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Stargazin differentially modulates ampakine gating kinetics and pharmacology.
Abstract It was previously reported that Stargazin (STG) enhances the surface expression of AMPA receptors, controls receptor gating and slows channel desensitization as an auxiliary subunit of the receptors. Ampakines are a class of AMPA receptor positive allosteric modulators that modify rates of transmitter binding, channel activity and desensitization parameters. As such, they have shown efficacy in animal models of neurodegenerative diseases, where excitatory synaptic transmission is compromised. Given the functional similarities between STG and ampakines, the current study sought to probe interactions betwee...
Source: Biochemical Pharmacology - January 9, 2018 Category: Drugs & Pharmacology Authors: Radin DP, Li YX, Rogers G, Purcell R, Lippa A Tags: Biochem Pharmacol Source Type: research

Regulation of vascular tone homeostasis by NO and H2S: Implications in hypertension.
Abstract Nitric oxide (NO) and hydrogen sulfide (H2S) are two gasotransmitters that are produced in the vasculature and contribute to the regulation of vascular tone. NO and H2S are synthesized in both vascular smooth muscle and endothelial cells; NO functions primarily through the sGC/cGMP pathway, and H2S mainly through activation of the ATP-dependent potassium channels; both leading to relaxation of vascular smooth muscle cells. A deficit in the NO/H2S homeostasis is involved in the pathogenesis of various cardiovascular diseases, especially hypertension. It is now becoming increasingly clear that there are imp...
Source: Biochemical Pharmacology - January 9, 2018 Category: Drugs & Pharmacology Authors: Gheibi S, Jeddi S, Kashfi K, Ghasemi A Tags: Biochem Pharmacol Source Type: research

Protein complexes as psychiatric and neurological drug targets.
Discussion of the TARP-dependent AMPA receptor antagonists has been presented elsewhere. Here we review the diversity of protein complexes of neurotransmitter receptors in the nervous system to highlight the broad range of protein/protein drug targets. We briefly outline the structural basis of protein complexes as drug targets for G-protein-coupled receptors, voltage-gated ion channels, and ligand-gated ion channels. This review highlights heterodimers, subunit-specific receptor constructions, multiple signaling pathways, and auxiliary proteins with an emphasis on the later. We conclude that the use of auxiliary proteins ...
Source: Biochemical Pharmacology - January 9, 2018 Category: Drugs & Pharmacology Authors: Kato AS, Witkin JM Tags: Biochem Pharmacol Source Type: research

The structural determinants of the bitopic binding mode of a negative allosteric modulator of the dopamine D2 receptor.
In this study, we aimed to understand the ligand-receptor interactions that confer its allosteric action. We combined site-directed mutagenesis with molecular dynamics simulations using both SB269652 and derivatives from our previous structure activity studies. We identify residues within the conserved orthosteric binding site (OBS) and a secondary binding pocket (SBP) that determine affinity and cooperativity. Our results indicate that interaction with the SBP is a requirement for allosteric pharmacology, but that both competitive and allosteric derivatives of SB269652 can display sensitivity to the mutation of a glutamat...
Source: Biochemical Pharmacology - January 8, 2018 Category: Drugs & Pharmacology Authors: Draper-Joyce CJ, Michino M, Verma RK, Herenbrink CK, Shonberg J, Kopinathan A, Scammells PJ, Capuano B, Thal DM, Javitch JA, Christopoulos A, Shi L, Lane JR Tags: Biochem Pharmacol Source Type: research

Biochemical basis for pharmacological intervention as a reprogramming strategy against hypertension and kidney disease of developmental origin.
Abstract The concept of "developmental origins of health and disease" (DOHaD) stipulates that both hypertension and kidney disease may take origin from early-life insults. The DOHaD concept also offers reprogramming strategies aiming at shifting therapeutic interventions from adulthood to early life, even before clinical symptoms are evident. Based on those two concepts, this review will present the evidence for the existence of, and the programming mechanisms in, kidney developmental programming that may lead to hypertension and kidney disease. This will be followed by potential pharmacological interven...
Source: Biochemical Pharmacology - January 5, 2018 Category: Drugs & Pharmacology Authors: Tain YL, Chan SHH, Chan JYH Tags: Biochem Pharmacol Source Type: research

Dichotomous function of IL-33 in health and disease: from biology to clinical implications.
Abstract Interleukin (IL)-33 is a cytokine that is released from epithelial and endothelial cells at barrier surfaces upon tissue stress or damage to operate as an alarmin. IL-33 has been primarily implicated in the induction of T helper (Th) 2 type immune responses. Therefore, IL-33 has attracted a lot of interest as a potential therapeutic target in asthma and other allergic diseases. Over the years, it has become clear that IL-33 has a much broader activity and also contributes to Th1 immunity, expanding the possibilities for therapeutic modulation of IL-33 activity to multiple inflammatory diseases. However, m...
Source: Biochemical Pharmacology - January 5, 2018 Category: Drugs & Pharmacology Authors: Braun H, Afonina IS, Mueller C, Beyaert R Tags: Biochem Pharmacol Source Type: research

Doxorubicin resistance in breast cancer: A novel role for the human protein AHNAK.
We report here, for the first time, an association between AHNAK and resistance to doxorubicin. While treatment with doxorubicin modulated AHNAK protein expression both in vitro and in vivo in a dose-dependent manner, no changes in its cellular localization were observed. AHNAK knockdown prevented doxorubicin-induced modulation of cleaved caspase 7 protein expression and cell cycle arrest, while its overexpression decreased cleaved caspase 7 and cleaved PARP levels and induced S-phase arrest, changes that were comparable to the effects of doxorubicin. This novel association was restricted to doxorubicin-resistant cells, im...
Source: Biochemical Pharmacology - January 5, 2018 Category: Drugs & Pharmacology Authors: Davis T, van Niekerk G, Peres J, Prince S, Loos B, Engelbrecht AM Tags: Biochem Pharmacol Source Type: research

Anti-thrombotic efficacy of S007-867: pre-clinical evaluation in experimental models of thrombosis in vivo and in vitro.
Abstract Pharmacological inhibition of platelet collagen interaction is a promising therapeutic strategy to treat intra-vascular thrombosis. S007-867 is a novel synthetic inhibitor of collagen-induced platelet aggregation. It has shown better antithrombotic protection than aspirin and clopidogrel with minimal bleeding tendency in mice. The present study is aimed to systematically investigate the antithrombotic efficacy of S007-867 in comparison to aspirin and clopidogrel in vivo and to delineate its mechanism of action in vitro. Aspirin, clopidogrel, and S007-867 significantly reduced thrombus weight in arterio-ve...
Source: Biochemical Pharmacology - January 5, 2018 Category: Drugs & Pharmacology Authors: Misra A, Prakash P, Aggarwal H, Dhankani P, Kumar S, Pandey CP, Pugh N, Bihan D, Barthwal MK, Farndale RW, Dikshit DK, Dikshit M Tags: Biochem Pharmacol Source Type: research

Kinetics of Oxytocin and Deaminooxytocin Displacement from the Oxtr-Receptor Compartment in Rat Uterus Ex Vivo.
Abstract The oil immersion method suggested earlier by Kalsner and Nickerson for analysing actions of sympathomimetic drugs in smooth muscle tissues was applied to isometric preparations of rat myometrium stimulated by oxytocin and deaminooxytocin. An exchange of the aqueous medium by mineral oil allows monitoring the displacement of the peptides from their receptor compartment in absence of free diffusion transport between tissue and organ medium. Exponential analysis of the data from the uterotonic decay phase allows several inferences to be drawn: 1) Transport rate constants (roughly equal for the two peptides)...
Source: Biochemical Pharmacology - January 5, 2018 Category: Drugs & Pharmacology Authors: Pliska V, Jutz G Tags: Biochem Pharmacol Source Type: research

Heme oxygenase-1 induction by rosiglitazone via PKC α/AMPKα/p38 MAPKα/SIRT1/PPARγ pathway suppresses lipopolysaccharide-mediated pulmonary inflammation.
In this study, we found that upregulation of HO-1 in vitro or in vivo by rosiglitazone attenuated VCAM-1 gene expression and monocyte adhesion to HPAEpiCs challenged with lipopolysaccharide (LPS). The inhibitory effects of rosiglitazone on LPS-mediated responses were reversed by transfection with HO-1 siRNA. LPS-induced VCAM-1 expression was mediated through NF-κB activation which was attenuated by rosiglitazone via suppressing p65 activation and translocation into the nucleus. Moreover, pretreatment with the inhibitor of PKCs (H7), PKCα (Gö6976), AMPKα (Compound C), p38 MAPKα (p38i VIII), SIRT...
Source: Biochemical Pharmacology - January 5, 2018 Category: Drugs & Pharmacology Authors: Cho RL, Lin WN, Wang CY, Yang CC, Hsiao LD, Lin CC, Yang CM Tags: Biochem Pharmacol Source Type: research

Activation of nuclear receptor PXR impairs glucose tolerance and dysregulates GLUT2 expression and subcellular localization in liver.
, Hakkola J Abstract Pregnane X receptor (PXR) is a nuclear receptor that senses chemical environment and is activated by numerous clinically used drugs and environmental contaminants. Previous studies have indicated that several drugs known to activate PXR appear to induce glucose intolerance. We now aimed to reveal the role of PXR in drug-induced glucose intolerance and characterize the mechanisms involved. We used PXR knockout mice model to investigate the significance of this nuclear receptor in the regulation of glucose tolerance. PXR ligand pregnenolone-16ɑ-carbonitrile (PCN) impaired glucose tolerance in t...
Source: Biochemical Pharmacology - January 5, 2018 Category: Drugs & Pharmacology Authors: Hassani-Nezhad-Gashti F, Rysä J, Kummu O, Näpänkangas J, Buler M, Karpale M, Hukkanen J, Hakkola J Tags: Biochem Pharmacol Source Type: research

Cracking the Regulatory Code of Biosynthetic Gene Clusters as a Strategy for Natural Product Discovery.
Wezel GPV Abstract The World Health Organization (WHO) describes antibiotic resistance as "one of the biggest threats to global health, food security, and development today", as the number of multi- and pan-resistant bacteria is rising dangerously. Acquired resistance phenomena also impair antifungals, antivirals, anti-cancer drug therapy, while herbicide resistance in weeds threatens the crop industry. On the positive side, it is likely that the chemical space of natural products goes far beyond what has currently been discovered. This idea is fueled by genome sequencing of microorganisms which unveile...
Source: Biochemical Pharmacology - January 5, 2018 Category: Drugs & Pharmacology Authors: Rigali S, Anderssen S, Naômé A, Wezel GPV Tags: Biochem Pharmacol Source Type: research

Manipulating Cell Fate While Confronting Reproducibility Concerns.
Abstract Biomedical research is being transformed by the discovery and use of human pluripotent stem cells (hPSCs). Remarkable progress has been made, and assorted clinical trials are underway related to the application of stem cell therapy, including transplantation of hPSC-derived cells, in situ reprogramming or transdifferentiation, and utilization of targets and compounds identified from patient-derived stem cells. However, the pace of discovery is overwhelming efforts to replicate the work of others, prompting a concern over validity and reproducibility. Here, we address some sources of variability in reprogr...
Source: Biochemical Pharmacology - January 5, 2018 Category: Drugs & Pharmacology Authors: Osterloh JM, Mullane K Tags: Biochem Pharmacol Source Type: research

Adipokine apelin ameliorates chronic colitis in Il-10-/- mice by promoting intestinal lymphatic functions.
Abstract Both mesenteric adipose tissue (MAT) and lymphatic vessels (LVs) play important roles in the pathogenesis of Crohn's disease (CD), and adipokines have been implicated in the crosstalk between MAT and LVs. Apelin, a newly identified adipokine, has been demonstrated to be crucial in the development and stabilization of LVs. We aimed to identify the expression of apelin in MAT of CD patients and explore whether apelin influences the disease course in murine colitis and determine its contributions to LVs. Expression of apelin in MAT specimens from patients with CD (n=24) and without CD (control, n=12) was det...
Source: Biochemical Pharmacology - January 5, 2018 Category: Drugs & Pharmacology Authors: Ge Y, Li Y, Chen Q, Zhu W, Zuo L, Guo Z, Gong J, Cao L, Gu L, Li J Tags: Biochem Pharmacol Source Type: research

Molecular dissection of the human A3 adenosine receptor coupling with β-arrestin2.
In conclusion, other parts of the human A3AR, either cytosolic or exposed upon receptor activation, rather than the C-terminus alone, are responsible for βarr2 recruitment in a complementary or synergistic way. PMID: 29309765 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - January 5, 2018 Category: Drugs & Pharmacology Authors: Storme J, Cannaert A, Van Craenenbroeck K, Stove CP Tags: Biochem Pharmacol Source Type: research

Heme oxygnease-1 induction by methylene blue protects RAW264.7 cells from hydrogen peroxide-induced injury.
Abstract Althoughmethylene blue (MB) has showed strong antioxidant effect, its effect related with heme oxygenase-1(HO-1) is still unclear. Thus, we investigated the effects of MB on HO-1 protein content and enzyme activity, and its protective effect against hydrogen peroxide (H2O2)- induced oxidative damage in RAW264.7 macrophage. The cellviability and the release of lactate dehydrogenase of RAW264.7 were determined. The mitochondrial functions were valuated through these indexes: content of adenosine triphosphate, superoxide dismutase, concentration of reactive oxygen species and mitochondrial membrane potential...
Source: Biochemical Pharmacology - January 5, 2018 Category: Drugs & Pharmacology Authors: Zhang XT, Sun XQ, Wu C, Chen JL, Yuan JJ, Pang QF, Wang ZP Tags: Biochem Pharmacol Source Type: research

Time and dose-dependenceevaluation of nitroheterocyclic drugs for improving efficacy following Trypanosoma cruzi infection: a pre-clinical study.
This study was designed to evaluate the time and dose dependence for efficacy of the most important nitroheterocyclic drugs in use for Chagas disease. In order to evaluate time dependence, Y strain-infected mice received benznidazole for a total of 1, 3, 7, 10, 20, and 40 days. Treatment courses of 3 to 10-day were effective in clearing parasitaemia and suppressing mortality, but parasitological cure was not achieved. Extending the treatments to 20 or 40 days clearly improved benznidazole efficacy. The 20-day treatment induced cure in 57.1% of Y strain infections (partially drug resistant) but failed to cure Colombian stra...
Source: Biochemical Pharmacology - January 5, 2018 Category: Drugs & Pharmacology Authors: Lia Mazzeti A, de F Diniz L, Gonçalves KR, Nascimento AFS, Spósito PAF, Mosqueira VCF, Machado-Coelho GLL, Ribeiro I, Bahia MT Tags: Biochem Pharmacol Source Type: research

Hydrogen sulfide in the regulation of insulin secretion and insulin sensitivity: Implications for the pathogenesis and treatment of diabetes mellitus.
ska A Abstract Insulin secretion and sensitivity play an essential role in maintaining normal glucose level and their abnormalities result in diabetes mellitus. H2S-synthesizing enzymes, CBS and/or CSE, are expressed in insulin-secreting pancreatic β cells and H2S inhibits insulin secretion by activating ATP-sensitive K+ channels. In addition, H2S has been reported to have either pro- or antiapoptotic effects on β cells. Studies in the animal models suggest that excess of H2S in pancreatic islets may contribute to both type 1 and type 2 diabetes. H2S has also been demonstrated to regulate insulin sensiti...
Source: Biochemical Pharmacology - January 4, 2018 Category: Drugs & Pharmacology Authors: Bełtowski J, Wójcicka G, Jamroz-Wiśniewska A Tags: Biochem Pharmacol Source Type: research

Integration of biological/pathophysiogical contexts to help clarify genotype-phenotype mismatches in monogenetic diseases. Childhood epilepsies associated with SCN2A as a case study.
Abstract Monogenetic diseases offer clear human validation for launching drug discovery programs in Pharma designed to develop important new medicines for unmet medical needs. However, mismatches in the genotype-phenotype of presenting patients complicates both the preclinical 'research target profile' and the clinical development strategy. Additional biological and pathophysiological data associated with the identified mutations are necessary for more optimal prosecution of these drug discovery programs. This added contextual setting goes beyond identification of modifier genes and needs to encompass microenviron...
Source: Biochemical Pharmacology - January 4, 2018 Category: Drugs & Pharmacology Authors: Winquist RJ, Cohen CJ Tags: Biochem Pharmacol Source Type: research

Astrocytes in Primary Cultures Express Serine Racemase, Synthesize D-Serine and Acquire A1 Reactive Astrocyte Features.
Abstract D-Serine is a co-agonist at forebrain N-methyl-D-aspartate receptors (NMDAR) and is synthesized by serine racemase (SR). Although D-serine and SR were originally reported to be localized to glia, recent studies have provided compelling evidence that under healthy physiologic conditions both are localized primarily in neurons. However, in pathologic conditions, reactive astrocytes can also express SR and synthesize D-serine. Since cultured astrocytes exhibit features of reactive astrocytes, we have characterized D-serine synthesis and the expression of enzymes involved in its disposition in primary glial c...
Source: Biochemical Pharmacology - January 3, 2018 Category: Drugs & Pharmacology Authors: Li S, Uno Y, Rudolph U, Cobb J, Liu J, Anderson T, Levy D, Balu DT, Coyle JT Tags: Biochem Pharmacol Source Type: research

Microglia-derived extracellular vesicles in Alzheimer's Disease: a double-edged sword.
Abstract Extracellular vesicles (EVs), based on their origin or size, can be classified as apoptotic bodies, microvesicles (MVs)/microparticles (MPs), and exosomes. EVs are one of the new emerging modes of communication between cells that are providing new insights into the pathophysiology of several diseases. EVs released from activated or apoptotic cells contain specific proteins (signaling molecules, receptors, integrins, cytokines), bioactive lipids, nucleic acids (mRNA, miRNA, small non coding RNAs, DNA) from their progenitor cells. In the brain, EVs contribute to intercellular communication through their bas...
Source: Biochemical Pharmacology - January 3, 2018 Category: Drugs & Pharmacology Authors: Trotta T, Panaro MA, Cianciulli A, Mori G, Di Benedetto A, Porro C Tags: Biochem Pharmacol Source Type: research

Expression and regulation of proton-coupled oligopeptide transporters in colonic tissue and immune cells of mice.
Abstract A number of studies have implicated proton-coupled oligopeptide transporters (POTs) in the initiation and/or progression of inflammatory bowel disease and immune cell signaling. With this in mind, the aim of this study was to delineate the expression of POTs in mouse colonic tissues and immune cells, and characterize the potential role of these transporters in nucleotide-binding oligomerization domain (NOD) signaling. Using a dextran sodium sulfate (DSS)-induced colitis mouse model, we found that DSS down regulated Pht1 gene expression and up regulated Pht2 gene expression in colonic tissue and immune cel...
Source: Biochemical Pharmacology - January 3, 2018 Category: Drugs & Pharmacology Authors: Wang Y, Hu Y, Li P, Weng Y, Kamada N, Jiang H, Smith DE Tags: Biochem Pharmacol Source Type: research

A Binding Kinetics Study of Human Adenosine A3 Receptor Agonists.
In this study, we first validated a competition association assay for adenosine A3 receptor agonists to determine the target interaction kinetics. Affinities and Kinetic Rate Index (KRI) values of 11 ribofurano and 10 methanocarba nucleosides were determined in radioligand binding assays. Afterwards, 15 analogues were further selected (KRI 1.35) for full kinetics characterization. The structure-kinetics relationships (SKRs) were derived and longer residence times were associated with methanocarba and enlarged adenine N6 and C2 substitutions. In addition, from a kon-koff-KD kinetic map we divided the agonists into three sub...
Source: Biochemical Pharmacology - January 3, 2018 Category: Drugs & Pharmacology Authors: Xia L, Kyrizaki A, Tosh DK, van Duijl TT, Cornelia Roorda J, Jacobson KA, IJzerman AP, Heitman LH Tags: Biochem Pharmacol Source Type: research

Opening of Voltage Dependent Anion Channels Promotes Reactive Oxygen Species Generation, Mitochondrial Dysfunction and Cell Death in Cancer Cells.
Abstract Enhancement of aerobic glycolysis and suppression of mitochondrial metabolism characterize the pro-proliferative Warburg phenotype of cancer cells. High free tubulin in cancer cells closes voltage dependent anion channels (VDAC) to decrease mitochondrial membrane potential (ΔΨ), an effect antagonized by erastin, the canonical promotor of ferroptosis. Previously, we identified six compounds (X1-X6) that also block tubulin-dependent mitochondrial depolarization. Here, we hypothesized that VDAC opening after erastin and X1-X6 increases mitochondrial metabolism and reactive oxygen species (ROS) form...
Source: Biochemical Pharmacology - December 28, 2017 Category: Drugs & Pharmacology Authors: DeHart DN, Fang D, Heslop K, Li L, Lemasters JJ, Maldonado EN Tags: Biochem Pharmacol Source Type: research

The P2X7 receptor: a main player in inflammation.
Abstract Damage associated molecular patterns (DAMPs) are intracellular molecules released from infected or injured cells to activate inflammatory and reparatory responses. One of the most ancient and conserved DAMPs is extracellular ATP (eATP) that exerts its phlogistic activity mainly through activation of the P2X7 receptor (P2X7R). The P2X7 is an ATP gated ion channel, expressed by most immune cells, including the monocyte-derived cell lineages, T and B lymphocytes an their precursors. Here we give an overview of recent and established literature on the role of P2X7R in septic and sterile inflammation. P2X7R ab...
Source: Biochemical Pharmacology - December 27, 2017 Category: Drugs & Pharmacology Authors: Adinolfi E, Lisa Giuliani A, De Marchi E, Pegoraro A, Orioli E, Di Virgilio F Tags: Biochem Pharmacol Source Type: research

The biology and therapeutic management of melanoma brain metastases.
Abstract The recent years have seen significant progress in the development of systemic therapies to treat patients with advanced melanoma. Use of these new treatment modalities, which include immune checkpoint inhibitors and small molecule BRAF inhibitors, lead to increased overall survival and better outcomes. Although revolutionary, these therapies are often less effective against melanoma brain metastases, and frequently the CNS is the major site of treatment failure. The development of brain metastases remains a serious complication of advanced melanoma that is associated with significant morbidity and mortal...
Source: Biochemical Pharmacology - December 23, 2017 Category: Drugs & Pharmacology Authors: Abate-Daga D, Ramello MC, Smalley I, Forsyth PA, Smalley KSM Tags: Biochem Pharmacol Source Type: research

Genetic polymorphisms of drug-metabolizing cytochrome P450 enzymes in cynomolgus and rhesus monkeys and common marmosets in preclinical studies for humans.
Abstract Cynomolgus monkeys (Macaca fascicularis, Old World Monkeys) and common marmosets (Callithrix jacchus, New World Monkeys) have been widely, and expectedly, used as non-human primate models in drug development studies. Major drug-metabolizing cytochrome P450 (P450) enzymes information is now available that supports these primate species as animal models, and it is established that multiple forms of cynomolgus monkey and common marmoset P450 enzymes have generally similar substrate recognition functionality to human P450 enzymes. This research update provides information on genetic polymorphisms of P450 enzy...
Source: Biochemical Pharmacology - December 22, 2017 Category: Drugs & Pharmacology Authors: Uno Y, Uehara S, Yamazaki H Tags: Biochem Pharmacol Source Type: research

Characterisation of signalling and regulation of common calcitonin receptor splice variants and polymorphisms.
Abstract The calcitonin receptor (CTR) is a class B G protein-coupled receptor that is a therapeutic target for the treatment of hypercalcaemia of malignancy, Paget's disease and osteoporosis. In primates, the CTR is subject to alternative splicing, with a unique, primate-specific splice variant being preferentially expressed in reproductive organs, lung and kidney. In addition, humans possess a common non-synonymous single-nucleotide polymorphism (SNP) encoding a proline/leucine substitution in the C-terminal tail. In low power studies, the leucine polymorphism has been associated with increased risk of osteoporo...
Source: Biochemical Pharmacology - December 22, 2017 Category: Drugs & Pharmacology Authors: Dal Maso E, Just R, Hick C, Christopoulos A, Sexton PM, Wootten D, Furness SGB Tags: Biochem Pharmacol Source Type: research

Current mechanistic insights into the CCCP-induced cell survival response.
Abstract The ring-substituted derivatives of carbonyl cyanide phenylhydrazone, CCCP and FCCP, are routinely used for the analysis of the mitochondrial function in living cells, tissues, and isolated mitochondrial preparations. CCCP and FCCP are now being increasingly used for investigating the mechanisms of autophagy by inducing mitochondrial degradation through the disruption of the mitochondrial membrane potential (ΔΨm). Sustained perturbation of ΔΨm, which is normally tightly controlled to ensure cell proliferation and survival, triggers various stress pathways as part of the cellular adapti...
Source: Biochemical Pharmacology - December 22, 2017 Category: Drugs & Pharmacology Authors: Selma Kane M, Paris A, Codron P, Cassereau J, Procaccio V, Lenaers G, Reynier P, Chevrollier A Tags: Biochem Pharmacol Source Type: research

Saikosaponin A inhibits compound 48/80-induced pseudo-allergy via the Mrgprx2 pathway in vitro and in vivo.
Conclusion, SSA could inhibits IgE-independent allergy, but not IgE-dependent allergy, and this effect involves the Mrgprx2 pathway. This study provided a new sight on Pseudo-allergy and its therapy. PMID: 29274317 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - December 20, 2017 Category: Drugs & Pharmacology Authors: Wang N, Che D, Zhang T, Liu R, Cao J, Wang J, Zhao T, Ma P, Dong X, He L Tags: Biochem Pharmacol Source Type: research

Zerumbone Protects Human Skin Keratinocytes against UVA-irradiated Damages through Nrf2 Induction.
Abstract Ultraviolet A (UVA) irradiation is toxic to skin as it penetrates deep into the dermis and damages cellular components through excessive reactive oxygen species (ROS) production, which accelerates photoaging and skin cancer. We evaluated the dermato-protective efficacies of zerumbone (natural sesquiterpene of Zingiber zerumbet) in UVA-irradiated human skin keratinocyte (HaCaT) cells and mouse epidermis. Zerumbone pretreatment (2-10 μM) substantially suppressed UVA (15 J/cm2)-induced HaCaT cell death and lactate dehydrogenase release in a dose-dependent manner. UVA-induced excessive ROS production, DNA ...
Source: Biochemical Pharmacology - December 19, 2017 Category: Drugs & Pharmacology Authors: Yang HL, Lee CL, Korivi M, Liao JW, Rajendran P, Wu JJ, Hseu YC Tags: Biochem Pharmacol Source Type: research

LST-3TM12 is a member of the OATP1B family and a functional transporter.
In conclusion, LST-3TM12 is a functional splice variant of SLCO1B3 and SLCO1B7 expressed in the ER of human liver. PMID: 29248594 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - December 14, 2017 Category: Drugs & Pharmacology Authors: Malagnino V, Hussner J, Seibert I, Stolzenburg A, Sager CP, Meyer Zu Schwabedissen HE Tags: Biochem Pharmacol Source Type: research

Quantification of 11b-Hydroxysteroid Dehydrogenase 1 Kinetics and Pharmacodynamic Effects of Inhibitors in Brain using Mass Spectrometry Imaging and Stable-Isotope Tracers in Mice.
Abstract 11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1; EC 1.1.1.146) generates active glucocorticoid hormones. Small molecule inhibitors have been developed to target 11β-HSD1 for the treatment of dementia; these must enter brain subregions, such as the hippocampus, to be effective. We previously reported mass spectrometry imaging measurement of murine tissue steroids, and deuterated steroid tracer infusion quantification of 11 β -HSD1 turnover in humans. Here, these tools are combined to assess tissue pharmacokinetics and pharmacodynamics of an 11 β -HSD1 inhibitor that accesses the brain...
Source: Biochemical Pharmacology - December 14, 2017 Category: Drugs & Pharmacology Authors: Cobice DF, Livingstone DEW, McBride A, MacKay CL, Walker BR, Webster SP, Andrew R Tags: Biochem Pharmacol Source Type: research

The Wonderland of Neuronal Nicotinic Acetylcholine Receptors.
Abstract Nearly 30 years of experimental evidence supports the argument that ligands of nicotinic acetylcholine receptors (nAChRs) have potential as therapeutic agents. However, as in the famous Lewis Carroll novel "Alice in Wonderland", there have been many unexpected adventures along the pathway of development, and few nAChR ligands have been approved for any clinical condition to date with the exception of nicotine dependence. The recent failures of nAChR ligands in AD and schizophrenia clinical trials have reduced enthusiasm for this therapeutic strategy and many pharmaceutical companies have now aba...
Source: Biochemical Pharmacology - December 14, 2017 Category: Drugs & Pharmacology Authors: Bertrand D, Terry AV Tags: Biochem Pharmacol Source Type: research

H2S and Polysulfide Metabolism: Conventional and Unconventional Pathways.
Abstract It is now well established that hydrogen sulfide (H2S) is an effector of a wide variety of physiological processes. It is also clear that many of the effects of H2S are mediated through reactions with cysteine sulfur on regulatory proteins and most of these are not mediated directly by H2S but require prior oxidation of H2S and the formation of per-and polysulfides (H2Sn, n=2-8). Attendant with understanding the regulatory functions of H2S and H2Sn is an appreciation of the mechanisms that control, ie., both increase and decrease, their production and catabolism. Although number of standard "conventi...
Source: Biochemical Pharmacology - December 14, 2017 Category: Drugs & Pharmacology Authors: Olson KR Tags: Biochem Pharmacol Source Type: research

The Interaction of IGF-1/IGF-1R and Hydrogen Sulfide on the Proliferation of Mouse Primary Vascular Smooth Muscle Cells.
This study provides novel insight on the involvement of IGF-1/IGF-1R in H2S-inhibited SMC proliferation and suggests H2S-based innovative treatment strategies for proliferative cardiovascular diseases such as atherosclerosis. PMID: 29248598 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - December 14, 2017 Category: Drugs & Pharmacology Authors: Shuang T, Fu M, Yang G, Wu L, Wang R Tags: Biochem Pharmacol Source Type: research

How Often Should We Expect to be Wrong? Statistical Power, P Values, and the Expected Prevalence of False Discoveries.
Abstract There is a clear perception in the literature that there is a crisis in reproducibility in the biomedical sciences. Many underlying factors contributing to the prevalence of irreproducible results have been highlighted with a focus on poor design and execution of experiments along with the misuse of statistics. While these factors certainly contribute to irreproducibility, relatively little attention outside of the specialized statistical literature has focused on the expected prevalence of false discoveries under idealized circumstances. In other words, when everything is done correctly, how often should...
Source: Biochemical Pharmacology - December 14, 2017 Category: Drugs & Pharmacology Authors: Marino MJ Tags: Biochem Pharmacol Source Type: research

Mechanism implicated in the anti-allodynic and anti-hyperalgesic effects induced by the activation of heme oxygenase 1/carbon monoxide signaling pathway in the central nervous system of mice with neuropathic pain.
In conclusion, these data reveal new mechanism of action of CORM-2 and CoPP in the central nervous system of animals with persistent neuropathic pain. PMID: 29247614 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - December 13, 2017 Category: Drugs & Pharmacology Authors: Riego G, Redondo A, Leánez S, Pol O Tags: Biochem Pharmacol Source Type: research

Syk and Src-targeted anti-inflammatory activity of aripiprazole, an atypical antipsychotic.
In this study, peptidoglycan (PGN)-treated macrophages (RAW264.7 cells), reporter gene assay, an overexpression strategy, immunoprecipitation, and immunoblotting analysis were employed to clarify the anti-inflammatory mechanism of ARP. ARP was found to dose-dependently inhibit production of nitric oxide (NO) and prostaglandin E2 (PGE2) without exhibiting cytotoxicity. In agreement with this result, ARP was found to suppress the mRNA expression levels of inflammatory genes such as cyclooxygenase-2 (COX-2), inducible NO synthase (iNOS), and tumor necrosis factor (TNF)-α. Luciferase assay and immunoblotting analysis wit...
Source: Biochemical Pharmacology - December 11, 2017 Category: Drugs & Pharmacology Authors: Yoo S, Kim MY, Cho JY Tags: Biochem Pharmacol Source Type: research

Hydrogen sulfide as a regulatory factor in kidney health and disease.
Abstract Hydrogen sulfide (H2S) is synthesized in nearly all organ systems including the kidney. Recent findings have revealed that H2S functions as a gasotransmitter affecting a wide range of physiologic functions similar to other gasotransmitters nitric oxide (NO) and carbon monoxide (CO). Research on H2S regulation of kidney function is still in early stages. H2S increases glomerular filtration rate (GFR) and inhibits sodium absorption by the tubules. There is burgeoning evidence that H2S generation by kidney cells is reduced in acute and chronic disease states and that H2S donors ameliorate injury. However, th...
Source: Biochemical Pharmacology - December 7, 2017 Category: Drugs & Pharmacology Authors: Kasinath BS, Feliers D, Lee HJ Tags: Biochem Pharmacol Source Type: research

On the G protein-coupling selectivity of the native A2B adenosine receptor.
Abstract A2B adenosine receptor (A2BAR) activation induces Gs-dependent cyclic AMP accumulation. However, A2BAR G protein-coupling to other signaling events, e.g. ERK1/2 and calcium, is not well documented. We explored Gi, Gq/11 and Gs coupling in 1321N1 astrocytoma, HEK293, and T24 bladder cancer cells endogenously expressing human A2BAR, using NECA or nonnucleoside BAY60-6583 as agonist, selective Gi, Gs and Gq/11 blockers, and CRISPR/Cas9-based Gq- and Gs-null HEK293 cells. In HEK293 cells, A2BAR-mediated ERK1/2 activity occurred via both Gi and Gs, but not Gq/11. However, HEK293 cell calcium mobilization was c...
Source: Biochemical Pharmacology - December 7, 2017 Category: Drugs & Pharmacology Authors: Gao ZG, Inoue A, Jacobson KA Tags: Biochem Pharmacol Source Type: research

Role of tenofovir alafenamide (TAF) in the treatment and prophylaxis of HIV and HBV infections.
Abstract Tenofovir (TFV) is the cornerstone in the treatment and prophylaxis of HIV infections. It has been routinely used in its prodrug form TDF (tenofovir disoproxil fumarate) combined with emtricitabine ((-)FTC) and other antiretroviral agents. TDF has now been replaced by TAF (tenofovir alafenamide) which allows better uptake by the lymphoid tissue. In combination with elvitegravir (E), cobicistat (C), emtricitabine (F), TAF can be advocated as an STR (single tablet regimen, Genvoya®) for the treatment of HIV infections. In this combination, E and C may in the future be replaced by bictegravir. The prophy...
Source: Biochemical Pharmacology - December 7, 2017 Category: Drugs & Pharmacology Authors: De Clercq E Tags: Biochem Pharmacol Source Type: research

Ginsenoside Rh4 induces apoptosis and autophagic cell death through activation of the ROS/JNK/p53 pathway in colorectal cancer cells.
Abstract The use of ginsenosides in cancer therapy has been intensively investigated. The ginsenoside Rh4 (Rh4), a rare saponin obtained from Panax notoginseng, dissolves in water more readily than total saponins, making this compound easier to use in anti-cancer pharmaceutics. Here, we investigated the antiproliferative activity and mechanisms of Rh4 in colorectal cancer, both in vivo and in vitro. A colorectal cancer xenograft model showed that Rh4 significantly inhibited tumor growth with few side effects. CCK-8 assays, flow cytometric analysis, Western blotting and immunohistochemistry revealed that Rh4 effect...
Source: Biochemical Pharmacology - December 7, 2017 Category: Drugs & Pharmacology Authors: Wu Q, Deng J, Fan D, Duan Z, Zhu C, Fu R, Wang S Tags: Biochem Pharmacol Source Type: research

CK2 α promotes advanced glycation end products-induced expressions of fibronectin and intercellular adhesion molecule-1 via activating MRTF-A in glomerular mesangial cells.
CK2α promotes advanced glycation end products-induced expressions of fibronectin and intercellular adhesion molecule-1 via activating MRTF-A in glomerular mesangial cells. Biochem Pharmacol. 2017 Dec 06;: Authors: Chen Z, Chen Q, Huang J, Gong W, Zou Y, Zhang L, Liu P, Huang H Abstract Advanced glycation end products (AGEs) modification of extracellular matrix proteins induces crosslinking, which results in thickening of the basement membrane and activating several intracellular signaling cascades, eventually promoting the pathological progression of diabetic nephropathy (DN). We have previously...
Source: Biochemical Pharmacology - December 6, 2017 Category: Drugs & Pharmacology Authors: Chen Z, Chen Q, Huang J, Gong W, Zou Y, Zhang L, Liu P, Huang H Tags: Biochem Pharmacol Source Type: research

ATP-binding cassette transporter-2 (ABCA2) as a therapeutic target.
Abstract The ATP binding cassette transporter ABCA2 is primarily an endolysosomal membrane protein that demonstrates pleiotropic functionalities, coalescing around the maintenance of homeostasis of sterols, sphingolipids and cholesterol. It is most highly expressed in brain tissue and ABCA2 knockout mice express neurological defects consistent with aberrant myelination. Increased expression of the transporter has been linked with resistance to cancer drugs, particularly those possessing a steroid backbone and gene expression (in concert with other genes involved in cholesterol metabolism) was found to be regulated...
Source: Biochemical Pharmacology - December 6, 2017 Category: Drugs & Pharmacology Authors: Davis W, Tew KD Tags: Biochem Pharmacol Source Type: research

Dopamine promotes cellular iron accumulation and oxidative stress responses in macrophages.
Abstract Iron is essential for many biological functions including neurotransmitter synthesis, where the metal is a co-factor of tyrosine hydroxylase, which converts tyrosine to dopamine and further to norepinephrine. As the shared chemical structure, called catechol, may potentially bind iron we questioned whether tyrosine derived hormones would impact on cellular iron homeostasis in macrophages, which are central for the maintenance of body iron homeostasis. Using murine bone marrow-derived macrophages (BMDMs), we investigated the effect of catecholamines and found that only dopamine but neither tyrosine, nor no...
Source: Biochemical Pharmacology - December 2, 2017 Category: Drugs & Pharmacology Authors: Dichtl S, Haschka D, Nairz M, Seifert M, Volani C, Lutz O, Weiss G Tags: Biochem Pharmacol Source Type: research

Targeting PI3K, mTOR, ERK, and Bcl-2 signaling network shows superior antileukemic activity against AML ex vivo.
In this study, we show that while inhibition of PI3K, mTOR, and ERK showed superior induction of cell death compared to inhibition of PI3K and mTOR, the levels of cell death were modest in some AML cell lines and primary patient samples tested. Although simultaneous inhibition of PI3K, mTOR, and ERK caused downregulation of Mcl-1 and upregulation of Bim, immunoprecipitation of Bcl-2 revealed increased binding of Bim to Bcl-2, which was abolished by the addition of ABT-199, suggesting that Bim was bound to Bcl-2 which prevented cell death. Treatment with combined VS-5584, SCH772984, and ABT-199 showed significant increase o...
Source: Biochemical Pharmacology - December 2, 2017 Category: Drugs & Pharmacology Authors: Su Y, Li X, Ma J, Zhao J, Liu S, Wang G, Edwards H, Taub JW, Lin H, Ge Y Tags: Biochem Pharmacol Source Type: research

Cross-talk between hydrogen sulfide and carbon monoxide in the mechanism of experimental gastric ulcers healing, regulation of gastric blood flow and accompanying inflammation.
Abstract Hydrogen sulfide (H2S) and carbon monoxide (CO) exert gastroprotection against acute gastric lesions. We determined the cross-talk between H2S and CO in gastric ulcer healing process and regulation of gastric blood flow (GBF) at ulcer margin. Male Wistar rats with acetic acid-induced gastric ulcers were treated i.g. throughout 9 days with vehicle (control), NaHS (0.1-10 mg/kg) +/- zinc protoporphyrin (ZnPP, 10 mg/kg), D,L-propargylglycine (PAG, 30 mg/kg), CO-releasing CORM-2 (2.5 mg/kg) +/- PAG. GBF was assessed by laser flowmetry, ulcer area was determined by planimetry/histology. Gastric mucosal H2S pro...
Source: Biochemical Pharmacology - December 1, 2017 Category: Drugs & Pharmacology Authors: Magierowski M, Magierowska K, Hubalewska-Mazgaj M, Surmiak M, Sliwowski Z, Wierdak M, Kwiecien S, Chmura A, Brzozowski T Tags: Biochem Pharmacol Source Type: research

Modulating autophagy in cancer therapy: advancements and challenges for cancer cell death sensitization.
Abstract Autophagy is a major protein degradation pathway capable of upholding cellular metabolism under nutrient limiting conditions, making it a valuable resource to highly proliferating tumour cells. Although the regulatory machinery of the autophagic pathway has been well characterized, accurate modulation of this pathway remains complex in the context of clinical translatability for improved cancer therapies. In particular, the dynamic relationship between the rate of protein degradation through autophagy, i.e. autophagic flux, and the susceptibility of tumours to undergo apoptosis remains largely unclear. Ad...
Source: Biochemical Pharmacology - December 1, 2017 Category: Drugs & Pharmacology Authors: Bhat P, Kriel J, Shubha Priya B, Salundi B, Shivananju NS, Loos B Tags: Biochem Pharmacol Source Type: research

Gasotransmitter Hydrogen Sulfide Signaling in Neuronal Health and Disease.
Abstract Hydrogen sulfide is a gaseous signaling molecule or gasotransmitter which plays important roles in a wide spectrum of physiologic processes in the brain and peripheral tissues. Unlike nitric oxide and carbon monoxide, the other major gasotransmitters, research on hydrogen sulfide is still in its infancy. One of the modes by which hydrogen sulfide signals is via a posttranslational modification termed sulfhydration/persulfidation, which occurs on reactive cysteine residues on target proteins, where the reactive -SH group is converted to an -SSH group. Sulfhydration is a substantially prevalent modification...
Source: Biochemical Pharmacology - December 1, 2017 Category: Drugs & Pharmacology Authors: Paul BD, Snyder SH Tags: Biochem Pharmacol Source Type: research