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Biochemical Pharmacology

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https://www.readbyqxmd.com/read/28734777/inhibitor-mechanisms-in-the-s1-binding-site-of-the-dopamine-transporter-defined-by-multi-site-molecular-tethering-of-photoactive-cocaine-analogs
#1
Danielle Krout, Akula Bala Pramod, Rejwi Acharya Dahal, Michael J Tomlinson, Babita Sharma, James D Foster, Mu-Fa Zou, Comfort Boatang, Amy Hauck Newman, John R Lever, Roxanne A Vaughan, L Keith Henry
Dopamine transporter (DAT) blockers like cocaine and many other abused and therapeutic drugs bind and stabilize an inactive form of the transporter inhibiting reuptake of extracellular dopamine (DA). The resulting increases in DA lead to the ability of these drugs to induce psychomotor alterations and addiction, but paradoxical findings in animal models indicate that not all DAT antagonists induce cocaine-like behavioral outcomes. How this occurs is not known, but one possibility is that uptake inhibitors may bind at multiple locations or in different poses to stabilize distinct conformational transporter states associated with differential neurochemical endpoints...
July 19, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28728917/global-alteration-of-the-drug-binding-pocket-of-human-p-glycoprotein-abcb1-by-substitution-of-fifteen-conserved-residues-reveals-a-negative-correlation-between-substrate-size-and-transport-efficiency
#2
Shahrooz Vahedi, Eduardo E Chufan, Suresh V Ambudkar
P-glycoprotein (P-gp), an ATP-dependent efflux pump, is linked to the development of multidrug resistance in cancer cells. However, the drug-binding sites and translocation pathways of this transporter are not yet well-characterized. We recently demonstrated the important role of tyrosine residues in regulating P-gp ATP hydrolysis via hydrogen bond formations with high affinity modulators. Since tyrosine is both a hydrogen bond donor and acceptor, and non-covalent interactions are key in drug transport, in this study we investigated the global effect of enrichment of tyrosine residues in the drug-binding pocket on the drug binding and transport of P-gp...
July 17, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28716729/study-of-new-interactions-of-glitazone-s-stereoisomers-and-the-endogenous-ligand-15d-pgj2-on-six-different-ppar-gamma-proteins
#3
Samuel Álvarez-Almazán, Martiniano Bello, Feliciano Tamay-Cach, Marlet Martínez-Archundia, Diana Alemán-González-Duhart, José Correa-Basurto, Jessica Elena Mendieta-Wejebe
Diabetes mellitus is a chronic disease characterized by hyperglycemia, insulin resistance and hyperlipidemia. Glitazones or thiazolidinediones (TZD) are drugs that act as insulin-sensitizing agents whose molecular target is the peroxisome proliferator-activated receptor gamma (PPARγ). The euglycemic action of TZD has been linked with the induction of type 4 glucose transporter. However, it has been shown that the effect of TZD depends on the specific stereoisomer that interacts with PPARγ. Therefore, this work is focused on exploring the interactions and geometry adopted by glitazone's stereoisomers and one endogenous ligand on different conformations of the six crystals of the PPARγ protein using molecular docking and molecular dynamics (MD) simulations accompanied by the MMGBSA approach...
July 14, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28716728/cytochrome-p450-3a-selectively-affects-the-pharmacokinetic-interaction-between-erlotinib-and-docetaxel-in-rats
#4
Xuan Qin, Jian Lu, Peili Wang, Peipei Xu, Mingyao Liu, Xin Wang
Erlotinib as a first-line drug is used in non-small cell lung cancer (NSCLC) patients with sensitive EGFR mutations, while resistance to this drug will occur after several years of treatment. Therefore, the microtubule disturber docetaxel is introduced as combined regimen in clinical trials. This report investigated the potentials and mechanisms of drug-drug interaction (DDI) between erlotinib and docetaxel using wild type (WT) and Cyp3a1/2 knockout (KO) rats. The erlotinib O-demethylation and docetaxel hydroxylation reactions in the absence or the presence of another drug were analyzed in vitro via the assay of rat liver microsomes...
July 14, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28712932/pyrrolidine-dithiocarbamate-pdtc-inhibits-inflammatory-signaling-via-expression-of-regulator-of-calcineurin-activity-1-rcan1
#5
Eun Hye Lee, Seon Sook Kim, Su Ryeon Seo
Pyrrolidine dithiocarbamate (PDTC) is a thiol compound that elicits anti-inflammatory effects by inhibiting NF-κB signaling. In this study, we report that regulator of calcineurin activity 1 (RCAN1) expression is induced by PDTC treatment and that increased RCAN1 expression is dependent on the generation of reactive oxygen species (ROS) and activation of p38 MAPK and JNK signaling. We also report that the ability of PDTC to induce RCAN1 is mediated by activator protein-1 (AP-1)-dependent gene transcription, and identified a functional AP-1 binding site in the RCAN1 promoter by producing mutations and conducting chromatin immunoprecipitation (ChIP) analyses...
July 13, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28711625/suppressing-mpges-1-expression-by-sinomenine-ameliorates-inflammation-and-arthritis
#6
Hua Zhou, Jian-Xin Liu, Jin-Fang Luo, Chun-Song Cheng, Elaine Lai-Han Leung, Ying Li, Xiao-Hui Su, Zhong-Qiu Liu, Ting-Bo Chen, Fu-Gang Duan, Yan Dong, Yi-Han Zuo, Chong Li, Chon Kit Lio, Ting Li, Pei Luo, Ying Xie, Xiao-Jun Yao, Pei-Xun Wang, Liang Liu
Recently, microsomal prostaglandin E synthase 1 (mPGES-1) has attracted much attention from pharmacologists as a promising strategy and an attractive target for treating various types of diseases including rheumatoid arthritis (RA), which could preserve the anti-inflammatory effect while reducing the adverse effects often occur during administration of Non-steroidal anti-inflammatory drugs (NSAIDs). Here, we report that Sinomenine (SIN) decreased prostaglandin (PG)E2 levels without affecting prostacyclin (PG)I2 and thromboxane (TX)A2 synthesis via selective inhibiting mPGES-1 expression, a possible reason of low risk of cardiovascular event compared with NSAIDs...
July 12, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28711624/curcumin-attenuates-oxidative-stress-induced-nf%C3%AE%C2%BAb-mediated-inflammation-and-endoplasmic-reticulum-dependent-apoptosis-of-splenocytes-in-diabetes
#7
Kahkashan Rashid, Sayantani Chowdhury, Sumit Ghosh, Parames C Sil
The present study was aimed to determine the curative role of curcumin against diabetes induced oxidative stress and its associated splenic complications. Diabetes was induced in the experimental rats via the intraperitoneal administration of a single dose of STZ (65 mg kg(-1) body weight). Increased blood glucose and intracellular ROS levels along with decreased body weight, the activity of cellular antioxidant enzymes and GSH/GSSG ratio were observed in the diabetic animals. Histological assessment showed white pulp depletion and damaged spleen anatomy in these animals...
July 12, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28709952/potent-inhibitors-of-human-lat1-slc7a5-transporter-based-on-dithiazole-and-dithiazine-compounds-for-development-of-anticancer-drugs
#8
Lara Napolitano, Mariafrancesca Scalise, Maria Koyioni, Panayotis Koutentis, Marco Catto, Ivano Eberini, Chiara Parravicini, Luca Palazzolo, Leonardo Pisani, Michele Galluccio, Lara Console, Angelo Carotti, Cesare Indiveri
The LAT1 transporter is acknowledged as a pharmacological target of tumours since it is strongly overexpressed in many human cancers. The purpose of this work was to find novel compounds exhibiting potent and prolonged inhibition of the transporter. To this aim, compounds based on dithiazole and dithiazine scaffold have been screened in the proteoliposome experimental model. Inhibition was tested on the antiport catalysed by hLAT1 as transport of extraliposomal [(3)H]histidine in exchange with intraliposomal histidine...
July 11, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28709951/microrna-basic-concepts-and-implications-for-regeneration-and-repair-of-neurodegenerative-diseases
#9
REVIEW
Cláudia Saraiva, Marta Esteves, Liliana Bernardino
MicroRNAs (miRNA) are small non-coding molecules that revolutionized our knowledge about the regulation of gene expression. Capable to target a large number of mRNA, miRNA are thought to regulate around 30% of the entire human genome. Therefore, these molecules are able to regulate several biological processes, including neuronal survival, differentiation and regeneration. Additionally, miRNA might act as valuable clinical agents in brain pathological conditions: their specific expression patterns in the brain parenchyma and/or in circulating fluids have been highlighted as potential biomarkers while the modulation of their activity may have therapeutic value for several neurodegenerative diseases...
July 11, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28709950/characterization-of-potent-and-selective-iodonium-class-inhibitors-of-nadph-oxidases
#10
Jiamo Lu, Prabhakar Risbood, Charles T Kane, Md Tafazzal Hossain, Larry Anderson, Kimberly Hill, Anne Monks, Yongzhong Wu, Smitha Antony, Agnes Juhasz, Han Liu, Guojian Jiang, Erik Harris, Krishnendu Roy, Jennifer L Meitzler, Mariam Konaté, James H Doroshow
The NADPH oxidases (NOXs) play a recognized role in the development and progression of inflammation-associated disorders, as well as cancer. To date, several NOX inhibitors have been developed, through either high throughput screening or targeted disruption of NOX interaction partners, although only a few have reached clinical trials. To improve the efficacy and bioavailability of the iodonium class NOX inhibitor diphenylene iodonium (DPI), we synthesized 36 analogs of DPI, focusing on improved solubility and functionalization...
July 11, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28705698/receptor-activity-modifying-protein-dependent-and-independent-activation-mechanisms-in-the-coupling-of-calcitonin-gene-related-peptide-and-adrenomedullin-receptors-to-gs
#11
Michael J Woolley, Christopher A Reynolds, John Simms, Christopher S Walker, Juan Carlos Mobarec, Michael L Garelja, Alex C Conner, David R Poyner, Debbie L Hay
Calcitonin gene-related peptide (CGRP) or adrenomedullin (AM) receptors are heteromers of the calcitonin receptor-like receptor (CLR), a class B G protein-coupled receptor, and one of three receptor activity-modifying proteins (RAMPs). How CGRP and AM activate CLR and how this process is modulated by RAMPs is unclear. We have defined how CGRP and AM induce Gs-coupling in CLR-RAMP heteromers by measuring the effect of targeted mutagenesis in the CLR transmembrane domain on cAMP production, modeling the active state conformations of CGRP and AM receptors in complex with the Gs C-terminus and conducting molecular dynamics simulations in an explicitly hydrated lipidic bilayer...
July 10, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28690140/new-neurons-in-adult-brain-distribution-molecular-mechanisms-and-therapies
#12
REVIEW
Annachiara Pino, Guido Fumagalli, Francesco Bifari, Ilaria Decimo
"Are new neurons added in the adult mammalian brain?" "Do neural stem cells activate following CNS diseases?" "How can we modulate their activation to promote recovery?" Recent findings in the field provide novel insights for addressing these questions from a new perspective. In this review, we will summarize the current knowledge about adult neurogenesis and neural stem cell niches in healthy and pathological conditions. We will first overview the milestones that have led to the discovery of the classical ventricular and hippocampal neural stem cell niches...
July 8, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28690139/4-aroyl-3-hydroxy-5-phenyl-1h-pyrrol-2-5h-ones-as-n-formyl-peptide-receptor-1-fpr1-antagonists
#13
Liliya N Kirpotina, Igor A Schepetkin, Andrei I Khlebnikov, Olga I Ruban, Yunjun Ge, Richard D Ye, Douglas J Kominsky, Mark T Quinn
Formyl peptide receptors (FPRs) are expressed on a variety of leukocytes and play important roles in inflammation. Thus, FPR antagonists may represent novel therapeutics for modulating innate immunity and treating inflammatory diseases. Previously, 1H-pyrrol-2(5H)-ones were reported to be potent and competitive FPR1 antagonists. In the present studies, 42 additional 1H-pyrrol-2(5H)-one analogs were evaluated for FPR1 antagonist activity. We identified a number of novel competitive FPR1 antagonists that inhibited N-formylmethionyl-leucyl-phenylalanine (fMLF)-induced intracellular Ca(2+) mobilization in FPR1-transfected HL60 cells and effectively competed with WKYMVm-FITC for binding to FPR1 in FPR1-transfected RBL cells...
July 6, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28690138/chinese-herbal-medicine-for-alzheimer-s-disease-clinical-evidence-and-possible-mechanism-of-neurogenesis
#14
Wen-Ting Yang, Xia-Wei Zheng, Shuang Chen, Chun-Shuo Shan, Qing-Qing Xu, Jia-Zhen Zhu, Xiao-Yi Bao, Yan Lin, Guo-Qing Zheng, Yan Wang
Currently, there is lack of cure or disease-modifying treatment for Alzheimer's disease (AD). Chinese herbal medicine (CHM) is purported to ameliorate AD progression, perhaps by promoting hippocampal neurogenesis. Here, we conducted an updated systematic review to investigate the efficacy and safety of CHM for AD based on high-quality randomized controlled trials (RCTs) and reviewed its possible mechanisms of neurogenesis according to animal-based researches. Twenty eligible studies with 1,767 subjects were identified in eight database searches from inception to February 2017...
July 6, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28687465/on-the-way-to-find-a-cure-purging-latent-hiv-1-reservoirs
#15
REVIEW
Christian Schwartz, Sophie Bouchat, Céline Marban, Virginie Gautier, Carine Van Lint, Olivier Rohr, Valentin Le Douce
Introduction of cART in 1996 has drastically increased the life expectancy of people living with HIV-1. However, this treatment has not allowed cure as cessation of cART is associated with a rapid viral rebound. The main barrier to the eradication of the virus is related to the persistence of latent HIV reservoirs. Evidence is now accumulating that purging the HIV-1 reservoir might lead to a cure or a remission. The most studied strategy is the so called "shock and kill" therapy. This strategy is based on reactivation of dormant viruses from the latently-infected reservoirs (the shock) followed by the eradication of the reservoirs (the kill)...
July 4, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28684305/emerging-roles-of-protein-kinases-in-microglia-mediated-neuroinflammation
#16
REVIEW
Sun-Hwa Lee, Kyoungho Suk
Neuroinflammation is mediated by resident central nervous system glia, neurons, peripherally derived immune cells, blood-brain barrier, and inflammatory mediators secreted from these cells. Neuroinflammation has been implicated in stroke and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Protein kinases have been one of the most exploited therapeutic targets in the current pharmacological research, especially in studies on cancer and inflammation...
July 3, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28684304/sodium-butyrate-regulates-th17-treg-cell-balance-to-ameliorate-uveitis-via-the-nrf2-ho-1-pathway
#17
Xiaoqing Chen, Wenru Su, Taoshang Wan, Jianfeng Yu, Wenjie Zhu, Fen Tang, Guangming Liu, Nancy Olsen, Dan Liang, Song Guo Zheng
Autoimmune uveitis, a group of potentially blinding intraocular inflammatory diseases, remains a therapeutic challenge for ophthalmologists. Butyrates, which belong to the short-chain fatty acid family, possess immunomodulatory properties and therapeutic potential in several inflammatory disorders. However, the roles of butyrates in uveitis and their underlying immunomodulatory mechanisms remain elusive. Here, we report that treatment with sodium butyrate (NaB) significantly attenuated the ocular inflammatory response in mice with experimental autoimmune uveitis (EAU) at 14days after immunization, with significant decreases in inflammatory cell infiltration and inflammatory cytokine production in the retinas...
July 3, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28676433/the-neurotoxicant-pcb-95-by-increasing-the-neuronal-transcriptional-repressor-rest-down-regulates-caspase-8-and-increases-ripk1-ripk3-and-mlkl-expression-determining-necroptotic-neuronal-death
#18
Natascia Guida, Giusy Laudati, Angelo Serani, Luigi Mascolo, Pasquale Molinaro, Paolo Montuori, Gianfranco Di Renzo, Lorella Mt Canzoniero, Luigi Formisano
Our previous study showed that the environmental neurotoxicant non-dioxin-like polychlorinated biphenyl (PCB)-95 increases RE1-Silencing Transcription Factor (REST) expression, which is related to necrosis, but not apoptosis, of neurons. Meanwhile, necroptosis is a type of a programmed necrosis that is positively regulated by receptor interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like (MLKL) and negatively regulated by caspase-8. Here we evaluated whether necroptosis contributes to PCB-95-induced neuronal death through REST up-regulation...
July 1, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28673807/walsuronoid-b-induces-mitochondrial-and-lysosomal-dysfunction-leading-to-apoptotic-rather-than-autophagic-cell-death-via-ros-p53-signaling-pathways-in-liver-cancer
#19
Ya-di Geng, Chao Zhang, Jian-Li Lei, Pei Yu, Yuan-Zheng Xia, Hao Zhang, Lei Yang, Ling-Yi Kong
Walsuronoid B is a limonoid compound extracted from Walsura robusta. Previous studies have shown that limonoid compounds possess anti-cancer potential, although the molecular mechanism of this activity remains elusive. In this study, we demonstrated for the first time that walsuronoid B inhibited cell proliferation in several human cancer lines. Liver cancer cells (HepG2 and Bel-7402) were chosen for their high sensitivity to walsuronoid B. Walsuronoid B induced cell death through G2/M phase arrest and apoptosis and induced the accumulation of autophagosomes through the suppression of mTOR signaling, which serves as a cell survival mechanism and prevents cell death...
June 30, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28669564/eriocalyxin-b-a-novel-autophagy-inducer-exerts-anti-tumor-activity-through-the-suppression-of-akt-mtor-p70s6k-signaling-pathway-in-breast-cancer
#20
Xunian Zhou, Grace Gar-Lee Yue, Andrew Man-Lok Chan, Stephen Kwok-Wing Tsui, Kwok-Pui Fung, Handong Sun, Jianxin Pu, Clara Bik-San Lau
Eriocalyxin B (EriB), a natural ent-kaurane diterpenoid presented in the plant Isodon eriocalyx var. laxiflora, has been reported to diminish angiogenesis-dependent breast tumor growth. In the present study, the effects of EriBon human breast cancer and its underlying mechanisms were further investigated. The in vitro anti-breast cancer activity of EriB was determined using MCF-7 and MDA-MB-231 cell lines. MDA-MB-231 xenograft model of human breast cancer was also established to explore the anti-tumor effect in vivo...
June 29, 2017: Biochemical Pharmacology
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