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https://www.readbyqxmd.com/read/29055190/pinocembrin-attenuates-allergic-airway-inflammation-via-inhibition-of-nf-%C3%AE%C2%BAb-pathway-in-mice
#1
Xiaoyan Gu, Qian Zhang, Qiang Du, Hong Shen, Zhenghua Zhu
Pinocembrin, one of the primary flavonoids in propolis, possesses many biological activities, including anti-inflammation, anti-oxidation and immunoregulation. This study aimed to evaluate whether pinocembrin could attenuate ovalbumin (OVA)-induced allergic airway inflammation in mice and to explore the possible mechanism. BALB/c mice sensitized and challenged with OVA were administered intraperitoneally with pinocembrin. Airway inflammation and airway hyperresponsiveness were examined. T-helper type (Th) 2 cytokines in bronchoalveolar lavage fluid (BALF) and OVA-specific immunoglobulin E (IgE) in serum were determined...
October 18, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/29055187/an-effective-hiv-1-integrase-inhibitor-screening-platform-rationality-validation-of-drug-screening-conformational-mobility-and-molecular-recognition-analysis-for-pfv-integrase-complex-with-viral-dna
#2
Wenyi Du, Ke Zuo, Xin Sun, Wei Liu, Xiao Yan, Li Liang, Hua Wan, Fengzheng Chen, Jianping Hu
As an important target for the development of novel anti-AIDS drugs, HIV-1 integrase (IN) has been widely concerned. However, the lack of a complete accurate crystal structure of HIV-1 IN greatly blocks the discovery of novel inhibitors. In this work, an effective HIV-1 IN inhibitor screening platform, namely PFV IN, was filtered from all species of INs. Next, the 40.8% similarity with HIV-1 IN, as well as the high efficiency of virtual screening and the good agreement between calculated binding free energies and experimental ones all proved PFV IN is a promising screening platform for HIV-1 IN inhibitors...
October 5, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/29055186/designed-inhibitors-with-hetero-linkers-for-gastric-proton-pump-h-k-atpase-steered-molecular-dynamics-and-metadynamics-studies
#3
Kalyanashis Jana, Tusar Bandyopadhyay, Bishwajit Ganguly
Acid suppressant SCH28080 and its derivatives reversibly reduce acid secretion activity of the H(+),K(+)-ATPase in a K(+) competitive manner. The results on homologation of the SCH28080 by varying the linker chain length suggested the improvement in efficacy. However, the pharmacokinetic studies reveal that the hydrophobic nature of the CH2 linker units may not help it to function as a better acid suppressant. We have exploited the role of linker unit to enhance the efficacy of such reversible acid suppressant drug molecules using hetero linker, i...
October 12, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/29055152/predominance-of-regorafenib-over-sorafenib-restoration-of-membrane-bound-mica-in-hepatocellular-carcinoma-cells
#4
Jun Arai, Kaku Goto, Anthony Stephanou, Yasushi Tanoue, Sayaka Ito, Ryosuke Muroyama, Yasuo Matsubara, Ryo Nakagawa, Sayuri Morimoto, Yoshimi Kaise, Lay Ahyoung Lim, Hitoshi Yoshida, Naoya Kato
BACKGROUND AND AIM: The multi-kinase inhibitor regorafenib (REG) was recently demonstrated to be effective in patients with sorafenib (SOR)-resistant hepatocellular carcinoma (HCC). Interestingly, SOR is known to enhance the accumulation of membrane-bound MHC class I polypeptide-related sequence A (mMICA) in HCC cells, and to block production of soluble MICA (sMICA), an immunological decoy. In addition, MICA is associated with HCC in patients with chronic hepatitis C. We have now compared the impact of REG and SOR on MICA in HCC cells, as well as the immunotherapeutic implications thereof...
October 21, 2017: Journal of Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/29055144/increased-prevalence-of-diabetes-mellitus-in-bullous-pemphigoid-patients-during-the-last-decade
#5
Luca Fania, Giovanni Di Zenzo, Biagio Didona, Maria Antonietta Pilla, Luciano Sobrino, Annarita Panebianco, Cinzia Mazzanti, Damiano Abeni
Bullous pemphigoid (BP) is a rare autoimmune blistering disease. The association between BP and diabetes mellitus (DM) has been previously reported with inconsistent results(1-4) . Dipeptidyl peptidase (DPP)-IV inhibitors, approved in Europe by EMA in 2007 to treat type-2 DM, are antihyperglycemic drugs that could induce BP disease(5-9) . This article is protected by copyright. All rights reserved.
October 21, 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/29055107/targeting-class-i-histone-deacetylases-by-the-novel-small-molecule-inhibitor-4sc-202-blocks-oncogenic-hedgehog-gli-signaling-and-overcomes-smoothened-inhibitor-resistance
#6
Wolfgang Gruber, Elisabeth Peer, Dominik P Elmer, Christina Sternberg, Suzana Tesanovic, Pedro Del Burgo, Sonia Coni, Gianluca Canettieri, Daniel Neureiter, René Bartz, Hella Kohlhof, Daniel Vitt, Fritz Aberger
Aberrant activation of Hedgehog (HH)/GLI signaling is causally involved in numerous human malignancies, including basal cell carcinoma (BCC) and medulloblastoma. HH pathway antagonists targeting Smoothened (SMO), an essential effector of canonical HH/GLI signaling, show significant clinical success in BCC patients and have recently been approved for the treatment of advanced and metastatic BCC. However, rapid and frequent development of drug resistance to SMO inhibitors (SMOi) together with severe side effects caused by prolonged SMOi treatment call for alternative treatment strategies targeting HH/GLI signaling downstream of SMO...
October 21, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29055088/the-transcriptome-extracellular-proteome-and-active-secretome-of-agroinfiltrated-n-benthamiana-uncover-a-large-diverse-protease-repertoire
#7
Friederike Grosse-Holz, Steven Kelly, Svenja Blaskowski, Farnusch Kaschani, Markus Kaiser, Renier A L van der Hoorn
Infiltration of disarmed Agrobacterium tumefaciens into leaves of Nicotiana benthamiana (agroinfiltration) facilitates quick and safe production of antibodies, vaccines, enzymes and metabolites for industrial use (Molecular Farming). However, yield and purity of proteins produced by agroinfiltration are hampered by unintended proteolysis, restricting industrial viability of the agroinfiltration platform. Proteolysis may be linked to an immune response to agroinfiltration, but understanding of the response to agroinfiltration is limited...
October 21, 2017: Plant Biotechnology Journal
https://www.readbyqxmd.com/read/29055086/acute-mitogen-activated-protein-kinase-1-2-inhibition-improves-functional-recovery-and-vascular-changes-after-ischemic-stroke-in-rat-monitored-by-9-4-t-magnetic-resonance-imaging
#8
Maryam Mostajeran, Friedrich Wetterling, Frank W Blixt, Lars Edvinsson, Saema Ansar
AIM: The aim was to evaluate the beneficial effect of early mitogen activated protein kinase (MEK)1/2 inhibition administered at a clinical relevant time-point using the transient middle cerebral artery occlusion model and a dedicated rodent magnetic resonance imaging system (9.4T) to monitor cerebrovascular changes non-invasively for two weeks. METHOD: Transient middle cerebral artery occlusion was induced in male rats for two hours followed by reperfusion. The specific MEK1/2 inhibitor U0126 was administered i...
October 21, 2017: Acta Physiologica
https://www.readbyqxmd.com/read/29055025/contribution-of-equilibrative-nucleoside-transporter-s-to-intestinal-basolateral-and-apical-transports-of-anticancer-trifluridine
#9
Koichi Takahashi, Kunihiro Yoshisue, Masato Chiba, Takeo Nakanishi, Ikumi Tamai
Trifluridine (FTD) exhibits anticancer activities after its oral administration despite its hydrophilic nature. We previously reported that concentrative nucleoside transporter (CNT) 1 mediates the apical uptake of FTD in human small intestinal epithelial cells (HIECs). In the present study, FTD was also identified as a substrate for equilibrative nucleoside transporter (ENT) 1 and ENT2 in transporter gene-transfected cells. An immunocytochemical analysis revealed that ENT1 was expressed at the basolateral and apical membranes of HIECs...
October 20, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29055015/small-molecule%C3%A2-inhibition-of-pd-1-transcription-is-an-effective-alternative-to-antibody-blockade-in-cancer-therapy
#10
Alison Taylor, David Rothstein, Christopher Rudd
The impact of PD-1 immune checkpoint therapy prompts exploration of other strategies to downregulate PD-1 for cancer therapy. We previously showed that the serine/threonine kinase, glycogen synthase kinase GSK-3α/β, is a central regulator of PD-1 transcription in CD8+ T cells. Here, we show that the use of small molecule inhibitors of GSK-3α/β (GSK-3i) to reduce pcdc1 (PD-1) transcription and expression was as effective as anti-PD-1 and PDL-1 blocking antibodies in the control of B16 melanoma, or EL4 lymphoma, in primary tumor and metastatic settings...
October 20, 2017: Cancer Research
https://www.readbyqxmd.com/read/29055010/an-excitable-rho-gtpase-signaling-network-generates-dynamic-subcellular-contraction-patterns
#11
Melanie Graessl, Johannes Koch, Abram Calderon, Dominic Kamps, Soumya Banerjee, Tomáš Mazel, Nina Schulze, Jana Kathrin Jungkurth, Rutuja Patwardhan, Djamschid Solouk, Nico Hampe, Bernd Hoffmann, Leif Dehmelt, Perihan Nalbant
Rho GTPase-based signaling networks control cellular dynamics by coordinating protrusions and retractions in space and time. Here, we reveal a signaling network that generates pulses and propagating waves of cell contractions. These dynamic patterns emerge via self-organization from an activator-inhibitor network, in which the small GTPase Rho amplifies its activity by recruiting its activator, the guanine nucleotide exchange factor GEF-H1. Rho also inhibits itself by local recruitment of actomyosin and the associated RhoGAP Myo9b...
October 20, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29054992/suppression-of-adaptive-responses-to-targeted-cancer-therapy-by-transcriptional-repression
#12
Maria Rusan, Kapsok Li, Yvonne Li, Camilla L Christensen, Brian J Abraham, Nicholas Kwiatkowski, Kevin A Buczkowski, Bruno Bockorny, Ting Chen, Shuai Li, Kevin Rhee, Haikuo Zhang, Wankun Chen, Hideki Terai, Tiffany Tavares, Alan L Leggett, Tianxia Li, Yichen Wang, Tinghu Zhang, Tae-Jung Kim, Sook-Hee Hong, Neermala Poudel-Neupane, Michael Silkes, Tenny Mudianto, Li Tan, Takeshi Shimamura, Matthew Meyerson, Adam J Bass, Hideo Watanabe, Nathanael S Gray, Richard A Young, Kwok-Kin Wong, Peter S Hammerman
Acquired drug resistance is a major factor limiting the effectiveness of targeted cancer therapies. Targeting tumors with kinase inhibitors induces complex adaptive programs that promote the persistence of a fraction of the original cell population, facilitating the eventual outgrowth of inhibitor-resistant tumor clones. We show that the addition of a newly identified CDK7/12 inhibitor, THZ1, to targeted therapy enhances cell killing and impedes the emergence of drug-resistant cell populations in diverse cellular and in vivo cancer models...
October 20, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29054983/alk-inhibitor-response-in-melanomas-expressing-eml4-alk-fusions-and-alternate-alk-isoforms
#13
Kasey L Couts, Judson Bemis, Jacqueline A Turner, Stacey M Bagby, Danielle Murphy, Jason Christiansen, Jennifer D Hintzsche, Anh Le, Todd M Pitts, Keith Wells, Allison Applegate, Carol Amato, Pratik Multani, Edna Chow-Maneval, John J Tentler, Yiqun G Shellman, Matthew J Rioth, Aik-Choon Tan, Rene Gonzalez, Theresa Medina, Robert C Doebele, William A Robinson
Oncogenic ALK fusions occur in several types of cancer and can be effectively treated with ALK inhibitors; however, ALK fusions and treatment response have not been characterized in malignant melanomas. Recently, a novel isoform of ALK (ALKATI) was reported in 11% of melanomas but the response of melanomas expressing ALKATI to ALK inhibition has not been well characterized. We analyzed 45 melanoma patient-derived xenograft models for ALK mRNA and protein expression. ALK expression was identified in 11 out of 45 (24...
October 20, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29054982/discovery-of-a-highly-selective-nampt-inhibitor-that-demonstrates-robust-efficacy-and-improved-retinal-toxicity-with-nicotinic-acid-co-administration
#14
Genshi Zhao, Colin F Green, Yu-Hua Hui, Lourdes Prieto, Robert Shepard, Sucai Dong, Tao Wang, Bo Tan, Xueqian Gong, Lisa Kays, Robert L Johnson, Wenjuan Wu, Shobha Bhattachar, Miriam Del Prado, James R Gillig, Maria-Carmen Fernandez, Ken D Roth, Sean Buchanan, Ming-Shang Kuo, Sandaruwan Geeganage, Timothy P Burkholder
NAMPT, an enzyme essential for NAD+ biosynthesis, has been extensively studied as an anti-cancer target for developing potential novel therapeutics. Several NAMPT inhibitors have been discovered, some of which have been subjected to clinical investigations. Yet, the on-target hematological and retinal toxicities have hampered their clinical development. In this study, we report the discovery of a unique NAMPT inhibitor, LSN3154567. This molecule is highly selective, and has a potent and broad spectrum of anti-cancer activity...
October 20, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29054972/endothelial-function-is-impaired-in-the-cutaneous-microcirculation-of-adults-with-psoriasis-through-reductions-in-nitric-oxide-dependent-vasodilation
#15
Billie K Alba, Jody L Greaney, Sara B Ferguson, Lacy M Alexander
Psoriasis is an independent risk factor for cardiovascular disease, however the underlying mechanisms are not fully understood. Deficits in conduit arterial function are evident in psoriatics, but potential impairments in microcirculatory endothelial function remain unclear. We hypothesized that cutaneous microvascular dysfunction would be detectable in otherwise healthy psoriatics. Two intradermal microdialysis fibers were placed in (non-lesional) forearm skin of 9 patients with moderate plaque psoriasis (3M, 6F; 39±5 yr; 16±2 %BSA) and 9 non-psoriatic controls (3M, 6F; 38±5 yr) for local delivery of 1) lactated Ringer's (control) and 2) 10mM L-ascorbate (non-specific antioxidant)...
October 20, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/29054963/interleukin-12-mediated-expression-of-matrix-metalloproteinases-in-human-periodontal-ligament-fibroblasts-involves-in-nf-kappab-activation
#16
Li Miao, Shujun Zhan, Jiyan Liu
Interleukin (IL-12) is a pro-inflammatory cytokine, and its increased level correlates with the severity of periodontitis. However, its role in the pathogenesis of tooth periapical lesions is controversial and has not been completely clarified. This study aimed to investigate whether IL-12 affects the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in human periodontal ligament fibroblasts (hPDLFs). After treatment with IL-12 for different time, Real-time PCR and Western blotting were used to determine the mRNA and protein levels of MMP-1, MMP-2, MMP-3, MMP-9, MMP-13, TIMP-1 and TIMP-2, respectively...
October 20, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/29054936/a-case-of-autosplenectomy-associated-with-t-cell-checkpoint-inhibitor-treatment
#17
Rachel Delahunty, Margaret Lee, Mineesh Datta, Phillip Parente
No abstract text is available yet for this article.
October 19, 2017: BMJ Case Reports
https://www.readbyqxmd.com/read/29054928/the-type-ii-transmembrane-serine-protease-matriptase-cleaves-the-amyloid-precursor-protein-and-reduces-its-processing-to-%C3%AE-amyloid
#18
Erwan Lanchec, Antoine Désilets, François Béliveau, Anthony Flamier, Shaimaa Mahmoud, Gilbert Bernier, Denis Gris, Richard Leduc, Christine Lavoie
Recent studies have reported that many proteases, besides the canonical α-, β- and γ-secretases, cleave the amyloid precursor protein (APP) and modulate β amyloid (Aβ) peptide production. Moreover, specific APP isoforms contain Kunitz protease inhibitor (KPI) domains, which regulate the proteolytic activity of serine proteases. This prompted us to investigate the role of matriptase, a member of the type II transmembrane serine protease family, in APP processing. Using qRTPCR, we detected matriptase mRNA in several regions of the human brain, with an enrichment in neurons...
October 20, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29054922/protein-turnover-measurements-in-human-serum-by-serial-immunoaffinity-lc-ms-ms
#19
Vahid Farrokhi, Xiaoying Chen, Hendrik Neubert
BACKGROUND: The half-life of target proteins is frequently an important parameter in mechanistic pharmacokinetic and pharmacodynamic (PK/PD) modeling of biotherapeutics. Clinical studies for accurate measurement of physiologically relevant protein turnover can reduce the uncertainty in PK/PD model-based predictions, for example, of the therapeutic dose and dosing regimen in first-in-human clinical trials. METHODS: We used a targeted mass spectrometry work flow based on serial immunoaffinity enrichment of multiple human serum proteins from a [5,5,5-(2)H3]-L-leucine tracer pulse-chase study in healthy volunteers...
October 20, 2017: Clinical Chemistry
https://www.readbyqxmd.com/read/29054762/mir-34a-as-a-suppressor-enhance-the-susceptibility-of-gastric-cancer-cell-to-luteolin-by-directly-targeting-hk1
#20
Yan Zhou, Bao-Zhong Ding, Yun-Peng Lin, Hai-Bo Wang
Luteolin is a flavonoid compound derived from Lonicera japonica Thunb, which has been reported to exert anticancer effects on different types of tumors. miRNAs are a kind of endogenous non-coding small RNAs, which involved in occurrence and development of multi cancer, including miR-34a. However, the relationship between miR-34a and luteolin's susceptibility to cancer cells still remains unclear. In this study, we explored the roles of miR-34a and the effects of luteolin on GC cells as well as the underlying mechanism of miR-34a in mediating the susceptibility of GC cell to luteolin...
October 17, 2017: Gene
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