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https://www.readbyqxmd.com/read/29151072/the-lactate-receptor-hcar1-gpr81-contributes-to-doxorubicin-chemoresistance-via-abcb1-transporter-up-regulation-in-human-cervical-cancer-hela-cells
#1
W Wagner, K D Kania, A Blauz, W M Ciszewski
The lactate receptor, also known as hydroxycarboxylic acid receptor 1 (HCAR1/GPR81), plays a vital role in cancer biology. Recently, HCAR1 was reported to enhance metastasis, cell growth, and survival of pancreatic, breast, and cervical cancer cells. This study showed, for the first time, the mechanism of HCAR1-mediated chemoresistance to doxorubicin through regulation of ABCB1 transporter. We observed the HCAR1 agonists L-lactate, D-lactate and 3,5-dihydroxybenzoic acid (DHBA) induced up-regulation of ABCB1...
August 2017: Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society
https://www.readbyqxmd.com/read/29150677/phosphatidylserine-decarboxylase-ct699-lysophospholipid-acyltransferase-ct775-and-acyl-acp-synthase-ct776-provide-membrane-lipid-diversity-to-chlamydia-trachomatis
#2
Eric Soupene, Frans A Kuypers
De novo lipid synthesis and scavenging of fatty acids (FA) are processes essential for the formation of the membrane of the human pathogen Chlamydia trachomatis (C.t.). Host FA are assimilated via esterification by the bacterial acyl-acyl carrier protein (ACP) synthase AasC but inhibitors of the host acyl-CoA synthetase enymes ACSL also impaired growth of C.t. in human cells. In E. coli, activity of AasC was sensitive to triacsin C and rosiglitazone G. The absence of a triacsin C-insensitive pathway and the increased inhibition by rosiglitazone G confirmed the sensitivity of the bacterial acyl-ACP synthase to these drugs in infected human cells...
November 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29148558/ultrasound-propelled-nanowire-motors-enhance-asparaginase-enzymatic-activity-against-cancer-cells
#3
Murat Uygun, Beatriz Jurado-Sánchez, Deniz Aktas Uygun, Virendra Vikram Singh, Liangfang Zhang, Joseph Wang
Ultrasound-(US) propelled nanowires consisting of Au/Ni/Au/PEDOT-PPy-COOH segments are modified with asparaginase enzyme and applied as an effective anti-cancer agent. After immobilization of asparaginase onto the surface of the nanowire motors, the enzyme displays enhanced thermal and pH stabilities, improved resistance towards protease, and higher affinity for the substrate. The fast motion of the motor-carrying asparaginase leads to greatly accelerated biocatalytic depletion of asparagine and hence to a significantly enhanced inhibition efficacy against El4 lymphoma cancer cells (92%) as compared to free enzyme counterpart (17%) and other control groups...
November 17, 2017: Nanoscale
https://www.readbyqxmd.com/read/29146563/characterization-of-the-ipec-j2-mdr1-ip-gp-cell-line-as-a-tool-for-identification-of-p-gp-substrates
#4
Burak Ozgür, Lasse Saaby, Kristine Langthaler, Birger Brodin
Recently, we transfected the porcine intestinal cell line IPEC-J2, with human P-glycoprotein (P-gp, ABCB1). The resulting cell line, iP-gp, has a high expression of functional human P-gp in the apical membrane, and a low expression of nonhuman ATP-binding cassette (ABC) transporters. The aim of the present work was to investigate the usability of iP-gp cell line for determining transepithelial transport kinetics of the prototypical P-gp substrates digoxin and rhodamine 123. The cell line generated tight monolayers after 16days of culture, reflected by high transepithelial electrical resistance values (TEER>15,000Ω·cm(2)), immunocytochemistry and low fluxes of the paracellular flux marker [(14)C]-mannitol...
November 13, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29146133/synthesis-and-bio-evaluation-of-indole-chalcone-based-benzopyrans-as-promising-antiligase-and-antiproliferative-agents
#5
Sampa Gupta, Pooja Maurya, Akanksha Upadhyay, Pragati Kushwaha, Shagun Krishna, Mohammad Imran Siddiqi, Koneni V Sashidhara, Dibyendu Banerjee
DNA replication and repair are complex processes accomplished by the concerted action of a network of enzymes and proteins. DNA ligases play a crucial role in these processes by catalyzing the nick joining between DNA strands. As compared to normal cells, elevated levels of human DNA ligase I (hLigI) is reported in some cancers. We studied the inhibition of hLigI mediated DNA nick sealing activity followed by the antiproliferative activity of novel indole-chalcone based benzopyran compounds on cancer cells...
November 7, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29146131/dysregulation-of-autophagy-in-melanocytes-contributes-to-hypopigmented-macules-in-tuberous-sclerosis-complex
#6
Fei Yang, Lingli Yang, Mari Wataya-Kaneda, Junya Hasegawa, Tamotsu Yoshimori, Atsushi Tanemura, Daisuke Tsuruta, Ichiro Katayama
BACKGROUND: Tuberous sclerosis complex (TSC) gene mutations lead to constitutive activation of the mammalian target of rapamycin (mTOR) pathway, resulting in a broad range of symptoms. Hypopigmented macules are the earliest sign. Although we have already confirmed that topical rapamycin treatment (an mTOR inhibitor) protects patients with TSC against macular hypopigmentation, the pathogenesis of such lesions remains poorly understood. OBJECTIVE: Recently emerging evidence supports a role for autophagy in skin pigmentation...
November 11, 2017: Journal of Dermatological Science
https://www.readbyqxmd.com/read/29145480/engineering-the-gh1-%C3%AE-glucosidase-from-humicola-insolens-insights-on-the-stimulation-of-activity-by-glucose-and-xylose
#7
Luana Parras Meleiro, José Carlos Santos Salgado, Raquel Fonseca Maldonado, Sibeli Carli, Luiz Alberto Beraldo Moraes, Richard John Ward, João Atílio Jorge, Rosa Prazeres Melo Furriel
The activity of the GH1 β-glucosidase from Humicola insolens (Bglhi) against p-nitrophenyl-β-D-glucopyranoside (pNP-Glc) and cellobiose is enhanced 2-fold by glucose and/or xylose. Kinetic and transglycosylation data showed that hydrolysis is preferred in the absence of monosaccharides. Stimulation involves allosteric interactions, increased transglycosylation and competition of the substrate and monosaccharides for the -1 glycone and the +1/+2 aglycone binding sites. Protein directed evolution has been used to generate 6 mutants of Bglhi with altered stimulation patterns...
2017: PloS One
https://www.readbyqxmd.com/read/29144408/antioxidant-effect-of-barley-sprout-extract-via-enhancement-of-nuclear-factor-erythroid-2-related-factor-2-activity-and-glutathione-synthesis
#8
Yun-Hee Lee, Sou Hyun Kim, Seunghyun Lee, Kyung-Mi Kim, Jae-Chul Jung, Tae Gen Son, Sung Hwan Ki, Woo-Duck Seo, Jae-Hwan Kwak, Jin Tae Hong, Young-Suk Jung
We previously showed that barley sprout extract (BSE) prevents chronic alcohol intake-induced liver injury in mice. BSE notably inhibited glutathione (GSH) depletion and increased inflammatory responses, revealing its mechanism of preventing alcohol-induced liver injury. In the present study we investigated whether the antioxidant effect of BSE involves enhancing nuclear factor-erythroid 2 related factor 2 (Nrf2) activity and GSH synthesis to inhibit alcohol-induced oxidative liver injury. Mice fed alcohol for four weeks exhibited significantly increased oxidative stress, evidenced by increased malondialdehyde (MDA) level and 4-hydroxynonenal (4-HNE) immunostaining in the liver, whereas treatment with BSE (100 mg/kg) prevented these effects...
November 16, 2017: Nutrients
https://www.readbyqxmd.com/read/29142819/liposomes-modified-with-cardiolipin-can-act-as-a-platform-to-regulate-the-potential-flux-of-nadp-dependent-isocitrate-dehydrogenase
#9
Keishi Suga, Akari Hamasaki, Junpei Chinzaka, Hiroshi Umakoshi
Cardiolipin (CL) is a phospholipid found in the outer mitochondrial membrane (OMM) and inner mitochondrial membrane (IMM) in animal cells. Isocitrate dehydrogenase (ICDH) is an important catalytic enzyme that is localized at the cytosol and mitochondria; the metabolic pathway catalyzed by ICDH differs between the OMM and IMM. To estimate the possible role of lipid membrane in the enzymatic activity of NADP(+)-dependent ICDH, CL-modified liposomes were prepared using CL/1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)/cholesterol (Ch), and their characteristics were analyzed based on the fluorescent probe method...
December 2016: Metabolic Engineering Communications
https://www.readbyqxmd.com/read/29142193/pten-is-a-protein-phosphatase-that-targets-active-ptk6-and-inhibits-ptk6-oncogenic-signaling-in-prostate-cancer
#10
Darren J Wozniak, Andre Kajdacsy-Balla, Virgilia Macias, Susan Ball-Kell, Morgan L Zenner, Wenjun Bie, Angela L Tyner
PTEN activity is often lost in prostate cancer. We show that the tyrosine kinase PTK6 (BRK) is a PTEN substrate. Phosphorylation of PTK6 tyrosine 342 (PY342) promotes activation, while phosphorylation of tyrosine 447 (PY447) regulates auto-inhibition. Introduction of PTEN into a PTEN null prostate cancer cell line leads to dephosphorylation of PY342 but not PY447 and PTK6 inhibition. Conversely, PTEN knockdown promotes PTK6 activation in PTEN positive cells. Using a variety of PTEN mutant constructs, we show that protein phosphatase activity of PTEN targets PTK6, with efficiency similar to PTP1B, a phosphatase that directly dephosphorylates PTK6 Y342...
November 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/29141866/prostate-specific-membrane-antigen-cleavage-of-vitamin-b9-stimulates-oncogenic-signaling-through-metabotropic-glutamate-receptors
#11
Charalambos Kaittanis, Chrysafis Andreou, Haley Hieronymus, Ninghui Mao, Catherine A Foss, Matthias Eiber, Gregor Weirich, Palak Panchal, Anuradha Gopalan, Juan Zurita, Samuel Achilefu, Gabriela Chiosis, Vladimir Ponomarev, Markus Schwaiger, Brett S Carver, Martin G Pomper, Jan Grimm
Prostate-specific membrane antigen (PSMA) or folate hydrolase 1 (FOLH1) is highly expressed on prostate cancer. Its expression correlates inversely with survival and increases with tumor grade. However, the biological role of PSMA has not been explored, and its role in prostate cancer remained elusive. Filling this gap, we demonstrate that in prostate cancer, PSMA initiates signaling upstream of PI3K through G protein-coupled receptors, specifically via the metabotropic glutamate receptor (mGluR). PSMA's carboxypeptidase activity releases glutamate from vitamin B9 and other glutamated substrates, which activate mGluR I...
November 15, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29140686/the-regulatory-mechanism-of-mycobacterium-tuberculosis-phosphoserine-phosphatase-serb2
#12
Gregory A Grant
Almost all organisms contain the same biosynthetic pathway for the synthesis of l-serine from the glycolytic intermediate, D-3-phosphoglycerate. However, regulation of this pathway varies from organism to organism. Many organisms control the activity of the first enzyme in the pathway, D-3-phosphoglyerate dehydrogenase (PGDH), by feedback inhibition through the interaction of l-serine with the ACT domains within the enzyme. The last enzyme in the pathway, phosphoserine phosphatase (PSP) has also been reported to be inhibited by l-serine...
November 15, 2017: Biochemistry
https://www.readbyqxmd.com/read/29140585/timap-the-versatile-protein-phosphatase-1-regulator-in-endothelial-cells
#13
REVIEW
Anita Boratkó, Csilla Csortos
Transforming growth factor (TGF)-β inhibited membrane associated protein, TIMAP, is the member of the myosin phosphatase targeting protein (MYPT) family of protein phosphatase 1 (PP1) regulatory subunits. The N-terminal part of TIMAP has a typical MYPT family structure with a sequence element called MyPhone (myosin phosphatase N-terminal element), a putative bipartite nuclear localization signal, a PP1 catalytic subunit binding motif, and five ankyrin repeats. The C-terminal half of TIMAP is intrinsically disordered, but ends with a functional CAAX box for lipid modification which allows localization of TIMAP at the plasma membrane...
November 15, 2017: IUBMB Life
https://www.readbyqxmd.com/read/29139175/hax-1-regulates-the-proliferation-and-apoptosis-of-endothelial-progenitor-cells-through-akt-pathway-modulation
#14
Xin-Bin Guo, Xin Deng, Ying Wei
Endothelial precursor cells (EPCs) are involved in vasculogenesis of various physiological and pathological processes. The proliferation and survival mechanism of EPCs needs to be explored further for the purpose of developing an effective glioma treatment. Hematopoietic-substrate-1 associated protein X-1 (HAX-1) has been reported as an anti-apoptosis protein that plays an important role in several malignant tumors. However, the effect and mechanism of HAX-1 on EPCs remains unknown. This study aims to investigate the effect of HAX-1 on the proliferation and apoptosis EPCs and explore its mechanism...
November 15, 2017: Stem Cells
https://www.readbyqxmd.com/read/29138180/inhibition-of-vascular-c-jun-n-terminal-kinase-2-improves-obesity-induced-endothelial-dysfunction-after-roux-en-y-gastric-bypass
#15
Petia Doytcheva, Thomas Bächler, Erika Tarasco, Vincenzo Marzolla, Michael Engeli, Giovanni Pellegrini, Simona Stivala, Lucia Rohrer, Francesco Tona, Giovanni G Camici, Paul M Vanhoutte, Christian M Matter, Thomas A Lutz, Thomas F Lüscher, Elena Osto
BACKGROUND: Roux-en-Y gastric bypass (RYGB) reduces obesity-associated comorbidities and cardiovascular mortality. RYGB improves endothelial dysfunction, reducing c-Jun N-terminal kinase (JNK) vascular phosphorylation. JNK activation links obesity with insulin resistance and endothelial dysfunction. Herein, we examined whether JNK1 or JNK2 mediates obesity-induced endothelial dysfunction and if pharmacological JNK inhibition can mimic RYGB vascular benefits. METHODS AND RESULTS: After 7 weeks of a high-fat high-cholesterol diet, obese rats underwent RYGB or sham surgery; sham-operated ad libitum-fed rats received, for 8 days, either the control peptide D-TAT or the JNK peptide inhibitor D-JNKi-1 (20 mg/kg per day subcutaneous)...
November 14, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/29137864/synthesis-molecular-docking-and-qsar-study-of-sulfonamide-based-indoles-as-aromatase-inhibitors
#16
Ratchanok Pingaew, Prasit Mandi, Veda Prachayasittikul, Supaluk Prachayasittikul, Somsak Ruchirawat, Virapong Prachayasittikul
Thirty four of indoles bearing sulfonamides (11-44) were synthesized and evaluated for their anti-aromatase activities. Interestingly, all indole derivatives inhibited the aromatase with IC50 range of 0.7-15.3 μM. Indoles (27-36) exerted higher aromatase inhibitory activity than that of ketoconazole. The phenoxy analogs 28 and 34 with methoxy group were shown to be the most potent compounds with sub-micromolar IC50 values (i.e., 0.7 and 0.8 μM, respectively) without affecting to the normal cell line. Molecular docking demonstrated that the indoles 28, 30 and 34 could occupy the same binding site on the aromatase pocket and share several binding residues with those of the natural substrate (androstenedione), which suggested the competitive binding could be the mode of inhibition of the compounds...
October 20, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29137240/mutational-re-modeling-of-di-aspartyl-intramembrane-proteases-uncoupling-physiologically-relevant-activities-from-those-associated-with-alzheimer-s-disease
#17
Anastasia P Grigorenko, Youri K Moliaka, Olga V Plotnikova, Alexander Smirnov, Vera A Nikishina, Andrey Y Goltsov, Fedor Gusev, Tatiana V Andreeva, Omar Nelson, Ilya Bezprozvanny, Evgeny I Rogaev
The intramembrane proteolytic activities of presenilins (PSEN1/PS1 and PSEN2/PS2) underlie production of β-amyloid, the key process in Alzheimer's disease (AD). Dysregulation of presenilin-mediated signaling is linked to cancers. Inhibition of the γ-cleavage activities of PSENs that produce Aβ, but not the ε-like cleavage activity that release physiologically essential transcription activators, is a potential approach for the development of rational therapies for AD. In order to identify whether different activities of PSEN1 can be dissociated, we designed multiple mutations in the evolutionary conserved sites of PSEN1...
October 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29136681/assessment-of-multiple-cytochrome-p450-activities-in-metabolically-inactivated-human-liver-microsomes-and-roles-of-p450-2c-isoforms-in-reaction-phenotyping-studies
#18
Norie Murayama, Kanako Yajima, Mikiko Hikawa, Kanami Shimura, Yu Ishii, Masaki Takada, Yasuhiro Uno, Masahiro Utoh, Kazuhide Iwasaki, Hiroshi Yamazaki
The fraction of substrate metabolized (fm ) can be used to estimate drug interactions and can be determined by comparison of the intrinsic clearances (CLint ) of victim drugs obtained from inhibited and uninhibited hepatic enzymes. Commercially available human liver microsomes were recently developed in which one cytochrome P450 (P450) isoform is selectively inactivated. These inactivated liver microsomes were used to evaluate the roles of P450 2C isoforms in the depletion and oxidation of probe substrates...
November 14, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29136518/evidence-of-co-metabolic-bentazone-transformation-by-methanotrophic-enrichment-from-a-groundwater-fed-rapid-sand-filter
#19
Mathilde J Hedegaard, Hélène Deliniere, Carsten Prasse, Arnaud Dechesne, Barth F Smets, Hans-Jørgen Albrechtsen
The herbicide bentazone is recalcitrant in aquifers and is therefore frequently detected in wells used for drinking water production. However, bentazone degradation has been observed in filter sand from a rapid sand filter at a waterworks with methane-rich groundwater. Here, the association between methane oxidation and removal of bentazone was investigated with a methanotrophic enrichment culture derived from methane-fed column reactors inoculated with that filter sand. Several independent lines of evidence obtained from microcosm experiments with the methanotrophic enrichment culture, tap water and bentazone at concentrations below 2 mg/L showed methanotrophic co-metabolic bentazone transformation: The culture removed 53% of the bentazone in 21 days in presence of 5 mg/L of methane, while only 31% was removed in absence of methane...
November 3, 2017: Water Research
https://www.readbyqxmd.com/read/29135983/arginase-expression-modulates-nitric-oxide-production-in-leishmania-leishmania-amazonensis
#20
Stephanie Maia Acuña, Juliana Ide Aoki, Maria Fernanda Laranjeira-Silva, Ricardo Andrade Zampieri, Juliane Cristina Ribeiro Fernandes, Sandra Marcia Muxel, Lucile Maria Floeter-Winter
BACKGROUND: Arginase is an enzyme that converts L-arginine to urea and L-ornithine, an essential substrate for the polyamine pathway supporting Leishmania (Leishmania) amazonensis replication and its survival in the mammalian host. L-arginine is also the substrate of macrophage nitric oxide synthase 2 (NOS2) to produce nitric oxide (NO) that kills the parasite. This competition can define the fate of Leishmania infection. METHODOLOGY/PRINCIPAL FINDINGS: The transcriptomic profiling identified a family of oxidoreductases in L...
2017: PloS One
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