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https://www.readbyqxmd.com/read/28432980/discovery-of-potential-inhibitor-against-human-acetylcholinesterase-a-molecular-docking-and-molecular-dynamics-investigation
#1
Surya Pratap Singh, Dwijendra Gupta
Alzheimer's disease (AD) is a progressive neurodegenerative disease of central nervous system among elderly people. Human acetylcholinesterase (hAChE), an important enzyme in neuronal signaling, is responsible for the degradation of acetylcholine which in turn prevents the post synaptic signal transmissions. hAChE has been an attractive target of drug discovery for the search of therapeutics against AD. In the recent past hAChE has become hot target for the investigation of new potential therapeutics. We performed virtual screening of entire database against hAChE...
April 12, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/28432973/methane-explosion-suppression-characteristics-based-on-the-nahco3-red-mud-composite-powders-with-core-shell-structure
#2
Yan Wang, Yi-Shen Cheng, Ming-Gao Yu, Yao Li, Jian-Liang Cao, Li-Gang Zheng, Hong-Wei Yi
The NaHCO3/red-mud (RM) composite powders were successfully prepared by the solvent-anti-solvent method for methane explosion suppression. The RM was used as a carrier, and the NaHCO3 was used as a loaded inhibitor. The NaHCO3/RM composite powders showed a special core-shell structure and excellent endothermic performance. The suppression properties of NaHCO3/RM composite for 9.5% CH4 explosion were tested in a 20L spherical explosion vessel and a 5L Perspex duct. The results showed that the NaHCO3/RM composite powders displayed a much better suppression property than the pure RM or NaHCO3 powders...
April 12, 2017: Journal of Hazardous Materials
https://www.readbyqxmd.com/read/28432959/molecular-dynamics-simulation-studies-of-novel-%C3%AE-lactamase-inhibitor
#3
Farhan Ul Haq, Asma Abro, Saad Raza, Klaus R Liedl, Syed Sikander Azam
New Delhi Metallo-β-Lactamase-1 (NDM-1) has drawn great attention due to its diverse antibiotic resistant activity. It can hydrolyze almost all clinically available β-lactam antibiotics. To inhibit the activity of NDM-1 a new strategy is proposed using computational methods. Molecular dynamics (MD) simulations are used to analyze the molecular interactions between selected inhibitor candidates and NDM-1 structure. The enzyme-ligand complex is subject to binding free energy calculations using MM(PB/GB)SA methods...
April 4, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28432946/design-and-synthesis-of-sulfonamide-substituted-diphenylpyrimidines-sfa-dppys-as-potent-bruton-s-tyrosine-kinase-btk-inhibitors-with-improved-activity-toward-b-cell-lymphoblastic-leukemia
#4
He Liu, Menghua Qu, Lina Xu, Xu Han, Changyuan Wang, Xiaohong Shu, Jihong Yao, Kexin Liu, Jinyong Peng, Yanxia Li, Xiaodong Ma
A new series of diphenylpyrimidine derivatives (SFA-DPPYs) were synthesized by introducing a functional sulfonamide into the C-2 aniline moiety of pyrimidine template, and then were biologically evaluated as potent Bruton's tyrosine kinase (BTK) inhibitors. Among these molecules, inhibitors 10c, 10i, 10j and 10k displayed high potency against the BTK enzyme, with IC50 values of 1.18 nM, 0.92 nM, 0.42 nM and 1.05 nM, respectively. In particular, compound 10c could remarkably inhibit the proliferation of the B lymphoma cell lines at concentrations of 6...
April 14, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28432840/detection-of-egfr-mutations-in-patients-with-non-small-cell-lung-cancer-by-high-resolution-melting-comparison-with-other-methods
#5
Carlos Martínez-Carretero, Fernando Iguaz Pascual, Antonio Rus, Ivan Bernardo
BACKGROUND: The discovery of mutations in the epidermal growth factor receptor gene (EGFR) related to the clinical response to tyrosine kinase inhibitors, has transformed the management of non-small cell lung cancer (NSCLC). Several methods have been developed for determination of mutations in EGFR, with different sensitivity and potential ability to detect a different number of mutations. METHODS: We developed a screening method by high resolution melting (HRM) to detect EGFR mutations, and compared the results of 123 fixed in formalin and paraffin embedded (FFPE) tumor tissue samples with the detection of mutations by allele-specific PCR...
April 22, 2017: Clinical Chemistry and Laboratory Medicine: CCLM
https://www.readbyqxmd.com/read/28432815/immunoassays-for-the-quantification-of-alk-and-phosphorylated-alk-support-the-evaluation-of-on-target-alk-inhibitors-in-neuroblastoma
#6
Elizabeth R Tucker, Jennifer R Tall, Laura S Danielson, Sharon Gowan, Yann Jamin, Simon P Robinson, Udai Banerji, Louis Chesler
Targeted inhibition of Anaplastic Lymphoma Kinase (ALK) is a successful approach for the treatment of many ALK-aberrant malignancies, however the presence of resistant mutations necessitates both the development of more potent compounds and pharmacodynamic methods with which to determine their efficacy. We describe immunoassays designed to quantitate phosphorylation of ALK, and their use in preclinical models of neuroblastoma, a pediatric malignancy in which gain-of-function ALK mutations predict a poor overall outcome to conventional treatment...
April 22, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28432808/mechanism-of-the-vasorelaxant-effect-induced-by-trans-4-methyl-%C3%AE-nitrostyrene-a-synthetic-nitroderivative-in-rat-thoracic-aorta
#7
Taylena Maria Teófilo, Loeste Arruda-Barbosa, Jussara Mathyelle Rodrigues-Silva, Joyce Karen Lima Vale, Rosivaldo Dos Santos Borges, Gloria Pinto Duarte, Pedro Jorge Caldas Magalhães, Saad Lahlou
Mechanisms underlying the vasorelaxant effects of trans-4-methyl-β-nitrostyrene (T4MeN) were studied in rat aortic rings. In endothelium-intact preparations, T4MeN fully and similarly relaxed contractions induced by phenylephrine (PHE) (IC50 = 61.41 [35.40-87.42] μM) and KCl (IC50 = 83.50 [56.63-110.50] μM). The vasorelaxant effect of T4MeN was unchanged by endothelium removal, pretreatment with L-NAME, indomethacin, tetraethylammonium, ODQ or MDL-12,330A. Under Ca(2+) -free conditions, T4MeN significantly reduced with a similar potency: (i) phasic contractions induced by PHE, but not by caffeine; (ii) contractions due to CaCl2 in aortic preparations stimulated with PHE (in the presence of verapamil) or high KCl; (iii) contractions evoked by the restoration of external Ca(2+) levels after depletion of intracellular Ca(2+) stores in the presence of thapsigargin...
April 22, 2017: Clinical and Experimental Pharmacology & Physiology
https://www.readbyqxmd.com/read/28432778/cross-species-studies-of-cognition-relevant-to-drug-discovery-a-translational-approach
#8
REVIEW
T W Robbins
This Review advances the case that bidirectional, cross-species translation of findings from experimental animals to and from humans is an important strategy for drug discovery. Animal models of mental disorders require appropriate behavioural or cognitive outcome variables that can be generalized cross-species. One example is the treatment of impulsive behaviour in attention deficit hyperactivity disorder (ADHD) with stimulant drugs. Performance on the stop signal reaction task as an index of impulsivity is improved both in healthy human volunteers and in patients with adult ADHD by stimulant drugs and also by the selective noradrenergic reuptake blocker atomoxetine...
April 22, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28432754/intraclass-differences-in-the-risk-of-hospitalisazion-for-heart-failure-among-type-2-diabetic-patients-initiating-a-dipeptydil-peptidase-4-inhibitor-or-a-sulphonylurea-results-from-the-osmed-health-db-registry
#9
Gian Paolo Fadini, Stefania Saragoni, Pierluigi Russo, Luca Degli Esposti, Saula Vigili de Kreutzenberg, Mario Melazzini, Angelo Avogaro
AIMS: Heart failure (HF) is frequent in type 2 diabetes (T2D) and several glucose-lowering medications may increase HF risk. In the SAVOR-TIMI trial, patients on Saxagliptin experienced a 27% higher risk of hospitalisation for HF (HHF). In a retrospective study on 127,555 patients, we showed that DPP-4i therapy was associated with a lower HHF risk than sulphonylurea (SU) therapy. We herein re-analyzed such data to evaluate intraclass differences among DPP-4i and SU. MATERIALS AND METHODS: We included T2D patients initiating DPP-4i or SU alone or in combination with metformin...
April 21, 2017: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/28432752/incretin-based-glucose-lowering-medications-and-the-risk-for-acute-pancreatitis-and-or-pancreatic-cancer-risk-reassuring-data-from-cardio-vascular-outcome-trials
#10
Michael A Nauck, Juris J Meier, Wolfgang E Schmidt
Incretin-based medications (glucagon-like peptide-1 [GLP-1] receptor agonists and inhibitors of dipeptidyl peptidase-4 [DPP-4] are glucose-lowering drugs approved and introduced after 2006 (1). Although both classes of drugs appeared to be relatively safe based on results from clinical trials and standard animal toxicology studies, epidemiological data (2, 3) and histological findings (4) in genetically modified rodents exposed to such agents have raised concern that pancreatitis and pancreatic cancer may be long-term risks associated with this therapy...
April 22, 2017: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/28432726/combination-therapy-with-glp-1-receptor-agonist-and-sglt2-inhibitor
#11
REVIEW
Ralph A DeFronzo
The SGLT2 inhibitors (SGLTi) and glucagon-like-1 receptor agonists (GLP-1 RAs) effectively reduce HbA1c, but via very different mechanisms, making them an effective duet for combination therapy. Recently, drugs in both of these antidiabetic classes have been shown to reduce cardiovascular events, most likely by different mechanisms. SGLT2i appear to exert their CV protective actions by hemodynamic effects, while GLP-1 RAs work via anti-atherogenic/anti-inflammatory mechanisms, raising the possibility that combined therapy with these two classes may produce additive CV benefits...
April 22, 2017: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/28432716/deciphering-tacrolimus-induced-toxicity-in-pancreatic-%C3%AE-cells
#12
J Triñanes, A E Rodriguez-Rodriguez, Y Brito, A Wagner, A P J De Vries, G Cuesto, A Acebes, E Salido, A Torres, E Porrini
β-cell transcription factors like: FoxO1, MafA, PDX-1, NeuroD, are dysfunctional in type 2 diabetes (T2DM). PTDM resembles T2DM and reflects interaction between pre-transplant insulin resistance and immunosuppressants, mainly calcineurin inhibitors. We evaluated the effect of tacrolimus, cyclosporine-A and metabolic stressors (glucose+palmitate) on insulinoma β-cells (INS-1) in vitro and in pancreata of obese and lean Zucker rats. Cells were cultured for five days with 100μM palmitate and 22mM glucose; cyclosporin-A (250ng/mL) or tacrolimus (15ng/mL) were added the last 48h...
April 22, 2017: American Journal of Transplantation
https://www.readbyqxmd.com/read/28432707/suberoylanilide-hydroxamic-acid-a-novel-histone-deacetylase-inhibitor-improves-the-development-and-acetylation-level-of-miniature-porcine-handmade-cloning-embryos
#13
J M Sun, K Q Cui, Z P Li, X R Lu, Z F Xu, Q Y Liu, B Huang, D S Shi
Histone deacetylase inhibitors (HDACis) can change the histone acetylation and significantly enhance the developmental competence of the pre-implantation SCNT embryo. To select a proper histone deacetylase inhibitor to improve the success rate and potentially developmental ability of handmade cloning (HMC) embryos of miniature porcine, we compared the effect of two histone deacetylase inhibitors (SAHA vs. VPA) on HMC embryo development, their histone acetylation level and the expression level of relevant genes...
April 22, 2017: Reproduction in Domestic Animals, Zuchthygiene
https://www.readbyqxmd.com/read/28432691/tenapanor-administration-and-the-activity-of-the-h-coupled-transporter-pept1-in-healthy-volunteers
#14
Susanne Johansson, David P Rosenbaum, Johan Palm, Bergur Stefansson, Mikael Knutsson, Eleanor A Lisbon, Constanze Hilgendorf
AIM: Tenapanor (RDX5791/AZD1722), an inhibitor of gastrointestinal Na(+) /H(+) exchanger NHE3, is being evaluated for the treatment of patients with constipation-predominant irritable bowel syndrome and the treatment of hyperphosphataemia in patients with chronic kidney disease on dialysis. By reducing intestinal H(+) secretion, inhibition of NHE3 by tenapanor could indirectly affect H(+) -coupled transporter activity, leading to drug-drug interactions. We investigated the effect of tenapanor on the activity of the H(+) -coupled peptide transporter PepT1 via assessment of the pharmacokinetics of cefadroxil - a compound transported by PepT1 - in healthy volunteers...
April 22, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28432648/rationale-for-new-checkpoint-inhibitor-combinations-in-melanoma-therapy
#15
Mario Mandalà, Carlo Tondini, Barbara Merelli, Daniela Massi
The use of monoclonal antibodies that block immunologic checkpoints, which mediate adaptive immune resistance, has revolutionized the treatment of metastatic melanoma patients. Specifically, targeting single immune suppressive molecules such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4), or programmed cell death protein 1 (PD-1) expressed on T cells or its primary ligand, programmed cell death ligand 1 (PD-L1), resulted in pronounced clinical benefit for a subset of melanoma patients. Although single-agent immune checkpoint inhibitor therapy has demonstrated promising clinical activity in metastatic melanoma patients, there is still a significant proportion of patients who show primary resistance to these therapies...
April 21, 2017: American Journal of Clinical Dermatology
https://www.readbyqxmd.com/read/28432646/is-there-a-role-for-ivabradine-in-the-contemporary-management-of-patients-with-chronic-heart-failure-in-academic-and-community-heart-failure-clinics-in-canada
#16
Sherryn Roth, Carlos Fernando, Sadia Azeem, Gordon W Moe
INTRODUCTION: In patients with heart failure (HF) and reduced ejection fraction, increased heart rate (HR) is an independent risk factor for adverse outcomes. In systolic HF treatment with the If inhibitor ivabradine trial (SHIFT), Ivabradine improved survival when added to conventional treatment including β-blockers. However, the extent of benefit in the real world is unclear. We examined the characteristics of patients on guideline-directed therapy and determined who had SHIFT-like characteristics...
April 21, 2017: Advances in Therapy
https://www.readbyqxmd.com/read/28432610/left-versus-right-does-location-matter-for-refractory-metastatic-colorectal-cancer-patients-in-phase-1-clinical-trials
#17
Sukeshi Patel Arora, Norma S Ketchum, Joel Michalek, Jonathon Gelfond, Devalingam Mahalingam
PURPOSE: Location of the primary tumor is prognostic and predictive of efficacy with VEGF-inhibitors (I) versus EGFR-I given first-line to metastatic colorectal cancer (mCRC) patients. However, little is known regarding the effect of location on prognosis and prediction in refractory mCRC. We assessed the efficacy of VEGF-I and EGFR-I in regards to location of the primary tumor in patients with refractory mCRC enrolled in early phase studies. METHODS: A historical cohort analysis of mCRC patients, including 44 phase I trials our institution, from March 2004 to September 2012...
April 22, 2017: Journal of Gastrointestinal Cancer
https://www.readbyqxmd.com/read/28432600/potentially-inappropriate-antihypertensive-prescriptions-to-elderly-patients-results-of-a-prospective-observational-study
#18
Paola H Ponte Márquez, Olga H Torres, Anonio San-José, Xavier Vidal, Antonia Agustí, Francesc Formiga, Alfonso López-Soto, Nieves Ramírez-Duque, Antonio Fernández-Moyano, Juana Garcia-Moreno, Juan A Arroyo, Domingo Ruiz
INTRODUCTION: Previous studies of antihypertensive treatment of older patients have focused on blood pressure control, cardiovascular risk or adherence, whereas data on inappropriate antihypertensive prescriptions to older patients are scarce. OBJECTIVES: The aim of the study was to assess inappropriate antihypertensive prescriptions to older patients. METHODS: An observational, prospective multicentric study was conducted to assess potentially inappropriate prescription of antihypertensive drugs, in patients aged 75 years and older with arterial hypertension (HTN), in the month prior to hospital admission, using four instruments: Beers, Screening Tool of Older Person's Prescriptions (STOPP), Screening Tool to Alert Doctors to the Right Treatment (START) and Assessing Care of Vulnerable Elders 3 (ACOVE-3)...
April 21, 2017: Drugs & Aging
https://www.readbyqxmd.com/read/28432589/expression-and-function-of-abcg2-and-xiap-in-glioblastomas
#19
Ivette F Emery, Archana Gopalan, Stephanie Wood, Kin-Hoe Chow, Chiara Battelli, Joshy George, Hagen Blaszyk, Jeffrey Florman, Kyuson Yun
Despite multimodal treatment that includes surgery, radiation and chemotherapy, virtually all glioblastomas (GBM) recur, indicating that these interventions are insufficient to eradicate all malignant cells. To identify potential new therapeutic targets in GBMs, we examined the expression and function of proteins that are associated with therapy resistance and cancer cell survival. We measured the expression of eight such proteins in 50 GBM samples by immunohistochemistry and analyzed patient survival. We report that GBM patients with high expression of ABCG2 (also called BCRP) or XIAP at the protein level had worse survival than those with low expression...
April 21, 2017: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/28432555/rotundarpene-inhibits-tnf-%C3%AE-induced-activation-of-the-akt-mtor-and-nf-%C3%AE%C2%BAb-pathways-and-the-jnk-and-p38-associated-with-production-of-reactive-oxygen-species
#20
Arum Kim, Yoon Jeong Nam, Yong Kyoo Shin, Min Sung Lee, Dong Suep Sohn, Chung Soo Lee
Ilex Rotunda Thunb has been shown to have anti-inflammatory and antioxidant effects. In human keratinocytes, we investigated the effect of rotundarpene (4-caffeoyl-3-methyl-but-2-ene-1,4-diol) on the TNF-α-stimulated production of inflammatory mediators in relation to the Akt, mTOR, and NF-κB pathways, and the JNK and p38-MAPK. Rotundarpene, Akt inhibitor, Bay 11-7085, rapamycin, and N-acetylcysteine inhibited the TNF-α-stimulated production of cytokines and chemokines, increase in the levels of p-Akt and mTOR, activation of NF-κB, and production of reactive oxygen species in keratinocytes...
April 21, 2017: Molecular and Cellular Biochemistry
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