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https://www.readbyqxmd.com/read/29351078/asymmetric-peptidomimetics-containing-l-tartaric-acid-core-inhibit-the-aspartyl-peptidase-activity-and-growth-of-leishmania-amazonensis-promastigotes
#1
André L S Santos, Filipe P Matteoli, Leandro S Sangenito, Marta H Branquinha, Bruno A Cotrim, Gabriel O Resende
Aspartyl-type peptidases are promising chemotherapeutic targets in protozoan parasites. In the present work, we identified an aspartyl peptidase activity from the soluble extract of Leishmania amazonensis promastigotes, which cleaved the fluorogenic peptide 7-methoxycoumarin-4-acetyl-Gly-Lys-Pro-Ile-Leu-Phe-Phe-Arg-Leu-Lys(DNP)-D-Arg-amide (cathepsin D substrate) under acidic pH conditions at 37°C, showing a KM of 0.58 μM and Vmax of 129.87 fluorescence arbitrary units/s mg protein. The leishmanial aspartyl peptidase activity was blocked by pepstatin A (IC50 = 6...
March 26, 2018: Acta Parasitologica
https://www.readbyqxmd.com/read/29349512/photobiomodulation-induces-in-vitro-re-epithelialization-via-nitric-oxide-production
#2
Manuela Rizzi, Mario Migliario, Stelvio Tonello, Vincenzo Rocchetti, Filippo Renò
Photobiomodulation is a widely used tool in regenerative medicine thanks to its ability to modulate a plethora of physiological responses. Wound re-epithelialization is strictly regulated by locally produced chemical mediators, such as nitric oxide (NO), a highly reactive free radical generated by the nitric oxide synthase (NOS) enzymatic family. In this study, it has been hypothesized that a 980-nm low-level laser stimulation could increase NO production in human keratinocytes and that such event might be directly related to the re-epithelialization process...
January 18, 2018: Lasers in Medical Science
https://www.readbyqxmd.com/read/29348721/rare-ginsenoside-ia-synthesized-from-f1-by-cloning-and-overexpression-of-the-udp-glycosyltransferase-gene-from-bacillus%C3%A2-subtilis-synthesis-characterization-and-in%C3%A2-vitro-melanogenesis%C3%A2-inhibition-activity-in-bl6b16-cells
#3
Dan-Dan Wang, Yan Jin, Chao Wang, Yeon-Ju Kim, Zuly Elizabeth Jimenez Perez, Nam In Baek, Ramya Mathiyalagan, Josua Markus, Deok-Chun Yang
Background: Ginsenoside F1 has been described to possess skin-whitening effects on humans. We aimed to synthesize a new ginsenoside derivative from F1 and investigate its cytotoxicity and melanogenesis inhibitory activity in B16BL6 cells using recombinant glycosyltransferase enzyme. Glycosylation has the advantage of synthesizing rare chemical compounds from common compounds with great ease. Methods: UDP-glycosyltransferase (BSGT1) gene from Bacillus subtilis was selected for cloning...
January 2018: Journal of Ginseng Research
https://www.readbyqxmd.com/read/29348557/sensitizing-tumor-cells-to-conventional-drugs-hsp70-chaperone-inhibitors-their-selection-and-application-in-cancer-models
#4
Vladimir F Lazarev, Dmitry V Sverchinsky, Elena R Mikhaylova, Pavel I Semenyuk, Elena Y Komarova, Sergey A Niskanen, Alina D Nikotina, Anton V Burakov, Viktor G Kartsev, Irina V Guzhova, Boris A Margulis
Hsp70 chaperone controls proteostasis and anti-stress responses in rapidly renewing cancer cells, making it an important target for therapeutic compounds. To date several Hsp70 inhibitors are presented with remarkable anticancer activity, however their clinical application is limited by the high toxicity towards normal cells. This study aimed to develop assays to search for the substances that reduce the chaperone activity of Hsp70 and diminish its protective function in cancer cells. On our mind the resulting compounds alone should be safe and function in combination with drugs widely employed in oncology...
January 18, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29348442/a-neutral-ceramidase-nlncdase-is-involved-in-the-stress-responses-of-brown-planthopper-nilaparvata-lugens-st%C3%A3-l
#5
Xiao-Xiao Shi, Yuan-Jie Huang, Mahfuj-Ara Begum, Mu-Fei Zhu, Fei-Qiang Li, Min-Jing Zhang, Wen-Wu Zhou, Cungui Mao, Zeng-Rong Zhu
Ceramidases (CDases) are vital enzymes involved in the biosynthesis of sphingolipids, which are essential components of eukaryotic membranes. The function of these enzymes in insects, however, is poorly understood. We identified a neutral ceramidase (NlnCDase) from the brown planthopper, Nilaparvata lugens, one of the most destructive hemipteran pests of rice. The C12-ceramide was the most preferred substrate for the NlnCDase enzyme. The activity of the NlnCDase enzyme was highest in the neutral-pH range (pH 6...
January 18, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29345044/preclinical-characterisation-of-absorption-distribution-metabolism-and-excretion-properties-of-tak-063
#6
Kimio Tohyama, Miyako Sudo, Akio Morohashi, Suguru Kato, Junzo Takahashi, Yoshihiko Tagawa
TAK-063 is currently being developed to treat schizophrenia. In this study, we investigated the absorption, distribution, metabolism and excretion (ADME) properties of TAK-063 using several paradigms. Following oral administration of TAK-063 at 0.3 mg/kg, bioavailability of TAK-063 was 27.4% in rats and 49.5% in dogs with elimination half-lives of 3.1 hr in rats and 3.7 hr in dogs. TAK-063 is a highly permeable compound without P-glycoprotein (P-gp) or breast cancer resistance protein substrate liability and can be readily absorbed into systemic circulation via the intestine...
January 17, 2018: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29344818/dietary-chromium-picolinate-supplementation-affects-growth-whole-body-composition-and-gene-expression-related-to-glucose-metabolism-and-lipogenesis-in-juvenile-blunt-snout-bream-megalobrama-amblycephala
#7
Mingchun Ren, Ahmed Mokrani, Hualiang Liang, Ke Ji, Jun Xie, Xianping Ge, Bo Liu
An 11-week feeding trial was carried out to investigate the effects of supplemented chromium picolinate (Cr-Pic) on the growth, whole-body composition, and relative mRNA expression related to lipogenesis and glucose metabolism in juvenile blunt snout bream. Seven isonitrogenous and isoenergetic diets with graded Cr supplementation levels were fed to triplicate groups. The final weight (FW), feed conversion ratio (FCR), and specific growth rate (SGR) were improved with increasing dietary Cr supplementation levels up to 0...
January 18, 2018: Biological Trace Element Research
https://www.readbyqxmd.com/read/29344641/inhibition-of-rptor-overcomes-resistance-to-egfr-inhibition-in-triple-negative-breast-cancer-cells
#8
Kyu Sic You, Yong Weon Yi, Sahng-June Kwak, Yeon-Sun Seong
Triple-negative breast cancer (TNBC) cells frequently exhibit activated growth factor signaling and resistance to inhibitors for epidermal growth factor receptor (EGFR), despite the overexpression of EGFR protein, and this is associated with a malignant behavior and a poor prognosis. In this study, to elucidate the underlying mechanisms of resistance to EGFR inhibitor and identify inhibitors that exert a synergistic effect with EGFR inhibition, we examined the inhibitory effects of selected protein kinase inhibitors (PKIs) in combination with gefitinib on the viability of a mesenchymal stem-like (MSL) subtype TNBC cell line...
January 15, 2018: International Journal of Oncology
https://www.readbyqxmd.com/read/29344310/drug-repurposing-screening-identifies-tioconazole-as-an-atg4-inhibitor-that-suppresses-autophagy-and-sensitizes-cancer-cells-to-chemotherapy
#9
Pei-Feng Liu, Kun-Lin Tsai, Chien-Jen Hsu, Wei-Lun Tsai, Jin-Shiung Cheng, Hsueh-Wei Chang, Chung-Wai Shiau, Yih-Gang Goan, Ho-Hsing Tseng, Chih-Hsuan Wu, John C Reed, Lee-Wei Yang, Chih-Wen Shu
Background: Tumor cells require proficient autophagy to meet high metabolic demands and resist chemotherapy, which suggests that reducing autophagic flux might be an attractive route for cancer therapy. However, this theory in clinical cancer research remains controversial due to the limited number of drugs that specifically inhibit autophagy-related (ATG) proteins. Methods: We screened FDA-approved drugs using a novel platform that integrates computational docking and simulations as well as biochemical and cellular reporter assays to identify potential drugs that inhibit autophagy-required cysteine proteases of the ATG4 family...
2018: Theranostics
https://www.readbyqxmd.com/read/29343829/targeted-inhibitors-of-p-glycoprotein-increase-chemotherapeutic-induced-mortality-of-multidrug-resistant-tumor-cells
#10
Amila K Nanayakkara, Courtney A Follit, Gang Chen, Noelle S Williams, Pia D Vogel, John G Wise
Overexpression of ATP-binding cassette (ABC) transporters is often linked to multidrug resistance (MDR) in cancer chemotherapies. P-glycoprotein (P-gp) is one of the best studied drug transporters associated with MDR. There are currently no approved drugs available for clinical use in cancer chemotherapies to reverse MDR by inhibiting P-glycoprotein. Using computational studies, we previously identified several compounds that inhibit P-gp by targeting its nucleotide binding domain and avoiding its drug binding domains...
January 17, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29343546/p62-filaments-capture-and-present-ubiquitinated-cargos-for-autophagy
#11
Gabriele Zaffagnini, Adriana Savova, Alberto Danieli, Julia Romanov, Shirley Tremel, Michael Ebner, Thomas Peterbauer, Martin Sztacho, Riccardo Trapannone, Abul K Tarafder, Carsten Sachse, Sascha Martens
The removal of misfolded, ubiquitinated proteins is an essential part of the protein quality control. The ubiquitin-proteasome system (UPS) and autophagy are two interconnected pathways that mediate the degradation of such proteins. During autophagy, ubiquitinated proteins are clustered in a p62-dependent manner and are subsequently engulfed by autophagosomes. However, the nature of the protein substrates targeted for autophagy is unclear. Here, we developed a reconstituted system using purified components and show that p62 and ubiquitinated proteins spontaneously coalesce into larger clusters...
January 17, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29343520/evidence-for-the-isg15-specific-deubiquitinase-usp18-as-an-antineoplastic-target
#12
REVIEW
Lisa Maria Mustachio, Yun Lu, Masanori Kawakami, Jason Roszik, Sarah J Freemantle, Xi Liu, Ethan Dmitrovsky
Ubiquitination and ubiquitin-like posttranslational modifications (PTM) regulate activity and stability of oncoproteins and tumor suppressors. This implicates PTMs as antineoplastic targets. One way to alter PTMs is to inhibit activity of deubiquitinases (DUB) that remove ubiquitin or ubiquitin-like proteins from substrate proteins. Roles of DUBs in carcinogenesis have been intensively studied, yet few inhibitors exist. Prior work provides a basis for the ubiquitin-specific protease 18 (USP18) as an antineoplastic target...
January 17, 2018: Cancer Research
https://www.readbyqxmd.com/read/29342480/phenolic-compounds-as-arginase-inhibitors-new-insights-regarding-endothelial-dysfunction-treatment
#13
Bruno Rodrigo Minozzo, Daniel Fernandes, Flávio Luís Beltrame
Endothelial dysfunction is characterised by the low bioavailability of nitric oxide with a relevant negative impact on the nitric oxide/cGMP pathway. The loss of nitric oxide/cGMP signaling may be caused by an increased arginase activity. Plant-derived substances, especially polyphenols, are compounds that have the potential to inhibit arginase activity and they may represent an attractive therapeutic option to combat clinical outcomes related to endothelial dysfunction. An extensive review was carried out using all available data published in English in the Pubmed database, and without restriction regarding the year of publication...
January 17, 2018: Planta Medica
https://www.readbyqxmd.com/read/29342419/investigation-of-the-transport-of-xanthine-dehydrogenase-inhibitors-by-the-urate-transporter-abcg2
#14
Makiko Nakamura, Kyoko Fujita, Yu Toyoda, Tappei Takada, Hiroshi Hasegawa, Kimiyoshi Ichida
Hyperuricemia induces gout and kidney stones and accelerates the progression of renal and cardiovascular diseases. Adenosine 5'-triphosphate-binding cassette subfamily G member 2 (ABCG2) is a urate transporter, and common dysfunctional variants of ABCG2, non-functional Q126X (rs72552713) and semi-functional Q141K (rs2231142), are risk factors for hyperuricemia and gout. A recent genome wide association study suggested that allopurinol, a serum uric acid-lowering drug that inhibits xanthine dehydrogenase, is a potent substrate of ABCG2...
November 22, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29342140/atomic-structure-of-the-eukaryotic-intramembrane-ras-methyltransferase-icmt
#15
Melinda M Diver, Leanne Pedi, Akiko Koide, Shohei Koide, Stephen B Long
The maturation of RAS GTPases and approximately 200 other cellular CAAX proteins involves three enzymatic steps: addition of a farnesyl or geranylgeranyl prenyl lipid to the cysteine (C) in the C-terminal CAAX motif, proteolytic cleavage of the AAX residues and methylation of the exposed prenylcysteine residue at its terminal carboxylate. This final step is catalysed by isoprenylcysteine carboxyl methyltransferase (ICMT), a eukaryote-specific integral membrane enzyme that resides in the endoplasmic reticulum...
January 17, 2018: Nature
https://www.readbyqxmd.com/read/29341842/purification-characterization-of-fibrinolytic-protease-from-bacillus-amyloliquefaciens-mcc2606-and-analysis-of-fibrin-degradation-product-by-ms-ms
#16
Yogesh Devaraj, Savita Kumari Rajender, Prakash Motiram Halami
A serine protease with preference for fibrin protein was purified and characterized from B.amyloliquefaciens MCC2606, isolated from dosa batter. The protease was purified using ammonium sulphate precipitation, ion-exchange and gel filtration chromatography. The degradation activity of the protease towards the fibrin was significantly higher compared with other protein substrates in the study. The molecular weight of the CFR15-protease was estimated to be 32 kDa based on SDS-PAGE. The purified enzyme exhibited both fibrinolytic and fibrinogenolytic activity...
January 17, 2018: Preparative Biochemistry & Biotechnology
https://www.readbyqxmd.com/read/29341802/portulaca-oleracea-l-extract-enhances-glucose-uptake-by-stimulating-glut4-translocation-to-the-plasma-membrane-in-3t3-l1-adipocytes
#17
Jae Eun Park, Ji Soo Lee, Hyun Ah Lee, Ji Sook Han
This study investigated the effects of Portulaca oleracea L. extract on glucose uptake in 3T3-L1 adipocytes. P. oleracea extract (POE) markedly enhanced glucose uptake, which was caused by increased GLUT4 expression at the plasma membrane (PM) in 3T3-L1 adipocytes. This increase in PM-GLUT4 expression was associated with insulin receptor substrate-1 (IRS-1) phosphorylation, phosphatidylinositol 3-kinase (PI3K) activation, and Akt phosphorylation, and finally, enhanced intracellular glucose uptake. POE was not associated with protein kinase C (PKC)λ/ζ phosphorylation in the insulin signaling pathway, but did promote 5'-AMP-activated kinase (AMPK) phosphorylation...
January 17, 2018: Journal of Medicinal Food
https://www.readbyqxmd.com/read/29341308/stiffness-regulates-the-proliferation-and-osteogenic-odontogenic-differentiation-of-human-dental-pulp-stem-cells-via-the-wnt-signalling-pathway
#18
Nanxin Liu, Mi Zhou, Qi Zhang, Tao Zhang, Taoran Tian, Quanquan Ma, Changyue Xue, Shiyu Lin, Xiaoxiao Cai
OBJECTIVES: Researches showed that stiffness of the extracellular matrix can affect the differentiation of many stem cells. Dental pulp stem cells (DPSCs) are a promising type of adult stem cell. However, we know little about whether and how the behaviour of DPSCs is influenced by stiffness. MATERIALS AND METHODS: We carried out a study that cultured DPSCs on tunable elasticity polydimethylsiloxane substrates to investigate the influence on morphology, proliferation, osteogenic/odontogenic differentiation and its possible mechanism...
January 17, 2018: Cell Proliferation
https://www.readbyqxmd.com/read/29340974/inhibiting-6-phosphogluconate-dehydrogenase-selectively-targets-breast-cancer-through-ampk-activation
#19
Xiaoyu Yang, Xiaochun Peng, Jiangrong Huang
PURPOSE: 6-phosphogluconate dehydrogenase (6PGD), a key enzyme of the oxidative pentose phosphate pathway, is involved in tumor growth and metabolism. Although high 6PGD activity has been shown to be associated with poor prognosis, its role and therapeutic value in breast cancer remain unknown. METHODS: The levels and roles of 6PGD were analyzed in breast cancer cells and their normal counterparts. The underlying mechanisms of 6PGD's roles are also analyzed. RESULTS: We found that 6PGD is aberrantly activated in breast cancer as shown by its increased transcriptional and translational levels as well as enzyme activity in breast cancer tissues and cell lines compared to normal counterparts...
January 16, 2018: Clinical & Translational Oncology
https://www.readbyqxmd.com/read/29339398/assay-conditions-influence-affinities-of-rat-organic-cation-transporter-1-analysis-of-mutagenesis-in-the-modeled-outward-facing-cleft-by-measuring-effects-of-substrates-and-inhibitors-on-initial-uptake
#20
Valentin Gorboulev, Saba Rehman, Christoph Michael Albert, Ursula Roth, Marleen Julia Meyer, Mladen Vassielev Tzvetkov, Thomas Dieter Mueller, Hermann Koepsell
Effects of mutations in the modeled outward-open cleft of rat organic cation transporter 1 (rOCT1) on affinities of substrates and inhibitors were investigated. Human embryonic kidney (HEK) 293 cells were stably transfected with rOCT1 or rOCT1 mutants, and uptake of the substrates 1-methyl-4-phenylpyridinium+ (MPP+) and tetraethylammonium+ (TEA+) or inhibition of MPP+ uptake by the non-transported inhibitors tetrabutylammonium+ (TBuA+), tetrapentylammonium+ (TPeA+) and corticosterone was measured. Uptake measurements were performed on confluent cell layers using 2 min-incubation or in dissociated cells using incubation times of 1, 5, or 10 s...
January 16, 2018: Molecular Pharmacology
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