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https://www.readbyqxmd.com/read/27914365/developing-piperlongumine-directed-glutathione-s-transferase-inhibitors-by-an-electrophilicity-based-strategy
#1
Hai-Bo Wang, Xiao-Ling Jin, Jia-Fang Zheng, Fu Wang, Fang Dai, Bo Zhou
We report a case of successful design of glutathione S-transferase (GST) inhibitors via a natural product-inspired and electrophilicity-based strategy. Based on this strategy, a novel piperlongumine analog (PL-13) bearing a para-trifluoromethyl group and an α-chlorine on its aromatic and lactam rings, respectively, surfaced as a promising GST inhibitor, thereby overcoming cisplatin resistance in lung cancer A549 cells.
November 15, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27914364/structure-based-exploration-and-exploitation-of-the-s4-subsite-of-norovirus-3cl-protease-in-the-design-of-potent-and-permeable-inhibitors
#2
Anushka C Galasiti Kankanamalage, Yunjeong Kim, Athri D Rathnayake, Vishnu C Damalanka, Pathum M Weerawarna, Sean T Doyle, Amer F Alsoudi, D M Padmasankha Dissanayake, Gerald H Lushington, Nurjahan Mehzabeen, Kevin P Battaile, Scott Lovell, Kyeong-Ok Chang, William C Groutas
Human noroviruses are the primary cause of epidemic and sporadic acute gastroenteritis. The worldwide high morbidity and mortality associated with norovirus infections, particularly among the elderly, immunocompromised patients and children, constitute a serious public health concern. There are currently no approved human vaccines or norovirus-specific small-molecule therapeutics or prophylactics. Norovirus 3CL protease has recently emerged as a potential therapeutic target for the development of anti-norovirus agents...
November 14, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27914363/new-insights-into-the-sar-and-drug-combination-synergy-of-2-quinolin-4-yloxy-acetamides-against-mycobacterium-tuberculosis
#3
Bruno Couto Giacobbo, Kenia Pissinate, Valnês Rodrigues-Junior, Anne Drumond Villela, Estêvão Silveira Grams, Bruno Lopes Abbadi, Fernanda Teixeira Subtil, Nathalia Sperotto, Rogério Valim Trindade, Davi Fernando Back, Maria Martha Campos, Luiz Augusto Basso, Pablo Machado, Diógenes Santiago Santos
2-(Quinolin-4-yloxy)acetamides have been described as potent and selective in vitro inhibitors of Mycobacterium tuberculosis (Mtb) growth. Herein, a new series of optimized compounds were found to demonstrate highly potent antitubercular activity, with minimum inhibitory concentration (MIC) values against drug-susceptible and drug-resistant Mycobacterium tuberculosis strains in the submicromolar range. Furthermore, the most active compounds had no apparent toxicity to mammalian cells, and they showed intracellular activities similar to those of isoniazid and rifampin in a macrophage model of Mtb infection...
November 23, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27914362/an-overview-of-the-binding-models-of-fgfr-tyrosine-kinases-in-complex-with-small-molecule-inhibitors
#4
REVIEW
Weiyan Cheng, Mixiang Wang, Xin Tian, Xiaojian Zhang
The fibroblast growth factor receptor (FGFR) family receptor tyrosine kinase (RTK) includes four structurally related members, termed as FGFR1, FGFR2, FGFR3, and FGFR4. Given its intimate role in the progression of several solid tumors, excessive FGFR signaling provides an opportunity for anticancer therapy. Along with extensive pharmacological studies validating the therapeutic potential of targeting the FGFRs for cancer treatment, co-crystal structures of FGFRs/inhibitors are continuously coming up to study the mechanism of actions and explore new inhibitors...
November 25, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27914344/evaluation-of-thymus-vulgaris-plant-extract-as-an-eco-friendly-corrosion-inhibitor-for-stainless-steel-304-in-acidic-solution-by-means-of-electrochemical-impedance-spectroscopy-electrochemical-noise-analysis-and-density-functional-theory
#5
A Ehsani, M G Mahjani, M Hosseini, R Safari, R Moshrefi, H Mohammad Shiri
Inhibition performance of Thymus vulgaris plant leaves extract (thyme) as environmentally friendly (green) inhibitor for the corrosion protection of stainless steel (SS) type 304 in 1.0molL(-1) HCl solution was studied by potentiodynamic polarization, electrochemical impedance (EIS) and electrochemical noise measurements (EN) techniques. The EN data were analyzed with FFT technique to make the spectral power density plots. The calculations were performed by MATLAB 2014a software. Geometry optimization and calculation of the structural and electronic properties of the molecular system of inhibitor have been carried out using UB3LYP/6-311++G(∗∗) level...
November 16, 2016: Journal of Colloid and Interface Science
https://www.readbyqxmd.com/read/27914297/long-term-efficacy-and-safety-of-vildagliptin-add-on-therapy-in-type-2-diabetes-mellitus-with-insulin-treatment
#6
Ippei Kanazawa, Ken-Ichiro Tanaka, Masakazu Notsu, Sayuri Tanaka, Nobuaki Kiyohara, Sayo Koike, Yuko Yamane, Yuko Tada, Motofumi Sasaki, Mika Yamauchi, Toshitsugu Sugimoto
BACKGROUND: The use of dipeptidyl peptidase (DPP)-4 inhibitors in patients with type 2 diabetes treated with insulin may be beneficial. However, the long-term efficacy and safety of vildagliptin add-on therapy in these patients remains unclear. SUBJECTS AND METHODS: A total of 73 patients with type 2 diabetes treated with insulin were randomly assigned to receive either add-on therapy of vildagliptin (n=37) or conventional therapy without DPP-4 inhibitors (n=36) for glucose control...
November 20, 2016: Diabetes Research and Clinical Practice
https://www.readbyqxmd.com/read/27914215/lysine-specific-demethylase-1-lsd1-inhibitor-s2101-induces-autophagy-via-the-akt-mtor-pathway-in-skov3-ovarian-cancer-cells
#7
Shujun Feng, Ye Jin, Mengjiao Cui, Jianhua Zheng
BACKGROUND S2101 is one of the most potent LSD1 inhibitors, which can inhibit ovarian cancer cells viability. This study aimed to detect the mechanism behind the anticancer properties of S2101 in SKOV3 ovarian cells. MATERIAL AND METHODS Cell viability was tested by Cell Counting Kit-8 (CCK-8) assay. Cellular apoptosis and autophagy were evaluated by flow cytometric analysis using Annexin-V/PI staining methods and Green fluorescent protein (GFP)-fused-LC3 (GFP-LC3), respectively. Western blotting was performed for analyzing the Bax, Bcl-2, mTOR, p- mTOR, p62, LC3-I, LC3-II, AKT, and p-AKT protein expression...
December 3, 2016: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/27914096/successful-treatment-of-multiple-in-transit-melanomas-on-the-leg-with-intensity-modulated-radiotherapy-and-immune-checkpoint-inhibitors-report-of-two-cases
#8
Taku Fujimura, Yumi Kambayashi, Sadanori Furudate, Takanori Hidaka, Yota Sato, Kayo Tanita, Hisayuki Tono, Akira Tsukada, Akira Hashimoto, Setsuya Aiba
Because the efficacy rates of monotherapy with immune checkpoint inhibitors such as nivolumab or ipilimumab are not sufficient, to enhance the antitumor effects of these reagents is of great interest among dermato-oncologists. In this report, we describe two cases of multiple in-transit metastatic melanomas on the leg successfully treated with intensity-modulated radiotherapy (IMRT) using a CyberKnife in combination with ipilimumab or nivolumab. Our cases suggested that IMRT could enhance the antitumor effects of immune checkpoint inhibitors in patients with multiple in-transit melanomas...
December 3, 2016: Journal of Dermatology
https://www.readbyqxmd.com/read/27914058/osprey-predicts-resistance-mutations-using-positive-and-negative-computational-protein-design
#9
Adegoke Ojewole, Anna Lowegard, Pablo Gainza, Stephanie M Reeve, Ivelin Georgiev, Amy C Anderson, Bruce R Donald
Drug resistance in protein targets is an increasingly common phenomenon that reduces the efficacy of both existing and new antibiotics. However, knowledge of future resistance mutations during pre-clinical phases of drug development would enable the design of novel antibiotics that are robust against not only known resistant mutants, but also against those that have not yet been clinically observed. Computational structure-based protein design (CSPD) is a transformative field that enables the prediction of protein sequences with desired biochemical properties such as binding affinity and specificity to a target...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27914004/hybrid-receptor-bound-mm-gbsa-per-residue-energy-based-pharmacophore-modelling-enhanced-approach-for-identification-of-selective-lta4h-inhibitors-as-potential-anti-inflammatory-drugs
#10
Patrick Appiah-Kubi, Mahmoud Soliman
Leukotriene A4 hydrolase has been identified as an enzyme with dual anti- and pro-inflammatory role, thus, the conversion of leukotriene to leukotriene B4 in the initiation stage of inflammation and the removal of the chemotactic Pro-Gly-Pro tripeptide. These findings make leukotriene A4 hydrolase an attractive drug target: suggesting an innovative approach towards the identification and design of novel class of compounds that can selectively inhibit leukotriene B4 synthesis while sparing the aminopeptidase activity...
December 2, 2016: Cell Biochemistry and Biophysics
https://www.readbyqxmd.com/read/27914001/subtilosin-prevents-biofilm-formation-by-inhibiting-bacterial-quorum-sensing
#11
Ammar Algburi, Saskia Zehm, Victoria Netrebov, Anzhelica B Bren, Vladimir Chistyakov, Michael L Chikindas
Subtilosin, the cyclic lantibiotic protein produced by Bacillus subtilis KATMIRA1933, targets the surface receptor and electrostatically binds to the bacterial cell membrane. In this study, subtilosin was purified using ammonium sulfate ((NH4)2SO4) precipitation and purified via column chromatography. Subtilosin's antibacterial minimum and sub-minimum inhibitory concentrations (MIC and sub-MIC) and anti-biofilm activity (biofilm prevention) were established. Subtilosin was evaluated as a quorum sensing (QS) inhibitor in Gram-positive bacteria using Fe(III) reduction assay...
December 2, 2016: Probiotics and Antimicrobial Proteins
https://www.readbyqxmd.com/read/27913953/neuroinflammation-induced-downregulation-of-hippocampacal-neuregulin-1-erbb4-signaling-in-the-parvalbumin-interneurons-might-contribute-to-cognitive-impairment-in-a-mouse-model-of-sepsis-associated-encephalopathy
#12
Rong Gao, Mu-Huo Ji, Da-Peng Gao, Run-Hua Yang, Shao-Gang Zhang, Jian-Jun Yang, Jin-Chun Shen
Sepsis-associated encephalopathy (SAE) is a common complication associated with poor prognosis in septic patients, but the underlying mechanism remains unclear. We hypothesized that disturbed neuregulin 1 (NRG1)-ErbB4 signaling in the parvalbumin interneurons was involved in sepsis-induced cognitive impairment in a mouse model of SAE. The SAE model was induced by cecal ligation/perforation (CLP). Animals were randomly divided into the following six groups: sham + vehicle group, sham + NRG1 group, CLP + vehicle group, CLP + NRG1 group, CLP + NRG1 + AG1478 (ErbB4 inhibitor) group, and CLP + minocycline group...
December 2, 2016: Inflammation
https://www.readbyqxmd.com/read/27913948/branched-chain-amino-acids-administration-suppresses-endurance-exercise-related-activation-of-ubiquitin-proteasome-signaling-in-trained-human-skeletal-muscle
#13
Evgeny A Lysenko, Tatiana F Vepkhvadze, Egor M Lednev, Olga L Vinogradova, Daniil V Popov
We tested whether post exercise ingestion of branched-chain amino acids (BCAA < 10 g) is sufficient to activate signaling associated with muscle protein synthesis and suppress exercise-induced activation of mechanisms associated with proteolysis in endurance-trained human skeletal muscle. Nine endurance-trained athletes performed a cycling bout with and without BCAA ingestion (0.1 g/kg). Post exercise ACC(Ser79/222) phosphorylation (endogenous marker of AMPK activity) was increased (~3-fold, P < 0...
December 3, 2016: Journal of Physiological Sciences: JPS
https://www.readbyqxmd.com/read/27913894/use-and-effectiveness-of-tocilizumab-among-patients-with-rheumatoid-arthritis-an-observational-study-from-the-british-society-for-rheumatology-biologics-register-for-rheumatoid-arthritis
#14
Mari Kihara, Rebecca Davies, Lianne Kearsley-Fleet, Kath D Watson, Mark Lunt, Deborah P M Symmons, Kimme L Hyrich
The aims of the present study are to describe the characteristics of rheumatoid arthritis (RA) patients selected for tocilizumab (TCZ), compare the "real-world" effectiveness of TCZ and tumour necrosis factor inhibitors (TNFi) when used as a first biologic and assess the influence of past biologic exposure/concurrent methotrexate (MTX) therapy on post-TCZ treatment outcomes. The British Society for Rheumatology Biologics Register (BSRBR-RA) is a prospective cohort study following RA patients starting biologics in the UK...
December 2, 2016: Clinical Rheumatology
https://www.readbyqxmd.com/read/27913861/cxcl12-expression-and-pd-l1-expression-serve-as-prognostic-biomarkers-in-hcc-and-are-induced-by-hypoxia
#15
Alexander Semaan, Dimo Dietrich, Dominik Bergheim, Jörn Dietrich, Jörg C Kalff, Vittorio Branchi, Hanno Matthaei, Glen Kristiansen, Hans-Peter Fischer, Diane Goltz
Anti-PD-1 treatment increases anti-tumour immune responses in animal models of hepatocellular carcinoma (HCC). Sorafenib, the mainstay of treatment of HCC patients, however, leads to tumour hypoxia and thereby abrogates the efficacy of anti-PD-1 treatment. This served as a rationale to implement CXCR4 inhibition as adjunct to sorafenib and anti-PD-1 treatment in murine HCC models. We studied the relationship between tumour hypoxia, PD-L1 and CXCL12 expression in human HCC, aiming to test the rationale for triple therapy combining sorafenib, PD-1 immune checkpoint inhibitors and CXCR4 inhibitors...
December 2, 2016: Virchows Archiv: An International Journal of Pathology
https://www.readbyqxmd.com/read/27913845/mitogen-activated-protein-kinases-are-involved-in-hepatocanalicular-dysfunction-and-cholestasis-induced-by-oxidative-stress
#16
Flavia D Toledo, Cecilia L Basiglio, Ismael R Barosso, Andrea C Boaglio, Andrés E Zucchetti, Enrique J Sánchez Pozzi, Marcelo G Roma
In previous studies, we showed that the pro-oxidant model agent tert-butyl hydroperoxide (tBuOOH) induces alterations in hepatocanalicular secretory function by activating Ca(2+)-dependent protein kinase C isoforms (cPKC), via F-actin disorganization followed by endocytic internalization of canalicular transporters relevant to bile formation (Mrp2, Bsep). Since mitogen-activated protein kinases (MAPKs) may be downstream effectors of cPKC, we investigated here the involvement of the MAPKs of the ERK1/2, JNK1/2, and p38(MAPK) types in these deleterious effects...
December 2, 2016: Archives of Toxicology
https://www.readbyqxmd.com/read/27913816/genetic-ablation-or-pharmacologic-inhibition-of-autophagy-mitigated-nsaid-associated-gastric-damages
#17
Chan Young Ock, Jong-Min Park, Young-Min Han, Migyeong Jeong, Mi-Young Kim, Ho Jae Lee, Ki Baik Hahm
: Non-steroidal anti-inflammatory drug (NSAID)-associated endoplasmic reticulum (ER) stress (a cyclooxygenase-2-independent mechanism) and consequent autophagic cell death are responsible for NSAID-associated gastric damage. Therefore, alleviating cytotoxicity executed via ER stress and autophagy can be a strategy to prevent NSAID-associated gastric damage. Here, we explored whether genetic or pharmacologic inhibition of autophagy can mitigate NSAID-associated gastric damage in in vitro and in vivo models...
December 2, 2016: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/27913794/tlr-ligands-but-not-modulators-of-histone-modifiers-can-induce-the-complex-immune-response-pattern-of-endotoxin-tolerance-in-mammary-epithelial-cells
#18
Juliane Günther, Wolfram Petzl, Holm Zerbe, Hans-Joachim Schuberth, Hans-Martin Seyfert
Excessive stimulation of the TLR4 axis through LPS reduces the expression of some cytokine genes in immune cells, while stimulating the expression of immune defense genes during a subsequent bacterial infection. This endotoxin tolerance (ET) is mediated via epigenetic mechanisms. Priming the udder of cows with LPS was shown to induce ET in mammary epithelial cells (MEC), thereby protecting the udder against reinfection for some time. Seeking alternatives to LPS priming we tried to elicit ET by priming MEC with either lipopeptide (Pam2CSK4) via the TLR2/6 axis or inhibitors of histone-modifying enzymes...
December 1, 2016: Innate Immunity
https://www.readbyqxmd.com/read/27913793/inflammatory-signaling-pathways-induced-by-helicobacter-pylori-in-primary-human-gastric-epithelial-cells
#19
Cong Tri Tran, Magali Garcia, Martine Garnier, Christophe Burucoa, Charles Bodet
Inflammatory signaling pathways induced by Helicobacter pylori remain unclear, having been studied mostly on cell-line models derived from gastric adenocarcinoma with potentially altered signaling pathways and nonfunctional receptors. Here, H. pylori-induced signaling pathways were investigated in primary human gastric epithelial cells. Inflammatory response was analyzed on chemokine mRNA expression and production after infection of gastric epithelial cells by H. pylori strains, B128 and B128ΔcagM, a cag type IV secretion system defective strain...
December 1, 2016: Innate Immunity
https://www.readbyqxmd.com/read/27913785/safety-assessment-of-alumina-and-aluminum-hydroxide-as-used-in-cosmetics
#20
Lillian C Becker, Ivan Boyer, Wilma F Bergfeld, Donald V Belsito, Ronald A Hill, Curtis D Klaassen, Daniel C Liebler, James G Marks, Ronald C Shank, Thomas J Slaga, Paul W Snyder, F Alan Andersen
This is a safety assessment of alumina and aluminum hydroxide as used in cosmetics. Alumina functions as an abrasive, absorbent, anticaking agent, bulking agent, and opacifying agent. Aluminum hydroxide functions as a buffering agent, corrosion inhibitor, and pH adjuster. The Food and Drug Administration (FDA) evaluated the safe use of alumina in several medical devices and aluminum hydroxide in over-the-counter drugs, which included a review of human and animal safety data. The Cosmetic Ingredient Review (CIR) Expert Panel considered the FDA evaluations as part of the basis for determining the safety of these ingredients as used in cosmetics...
November 2016: International Journal of Toxicology
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