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https://www.readbyqxmd.com/read/28550802/mechanism-of-action-of-three-newly-registered-drugs-for-multiple-sclerosis-treatment
#1
REVIEW
Kaja Kasarełło, Agnieszka Cudnoch-Jędrzejewska, Andrzej Członkowski, Dagmara Mirowska-Guzel
Multiple sclerosis (MS) is a disease of suspected autoimmune origin leading to neurodegeneration. The disease pathomechanism is considered to be primarily based on neuroinflammation directed against myelin antigens caused by autoreactive T cells. MS etiology remains still unknown, which makes it difficult to create an efficient therapy, therefore, MS treatment targets mechanisms involved in disease pathology. In this review, we present the mechanism of action of three newly registered drugs for MS. Dimethyl fumarate (DMF) is an agent presenting a broad spectrum of action...
February 22, 2017: Pharmacological Reports: PR
https://www.readbyqxmd.com/read/28550653/phytochemical-profile-and-angiotensin-i-converting-enzyme-ace-inhibitory-activity-of-limonium-michelsonii-lincz
#2
Janar Jenis, Jeong Yoon Kim, Zia Uddin, Yeong Hun Song, Hyeong-Hwan Lee, Ki Hun Park
Members of the genus Limonium are widely used as medicinal herbs due to their health-promoting effects, such as an ability to improve blood circulation by inhibiting angiotensin I converting enzyme (ACE). While the potential of L. michelsonii Lincz. (a medicinal plant endemic to Kazakhstan) to inhibit ACE has been demonstrated, the inhibitory activities of its secondary metabolites have not been explored. In this work, the principal phenolic compounds (1-20) among these metabolites were isolated to determine the components responsible for ACE inhibition...
May 26, 2017: Journal of Natural Medicines
https://www.readbyqxmd.com/read/28550522/reduced-monocyte-adhesion-to-aortae-of-diabetic-plasminogen-activator-inhibitor-1-knockout-mice
#3
Ruozhi Zhao, Khuong Le, Mohammed H Moghadasian, Garry X Shen
OBJECTIVE AND DESIGN: To determine the requirement of plasminogen activator inhibitor-1-knockout (PAI-1) for monocyte adhesion in animals and cells under diabetic conditions. METHODS AND SUBJECTS: Monocyte adhesion assay, enzyme-linked immunosorbent assay, and Western blotting were used in analyzing samples from PAI-1-knockout (PAI-1-KO) mice or cultured human umbilical vein endothelial cells (HUVEC). TREATMENTS: Diabetes in PAI-1-KO and wild-type mice was induced by intraperitoneal injection of streptozotocin (STZ)...
May 26, 2017: Inflammation Research: Official Journal of the European Histamine Research Society ... [et Al.]
https://www.readbyqxmd.com/read/28550123/essential-role-for-histone-deacetylase-11-hdac11-in-neutrophil-biology
#4
Eva Sahakian, Jie Chen, John J Powers, Xianghong Chen, Kamira Maharaj, Susan L Deng, Maritza Lienlaf, Hong Wei Wang, Fengdong Cheng, Andressa L Sodré, Allison Distler, Limin Xing, Patricio Perez-Villarroel, Sheng Wei, Alejandro Villagra, Ed Seto, Eduardo M Sotomayor, Pedro Horna, Javier Pinilla-Ibarz
Epigenetic changes in chromatin structure have been recently associated with the deregulated expression of critical genes in normal and malignant processes. HDAC11, the newest member of the HDAC family of enzymes, functions as a negative regulator of IL-10 expression in APCs, as previously described by our lab. However, at the present time, its role in other hematopoietic cells, specifically in neutrophils, has not been fully explored. In this report, for the first time, we present a novel physiologic role for HDAC11 as a multifaceted regulator of neutrophils...
May 26, 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28549901/degradation-of-proteoglycan-4-lubricin-by-cathepsin-s-potential-mechanism-for-diminished-ocular-surface-lubrication-in-sj%C3%A3-gren-s-syndrome
#5
Suresh C Regmi, Michael L Samsom, Miriam Heynen, Gregory D Jay, Benjamin D Sullivan, Sruthi Srinivasan, Barbara Caffery, Lyndon Jones, Tannin A Schmidt
Sjögren's syndrome (SS) is an autoimmune disease affecting the lacrimal and salivary glands with hallmark clinical symptoms of dry eye and dry mouth. Recently, markedly increased cathepsin S (CTSS) activity has been observed in the tears of SS patients. Proteoglycan 4 (PRG4), also known as lubricin, is an effective boundary lubricant that is naturally present on the ocular surface. While PRG4 is susceptible to proteolytic digestion, the potential effect of CTSS on PRG4 remains unknown. The objective of this study was to assess the ability of CTSS to enzymatically degrade purified PRG4, and PRG4 naturally present in human tears, and alter ocular surface boundary lubricating properties...
May 23, 2017: Experimental Eye Research
https://www.readbyqxmd.com/read/28549802/design-synthesis-and-biological-evaluation-of-novel-androst-3-5-diene-3-carboxylic-acid-derivatives-as-inhibitors-of-5%C3%AE-reductase-type-1-and-2
#6
Kejing Lao, Jie Sun, Chong Wang, Weiting Lyu, Boshen Zhou, Ruheng Zhao, Qian Xu, Qidong You, Hua Xiang
5α-Reductase is a key enzyme responsible for dihydrotestosterone biosynthesis and has been recognized as an important target for discovering new drugs against benign prostatic hyperplasia (BPH). In this study, a series of novel steroidal androst-3,5-diene-3-carboxylic acids have been designed and synthesized. Biological evaluations were performed on their 5α-reductase inhibitory activities by both in vitro enzyme inhibition assay and in vivo by prostate weighing method. Results showed that most of them displayed excellent 5α-reductase inhibitory potency...
May 23, 2017: Steroids
https://www.readbyqxmd.com/read/28549423/glyoxalase-1-expression-is-associated-with-an-unfavorable-prognosis-of-oropharyngeal-squamous-cell-carcinoma
#7
Nele Kreycy, Christiane Gotzian, Thomas Fleming, Christa Flechtenmacher, Niels Grabe, Peter Plinkert, Jochen Hess, Karim Zaoui
BACKGROUND: Glyoxalase 1 is a key enzyme in the detoxification of reactive metabolites such as methylglyoxal and induced Glyoxalase 1 expression has been demonstrated for several human malignancies. However, the regulation and clinical relevance of Glyoxalase 1 in the context of head and neck squamous cell carcinoma has not been addressed so far. METHODS: Argpyrimidine modification as a surrogate for methylglyoxal accumulation and Glyoxalase 1 expression in tumor cells was assessed by immunohistochemical staining of tissue microarrays with specimens from oropharyngeal squamous cell carcinoma patients (n = 154)...
May 26, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28549333/endoplasmic-reticulum-er-stress-and-camp-pka-pathway-mediated-zn-induced-hepatic-lipolysis
#8
Yu-Feng Song, Christer Hogstrand, Chuan-Chuan Wei, Kun Wu, Ya-Xiong Pan, Zhi Luo
The present study was performed to determine the effect of Zn exposure influencing endoplasmic reticulum (ER) stress, explore the underlying molecular mechanism of Zn-induced hepatic lipolysis in a fish species of significance for aquaculture, yellow catfish Pelteobagrus fulvidraco. We found that waterborne Zn exposure evoked ER stress and unfolded protein response (UPR), and activated cAMP/PKA pathway, and up-regulated hepatic lipolysis. The increase in ER stress and lipolysis were associated with activation of cAMP/PKA signaling pathway...
May 23, 2017: Environmental Pollution
https://www.readbyqxmd.com/read/28549219/design-synthesis-and-properties-of-a-potent-inhibitor-of-pseudomonas-aeruginosa-deacetylase-lpxc
#9
Grazia Piizzi, David T Parker, Yunshan Peng, Markus Rolf Dobler, Anup Patnaik, Som Wattanasin, Eugene Liu, Francois Lenoir, Jill Nunez, John Kerrigan, David McKenney, Colin S Osborne, Donghui Yu, Leanne Lanieri, Jade Bojkovic, JoAnne Dzink-Fox, Maria-Dawn Lilly, Elizabeth R Sprague, Yipin Lu, Hongming Wang, Srijan Ranjitkar, Bing Wang, Meir Glick, Lawrence G Hamann, Ruben Tommasi, Xia Yang, Charles R Dean
Over the past several decades the frequency of antibacterial resistance in hospitals, including multi-drug resistance (MDR) and its association with serious infectious diseases, has increased at alarming rates. Pseudomonas aeruginosa is a leading cause of nosocomial infections, and resistance to virtually all approved antibacterial agents is emerging in this pathogen. To address the need for new agents to treat MDR P. aeruginosa, we focused on inhibiting the first committed step in the biosynthesis of lipid A, the deacetylation of uridyldiphospho-3-O-(R-hydroxydecanoyl)-N-acetylglucosamine by the enzyme LpxC...
May 26, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28548959/identification-of-the-histone-lysine-demethylase-kdm4a-jmjd2a-as-a-novel-epigenetic-target-in-m1-macrophage-polarization-induced-by-oxidized-ldl
#10
Xue Wang, Siqing Wang, Gang Yao, Dehai Yu, Kexin Chen, Qian Tong, Long Ye, Chuan Wu, Yue Sun, Haixia Li, Dirk M Hermann, Thorsten R Döppner, Fengyan Jin, Yun Dai, Jiang Wu
Oxidized low density lipoprotein (oxLDL) induces macrophage activation, an event essential for atherosclerosis. Emerging evidence supports that epigenetic regulation plays important roles in macrophage activation and function. However, it remains unclear which epigenetic modulator is responsible for oxLDL-induced macrophage activation. Here, we identify for the first time KDM4A (JMJD2A) as an epigenetic modifying enzyme that controls oxLDL-induced pro-inflammatory M1 polarization of macrophages. OxLDL triggered M1 polarization of murine and human macrophages, characterized by expression of iNOS and robust production of inflammatory cytokines (e...
May 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28548950/enolase-1-stimulates-glycolysis-to-promote-chemoresistance-in-gastric-cancer
#11
Xiaoling Qian, Wenxia Xu, Jinye Xu, Qiqi Shi, Jiaqiu Li, Yu Weng, Zhinong Jiang, Lifeng Feng, Xian Wang, Jianwei Zhou, Hongchuan Jin
Chemotherapy is the major choice for the cancer treatment of early and advanced stages. However, intrinsic or acquired drug resistance significantly restricts the clinical efficacy of chemotherapy. It is critical to develop novel approaches to detect and overcome drug resistance. In this study, we demonstrated that accelerated glycolysis played a pivotal role in both intrinsic and acquired cisplatin-resistance of gastric cancer cells. The metabolic reprogramming of cisplatin-resistant cells was characterized by increased glycolysis dependence...
May 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28548833/structure-activity-relationship-for-small-molecule-inhibitors-of-nicotinamide-n-methyltransferase
#12
Harshini Neelakantan, Hua-Yu Wang, Virginia Vance, Jonathan D Hommel, Stanton F McHardy, Stanley J Watowich
Nicotinamide N-methyltransferase (NNMT) is a fundamental cytosolic biotransforming enzyme that catalyzes the N-methylation of endogenous and exogenous xenobiotics. We have identified small molecule inhibitors of NNMT with >1000-fold range of activity and developed comprehensive structure-activity relationships (SARs) for NNMT inhibitors. Screening of N-methylated quinolinium, isoquinolinium, pyrididium, and benzimidazolium/benzothiazolium analogs resulted in the identification of quinoliniums as a promising scaffold with very low micromolar (IC50 ~1 μM) NNMT inhibition...
May 26, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28548386/design-and-synthesis-of-atglistatin-derivatives-as-adipose-triglyceride-lipase-inhibitors
#13
Jiyu Jin, Suling Huang, Lei Wang, Ying Leng, Wei Lu
Adipose triglyceride lipase (ATGL) is a rate-limiting enzyme that mobilizes fatty acids from cellular triglyceride stores. Metabolic syndrome, which refers to a group of abnormalities that occur together and increase the risk of coronary artery disease, stroke, type-2 diabetes, and cachexia, can be treated using ATGL-specific inhibitors. Atglistatin (1) is the first small-molecule inhibitor of ATGL. In this study, we designed and synthesized 29 Atglistatin derivatives and evaluated their inhibition of forskolin-stimulated lipolysis in 3T3-L1 adipocytes as an indicator of their potential to inhibit ATGL in adipose tissues...
May 26, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28548283/novel-selective-phosphodiesterase-type-1-inhibitors-cause-vasodilatation-and-lower-blood-pressure-in-rats
#14
Morten Laursen, Lilliana Beck, Jan Kehler, Claus Tornby Christoffersen, Christoffer Bundgaard, Susie Mogensen, Tomas Mow, Estefano Pinilla, Jakob Schöllhammer Knudsen, Elise Røge Hedegaard, Morten Grunnet, Ulf Simonsen
BACKGROUND AND PURPOSE: Phosphodiesterase enzymes (PDE1-11) break down cyclic nucleotides and are important in the regulation of the cardiovascular system. The purpose of the present study was to investigate the effect on the cardiovascular system of two novel selective PDE1 inhibitors, Lu AF41228 and Lu AF58027. EXPERIMENTAL APPROACH: We used rat mesenteric small arteries (internal diameters of 200-300 µm), RT-PCR and measurement of isometric wall tension. The effect of Lu AF41228 and Lu AF58027 on heart rate and blood pressure was assessed in both anesthetized and conscious male rats...
May 26, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28548030/everolimus-inhibited-multiple-isoforms-of-udp-glucuronosyltransferases-ugts
#15
Zuo Du, Guang Wang, Yun-Feng Cao, Cui-Min Hu, Kun Yang, Yong-Zhe Liu, Chun-Ze Zhang, Wei-Hua Zhang, Zhi-Tu Zhu, Hong-Zhi Sun, Xiao-Yu Sun, Mo Hong, Zhong-Ze Fang
1. Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) and has been clinically utilized to prevent the rejection of organ transplants. This study aims to determine the inhibition of everolimus on the activity of phase II drug-metabolizing enzymes UDP-glucuronosyltransferases (UGTs). 2. The results showed that 100 uM of everolimus exerted more than 80% inhibition towards UGT1A1, -1A3, and -2B7. UGT1A3 and UGT2B7 were selected to elucidate the inhibition mechanism, and in silico docking showed that hydrogen bonds and hydrophobic interactions mainly contributed to the strong binding of everolimus towards the activity cavity of UGT1A3 and UGT2B7...
May 26, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28547816/three-component-aminoalkylations-yielding-dihydronaphthoxazine-based-sirtuin-inhibitors-scaffold-modification-and-exploration-of-space-for-polar-side-chains
#16
Steffen Vojacek, Katja Beese, Zayan Alhalabi, Sören Swyter, Anja Bodtke, Carola Schulzke, Manfred Jung, Wolfgang Sippl, Andreas Link
Nonpolar derivatives of heterocyclic aromatic screening hits like the non-selective sirtuin inhibitor splitomicin tend to be poorly soluble in biological fluids. Unlike sp(3) -rich natural products, flat aromatic compounds are prone to stacking and often difficult to optimize into leads with activity in cellular systems. The aim of this work was to identify anchor points for the introduction of sp(3) -rich fragments with polar functional groups into the newly discovered active (IC50  = 5 μM) but nonpolar scaffold 1,2-dihydro-3H-naphth[1,2-e][1,3]oxazine-3-thione by a molecular modeling approach...
May 26, 2017: Archiv der Pharmazie
https://www.readbyqxmd.com/read/28546645/fluorination-at-the-4-position-alters-the-substrate-behavior-of-l-glutamine-and-l-glutamate-implications-for-positron-emission-tomography-of-neoplasias
#17
Thomas M Jeitner, Eva Kristoferson, Juan A Azcona, John T Pinto, Clint Stalnecker, Jon W Erickson, Hank F Kung, Jianyong Li, Karl Ploessl, Arthur J L Cooper
Two 4-fluoro-L-glutamine diastereoisomers [(2S,4R)-4-FGln, (2S,4S)-4-FGln] were previously developed for positron emission tomography. Label uptake into two tumor cell types was greater with [(18)F](2S,4R)-4-FGln than with [(18)F](2S,4S)-4-FGln. In the present work we investigated the enzymology of two diastereoisomers of 4-FGln, two diastereoisomers of 4-fluoroglutamate (4-FGlu) (potential metabolites of the 4-FGln diastereoisomers) and another fluoro-derivative of L-glutamine [(2S,4S)-4-(3-fluoropropyl)glutamine (FP-Gln)]...
December 2016: Journal of Fluorine Chemistry
https://www.readbyqxmd.com/read/28546425/the-first-crystal-structure-of-a-family-129-glycoside-hydrolase-from-a-probiotic-bacterium-reveals-critical-residues-and-metal-co-factors
#18
Mayo Sato, Dorothee Liebschner, Yusuke Yamada, Naohiro Matsugaki, Takatoshi Arakawa, Siobhan S Wills, Mitchell Hattie, Keith A Stubbs, Tasuku Ito, Toshiya Senda, Hisashi Ashida, Shinya Fushinobu
The α-N-acetylgalactosaminidase from the probiotic bacterium Bifidobacterium bifidum (NagBb) belongs to the glycoside hydrolase (GH) family 129 and hydrolyzes the glycosidic bond of Tn antigen (GalNAcα1-Ser/Thr). NagBb is involved in assimilation of O-glycans on mucin glycoproteins by B. bifidum in the human gastrointestinal tract, but its catalytic mechanism has remained elusive because of a lack of sequence homology around putative catalytic residues and of other structural information. Here we report the X-ray crystal structure of NagBb, representing the first GH129 family structure, solved by the single-wavelength anomalous dispersion method based on sulfur atoms of the native protein...
May 25, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28545814/carboxylated-aurone-derivatives-as-potent-inhibitors-of-xanthine-oxidase
#19
Oksana V Muzychka, Oleksandr L Kobzar, Antonina V Popova, Mykhaylo S Frasinyuk, Andriy I Vovk
Xanthine oxidase is a potential target for treatment of hyperuricemia and gout. In this study, a number of A- and B-ring carboxylated aurone derivatives were synthesized and evaluated for their ability to inhibit xanthine oxidase in vitro. According to the results obtained, two different ranges of inhibitory activity were observed. The aurones with carboxylic acid group at the 4'-position of B-ring were found to be potent inhibitors of the enzyme with IC50 values in the low micromolar range. The effects of these compounds were about 50 fold higher than of A-ring modified aurones with carboxymethoxy group at the 6-position...
May 6, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28545803/impact-of-a-multidisciplinary-heart-failure-postdischarge-management-clinic-on-medication-adherence
#20
Lingyun Lu, Cynthia A Jackevicius, Noelle K de Leon, Alberta L Warner, Donald S Chang, Freny Vaghaiwalla Mody
PURPOSE: Disease management programs have been associated with improved adherence to heart failure (HF) medications. However, there remain limited data on the benefit of a comprehensive multidisciplinary HF postdischarge management (PDM) clinic that promptly follows HF-related hospitalization on evidence-based HF medication adherence. OBJECTIVE: The aim of this study was to evaluate the effects of an HF-PDM clinic on adherence to evidence-based HF medication therapy...
May 22, 2017: Clinical Therapeutics
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