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https://www.readbyqxmd.com/read/29777905/coupling-of-the-polyamine-and-iron-metabolism-pathways-in-the-regulation-of-proliferation-mechanistic-links-to-alterations-in-key-polyamine-biosynthetic-and-catabolic-enzymes
#1
Darius J R Lane, Dong-Hun Bae, Aritee R Siafakas, Yohan Suryo Rahmanto, Lina Al-Akra, Patric J Jansson, Robert A Casero, Des R Richardson
Many biological processes result from the coupling of metabolic pathways. Considering this, proliferation depends on adequate iron and polyamines, and although iron-depletion impairs proliferation, the metabolic link between iron and polyamine metabolism has never been thoroughly investigated. This is important to decipher, as many disease states demonstrate co-dysregulation of iron and polyamine metabolism. Herein, for the first time, we demonstrate that cellular iron levels robustly regulate 13 polyamine pathway proteins...
May 16, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29777848/effects-on-mortality-and-cardiovascular-events-of-adherence-to-guideline-recommended-therapy-4-years-after-lower-extremity-arterial-revascularization
#2
M Thiney, N Della Schiava, R Ecochard, P Feugier, P Lermusiaux, A Millon, A Long
OBJECTIVES: All patients with lower extremity peripheral arterial disease (LE-PAD) should benefit from recommended pharmacologic therapies including antiplatelet agents, angiotensin converting enzyme inhibitors (ACE) or Angiotensin receptor blockers (ARB), and HMG-CoA-reductase inhibitors (statins). In the present study, this triple therapy was defined as the best medical treatment. This study was designed to determine the current risk for cardiovascular (CV) events and mortality and also to evaluate the effect of pharmacologic treatment on patient's survival, CV events and additional vascular surgery in vascularized LE-PAD patients...
May 16, 2018: Annals of Vascular Surgery
https://www.readbyqxmd.com/read/29777772/improving-maraviroc-oral-bioavailability-by-formation-of-solid-drug-nanoparticles
#3
Alison C Savage, Lee M Tatham, Marco Siccardi, Trevor Scott, Manoli Vourvahis, Andrew Clark, Steve P Rannard, Andrew Owen
Oral drug administration remains the preferred approach for treatment of HIV in most patients. Maraviroc (MVC) is the first in class co-receptor antagonist, which blocks HIV entry into host cells. MVC has an oral bioavailability of approximately 33%, which is limited by poor permeability as well as affinity for CYP3A and several drug transporters. While once-daily doses are now the favoured option for HIV therapy, dose-limiting postural hypotension has been of theoretical concern when administering doses high enough to achieve this for MVC (particularly during coadministration of enzyme inhibitors)...
May 16, 2018: European Journal of Pharmaceutics and Biopharmaceutics
https://www.readbyqxmd.com/read/29777624/characterisation-of-a-putative-glutamate-5-kinase-from-leishmania-donovani
#4
Natasha Sienkiewicz, Han B Ong, Alan H Fairlamb
Previous metabolic studies have demonstrated that leishmania parasites are able to synthesise proline from glutamic acid and threonine from aspartic acid. The first committed step in both biosynthetic pathways involves an amino acid kinase, either a glutamate 5-kinase (EC 2.7.2.11) or an aspartokinase (EC 2.7.2.4). Bioinformatic analysis of multiple leishmania genomes identifies a single amino-acid-kinase gene (LdBPK 262740.1) variously annotated as either a putative glutamate or aspartate kinase. To establish the catalytic function of this Leishmania donovani gene product, we have determined the physical and kinetic properties of the recombinant enzyme purified from Escherichia coli...
May 19, 2018: FEBS Journal
https://www.readbyqxmd.com/read/29777284/current-drug-therapy-for-heart-failure-with-reduced-ejection-fraction
#5
D Berliner, M Hallbaum, J Bauersachs
The prevalence of heart failure has been steadily increasing during the past few years, with a further increase predicted in the years to come. Without treatment, the syndrome of heart failure has a very poor prognosis. Advances in drug treatments and the consequent implementation of a guideline-recommended drug therapy have significantly improved the prognosis in heart failure with reduced ejection fraction (HFrEF). Besides angiotensin-converting enzyme (ACE) inhibitors (ACEi) or angiotensin receptor blockers, beta-blockers and diuretics treatment with mineralocorticoid receptor antagonists and ivabradine have become standard in the therapy of symptomatic patients with HFrEF...
May 18, 2018: Herz
https://www.readbyqxmd.com/read/29777255/inhibition-of-sialidase-activity-and-cellular-invasion-by-the-bacterial-vaginosis-pathogen-gardnerella-vaginalis
#6
G Govinden, J L Parker, K L Naylor, A M Frey, D O C Anumba, G P Stafford
Bacterial vaginosis is a genital tract infection, thought to be caused by transformation of a lactobacillus-rich flora to a dysbiotic microbiota enriched in mixed anaerobes. The most prominent of these is Gardnerella vaginalis (GV), an anaerobic pathogen that produces sialidase enzyme to cleave terminal sialic acid residues from human glycans. Notably, high sialidase activity is associated with preterm birth and low birthweight. We explored the potential of the sialidase inhibitor Zanamavir against GV whole cell sialidase activity using methyl-umbelliferyl neuraminic acid (MU-NANA) cleavage assays, with Zanamavir causing a 30% reduction in whole cell GV sialidase activity (p < 0...
May 18, 2018: Archives of Microbiology
https://www.readbyqxmd.com/read/29777253/translation-inhibition-corrects-aberrant-localization-of-mutant-alanine-glyoxylate-aminotransferase-possible-therapeutic-approach-for-hyperoxaluria
#7
Ruth Belostotsky, Roman Lyakhovetsky, Michael Y Sherman, Fanny Shkedy, Shimrit Tzvi-Behr, Roi Bar, Bernd Hoppe, Björn Reusch, Bodo B Beck, Yaacov Frishberg
Primary hyperoxaluria type 1 is a severe kidney stone disease caused by abnormalities of the peroxisomal alanine-glyoxylate aminotransferase (AGT). The most frequent mutation G170R results in aberrant mitochondrial localization of the active enzyme. To evaluate the population of peroxisome-localized AGT, we developed a quantitative Glow-AGT assay based on the self-assembly split-GFP approach and used it to identify drugs that can correct mislocalization of the mutant protein. In line with previous reports, the Glow-AGT assay showed that mitochondrial transport inhibitors DECA and monensin increased peroxisomal localization of the mutant...
May 18, 2018: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/29776833/novel-oxazolxanthone-derivatives-as-a-new-type-of-%C3%AE-glucosidase-inhibitor-synthesis-activities-inhibitory-modes-and-synergetic-effect
#8
Sen-Miao Ding, Tian Lan, Gao-Jie Ye, Jia-Jun Huang, You Hu, Yi-Ran Zhu, Bo Wang
Xanthone derivatives have shown good α-glucosidase inhibitory activity and have drawn increased attention as potential anti-diabetic compounds. In this study, a series of novel oxazolxanthones were designed, synthesized, and investigated as α-glucosidase inhibitors. Inhibition assays indicated that compounds 4-21 bearing oxazole rings exhibited up to 30-fold greater inhibitory activity compared to their corresponding parent compound 1b. Among them, compounds 5-21 (IC50  = 6.3 ± 0.4-38.5 ± 4...
May 15, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29776559/angioedema-in-heart-failure-patients-treated-with-sacubitril-valsartan-lcz696-or-enalapril-in-the-paradigm-hf-study
#9
Victor Shi, Michele Senni, Hendrik Streefkerk, Vikas Modgill, Wenchun Zhou, Allen Kaplan
BACKGROUND: PARADIGM-HF demonstrated significant clinical benefits for sacubitril/valsartan (LCZ696, an angiotensin receptor neprilysin inhibitor) versus the angiotensin-converting enzyme inhibitor (ACEI) enalapril in patients with heart failure with reduced ejection fraction. As inhibition of ACE, and co-inhibition of ACE and neprilysin, may increase the risk of angioedema, this was an adverse event of special interest. METHODS: Following sequential enalapril and sacubitril/valsartan run-ins, patients were randomized to twice-daily sacubitril/valsartan 200 mg or enalapril 10 mg...
August 1, 2018: International Journal of Cardiology
https://www.readbyqxmd.com/read/29776409/calcitriol-downregulates-fibroblast-growth-factor-receptor-1-through-histone-deacetylase-activation-in-hl-1-atrial-myocytes
#10
Ting-Wei Lee, Ting-I Lee, Yung-Kuo Lin, Yu-Hsun Kao, Yi-Jen Chen
BACKGROUND: Fibroblast growth factor (FGF)-2 plays a crucial role in the pathophysiology of cardiovascular diseases (CVDs). FGF-2 was reported to induce cardiac hypertrophy through activation of FGF receptor 1 (FGFR1). Multiple laboratory findings indicate that calcitriol may be a potential treatment for CVDs. In this study, we attempted to investigate whether calcitriol regulates FGFR1 expression to modulate the effects of FGF-2 signaling in cardiac myocytes and explored the potential regulatory mechanism...
May 18, 2018: Journal of Biomedical Science
https://www.readbyqxmd.com/read/29776373/metabolic-therapy-with-peg-arginase-induces-a-sustained-complete-remission-in-immunotherapy-resistant-melanoma
#11
Carmela De Santo, Paul Cheng, Andrew Beggs, Sharon Egan, Alberto Bessudo, Francis Mussai
BACKGROUND: Metastatic melanoma is an aggressive skin cancer with a poor prognosis. Current treatment strategies for high-stage melanoma are based around the use of immunotherapy with immune checkpoint inhibitors such as anti-PDL1 or anti-CTLA4 antibodies to stimulate anti-cancer T cell responses, yet a number of patients will relapse and die of disease. Here, we report the first sustained complete remission in a patient with metastatic melanoma who failed two immunotherapy strategies, by targeting tumour arginine metabolism...
May 18, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29775893/puerarin-prevents-vascular-endothelial-injury-through-suppression-of-nf-%C3%AE%C2%BAb-activation-in-lps-challenged-human-umbilical-vein-endothelial-cells
#12
Hua-Fei Deng, Sha Wang, Lian Li, Qin Zhou, Wan-Bei Guo, Xiao-Li Wang, Mei-Dong Liu, Ke Liu, Xian-Zhong Xiao
OBJECTIVE: In the present study, we aimed to explore the effects of puerarin on vascular endothelial cell injury induced by lipopolysaccharide (LPS) and its underlying mechanisms. METHODS: The cell viability and morphological changes were assessed using the cell counting kit-8 (CCK-8) assay and 4´,6-diamidino-2-phenylindole (DAPI) staining, respectively. The levels of tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), monocyte/macrophage chemotactic protein-1 (MCP-1), IL-8, intercellular cell adhesion molecule-1 (ICAM-1), thrombomodulin (TM) and plasminogen activator inhibitor-1 (PAI-1) in cell culture supernatant were determined by the enzyme-linked immunosorbent assay (ELISA)...
May 15, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29775412/inhibitor-of-lysyl-oxidase-improves-cardiac-function-and-the-collagen-mmp-profile-in-response-to-volume-overload
#13
Elia C El Hajj, Milad C El Hajj, Van K Ninh, Jason D Gardner
The cardiac extracellular matrix is a complex architectural network that serves many functions including providing structural and biochemical support to surrounding cells, and regulating intercellular signaling pathways. Cardiac function is directly affected by extracellular matrix (ECM) composition, and alterations of the ECM contribute to progression of heart failure. Initially, collagen deposition is an adaptive response that aims to preserve tissue integrity and maintain normal ventricular function. However, the synergistic effects of the pro-inflammatory and pro-fibrotic responses induce a vicious cycle which causes excess activation of myofibroblasts, significantly increasing collagen deposition and accumulation in the matrix...
May 18, 2018: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/29775277/cid-9998128-compound-is-a-potential-multi-target-drug-for-alzheimer-s-disease
#14
Nguyen Quoc Thai, Zuzana Bednarikova, Miroslav Gancar, Huynh Quang Linh, Chin-Kun Hu, Mai Suan Li, Zuzana Gazova
We have probed capability of small CID 9998128 compound as a potential multi-target drug for the Alzheimer's disease (AD) using in silico and in vitro experiments. By all-atom simulation and MM-PBSA method we have demonstrated that this compound strongly binds to both amyloid beta 42 (Aβ42 ) fibrils and β-secretase and the van der Waals interaction is dominating over the electrostatic interaction in binding affinity. A detailed analysis at the atomic level revealed that indazole in CID 99998128 structure made a major contribution to instability of all studied complexes...
May 18, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29775215/development-of-a-fast-ce-method-for-high-throughput-screening-of-ecto-5-nucleotidase-inhibitors
#15
Rabia Raza, Yu Bai, Huwei Liu
Overexpression of ecto-5'-nucleotidase is found to be linked to cancer progression and other diseases which makes screening of its inhibitors on demand. Unfortunately, there is scarcity of reported ecto-5'-nucleotidase inhibitors because of unavailability of simple, fast and efficient methods to study its inhibition. In this study, we have developed a very fast, reverse polarity capillary electrophoresis based method for screening of ecto-5'-nucleotidase inhibitors. Both EOF and electrophoretic mobility were maintained in same direction by dynamically coating lining of capillary and applying negative voltage, resulting in appearance of both adenosine monophosphate (AMP) and adenosine peaks in less than two minutes...
May 18, 2018: Electrophoresis
https://www.readbyqxmd.com/read/29774413/alterations-in-histone-acetylation-following-exposure-to-60-co-%C3%AE-rays-and-their-relationship-with-chromosome-damage-in-human-lymphoblastoid-cells
#16
Xue-Lei Tian, Xue Lu, Jiang-Bin Feng, Tian-Jing Cai, Shuang Li, Mei Tian, Qing-Jie Liu
Chromosome damage is related to DNA damage and erroneous repair. It can cause cell dysfunction and ultimately induce carcinogenesis. Histone acetylation is crucial for regulating chromatin structure and DNA damage repair. Ionizing radiation (IR) can alter histone acetylation. However, variations in histone acetylation in response to IR exposure and the relationship between histone acetylation and IR-induced chromosome damage remains unclear. Hence, this study investigated the variation in the total acetylation levels of H3 and H4 in human lymphocytes exposed to 0-2 Gy 60 Co γ-rays...
May 17, 2018: Radiation and Environmental Biophysics
https://www.readbyqxmd.com/read/29774407/beta-blockers-and-chronic-heart-failure-patients-prognostic-impact-of-a-dose-targeted-beta-blocker-therapy-vs-heart-rate-targeted-strategy
#17
Anna Corletto, Hanna Fröhlich, Tobias Täger, Matthias Hochadel, Ralf Zahn, Caroline Kilkowski, Ralph Winkler, Jochen Senges, Hugo A Katus, Lutz Frankenstein
BACKGROUND: Beta blockers improve survival in patients with chronic systolic heart failure (CHF). Whether physicians should aim for target dose, target heart rate (HR), or both is still under debate. METHODS AND RESULTS: We identified 1,669 patients with systolic CHF due to ischemic heart disease or idiopathic dilated cardiomyopathy from the University Hospital Heidelberg and the Clinic of Ludwigshafen, Germany. All patients were treated with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker and had a history of CHF known for at least 6 months...
May 17, 2018: Clinical Research in Cardiology: Official Journal of the German Cardiac Society
https://www.readbyqxmd.com/read/29774044/identification-and-functional-characterization-of-sugarcane-invertase-inhibitor-shinh1-a-potential-candidate-for-reducing-pre-and-post-harvest-loss-of-sucrose-in-sugarcane
#18
Suresha G Shivalingamurthy, Raveendra Anangi, Sundaravelpandian Kalaipandian, Donna Glassop, Glenn F King, Anne L Rae
In sugarcane, invertase enzymes play a key role in sucrose accumulation and are also involved in futile reactions where sucrose is continuously degraded during the pre- and post-harvest period, thereby reducing sugar yield and recovery. Invertase inhibitor (INVINH) proteins play a key role in post-translation regulation of plant invertases through which sucrose hydrolysis is controlled. INVINH proteins are small (18 kDa) members of the pectin methylesterase inhibitor superfamily and they are moderately conserved across plants...
2018: Frontiers in Plant Science
https://www.readbyqxmd.com/read/29773653/inhibition-of-protein-arginine-methyltransferase-5-enhances-hepatic-mitochondrial-biogenesis
#19
Lei Huang, Jehnan Liu, Xiao-Ou Zhang, Katelyn Sibley, Sonia M Najjar, Mary M Lee, Joae Qiong Wu
Protein arginine methyltransferase 5 (PRMT5) regulates gene expression either transcriptionallyly by symmetric dimethylation of arginine residues on histones H4R3, H3R8 and H2AR3, or at the post-translational level by methylation of non-histone target proteins. While emerging evidence suggests that PRMT5 functions as an oncogene, its role in metabolic diseases is not well defined. We investigated the role of PRMT5 in promoting high fat-induced hepatic steatosis. High fat diet up-regulated PRMT5 levels in the liver, but not in other metabolically relevant tissues such as skeletal muscle or white and brown adipose tissue...
May 17, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29773554/nitidine-chloride-is-a-mechanism-based-inactivator-of-cyp2d6
#20
Xu Mao, Zi Xia Hu, Qian Wang, Na Zhang, Shen Zhi Zhou, Ying Peng, Jiang Zheng
Nitidine chloride (NC) is a benzophenanthridine alkaloid isolated from the roots of Zanthoxylum nitidum (Roxb.) DC, a widely used traditional herbal medicine. NC has been reported to reveal multiple pharmacologic properties. The inhibitory effects of NC on human cytochrome P450 enzymes were investigated in the present study. We found that NC caused time- and concentration-dependent inhibition of CYP2D6, and more than 50% of CYP2D6 activity was suppressed after 15 min incubation with NC at 100 μM in the primary incubation mixtures, with KI of 4...
May 17, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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