Search our Database of Scientific Publications and Authors

I’m looking for a

    25997 results match your criteria Biochemical Pharmacology[Journal]

    1 OF 520

    Investigations into the Carbonic Anhydrase Inhibition of COS-Releasing Donor Core Motifs.
    Biochem Pharmacol 2017 Nov 10. Epub 2017 Nov 10.
    Department of Chemistry and Biochemistry, Institute of Molecular Biology, 1253 University of Oregon, Eugene, OR 97403, USA. Electronic address:
    Carbonyl sulfide (COS) releasing scaffolds are gaining popularity as hydrogen sulfide (H2S) donors through exploitation of the carbonic anhydrase (CA)-mediated hydrolysis of COS to H2S. The majority of compounds in this emerging class of donors undergo triggerable decomposition (often referred to as self-immolation) to release COS, and a handful of different COS-releasing structures have been reported. One benefit of this donation strategy is that numerous caged COS-containing core motifs are possible and are poised for development into self-immolative COS/H2S donors. Read More

    Pharmacological evaluation of new bioavailable small molecules targeting Eph/ephrin interaction.
    Biochem Pharmacol 2017 Nov 9. Epub 2017 Nov 9.
    Department of Food and Drugs, University of Parma, 43124 Parma, Italy. Electronic address:
    Eph/ephrin system is an emerging target for cancer therapy but the lack of potent, stable and orally bioavailable compounds is impairing the development of the field. Since 2009 our research group has been devoted to the discovery and development of small molecules targeting Eph/ephrin system and our research culminated with the synthesis of UniPR129, a potent but problematic Eph/ephrin antagonist. Herein, we describe the in vitro pharmacological properties of two derivatives (UniPR139 and UniPR502) stemmed from structure of UniPR129. Read More

    A look into centrosome abnormalities in colon cancer cells, how they arise and how they might be targeted therapeutically.
    Biochem Pharmacol 2017 Nov 8. Epub 2017 Nov 8.
    Department of Molecular and Cell Biology, 91 North Eagleville Road, U3125, University of Connecticut, Storrs, CT 06269, United States. Electronic address:
    Cancer cells have long been noted for alterations in centrosome structure, number, and function. Colorectal cancers are interesting in this regard since two frequently mutated genes, APC and CTNNB1 (ß-catenin), encode proteins that directly interact with the centrosome and affect its ability to direct microtubule growth and establish cell polarity. Colorectal cancers also frequently display centrosome over-duplication and clustering. Read More

    Characterisation of endogenous A2A and A2B receptor-mediated cyclic AMP responses in HEK 293 cells using the GloSensor™ biosensor: Evidence for an allosteric mechanism of action for the A2B-selective antagonist PSB 603.
    Biochem Pharmacol 2017 Oct 26. Epub 2017 Oct 26.
    Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, United Kingdom NG7 2UH, UK; Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands, UK. Electronic address:
    Endogenous adenosine A2B receptors (A2BAR) mediate cAMP accumulation in HEK 293 cells. Here we have used a biosensor to investigate the mechanism of action of the A2BAR antagonist PSB 603 in HEK 293 cells. The A2A agonist CGS 21680 elicited a small response in these cells (circa 20% of that obtained with NECA), suggesting that they also contain a small population of A2A receptors. Read More

    A monoclonal antibody raised against a thermo-stabilised β1-adrenoceptor interacts with extracellular loop 2 and acts as a negative allosteric modulator of a sub-set of β1-adrenoceptors expressed in stable cell lines.
    Biochem Pharmacol 2017 Nov 1. Epub 2017 Nov 1.
    Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK; Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands, UK. Electronic address:
    Recent interest has focused on antibodies that can discriminate between different receptor conformations. Here we have characterised the effect of a monoclonal antibody (mAb3), raised against a purified thermo-stabilised turkey β1-adrenoceptor (β1AR-m23 StaR), on β1-ARs expressed in CHO-K1 or HEK 293 cells. Immunohistochemical and radioligand-binding studies demonstrated that mAb3 was able to bind to ECL2 of the tβ1-AR, but not its human homologue. Read More

    Kinetics of human Cannabinoid 1 (CB1) receptor antagonists: structure-kinetics relationships (SKRs) and implications for insurmountable antagonism.
    Biochem Pharmacol 2017 Nov 1. Epub 2017 Nov 1.
    Division of Medicinal Chemistry, LACDR, Leiden University, the Netherlands. Electronic address:
    While equilibrium binding affinities and in vitro functional antagonism of CB1 receptor antagonists have been studied in detail, little is known on the kinetics of their receptor interaction. In this study, we therefore conducted kinetic assays for nine 1-(4,5-diarylthiophene-2-carbonyl)-4-phenylpiperidine-4-carboxamide derivatives and included the CB1 antagonist rimonabant as a comparison. For this we newly developed a dual-point competition association assay with [(3)H]CP55940 as the radioligand. Read More

    A partnership with the proteasome; the destructive nature of GSK3.
    Biochem Pharmacol 2017 Nov 1. Epub 2017 Nov 1.
    Division of Molecular and Clinical Medicine, University of Dundee, Dundee DD1 9SY, United Kingdom. Electronic address:
    Glycogen Synthase Kinase-3 (GSK3) was originally reported as a key enzyme of glucose homeostasis through regulation of the rate of glycogen synthesis. It has subsequently been found to influence most cellular processes, including growth, differentiation and death, as part of its role in modulating response to hormonal, nutritional and cellular stress stimuli. More than 100 protein targets for GSK3 have been proposed although only a small fraction of these have been convincingly validated in physiological cell systems. Read More

    Role of endogenous and exogenous nitric oxide, carbon monoxide and hydrogen sulfide in HCT116 colon cancer cell proliferation.
    Biochem Pharmacol 2017 Oct 23. Epub 2017 Oct 23.
    Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX, USA. Electronic address:
    The role of the three gasotransmitter systems - nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) - in cancer cells has not yet been studied simultaneously in the same experimental system. We measured the expression of NO and CO and H2S generating enzymes in primary colon cancer tissues and HCT116 colon cancer cells, and evaluated the effect of their pharmacological inhibition or pharmacological donation on cell proliferation. Increased expression of iNOS, nNOS, HO-1, CBS and 3-MST was detected in colon cancer. Read More

    Endogenous hydrogen sulfide regulates histone demethylase JMJD3-mediated inflammatory response in LPS-stimulated macrophages and in a mouse model of LPS-induced septic shock.
    Biochem Pharmacol 2017 Oct 23. Epub 2017 Oct 23.
    State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau; Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address:
    Overproduction of inflammatory mediators contributes to uncontrolled inflammation during endotoxin shock. Cystathionine-γ-lyase (CSE), an enzyme involved in hydrogen sulfide (H2S) biosynthesis, has potential anti-inflammatory activity in a variety of inflammatory diseases. Jumonji domain-containing protein 3 (JMJD3), a histone 3 Lys27 (H3K27) demethylase, has been implicated in macrophage activation, but its function in CSE-mediated anti-inflammatory activities remains unknown. Read More

    The cycloartane triterpenoid ADCX impairs autophagic degradation through Akt overactivation and promotes apoptotic cell death in multidrug-resistant HepG2/ADM cells.
    Biochem Pharmacol 2017 Oct 24. Epub 2017 Oct 24.
    Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; State Key Laboratory of Chinese Medicine and Molecular Pharmacology, Hong Kong Polytechnic University, Hong Kong, China. Electronic address:
    Multidrug resistance is the main obstacle in cancer chemotherapy. Emerging evidence demonstrates the important role of autophagy in cancer cell resistance to chemotherapy. Therefore, autophagy inhibition by natural compounds may be a promising strategy for overcoming drug resistance in liver cancer cells. Read More

    Identification of new shikonin derivatives as STAT3 inhibitors.
    Biochem Pharmacol 2017 Oct 21. Epub 2017 Oct 21.
    State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, Nanjing University, Nanjing 210023, China; Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing 210037, China. Electronic address:
    The signal transducer and activator of transcription 3 is a constitutively activated oncogenic protein in various human tumors and represents a valid target for anticancer drug design. In this study, we have achieved a new type of STAT3 inhibitors based on structural modifications on shikonin scaffold, guided by computational modelling. By tests, PMMB-187 exhibited a more outstanding profile than shikonin on a small panel of human breast cancer cells, especially for the MDA-MB-231 cells. Read More

    Pharmacological targeting of exercise adaptations in skeletal muscle: Benefits and pitfalls.
    Biochem Pharmacol 2017 Oct 20. Epub 2017 Oct 20.
    Biozentrum, University of Basel, Basel, Switzerland. Electronic address:
    Exercise exerts significant effects on the prevention and treatment of many diseases. However, even though some of the key regulators of training adaptation in skeletal muscle have been identified, this biological program is still poorly understood. Accordingly, exercise-based pharmacological interventions for many muscle wasting diseases and also for pathologies that are triggered by a sedentary lifestyle remain scarce. Read More

    Drug resistance induces the upregulation of H2S-producing enzymes in HCT116 colon cancer cells.
    Biochem Pharmacol 2017 Oct 20. Epub 2017 Oct 20.
    Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX 77555, USA. Electronic address:
    Hydrogen sulfide (H2S) production in colon cancer cells supports cellular bioenergetics and proliferation. The aim of the present study was to investigate the alterations in H2S homeostasis during the development of resistance to 5-fluorouracil (5-FU), a commonly used chemotherapeutic agent. A 5-FU-resistant HCT116 human colon cancer cell line was established by serial passage in the presence of increasing 5-FU concentrations. Read More

    Lawsone derivatives target the Wnt/β-catenin signaling pathway in multidrug-resistant acute lymphoblastic leukemia cells.
    Biochem Pharmacol 2017 Oct 20. Epub 2017 Oct 20.
    Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany. Electronic address:
    Multidrug resistance (MDR) represents a serious problem in cancer treatment. One strategy to overcome this obstacle is to identify agents that are selectively lethal to MDR cells. The aim of this study was to discover novel compounds against MDR leukemia and to determine the molecular mechanisms behind collateral sensitivity. Read More

    The Ca(2+)/CaMKK2 axis mediates the telbivudine induced upregulation of creatine kinase: Implications for mechanism of antiviral nucleoside analogs' side effect.
    Biochem Pharmacol 2017 Oct 14. Epub 2017 Oct 14.
    Department of Pharmacy, HuaShan Hospital, Fudan University, Shanghai, China. Electronic address:
    Telbivudine (LdT), a widely prescribed anti-hepatitis B virus (HBV) drug for the treatment of chronic Hepatitis B (CHB), causes adverse reactions ranging from creatine kinase (CK) elevation to myopathy. The purpose of this study was to explore the mechanism(s) of LdT induced CK elevation. The effects of LdT on mitochondrial morphology and proteins (TK2 and β-actin), oxidative stress, intracellular Ca(2+) levels, Ca(2+)-related signaling pathway (CaMKK2/AMPK), and Ca(2+)-related biomarkers such as superoxide dismutase (SOD) and malondialdehyde (MDA) were assessed in human skeletal muscle cells (HSKMCs). Read More

    Camptothecin and its analog SN-38, the active metabolite of irinotecan, inhibit binding of the transcriptional regulator and oncoprotein FUBP1 to its DNA target sequence FUSE.
    Biochem Pharmacol 2017 Oct 13. Epub 2017 Oct 13.
    Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Paul-Ehrlich-Strasse 42-44, D-60596 Frankfurt/Main, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. Electronic address:
    The transcriptional regulator FUSE Binding Protein 1 (FUBP1) is overexpressed in more than 80% of all human hepatocellular carcinomas (HCCs) and other solid tumor entities including prostate and colorectal carcinoma. FUBP1 expression is required for HCC tumor cell expansion, and it functions as an important pro-proliferative and anti-apoptotic oncoprotein that binds to the single-stranded DNA sequence FUSE to regulate the transcription of a variety of target genes. In this study, we screened an FDA-approved drug library and discovered that the Topoisomerase I (TOP1) inhibitor camptothecin (CPT) and its derivative 7-ethyl-10-hydroxycamptothecin (SN-38), the active irinotecan metabolite that is used in the clinics in combination with other chemotherapeutics to treat carcinoma, inhibit FUBP1 activity. Read More

    BCRP/ABCG2 and high-alert medications: Biochemical, pharmacokinetic, pharmacogenetic, and clinical implications.
    Biochem Pharmacol 2017 Oct 13. Epub 2017 Oct 13.
    Department of Pharmacy, Shiga University of Medical Science Hospital, Otsu, Shiga, Japan. Electronic address:
    The human breast cancer resistance protein (BCRP/ABCG2) is an ATP-binding cassette efflux transporter that uses ATP hydrolysis to expel xenobiotics from cells, including anti-cancer medications. It is expressed in the gastrointestinal tract, liver, kidney, and brain endothelium. Thus, ABCG2 functions as a tissue barrier to drug transport that strongly influences the pharmacokinetics of substrate medications. Read More

    Computational discovery and experimental verification of farnesoid X receptor agonist auraptene to protect against cholestatic liver injury.
    Biochem Pharmacol 2017 Oct 4. Epub 2017 Oct 4.
    Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian 116044, China; Key Laboratory of Pharmacokinetics and Transport of Liaoning Province, Dalian Medical University, Dalian 116044, China. Electronic address:
    Recently obeticholic acid (OCA) which is a farnesoid X receptor (FXR) agonist was approved by FDA to treat cholestatic liver diseases, which provided us a novel therapeutic strategy against cholestasis. Herein, we used a novel computational strategy with two-dimensional virtual screening for FXR agonists. For the first time, we found that auraptene (AUR), a natural product, can activate FXR to exert hepatoprotective effect against cholestatic liver injury in vivo and in vitro. Read More

    Acylated apelin-13 amide analogues exhibit enzyme resistance and prolonged insulin releasing, glucose lowering and anorexic properties.
    Biochem Pharmacol 2017 Oct 4. Epub 2017 Oct 4.
    School of Biomedical Sciences, SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine BT52 1SA, UK.
    The adipokine, apelin has many biological functions but its activity is curtailed by rapid plasma degradation. Fatty acid derived apelin analogues represent a new and exciting avenue for the treatment of obesity-diabetes. This study explores four novel fatty acid modified apelin-13 analogues, namely, (Lys(8)GluPAL)apelin-13 amide, pGlu(Lys(8)GluPAL)apelin-13 amide, Lys(8)GluPAL(Tyr(13))apelin-13 and Lys(8)GluPAL(Val(13))apelin-13. Read More

    Auxiliary subunits of AMPA receptors: The discovery of a forebrain-selective antagonist, LY3130481/CERC-611.
    Biochem Pharmacol 2017 Oct 5. Epub 2017 Oct 5.
    Neuroscience Discovery Research, Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 46285-0510, United States. Electronic address:
    Drugs originate from the discovery of compounds, natural or synthetic, that bind to proteins (receptors, enzymes, transporters, etc.), the interaction of which modulates biological cascades that have potential therapeutic benefit. Rational strategies for identifying novel drug therapies are typically based on knowledge of the structure of the target proteins and the design of new chemical entities that modulate these proteins in a beneficial manner. Read More

    MRGPRX2 is essential for sinomenine hydrochloride induced anaphylactoid reactions.
    Biochem Pharmacol 2017 Oct 4. Epub 2017 Oct 4.
    School of Pharmacy, Xi'an Jiaotong University, Xi'an 710061, China. Electronic address:
    Mast cells are unique immunocytes that function as sentinel cells in host defense reactions such as immediate hypersensitivity responses and anaphylactic responses. The mast cell specific receptor MRGPRX2 (Mas-related G protein-coupled receptor X2) triggers mast cell degranulation-a key process in anaphylactic reactions. We sought to better understand anaphylactic reaction induced by sinomenine hydrochloride (SH). Read More

    Cathepsin S inhibition suppresses autoimmune-triggered inflammatory responses in macrophages.
    Biochem Pharmacol 2017 Oct 4. Epub 2017 Oct 4.
    Laboratory of Clinical Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, Hebelstrasse 20, 4031 Basel, Switzerland; Division of Internal Medicine, University Hospital Basel, University of Basel, Petersgraben 4, 4031 Basel, Switzerland.
    In several types of antigen-presenting cells (APCs), Cathepsin S (CatS) plays a crucial role in the regulation of MHC class II surface expression and consequently influences antigen (Ag) presentation of APCs to CD4(+) T cells. During the assembly of MHC class II-Ag peptide complexes, CatS cleaves the invariant chain p10 (Lip10) - a fragment of the MHC class II-associated invariant chain peptide. In this report, we used a selective, high-affinity CatS inhibitor to suppress the proteolytic activity of CatS in lymphoid and myeloid cells. Read More

    Cyclic guanosine monophosphate modulates accumulation of phosphodiesterase 5 inhibitors in human platelets.
    Biochem Pharmacol 2017 Dec 28;145:54-63. Epub 2017 Sep 28.
    Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Electronic address:
    Sildenafil and tadalafil are widely-used phosphodiesterase 5 (PDE5) inhibitors for which no clear dose-response relationship could be established. Using isolated and/or recombinant PDE5, it has been demonstrated that cGMP can increase the affinity of this enzyme for sildenafil and tadalafil. We thus hypothesized that in cells expressing the nitric oxide - soluble guanylyl cyclase - cyclic guanosine monophosphate - PDE5 (NO-sGC-cGMP-PDE5) pathway such as platelets, the presence of NO increases the intracellular cGMP content and thus promotes the intracellular accumulation of sildenafil or tadalafil. Read More

    Effect of mutation of Phe 243(6.44) of the histamine H2 receptor on cimetidine and ranitidine mechanism of action.
    Biochem Pharmacol 2017 Sep 28. Epub 2017 Sep 28.
    Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica, Buenos Aires, Argentina; CONICET - Universidad de Buenos Aires, Instituto de Investigaciones Farmacológicas (ININFA), Buenos Aires, Argentina. Electronic address:
    Despite the pivotal role GPCRs play in cellular signaling, it is only in the recent years that structural biology has begun to elucidate how GPCRs function and to provide a platform for structure-based drug design. It is postulated that GPCR activation involves the movement of transmembrane helices. The finding that many residues, which have been shown to be critical for receptor activation and are highly conserved among different GPCRs, are clustered in particular positions of transmembrane helices suggests that activation of GPCRs may involve common molecular mechanisms. Read More

    Identification and validation of the microRNA response elements in the 3'-untranslated region of the UDP glucuronosyltransferase (UGT) 2B7 and 2B15 genes by a functional genomics approach.
    Biochem Pharmacol 2017 Sep 28. Epub 2017 Sep 28.
    Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA, USA. Electronic address:
    Posttranscriptional repression of UDP-glucuronosyltransferase (UGT) 2B7 and 2B15 expression by microRNAs (miRNAs) may be an important mechanism underlying inter-individual variability in drug glucuronidation. Furthermore, the UGT2B15 3'-UTR contains a common SNP (rs3100) that could influence miRNA binding. The aim of this study was to identify the complete complement of miRNAs that could regulate UGT2B7 and UGT2B15 expression through binding to the reference and/or variant 3'-UTRs. Read More

    Effects of dronedarone, amiodarone and their active metabolites on sequential metabolism of arachidonic acid to epoxyeicosatrienoic and dihydroxyeicosatrienoic acids.
    Biochem Pharmacol 2017 Sep 25. Epub 2017 Sep 25.
    Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore; Singapore Institute for Clinical Sciences, Brenner Centre for Molecular Medicine, 30 Medical Drive, Singapore 117609, Singapore. Electronic address:
    Cardiac enzymes such as cytochrome P450 2J2 (CYP2J2) metabolize arachidonic acid (AA) to cardioprotective epoxyeicosatrienoic acids (EETs), which in turn are metabolized by soluble epoxide hydrolase (sEH) to dihydroxyeicosatrienoic acids (DHETs). As EETs and less potent DHETs exhibit cardioprotective and vasoprotective functions, optimum levels of cardiac EETs are paramount in cardiac homeostasis. Previously, we demonstrated that dronedarone, amiodarone and their main metabolites, namely N-desbutyldronedarone (NDBD) and N-desethylamiodarone (NDEA), potently inhibit human cardiac CYP2J2-mediated astemizole metabolism in vitro. Read More

    Efficient substrate screening and inhibitor testing of human CYP4Z1 using permeabilized recombinant fission yeast.
    Biochem Pharmacol 2017 Sep 23. Epub 2017 Sep 23.
    School of Pharmaceutical Science and Technology, Health Sciences Platform, Tianjin University, Tianjin 30072, China. Electronic address:
    We have established a protocol for the preparation of permeabilized fission yeast cells (enzyme bags) that recombinantly express human cytochrome P450 enzymes (CYPs). A direct comparison of CYP3A4 activity gave an eightfold higher space-time yield for enzyme bag-catalyzed biotransformation as compared to whole-cell biotransformation, even though the total number of cells employed was lower by a factor of 150. Biotransformation of the luminogenic substrate Luciferin-H using CYP2C9-containing enzyme bags proceeded efficiently and stably for 24h. Read More

    A timeline of hydrogen sulfide (H2S) research: From environmental toxin to biological mediator.
    Biochem Pharmacol 2017 Sep 22. Epub 2017 Sep 22.
    Department of Anesthesiology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA. Electronic address:
    The history of H2S - as an environmental toxin - dates back to 1700, to the observations of the Italian physician Bernardino Ramazzini, whose book "De Morbis Artificum Diatriba" described the painful eye irritation and inflammation of "sewer gas" in sewer workers. The gas has subsequently been identified as hydrogen sulfide (H2S), and opened three centuries of research into the biological roles of H2S. The current article highlights the key discoveries in the field of H2S research, including (a) the toxicological studies, which characterized H2S as an environmental toxin, and identified some of its modes of action, including the inhibition of mitochondrial respiration; (b) work in the field of bacteriology, which, starting in the early 1900s, identified H2S as a bacterial product - with subsequently defined roles in the regulation of periodontal disease (oral bacterial flora), intestinal epithelial cell function (enteral bacterial flora) as well as in the regulation of bacterial resistance to antibiotics; and (c), work in diverse fields of mammalian biology, which, starting in the 1940s, identified H2S as an endogenous mammalian enzymatic product, the functions of which - among others, in the cardiovascular and nervous system - have become subjects of intensive investigation for the last decade. Read More

    Selective inhibition of endogenous antioxidants with Auranofin causes mitochondrial oxidative stress which can be countered by selenium supplementation.
    Biochem Pharmacol 2017 Sep 22. Epub 2017 Sep 22.
    School of Medical Science, Menzies Health Institute Queensland, Griffith University, Southport 9726, Queensland, Australia. Electronic address:
    Auranofin is a thiol-reactive gold (I)-containing compound with potential asa chemotherapeutic. Auranofin has the capacity to selectively inhibit endogenous antioxidant enzymes thioredoxin reductase (TrxR) and glutathione peroxidase (GPx), resulting in oxidative stress and the initiation of a pro-apoptotic cascade. The effect of Auranofin exposure on TrxR and GPx, and the potential for cellular protection through selenium supplementation was examined in the non-cancerous human cell line Swan-71. Read More

    How to effectively treat acute leukemia patients bearing MLL-rearrangements ?
    Biochem Pharmacol 2017 Sep 21. Epub 2017 Sep 21.
    Institute of Pharm. Biology/DCAL, Goethe-University, Frankfurt/Main, Germany. Electronic address:
    Chromosomal translocations - leading to the expression of fusion genes - are well-studied genetic abberrations associated with the development of leukemias. Most of them represent altered transcription factors that affect transcription or epigenetics, while others - like BCR-ABL - are enhancing signaling. BCR-ABL has become the prototype for rational drug design, and drugs like Imatinib and subsequently improved drugs have a great impact on cancer treatments. Read More

    Free-fatty acid receptor-4 (FFA4) modulates ROS generation and COX-2 expression via the C-terminal β-arrestin phosphosensor in Raw 264.7 macrophages.
    Biochem Pharmacol 2017 Sep 21. Epub 2017 Sep 21.
    Department of Pharmaceutical Sciences, College of Pharmacy, Mercer University Health Sciences Center, Mercer University, Atlanta, GA 30341, USA. Electronic address:
    Agonism of the G protein-coupled free-fatty acid receptor-4 (FFA4) has been shown to promote numerous anti-inflammatory effects in macrophages that arise due to interaction with β-arrestin partner proteins. Humans express functionally distinct short and long FFA4 splice variants, such that FFA4-S signals through Gαq/11 and β-arrestin, while FFA4-L is intrinsically biased solely towards β-arrestin signaling. Recently, we and others have shown that phosphorylation of the FFA4 C-terminal tail is responsible for β-arrestin interactability and signaling. Read More

    Exploiting homing abilities of cell carriers: Targeted delivery of nanoparticles for cancer therapy.
    Biochem Pharmacol 2017 Dec 21;145:18-26. Epub 2017 Sep 21.
    Department of Molecular Medicine, Beckman Research Institute at City of Hope, 11500 East Duarte Road, Duarte, CA 91010, United States. Electronic address:
    Off target toxicities is one of the hallmarks of conventional chemotherapy as only a tiny percentage of the injected dose actually reaches the tumor(s). Numerous strategies have been employed in attempts to achieve targeted therapeutic delivery to tumors. One strategy that has received immense attention has been the packaging of these chemotherapeutics into nanoparticles and relying on the enhanced permeation and retention (EPR) effect for targeting. Read More

    Angiogenic imbalance and diminished matrix metalloproteinase-2 and -9 underlie regional decreases in uteroplacental vascularization and feto-placental growth in hypertensive pregnancy.
    Biochem Pharmacol 2017 Sep 11. Epub 2017 Sep 11.
    Vascular Surgery Research Laboratories, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, United States. Electronic address:
    Preeclampsia is a form of hypertension-in-pregnancy (HTN-Preg) with unclear mechanism. Generalized reduction of uterine perfusion pressure (RUPP) could be an initiating event leading to uteroplacental ischemia, angiogenic imbalance, and HTN-Preg. Additional regional differences in uteroplacental blood flow could further affect the pregnancy outcome and increase the risk of preeclampsia in twin or multiple pregnancy, but the mechanisms involved are unclear. Read More

    Farnesoid X receptor regulates SULT1E1 expression through inhibition of PGC1α binding to HNF4α.
    Biochem Pharmacol 2017 Dec 11;145:202-209. Epub 2017 Sep 11.
    Research Center for Biopharmaceutics and Pharmacokinetics, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, China. Electronic address:
    Sulfotransferase 1E1 (SULT1E1, also known as estrogen sulfotransferase) plays an important role in metabolism and detoxification of many endogenous and exogenous compounds (e.g., estrogens and flavonoids). Read More

    The cAMP effectors PKA and Epac activate endothelial NO synthase through PI3K/Akt pathway in human endothelial cells.
    Biochem Pharmacol 2017 Dec 11;145:94-101. Epub 2017 Sep 11.
    Pharmacology of Chronic Diseases (CD Pharma), Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain. Electronic address:
    3',5'-Cyclic adenosine monophosphate (cAMP) exerts an endothelium-dependent vasorelaxant action by stimulating endothelial NO synthase (eNOS) activity, and the subsequent NO release, through cAMP protein kinase (PKA) and exchange protein directly activated by cAMP (Epac) activation in endothelial cells. Here, we have investigated the mechanism by which the cAMP-Epac/PKA pathway activates eNOS. cAMP-elevating agents (forskolin and dibutyryl-cAMP) and the joint activation of PKA (6-Bnz-cAMP) and Epac (8-pCPT-2'-O-Me-cAMP) increased cytoplasmic Ca(2+) concentration ([Ca(2+)]c) in ≤30% of fura-2-loaded isolated human umbilical vein endothelial cells (HUVEC). Read More

    Therapeutic potential of carbohydrates as regulators of macrophage activation.
    Biochem Pharmacol 2017 Sep 8. Epub 2017 Sep 8.
    Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 R590 Dublin 2, Ireland. Electronic address:
    It is well established for a broad range of disease states, including cancer and Mycobacterium tuberculosis infection, that pathogenesis is bolstered by polarisation of macrophages towards an anti-inflammatory phenotype, known as M2. As these innate immune cells are relatively long-lived, their re-polarisation to pro-inflammatory, phagocytic and bactericidal "classically activated" M1 macrophages is an attractive therapeutic approach. On the other hand, there are scenarios where the resolving inflammation, wound healing and tissue remodelling properties of M2 macrophages are beneficial - for example the successful introduction of biomedical implants. Read More

    The two faces of aldehyde oxidase: Oxidative and reductive transformations of 5-nitroquinoline.
    Biochem Pharmacol 2017 Dec 6;145:210-217. Epub 2017 Sep 6.
    Department of Chemistry, Washington State University, Pullman, WA 99164, United States. Electronic address:
    Aldehyde oxidase (AOX) is a cytosolic enzyme responsible for the metabolism of some drugs and drug candidates. AOX catalyzes the oxidative hydroxylation of substrates including several aliphatic and aromatic aldehydes, and nitrogen-containing heterocyclic compounds. AOX is also reported to catalyze the reductive metabolism of nitro-compounds, N-oxides, sulfoxides, isoxazoles, isothiazoles, nitrite and hydroxamic acids. Read More

    Deficiency of N-acetyltransferase increases the interactions of isoniazid with endobiotics in mouse liver.
    Biochem Pharmacol 2017 Dec 6;145:218-225. Epub 2017 Sep 6.
    Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA. Electronic address:
    Acetylation is the major metabolic pathway of isoniazid (INH) mediated by N-acetyltransferases (NATs). Previous reports suggest that slow acetylators have higher risks of INH hepatotoxicity than rapid acetylators, but the detailed mechanisms remain elusive. The current study used Nat1/2(-/-) mice to mimic NAT slow metabolizers and to investigate INH metabolism in the liver. Read More

    Drug repurposing strategy against Trypanosoma cruzi infection: In vitro and in vivo assessment of the activity of metronidazole in mono- and combined therapy.
    Biochem Pharmacol 2017 Dec 7;145:46-53. Epub 2017 Sep 7.
    Laboratório de Biologia Celular do Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil. Electronic address:
    Metronidazole (Mtz) is a commercial broad-spectrum nitroimidazolic derivative with relevant antimicrobial activity and relative safety profile. Therefore, it is fair to consider Mtz a candidate for drug repurposing for other neglected conditions such as Chagas disease (CD), a parasitic pathology caused by Trypanosoma cruzi. CD is treated only with benznidazole (Bz) and nifurtimox, both introduced in clinics decades ago despite important limitations, including low efficacy on the later disease stage (chronic form) and severe side effects. Read More

    5-Fluorouracil induces inflammation and oxidative stress in the major salivary glands affecting salivary flow and saliva composition.
    Biochem Pharmacol 2017 Dec 1;145:34-45. Epub 2017 Sep 1.
    Department of Medical Sciences, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil; Postgraduate Program in Morphofunctional Sciences, Department of Morphology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil; Department of Physiology and Pharmacology, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil. Electronic address:
    This study aimed to elucidate the effect of 5-fluorouracil (5-FU) on the histological aspects of the major salivary glands, salivary flow and saliva composition using an established oral mucositis model in hamsters. Oral mucositis was induced by two intraperitoneal administrations of 5-FU in two consecutive days (60 and 40mg/kg), followed by cheek pouch mucosa scratch, on day 4. The Pilocarpine-stimulated salivary flow was measured 4 and 10days after the first 5-FU injection. Read More

    Statin therapy exacerbates alcohol-induced constriction of cerebral arteries via modulation of ethanol-induced BK channel inhibition in vascular smooth muscle.
    Biochem Pharmacol 2017 Dec 1;145:81-93. Epub 2017 Sep 1.
    Dept. Pharmacology, University of Tennessee HSC, Memphis, TN 38103, United States. Electronic address:
    Statins constitute the most commonly prescribed drugs to decrease cholesterol (CLR). CLR is an important modulator of alcohol-induced cerebral artery constriction (AICAC). Using rats on a high CLR diet (2% CLR) we set to determine whether atorvastatin administration (10mg/kg daily for 18-23weeks) modified AICAC. Read More

    Dipeptidyl peptidase-4 independent cardiac dysfunction links saxagliptin to heart failure.
    Biochem Pharmacol 2017 Dec 30;145:64-80. Epub 2017 Aug 30.
    Department of Internal Medicine, Division of Cardiology, Medical University of Graz, Austria.
    Saxagliptin treatment has been associated with increased rate of hospitalization for heart failure in type 2 diabetic patients, though the underlying mechanism(s) remain elusive. To address this, we assessed the effects of saxagliptin on human atrial trabeculae, guinea pig hearts and cardiomyocytes. We found that the primary target of saxagliptin, dipeptidyl peptidase-4, is absent in cardiomyocytes, yet saxagliptin internalized into cardiomyocytes and impaired cardiac contractility via inhibition of the Ca(2+)/calmodulin-dependent protein kinase II-phospholamban-sarcoplasmic reticulum Ca(2+)-ATPase 2a axis and Na(+)-Ca(2+) exchanger function in Ca(2+) extrusion. Read More

    A Jak2-selective inhibitor potently reverses the immune suppression by modulating the tumor microenvironment for cancer immunotherapy.
    Biochem Pharmacol 2017 Dec 30;145:132-146. Epub 2017 Aug 30.
    State Key Laboratory of Pharmaceutical Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210093, China. Electronic address:
    Small molecule therapeutics can be potent tools for cancer immunotherapy. They may be devised to target the tumor associated macrophages (TAMs) and regulatory T cells (Treg), which are major immunosuppressive cells in the tumor microenvironment. The infiltration and functionalization of these cells, which essentially promote tumor development, are mediated by the hyper-activation of the Jak-STAT3 signaling pathway. Read More

    Relative distribution and biological characterization of CXCL4L1 isoforms in platelets from healthy donors.
    Biochem Pharmacol 2017 Dec 30;145:123-131. Epub 2017 Aug 30.
    KU Leuven, University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Molecular Immunology, B-3000 Leuven, Belgium. Electronic address:
    CXCL4L1, a platelet-derived ELR-negative CXC chemokine, is a powerful angiostatic and anti-tumoral chemokine. We developed a mass spectrometric assay for the detection of different natural CXCL4L1 isoforms. Using this assay, we identified 4 different CXCL4L1 isoforms in the supernatant of thrombin-stimulated platelets from healthy volunteers: the classical isoform CXCL4L1(1-70), CXCL4L1(-4-70), which probably arises through alternative signal peptide removal and two COOH-terminally truncated isoforms CXCL4L1(1-69) and CXCL4L1(-4-69). Read More

    FPR2 signaling without β-arrestin recruitment alters the functional repertoire of neutrophils.
    Biochem Pharmacol 2017 Dec 30;145:114-122. Epub 2017 Aug 30.
    Department of Rheumatology and Inflammation Research, University of Gothenburg, Gothenburg, Sweden. Electronic address:
    G-protein coupled receptor (GPCR) biased agonism or functional selectivity has become an essential concept in GPCR research over the last years. Receptor-specific biased agonists selectively trigger one signaling pathway over another and induce a restricted/directed functional response. In this study, we aimed to characterize the concept of biased agonism for FPR2, a member of the formyl peptide receptor (FPR) subfamily of GPCRs. Read More

    Parathyroid hormone contributes to the down-regulation of cytochrome P450 3A through the cAMP/PI3K/PKC/PKA/NF-κB signaling pathway in secondary hyperparathyroidism.
    Biochem Pharmacol 2017 Dec 24;145:192-201. Epub 2017 Aug 24.
    Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; Center for Clinical Pharmaceutical Sciences, School of Pharmacy, Kumamoto University, Kumamoto, Japan. Electronic address:
    Chronic kidney disease (CKD), which affects, not only renal clearance, but also non-renal clearance, is accompanied by a decline in renal function. Although it has been suggested that humoral factors, such as uremic toxins that accumulate in the body under CKD conditions, could be involved in the changes associated with non-renal drug clearance, the overall process is not completely understood. In this study, we report on the role of parathyroid hormone (PTH), a middle molecule uremic toxin, on the expression of drug metabolizing or transporting proteins using rats with secondary hyperparathyroidism (SHPT) as models. Read More

    A short cross-linker activates human P-glycoprotein missing a catalytic carboxylate.
    Biochem Pharmacol 2017 Dec 29;145:27-33. Epub 2017 Aug 29.
    Department of Medicine and Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Electronic address:
    P-glycoprotein (P-gp) is an ATP-dependent drug pump that protects us from toxic agents and confers multidrug resistance. It has a tweezer-like structure with each arm consisting of a transmembrane domain (TMD) and a nucleotide-binding domain (NBD). Drug substrates bind to sites within the TMDs to activate ATPase activity by promoting a tweezer-like closing of the gap between the NBDs. Read More

    Inducing rat brain CYP2D with nicotine increases the rate of codeine tolerance; predicting the rate of tolerance from acute analgesic response.
    Biochem Pharmacol 2017 Dec 21;145:158-168. Epub 2017 Aug 21.
    Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH) and Departments of Psychiatry, Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada. Electronic address:
    Repeated opioid administration produces analgesic tolerance, which may lead to dose escalation. Brain CYP2D metabolizes codeine to morphine, a bioactivation step required for codeine analgesia. Higher brain, but not liver, CYP2D is found in smokers and nicotine induces rat brain, but not liver, CYP2D expression and activity. Read More

    Chromofungin (CHR: CHGA47-66) is downregulated in persons with active ulcerative colitis and suppresses pro-inflammatory macrophage function through the inhibition of NF-κB signaling.
    Biochem Pharmacol 2017 Dec 19;145:102-113. Epub 2017 Aug 19.
    Immunology Department, University of Manitoba, Winnipeg, MB, Canada; Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB, Canada; Section of Gastroenterology, Department of Internal Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; University of Manitoba IBD Clinical and Research Centre, University of Manitoba, Winnipeg, MB, Canada. Electronic address:
    Chromogranin-A (CHGA) is a prohormone secreted by neuroendocrine cells and is a precursor of several bioactive peptides, which are implicated in different and distinctive biological and immune functions. Chromofungin (CHR: CHGA47-66) is a short peptide with antimicrobial effects and encodes from CHGA exon-IV. Inflammatory bowel disease (IBD) is characterized by alterations in the activation of pro-inflammatory pathways, pro-inflammatory macrophages (M1), and nuclear transcription factor kappa B (NF-κB) signaling leading to the perpetuation of the inflammatory process. Read More

    1 OF 520