. Methods: We developed FK866-resistant CCRF-CEM (T cell acute lymphoblastic leukemia) and MDA MB231 (breast cancer) models, and by exploiting an integrated approach based on genetic, biochemical, and genome wide analyses, we annotated the drug resistance mechanisms...
2018: Cancer & Metabolism
Andreas Kling, Katja Jantos, Helmut Mack, Wilfried Hornberger, Gisela Backfisch, Yanbin Lao, Marjoleen Nijsen, Beatrice Rendenbach-Mueller, Achim Moeller
Dysregulation of calpains 1 and 2 has been implicated in a variety of pathological disorders including ischemia/reperfusion injuries, kidney diseases, cataract formation, and neurodegenerative diseases such as Alzheimer's disease (AD). 2-(3-Phenyl-1 H )-pyrazol-1-yl)nicotinamides represent a series of novel and potent calpain inhibitors with high selectivity and in vivo efficacy. However, carbonyl reduction leading to the formation of the inactive hydroxyamide was identified as major metabolic liability in monkey and human, a pathway not reflected by routine absorption, distribution, metabolism, and excretion (ADME) assays...
March 8, 2018: ACS Medicinal Chemistry Letters
Liang Liang, Ming Zeng, Haixia Pan, Hao Liu, Yangke He
Previous studies have demonstrated that nicotinamide N-methyltransferase (NNMT) is aberrantly expressed in a number of tumors. In the present study, it was demonstrated that the gene and protein levels of NNMT were significantly increased in gastric cancer cells. Furthermore, upregulation of NNMT significantly increased the expression of mesenchymal markers, including α-smooth muscle actin (SMA), vimentin and fibronectin, but decreased the levels of epithelial cadherin. Since transforming growth factor (TGF)-β1 may serve a key function in epithelial-mesenchymal transition (EMT), the effects of NNMT on the expression of TGF-β1 were investigated in BGC-823 cells...
April 2018: Oncology Letters
Uma Mahesh R Avula, Jonathan J Hernandez, Masatoshi Yamazaki, Carmen R Valdivia, Antony Chu, Alvaro Rojas-Pena, Kuljeet Kaur, Roberto Ramos-Mondragón, Justus M Anumonwo, Stanley Nattel, Héctor H Valdivia, Jérôme Kalifa
BACKGROUND: The mechanisms underlying spontaneous atrial fibrillation (AF) associated with atrial ischemia/infarction are incompletely elucidated. Here, we investigate the mechanisms underlying spontaneous AF in an ovine model of left atrial myocardial infarction (LAMI). METHODS AND RESULTS: LAMI was created by ligating the atrial branch of the left anterior descending coronary artery. ECG loop recorders were implanted to monitor AF episodes. In 7 sheep, dantrolene-a ryanodine receptor blocker-was administered in vivo during the 8-day observation period (LAMI-D, 2...
March 2018: Circulation. Arrhythmia and Electrophysiology
Zhiyi Liu, Dimitra Pouli, Carlo A Alonzo, Antonio Varone, Sevasti Karaliota, Kyle P Quinn, Karl Münger, Katia P Karalis, Irene Georgakoudi
Monitoring subcellular functional and structural changes associated with metabolism is essential for understanding healthy tissue development and the progression of numerous diseases, including cancer, diabetes, and cardiovascular and neurodegenerative disorders. Unfortunately, established methods for this purpose either are destructive or require the use of exogenous agents. Recent work has highlighted the potential of endogenous two-photon excited fluorescence (TPEF) as a method to monitor subtle metabolic changes; however, mechanistic understanding of the connections between the detected optical signal and the underlying metabolic pathways has been lacking...
March 2018: Science Advances
Shuyi Wang, Cong Wang, Subat Turdi, Kacy L Richmond, Yingmei Zhang, Jun Ren
BACKGROUND AND AIMS: Uncorrected obesity contributes to cardiac remodeling and contractile dysfunction although the underlying mechanism remains poorly understood. Mitochondrial aldehyde dehydrogenase (ALDH2) is a mitochondrial enzyme with some promises in a number of cardiovascular diseases. This study was designed to evaluate the impact of ALDH2 on cardiac remodeling and contractile property in high fat diet-induced obesity. METHODS: Wild-type (WT) and ALDH2 transgenic mice were fed low (10% calorie from fat) or high (45% calorie from fat) fat diet for 5 months prior to the assessment of cardiac geometry and function using echocardiography, IonOptix system, Lectin, and Masson Trichrome staining...
March 13, 2018: International Journal of Obesity: Journal of the International Association for the Study of Obesity
George Cătălin Marinescu, Roua-Gabriela Popescu, Anca Dinischiotu
Over 12% of the world's health resources are spent on treating diabetes, as high blood glucose is the third cause of mortality worldwide. Insulin resistance is the basis of the most common form of diabetes: type 2 diabetes. Recent animal studies report successful attempts at reversing type 2 diabetes by the administering of the NAD+ precursor nicotinamide mononucleotide (NMN). However, the current high price of this molecule urges for more efficient and cost-effective production methods. This work proposes a method for purifying NMN by Size Exclusion Chromatography (SEC) on silica with a covalently attached coating of poly(2-hydroxyethyl aspartamide) (PolyHEA) stationary phase using an isocratic elution with a denaturing mobile phase (50 mM formic acid) from a complex molecular mixture such as a fermentation broth...
March 13, 2018: Scientific Reports
Jue Hou, Joshua Williams, Elliot Botvinick, Eric Potma, Bruce J Tromberg
Label-free non-linear optical microscopy (NLOM) based on two-photon excited fluorescence (TPEF) from cofactors Nicotinamide Adenine Dinucleotide (NADH) and Flavin Adenine Dinucleotide (FAD+) is widely used for high-resolution cellular redox imaging. In this work, we combined three, label-free NLOM imaging methods to quantitatively characterize breast cancer cells and their relative invasive potential: 1) TPEF optical redox ratio (ORR = FAD+/NADH + FAD+), 2) coherent Raman scattering (CRS) of cellular lipids, and 3) second harmonic generation (SHG) of extracellular matrix (ECM) collagen...
March 13, 2018: Cancer Research
Lu Li, Hai-Dong Fu
Neutrophil extracellular traps (NETs) represent a form of cell death distinct from apoptosis or necrosis. The imbalance between the formation and degradation of NETs has long been considered to be closely associated with the activity of autoimmune diseases such as systemic lupus erythematous (SLE). Reactive oxygen species derived from the nicotinamide adenine dinucleotide phosphate oxidase pathway or mitochondrial DNA pathway play a key role in the primary stage of NETs formation. The exposure or delayed degradation of abundant autoantigens, such as double-strand DNA, caused by abnormal activation of neutrophils can induce autoantibody to form immune complexes that deposit in local tissues and then induce the plasmacytoid dendritic cells to secrete the interferon alpha and other inflammatory factors...
March 2018: Zhongguo Dang Dai Er Ke za Zhi, Chinese Journal of Contemporary Pediatrics
Ying Huang, Gui-Quan Cai, Jian-Ping Peng, Chao Shen
Based on the results from our previous study, dexamethasone (Dex) increases reactive oxygen species (ROS) levels and subsequently induces cell death and matrix catabolism in chondrocytes. Nevertheless, the mechanism underlying this phenomenon remains unclear. Nicotinamide adenine dinucleotide (phosphate) (NADPH) oxidase 4 (NOX4) is one of the major enzymes responsible for intracellular ROS production during the inflammatory process. The objective of the current study was to investigate the role of NOX4 in Dex-induced ROS over-production...
March 8, 2018: Journal of Steroid Biochemistry and Molecular Biology
Filipa V Sena, Filipe M Sousa, A Sofia F Oliveira, Cláudio M Soares, Teresa Catarino, Manuela M Pereira
Type-II NADH:quinone oxidoreductases (NDH-2s) are membrane proteins involved in respiratory chains and the only enzymes with NADH:quinone oxidoreductase activity expressed in Staphylococcus aureus (S. aureus), one of the most common causes of clinical infections. NDH-2s are members of the two-Dinucleotide Binding Domains Flavoprotein (tDBDF) superfamily, having a flavin adenine dinucleotide, FAD, as prosthetic group and NAD(P)H as substrate. The establishment of a Charge-Transfer Complex (CTC) between the isoalloxazine ring of the reduced flavin and the nicotinamide ring of NAD+ in NDH-2 was described, and in this work we explored its role in the kinetic mechanism using different electron donors and electron acceptors...
February 17, 2018: Redox Biology
Takashi Otaki, Yuta Tanabe, Takashi Kojima, Masaru Miura, Yukihiro Ikeda, Tatsuo Koide, Toshiro Fukami
In recent years, to guarantee a quality-by-design approach to the development of pharmaceutical products, it is important to identify properties of raw materials and excipients in order to determine critical process parameters and critical quality attributes. Feedback obtained from real-time analyses using various process analytical technology (PAT) tools has been actively investigated. In this study, in situ monitoring using low-frequency (LF) Raman spectroscopy (10-200cm-1 ), which may have higher discriminative ability among polymorphs than near-infrared spectroscopy and conventional Raman spectroscopy (200-1800 cm-1 ), was investigated as a possible application to PAT...
March 7, 2018: International Journal of Pharmaceutics
Gui Pan, Haojie Hao, Jianping Liu
The transplantation of insulin-producing cells (IPCs) or pancreatic progenitor cells is a theoretical therapy for diabetes with insulin insufficiency. Isolated hepatocytes from newborn rats (within 24 h after birth) were progressively induced into IPCs using 5-aza-2'-deoxycytidine, Trichostatin A, retinoic acid, insulin-transferrin-selenium, and nicotinamide. We transplanted Pdx1+ pancreatic progenitors into STZ-induced diabetic mice and found the decreased blood glucose and increased insulin level in comparison with diabetic model...
March 7, 2018: Biochemical and Biophysical Research Communications
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