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  Subjects -> CHEMISTRY (Total: 876 journals)
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CHEMISTRY (614 journals)                  1 2 3 4 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 13)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 26)
ACS Catalysis     Full-text available via subscription   (Followers: 42)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 20)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 20)
ACS Macro Letters     Full-text available via subscription   (Followers: 25)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 40)
ACS Nano     Full-text available via subscription   (Followers: 265)
ACS Photonics     Full-text available via subscription   (Followers: 13)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 23)
Acta Chemica Iasi     Open Access   (Followers: 2)
Acta Chimica Sinica     Full-text available via subscription   (Followers: 1)
Acta Chimica Slovaca     Open Access   (Followers: 1)
Acta Chimica Slovenica     Open Access  
Acta Chromatographica     Full-text available via subscription   (Followers: 8)
Acta Facultatis Medicae Naissensis     Open Access  
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 6)
Acta Scientifica Naturalis     Open Access   (Followers: 2)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 5)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 8)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 5)
Advanced Functional Materials     Hybrid Journal   (Followers: 54)
Advanced Science Focus     Free   (Followers: 5)
Advances in Chemical Engineering and Science     Open Access   (Followers: 65)
Advances in Chemical Science     Open Access   (Followers: 16)
Advances in Chemistry     Open Access   (Followers: 20)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 19)
Advances in Drug Research     Full-text available via subscription   (Followers: 21)
Advances in Enzyme Research     Open Access   (Followers: 9)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 7)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 15)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 9)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 25)
Advances in Nanoparticles     Open Access   (Followers: 15)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15)
Advances in Polymer Science     Hybrid Journal   (Followers: 43)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 17)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 18)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6)
Advances in Science and Technology     Full-text available via subscription   (Followers: 12)
African Journal of Bacteriology Research     Open Access  
African Journal of Chemical Education     Open Access   (Followers: 3)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 7)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Al-Kimia : Jurnal Penelitian Sains Kimia     Open Access  
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 2)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 61)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 15)
American Journal of Chemistry     Open Access   (Followers: 29)
American Journal of Plant Physiology     Open Access   (Followers: 11)
American Mineralogist     Hybrid Journal   (Followers: 15)
Analyst     Full-text available via subscription   (Followers: 38)
Angewandte Chemie     Hybrid Journal   (Followers: 164)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 236)
Annales UMCS, Chemia     Open Access  
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 5)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 3)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 4)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 9)
Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 12)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 13)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antiviral Chemistry and Chemotherapy     Hybrid Journal   (Followers: 1)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 8)
Applied Spectroscopy     Full-text available via subscription   (Followers: 22)
Applied Surface Science     Hybrid Journal   (Followers: 31)
Arabian Journal of Chemistry     Open Access   (Followers: 5)
ARKIVOC     Open Access   (Followers: 1)
Asian Journal of Biochemistry     Open Access   (Followers: 1)
Atomization and Sprays     Full-text available via subscription   (Followers: 4)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 7)
Autophagy     Hybrid Journal   (Followers: 2)
Avances en Quimica     Open Access  
Biochemical Pharmacology     Hybrid Journal   (Followers: 10)
Biochemistry     Full-text available via subscription   (Followers: 337)
Biochemistry Insights     Open Access   (Followers: 6)
Biochemistry Research International     Open Access   (Followers: 6)
BioChip Journal     Hybrid Journal  
Bioinorganic Chemistry and Applications     Open Access   (Followers: 9)
Bioinspired Materials     Open Access   (Followers: 5)
Biointerface Research in Applied Chemistry     Open Access   (Followers: 2)
Biointerphases     Open Access   (Followers: 1)
Biology, Medicine, & Natural Product Chemistry     Open Access   (Followers: 1)
Biomacromolecules     Full-text available via subscription   (Followers: 20)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 10)
Biomedical Chromatography     Hybrid Journal   (Followers: 7)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 3)
BioNanoScience     Partially Free   (Followers: 5)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 119)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 84)
Bioorganic Chemistry     Hybrid Journal   (Followers: 10)
Biopolymers     Hybrid Journal   (Followers: 18)
Biosensors     Open Access   (Followers: 2)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 2)
Bitácora Digital     Open Access  
Boletin de la Sociedad Chilena de Quimica     Open Access  
Bulletin of the Chemical Society of Ethiopia     Open Access   (Followers: 2)
Bulletin of the Chemical Society of Japan     Full-text available via subscription   (Followers: 24)
Bulletin of the Korean Chemical Society     Hybrid Journal   (Followers: 1)
C - Journal of Carbon Research     Open Access   (Followers: 3)
Cakra Kimia (Indonesian E-Journal of Applied Chemistry)     Open Access  
Canadian Association of Radiologists Journal     Full-text available via subscription   (Followers: 2)
Canadian Journal of Chemistry     Hybrid Journal   (Followers: 10)
Canadian Mineralogist     Full-text available via subscription   (Followers: 6)
Carbohydrate Research     Hybrid Journal   (Followers: 26)
Carbon     Hybrid Journal   (Followers: 71)
Catalysis for Sustainable Energy     Open Access   (Followers: 7)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 7)
Catalysis Science and Technology     Free   (Followers: 8)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 9)
Cellulose     Hybrid Journal   (Followers: 7)
Cereal Chemistry     Full-text available via subscription   (Followers: 4)
ChemBioEng Reviews     Full-text available via subscription   (Followers: 1)
ChemCatChem     Hybrid Journal   (Followers: 8)
Chemical and Engineering News     Free   (Followers: 18)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 73)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 26)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 22)
Chemical Reviews     Full-text available via subscription   (Followers: 181)
Chemical Science     Open Access   (Followers: 23)
Chemical Technology     Open Access   (Followers: 22)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 5)
Chemical Week     Full-text available via subscription   (Followers: 7)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 56)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 24)
ChemInform     Hybrid Journal   (Followers: 8)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 7)
Chemistry & Biology     Full-text available via subscription   (Followers: 32)
Chemistry & Industry     Hybrid Journal   (Followers: 6)
Chemistry - A European Journal     Hybrid Journal   (Followers: 151)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 16)
Chemistry and Materials Research     Open Access   (Followers: 20)
Chemistry Central Journal     Open Access   (Followers: 4)
Chemistry Education Research and Practice     Free   (Followers: 5)
Chemistry in Education     Open Access   (Followers: 9)
Chemistry International     Hybrid Journal   (Followers: 2)
Chemistry Letters     Full-text available via subscription   (Followers: 44)
Chemistry of Materials     Full-text available via subscription   (Followers: 245)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
Chemistry World     Full-text available via subscription   (Followers: 19)
Chemistry-Didactics-Ecology-Metrology     Open Access   (Followers: 1)
ChemistryOpen     Open Access   (Followers: 1)
Chemkon - Chemie Konkret, Forum Fuer Unterricht Und Didaktik     Hybrid Journal  
Chemoecology     Hybrid Journal   (Followers: 4)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 14)
Chemosensors     Open Access  
ChemPhysChem     Hybrid Journal   (Followers: 11)
ChemPlusChem     Hybrid Journal   (Followers: 2)
ChemTexts     Hybrid Journal  
CHIMIA International Journal for Chemistry     Full-text available via subscription   (Followers: 2)
Chinese Journal of Chemistry     Hybrid Journal   (Followers: 6)
Chinese Journal of Polymer Science     Hybrid Journal   (Followers: 11)
Chromatographia     Hybrid Journal   (Followers: 24)
Chromatography     Open Access   (Followers: 2)
Chromatography Research International     Open Access   (Followers: 6)
Clay Minerals     Full-text available via subscription   (Followers: 10)
Cogent Chemistry     Open Access  
Colloid and Interface Science Communications     Open Access  
Colloid and Polymer Science     Hybrid Journal   (Followers: 11)
Colloids and Interfaces     Open Access  
Colloids and Surfaces B: Biointerfaces     Hybrid Journal   (Followers: 6)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 5)
Combustion Science and Technology     Hybrid Journal   (Followers: 22)
Comments on Inorganic Chemistry: A Journal of Critical Discussion of the Current Literature     Hybrid Journal   (Followers: 2)
Composite Interfaces     Hybrid Journal   (Followers: 7)
Comprehensive Chemical Kinetics     Full-text available via subscription   (Followers: 1)
Comptes Rendus Chimie     Full-text available via subscription  
Comptes Rendus Physique     Full-text available via subscription   (Followers: 1)
Computational and Theoretical Chemistry     Hybrid Journal   (Followers: 9)
Computational Biology and Chemistry     Hybrid Journal   (Followers: 11)
Computational Chemistry     Open Access   (Followers: 2)
Computers & Chemical Engineering     Hybrid Journal   (Followers: 10)
Coordination Chemistry Reviews     Full-text available via subscription   (Followers: 3)
Copernican Letters     Open Access   (Followers: 1)
Corrosion Series     Full-text available via subscription   (Followers: 6)
Critical Reviews in Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 5)
Croatica Chemica Acta     Open Access  
Crystal Structure Theory and Applications     Open Access   (Followers: 4)
CrystEngComm     Full-text available via subscription   (Followers: 13)
Current Catalysis     Hybrid Journal   (Followers: 2)
Current Chromatography     Hybrid Journal  
Current Green Chemistry     Hybrid Journal  
Current Metabolomics     Hybrid Journal   (Followers: 5)
Current Microwave Chemistry     Hybrid Journal  
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 9)
Current Opinion in Molecular Therapeutics     Full-text available via subscription   (Followers: 14)
Current Research in Chemistry     Open Access   (Followers: 8)
Current Science     Open Access   (Followers: 70)
Current Trends in Biotechnology and Chemical Research     Open Access   (Followers: 3)
Dalton Transactions     Full-text available via subscription   (Followers: 23)
Detection     Open Access   (Followers: 2)
Developments in Geochemistry     Full-text available via subscription   (Followers: 2)
Diamond and Related Materials     Hybrid Journal   (Followers: 12)
Dislocations in Solids     Full-text available via subscription  
Doklady Chemistry     Hybrid Journal  

        1 2 3 4 | Last

Journal Cover Biochemical Pharmacology
  [SJR: 2.263]   [H-I: 160]   [10 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0006-2952
   Published by Elsevier Homepage  [3177 journals]
  • In vitro assessment of competitive and time-dependent inhibition of the
           nevirapine metabolism by nortriptyline in rats
    • Authors: Iris Usach; José-Maria Ferrer; José-Esteban Peris
      Pages: 1 - 9
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Iris Usach, José-Maria Ferrer, José-Esteban Peris
      Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1) widely used as a component of High Active Antiretroviral Therapy (HAART) since it is inexpensive, readily absorbed after oral administration and non-teratogenic. In the present work, the mechanism of a previously described pharmacokinetic interaction between NVP and the antidepressant drug nortriptyline (NT) was studied using rat hepatic microsomes. The obtained results showed a competitive inhibition of the NVP metabolism by NT. The three main NVP metabolites (2-OH-NVP, 3-OH-NVP and 12-OH-NVP) where competitively inhibited with similar inhibitory constant values (Ki = 4.01, 3.97 and 4.40 μM, respectively). Time-dependent inhibition of the NVP metabolism was also detected, with a 2.5-fold reduction in the IC50 values of NT for 2-, 3-, and 12-OH-NVP formation when NT was preincubated with the microsomal suspension in the presence of an NADPH-generating system. A concentration-dependent inhibition of the formation of NVP metabolites by the main NT metabolite (10-OH-NT) was also observed, however, the inhibitory potency of 10-OH-NT was much lower than that of the parent drug. The apparent hepatic intrinsic clearance of NVP determined in these in vitro experiments was used to predict the in vivo clearance of NVP using the “well-stirred” and the “parallel-tube” models, resulting in values close to those previously observed in vivo clearance. Finally, a good prediction of the increase in the plasma concentrations of NVP when co-administered with NT was obtained employing the inhibitory constant of NT determined in vitro and the estimated plasma concentration of NT entering the liver.
      Graphical abstract image

      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.04.016
      Issue No: Vol. 154 (2018)
  • Ribociclib shows potential for pharmacokinetic drug-drug interactions
           being a substrate of ABCB1 and potent inhibitor of ABCB1, ABCG2 and CYP450
           isoforms in vitro
    • Authors: Ales Sorf; Jakub Hofman; Radim Kučera; Frantisek Staud; Martina Ceckova
      Pages: 10 - 17
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Ales Sorf, Jakub Hofman, Radim Kučera, Frantisek Staud, Martina Ceckova
      Ribociclib is a novel cyclin-dependent kinase (CDK) 4 and 6 selective inhibitor that recently gained breakthrough therapy status and global approval for advanced breast cancer treatment. ATP-binding cassette (ABC) transporters may become a site of severe drug interactions and a mechanism of multidrug resistance (MDR) development. With respect to rapid progress of ribociclib in the clinical field, we aimed to identify its interactions with ABC transporters and cytochrome P450 (CYP) isoenzymes and evaluate its potential to overcome transporter-mediated MDR using established in vitro methods. Our data showed accelerated ABCB1 inhibitor LY335979-sensitive, basolateral-to-apical transport of ribociclib across MDCKII-ABCB1 cell monolayers, which identified ribociclib as an ABCB1 substrate. The antiproliferative studies supported this finding by demonstrating significantly higher EC50 value in ABCB1-, but not ABCG2- or ABCC1-expressing MDCKII cells, than in the parent MDCKII cell line. Furthermore, we observed significant inhibitory effects of ribociclib on ABCB1 and ABCG2 transporters and CYP1A2, CYP3A4, CYP3A5, and CYP2C9 isoform activity in human CYP-expressing insect microsomes. The ribociclib-induced ABCB1 and ABCG2 inhibition further reversed daunorubicin and mitoxantrone resistance in MDCKII and human MCF-7 breast carcinoma cell lines, indicating a synergistic antiproliferative effect, without affecting ABCB1 or ABCG2 expression. In summary, our data indicate that ABCB1 affects ribociclib transport across the membranes and the high potential of ribociclib for drug-drug interactions (DDIs) through ABCB1 and ABCG2 transporters and CYP isoforms. Moreover, we demonstrate the beneficial MDR-reversing potential of ribociclib, which could be further exploited in novel anticancer treatment strategies.
      Graphical abstract image

      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.04.013
      Issue No: Vol. 154 (2018)
  • Baicalin modulates the Treg/Teff balance to alleviate uveitis by
           activating the aryl hydrocarbon receptor
    • Authors: Wenjie Zhu; Xiaoqing Chen; Jianfeng Yu; Yichen Xiao; Yingqi Li; Shangtao Wan; Wenru Su; Dan Liang
      Pages: 18 - 27
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Wenjie Zhu, Xiaoqing Chen, Jianfeng Yu, Yichen Xiao, Yingqi Li, Shangtao Wan, Wenru Su, Dan Liang
      Autoimmune uveitis is a sight-threatening ocular inflammatory disorder. Immunological inflammation is regarded as the key to pathogenesis in autoimmune uveitis. Baicalin, the major bioactive component of Scutellaria baicalensis, possesses immunomodulatory properties. However, the role of baicalin in uveitis and its underlying mechanisms remain unclear. In the current study, we found that baicalin treatment obviously inhibited the intraocular inflammatory process in mice with experimental autoimmune uveitis, along with clear declines in infiltrated inflammatory cells and inflammatory cytokine transcription in the retina and draining lymph nodes. Furthermore, baicalin treatment increased the frequency and number of regulatory T cells and decreased the frequency and number of effector T cells (Th1 and Th17 cells) in the draining lymph nodes of mice with experimental autoimmune uveitis. In vitro, baicalin treatment suppressed interphotoreceptor retinoid binding protein-specific CD4+ T cell proliferation and converted CD4+ T cell differentiation. Furthermore, the expression of aryl hydrocarbon receptor was activated by baicalin treatment. Baicalin-mediated modulation of CD4+ T cell differentiation was partially abrogated by the suppression of aryl hydrocarbon receptor. These findings suggest that baicalin modulates the Treg/Teff balance and CD4+ T cell proliferation to ameliorate experimental autoimmune uveitis by activating the aryl hydrocarbon receptor.
      Graphical abstract image

      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.04.006
      Issue No: Vol. 154 (2018)
  • Inhibitory effects of drugs on the metabolic activity of mouse and human
           aldehyde oxidases and influence on drug–drug interactions
    • Authors: Naoki Takaoka; Seigo Sanoh; Katsuhiro Okuda; Yaichiro Kotake; Go Sugahara; Ami Yanagi; Yuji Ishida; Chise Tateno; Yoshitaka Tayama; Kazumi Sugihara; Shigeyuki Kitamura; Mami Kurosaki; Mineko Terao; Enrico Garattini; Shigeru Ohta
      Pages: 28 - 38
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Naoki Takaoka, Seigo Sanoh, Katsuhiro Okuda, Yaichiro Kotake, Go Sugahara, Ami Yanagi, Yuji Ishida, Chise Tateno, Yoshitaka Tayama, Kazumi Sugihara, Shigeyuki Kitamura, Mami Kurosaki, Mineko Terao, Enrico Garattini, Shigeru Ohta
      As aldehyde oxidase (AOX) plays an emerging role in drug metabolism, understanding its significance for drug–drug interactions (DDI) is important. Therefore, we tested 10 compounds for species-specific and substrate-dependent differences in the inhibitory effect of AOX activity using genetically engineered HEK293 cells over-expressing human AOX1, mouse AOX1 or mouse AOX3. The IC50 values of 10 potential inhibitors of the three AOX enzymes were determined using phthalazine and O 6-benzylguanine as substrates. 17β-Estradiol, menadione, norharmane and raloxifene exhibited marked differences in inhibitory effects between the human and mouse AOX isoforms when the phthalazine substrate was used. Some of the compounds tested exhibited substrate-dependent differences in their inhibitory effects. Docking simulations with human AOX1 and mouse AOX3 were conducted for six representative inhibitors. The rank order of the minimum binding energy reflected the order of the corresponding IC50 values. We also evaluated the potential DDI between an AOX substrate (O 6-benzylguanine) and an inhibitor (hydralazine) using chimeric mice with humanized livers. Pretreatment of hydralazine increased the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC0–24) of O 6-benzylguanine compared to single administration. Our in vitro data indicate species-specific and substrate-dependent differences in the inhibitory effects on AOX activity. Our in vivo data demonstrate the existence of a DDI which may be of relevance in the clinical context.
      Graphical abstract image

      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.04.017
      Issue No: Vol. 154 (2018)
  • Sorafenib suppresses TGF-β responses by inducing caveolae/lipid
           raft-mediated internalization/degradation of cell-surface type II TGF-β
           receptors: Implications in development of effective adjunctive therapy for
           hepatocellular carcinoma
    • Authors: Chih-Ling Chung; Shih-Wei Wang; Wei-Chih Sun; Chih-Wen Shu; Yu-Chen Kao; Meng-Shin Shiao; Chun-Lin Chen
      Pages: 39 - 53
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Chih-Ling Chung, Shih-Wei Wang, Wei-Chih Sun, Chih-Wen Shu, Yu-Chen Kao, Meng-Shin Shiao, Chun-Lin Chen
      Sorafenib is the only FDA approved drug for the treatment of advanced hepatocellular carcinoma (HCC) and other malignancies. Studies indicate that TGF-β signalling is associated with tumour progression in HCC. Autocrine and paracrine TGF-β promotes tumour growth and malignancy by inducing epithelial-mesenchymal transition (EMT). Sorafenib is believed to antagonize tumour progression by inhibiting TGF-β-induced EMT. It improves survival of patients but HCC later develops resistance and relapses. The underlying mechanism of resistance is unknown. Understanding of the molecular mechanism of sorafenib inhibition of TGF-β-induced signalling or responses in HCC may lead to development of adjunctive effective therapy for HCC. In this study, we demonstrate that sorafenib suppresses TGF-β responsiveness in hepatoma cells, hepatocytes, and animal liver, mainly by downregulating cell-surface type II TGF-β receptors (TβRII) localized in caveolae/lipid rafts and non-lipid raft microdomains via caveolae/lipid rafts-mediated internalization and degradation. Furthermore, sorafenib-induced downregulation and degradation of cell-surface TβRII is prevented by simultaneous treatment with a caveolae disruptor or lysosomal inhibitors. On the other hand, sorafenib only downregulates cell-surface TβRII localized in caveolae/lipid rafts but not localized in non-lipid raft microdomains in hepatic stellate cells. These results suggest that sorafenib inhibits TGF-β signalling mainly by inducing caveolae/lipid raft-mediated internalization and degradation of cell-surface TβR-II in target cells. They may also imply that treatment with agents which promote formation of caveolae/lipid rafts, TGF-β receptor kinase inhibitors (e.g., LY2157299) or TGF-β peptide antagonists (by liver-targeting delivery) may be considered as effective adjunct therapy with sorafenib for HCC.
      Graphical abstract image

      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.04.014
      Issue No: Vol. 154 (2018)
  • Dengue virus NS2 and NS4: Minor proteins, mammoth roles
    • Authors: Sindhoora Bhargavi Gopala Reddy; Wei-Xin Chin; Nanjunda Swamy Shivananju
      Pages: 54 - 63
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Sindhoora Bhargavi Gopala Reddy, Wei-Xin Chin, Nanjunda Swamy Shivananju
      Despite the ever-increasing global incidence of dengue fever, there are no specific chemotherapy regimens for its treatment. Structural studies on dengue virus (DENV) proteins have revealed potential drug targets. Major DENV proteins such as the envelope protein and non-structural (NS) proteins 3 and 5 have been extensively investigated in antiviral studies, but with limited success in vitro. However, the minor NS proteins NS2 and NS4 have remained relatively underreported. Emerging evidence indicating their indispensable roles in virus propagation and host immunomodulation should encourage us to target these proteins for drug discovery. This review covers current knowledge on DENV NS2 and NS4 proteins from structural and functional perspectives and assesses their potential as targets for antiviral design. Antiviral targets in NS2A include surface-exposed transmembrane regions involved in pathogenesis, while those in NS2B include protease-binding sites in a conserved hydrophilic domain. Ideal drug targets in NS4A include helix α4 and the PEPEKQR sequence, which are essential for NS4A–2K cleavage and NS4A–NS4B association, respectively. In NS4B, the cytoplasmic loop connecting helices α5 and α7 is an attractive target for antiviral design owing to its role in dimerization and NS4B–NS3 interaction. Findings implicating NS2A, NS2B, and NS4A in membrane-modulation and viroporin-like activities indicate an opportunity to target these proteins by disrupting their association with membrane lipids. Despite the lack of 3D structural data, recent topological findings and progress in structure-prediction methods should be sufficient impetus for targeting NS2 and NS4 for drug design.
      Graphical abstract image

      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.04.008
      Issue No: Vol. 154 (2018)
  • Drug-DNA adducts as biomarkers for metabolic activation of the
           nitro-aromatic nitrogen mustard prodrug PR-104A
    • Authors: Alessia Stornetta; Kai-Cheng Kieren Deng; Sara Danielli; H.D. Sarath Liyanage; Shana J. Sturla; William R. Wilson; Yongchuan Gu
      Pages: 64 - 74
      Abstract: Publication date: August 2018
      Source:Biochemical Pharmacology, Volume 154
      Author(s): Alessia Stornetta, Kai-Cheng Kieren Deng, Sara Danielli, H.D. Sarath Liyanage, Shana J. Sturla, William R. Wilson, Yongchuan Gu
      PR-104A is a clinical-stage nitrogen mustard prodrug that is activated for DNA alkylation by reduction of a nitro group to the corresponding hydroxylamine (PR-104H) or amine (PR-104M). Metabolic reduction is catalysed by flavoreductases such as cytochrome P450 oxidoreductase (POR) under hypoxia, or by aldo-ketoreductase 1C3 (AKR1C3) independently of hypoxia. The unstable reduced metabolites are challenging to measure in biological samples, and biomarkers of the metabolic activation of PR-104A have not been used in the clinical evaluation of PR-104 to date. Here, we employ a selected reaction monitoring mass spectrometry assay for DNA crosslinks to assess the capacity of human cancer cells to bioactivate PR-104A. We also test whether the more abundant DNA monoadducts could be used for the same purpose. DNA monoadducts and crosslinks from PR-104A itself, and from its reduced metabolites, accumulated over 4 h in AKR1C3-expressing TF1 erythroleukaemia cells under hypoxia, whereas intracellular concentrations of unstable PR-104H and PR-104M reached steady state within 1 h. We then varied rates of PR-104A reduction by manipulating hypoxia or reductase expression in a panel of cell lines, in which AKR1C3 and POR were quantified by targeted proteomics. Hypoxia or reductase overexpression induced large increases in PR-104A sensitivity (inhibition of proliferation), DNA damage response (γH2AX formation), steady-state concentrations of PR-104H/M and formation of reduced drug-DNA adducts but not DNA adducts retaining the dinitro groups of PR-104A. The fold-change in the sum of PR-104H and PR-104M correlated with the fold-change in reduced crosslinks or monoadducts (R2 = 0.87 for both), demonstrating their potential for assessing the capacity of cancer cells to bioactivate PR-104A.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.04.004
      Issue No: Vol. 154 (2018)
  • Didymin prevents hyperglycemia-induced human umbilical endothelial cells
           dysfunction and death
    • Authors: Kirtikar Shukla; Himangshu Sonowal; Ashish Saxena; Kota V. Ramana
      Pages: 1 - 10
      Abstract: Publication date: June 2018
      Source:Biochemical Pharmacology, Volume 152
      Author(s): Kirtikar Shukla, Himangshu Sonowal, Ashish Saxena, Kota V. Ramana
      Although didymin, a flavonoid-O-glycosides compound naturally found in the citrus fruits, has been reported to be a potent anticancer agent in the prevention of various cancers, its role in the prevention of cardiovascular complications is unclear. Most importantly, its effect in the prevention of endothelial dysfunction, a pathological process involved in the atherogenesis, is unknown. We have examined the efficacy of didymin in preventing the high glucose (HG; 25 mM)-induced human umbilical vein endothelial cells (HUVECs) dysfunction. Our results indicate that incubation of HUVECs with HG resulted in the loss of cell viability, and pre-incubation of didymin prevented it. Further, didymin prevented the HG-induced generation of reactive oxygen species (ROS) as well as lipid peroxidation product, malondialdehyde. Pretreatment of HUVECs with didymin also prevented the HG-induced decrease in eNOS and increase in iNOS expressions. Further, didymin prevented the HG-induced monocytes cell adhesion to endothelial cells, expressions of ICAM-1 and VCAM-1 and activation of NF-κB. Didymin also prevented the release of various inflammatory cytokines and chemokines in HG-treated HUVECs. In conclusion, our results demonstrate that didymin with its anti-oxidative and anti-inflammatory actions prevents hyperglycemia-induced endothelial dysfunction and death. Thus, it could be developed as a potential natural therapeutic agent for the prevention of cardiovascular complications in diabetes.
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      PubDate: 2018-03-20T08:42:23Z
      DOI: 10.1016/j.bcp.2018.03.012
      Issue No: Vol. 152 (2018)
  • Long noncoding RNA MALAT1 regulates generation of reactive oxygen species
           and the insulin responses in male mice
    • Authors: Jingshu Chen; Sui Ke; Lei Zhong; Jing Wu; Alexander Tseng; Benjamin Morpurgo; Andrei Golovko; Gang Wang; James J. Cai; Xi Ma; Defa Li; Yanan Tian
      Pages: 94 - 103
      Abstract: Publication date: June 2018
      Source:Biochemical Pharmacology, Volume 152
      Author(s): Jingshu Chen, Sui Ke, Lei Zhong, Jing Wu, Alexander Tseng, Benjamin Morpurgo, Andrei Golovko, Gang Wang, James J. Cai, Xi Ma, Defa Li, Yanan Tian
      The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long noncoding RNA and its overexpression is associated with the development of many types of malignancy. MALAT1 null mice show no overt phenotype. However, in transcriptome analysis of MALAT1 null mice we found significant upregulation of nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) regulated antioxidant genes including Nqo1 and Cat with significant reduction in reactive oxygen species (ROS) and greatly reduced ROS-generated protein carbonylation in hepatocyte and islets. We performed lncRNA pulldown assay using biotinylated antisense oligonucleotides against MALAT1 and found MALAT1 interacted with Nrf2, suggesting Nrf2 is transcriptionally regulated by MALAT1. Exposure to excessive ROS has been shown to cause insulin resistance through activation of c-Jun N-terminal kinase (JNK) which leads to inhibition of insulin receptor substrate 1 (IRS-1) and insulin-induced phosphorylation of serine/threonine kinase Akt. We found MALAT1 ablation suppressed JNK activity with concomitant insulin-induced activation of IRS-1 and phosphorylation of Akt suggesting MALAT1 regulated insulin responses. MALAT1 null mice exhibited sensitized insulin-signaling response to fast-refeeding and glucose/insulin challenges and significantly increased insulin secretion in response to glucose challenge in isolated MALAT1 null islets, suggesting an increased insulin sensitivity. In summary, we demonstrate that MALAT1 plays an important role in regulating insulin sensitivity and has the potential as a therapeutic target for the treatment of diabetes as well as other diseases caused by excessive exposure to ROS.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.03.019
      Issue No: Vol. 152 (2018)
  • Forskolin improves sensitivity to doxorubicin of triple negative breast
           cancer cells via Protein Kinase A-mediated ERK1/2 inhibition
    • Authors: Michela Illiano; Luigi Sapio; Alessia Salzillo; Lucia Capasso; Ilaria Caiafa; Emilio Chiosi; Annamaria Spina; Silvio Naviglio
      Pages: 104 - 113
      Abstract: Publication date: June 2018
      Source:Biochemical Pharmacology, Volume 152
      Author(s): Michela Illiano, Luigi Sapio, Alessia Salzillo, Lucia Capasso, Ilaria Caiafa, Emilio Chiosi, Annamaria Spina, Silvio Naviglio
      Triple negative breast cancer (TNBC) is an invasive, metastatic, highly aggressive tumor. Cytotoxic chemotherapy represents the current treatment for TNBC. However, relapse and chemo-resistance are very frequent. Therefore, new therapeutic approaches that are able to increase the sensitivity to cytotoxic drugs are needed. Forskolin, a natural cAMP elevating agent, has been used for several centuries in medicine and its safeness has also been demonstrated in modern studies. Recently, forskolin is emerging as a possible novel molecule for cancer therapy. Here, we investigate the effects of forskolin on the sensitivity of MDA-MB-231 and MDA-MB-468 TNBC cells to doxorubicin through MTT assay, flow cytometry-based assays (cell-cycle progression and cell death), cell number counting and immunoblotting experiments. We demonstrate that forskolin strongly enhances doxorubicin-induced antiproliferative effects by cell death induction. Similar effects are observed with IBMX and isoproterenol cAMP elevating agents and 8-Br-cAMP analog, but not by using 8-pCPT-2′-O-Me-cAMP Epac activator. It is important to note that the forskolin-induced potentiation of sensitivity to doxorubicin is accompanied by a strong inhibition of ERK1/2 phosphorylation, is mimicked by ERK inhibitor PD98059 and is prevented by pre-treatment with Protein Kinase A (PKA) and adenylate cyclase inhibitors. Altogether, our data indicate that forskolin sensitizes TNBC cells to doxorubicin via a mechanism depending on the cAMP/PKA-mediated ERK inhibition. Our findings sustain the evidence of anticancer activity mediated by forskolin and encourage the design of future in-vivo/clinical studies in order to explore forskolin as a doxorubicin sensitizer for possible use in TNBC patients.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.03.023
      Issue No: Vol. 152 (2018)
  • Impaired Ca2+ handling in resistance arteries from genetically obese
           Zucker rats: Role of the PI3K, ERK1/2 and PKC signaling pathways
    • Authors: Ana Sánchez; Cristina Contreras; Belén Climent; Alejandro Gutiérrez; Mercedes Muñoz; Albino García-Sacristán; Miguel López; Luis Rivera; Dolores Prieto
      Pages: 114 - 128
      Abstract: Publication date: June 2018
      Source:Biochemical Pharmacology, Volume 152
      Author(s): Ana Sánchez, Cristina Contreras, Belén Climent, Alejandro Gutiérrez, Mercedes Muñoz, Albino García-Sacristán, Miguel López, Luis Rivera, Dolores Prieto
      The impact of obesity on vascular smooth muscle (VSM) Ca2+ handling and vasoconstriction, and its regulation by the phosphatidylinositol 3-kinase (PI3K), mitogen activated protein kinase (MAPK) and protein kinase C (PKC) were assessed in mesenteric arteries (MA) from obese Zucker rats (OZR). Simultaneous measurements of intracellular Ca2+ ([Ca2+]i) and tension were performed in MA from OZR and compared to lean Zucker rats (LZR), and the effects of selective inhibitors of PI3K, ERK-MAPK kinase and PKC were assessed on the functional responses of VSM voltage-dependent L-type Ca2+ channels (CaV1.2). Increases in [Ca2+]i induced by α1-adrenoceptor activation and high K+ depolarization were not different in arteries from LZR and OZR although vasoconstriction was enhanced in OZR. Blockade of the ryanodine receptor (RyR) and of Ca2+ release from the sarcoplasmic reticulum (SR) markedly reduced depolarization-induced Ca2+ responses in arteries from lean but not obese rats, suggesting impaired Ca2+-induced Ca2+ release (CICR) from SR in arteries from OZR. Enhanced Ca2+ influx after treatment with ryanodine was abolished by nifedipine and coupled to up-regulation of CaV1.2 channels in arteries from OZR. Increased activation of ERK-MAPK and up-regulation of PI3Kδ, PKCβ and δ isoforms were associated to larger inhibitory effects of PI3K, MAPK and PKC blockers on VSM L-type channel Ca2+ entry in OZR. Changes in arterial Ca2+ handling in obesity involve SR Ca2+ store dysfunction and enhanced VSM Ca2+ entry through L-type channels, linked to a compensatory up-regulation of CaV1.2 proteins and increased activity of the ERK-MAPK, PI3Kδ and PKCβ and δ, signaling pathways.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.03.020
      Issue No: Vol. 152 (2018)
  • Structure-kinetic relationship studies of cannabinoid CB2 receptor
    • Authors: Marjolein Soethoudt; Mark W.H. Hoorens; Ward Doelman; Andrea Martella; Mario van der Stelt; Laura H. Heitman
      Pages: 129 - 142
      Abstract: Publication date: June 2018
      Source:Biochemical Pharmacology, Volume 152
      Author(s): Marjolein Soethoudt, Mark W.H. Hoorens, Ward Doelman, Andrea Martella, Mario van der Stelt, Laura H. Heitman
      A decade ago, the drug-target residence time model has been (re-)introduced, which describes the importance of binding kinetics of ligands on their protein targets. Since then, it has been applied successfully for multiple protein targets, including GPCRs, for the development of lead compounds with slow dissociation kinetics (i.e. long target residence time) to increase in vivo efficacy or with short residence time to prevent on-target associated side effects. To date, this model has not been applied in the design and pharmacological evaluation of novel selective ligands for the cannabinoid CB2 receptor (CB2R), a GPCR with therapeutic potential in the treatment of tissue injury and inflammatory diseases. Here, we have investigated the relationships between physicochemical properties, binding kinetics and functional activity in two different signal transduction pathways, G protein activation and β-arrestin recruitment. We synthesized 24 analogues of 3-cyclopropyl-1-(4-(6-((1,1-dioxidothiomorpholino)methyl)-5-fluoropyridin-2-yl)benzyl)imidazoleidine-2,4-dione (LEI101), our previously reported in vivo active and CB2R-selective agonist, with varying basicity and lipophilicity. We identified a positive correlation between target residence time and functional potency due to an increase in lipophilicity on the alkyl substituents, which was not the case for the amine substituents. Basicity of the agonists did not show a relationship with affinity, residence time or functional activity. Our findings provide important insights about the effects of physicochemical properties of the specific substituents of this scaffold on the binding kinetics of agonists and their CB2R pharmacology. This work therefore shows how CB2R agonists can be designed to have optimal kinetic profiles, which could aid the lead optimization process in drug discovery for the study or treatment of inflammatory diseases.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.03.018
      Issue No: Vol. 152 (2018)
  • Cross-talk between endogenous H2S and NO accounts for vascular protective
           activity of the metal-nonoate Zn(PipNONO)Cl
    • Authors: Martina Monti; I. Hyseni; Aurora Pacini; Enrico Monzani; Luigi Casella; Lucia Morbidelli
      Pages: 143 - 152
      Abstract: Publication date: June 2018
      Source:Biochemical Pharmacology, Volume 152
      Author(s): Martina Monti, I. Hyseni, Aurora Pacini, Enrico Monzani, Luigi Casella, Lucia Morbidelli
      Nitric oxide (NO) and hydrogen sulfide (H2S) are now recognized as gaseous transmitters with many cardiovascular protective properties. The present study concerns the possibility that NO donors can also function through endogenous activation of NO and H2S pathways. Based on the previous characterization of a novel metal-nonoate, Ni(PipNONO)Cl, our aim was: 1) to study the effects of a zinc based compound, Zn(PipNONO)Cl, on vascular endothelial and smooth muscle cells, and 2) to assess the role and interplay between endogenous NO and H2S promoted by the nonoate. Zn(PipNONO)Cl completely reproduced the vasodilation elicited by Ni(PipNONO)Cl. In the presence of endothelium, preincubation with Zn(PipNONO)Cl sensitized the intima to acetylcholine-induced vasodilation. When tested on cultured endothelial cells, Zn(PipNONO)Cl prompted PI-3K/Akt- and MAPK/ERK1/2-mediated survival. Nitrite levels indicated fast NO release (due to the molecule) and delayed (1–6 h) NO production linked to PI-3K/Akt-dependent eNOS activation. In the same time frame (1–6 h), significant CSE-dependent H2S levels were detected in response to Zn(PipNONO)Cl. The mechanisms responsible for H2S increase seemed to depend on the NONO moiety/sGC/cGMP pathway and zinc-associated ROS production. Our results indicate that endogenous H2S and NO were produced after fast NO release from Zn(PipNONO)Cl, contributing to the vascular endothelium protective effect. The effect was partially reproduced on smooth muscle cells, where Zn(PipNONO)Cl inhibited cell proliferation and migration. In conclusion, vasorelaxant effects, with complementary activities on endothelium and smooth muscle cells, are elicited by the novel metal-nonoate Zn(PipNONO)Cl.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.03.025
      Issue No: Vol. 152 (2018)
  • Natural product toosendanin reverses the resistance of human breast cancer
           cells to adriamycin as a novel PI3K inhibitor
    • Authors: Wang Kai; Shan Yating; Ma Lin; Yang Kaiyong; Hua Baojin; Yin Wu; Yin Fangzhou; Chen Yan
      Pages: 153 - 164
      Abstract: Publication date: June 2018
      Source:Biochemical Pharmacology, Volume 152
      Author(s): Wang Kai, Shan Yating, Ma Lin, Yang Kaiyong, Hua Baojin, Yin Wu, Yin Fangzhou, Chen Yan
      Adriamycin (ADM) is a commonly used drug in clinical breast cancer treatment. However, some breast cancer types or breast cancers subjected to repeated ADM exposure develop strong resistance to ADM thus limiting its clinical efficacy. In this study, we found for the first time that toosendanin (TSN), a triterpenoid extracted from the traditional Chinese medicine Melia toosendan Sieb et Zucc, could successfully reverse adriamycin resistance in human breast cancer cells. Immunofluorescence and HPLC analysis demonstrated that TSN promoted adriamycin accumulation in breast cancer cells, especially in the nucleus. Furthermore, TSN could significantly reduce ABCB1 expression. We then found that TSN was capable of suppressing adriamycin-induced Akt phosphorylation, probably due to downregulation of the PI3K catalytic subunits P110α and P110β, and inhibition of DNA-PKcs. Importantly, the inhibitory effect of TSN on PI3K P110α and P110β expression was specifically observed in breast cancer cells but not in normal human cells. Moreover, TSN significantly potentiated the anti-cancer effect of ADM in the 4T1 breast cancer model and its inhibition rate was nearly 90%. Thus, TSN could be used as a novel PI3K inhibitor to reverse breast cancer resistance. The combination of ADM and TSN may represent a useful strategy for human breast cancer therapy.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.03.022
      Issue No: Vol. 152 (2018)
  • Activation of soluble guanylyl cyclase with inhibition of multidrug
           resistance protein inhibitor-4 (MRP4) as a new antiplatelet therapy
    • Authors: Camila B. Mendes-Silverio; Caroline H. Lescano; Tiago Zaminelli; Carolina Sollon; Gabriel F. Anhê; Edson Antunes; Fabíola Z. Mónica
      Pages: 165 - 173
      Abstract: Publication date: June 2018
      Source:Biochemical Pharmacology, Volume 152
      Author(s): Camila B. Mendes-Silverio, Caroline H. Lescano, Tiago Zaminelli, Carolina Sollon, Gabriel F. Anhê, Edson Antunes, Fabíola Z. Mónica
      The intracellular levels of cyclic GMP are controlled by its rate of formation through nitric oxide-mediated stimulation of soluble guanylate cyclase (sGC) and its degradation by phosphodiesterases. Multidrug resistance protein 4 (MRP4) expressed in human platelets pumps cyclic nucleotides out of cells. In search for new antiplatelet strategies, we tested the hypothesis that sGC activation concomitant with MRP4 inhibition confers higher antiplatelet efficacy compared with monotherapy alone. This study was undertaken to investigate the pharmacological association of the sGC activator BAY 60-2770 with the MRP4 inhibitor MK571 on human washed platelets. Collagen- and thrombin-induced platelet aggregation and ATP-release reaction assays were performed. BAY 60-2770 (0.001–10 µM) produced significant inhibitions of agonist-induced platelet aggregation accompanied by reduced ATP-release. Pre-incubation with 10 µM MK571 alone had no significant effect on platelet aggregation and ATP release, but it produced a left displacement by about of 10–100-fold in the concentration-response curves to BAY 60-2770. Pre-incubation with MK571increased and decreased, respectively, the intracellular and extracellular levels of cGMP to BAY 60-2770, whereas the cAMP levels remained unchanged. The increased VASP-serine 239 phosphorylation in BAY 60-2770-treated platelets was enhanced by MK571. In Fluo-4-loaded platelets, BAY 60-2770 reduced the intracellular Ca2+ levels, an effect significantly potentiated by MK571. Flow cytometry assays showed that BAY 60-2770 reduces the αIIbβ3 integrin activation, which was further reduced by MK571 association. Blocking the MRP4-mediated efflux of cGMP may be a potential mechanism to enhance the antiplatelet efficacy of sGC activators.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.03.028
      Issue No: Vol. 152 (2018)
  • Activation of autophagy by stress-activated signals as a cellular
           self-defense mechanism against the cytotoxic effects of MBIC in human
           breast cancer cells in vitro
    • Authors: Mohadeseh Hasanpourghadi; Nazia Abdul Majid; Mohd Rais Mustafa
      Pages: 174 - 186
      Abstract: Publication date: June 2018
      Source:Biochemical Pharmacology, Volume 152
      Author(s): Mohadeseh Hasanpourghadi, Nazia Abdul Majid, Mohd Rais Mustafa
      We recently reported that methyl 2-(-5-fluoro-2-hydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylate (MBIC) is a microtubule targeting agent (MTA) with multiple mechanisms of action including apoptosis in two human breast cancer cell-lines MCF-7 and MDA-MB-231. In the present study, investigation of early molecular events following MBIC treatment demonstrated the induction of autophagy. This early (<24 h) response to MBIC was characterized by accumulation of autophagy markers; LC3-II, Beclin1, autophagic proteins (ATGs) and collection of autophagosomes but with different variations in the two cell-lines. MBIC-induced autophagy was associated with generation of reactive oxygen species (ROS). In parallel, an increased activation of SAPK/JNK pathway was detected, as an intersection of ROS production and induction of autophagy. The cytotoxic effect of MBIC was enhanced by inhibition of autophagy through blockage of SAPK/JNK signaling, suggesting that MBIC-induced autophagy, is a possible cellular self-defense mechanism against toxicity of this agent in both breast cancer cell-lines. The present findings suggest that inhibition of autophagy eliminates the cytoprotective activity of MDA-MB-231 and MCF-7 cells, and sensitizes both the aggressive and non-aggressive human breast cancer cell-lines to the cytotoxic effects of MBIC.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.03.030
      Issue No: Vol. 152 (2018)
  • Novel regulations of the angiotensin II receptor type 1 by calmodulin
    • Authors: Kevin Ehlers; Robert Clements; Mark VerMeer; Jennifer Giles; Quang-Kim Tran
      Pages: 187 - 200
      Abstract: Publication date: June 2018
      Source:Biochemical Pharmacology, Volume 152
      Author(s): Kevin Ehlers, Robert Clements, Mark VerMeer, Jennifer Giles, Quang-Kim Tran
      The angiotensin II receptor type 1 (AT1R) mediates many Ca2+-dependent actions of angiotensin II (AngII). Calmodulin (CaM) is a key transducer of Ca2+ signals in cells. Two locations on the receptor’s submembrane domains (SMD) 3 and 4 are known to interact with CaM. However, the binding sites for CaM, biochemical properties of the interactions, and their functional impact are not fully understood. Using a FRET-based screening method, we identified a new binding site for CaM on SMD2 (a.a. 125–141), in addition to SMD3 and the juxtamembranous region of SMD4 (SMD4JM, a.a., 309–327). Simultaneous measurements of CaM binding and free Ca2+ show that the interactions are Ca2+-dependent, with disparate K d and EC50(Ca2+) values within the physiological range of cytoplasmic Ca2+. Full interaction between CaM and SMD3 requires the entire domain (a.a. 215–242) and has an EC50(Ca2+) value in the range of resting cytoplasmic Ca2+, suggesting AT1R-CaM interaction can occur in resting conditions in cells. AngII induces robust ERK1/2 phosphorylation in primary vascular smooth muscle cells. This effect is suppressed by AT1R inhibitor losartan and virtually abolished by CaM antagonist W-7. AngII-induced ERK1/2 phosphorylation is suppressed in cells expressing mutant AT1R with reduced CaM binding at each identified binding domain. AngII triggers transient Ca2+ signals in cells expressing wild-type AT1R. These signals are reduced in cells expressing mutant AT1R with reduced CaM binding at SMD3 or SMD4JM, but are very slow-rising, low amplitude signal in cells expressing AT1R with reduced CaM binding at SMD2. The data indicate that CaM interactions with AT1R can occur at various domains, with different affinities, at different physiological Ca2+ levels, and are important for AT1R-mediated signaling.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.03.027
      Issue No: Vol. 152 (2018)
  • Constitutive activity of the metabotropic glutamate receptor 2 explored
           with a whole-cell label-free biosensor
    • Authors: Maarten L.J. Doornbos; Ilse Van der Linden; Liesbeth Vereyken; Gary Tresadern; Adriaan P. IJzerman; Hilde Lavreysen; Laura H. Heitman
      Pages: 201 - 210
      Abstract: Publication date: June 2018
      Source:Biochemical Pharmacology, Volume 152
      Author(s): Maarten L.J. Doornbos, Ilse Van der Linden, Liesbeth Vereyken, Gary Tresadern, Adriaan P. IJzerman, Hilde Lavreysen, Laura H. Heitman
      Label-free cellular assays using a biosensor provide new opportunities for studying G protein-coupled receptor (GPCR) signaling. As opposed to conventional in vitro assays, integrated receptor-mediated cellular responses are determined in real-time rather than a single downstream signaling pathway. In this study, we examined the potential of a label-free whole cell impedance-based biosensor system (i.e. xCELLigence) to study the pharmacology of one GPCR in particular, the mGlu2 receptor. This receptor is a target for the treatment of several psychiatric diseases such as schizophrenia and depression. After optimization of assay conditions to prevent interference of endogenous glutamate in the culture medium, detailed pharmacological assessments were performed. Concentration-response curves showed a concentration-dependent increase in impedance for agonists and positive allosteric modulators, whereas receptor inhibition by an antagonist or negative allosteric modulator resulted in a concentration-dependent decrease in cellular impedance. Interestingly, constitutive receptor activity was observed that was decreased by LY341495, which therefore behaved as an inverse agonist here, a property that was heretofore unappreciated. This was confirmed by concentration-dependent modulation of LY341495 potency and efficacy by a allosteric modulators. In summary, the use of the xCELLigence system to study mGlu2 receptor pharmacology was validated. This is the first class C GPCR to be characterized extensively by such method, opening new avenues to study receptor pharmacology including inverse agonism and demonstrating its value for future drug discovery efforts of mGlu receptors as well as other GPCRs.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.03.026
      Issue No: Vol. 152 (2018)
  • CINPA1 binds directly to constitutive androstane receptor and inhibits its
    • Authors: Milu T. Cherian; Sergio C. Chai; William C. Wright; Aman Singh; Morgan Alexandra Casal; Jie Zheng; Jing Wu; Richard E. Lee; Patrick R. Griffin; Taosheng Chen
      Pages: 211 - 223
      Abstract: Publication date: June 2018
      Source:Biochemical Pharmacology, Volume 152
      Author(s): Milu T. Cherian, Sergio C. Chai, William C. Wright, Aman Singh, Morgan Alexandra Casal, Jie Zheng, Jing Wu, Richard E. Lee, Patrick R. Griffin, Taosheng Chen
      The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are xenobiotic sensors that regulate the expression of drug-metabolizing enzymes and efflux transporters. CAR activation promotes drug elimination, thereby reducing therapeutic effectiveness, or causes adverse drug effects via toxic metabolites. CAR inhibitors could be used to attenuate these adverse drug effects. CAR and PXR share ligands and target genes, confounding the understanding of the regulation of receptor-specific activity. We previously identified a small-molecule inhibitor, CINPA1, that inhibits CAR (without activating PXR at lower concentrations) by altering CAR-coregulator interactions and reducing CAR recruitment to DNA response elements of regulated genes. However, solid evidence was not presented for the direct binding of CINPA1 to CAR. In this study, we demonstrate direct interaction of CINPA1 with the CAR ligand-binding domain (CAR-LBD) and identify key residues involved in such interactions through a combination of biophysical and computational methods. We found that CINPA1 resides in the ligand-binding pocket to stabilize the CAR-LBD in a more rigid, less fluid state. Molecular dynamics simulations, together with our previously reported docking model, enabled us to predict which CAR residues were critical for interactions with CINPA1. The importance of these residues for CINPA1 binding were then validated by directed mutations and testing the mutant CAR proteins in transcription reporter and coregulatory interaction assays. We demonstrated strong hydrogen bonding of CINPA1 with N165 and H203 and identified other residues involved in hydrophobic contacts with CINPA1. Overall, our data confirm that CINPA1 directly binds to CAR.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.03.029
      Issue No: Vol. 152 (2018)
  • Pre-clinical and translational pharmacology of a human interleukin-22 IgG
           fusion protein for potential treatment of infectious or inflammatory
    • Authors: Eric G. Stefanich; Julie Rae; Siddharth Sukumaran; Jeff Lutman; Annemarie Lekkerkerker; Wenjun Ouyang; Xiaoting Wang; Donna Lee; Dimitry M. Danilenko; Lauri Diehl; Kelly M. Loyet; Ann Herman
      Pages: 224 - 235
      Abstract: Publication date: June 2018
      Source:Biochemical Pharmacology, Volume 152
      Author(s): Eric G. Stefanich, Julie Rae, Siddharth Sukumaran, Jeff Lutman, Annemarie Lekkerkerker, Wenjun Ouyang, Xiaoting Wang, Donna Lee, Dimitry M. Danilenko, Lauri Diehl, Kelly M. Loyet, Ann Herman
      Interleukin (IL)-22 plays protective roles in infections and in inflammatory diseases that have been linked to its meditation of innate immunity via multiple mechanisms. IL-22 binds specifically to its heterodimeric receptor, which is expressed on a variety of epithelial tissues. UTTR1147A is a recombinant fusion protein that links the human cytokine IL-22 with the Fc portion of human immunoglobulin (Ig) G4. Here, we report extensive in vitro and in vivo nonclinical studies that were conducted to characterize the pharmacological activity of UTTR1147A. The in vitro activity and potency of UTTR1147A were analyzed using primary human hepatocytes and human colonic epithelial cell lines. Assessment of in vivo efficacy was performed in a mouse colitis model and by measuring relevant pharmacodynamic biomarkers, including antimicrobial peptides REG3A/β, serum amyloid protein A (SAA) and lipopolysaccharide binding protein (LBP). The pharmacokinetic and pharmacodynamic characteristics of UTTR1147A were assessed in healthy mice, rats and cynomolgus monkeys. UTTR1147A induced STAT3 activation through binding to IL-22 receptor expressed in primary human hepatocytes and human colon cell lines. In both, activation occurred in a concentration-dependent manner with similar potencies. In the mouse colitis model, murine IL-22Fc- (muIL-22Fc) treated groups at doses of 1.25 μg and above had statistically lower average histologic colitis scores compared to the control treated group. Administration of muIL-22Fc or UTTR1147A was associated with a dose-dependent induction of PD markers REG3β and SAA in rodents as well as REG3A, SAA and LBP in cynomolgus monkeys. The combined data confirm pharmacological activity of IL-22Fc and support potential regenerative and protective mechanisms in epithelial tissues.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.03.031
      Issue No: Vol. 152 (2018)
  • Regulation of dichloroacetate biotransformation in rat liver and
           extrahepatic tissues by GSTZ1 expression and chloride concentration
    • Authors: Stephan C. Jahn; Marci G. Smeltz; Zhiwei Hu; Laura Rowland-Faux; Guo Zhong; Ryan J. Lorenzo; Katherine V. Cisneros; Peter W. Stacpoole; Margaret O. James
      Pages: 236 - 243
      Abstract: Publication date: June 2018
      Source:Biochemical Pharmacology, Volume 152
      Author(s): Stephan C. Jahn, Marci G. Smeltz, Zhiwei Hu, Laura Rowland-Faux, Guo Zhong, Ryan J. Lorenzo, Katherine V. Cisneros, Peter W. Stacpoole, Margaret O. James
      Biotransformation of dichloroacetate (DCA) to glyoxylate by hepatic glutathione transferase zeta 1 (GSTZ1) is considered the principal determinant of the rate of plasma clearance of the drug. However, several other organismal and subcellular factors are also known to influence DCA metabolism. We utilized a female rat model to study these poorly understood processes. Rats aged 4 weeks (young) and 42–52 weeks (adult) were used to model children and adults, respectively. Hepatic chloride concentrations, which influence the rate of GSTZ1 inactivation by DCA, were lower in rat than in human tissues and rats did not show the age dependence previously seen in humans. We found GSTZ1 expression and activity in rat brain, heart, and kidney cell-free homogenates that were age-dependent. GSTZ1 expression in brain was higher in young rats than adult rats, whereas cardiac and renal GSTZ1 expression levels were higher in adult than young rats. GSTZ1 activity with DCA could not be measured accurately in kidney cell-free homogenates due to rapid depletion of glutathione by γ-glutamyl transpeptidase. Following oral administration of DCA, 100 mg/kg, to rats, GSTZ1 expression and activity were reduced in all rat tissues, but chloride concentrations were not affected. Together, these data extend our understanding of factors that determine the in vivo kinetics of DCA.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.04.001
      Issue No: Vol. 152 (2018)
  • Phyto and endocannabinoids exert complex actions on calcium and zinc
           signaling in mouse cortical neurons
    • Authors: Alexandre Bouron
      Pages: 244 - 251
      Abstract: Publication date: June 2018
      Source:Biochemical Pharmacology, Volume 152
      Author(s): Alexandre Bouron
      Live-cell imaging experiments were performed with the fluorescent Ca2+ and Zn2+ probes Fluo-4 and FluoZin-3 on cultured cortical neurons dissociated from embryonic mice to investigate the effects of the cannabinoids anandamide (AEA), cannabidiol (CBD), and N-arachidonoyl glycine (NAGly) on neuronal store-operated Ca2+ entry (SOCE). When tested individually AEA, CBD or NAGly inhibited SOCE. CBD and NAGly also released Ca2+ from the endoplasmic reticulum. Furthermore, NAGly mobilized Zn2+ from a store distinct from the endoplasmic reticulum and mitochondria, and up-regulated the thapsigargin-evoked Ca2+ release. All these effects developed in a cannabinoid receptor CB1/2 independent manner via an intracellular pathway sensitive to the GPR55 antagonist ML193. Evidence is presented that cannabinoids influence Ca2+ and Zn2+ signaling in central nervous system neurons. The lipid sensing receptor GPR55 seems to be a central actor governing these responses. In addition, the alteration of the cytosolic Zn2+ levels produced by NAGly provides support for the existence of a connection between endocannabinoids and Zn2+ signaling in the brain.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.04.003
      Issue No: Vol. 152 (2018)
  • Adaptive reduction of human myometrium contractile activity in response to
           prolonged uterine stretch during term and twin pregnancy. Role of TREK-1
    • Authors: Zongzhi Yin; Wenzhu He; Yun Li; Dan Li; Hongyan Li; Yuanyuan Yang; Zhaolian Wei; Bing Shen; Xi Wang; Yunxia Cao; Raouf A. Khalil
      Pages: 252 - 263
      Abstract: Publication date: June 2018
      Source:Biochemical Pharmacology, Volume 152
      Author(s): Zongzhi Yin, Wenzhu He, Yun Li, Dan Li, Hongyan Li, Yuanyuan Yang, Zhaolian Wei, Bing Shen, Xi Wang, Yunxia Cao, Raouf A. Khalil
      Quiescence of myometrium contractile activity allows uterine expansion to accommodate the growing fetus and prevents preterm labor particularly during excessive uterine stretch in multiple pregnancy. However, the mechanisms regulating uterine response to stretch are unclear. We tested the hypothesis that prolonged uterine stretch is associated with decreased myometrium contractile activity via activation of TWIK-related K+ channel (TREK-1). Pregnant women at different gestational age (preterm and term) and uterine stretch (singleton and twin pregnancy) were studied, and uterine strips were isolated for measurement of contractile activity and TREK-1 channel expression/activity. Both oxytocin- and KCl-induced contraction were reduced in term vs preterm pregnancy and in twin vs singleton pregnancy. Oxytocin contraction was reduced in uterine segments exposed to 8 g stretch compared to control tissues under 2 g basal tension. TREK-1 mRNA expression and protein levels were augmented in Singleton-Term vs Singleton-Preterm, and in uterine strips exposed to 8 g stretch. The TREK-1 activator arachidonic acid reduced oxytocin contraction in preterm and term, singleton and twin pregnant uterus. The TREK-1 blocker l-methionine enhanced oxytocin contraction in Singleton-Term and twin pregnant uterus, and reversed the decreases in contraction in uterine strips exposed to prolonged stretch. Carboprost-induced uterine contraction was also reduced by arachidonic acid and enhanced by l-methionine. Thus, myometrium contraction decreases with gestational age and uterine expansion in twin pregnancy. The results suggest that prolonged stretch enhances the expression/activity of TREK-1 channel, leading to decreased myometrium contractile activity and maintained healthy term pregnancy particularly in multiple pregnancy.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.03.021
      Issue No: Vol. 152 (2018)
  • Molecular determinants of Kv7.1/KCNE1 channel inhibition by amitriptyline
    • Authors: Kathya Villatoro-Gómez; David O. Pacheco-Rojas; Eloy G. Moreno-Galindo; Ricardo A. Navarro-Polanco; Martin Tristani-Firouzi; Dimitris Gazgalis; Meng Cui; José A. Sánchez-Chapula; Tania Ferrer
      Pages: 264 - 271
      Abstract: Publication date: June 2018
      Source:Biochemical Pharmacology, Volume 152
      Author(s): Kathya Villatoro-Gómez, David O. Pacheco-Rojas, Eloy G. Moreno-Galindo, Ricardo A. Navarro-Polanco, Martin Tristani-Firouzi, Dimitris Gazgalis, Meng Cui, José A. Sánchez-Chapula, Tania Ferrer
      Amitriptyline (AMIT) is a compound widely prescribed for psychiatric and non-psychiatric conditions including depression, migraine, chronic pain, and anorexia. However, AMIT has been associated with risks of cardiac arrhythmia and sudden death since it can induce prolongation of the QT interval on the surface electrocardiogram and torsade de pointes ventricular arrhythmia. These complications have been attributed to the inhibition of the rapid delayed rectifier potassium current (IKr). The slow delayed rectifier potassium current (IKs) is the main repolarizing cardiac current when IKr is compromised and it has an important role in cardiac repolarization at fast heart rates induced by an elevated sympathetic tone. Therefore, we sought to characterize the effects of AMIT on Kv7.1/KCNE1 and homomeric Kv7.1 channels expressed in HEK-293H cells. Homomeric Kv7.1 and Kv7.1/KCNE1 channels were inhibited by AMIT in a concentration-dependent manner with IC50 values of 8.8 ± 2.1 μM and 2.5 ± 0.8 μM, respectively. This effect was voltage-independent for both homomeric Kv7.1 and Kv7.1/KCNE1 channels. Moreover, mutation of residues located on the P-loop and S6 domain along with molecular docking, suggest that T312, I337 and F340 are the most important molecular determinants for AMIT-Kv7.1 channel interaction. Our experimental findings and modeling suggest that AMIT preferentially blocks the open state of Kv7.1/KCNE1 channels by interacting with specific residues that were previously reported to be important for binding of other compounds, such as chromanol 293B and the benzodiazepine L7.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.03.016
      Issue No: Vol. 152 (2018)
  • In vivo and in vitro diclofenac 5-hydroxylation mediated primarily by
           cytochrome P450 3A enzymes in common marmoset livers genotyped for P450
           2C19 variants
    • Authors: Kazuyuki Nakanishi; Shotaro Uehara; Takashi Kusama; Takashi Inoue; Kanami Shimura; Yusuke Kamiya; Norie Murayama; Makiko Shimizu; Yasuhiro Uno; Erika Sasaki; Hiroshi Yamazaki
      Pages: 272 - 278
      Abstract: Publication date: June 2018
      Source:Biochemical Pharmacology, Volume 152
      Author(s): Kazuyuki Nakanishi, Shotaro Uehara, Takashi Kusama, Takashi Inoue, Kanami Shimura, Yusuke Kamiya, Norie Murayama, Makiko Shimizu, Yasuhiro Uno, Erika Sasaki, Hiroshi Yamazaki
      Common marmosets (Callithrix jacchus) are potentially useful nonhuman primate models for preclinical studies. An anti-inflammatory drug, diclofenac is reportedly metabolized mainly by human cytochrome P450 (P450) 2C9 to 4′-hydroxydiclofenac and minorly by P450 3A4 to 5-hydroxydiclofenac that leads to reactive intermediates. In this study, in vivo pharmacokinetics in six marmosets and in vitro metabolism in nine marmoset liver microsomes were analyzed using diclofenac to evaluate marmosets as preclinical drug metabolism models. In wild-type marmosets genotyped for P450 2C19 p.[(Phe7Leu; Ser254Leu; Ile469Thr)], plasma levels of 5-hydroxydiclofenac and 4′-hydroxydiclofenac were roughly similar, but the homozygotes showed approximately three-times higher plasma levels of 5-hydroxydiclofenac than those of 4′-hydroxydiclofenac after oral administrations of diclofenac (50 mg/kg). Nine marmoset liver microsomes catalyzed mainly diclofenac 5-hydroxylation with no significant effects of the the P450 2C19 genotype, and partly diclofenac 4′-hydroxylation that depended on the P450 2C19 genotype, at substrate concentrations of 10 µM and 100 µM. Both Michaels-Menten constant K m values for diclofenac 4′-hydroxylation in human and marmoset liver microsomes were ∼30 μM and those for diclofenac 5-hydroxylation were ∼120 μM. Ketoconazole significantly suppressed only diclofenac 5-hydroxylation in marmoset or human liver microsomes at 0.030 μM, indicating main contribution of P450 3A enzymes, which were found to be P450 3A5/90 using recombinant marmoset P450 3A enzymes. These results suggest that marmosets would be a functional animal model for in vivo and in vitro metabolites likely generated via arene oxide intermediates of diclofenac by P450 3A enzymes in humans, primarily because marmosets lack the ortholog of human P450 2C9.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.04.002
      Issue No: Vol. 152 (2018)
  • Ketamine and ketamine metabolites as novel estrogen receptor ligands:
           Induction of cytochrome P450 and AMPA glutamate receptor gene expression
    • Authors: Ming-Fen Ho; Cristina Correia; James N. Ingle; Rima Kaddurah-Daouk; Liewei Wang; Scott H. Kaufmann; Richard M. Weinshilboum
      Pages: 279 - 292
      Abstract: Publication date: June 2018
      Source:Biochemical Pharmacology, Volume 152
      Author(s): Ming-Fen Ho, Cristina Correia, James N. Ingle, Rima Kaddurah-Daouk, Liewei Wang, Scott H. Kaufmann, Richard M. Weinshilboum
      Major depressive disorder (MDD) is the most common psychiatric illness worldwide, and it displays a striking sex-dependent difference in incidence, with two thirds of MDD patients being women. Ketamine treatment can produce rapid antidepressant effects in MDD patients, effects that are mediated—at least partially—through glutamatergic neurotransmission. Two active metabolites of ketamine, (2R,6R)-hydroxynorketamine (HNK) and (2S,6S)-HNK, also appear to play a key role in ketamine’s rapid antidepressant effects through the activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors. In the present study, we demonstrated that estrogen plus ketamine or estrogen plus active ketamine metabolites displayed additive effects on the induction of the expression of AMPA receptor subunits. In parallel, the expression of estrogen receptor alpha (ERα) was also significantly upregulated. Even more striking, radioligand binding assays demonstrated that [3H]-ketamine can directly bind to ERα (K D: 344.5 ± 13 nM). Furthermore, ketamine and its (2R,6R)-HNK and (2S,6S)-HNK metabolites displayed similar affinity for ERα (IC50: 2.31 ± 0.1, 3.40 ± 0.2, and 3.53 ± 0.2 µM, respectively) as determined by [3H]-ketamine displacement assays. Finally, induction of AMPA receptors by either estrogens or ketamine and its metabolites was lost when ERα was knocked down or silenced pharmacologically. These results suggest a positive feedback loop by which estrogens can augment the effects of ketamine and its (2R,6R)-HNK and (2S,6S)-HNK metabolites on the ERα-induced transcription of CYP2A6 and CYP2B6, estrogen inducible enzymes that catalyze ketamine’s biotransformation to form the two active metabolites. These observations provide novel insight into ketamine’s molecular mechanism(s) of action and have potential implications for the treatment of MDD.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.03.032
      Issue No: Vol. 152 (2018)
  • E4bp4 regulates carboxylesterase 2 enzymes through repression of the
           nuclear receptor Rev-erbα in mice
    • Authors: Mengjing Zhao; Tianpeng Zhang; Fangjun Yu; Lianxia Guo; Baojian Wu
      Pages: 293 - 301
      Abstract: Publication date: June 2018
      Source:Biochemical Pharmacology, Volume 152
      Author(s): Mengjing Zhao, Tianpeng Zhang, Fangjun Yu, Lianxia Guo, Baojian Wu
      Carboxylesterases (CES) are a family of phase I enzymes that play an important role in xenobiotic clearance and lipid metabolism. Here, we investigate a potential role of E4 promoter-binding protein 4 (E4bp4) in regulation of Ces and CPT-11 (irinotecan, a first-line drug for treating colorectal cancer) pharmacokinetics in mice. Mouse hepatoma Hepa-1c1c7 cells were transfected with Rev-erbα expression plasmid or siRNA targeting E4bp4. The relative mRNA and protein levels of Ces enzymes in the cells or the livers of wild-type and E4bp4-deficient (E4bp4−/−) mice were determined by qPCR and Western blotting, respectively. Transcriptional regulation of Ces by E4bp4/Rev-erbα were investigated using luciferase reporter, mobility shift, and co-immunoprecipitation (Co-IP) assays. Pharmacokinetic studies were performed with wild-type and E4bp4−/− mice after intraperitoneal injection of CPT-11. E4bp4 ablation down-regulated an array of hepatic Ces genes in mice. E4bp4−/− mice also showed reduced Ces-mediated metabolism and elevated systemic exposure of CPT-11, a well-known Ces substrate. Consistently, E4bp4 knockdown reduced the expression of Ces genes (Ces2b, Ces2e and Ces2f) in Hepa-1c1c7 cells. Furthermore, Rev-erbα repressed the transcription of Ces2b, whereas E4bp4 antagonized this repressive action. Co-IP experiment confirmed a direct interaction between E4bp4 and Rev-erbα. Through a combination of promoter analysis and mobility shift assays, we demonstrated that Rev-erbα trans-repressed Ces (Ces2b) through its specific binding to the -767 to-754 bp promoter region. In conclusion, E4bp4 regulates Ces enzymes through inhibition of the transrepression activity of Rev-erbα, thereby impacting the metabolism and pharmacokinetics of Ces substrates.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.04.005
      Issue No: Vol. 152 (2018)
  • Using chemical bond-based method to predict site of metabolism for five
           biotransformations mediated by CYP 3A4, 2D6, and 2C9
    • Authors: XuYan Fu; ShuaiBing He; Li Du; ZhaoLei Lv; Yi Zhang; Qian Zhang; Yun Wang
      Pages: 302 - 314
      Abstract: Publication date: June 2018
      Source:Biochemical Pharmacology, Volume 152
      Author(s): XuYan Fu, ShuaiBing He, Li Du, ZhaoLei Lv, Yi Zhang, Qian Zhang, Yun Wang
      Although it has been proposed for decades to predict site of metabolism (SOM) by in silico methods, identifying SOM correctly remains an unsolved fundamental problem and is an active area of research. In our prior works, we proposed a chemical bond-based approach to construction of SOM prediction models by integrating chemical bond descriptors and drug-metabolizing enzymes data. Although it has been evaluated with both 10-fold cross-validation and independent validation, we believe comparisons between this method and prior methods using publicly accessible external datasets are indispensable and more desirable. In the current study, based on chemical bond-based method, metabolism data released by Sheridan et al. and Zaretzki et al. was utilized to establish metabolite prediction models for CYP450 3A4, 2D6, and 2C9. Five major reaction types were involved, including Aliphatic C-hydroxylation, Aromatic C-hydroxylation, N-dealkylation, O-dealkylation, and S-Oxidation. Consequently, all our five models showed impressive performance on predicting SOMs, with accuracy and area under curve exceeded 0.940 and 0.953, respectively. Compared to prior works, our models were better than SOMP both in “SOM-scale” and “molecule-scale”. In conclusion, comparisons between chemical-bond based method and prior works were conducted for the first time, which demonstrated that chemical-bond based method is better than or at least comparable to prior works.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.03.024
      Issue No: Vol. 152 (2018)
  • Chromogranin-A and its derived peptides and their pharmacological effects
           during intestinal inflammation
    • Authors: Nour Eissa; Hayam Hussein; Geoffrey N. Hendy; Charles N. Bernstein; Jean-Eric Ghia
      Pages: 315 - 326
      Abstract: Publication date: June 2018
      Source:Biochemical Pharmacology, Volume 152
      Author(s): Nour Eissa, Hayam Hussein, Geoffrey N. Hendy, Charles N. Bernstein, Jean-Eric Ghia
      The gastrointestinal tract is the largest endocrine organ that produces a broad range of active peptides. Mucosal changes during inflammation alter the distribution and products of enteroendocrine cells (EECs) that play a role in immune activation and regulation of gut homeostasis by mediating communication between the nervous, endocrine and immune systems. Patients with inflammatory bowel disease (IBD) typically have altered expression of chromogranin (CHG)-A (CHGA), a major soluble protein secreted by EECs that functions as a pro-hormone. CHGA gives rise to several bioactive peptides that have direct or indirect effects on intestinal inflammation. In IBD, CHGA and its derived peptides are correlated with the disease activity. In this review we describe the potential immunomodulatory roles of CHGA and its derived peptides and their clinical relevance during the progression of intestinal inflammation. Targeting CHGA and its derived peptides could be of benefit for the diagnosis and clinical management of IBD patients.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.04.009
      Issue No: Vol. 152 (2018)
  • Metronomic vinorelbine is directly active on Non Small Cell Lung Cancer
           cells and sensitizes the EGFRL858R/T790M cells to reversible EGFR tyrosine
           kinase inhibitors
    • Authors: Paola Orlandi; Teresa Di Desidero; Giada Salvia; Beatrice Muscatello; Giulio Francia; Guido Bocci
      Pages: 327 - 337
      Abstract: Publication date: June 2018
      Source:Biochemical Pharmacology, Volume 152
      Author(s): Paola Orlandi, Teresa Di Desidero, Giada Salvia, Beatrice Muscatello, Giulio Francia, Guido Bocci
      Metronomic vinorelbine (mVNR) has been described primarily as an antiangiogenic therapy, and no direct effects of mVNR on Non Small Cell Lung Cancer (NSCLC) cells has yet been demonstrated. The aims of this study were i) to establish the direct activity of mVNR on NSCLC cells either EGFR wt or EGFRL858R/T790M , and ii) to quantify the synergism of the combination with reversible EGFR tyrosine kinase inhibitors (TKIs), investigating the underlying mechanism of action. Proliferation assays were performed on A-549 (wt EGFRhigh ), H-292 (EGFR-wt), H-358 (EGFR-wt), H-1975 (EGFRL858R/T790M ) NSCLC cell lines exposed to mVNR, its active metabolite deacetyl-VNR (D-VNR), gefitinib and erlotinib for 144 h treatments. The synergism between mVNR and EGFR TKIs was determined by the combination index (CI) in EGFR-wt and H-1975 NSCLC cells. Cyclin-D1 and ABCG2 genes expression and protein levels were measured by RT-PCR and ELISA assays, as well as the phosphorylation of ERK1/2 and Akt. Intracellular concentrations of EGFR TKIs and VNR were investigated with a mass spectrometry system. mVNR, and its active metabolite D-VNR, were extremely active on NSCLC cells, in particular on H-1975 (IC50 = 13.56 ± 2.77 pM), resistant to TKIs. mVNR inhibited the phosphorylation of ERK1/2 and Akt and significantly decreased the expression of both cyclin-D1 and ABCG2 m-RNA and protein. The simultaneous combination of VNR and reversible EGFR TKIs showed a strong synergism on EGFR-wt NSCLC cells and on H-1975 cells (e.g. CI = 0.501 for 50% of affected cells), increasing the intracellular concentrations of EGFR TKIs (e.g. +50.5% vs. gefitinib alone). In conclusions, mVNR has direct effects on NSCLC cells and sensitizes resistant cells to EGFR TKIs, increasing their intracellular concentrations.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.04.011
      Issue No: Vol. 152 (2018)
  • Nrf2 as a therapeutic target for rheumatic diseases
    • Authors: María Luisa Ferrándiz; Josep Nacher-Juan; Maria José Alcaraz
      Pages: 338 - 346
      Abstract: Publication date: June 2018
      Source:Biochemical Pharmacology, Volume 152
      Author(s): María Luisa Ferrándiz, Josep Nacher-Juan, Maria José Alcaraz
      Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a master regulator of cellular protective processes. Rheumatic diseases are chronic conditions characterized by inflammation, pain, tissue damage and limitations in function. Main examples are rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis and osteoporosis. Their high prevalence constitutes a major health problem with an important social and economic impact. A wide range of evidence indicates that Nrf2 may control different mechanisms involved in the physiopathology of rheumatic conditions. Therefore, the appropriate expression and balance of Nrf2 is necessary for regulation of oxidative stress, inflammation, immune responses, and cartilage and bone metabolism. Numerous studies have demonstrated that Nrf2 deficiency aggravates the disease in experimental models while Nrf2 activation results in immunoregulatory and anti-inflammatory effects. These reports reinforce the increasing interest in the pharmacologic regulation of Nrf2 and its potential applications. Nevertheless, a majority of Nrf2 inducers are electrophilic molecules which may present off-target effects. In recent years, novel strategies have been sought to modulate the Nrf2 pathway which has emerged as a therapeutic target in rheumatic conditions.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.04.010
      Issue No: Vol. 152 (2018)
  • Autophagy as a pharmacological target in hematopoiesis and hematological
    • Authors: Marion Orsini; Franck Morceau; Mario Dicato; Marc Diederich
      Pages: 347 - 361
      Abstract: Publication date: June 2018
      Source:Biochemical Pharmacology, Volume 152
      Author(s): Marion Orsini, Franck Morceau, Mario Dicato, Marc Diederich
      Autophagy is involved in many cellular processes, including cell homeostasis, cell death/survival balance and differentiation. Autophagy is essential for hematopoietic stem cell survival, quiescence, activation and differentiation. The deregulation of this process is associated with numerous hematological disorders and pathologies, including cancers. Thus, the use of autophagy modulators to induce or inhibit autophagy emerges as a potential therapeutic approach for treating these diseases and could be particularly interesting for differentiation therapy of leukemia cells. This review presents therapeutic strategies and pharmacological agents in the context of hematological disorders. The pros and cons of autophagy modulators in therapy will also be discussed.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.04.007
      Issue No: Vol. 152 (2018)
  • Tanshinone IIA suppresses FcεRI-mediated mast cell signaling and
           anaphylaxis by activation of the Sirt1/LKB1/AMPK pathway
    • Authors: Xian Li; Soon Jin Park; Fansi Jin; Yifeng Deng; Ju Hye Yang; Jae-Hoon Chang; Dong-Young Kim; Jung-Ae Kim; Youn Ju Lee; Makoto Murakami; Kun Ho Son; Hyeun Wook Chang
      Pages: 362 - 372
      Abstract: Publication date: June 2018
      Source:Biochemical Pharmacology, Volume 152
      Author(s): Xian Li, Soon Jin Park, Fansi Jin, Yifeng Deng, Ju Hye Yang, Jae-Hoon Chang, Dong-Young Kim, Jung-Ae Kim, Youn Ju Lee, Makoto Murakami, Kun Ho Son, Hyeun Wook Chang
      AMP-activated protein kinase (AMPK) and its upstream mediators liver kinase B1 (LKB1) and sirtuin 1 (Sirt1) are generally known as key regulators of metabolism. We have recently reported that the AMPK pathway negatively regulates mast cell activation and anaphylaxis. Tanshinone IIA (Tan IIA), an active component of Salvia miltiorrhiza extract that is currently used for the treatment of cardiovascular and cerebrovascular diseases, shows anti-diabetic activity and improves insulin resistance in db/db mice through activation of AMPK. The aim of this study was to evaluate the anti-allergic activity of Tan IIA in vivo and to investigate the underlying mechanism in vitro in the context of AMPK signaling. The anti-allergic effect of Tan IIA was evaluated using mouse bone marrow-derived mast cells (BMMCs) from AMPKα2 −/− or Sirt1 −/− mice, or BMMCs transfected with siRNAs specific for AMPKα2, LKB1, or Sirt1. AMPKα2 −/− and Sirt1 −/− mice were used to confirm the anti-allergic effect of Tan IIA in anaphylaxis in vivo. Tan IIA dose-dependently inhibited FcεRI-mediated degranulation and production of eicosanoids and cytokines in BMMCs. These inhibitory effects were diminished by siRNA-mediated knockdown or genetic deletion of AMPKα2 or Sirt1. Moreover, Tan IIA inhibited a mast cell-mediated local passive anaphylactic reaction in wild-type mice, but not in AMPKα2 −/− or Sirt1 −/− mice. In conclusion, Tan IIA suppresses FcεRI-mediated mast cell activation and anaphylaxis through activation of the inhibitory Sirt1-LKB1-AMPK pathway. Thus, Tan IIA may be useful as a new therapeutic agent for mast cell-mediated allergic diseases.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.04.015
      Issue No: Vol. 152 (2018)
  • Editorial
    • Authors: Michael F. Jarvis; S.J. Enna
      First page: 143
      Abstract: Publication date: May 2018
      Source:Biochemical Pharmacology, Volume 151
      Author(s): Michael F. Jarvis, S.J. Enna

      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.01.020
      Issue No: Vol. 151 (2018)
  • Manipulating cell fate while confronting reproducibility concerns
    • Authors: Jeannette M. Osterloh; Kevin Mullane
      Pages: 144 - 156
      Abstract: Publication date: May 2018
      Source:Biochemical Pharmacology, Volume 151
      Author(s): Jeannette M. Osterloh, Kevin Mullane
      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 reprogramming, maintaining, and differentiating hPSCs that impact interpretation of studies involving their use, and how it relates to efforts to move the field forward. The commitment in time and resources required to generate and maintain cell-lines, coupled with marked variations between hPSCs derived from patients with the same disease, has resulted in a fundamental change in how research is conducted. Dr. Michael Williams has championed the need to appropriately validate all cell-lines before use to limit sources of variability, although defining what constitutes a validated hPSC in the era of single cell-omics can be challenging.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2018.01.016
      Issue No: Vol. 151 (2018)
  • The therapeutic potential of purinergic signalling
    • Authors: Geoffrey Burnstock
      Pages: 157 - 165
      Abstract: Publication date: May 2018
      Source:Biochemical Pharmacology, Volume 151
      Author(s): Geoffrey Burnstock
      This review is focused on the pathophysiology and therapeutic potential of purinergic signalling. A wide range of diseases are considered, including those of the central nervous system, skin, kidney, musculoskeletal, liver gut, lower urinary tract, cardiovascular, airways and reproductive systems, the special senses, infection, diabetes and obesity. Several purinergic drugs are already on the market, including P2Y12 receptor antagonists for stroke and thrombosis, P2Y2 receptor agonists for dry eye, and A1 receptor agonists for supraventricular tachycardia. Clinical trials are underway for the use of P2X3 receptor antagonists for the treatment of chronic cough, visceral pain and hypertension, and many more compounds are being explored for the treatment of other diseases. Most experiments are ‘proof of concept’ studies on animal or cellular models, which hopefully will lead to further clinical trials. The review summarises the topic, mostly referring to recent review articles.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2017.07.016
      Issue No: Vol. 151 (2018)
  • Kinetics of human cannabinoid 1 (CB1) receptor antagonists:
           Structure-kinetics relationships (SKR) and implications for insurmountable
    • Authors: Lizi Xia; Henk de Vries; Xue Yang; Eelke B. Lenselink; Athina Kyrizaki; Francis Barth; Julien Louvel; Matthias K. Dreyer; Daan van der Es; Adriaan P. IJzerman; Laura H. Heitman
      Pages: 166 - 179
      Abstract: Publication date: May 2018
      Source:Biochemical Pharmacology, Volume 151
      Author(s): Lizi Xia, Henk de Vries, Xue Yang, Eelke B. Lenselink, Athina Kyrizaki, Francis Barth, Julien Louvel, Matthias K. Dreyer, Daan van der Es, Adriaan P. IJzerman, Laura H. Heitman
      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 [3H]CP55940 as the radioligand. This assay yielded Kinetic Rate Index (KRI) values from which structure-kinetics relationships (SKR) of hCB1 receptor antagonists could be established. The fast dissociating antagonist 6 had a similar receptor residence time (RT) as rimonabant, i.e. 19 and 14 min, respectively, while the slowest dissociating antagonist (9) had a very long RT of 2222 min, i.e. pseudo-irreversible dissociation kinetics. In functional assays, 9 displayed insurmountable antagonism, while the effects of the shortest RT antagonist 6 and rimonabant were surmountable. Taken together, this study shows that hCB1 receptor antagonists can have very divergent RTs, which are not correlated to their equilibrium affinities. Furthermore, their RTs appear to define their mode of functional antagonism, i.e. surmountable vs. insurmountable. Finally, based on the recently resolved hCB1 receptor crystal structure, we propose that the differences in RT can be explained by a different binding mode of antagonist 9 from short RT antagonists that is able to displace unfavorable water molecules. Taken together, these findings are of importance for future design and evaluation of potent and safe hCB1 receptor antagonists.
      Graphical abstract image

      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2017.10.014
      Issue No: Vol. 151 (2018)
  • Tropisetron enhances recognition memory in rats chronically treated with
           risperidone or quetiapine
    • Authors: Indrani Poddar; Patrick M. Callahan; Caterina M. Hernandez; Xiangkun Yang; Michael G. Bartlett; Alvin V. Terry
      Pages: 180 - 187
      Abstract: Publication date: May 2018
      Source:Biochemical Pharmacology, Volume 151
      Author(s): Indrani Poddar, Patrick M. Callahan, Caterina M. Hernandez, Xiangkun Yang, Michael G. Bartlett, Alvin V. Terry
      While impairments of cognition in schizophrenia have the greatest impact on long-term functional outcome, the currently prescribed treatments, antipsychotic drugs (APDs), do not effectively improve cognition. Moreover, while more than 20 years have been devoted to the development of new drugs to treat cognitive deficits in schizophrenia, none have been approved to date. One area that has not been given proper attention at the preclinical or clinical stage of drug development is the chronic medication history of the test subject. Hence, very little is known about how chronic treatment with drugs that affect multiple receptors like APDs influence the response to a potential pro-cognitive agent. Therefore, the purpose of this study was to evaluate the α7 nicotinic acetylcholine receptor (α7 nAChR) partial agonist, tropisetron in rats chronically treated with APDs with distinct pharmacological profiles. Rats were treated orally with either risperidone (2.5 mg/kg/day) or quetiapine (25.0 mg/kg/day) for 30 or 90 days and then an acute injection of vehicle or tropisetron (3.0 mg/kg) was administered before training in a novel object recognition (NOR) task. After a 48 h delay (when recollection of the familiar object was impaired in vehicle-treated animals) neither 30 nor 90 days of risperidone or quetiapine treatment improved NOR performance. In contrast, tropisetron markedly improved NOR performance in rats treated with either APD for 30 or 90 days. These animal data reinforce the argument that two commonly prescribed APDs are not pro-cognitive agents and that α7 nAChR ligands like tropisetron have potential as adjunctive treatments in schizophrenia.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2017.11.017
      Issue No: Vol. 151 (2018)
  • ATP-binding cassette transporter-2 (ABCA2) as a therapeutic target
    • Authors: Warren Davis; Kenneth D. Tew
      Pages: 188 - 200
      Abstract: Publication date: May 2018
      Source:Biochemical Pharmacology, Volume 151
      Author(s): Warren Davis, Kenneth D. Tew
      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 by sterols. Moreover, in macrophages ABCA2 is influenced by sterols and has a role in regulating cholesterol sequestration, potentially important in cardiovascular disease. Accumulating data indicate the critical importance of ABCA2 in mediating movement of sphingolipids within cellular compartments and these have been implicated in various aspects of cholesterol trafficking. Perhaps because the functions of ABCA2 are linked with membrane building blocks, there are reports linking it with human pathologies, including, cholesterolemias and cardiovascular disease, Alzheimer’s and cancer. The present review addresses whether there is now sufficient information to consider ABCA2 as a plausible therapeutic target.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2017.11.018
      Issue No: Vol. 151 (2018)
  • On the G protein-coupling selectivity of the native A2B adenosine receptor
    • Authors: Zhan-Guo Gao; Asuka Inoue; Kenneth A. Jacobson
      Pages: 201 - 213
      Abstract: Publication date: May 2018
      Source:Biochemical Pharmacology, Volume 151
      Author(s): Zhan-Guo Gao, Asuka Inoue, Kenneth A. Jacobson
      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 1321 N1 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 completely blocked by Gq/11 inhibitor UBO-QIC and by Gq/11 knockout. In T24 cells, Gi was solely responsible for A2BAR-mediated ERK1/2 stimulation, and Gs suppressed ERK1/2 activity. A2BAR-mediated intracellular calcium mobilization in T24 cells was mainly via Gi, although Gs may also play a role, but Gq/11 is not involved. In 1321 N1 astrocytoma cells A2BAR activation suppressed rather than stimulated ERK1/2 activity. The ERK1/2 activity decrease was reversed by Gs downregulation using cholera toxin, but potentiated by Gi inhibitor pertussis toxin, and UBO-QIC had no effect. EPACs played an important role in A2BAR-mediated ERK1/2 signaling in all three cells. Thus, A2BAR may: couple to the same downstream pathway via different G proteins in different cell types; activate different downstream events via different G proteins in the same cell type; activate Gi and Gs, which have opposing or synergistic roles in different cell types/signaling pathways. The findings, relevant to drug discovery, address some reported controversial roles of A2BAR and could apply to signaling mechanisms in other GPCRs.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2017.12.003
      Issue No: Vol. 151 (2018)
  • The wonderland of neuronal nicotinic acetylcholine receptors
    • Authors: Daniel Bertrand; A.V. Terry
      Pages: 214 - 225
      Abstract: Publication date: May 2018
      Source:Biochemical Pharmacology, Volume 151
      Author(s): Daniel Bertrand, A.V. Terry
      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 abandoned this field of research. As with other clinical failures, multiple questions arise as to the basis for the failure. More generic questions focus on a potential translational gap between the animal models used and the human clinical condition they are meant to simulate, or the clinical trial mindset that large Ns have to be achieved for statistical power (often requiring multiple trial sites) as opposed to smaller patient cohorts at limited sites where conditions can be better controlled and replicated. More specific to the nAChR field are questions about subtype selectivity, dose selection, whether an agonist, antagonist, or allosteric modulator strategy is best, etc. The purpose of this review is to discuss each of these questions, but also to provide a brief overview of the remarkable progress that has been made over the last three decades in our understanding of this unique ligand-gated ion channel and how this new knowledge may help us improve drug development successes in the future.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2017.12.008
      Issue No: Vol. 151 (2018)
  • How often should we expect to be wrong' Statistical power, P values,
           and the expected prevalence of false discoveries
    • Authors: Michael J. Marino
      Pages: 226 - 233
      Abstract: Publication date: May 2018
      Source:Biochemical Pharmacology, Volume 151
      Author(s): Michael J. Marino
      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 we expect to be wrong? Using a simple simulation of an idealized experiment, it is possible to show the central role of sample size and the related quantity of statistical power in determining the false discovery rate, and in accurate estimation of effect size. According to our calculations, based on current practice many subfields of biomedical science may expect their discoveries to be false at least 25% of the time, and the only viable course to correct this is to require the reporting of statistical power and a minimum of 80% power (1 − β = 0.80) for all studies.
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      PubDate: 2018-04-25T09:13:30Z
      DOI: 10.1016/j.bcp.2017.12.011
      Issue No: Vol. 151 (2018)
  • p23 protects the human aryl hydrocarbon receptor from degradation via a
           heat shock protein 90-independent mechanism
    • Authors: Beverly Pappas; Yujie Yang; Yu Wang; Kyung Kim; Hee Jae Chung; Michael Cheung; Katie Ngo; Annie Shinn; William K. Chan
      Abstract: Publication date: Available online 17 March 2018
      Source:Biochemical Pharmacology
      Author(s): Beverly Pappas, Yujie Yang, Yu Wang, Kyung Kim, Hee Jae Chung, Michael Cheung, Katie Ngo, Annie Shinn, William K. Chan
      The aryl hydrocarbon receptor (AHR) is a ligand-activated signaling molecule which involves in diverse biological functions ranging from cancer metastasis to immune regulation. This receptor forms a cytoplasmic complex with Hsp90, p23, and XAP2. We have previously reported that down-regulation of p23 triggers degradation of the AHR protein, uncovering a potentially dynamic event which controls the cellular AHR levels without ligand treatment. Here we investigate the underlying mechanisms for this p23 effect using wild-type HeLa and the p23 knockdown HeLa cells. Reduction of the Hsp90 and XAP2 contents, however, did not affect the AHR protein levels, implying that this p23 effect on AHR is more than just alteration of the cytoplasmic complex dynamics. Association of p23 with Hsp90 is not important for the modulation of the AHR levels since exogenous expression of p23 mutants with modest Hsp90-binding affinity effectively restored the AHR message and protein levels. The protein folding property of p23 which resides at the terminal 50-amino acid region is not involved for this p23 effect. Results from our interaction study using the affinity purified thioredoxin fusion proteins and GST fusion proteins showed that p23 directly interacts with AHR and the interaction surface lies within AHR amino acid 1 to 216 and p23 amino acid 1 to 110. Down-regulation of the p23 protein content promotes the ubiquitination of AHR, indicating that p23 protects AHR from the ubiquitin-meditated protein degradation.
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      PubDate: 2018-03-20T08:42:23Z
      DOI: 10.1016/j.bcp.2018.03.015
  • Anti-tumour effects of beta-sitosterol are mediated by AMPK/PTEN/HSP90
    • Authors: Eun Ju Shin; Hyo-Kyoung Choi; Mi Jeong Sung; Jae Ho Park; Min-Yu Chung; Sangwon Chung; Jin-Taek Hwang
      Abstract: Publication date: Available online 17 March 2018
      Source:Biochemical Pharmacology
      Author(s): Eun Ju Shin, Hyo-Kyoung Choi, Mi Jeong Sung, Jae Ho Park, Min-Yu Chung, Sangwon Chung, Jin-Taek Hwang
      We investigated the anti-cancer effects of beta-sitosterol (BS), a plant-derived sterol in AGS human gastric adenocarcinoma cells and xenograft mouse models. BS significantly reduced cell viability by inducing apoptosis in AGS adenocarcinoma cells. This was accompanied by the formation of apoptotic bodies, as detected by Annexin V, caspase 3/7 activity, and MitoPotential assay. BS stimulated phosphatase and tensin homolog (PTEN) and phospho-AMP-activated protein kinase (p-AMPK) expression. Pharmacological inhibitors or siRNA were used to further analyse the relationship between the two proteins. AMPK was found to represent a likely upstream regulator of PTEN. Additionally, two-dimensional gel electrophoresis was used to identify related proteins in the treatment of BS. The decrease of Hsp90 protein by BS was observed. Induction of PTEN protein and reduction of Hsp90 was mediated by AICAR, an AMPK activator, indicating that AMPK is necessary for PTEN and Hsp90 expression. Additionally, BS was found to be effective through the regulation of cancer biomarker. Furthermore, BS suppressed tumour growth without toxicity in the AGS xenograft mouse models-. Taken together, the present results demonstrate that BS exerts anti-cancer effects in AGS cells and xenograft mouse models by mediating AMPK, PTEN, and Hsp90.
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      PubDate: 2018-03-20T08:42:23Z
      DOI: 10.1016/j.bcp.2018.03.010
  • Inhibition of O-Linked N-Acetylglucosamine Transferase Activity in PC12
           Cells - A Molecular Mechanism of Organophosphate Flame Retardants
           Developmental Neurotoxicity
    • Authors: Yuxin Gu; Yu Yang; Bin Wan; Minjie Li; Liang-Hong Guo
      Abstract: Publication date: Available online 17 March 2018
      Source:Biochemical Pharmacology
      Author(s): Yuxin Gu, Yu Yang, Bin Wan, Minjie Li, Liang-Hong Guo
      Organophosphate flame retardants (OPFRs), as alternatives of brominated flame retardants, can cause neurodevelopmental effects similar to organophosphate pesticides. However, the molecular mechanisms underlying the toxicity remain elusive. O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) regulates numerous neural processes through the O-GlcNAcylation modification of nuclear and cytoplasmic proteins. In this study, we aimed to investigate the molecular mechanisms accounting for the developmental neurotoxicity of OPFRs by identifying potential targets of OPFRs and the attendant effects. Twelve OPFRs were evaluated for inhibition of OGT activity using an electrochemical biosensor. Their potency differed with substituent groups. The alkyl group substituted OPFRs had no inhibitory effect. Instead, the six OPFRs substituted with aromatic or chlorinated alkyl groups inhibited OGT activity significantly, with tri-m-cresyl phosphate (TCrP) being the strongest. The six OPFRs (0-100 μM exposure) also inhibited OGT activity in PC12 cells and decreased protein O-GlcNAcylation level. Inhibition of OGT by OPFRs might be involved in the subsequent toxic effects, including intracellular reactive oxygen species (ROS), calcium level, as well as cell proliferation and autophagy. Molecular docking of the OGT/OPFR complexes provided rationales for the difference in their structure-dependent inhibition potency. Our findings may provide a new biological target of OPFRs in their neurotoxicological actions, which might be a major molecular mechanism of OPFRs developmental neurotoxicity.
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      PubDate: 2018-03-20T08:42:23Z
      DOI: 10.1016/j.bcp.2018.03.017
  • Canagliflozin exerts anti-inflammatory effects by inhibiting intracellular
           glucose metabolism and promoting autophagy in immune cells
    • Authors: Chenke Xu; Wei Wang; Jin Zhong; Fan Lei; Naihan Xu; Yaou Zhang; Weidong Xie
      Abstract: Publication date: Available online 15 March 2018
      Source:Biochemical Pharmacology
      Author(s): Chenke Xu, Wei Wang, Jin Zhong, Fan Lei, Naihan Xu, Yaou Zhang, Weidong Xie
      Canagliflozin (CAN) regulates intracellular glucose metabolism by targeting sodium-glucose co-transporter 2 (SGLT2) and intracellular glucose metabolism affects inflammation. In this study, we hypothesized that CAN might exert anti-inflammatory effects. The anti-inflammatory effects and action mechanisms of CAN were assayed in lipopolysaccharide (LPS)-induced RAW264.7 and THP-1 cells and NIH mice. Results showed that CAN significantly inhibited the production and release of interleukin (IL)-1, IL-6, or tumor necrosis factor-α (TNF-α) in the LPS-induced RAW264.7 and THP-1 cells, and mice. CAN also significantly inhibited intracellular glucose metabolism and 6-phosphofructo-2-kinase (PFK2) expression. CAN increased the levels of Sequestosome-1 (SQSTM1/p62), upregulated the ratios of microtubule-associated protein 1A/1B-light chain 3 (LC3) II to I, promoted the formation of LC3 puncta, and enhanced the activities of lysosome. The inhibition of autophagy by 3-methyladenine (3-MA) reversed the effects of CAN on IL-1α levels. Increased autophagy might be associated with increased AMP-activated protein kinase (AMPK) phosphorylation. Interestingly, p62 demonstrated good co-localization with IL-1α and possibly mediated IL-1α degradation. CAN-induced increase in p62 was dependent on the nuclear factor kappa B (NFκB) signaling pathway. These results indicated that CAN might exert anti-inflammatory effects by inhibiting intracellular glucose metabolism and promoting autophagy. Attenuated glucose metabolism by PFK2, increased autophagy flow by AMPK, and increased p62 levels by NFκB might be responsible for the molecular mechanisms of CAN. This drug might serve as a new promising anti-inflammatory drug for acute or chronic inflammatory diseases via independent hypoglycemic mechanisms. This drug might also be used as an important reference for similar drug research and development by targeting intracellular glucose metabolism and autophagy in immune cells.
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      PubDate: 2018-03-20T08:42:23Z
      DOI: 10.1016/j.bcp.2018.03.013
  • “Integrity, standards, and QC-related issues with big-data in
           pre-clinical drug discovery”
    • Authors: John F. Brothers; Matthew Ung; Renan Escalante-Chong; Jermaine Ross; Jenny Zhang; Yoonjeong Cha; Andrew Lysaght; Jason Funt; Rebecca Kusko
      Abstract: Publication date: Available online 15 March 2018
      Source:Biochemical Pharmacology
      Author(s): John F. Brothers, Matthew Ung, Renan Escalante-Chong, Jermaine Ross, Jenny Zhang, Yoonjeong Cha, Andrew Lysaght, Jason Funt, Rebecca Kusko
      The tremendous expansion of data analytics and public and private big datasets presents an important opportunity for pre-clinical drug discovery and development. In the field of life sciences, the growth of genetic, genomic, transcriptomic and proteomic data is partly driven by a rapid decline in experimental costs as biotechnology improves throughput, scalability, and speed. Yet far too many researchers tend to underestimate the challenges and consequences involving data integrity and quality standards. Given the effect of data integrity on scientific interpretation, these issues have significant implications during preclinical drug development. We describe standardized approaches for maximizing the utility of publicly available or privately generated biological data and address some of the common pitfalls. We also discuss the increasing interest to integrate and interpret cross-platform data. Principles outlined here should serve as a useful broad guide for existing analytical practices and pipelines and as a tool for developing additional insights into therapeutics using big data.
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      PubDate: 2018-03-20T08:42:23Z
      DOI: 10.1016/j.bcp.2018.03.014
  • Differential patterns of inhibition of the sugar transporters GLUT2, GLUT5
           and GLUT7 by flavonoids
    • Authors: Julia S. Gauer; Sarka Tumova; Jonathan D. Lippiat; Asimina Kerimi; Gary Williamson
      Abstract: Publication date: Available online 14 March 2018
      Source:Biochemical Pharmacology
      Author(s): Julia S. Gauer, Sarka Tumova, Jonathan D. Lippiat, Asimina Kerimi, Gary Williamson
      Only limited data are available on the inhibition of the sugar transporter GLUT5 by flavonoids or other classes of bioactives. Intestinal GLUT7 is poorly characterised and no information exists concerning its inhibition. We aimed to study the expression of GLUT7 in Caco-2/TC7 intestinal cells, and evaluate inhibition of glucose transport by GLUT2 and GLUT7, and of fructose transport by GLUT2, GLUT5 and GLUT7, by flavonoids. Differentiated Caco-2/TC7 cell monolayers were used to investigate GLUT7 expression, as well as biotinylation and immunofluorescence to assess GLUT7 location. For mechanistic sugar transport studies, X. laevis oocytes were injected with individual mRNA, and GLUT protein expression on oocyte membranes was confirmed. Oocytes were incubated with D-[14C(U)]-glucose or D-[14C(U)]-fructose in the presence of flavonoids, and uptake was estimated by liquid scintilation counting. In differentiated Caco-2/TC7 cell monolayers, GLUT7 was mostly expressed apically. When applied apically, or to both compartments, sorbitol, galactose, L-glucose or sucrose did not affect GLUT7 mRNA expression. Fructose applied to both sides increased GLUT7 mRNA (13%, p ≤ 0.001) and total GLUT7 protein (2.7-fold, p ≤ 0.05), while the ratio between apical, basolateral and total GLUT7 protein was unchanged. In the X. laevis oocyte model, GLUT2-mediated glucose and fructose transport were inhibited by quercetin, (-)-epigallocatechin gallate (EGCG) and apigenin, GLUT5-mediated fructose transport was inhibited by apigenin and EGCG, but not by quercetin, and GLUT7-mediated uptake of both glucose and fructose was inhibited by apigenin, but not by quercetin nor EGCG. Expression of GLUT7 was increased by fructose, but only when applied to Caco-2/TC7 cells both apically and basolaterally. Since GLUT2, GLUT5 and GLUT7 show different patterns of inhibition by the tested flavonoids, we suggest that they have the potential to be used as investigational tools to distinguish sugar transporter activity in different biological settings.
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      PubDate: 2018-03-20T08:42:23Z
      DOI: 10.1016/j.bcp.2018.03.011
  • Esculetin suppresses tumor growth and metastasis by targeting
           Axin2/E-cadherin axis in colorectal cancer
    • Authors: Won Kyung Kim; Woong Sub Byun; Hwa-Jin Chung; Jedo Oh; Hyen Joo Park; Jae Sue Choi; Sang Kook Lee
      Abstract: Publication date: Available online 10 March 2018
      Source:Biochemical Pharmacology
      Author(s): Won Kyung Kim, Woong Sub Byun, Hwa-Jin Chung, Jedo Oh, Hyen Joo Park, Jae Sue Choi, Sang Kook Lee
      Colorectal cancer (CRC) is the most common malignant disease worldwide due to its metastasis via the epithelial-mesenchymal transition (EMT) process. E-cadherin and Wnt signaling are emerging as potential targets for suppressing the EMT. In this context, Axin2 has been recognized as a negative regulator that inhibits glycogen synthase kinase 3β (GSK3β)-mediated degradation of Snail1, a transcriptional repressor of E-cadherin. However, Axin2 can also impede Wnt signaling via β-catenin degradation. Therefore, Axin2 may serve as either a promoter or suppressor of tumors, and the effects of its inhibition on the cell proliferation and metastasis of CRC require further elucidation. Here, esculetin (ES), a coumarin, was found to have the most potential effects on both β-catenin-responsive transcriptional and E-cadherin promoter activities. ES also showed anti-proliferative and anti-invasive activities in CRC cells. Mechanistically, Axin2 suppression by ES contributed to E-cadherin-mediated Wnt signaling inhibition. Moreover, the ability of ES to inhibit tumor growth and metastasis via Axin2 suppression was further supported in an HCT116-implanted orthotopic mouse model. Collectively, these findings suggest that targeting the Axin2/E-cadherin axis by ES may be an attractive therapeutic strategy for the treatment of metastatic CRC.
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      PubDate: 2018-03-20T08:42:23Z
      DOI: 10.1016/j.bcp.2018.03.009
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