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Biochemical Pharmacology | Page 2

Alexandre Connolly, Brian Holleran, Élie Simard, Jean-Patrice Baillargeon, Pierre Lavigne, Richard Leduc
The signaling mechanisms of the angiotensin II type 2 receptor (AT2 R), a heptahelical receptor, have not yet been clearly and completely defined. In the present contribution, we set out to identify the molecular determinants involved in AT2 R activation. Although AT2 R has not been shown to engage Gq/11 , G12 , Gi2 , and β-arrestin (βarr) pathways as does the AT1 R upon angiotensin II (AngII) stimulation, the atypical positioning of helix VIII in the recently published AT2 R structure may play a role in the receptor's capacity to couple to downstream effectors...
July 23, 2019: Biochemical Pharmacology
Lichao Chen, Akemi Gunji, Akiko Uemura, Hisako Fujihara, Kentaro Nakamoto, Takae Onodera, Yuka Sasaki, Shoji Imamichi, Mayu Isumi, Tadashige Nozaki, Nobuo Kamada, Kou-Ichi Jishage, Mitsuko Masutani
Poly(ADP-ribose) glycohydrolase (Parg) is a central enzyme for poly(ADP-ribose) degradation. We established a Parg+/- mice strain by deletion of a part of exon 1 and around 0.4-kb upstream of sequences of the Parg gene. Parg-/- embryos obtained by intercrossing the Parg+/- mice died in utero between 4.5 and 9.5 days postcoitum. We examined whether poly(ADP-ribose) polymerase-1 (Parp-1) deficiency could rescue embryonic lethality of Parg-/- mice. Parg-/- Parp-1-/- mice were born viable at a reduced frequency from the expected mendelian ratio in the intercross progeny of Parg+/- Parp-1-/- mice...
July 18, 2019: Biochemical Pharmacology
M A Karwad, D G Couch, K L Wright, C Tufarelli, M Larvin, J Lund, S E O'Sullivan
BACKGROUND AND PURPOSE: We have previously reported that endocannabinoids modulate permeability in Caco-2 cells under inflammatory conditions and hypothesised in the present study that endocannabinoids could also modulate permeability in ischemia/reperfusion. EXPERIMENTAL APPROACH: Caco-2 cells were grown on cell culture inserts to confluence. Trans-epithelial electrical resistance (TEER) was used to measure permeability. To generate hypoxia (0% O2 ), a GasPak™ EZ anaerobe pouch system was used...
July 17, 2019: Biochemical Pharmacology
Katia Beider, Hanna Bitner, Valeria Voevoda-Dimenshtein, Evgenia Rosenberg, Yaarit Sirovsky, Hila Magen, Jonathan Canaani, Olga Ostrovsky, Noya Shilo, Avichai Shimoni, Michal Abraham, Lola Weiss, Michael Milyavsky, Amnon Peled, Arnon Nagler
Although having promising anti-myeloma properties, the pan-histone deacetylase inhibitor (HDACi) panobinostat lacks therapeutic activity as a single agent. The aim of the current study was to elucidate the mechanisms underlying multiple myeloma (MM) resistance to panobinostat monotherapy and to define strategies to overcome it. Sensitivity of MM cell lines and primary CD138+ cells from MM patients to panobinostat correlated with reduced expression of the chemokine receptor CXCR4, whereas overexpression of CXCR4 in MM cell lines increased their resistance to panobinostat...
July 17, 2019: Biochemical Pharmacology
Hans-Peter Gerber, Leah V Sibener, Luke J Lee, Marvin Gee
High-potency oncology compounds such as antibody- drug conjugates, T cell redirecting, and CAR-T cell therapies have provided transformational responses in patients with liquid tumors. However, they delivered only limited benefit to solid tumor patients due to the frequent onset of dose limiting toxicities in normal tissues. Such on-target, off-tumor toxicities are caused by recognition of targets present at low-levels on normal tissues. The apparent imbalance between the rapid development of high-potency therapeutic modalities and the slow progress in identification of cleaner targets is illustrated by the fact that most high-potency compounds currently developed in the clinic target cell surface antigens identified over 20 years ago...
July 16, 2019: Biochemical Pharmacology
George Anderson
A plethora of factors contribute to the biochemical underpinnings of breast cancer, in the absence of any clear, integrative framework. This article proposes that melatonergic pathway regulation within mitochondria provides an integrative framework for the wide array of data driving breast cancer pathophysiology. As melatonin is toxic to breast cancer cells, its production within mitochondria poses a significant challenge to breast cancer cell survival. Consequently, the diverse plasticity in breast cancer cells may arise from a requirement to decrease mitochondria melatonin synthesis...
July 13, 2019: Biochemical Pharmacology
Bryan Mackowiak, Linhao Li, Caitlin Lynch, Andrew Ziman, Scott Heyward, Menghang Xia, Hongbing Wang
The constitutive androstane receptor (CAR) plays an important role in hepatic drug metabolism and detoxification but has recently been projected as a potential drug target for metabolic disorders due to its repression of lipogenesis and gluconeogenesis. Thus, identification of physiologically-relevant CAR modulators has garnered significant interest. Here, we adapted the previously characterized human CAR (hCAR) nuclear translocation assay in human primary hepatocytes (HPH) to a high-content format and screened an FDA-approved drug library containing 978 compounds...
July 12, 2019: Biochemical Pharmacology
Gregory C Sartor
Identifying novel therapeutics for the treatment of substance use disorder (SUD) is an area of intensive investigation. Prior strategies that have attempted to modify one or a few neurotransmitter receptors have had limited success, and currently there are no FDA-approved medications for the treatment of cocaine, methamphetamine, and marijuana use disorders. Because drugs of abuse are known to alter the expression of numerous genes in reward-related brain regions, epigenetic-based therapies have emerged as intriguing targets for therapeutic innovation...
July 12, 2019: Biochemical Pharmacology
Xi Feng, Pei Shen, Yinuo Wang, Zhiyu Li, Jinlei Bian
Targeting Trp-Kyn pathways has been identified as an attractive approach for the cancer immunotherapies. In this study, a novel phosphonamidate containing compound was designed, synthesized and evaluated for its inhibitory activity against key dioxygenases in Trp-Kyn pathway, including IDO1, IDO2 and TDO. This compound showed potent IDO1 inhibitory activity with an IC50 value of 94 nM in an enzymatic assay and 12.6 nM in HeLa cells. In addition, this compound showed promising IDO2 inhibition and TDO inhibition with IC50 values of 310 nM and 2...
July 12, 2019: Biochemical Pharmacology
Chiara Bianca Maria Platania, Francesca Lazzara, Annamaria Fidilio, Claudia Fresta, Federica Conti, Giovanni Giurdanella, Gian Marco Leggio, Salvatore Salomone, Filippo Drago, Claudio Bucolo
Blood retinal barrier (BRB) breakdown is a hallmark of diabetic retinopathy, whose occurrence in early or later phases of the disease has not yet been completely clarified. Recent evidence suggests that hyperglycemia induces activation of the P2X7 receptor (P2X7R) leading to pericyte cell death. We herein investigated the role of P2X7R on retinal endothelial cells viability and expression of tight- and adherens-junctions following high glucose (HG) exposure. We found that HG elicited P2X7R activation and expression and release of the pro-inflammatory cytokine IL-1β in human retinal endothelial cells (HRECs)...
July 11, 2019: Biochemical Pharmacology
Christine C Gana, Kimberley M Hanssen, Denise M T Yu, Claudia L Flemming, Madeleine S Wheatley, Gwenaëlle Conseil, Susan P C Cole, Murray D Norris, Michelle Haber, Jamie I Fletcher
Members of the ABC transporter family, particularly P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP, ABCG2) and multidrug resistance protein 1 (MRP1, ABCC1) are well characterized mediators of multidrug resistance, however their pharmacological inhibition has so far failed as a clinical strategy. Harnessing collateral sensitivity, a form a synthetic lethality where cells with acquired multidrug resistance exhibit hypersensitivity to unrelated agents, may be an alternative approach to targeting multidrug resistant tumour cells...
July 11, 2019: Biochemical Pharmacology
Yannan Liu, Daidi Fan
Ginsenoside Rg5, a rare saponin belonging to the family of protopanaxadiol ginsenosides, has been demonstrated to have potential anti-tumor effects in various cancers. However, the effect of Rg5 on human gastric cancer and the underlying molecular mechanisms remain to be elucidated. In this study, Rg5 could suppress cell proliferation by causing G2/M phase arrest. Treatment with Rg5 could induce apoptosis through the extrinsic death receptor and intrinsic mitochondrial pathways. Autophagy induction was demonstrated by the formation of autophagosomes and autophagy-related proteins...
July 10, 2019: Biochemical Pharmacology
Magdalena Kotańska, Kamil Mika, Karolina Reguła, Katarzyna Szczepańska, Małgorzata Szafarz, Marek Bednarski, Agnieszka Olejarz-Maciej, Katarzyna Nowak, Gniewomir Latacz, Szczepan Mogilski, Kamil J Kuder, Katarzyna Kieć-Kononowicz, Jacek Sapa
AIMS: Histamine H3 receptors ligands act anorectic by blocking the H3 autoreceptors in the CNS, that results in increased synthesis and disinhibition of histamine release. Histamine further influencing H1 receptors participates in the leptin-dependent inhibition of food intake. It also affects the peripheral metabolism by increasing white adipose tissue lipolysis. Thus, ligands such as KSK19 with significant antagonistic properties at the H3 receptor might serve as an useful treatment for obesity...
July 8, 2019: Biochemical Pharmacology
Heather K Knych, Russell W Baden, Sophie R Gretler, Daniel S McKemie
Despite their widespread popularity as sport and companion animals and published and anecdotal reports of vast difference in drug disposition and pharmacokinetics between individuals, studies describing equine drug metabolism are limited. It has been theorized that similar to humans, members of the CYP2D family in horses may be polymorphic in nature leading to differences in metabolism of substrates. This study aims to build on the limited current knowledge regarding P450 mediated metabolism in horses by describing the metabolism of the polymorphic CYP2D6 probe drug codeine in vitro...
July 8, 2019: Biochemical Pharmacology
Brionna D Davis-Reyes, Veronica M Campbell, Michelle A Land, Holly L Chapman, Susan J Stafford, Noelle C Anastasio
Impulsivity is a multifaceted behavioral manifestation with implications in several neuropsychiatric disorders. Glutamate neurotransmission through the N-methyl-D-aspartate receptors (NMDARs) in the medial prefrontal cortex (mPFC), an important brain region in decision-making and goal-directed behaviors, plays a key role in motor impulsivity. We discovered that inherent motor impulsivity predicted responsiveness to D-cycloserine (DCS), a partial NMDAR agonist, which prompted the hypothesis that inherent motor impulsivity is associated with the pattern of expression of cortical NMDAR subunits (GluN1, GluN2A, GluN2B), specifically the protein levels and synaptosomal trafficking of the NMDAR subunits...
July 8, 2019: Biochemical Pharmacology
Maria Di Girolamo, Gaia Fabrizio
Mono-ADP-ribosylation is a reversible post-translational protein modification that modulates the function of proteins involved in different cellular processes, including signal transduction, protein transport, transcription, cell cycle regulation, DNA repair and apoptosis. In mammals, mono-ADP-ribosylation is mainly catalyzed by members of two different classes of enzymes: ARTCs and ARTDs. The human ARTC family is composed of four structurally related ecto-mono-ARTs, expressed at the cell surface or secreted into the extracellular compartment that are either active mono-ARTs (hARTC1, hARTC5) or inactive proteins (hARTC3, hARTC4)...
July 5, 2019: Biochemical Pharmacology
Jonasz Jeremiasz Weber, Laura Emily Clemensson, Helgi Birgir Schiöth, Huu Phuc Nguyen
Over the last years, the experimental compound olesoxime, a mitochondria-targeting cholesterol derivative, has emerged as a promising drug candidate for neurodegenerative diseases. Numerous preclinical studies have successfully proved olesoxime's neuroprotective properties in cell and animal models of clinical conditions such as amyotrophic lateral sclerosis, Huntington disease, Parkinson disease, peripheral neuropathy and spinal muscular atrophy. The beneficial effects were attributed to olesoxime's potential impact on oxidative stress, mitochondrial permeability transition or cholesterol homoeostasis...
July 5, 2019: Biochemical Pharmacology
Daniel Lavall, Nadine Jacobs, Felix Mahfoud, Peter Kolkhof, Michael Böhm, Ulrich Laufs
Mineralocorticoid receptor (MR) overactivation promotes cardiac fibrosis. We studied the ability of the non-steroidal MR antagonist finerenone to prevent fibrotic remodeling. In neonatal rat cardiac fibroblasts, finerenone prevented aldosterone-induced nuclear MR translocation. Treatment with finerenone decreased the expression of connective tissue growth factor (CTGF) (74±15% of control, p=0.005) and prevented aldosterone-induced upregulation of CTGF and lysyl oxidase (LOX) completely. Finerenone attenuated the upregulation of transforming growth factor ß (TGF-ß), which was induced by the Rac1 GTPase activator L-buthionine sulfoximine...
July 5, 2019: Biochemical Pharmacology
Jorge William Vargas-Franco, Beatriz Castaneda, Andrea Gama, Christopher Mueller, Dominique Heymann, Françoise Rédini, Frédéric Lézot
Zoledronic acid (ZOL), a nitrogen bisphosphonate (N-BP), is currently used to treat and control pediatric osteolytic diseases. Variations in the intensity of the effects and side effects of N-BPs have been reported with no clear explanations regarding their origins. We wonder if such variations could be associated with different levels of RANKL signaling activity in growing bone during and after the treatment with N-BPs. To answer this question, ZOL was injected into neonate C57BL/6J mice with different genetically-determined RANKL signaling activity levels (Opg+/+ \RankTg- , Opg+/+ \RankTg+ , Opg+/- \RankTg- , Opg+/- \RankTg+ , Opg-/- \RankTg- and Opg-/- \RankTg+ mice) following a protocol (4 injections from post-natal day 1 to 7 at the dose of 50 μg/kg) that mimics those used in onco-pediatric patients...
June 28, 2019: Biochemical Pharmacology
Peter Bai, Palmiro Poltronieri, Mariella Di Girolamo
No abstract text is available yet for this article.
June 27, 2019: Biochemical Pharmacology
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