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https://www.readbyqxmd.com/read/28941392/liquid-phase-combinatorial-synthesis-of-1-2-5-trisubstituted-benzimidazole-derivatives-as-human-dhodh-inhibitors
#1
Nikum D Sitwala, Vivek K Vyas, Bhavesh C Variya, Snehal S Patel, Chirag C Mehta, Dharmraj N Rana, Manjunath D Ghate
The synthesis of 1,2,5-trisubstituted benzimidazole derivatives was carried out using liquid phase combinatorial approach using soluble polymer assisted support (PEG5000). Synthesised compounds were characterised by FTIR, ESI-MS, (1)H NMR and (13)C NMR. The purity of compounds was confirmed with HPLC analysis. Compounds were also docked into the binding site of human dihydroorotate dehydrogenase (hDHODH). The synthesised compounds were screened for hDHODH enzyme inhibition assay using brequinar as standard compound...
August 30, 2017: Bioorganic Chemistry
https://www.readbyqxmd.com/read/28939533/comparative-mapping-of-on-targets-and-off-targets-for-the-discovery-of-anti-trypanosomatid-folate-pathway-inhibitors
#2
Joanna Panecka-Hofman, Ina Pöhner, Francesca Spyrakis, Talia Zeppelin, Flavio Di Pisa, Lucia Dello Iacono, Alessio Bonucci, Antonio Quotadamo, Alberto Venturelli, Stefano Mangani, Maria Paola Costi, Rebecca C Wade
BACKGROUND: Multi-target approaches are necessary to properly analyze or modify the function of a biochemical pathway or a protein family. An example of such a problem is the repurposing of the known human anti-cancer drugs, antifolates, as selective anti-parasitic agents. This requires considering a set of experimentally validated protein targets in the folate pathway of major pathogenic trypanosomatid parasites and humans: (i) the primary parasite on-targets: pteridine reductase 1 (PTR1) (absent in humans) and bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS), (ii) the primary off-targets: human DHFR and TS, and (iii) the secondary on-target: human folate receptor β, a folate/antifolate transporter...
September 20, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28938597/3-decylcatechol-induces-autophagy-mediated-cell-death-through-the-ire1%C3%AE-jnk-p62-in-hepatocellular-carcinoma-cells
#3
Da-Hye Go, Yu Geon Lee, Da-Hye Lee, Jin-A Kim, In-Hwa Jo, Yeon Soo Han, Yong Hun Jo, Kwang-Youn Kim, Young-Kyo Seo, Jae-Hak Moon, Chang Hwa Jung, Tae-Il Jeon
The natural, phenolic lipid urushiol exhibits both antioxidant and anticancer activities; however, its biological activity on hepatocellular carcinoma (HCC) has not been previously investigated. Here, we demonstrate that an urushiol derivative, 3-decylcatechol (DC), induces human HCC Huh7 cell death by induction of autophagy. DC initiates the autophagic process by activation of the mammalian target of rapamycin signaling pathway via Unc-51-like autophagy activating kinase 1, leading to autophagosome formation...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28938583/ppa1-regulates-tumor-malignant-potential-and-clinical-outcome-of-colon-adenocarcinoma-through-jnk-pathways
#4
Ping Wang, Yi Zhou, Qi Mei, Jing Zhao, Liu Huang, Qiang Fu
Colorectal cancer (CRC) represents one of the most prevalent malignancies and the third leading cause of cancer death worldwide. Inorganic pyrophosphatase (PPA1) is an enzyme that catalyzes the hydrolysis of pyrophosphate to inorganic phosphate, therefore participates in the energy metabolism. Proteomic studies have demonstrated the up-regulated expression of PPA1 in various tumors, however, its expression pattern in CRC hasn't been reported. In the current study, we used RT-qCR, Western Blot and immunohistochemical (IHC) staining to explore the expression of PPA1 in 113 paired colon cancer tissues and adjacent normal tissues, which revealed that PPA1 was correlated with lymph node metastasis...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28938552/novel-pleiotropic-effects-of-bioactive-phospholipids-in-human-lung-cancer-metastasis
#5
Gabriela Schneider, Zachariah Payne Sellers, Kamila Bujko, Sham S Kakar, Magda Kucia, Mariusz Z Ratajczak
We previously proposed that one of the unwanted side effects of chemotherapy and radiotherapy is the increase in several peptide- and non-peptide based chemoattractants in damaged tissues, leading to induction of a prometastatic microenvironment for remaining cancer cells. Herein, we turned out our attention to a potential role of bioactive phospholipids (BphsLs), such as sphingosine-1-phosphate (S1P), ceramide-1-phosphate (C1P), lysophosphatidylcholine (LPC), and lysophosphatidic acid (LPA) in lung cancer (LC) metastasis...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28938428/glp-1-receptor-activation-inhibits-palmitate-induced-apoptosis-via-ceramide-in-human-cardiac-progenitor-cells
#6
Anna Leonardini, Rossella D'Oria, Maria Angela Incalza, Cristina Caccioppoli, Valentina Andrulli Buccheri, Angelo Cignarelli, Domenico Paparella, Vito Margari, Annalisa Natalicchio, Sebastio Perrini, Francesco Giorgino, Luigi Laviola
Context: Increased apoptosis of cardiomyocytes and cardiac progenitor cells (CPCs) in response to saturated fatty acids (SFA) can lead to myocardial damage and dysfunction. Ceramides mediate lipotoxicity-induced apoptosis. GLP-1 receptor (GLP1R) agonists exert beneficial effects on cardiac cells in experimental models. Objective: To investigate the protective effects of GLP1R activation on SFA-mediated apoptotic death of human CPCs. Design: Human CPCs were isolated from cardiac appendages of non-diabetic donors and then exposed to palmitate with or without pre-treatment with the GLP1R agonist exendin-4...
August 16, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28938188/induction-of-heme-oxygenas-1-attenuates-nlrp3-inflammasome-activation-in-lipopolysaccharide-induced-mastitis-in-mice
#7
Hu Xiaoyu, Hongbin Si, Shumin Li, Wenqing Wang, Jian Guo, Yanyi Li, Yongguo Cao, Yunhe Fu, Naisheng Zhang
Mastitis is one of most prevalent production disease in dairy herds worldwide, and is responsible for enormous economic losses. Heme oxygenase-1 (HO-1) is a cytoprotective enzyme, which is involved in the response to oxidative stress and inflammatory response. The purpose of this study was to detect the protective effect of HO-1 on LPS-induced mastitis in mice. BALB/c mice were pretreated with hemin (HO-1 inducer) and zinc protoporphyrin (ZnPP; HO-1 inhibitor) at 2h before LPS stimulation. The results showed that the mammary gland damage, production of inflammatory cytokines IL-1β, and MPO activity in mammary gland tissues were significantly reduced after pretreated with hemin compared with the group of LPS stimulation only...
September 19, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28937985/interference-with-plastome-gene-expression-and-clp-protease-activity-in-arabidopsis-triggers-a-chloroplast-unfolded-protein-response-to-restore-protein-homeostasis
#8
Ernesto Llamas, Pablo Pulido, Manuel Rodriguez-Concepcion
Disruption of protein homeostasis in chloroplasts impairs the correct functioning of essential metabolic pathways, including the methylerythritol 4-phosphate (MEP) pathway for the production of plastidial isoprenoids involved in photosynthesis and growth. We previously found that misfolded and aggregated forms of the first enzyme of the MEP pathway are degraded by the Clp protease with the involvement of Hsp70 and Hsp100/ClpC1 chaperones in Arabidopsis thaliana. By contrast, the combined unfolding and disaggregating actions of Hsp70 and Hsp100/ClpB3 chaperones allow solubilization and hence reactivation of the enzyme...
September 22, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28937657/synthesis-of-2-4-diaminopyrimidine-core-based-derivatives-and-biological-evaluation-of-their-anti-tubercular-activities
#9
Yifan Ouyang, Hao Yang, Peng Zhang, Yu Wang, Sargit Kaur, Xuanli Zhu, Zhe Wang, Yutong Sun, Wei Hong, Yun Fong Ngeow, Hao Wang
Tuberculosis (TB) is a chronic, potentially fatal disease caused by Mycobacterium tuberculosis (Mtb). The dihyrofolate reductase in Mtb (mt-DHFR) is believed to be an important drug target in anti-TB drug development. This enzyme contains a glycerol (GOL) binding site, which is assumed to be a useful site to improve the selectivity towards human dihyrofolate reductase (h-DHFR). There have been previous attempts to design drugs targeting the GOL binding site, but the designed compounds contain a hydrophilic group, which may prevent the compounds from crossing the cell wall of Mtb to function at the whole cell level...
September 22, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28937283/engineering-rubisco-activase-from-thermophilic-cyanobacteria-into-high-temperature-sensitive-plants
#10
Chukwuma C Ogbaga, Piotr Stepien, Habib-Ur-Rehman Athar, Muhammad Ashraf
In the past decade, various strategies to improve photosynthesis and crop yield, such as leaf morphology, light interception and use efficiency, biochemistry of light reactions, stomatal conductance, carboxylation efficiency, and source to sink regulation, have been discussed at length. Leaf morphology and physiology are tightly coupled to light capturing efficiency, gas exchange capacity, and temperature regulation. However, apart from the photoprotective mechanism of photosystem-II (PSII), i.e. non-photochemical quenching, very low genetic variation in the components of light reactions has been observed in plants...
September 22, 2017: Critical Reviews in Biotechnology
https://www.readbyqxmd.com/read/28937220/a-fluorescence-polarization-activity-based-protein-profiling-assay-in-the-discovery-of-potent-selective-inhibitors-for-human-non-lysosomal-glucosylceramidase
#11
Daniel Lahav, Bing Liu, Richard J B H N van den Berg, Adrianus M C H van den Nieuwendijk, Tom Wennekes, Amar T Ghisaidoobe, Imogen Breen, Maria J Ferraz, Chi-Lin Kuo, Liang Wu, Paul P Geurink, Huib Ovaa, Gijsbert A van der Marel, Mario van der Stelt, Rolf G Boot, Gideon J Davies, Johannes M F G Aerts, Herman S Overkleeft
Human non-lysosomal glucosylceramidase (GBA2) is one of several enzymes that controls levels of glycolipids and whose activity is linked to several human disease states. There is a major need to design or discover selective GBA2 inhibitors both as chemical tools and as potential therapeutic agents. Here, we describe the development of a fluorescence polarization activity-based protein profiling (FluoPol-ABPP) assay for the rapid identification, from a 350+ library of iminosugars, of GBA2 inhibitors. A focused library is generated based on leads from the FluoPol-ABPP screen and assessed on GBA2 selectivity offset against the other glucosylceramide metabolizing enzymes, glucosylceramide synthase (GCS), lysosomal glucosylceramidase (GBA) and the cytosolic retaining β-glucosidase, GBA3...
September 22, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28937042/sirtuin-1-mediates-hydrogen-sulfide-induced-cytoprotection-effects-in-neonatal-mouse-cardiomyocytes
#12
Ai-Jun Liu, Bin Li, Ming Yang, Yang Liu, Ying-Long Liu, Jun-Wu Su
BACKGROUND: Current knowledge indicates that oxidative damage and the following inflammation is pivotal pathway for myocardial cell death. In recent decades, hydrogen sulfide (H2S) has been identified as a novel endogenous vasodilator and neuromodulator due to its antioxidation capacity. However, whether H2S pretreatment in neonatal mouse cardiomyocytes is a protection effect against oxidative stress remains elusive. METHODS: Primary neonatal mouse cardiomyocytes were isolated and cultured, subsequently, pretreated with the H2S donor, sodium hydrosulfide (NaHS)...
October 5, 2017: Chinese Medical Journal
https://www.readbyqxmd.com/read/28936788/isorhamnetin-derivatives-and-piscidic-acid-for-hypercholesterolemia-cholesterol-permeability-hmg-coa-reductase-inhibition-and-docking-studies
#13
Asma Ressaissi, Nebil Attia, Pedro Luis Falé, Rita Pacheco, Bruno L Victor, Miguel Machuqueiro, Maria Luísa M Serralheiro
Bioactive compounds, such as isorhamnetin and piscidic acid, were obtained from decoctions of cladodes (stem pads from Opuntia ficus-indica). The effect of these phenolic compounds, in a fiber-free extract, were evaluated as inhibitors of cholesterol permeation through a Caco-2 cell monolayer and as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. A reduction of 38% in cholesterol permeation through the Caco-2 cell monolayer was obtained, and the phenolic compounds all permeated between 6 and 9%. A mixture of these compounds showed an IC50 of 20...
September 21, 2017: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/28936766/use-of-lactobacilli-in-cereal-legume-fermentation-and-as-potential-probiotics-towards-phytate-hydrolysis
#14
Girish K Amritha, G Venkateswaran
Phytate is a potent inhibitor of mineral absorption in humans occurring in plant-based food. Application of lactobacilli that produce phytate-degrading enzymes (phytases) to reduce phytate is an interesting yet a not much explored sector of research. Therefore, phytate dephosphorylation by Lactobacillus plantarum MTCC 1325 was evaluated. Cells at stationary phase showed phytase activity which was maximal at 24 h of growth. Glucose concentration and the type of phosphorous source in the media modulated the enzyme activity...
September 21, 2017: Probiotics and Antimicrobial Proteins
https://www.readbyqxmd.com/read/28936485/a-randomized-controlled-trial-of-lisinopril-to-decrease-lymphoid-fibrosis-in-antiretroviral-treated-hiv-infected-individuals
#15
Leslie R Cockerham, Steven A Yukl, Kara Harvill, Ma Somsouk, Sunil K Joshi, Elizabeth Sinclair, Teri Liegler, Rebecca Hoh, Sophie Lyons, Peter W Hunt, Adam Rupert, Irini Sereti, David R Morcock, Ajantha Rhodes, Claire Emson, Marc K Hellerstein, Jacob D Estes, Sharon Lewin, Steven G Deeks, Hiroyu Hatano
BACKGROUND: In HIV infection, lymphoid tissue is disrupted by fibrosis. Angiotensin converting enzyme inhibitors have anti-fibrotic properties. We completed a pilot study to assess whether the addition of lisinopril to antiretroviral therapy (ART) reverses fibrosis of gut tissue, and whether this leads to reduction of HIV RNA and DNA levels. METHODS: Thirty HIV-infected individuals on ART were randomized to lisinopril at 20mg daily or matching placebo for 24 weeks...
2017: Pathogens & Immunity
https://www.readbyqxmd.com/read/28936205/homologous-recombination-in-protozoan-parasites-and-recombinase-inhibitors
#16
REVIEW
Andrew A Kelso, Sarah M Waldvogel, Adam J Luthman, Michael G Sehorn
Homologous recombination (HR) is a DNA double-strand break (DSB) repair pathway that utilizes a homologous template to fully repair the damaged DNA. HR is critical to maintain genome stability and to ensure genetic diversity during meiosis. A specialized class of enzymes known as recombinases facilitate the exchange of genetic information between sister chromatids or homologous chromosomes with the help of numerous protein accessory factors. The majority of the HR machinery is highly conserved among eukaryotes...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28936150/prevalence-of-poor-glycemic-and-blood-pressure-control-and-pattern-of-drug-use-among-primary-health-care-outpatients-in-al-ahsa-saudi-arabia
#17
Promise M Emeka, Ahmed Al Mukalaf, Hussien Al Helal, Tahir M Khan, Mishial A Almukalf
OBJECTIVES: To assess drug use pattern and the effect on glycemic and blood pressure (BP) control in type 2 diabetes mellitus (T2DM) and hypertensive patients. Furthermore, to evaluate the duration of drug use and antecedence in diagnosis. METHODOLOGY: A cross-sectional study design, comprising interview/questionnaire targeting outpatients attending primary health centers in Al Ahsa was adopted. During the interview, their fasting blood glucose, weight, and height were measured, along with their BP...
July 2017: International Journal of Health Sciences
https://www.readbyqxmd.com/read/28935975/tumor-necrosis-factor-inducible-gene-6-protein-ameliorates-chronic-liver-damage-by-promoting-autophagy-formation-in-mice
#18
Sihyung Wang, Chanbin Lee, Jieun Kim, Jeongeun Hyun, Minso Lim, Hyuk-Jin Cha, Seh-Hoon Oh, Yung Hyun Choi, Youngmi Jung
Tumor necrosis factor-inducible gene 6 protein (TSG-6) has recently been shown to protect the liver from acute damage. However, the mechanism underlying the effect of TSG-6 on the liver remains unclear. Autophagy is a catabolic process that targets cell components to lysosomes for degradation, and its functions are reported to be dysregulated in liver diseases. Here we investigate whether TSG-6 promotes liver regeneration by inducing autophagic clearance in damaged livers. Mice fed a methionine choline-deficient diet supplemented with 0...
September 22, 2017: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/28935542/phase-i-trial-of-veliparib-a-poly-adp-ribose-polymerase-inhibitor-plus-metronomic-cyclophosphamide-in-metastatic-her2-negative-breast-cancer
#19
Jesus Anampa, Alice Chen, John Wright, Margi Patel, Christine Pellegrino, Karen Fehn, Joseph A Sparano, Eleni Andreopoulou
BACKGROUND: Poly-ADP-ribose-polymerase is an essential nuclear enzyme, involved in base-excision repair of damaged DNA. Poly-ADP-ribose-polymerase inhibition sensitizes tumor cells to cytotoxic agents, which induce DNA damage, including cyclophosphamide (C), and metronomic dosing of C may optimize potential for synergy. METHODS: The primary objective of this phase I trial was to determine the safety and identify the recommended phase II dose of the combination of low-dose oral C (50, 75, 100, and 125 mg) once daily in combination with veliparib (V) (100, 200, and 300 mg) administered twice a day (BID) for 21-day cycles using a standard 3 + 3 design in patients with metastatic human epidermal growth factor receptor 2/neu-negative breast cancer...
September 1, 2017: Clinical Breast Cancer
https://www.readbyqxmd.com/read/28935286/mercury-exposure-induces-proinflammatory-enzymes-in-vascular-fibroblasts
#20
Alberto Millán Longo, Óscar Montero Saiz, Claudia Sarró Fuente, Andrea Aguado Martínez, Mercedes Salaices Sánchez
INTRODUCTION: Previous studies show that mercury exposure increases cardiovascular risk, although the underlying cellular mechanisms have still not been fully studied. The aim of this project is to study, in vascular fibroblasts (VF), the effect of HgCl2 exposure on the expression of enzymes involved in the synthesis of prostanoids and reactive oxygen species (ROS). These molecules have been shown to participate in the inflammatory response associated with cardiovascular diseases. MATERIAL AND METHODS: Adventitial VF cultures of Sprague-Dawley rat aortas, shown to be α-actin negative by immunofluorescence, were exposed to HgCl2 (0...
September 18, 2017: Clínica e Investigación en Arteriosclerosis
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