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https://www.readbyqxmd.com/read/29454290/ligand-based-computer-aided-drug-design-reveals-new-tropomycin-receptor-kinase-a-trka-inhibitors
#1
Rand Shahin, Iman Mansi, Lubna Swellmeen, Tahani Alwidyan, Nabil Al-Hashimi, Yaser Al-Qarar'h, Omar Shaheen
Targeting tropomycin kinase A (TrkA) by small molecule inhibitors is considered as a promising strategy for treating several human cancers. To achieve this goal, a ligand based QSAR model was applied using the Discovery studio 4.5 (DS 4.5). Hence, a total list of 161 TrkA inhibitors was investigated. The TrkA inhibitors were extensively explored to detect their optimal physicochemical properties and pharmacophoric binding modes, which were converted into numeric descriptors and allowed to compete within the context of the Genetic Function Algorithm (GFA) approximations to find the subset of terms that correlates best with the activity...
January 13, 2018: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/29454281/probing-the-%C3%AE-pocket-of-the-active-site-of-human-liver-glycogen-phosphorylase-with-3-c-%C3%AE-d-glucopyranosyl-5-4-substituted-phenyl-1-2-4-triazole-inhibitors
#2
Efthimios Kyriakis, Theodora G A Solovou, Sándor Kun, Katalin Czifrák, Béla Szőcs, László Juhász, Éva Bokor, George A Stravodimos, Anastassia L Kantsadi, Demetra S M Chatzileontiadou, Vassiliki T Skamnaki, László Somsák, Demetres D Leonidas
Human liver glycogen phosphorylase (hlGP), a key enzyme in glycogen metabolism, is a valid pharmaceutical target for the development of new anti-hyperglycaemic agents for type 2 diabetes. Inhibitor discovery studies have focused on the active site and in particular on glucopyranose based compounds with a β-1 substituent long enough to exploit interactions with a cavity adjacent to the active site, termed the β-pocket. Recently, C-β-d-glucopyranosyl imidazoles and 1, 2, 4-triazoles proved to be the best known glucose derived inhibitors of hlGP...
February 12, 2018: Bioorganic Chemistry
https://www.readbyqxmd.com/read/29454280/8-chrysoeriol-as-a-potential-bcl-2-inhibitor-triggers-apoptosis-of-sw1990-pancreatic-cancer-cells
#3
Yiwen Zhang, Zhimei Li, Qiuxia Min, Abulizi Palida, Yiyuan Zhang, Ruotian Tang, Lixia Chen, Hua Li
8-Chrysoeriol, a bioactive flavanoid, was firstly identified to bind directly to BCL-2 as BH3 mimetics by structure-based virtual ligand screening. And 3D docking model revealed the molecular basis of 8-Chrysoeriol targeting to BCL-2. The interaction between 8-Chrysoeriol and BCL-2 was further confirmed using Microscale Thermophoresis (MST) technique. Meanwhile, high expression level of antiapoptotic protein BCL-2 was detected in SW1990 pancreatic cancer cells and 8-Chrysoeriol showed obvious proapoptosis effect against SW1990 in vitro...
February 2, 2018: Bioorganic Chemistry
https://www.readbyqxmd.com/read/29454190/potholing-of-the-hydrophobic-heme-oxygenase-1-western-region-for-the-search-of-potent-and-selective-imidazole-based-inhibitors
#4
Loredana Salerno, Emanuele Amata, Giuseppe Romeo, Agostino Marrazzo, Orazio Prezzavento, Giuseppe Floresta, Valeria Sorrenti, Ignazio Barbagallo, Antonio Rescifina, Valeria Pittalà
Here we report the design, synthesis, and molecular modeling of new potent and selective imidazole-based HO-1 inhibitors in which the imidazole nucleus and the hydrophobic groups are linked by a phenylethanolic spacer. Most of the tested compounds showed a good inhibitor activity with IC 50 values in the low micromolar range, with two of them (1b and 1j) exhibiting also high selectivity toward HO-2. These results were obtained by the idea of potholing the entire volume of the principal hydrophobic western region with an appropriate ligand volume...
February 9, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29454172/toxicity-of-lanthanum-oxide-nanoparticles-to-the-fungus-moniliella-wahieum-y12-t-isolated-from-biodiesel
#5
Lin Zhang, Lingyan Zhou, Qing X Li, Hong Liang, Huaming Qin, Stephen Masutani, Brandon Yoza
Moniliella wahieum Y12 T , isolated from biodiesel was used as a model organism to assess the use of lanthanum oxide (La 2 O 3 ) (60-80 nm) and silver oxide (AgO) (10-40 nm) nanoparticles as potential fungal inhibitors. This is the first study to investigate the use of nanoscale La 2 O 3 as a eukaryotic bio-inhibitor. The AgO nanoparticles were relatively effective at inhibiting the growth of M. wahieum Y12 T . The half maximal effective concentration (EC 50 ) for AgO was 0.012 mg/mL as compared with 4.63 mg/mL of La 2 O 3 ...
February 8, 2018: Chemosphere
https://www.readbyqxmd.com/read/29454155/immune-checkpoint-inhibitors-in-non-small-cell-lung-cancer-nsclc-approaches-on-special-subgroups-and-unresolved-burning-questions
#6
REVIEW
J Remon, N Vilariño, N Reguart
Immune checkpoint inhibitors (ICIs) have been incorporated in the treatment strategy of advanced non-small cell lung cancer (NSCLC). Beyond the already approved indications in first- and second-line setting of advanced NSCLC, new data has recently emerged demonstrating its efficacy in locally advanced disease as maintenance after chemo-radiotherapy and currently several trials are also exploring its efficacy in earlier stages of the disease to evaluate whether these results could be extrapolated to the adjuvant setting...
February 8, 2018: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/29454096/jak-stat-inhibitors-and-other-small-molecule-cytokine-antagonists-for-the-treatment-of-allergic-disease
#7
REVIEW
Michael D Howell, Carolyn Fitzsimons, Paul Smith
OBJECTIVE: To provide an overview of janus kinase (JAK), chemoattractant receptor-homologous molecule expressed on T-helper 2 cells (CRTH2), and phosphodiesterase 4 (PDE4) inhibitors in allergic disorders. DATA SOURCES: PubMed literature review. STUDY SELECTIONS: Articles included in this review discuss the emerging mechanism of action of small molecule inhibitors and their utilization in atopic dermatitis (AD), asthma, and allergic rhinitis (AR)...
February 14, 2018: Annals of Allergy, Asthma & Immunology
https://www.readbyqxmd.com/read/29454094/synergistic-activity-of-bet-inhibitor-bi-894999-with-plk-inhibitor-volasertib-in-aml-in-vitro-and-in-vivo
#8
Ulrike Tontsch-Grunt, Dorothea Rudolph, Irene Waizenegger, Anke Baum, Daniel Gerlach, Harald Engelhardt, Melanie Wurm, Fabio Savarese, Norbert Schweifer, Norbert Kraut
Interactions between a new potent Bromodomain and extraterminal domain (BET) inhibitor BI 894999 and the polo-like kinase (PLK) inhibitor volasertib were studied in acute myeloid leukemia cell lines in vitro and in vivo. We provide data for the distinct mechanisms of action of these two compounds with a potential utility in AML based on gene expression, cell cycle profile and modulation of PD biomarkers such as MYC and HEXIM1. In contrast to BI 894999, volasertib treatment neither affects MYC nor HEXIM1 expression, but augments and prolongs the decrease of MYC expression caused by BI 894999 treatment...
February 14, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29454093/silencing-circular-rna-hsa_circ_0000977-suppresses-pancreatic-ductal-adenocarcinoma-progression-by-stimulating-mir-874-3p-and-inhibiting-plk1-expression
#9
Wen-Jie Huang, Yun-Chao Wang, Song-Song Liu, Jia-Li Yang, Shi-Xiang Guo, Li-Jiang Wang, Huai-Zhi Wang, Ying-Fang Fan
Circular RNAs (CircRNAs) are a novel type of endogenous noncoding RNAs that regulate target gene expression by interacting with microRNA (miRNA). Emerging evidence shows that dysregulation of circRNAs plays important roles in biological and pathological processes, including cancer development and progression. The functional role of circRNA in PDAC (pancreatic ductal adenocarcinoma) remains to be investigated. In this study, high throughput microarray assay revealed that hsa_circ_0000977 was aberrantly up-regulated in pancreatic cancer tissues; this was also validated by qRT-PCR...
February 14, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29454091/anlotinib-inhibits-angiogenesis-via-suppressing-the-activation-of-vegfr2-pdgfr%C3%AE-and-fgfr1
#10
Binyan Lin, Xiuming Song, Dawei Yang, Dongsheng Bai, Yuyuan Yao, Na Lu
Tumor cells recruit vascular endothelial cells and circulating endothelial progenitor cells to form new vessels to support their own growth and metastasis. VEGF, PDGF-BB and FGF-2 are three major pro-angiogenic factors and applied to promote angiogenesis. In this research, we demonstrated that anlotinib, a potent multi-tyrosine kinases inhibitor (TKI), showed a significant inhibitory effect on VEGF/PDGF-BB/FGF-2-induced angiogenesis in vitro and in vivo. Wound healing assay, chamber directional migration assay and tube formation assay indicated that anlotinib inhibited VEGF/PDGF-BB/FGF-2-induced cell migration and formation of capillary-like tubes in endothelial cells...
February 14, 2018: Gene
https://www.readbyqxmd.com/read/29454075/the-g-protein-coupled-p2y-6-receptor-promotes-colorectal-cancer-tumorigenesis-by-inhibiting-apoptosis
#11
Morgane Placet, Guillaume Arguin, Caroline M Molle, Jean-Philippe Babeu, Christine Jones, Julie C Carrier, Bernand Robaye, Sameh Geha, Francois Boudreau, Fernand-Pierre Gendron
Colorectal tumors are immersed in an array of tumor-promoting factors including extracellular nucleotides such as uridine 5'‑diphosphate (UDP). UDP is the endogenous agonist of the G protein-coupled P2Y 6 receptor (P2Y 6 R), which may contribute to the formation of a tumor-promoting microenvironment by coordinating resistance to apoptosis. Colorectal cancer (CRC) was chemically induced in P2ry6 knockout (P2ry6 -/- ) mice using azoxymethane and dextran sulfate sodium challenges. Mice were euthanatized and their tumor load determined...
February 14, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29454048/new-insights-into-the-molecular-characteristics-of-pulmonary-carcinoids-and-large-cell-neuroendocrine-carcinomas-and-the-impact-on-their-clinical-management
#12
REVIEW
J L Derks, N Leblay, S Lantuejoul, A M Dingemans, E J M Speel, L Fernandez-Cuesta
Carcinoids and large-cell neuroendocrine carcinomas (LCNEC) are rare neuroendocrine lung tumors. Here we provide an overview of the most updated data on the molecular characteristics of these diseases. Recent genomic studies showed that carcinoids generally contain a low mutational burden and few recurrently mutated genes. Most of the reported mutations occur in chromatin-remodeling genes (e.g. MEN1), and few affect genes of the PI3K-AKT-mTOR pathway. Aggressive disease has been related to chromothripsis, DNA-repair gene mutations, loss of OTP/CD44, and upregulation of RET gene expression...
February 14, 2018: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/29454047/renal-perivascular-adipose-tissue-form-and-function
#13
Carolina Baraldi A Restini, Alex Ismail, Ramya K Kumar, Robert Burnett, Hannah Garver, Gregory D Fink, Stephanie W Watts
Renal sympathetic activity affects blood pressure in part by increasing renovascular resistance via release of norepinephrine (NE) from sympathetic nerves onto renal arteries. Here we test the idea that adipose tissue adjacent to renal blood vessels, i.e. renal perivascular adipose tissue (RPVAT), contains a pool of NE which can be released to alter renal vascular function. RPVAT was obtained from around the main renal artery/vein of the male Sprague Dawley rats. Thoracic aortic PVAT and mesenteric PVAT also were studied as brown-like and white fat comparators respectively...
February 14, 2018: Vascular Pharmacology
https://www.readbyqxmd.com/read/29454024/development-of-an-in-vitro-screening-method-of-acute-cytotoxicity-of-the-pyrrolizidine-alkaloid-lasiocarpine-in-human-and-rodent-hepatic-cell-lines-by-increasing-susceptibility
#14
Kristina Forsch, Verena Schöning, Lucia Disch, Beate Siewert, Matthias Unger, Jürgen Drewe
ETHNOPHARMACOLOGICAL RELEVANCE: Pyrrolizidine alkaloids (PAs) are secondary plant ingredients formed in many plant species to protect against predators. PAs are generally considered acutely hepatotoxic, genotoxic and carcinogenic. Up to now, only few in vitro and in vivo investigations were performed to evaluate their relative toxic potential. AIM OF THE STUDY: The aim was to develop an in vitro screening method of their cytotoxicity. MATERIALS AND METHODS: Human and rodent hepatocyte cell lines (HepG2 and H-4-II-E) were used to assess cytotoxicity of the PA lasiocarpine...
February 14, 2018: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/29454012/immunologic-effects-of-chronic-administration-of-tofacitinib-a-janus-kinase-inhibitor-in-cynomolgus-monkeys-and-rats-comparison-of-juvenile-and-adult-responses
#15
Mark Collinge, Douglas J Ball, Christopher J Bowman, Andrea L Nilson, Zaher A Radi, W Mark Vogel
Tofacitinib, an oral Janus kinase (JAK) inhibitor for treatment of rheumatoid arthritis, targets JAK1, JAK3, and to a lesser extent JAK2 and TYK2. JAK1/3 inhibition impairs gamma common chain cytokine receptor signaling, important in lymphocyte development, homeostasis and function. Adult and juvenile cynomolgus monkey and rat studies were conducted and the impact of tofacitinib on immune parameters (lymphoid tissues and lymphocyte subsets) and function (T-dependent antibody response (TDAR), mitogen-induced T cell proliferation) assessed...
February 14, 2018: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/29454007/destruction-of-noradrenergic-terminals-increases-dopamine-concentration-and-reduces-dopamine-metabolism-in-the-medial-prefrontal-cortex
#16
Rita Gálosi, Zoltán Petykó, Veronika Kállai, Attila Tóth, Tamás Ollmann, László Péczely, Anita Kovács, Beata Berta, László Lénárd
Effects of destroyed noradrenergic (NE) innervation in the medial prefrontal cortex (mPFC) were examined on dopamine (DA) content and metabolism. 6-hydroxy-DOPA (6-OHDOPA) or 6-hydroxy-dopamine (6-OHDA) in combination with a potent DA reuptake inhibitor GBR 12935 or 6-OHDA were injected bilaterally into the mPFC in separate groups of animals. In addition, GBR 12935 or vehicle was injected into the mPFC in two other groups of animals as control experiments. NE and DA concentrations from postmortem tissue of the mPFC were measured using HPLC with electrochemical detection...
February 14, 2018: Behavioural Brain Research
https://www.readbyqxmd.com/read/29454001/brain-bioenergetics-in-rats-with-acute-hyperphenylalaninemia
#17
Nádia Weber Dimer, Bruna Klippel Ferreira, Jotele Fontana Agostini, Maria Luiza Gomes, Luiza Wilges Kist, Fernanda Malgarin, Milena Carvalho-Silva, Lara Mezari Gomes, Joyce Rebelo, Marisa Jádna Silva Frederico, Fátima Regina Mena Barreto Silva, Eduardo Pacheco Rico, Mauricio Reis Bogo, Emilio Luiz Streck, Gustavo Costa Ferreira, Patrícia Fernanda Schuck
Phenylketonuria (PKU) is a disorder of phenylalanine (Phe) metabolism caused by deficient phenylalanine hydroxylase activity. The deficiency results in increased levels of Phe and its metabolites in fluids and tissues of patients. PKU patients present neurological signals and symptoms including hypomyelination and intellectual deficit. This study assessed brain bioenergetics at 1 h after acute Phe administration to induce hyperphenylalaninemia (HPA) in rats. Wistar rats were randomized in two groups: HPA animals received a single subcutaneous administration of Phe (5...
February 14, 2018: Neurochemistry International
https://www.readbyqxmd.com/read/29453998/ctl14-a-recognition-receptor-induced-in-late-stage-larvae-modulates-anti-fungal-immunity-in-cotton-bollworm-helicoverpa-armigera
#18
Yang Cheng, Zhe Lin, Ju-Mei Wang, Long-Sheng Xing, Guang-Hua Xiong, Zhen Zou
C-type lectin (CTL) is usually considered as pattern recognition receptors in insect innate immunity. Here we found that CTL14 of Helicoverpa armigera was only activated in the fifth instar larvae not in the second instar by entomopathogen Beauveria bassiana infection. Recombinant CTL14 protein was found to form aggregates with zymosan and B. bassiana in vitro. Immunoprecipitation studies demonstrated that CTL14 interacted with serine proteinases (SP), serine proteinase inhibitor (serpin), prophenoloxidases (PPO) and vitellogenin (Vg) in the larval hemolymph...
February 14, 2018: Developmental and Comparative Immunology
https://www.readbyqxmd.com/read/29453982/glucagon-like-peptide-1-contributes-to-increases-abca1-expression-by-downregulating-mir-758-to-regulate-cholesterol-homeostasis
#19
Yue Yao, Qiang Li, Ping Gao, Wei Wang, Lili Chen, Jinchao Zhang, Yi Xu
Abnormal regulation of lipid metabolism is associated with type 2 diabetes mellitus (T2DM). GLP-1 as a new treatment for T2DM, has unique effects in modulating cholesterol homeostasis. However, the mechanism of this effect is largely missing. The aim of this study was to determine the effects of GLP-1 on cholesterol-induced lipotoxicity in hepatocytes and examine the underlying mechanisms. The cell viability was determined, and caspase-3 was used to detect the effects of GLP-1 on cholesterol-induced apoptosis...
February 14, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29453978/venlafaxine-prevents-morphine-antinociceptive-tolerance-the-role-of-neuroinflammation-and-the-l-arginine-nitric-oxide-pathway
#20
Mohammad Taghi Mansouri, Bahareh Naghizadeh, Behnam Ghorbanzadeh, Soheila Alboghobeish, Neda Amirgholami, Gholamreza Houshmand, Omar Cauli
Opioid-induced neuroinflammation and the nitric oxide (NO) signal-transduction pathway are involved in the development of opioid analgesic tolerance. The antidepressant venlafaxine (VLF) modulates NO in nervous tissues, and so we investigated its effect on induced tolerance to morphine, neuroinflammation, and oxidative stress in mice. Tolerance to the analgesic effects of morphine were induced by injecting mice with morphine (50 mg/kg) once a day for three consecutive days; the effect of co-administration of VLF (5 or 40 mg/kg) with morphine was similarly tested in a separate group...
February 14, 2018: Experimental Neurology
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