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CHEMISTRY (598 journals)                  1 2 3 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 8)
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: 32)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 17)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 23)
ACS Macro Letters     Full-text available via subscription   (Followers: 23)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 39)
ACS Nano     Full-text available via subscription   (Followers: 227)
ACS Photonics     Full-text available via subscription   (Followers: 11)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 21)
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 Chromatographica     Full-text available via subscription   (Followers: 9)
Acta Facultatis Medicae Naissensis     Open Access  
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 5)
Acta Scientifica Naturalis     Open Access   (Followers: 2)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 5)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 7)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 5)
Advanced Functional Materials     Hybrid Journal   (Followers: 50)
Advanced Science Focus     Free   (Followers: 3)
Advances in Chemical Engineering and Science     Open Access   (Followers: 53)
Advances in Chemical Science     Open Access   (Followers: 13)
Advances in Chemistry     Open Access   (Followers: 14)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 18)
Advances in Drug Research     Full-text available via subscription   (Followers: 22)
Advances in Enzyme Research     Open Access   (Followers: 9)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 15)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 19)
Advances in Nanoparticles     Open Access   (Followers: 14)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15)
Advances in Polymer Science     Hybrid Journal   (Followers: 41)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 19)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5)
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: 2)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 7)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 67)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 14)
American Journal of Chemistry     Open Access   (Followers: 26)
American Journal of Plant Physiology     Open Access   (Followers: 13)
American Mineralogist     Hybrid Journal   (Followers: 13)
Analyst     Full-text available via subscription   (Followers: 38)
Angewandte Chemie     Hybrid Journal   (Followers: 164)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 212)
Annales UMCS, Chemia     Open Access   (Followers: 1)
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 1)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 3)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 3)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 8)
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: 14)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antiviral Chemistry and Chemotherapy     Hybrid Journal  
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 7)
Applied Spectroscopy     Full-text available via subscription   (Followers: 23)
Applied Surface Science     Hybrid Journal   (Followers: 28)
Arabian Journal of Chemistry     Open Access   (Followers: 6)
ARKIVOC     Open Access   (Followers: 2)
Asian Journal of Biochemistry     Open Access   (Followers: 1)
Atomization and Sprays     Full-text available via subscription   (Followers: 3)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 7)
Autophagy     Hybrid Journal   (Followers: 2)
Avances en Quimica     Open Access   (Followers: 1)
Biochemical Pharmacology     Hybrid Journal   (Followers: 10)
Biochemistry     Full-text available via subscription   (Followers: 284)
Biochemistry Insights     Open Access   (Followers: 5)
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: 19)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 10)
Biomedical Chromatography     Hybrid Journal   (Followers: 6)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 3)
BioNanoScience     Partially Free   (Followers: 4)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 110)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 93)
Bioorganic Chemistry     Hybrid Journal   (Followers: 10)
Biopolymers     Hybrid Journal   (Followers: 18)
Biosensors     Open Access   (Followers: 2)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 1)
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: 3)
Carbohydrate Research     Hybrid Journal   (Followers: 26)
Carbon     Hybrid Journal   (Followers: 67)
Catalysis for Sustainable Energy     Open Access   (Followers: 6)
Catalysis Reviews: Science and Engineering     Hybrid Journal   (Followers: 8)
Catalysis Science and Technology     Free   (Followers: 6)
Catalysis Surveys from Asia     Hybrid Journal   (Followers: 3)
Catalysts     Open Access   (Followers: 7)
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: 12)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 70)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 23)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 19)
Chemical Reviews     Full-text available via subscription   (Followers: 174)
Chemical Science     Open Access   (Followers: 21)
Chemical Technology     Open Access   (Followers: 16)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 5)
Chemical Week     Full-text available via subscription   (Followers: 8)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 55)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 25)
ChemInform     Hybrid Journal   (Followers: 8)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 6)
Chemistry & Biology     Full-text available via subscription   (Followers: 30)
Chemistry & Industry     Hybrid Journal   (Followers: 5)
Chemistry - A European Journal     Hybrid Journal   (Followers: 150)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 15)
Chemistry and Materials Research     Open Access   (Followers: 18)
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: 45)
Chemistry of Materials     Full-text available via subscription   (Followers: 243)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
Chemistry World     Full-text available via subscription   (Followers: 22)
Chemistry-Didactics-Ecology-Metrology     Open Access  
ChemistryOpen     Open Access   (Followers: 2)
Chemkon - Chemie Konkret, Forum Fuer Unterricht Und Didaktik     Hybrid Journal  
Chemoecology     Hybrid Journal   (Followers: 2)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 15)
Chemosensors     Open Access  
ChemPhysChem     Hybrid Journal   (Followers: 9)
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: 10)
Chromatographia     Hybrid Journal   (Followers: 24)
Chromatography Research International     Open Access   (Followers: 7)
Clay Minerals     Full-text available via subscription   (Followers: 9)
Cogent Chemistry     Open Access  
Colloid and Interface Science Communications     Open Access  
Colloid and Polymer Science     Hybrid Journal   (Followers: 10)
Colloids and Surfaces B: Biointerfaces     Hybrid Journal   (Followers: 8)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 3)
Combustion Science and Technology     Hybrid Journal   (Followers: 18)
Comments on Inorganic Chemistry: A Journal of Critical Discussion of the Current Literature     Hybrid Journal   (Followers: 2)
Composite Interfaces     Hybrid Journal   (Followers: 6)
Comprehensive Chemical Kinetics     Full-text available via subscription   (Followers: 2)
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: 12)
Computational Chemistry     Open Access   (Followers: 2)
Computers & Chemical Engineering     Hybrid Journal   (Followers: 9)
Coordination Chemistry Reviews     Full-text available via subscription   (Followers: 2)
Copernican Letters     Open Access  
Critical Reviews in Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 5)
Crystal Structure Theory and Applications     Open Access   (Followers: 3)
CrystEngComm     Full-text available via subscription   (Followers: 11)
Current Catalysis     Hybrid Journal   (Followers: 2)
Current Metabolomics     Hybrid Journal   (Followers: 5)
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 9)
Current Research in Chemistry     Open Access   (Followers: 8)
Current Science     Open Access   (Followers: 56)
Dalton Transactions     Full-text available via subscription   (Followers: 19)
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  
Drying Technology: An International Journal     Hybrid Journal   (Followers: 4)
Eclética Química     Open Access   (Followers: 1)
Ecological Chemistry and Engineering S     Open Access   (Followers: 4)
Ecotoxicology and Environmental Contamination     Open Access  
Educación Química     Open Access   (Followers: 1)
Education for Chemical Engineers     Hybrid Journal   (Followers: 5)
EJNMMI Radiopharmacy and Chemistry     Open Access  
Elements     Full-text available via subscription   (Followers: 2)
Environmental Chemistry     Hybrid Journal   (Followers: 9)
Environmental Chemistry Letters     Hybrid Journal   (Followers: 4)
Environmental Science & Technology Letters     Full-text available via subscription   (Followers: 5)

        1 2 3 | 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  [3042 journals]
  • Restore the brake on tumor progression
    • Authors: Renata E. Gordon; Li Zhang; Zeng-Jie Yang
      Pages: 1 - 6
      Abstract: Publication date: 15 August 2017
      Source:Biochemical Pharmacology, Volume 138
      Author(s): Renata E. Gordon, Li Zhang, Zeng-Jie Yang
      Sonic hedgehog (Shh) signaling plays a key role in regulation of normal development. The negative feedback mechanism mediated by the transcriptional factor, Gli3, acts to finely tune Shh signaling, providing tight control of normal developmental processes. Hyperactivation of Shh signaling often leads to many human malignancies, including basal cell carcinoma and medulloblastoma (MB). However, how tumor cells sustain the aberrant activation of Shh signaling is still not completely understood. We recently revealed that during MB formation, tumor cells express Nestin, a type VI intermediate filament protein, which maintains uncontrolled Shh signaling by abolishing negative feedback by Gli3. Therefore, Nestin expression is a necessary step for MB formation. These findings highlight the novel function of Nestin in regulating Shh signaling, as well as the important role of a disrupted negative feedback mechanism in MB tumorigenesis. Further, restoration of the intrinsic negative feedback by repressing Nestin expression represents a promising approach to treat MB as well as other Shh signaling associated malignancies.
      Graphical abstract image

      PubDate: 2017-07-07T02:46:43Z
      DOI: 10.1016/j.bcp.2017.04.003
      Issue No: Vol. 138 (2017)
  • Enhancing reproducibility: Failures from Reproducibility Initiatives
           underline core challenges
    • Authors: Kevin Mullane; Michael Williams
      Pages: 7 - 18
      Abstract: Publication date: 15 August 2017
      Source:Biochemical Pharmacology, Volume 138
      Author(s): Kevin Mullane, Michael Williams
      Efforts to address reproducibility concerns in biomedical research include: initiatives to improve journal publication standards and peer review; increased attention to publishing methodological details that enable experiments to be reconstructed; guidelines on standards for study design, implementation, analysis and execution; meta-analyses of multiple studies within a field to synthesize a common conclusion and; the formation of consortia to adopt uniform protocols and internally reproduce data. Another approach to addressing reproducibility are Reproducibility Initiatives (RIs), well-intended, high-profile, systematically peer-vetted initiatives that are intended to replace the traditional process of scientific self-correction. Outcomes from the RIs reported to date have questioned the usefulness of this approach, particularly when the RI outcome differs from other independent self-correction studies that have reproduced the original finding. As a failed RI attempt is a single outcome distinct from the original study, it cannot provide any definitive conclusions necessitating additional studies that the RI approach has neither the ability nor intent of conducting making it a questionable replacement for self-correction. A failed RI attempt also has the potential to damage the reputation of the author of the original finding. Reproduction is frequently confused with replication, an issue that is more than semantic with the former denoting “similarity” and the latter an “exact copy” – an impossible outcome in research because of known and unknown technical, environmental and motivational differences between the original and reproduction studies. To date, the RI framework has negatively impacted efforts to improve reproducibility, confounding attempts to determine whether a research finding is real.
      Graphical abstract image

      PubDate: 2017-07-07T02:46:43Z
      DOI: 10.1016/j.bcp.2017.04.008
      Issue No: Vol. 138 (2017)
  • Voacamine alters Leishmania ultrastructure and kills parasite by poisoning
           unusual bi-subunit topoisomerase IB
    • Authors: Somenath Roy Chowdhury; Ashish Kumar; Joseane Lima Prado Godinho; Sara Teixeira De Macedo Silva; Aline Araujo Zuma; Sourav Saha; Neha Kumari; Juliany Cola Fernandes Rodrigues; Shyam Sundar; Jean-Claude Dujardin; Syamal Roy; Wanderley De Souza; Sibabrata Mukhopadhyay; Hemanta K. Majumder
      Pages: 19 - 30
      Abstract: Publication date: 15 August 2017
      Source:Biochemical Pharmacology, Volume 138
      Author(s): Somenath Roy Chowdhury, Ashish Kumar, Joseane Lima Prado Godinho, Sara Teixeira De Macedo Silva, Aline Araujo Zuma, Sourav Saha, Neha Kumari, Juliany Cola Fernandes Rodrigues, Shyam Sundar, Jean-Claude Dujardin, Syamal Roy, Wanderley De Souza, Sibabrata Mukhopadhyay, Hemanta K. Majumder
      Indole alkaloids possess a large spectrum of biological activities including anti-protozoal action. Here we report for the first time that voacamine, isolated from the plant Tabernaemontana coronaria, is an antiprotozoal agent effective against a large array of trypanosomatid parasites including Indian strain of Leishmania donovani and Brazilian strains of Leishmania amazonensis and Trypanosoma cruzi. It inhibits the relaxation activity of topoisomerase IB of L. donovani (LdTop1B) and stabilizes the cleavable complex. Voacamine is probably the first LdTop1B-specific poison to act uncompetitively. It has no impact on human topoisomerase I and II up to 200μM concentrations. The study also provides a thorough insight into ultrastructural alterations induced in three kinetoplastid parasites by a specific inhibitor of LdTop1B. Voacamine is also effective against intracellular amastigotes of different drug unresponsive field isolates of Leishmania donovani obtained from endemic zones of India severely affected with visceral leishmaniasis. Most importantly, this is the first report demonstrating the efficacy of a compound to reduce the burden of drug resistant parasites, unresponsive to SAG, amphotericin B and miltefosine, in experimental BALB/c mice model of visceral leishmaniasis. The findings cumulatively provide a strong evidence that voacamine can be a promising drug candidate against trypanosomatid infections.
      Graphical abstract image

      PubDate: 2017-07-07T02:46:43Z
      DOI: 10.1016/j.bcp.2017.05.002
      Issue No: Vol. 138 (2017)
  • Anti-tumor effects of differentiation-inducing factor-1 in malignant
           melanoma: GSK-3-mediated inhibition of cell proliferation and
           GSK-3-independent suppression of cell migration and invasion
    • Authors: Masaki Arioka; Fumi Takahashi-Yanaga; Momoko Kubo; Kazunobu Igawa; Katsuhiko Tomooka; Toshiyuki Sasaguri
      Pages: 31 - 48
      Abstract: Publication date: 15 August 2017
      Source:Biochemical Pharmacology, Volume 138
      Author(s): Masaki Arioka, Fumi Takahashi-Yanaga, Momoko Kubo, Kazunobu Igawa, Katsuhiko Tomooka, Toshiyuki Sasaguri
      Differentiation-inducing factor-1 (DIF-1) isolated from Dictyostelium discoideum strongly inhibits the proliferation of various mammalian cells through the activation of glycogen synthase kinase-3 (GSK-3). To evaluate DIF-1 as a novel anti-cancer agent for malignant melanoma, we examined whether DIF-1 has anti-proliferative, anti-migratory, and anti-invasive effects on melanoma cells using in vitro and in vivo systems. DIF-1 reduced the expression levels of cyclin D1 and c-Myc by facilitating their degradation via GSK-3 in mouse (B16BL6) and human (A2058) malignant melanoma cells, and thereby strongly inhibited their proliferation. DIF-1 suppressed the canonical Wnt signaling pathway by lowering the expression levels of transcription factor 7-like 2 and β-catenin, key transcription factors in this pathway. DIF-1 also inhibited cell migration and invasion, reducing the expression of matrix metalloproteinase-2; however, this effect was not dependent on GSK-3 activity. In a mouse lung tumor formation model, repeated oral administrations of DIF-1 markedly reduced melanoma colony formation in the lung. These results suggest that DIF-1 inhibits cell proliferation by a GSK-3-dependent mechanism and suppresses cell migration and invasion by a GSK-3-independent mechanism. Therefore, DIF-1 may have a potential as a novel anti-cancer agent for the treatment of malignant melanoma.
      Graphical abstract image

      PubDate: 2017-07-07T02:46:43Z
      DOI: 10.1016/j.bcp.2017.05.004
      Issue No: Vol. 138 (2017)
  • Protein phosphatase 5 promotes hepatocarcinogenesis through interaction
           with AMP-activated protein kinase
    • Authors: Yao-Li Chen; Man-Hsin Hung; Pei-Yi Chu; Tzu-I Chao; Ming-Hsien Tsai; Li-Ju Chen; Yung-Jen Hsiao; Chih-Ting Shih; Feng-Shu Hsieh; Kuen-Feng Chen
      Pages: 49 - 60
      Abstract: Publication date: 15 August 2017
      Source:Biochemical Pharmacology, Volume 138
      Author(s): Yao-Li Chen, Man-Hsin Hung, Pei-Yi Chu, Tzu-I Chao, Ming-Hsien Tsai, Li-Ju Chen, Yung-Jen Hsiao, Chih-Ting Shih, Feng-Shu Hsieh, Kuen-Feng Chen
      The serine-threonine protein phosphatase family members are known as critical regulators of various cellular functions, such as survival and transformation. Growing evidence suggests that pharmacological manipulation of phosphatase activity exhibits therapeutic benefits. Ser/Thr protein phosphatase 5 (PP5) is known to participate in glucocorticoid receptor (GR) and stress-induced signaling cascades that regulate cell growth and apoptosis, and has been shown to be overexpressed in various human malignant diseases. However, the role of PP5 in hepatocellular carcinoma (HCC) and whether PP5 may be a viable therapeutic target for HCC treatment are unknown. Here, by analyzing HCC clinical samples obtained from 215 patients, we found that overexpression of PP5 is tumor specific and associated with worse clinical outcomes. We further characterized the oncogenic properties of PP5 in HCC cells. Importantly, both silencing of PP5 with lentiviral-mediated short hairpin RNA (shRNA) and chemical inhibition of PP5 phosphatase activity using the natural compound cantharidin/norcantharidin markedly suppressed the growth of HCC cells and tumors in vitro and in vivo. Moreover, we identified AMP-activated protein kinase (AMPK) as a novel downstream target of oncogenic PP5 and demonstrated that the antitumor mechanisms underlying PP5 inhibition involve activation of AMPK signaling. Overall, our results establish a pathological function of PP5 in hepatocarcinogenesis via affecting AMPK signaling and suggest that PP5 inhibition is an attractive therapeutic approach for HCC.
      Graphical abstract image

      PubDate: 2017-07-07T02:46:43Z
      DOI: 10.1016/j.bcp.2017.05.010
      Issue No: Vol. 138 (2017)
  • T-type voltage gated calcium channels are involved in
           endothelium-dependent relaxation of mice pulmonary artery
    • Authors: Guillaume Gilbert; Arnaud Courtois; Mathilde Dubois; Laure-Anne Cussac; Thomas Ducret; Philippe Lory; Roger Marthan; Jean-Pierre Savineau; Jean-François Quignard
      Pages: 61 - 72
      Abstract: Publication date: 15 August 2017
      Source:Biochemical Pharmacology, Volume 138
      Author(s): Guillaume Gilbert, Arnaud Courtois, Mathilde Dubois, Laure-Anne Cussac, Thomas Ducret, Philippe Lory, Roger Marthan, Jean-Pierre Savineau, Jean-François Quignard
      In pulmonary arterial endothelial cells, Ca2+ channels and intracellular Ca2+ concentration ([Ca2+]i) control the release of vasorelaxant factors such as nitric oxide and are involved in the regulation of pulmonary arterial blood pressure. The present study was undertaken to investigate the implication of T-type voltage-gated Ca2+ channels (T-VGCCs, Cav3.1 channel) in the endothelium-dependent relaxation of intrapulmonary arteries. Relaxation was quantified by means of a myograph in wild type and Cav3.1−/− mice. Endothelial [Ca2+]i and NO production were measured, on whole vessels, with the fluo-4 and DAF-fm probes. Acetylcholine (ACh) induced a nitric oxide- and endothelium-dependent relaxation that was significantly reduced in pulmonary arteries from Cav3.1−/− compared to wild type mice as well as in the presence of T-VGCC inhibitors (NNC 55-0396 or mibefradil). ACh also increased endothelial [Ca2+]i and NO production that were both reduced in Cav3.1−/− compared to wild type mice or in the presence of T-VGCC inhibitors. Immunofluorescence labeling revealed the presence of Cav3.1 channels in endothelial cells that co-localized with endothelial nitric oxide synthase in arteries from wild type mice. TRPV4-, beta2 adrenergic- and nitric oxide donors (SNP)-mediated relaxation were not altered in Cav3.1−/− compared to wild type mice. Finally, in chronically hypoxic mice, a model of pulmonary hypertension, ACh relaxation was reduced but still depended on Cav3.1 channels activity. The present study thus demonstrates that T-VGCCs, mainly Cav3.1 channel, contribute to intrapulmonary vascular reactivity in mice by controlling endothelial [Ca2+]i and ACh-mediated relaxation.
      Graphical abstract image

      PubDate: 2017-07-07T02:46:43Z
      DOI: 10.1016/j.bcp.2017.04.021
      Issue No: Vol. 138 (2017)
  • Ablation of IL-33 gene exacerbate myocardial remodeling in mice with heart
           failure induced by mechanical stress
    • Authors: Punniyakoti T. Veeraveedu; Shoji Sanada; Keiji Okuda; Hai Ying Fu; Takashi Matsuzaki; Ryo Araki; Masaki Yamato; Koubun Yasuda; Yasushi Sakata; Tomohiro Yoshimoto; Tetsuo Minamino
      Pages: 73 - 80
      Abstract: Publication date: 15 August 2017
      Source:Biochemical Pharmacology, Volume 138
      Author(s): Punniyakoti T. Veeraveedu, Shoji Sanada, Keiji Okuda, Hai Ying Fu, Takashi Matsuzaki, Ryo Araki, Masaki Yamato, Koubun Yasuda, Yasushi Sakata, Tomohiro Yoshimoto, Tetsuo Minamino
      Background and purpose ST2 is one of the interleukin (IL)-1 receptor family members comprising of membrane-bound (ST2L) and soluble (sST2) isoforms. Clinical trials have revealed that serum sST2 levels predict outcome in patient with myocardial infarction or chronic heart failure (HF). Meanwhile, we and others have reported that ablation of ST2 caused exaggerated cardiac remodeling in both ischemic and non-ischemic HF. Here, we tested whether IL-33, the ligand for ST2, protects myocardium against HF induced by mechanical overload using ligand specific knockout (IL-33−/−) mice. Methods and results Transverse aortic constriction (TAC)/sham surgery were carried out in both IL-33 and WT-littermates. Echocardiographic measurements were performed at frequent interval during the study period. Heart was harvested for RNA and histological measurements. Following mechanical overload by TAC, myocardial mRNA expressions of Th1 cytokines, such as TNF-α were enhanced in IL-33−/− mice than in WT mice. After 8-weeks, IL-33−/− mice exhibited exacerbated left ventricular hypertrophy, increased chamber dilation, reduced fractional shortening, aggravated fibrosis, inflammation, and impaired survival compared with WT littermates. Accordingly, myocardial mRNA expressions of hypertrophic (c-Myc/BNP) molecular markers were also significantly enhanced in IL-33−/− mice than those in WT mice. Conclusions We report for the first time that ablation of IL-33 directly and significantly leads to exacerbate cardiac remodeling with impaired cardiac function and survival upon mechanical stress. These data highlight the cardioprotective role of IL-33/ST2 system in the stressed myocardium and reveal a potential therapeutic role for IL-33 in non-ischemic HF.
      Graphical abstract image

      PubDate: 2017-07-07T02:46:43Z
      DOI: 10.1016/j.bcp.2017.04.022
      Issue No: Vol. 138 (2017)
  • Decreased homodimerization and increased TIMP-1 complexation of
           uteroplacental and uterine arterial matrix metalloproteinase-9 during
    • Authors: Juanjuan Chen; Zongli Ren; Minglin Zhu; Raouf A. Khalil
      Pages: 81 - 95
      Abstract: Publication date: 15 August 2017
      Source:Biochemical Pharmacology, Volume 138
      Author(s): Juanjuan Chen, Zongli Ren, Minglin Zhu, Raouf A. Khalil
      Preeclampsia is a complication of pregnancy manifested as hypertension-in-pregnancy (HTN-Preg) and often intrauterine growth restriction (IUGR). Placental ischemia could be an initiating event, but the molecular mechanisms are unclear. To test the hypothesis that dimerization of matrix metalloproteinases (MMPs) plays a role in HTN-Preg and IUGR, the levels/activity of MMP-9, tissue inhibitor of metalloproteinase (TIMP-1), and their dimerization forms were measured in the placenta, uterus, and uterine artery of normal pregnant (Preg) rats and a rat model of reduced uteroplacental perfusion pressure (RUPP). Consistent with our previous report, blood pressure (BP) was higher, pup weight was lower, and gelatin zymography showed different gelatinolytic activity for pro-MMP-9, MMP-9, pro-MMP-2 and MMP-2 in RUPP vs Preg rats. Careful examination of the zymograms showed additional bands at 200 and 135kDa. Western blots with MMP-9 antibody suggested that the 200kDa band was a MMP-9 homodimer. Western blots with TIMP-1 antibody as well as reverse zymography suggested that the 135kDa band was a MMP-9/TIMP-1 complex. The protein levels and gelatinase activity of MMP-9 homodimer were decreased while MMP-9/TIMP-1 complex was increased in placenta, uterus and uterine artery of RUPP vs Preg rats. The epidermal growth factor (EGF) receptor blocker erlotinib and protein kinase C (PKC) inhibitor bisindolylmaleimide decreased MMP-9 homodimer and increased MMP-9/TIMP-1 complex in placenta, uterus and uterine artery of Preg rats. EGF and the PKC activator phorbol-12,13-dibutyrate (PDBu) reversed the decreases in MMP-9 homodimer and the increases in MMP-9/TIMP-1 complex in tissues of RUPP rats. Thus, the increased BP and decreased pup weight in placental ischemia model of HTN-Preg are associated with a decrease in MMP-9 homodimer and an increase in MMP-9/TIMP-1 complex in placenta, uterus, and uterine artery, which together would cause a net decrease in MMP-9 activity and reduce uteroplacental and vascular remodeling in the setting of HTN-Preg and IUGR. Enhancing EGFR/PKC signaling may reverse the MMP-9 unfavorable dimerization patterns and thereby promote uteroplacental and vascular remodeling in preeclampsia.
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      PubDate: 2017-07-07T02:46:43Z
      DOI: 10.1016/j.bcp.2017.05.005
      Issue No: Vol. 138 (2017)
  • Pharmacological PPARγ modulation regulates sebogenesis and
           inflammation in SZ95 human sebocytes
    • Authors: A. Mastrofrancesco; M. Ottaviani; G. Cardinali; E. Flori; S. Briganti; M. Ludovici; C.C. Zouboulis; V. Lora; E. Camera; M. Picardo
      Pages: 96 - 106
      Abstract: Publication date: 15 August 2017
      Source:Biochemical Pharmacology, Volume 138
      Author(s): A. Mastrofrancesco, M. Ottaviani, G. Cardinali, E. Flori, S. Briganti, M. Ludovici, C.C. Zouboulis, V. Lora, E. Camera, M. Picardo
      The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) controls the expression of genes involved in the regulation of lipid and glucose metabolism, cell proliferation/differentiation as well as inflammatory pathways. Pivotal studies in human sebocytes and isolated sebaceous glands have raised the interesting possibility that compounds acting on PPARγ can modulate sebaceous lipids and inflammation and, as such, may be useful in the treatment of acne. To investigate the role of this receptor in the regulation of lipid synthesis, proliferation and inflammation, we used the SZ95 sebaceous gland cell line stimulated with insulin. In sebocytes, insulin signaling activated the phosphatidylinositide 3-kinase-Akt (PI3K/Akt) and mammalian target of rapamycin (mTOR) pathways, which, in turn, induced high protein/lipid synthesis, increased cell growth and proliferation as well as inflammation. As regards lipogenesis, insulin initially stimulated the formation of unsaturated lipids and then the neosynthesis of lipids. The results showed, that the modulation of PPARγ, counteracted the insulin-induced altered lipogenesis, evident through a decrease in gene expression of key enzymes responsible for the synthesis of fatty acids, and through a reduction of lipid species synthesis analyzed by Oil/Nile Red staining and GC–MS. PPARγ modulation also regulated the insulin-induced proliferation, inhibiting the cell cycle progression and p21WAF1/CIP1 (p21) protein reduction. Moreover, the expression of inflammatory cytokines, induced by insulin or lipopolysaccharide (LPS), was down-modulated. In PPARγ-deficient cells or in the presence of GW9662 antagonist, all these observed effects were abolished, indicating that PPARγ activation plays a role in regulating alteration of lipogenesis, cell proliferation and inflammatory signaling. We demonstrated that selective modulation of PPARγ activity is likely to represent a therapeutic strategy for the treatment of acne.
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      PubDate: 2017-07-07T02:46:43Z
      DOI: 10.1016/j.bcp.2017.04.030
      Issue No: Vol. 138 (2017)
  • In vivo α-hydroxylation of a 2-alkylindole antagonist of the OXE receptor
           for the eosinophil chemoattractant 5-oxo-6,8,11,14-eicosatetraenoic acid
           in monkeys
    • Authors: Shishir Chourey; Qiuji Ye; Chintam Nagendra Reddy; Chantal Cossette; Sylvie Gravel; Matthias Zeller; Irina Slobodchikova; Dajana Vuckovic; Joshua Rokach; William S. Powell
      Pages: 107 - 118
      Abstract: Publication date: 15 August 2017
      Source:Biochemical Pharmacology, Volume 138
      Author(s): Shishir Chourey, Qiuji Ye, Chintam Nagendra Reddy, Chantal Cossette, Sylvie Gravel, Matthias Zeller, Irina Slobodchikova, Dajana Vuckovic, Joshua Rokach, William S. Powell
      We have developed a selective indole antagonist (230) targeting the OXE receptor for the potent eosinophil chemoattractant 5-oxo-ETE (5-oxo-6,8,11,14-eicosatetraenoic acid), that may be useful for the treatment of eosinophilic diseases such as asthma. In previous studies we identified ω2-oxidation of the hexyl side chain of racemic 230 as a major metabolic route in monkeys, but also obtained evidence for another pathway that appeared to involve hydroxylation of the hexyl side chain close to the indole. The present study was designed to investigate the metabolism of the active S-enantiomer of 230 (S230) and to identify the novel hydroxy metabolite and its chirality. Following oral administration, S230 rapidly appeared in the blood along with metabolites formed by a novel and highly stereospecific α-hydroxylation pathway, resulting in the formation of αS-hydroxy-S230. The chirality of α-hydroxy-S230 was determined by the total synthesis of the relevant diastereomers. Of the four possible diastereomers of α-hydroxy-230 only αS-hydroxy-S230 has significant OXE receptor antagonist activity and only this diastereomer was found in significant amounts in blood following oral administration of S230. Other novel metabolites of S230 identified in plasma by LC–MS/MS were αS,ω2-dihydroxy-S230 and glucuronides of S230 and ω2-hydroxy-S230. Thus the alkyl side chain of S230, which is essential for its antagonist activity, is also the major target of the metabolic enzymes that terminate its antagonist activity. Modification of this side chain might result in the development of related antagonists with improved metabolic stability and efficacy.
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      PubDate: 2017-07-07T02:46:43Z
      DOI: 10.1016/j.bcp.2017.04.031
      Issue No: Vol. 138 (2017)
  • Therapeutic effect of Cryptotanshinone on experimental rheumatoid
           arthritis through downregulating p300 mediated-STAT3 acetylation
    • Authors: Ying Wang; Chun Zhou; Hui Gao; Cuixian Li; Dong Li; Peiqing Liu; Min Huang; Xiaoyan Shen; Liang Liu
      Pages: 119 - 129
      Abstract: Publication date: 15 August 2017
      Source:Biochemical Pharmacology, Volume 138
      Author(s): Ying Wang, Chun Zhou, Hui Gao, Cuixian Li, Dong Li, Peiqing Liu, Min Huang, Xiaoyan Shen, Liang Liu
      Background and purpose The balance between T helper 17 (Th17) cells and regulatory T (Treg) cells, plays a critical role in rheumatoid arthritis (RA). The differentiation of Th17 cells requires the activation of STAT3, which determines the balance of Th17/Treg. Here, we investigated the therapeutic effect of Cryptotanshinone (CTS) on collagen induced mouse arthritis and explored the underlying mechanisms. Experimental approach Arthritis was induced in DBA/1 mice with bovine collagen type II and complete Freund’s adjuvant. CTS was given at 20mgkg−1 d−1 or 60mgkg−1 d−1 by gavage for 6weeks. The immuno-inflammation and joint destruction were evaluated and the balance of Th17/Treg was determined. STAT3 acetylation and phosphorylation were detected by western blotting, and the involvement of p300 was investigated by siRNA and plasmid overexpression. Key results CTS at a dose of 60mgkg−1 d−1 ameliorated the inflammation and joint destruction in CIA mice. It improved Th17/Treg imbalance, and inhibited both acetylation and phosphorylation of STAT3. CTS reduced p300 expression and its binding to STAT3, but increased phosphorylated AMPK. Knockdown of p300 mimicked the inhibitory effect of CTS on STAT3 acetylation and phosphorylation, which could be partially rescued by overexpression of p300-WT, but not p300-dominant negative (DN) construct. Conclusion and implications Our study suggested that the anti-arthritis effects of CTS were attained through suppression of p300-mediated STAT3 acetylation. Our data suggest that CTS might be a potential immune modulator for RA treatment.
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      PubDate: 2017-07-07T02:46:43Z
      DOI: 10.1016/j.bcp.2017.05.006
      Issue No: Vol. 138 (2017)
  • P2X7 receptor antagonism: Implications in diabetic retinopathy
    • Authors: Chiara Bianca Maria Platania; Giovanni Giurdanella; Luisa Di Paola; Gian Marco Leggio; Filippo Drago; Salvatore Salomone; Claudio Bucolo
      Pages: 130 - 139
      Abstract: Publication date: 15 August 2017
      Source:Biochemical Pharmacology, Volume 138
      Author(s): Chiara Bianca Maria Platania, Giovanni Giurdanella, Luisa Di Paola, Gian Marco Leggio, Filippo Drago, Salvatore Salomone, Claudio Bucolo
      Diabetic retinopathy (DR) is the most frequent complication of diabetes and one of leading causes of blindness worldwide. Early phases of DR are characterized by retinal pericyte loss mainly related to concurrent inflammatory process. Recently, an important link between P2X7 receptor (P2X7R) and inflammation has been demonstrated indicating this receptor as potential pharmacological target in DR. Here we first carried out an in silico molecular modeling study in order to characterize the allosteric pocket in P2X7R, and identify a suitable P2X7R antagonist through molecular docking. JNJ47965567 was identified as the hit compound in docking calculations, as well as for its absorption, distribution, metabolism and excretion (ADME) profile. As an in vitro model of early diabetic retinopathy, human retinal pericytes were exposed to high glucose (25mM, 48h) that caused a significant (p<0.05) release of IL-1β and LDH. The block of P2X7R by JNJ47965567 significantly (p<0.05) reverted the damage elicited by high glucose, detected as IL-1β and LDH release. Overall, our findings suggest that the P2X7R represents an attractive pharmacological target to manage the early phase of diabetic retinopathy, and the compound JNJ47965567 is a good template to discover other P2X7R selective antagonists.
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      PubDate: 2017-07-07T02:46:43Z
      DOI: 10.1016/j.bcp.2017.05.001
      Issue No: Vol. 138 (2017)
  • High-throughput screening and bioinformatic analysis to ascertain
           compounds that prevent saturated fatty acid-induced β-cell apoptosis
    • Authors: Seung-Hee Lee; Daniel Cunha; Carlo Piermarocchi; Giovanni Paternostro; Anthony Pinkerton; Laurence Ladriere; Piero Marchetti; Decio L. Eizirik; Miriam Cnop; Fred Levine
      Pages: 140 - 149
      Abstract: Publication date: 15 August 2017
      Source:Biochemical Pharmacology, Volume 138
      Author(s): Seung-Hee Lee, Daniel Cunha, Carlo Piermarocchi, Giovanni Paternostro, Anthony Pinkerton, Laurence Ladriere, Piero Marchetti, Decio L. Eizirik, Miriam Cnop, Fred Levine
      Pancreatic β-cell lipotoxicity is a central feature of the pathogenesis of type 2 diabetes. To study the mechanism by which fatty acids cause β-cell death and develop novel approaches to prevent it, a high-throughput screen on the β-cell line INS1 was carried out. The cells were exposed to palmitate to induce cell death and compounds that reversed palmitate-induced cytotoxicity were ascertained. Hits from the screen were analyzed by an increasingly more stringent testing funnel, ending with studies on primary human islets treated with palmitate. MAP4K4 inhibitors, which were not part of the screening libraries but were ascertained by a bioinformatics analysis, and the endocannabinoid anandamide were effective at inhibiting palmitate-induced apoptosis in INS1 cells as well as primary rat and human islets. These targets could serve as the starting point for the development of therapeutics for type 2 diabetes.
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      PubDate: 2017-07-07T02:46:43Z
      DOI: 10.1016/j.bcp.2017.05.007
      Issue No: Vol. 138 (2017)
  • Modulation of HAT activity by the BRCA2 N372H variation is a novel
           mechanism of paclitaxel resistance in breast cancer cell lines
    • Authors: Woo Sun Kwon; Sun Young Rha; Hei-Cheul Jeung; Tae Soo Kim; Hyun Cheol Chung
      Pages: 163 - 173
      Abstract: Publication date: 15 August 2017
      Source:Biochemical Pharmacology, Volume 138
      Author(s): Woo Sun Kwon, Sun Young Rha, Hei-Cheul Jeung, Tae Soo Kim, Hyun Cheol Chung
      Paclitaxel stabilizes microtubule polymerization, enhances microtubule assembly, and G2/M arrests, leading to cell death. Paclitaxel resistance has been attributed to a variety of mechanisms. In the present study, we define a new resistance mechanism to paclitaxel based on BRCA2 variation. Chemo-sensitivity to paclitaxel based on the variations was compared. Restoration of paclitaxel sensitivity was induced indirectly with combined treatment of paclitaxel and HDAC inhibitor. Variant and wild type of BRCA2 clones were obtained from wild and variant cells, respectively. Chemo-sensitivity, P/CAF and BubR1 expression and acetylation, BRCA2-P/CAF and BRCA2-BubR1 interactions, and HAT activities of the clones with BRCA2 variation were compared. We identified an association between chemo-sensitivity and BRCA2 N372H variation. The IC50 of paclitaxel in heterozygous variation was higher than that of wild type. There were no differences in basic expression levels of BRCA2 among variant types. However, P/CAF expression, of BRCA2-P/CAF interaction, and HAT activity were significantly lower in heterozygous variants than in the wild type. After HDAC inhibitor treatment, HAT activity and paclitaxel sensitivity were restored in variant cells. Cell lines transformed from wild to variant or from variant to wild showed reciprocal changes in P/CAF expression, BRCA2-P/CAF interaction, HAT activity, and paclitaxel sensitivity. Forced expression of the BRCA2 heterozygous variant induced paclitaxel resistance due to altered HAT activity (p <0.001). This was reversed by the TSA combination. Restoration of wild BRCA2 from variant type improved paclitaxel sensitivity (p <0.001). Modulation of HAT activity by BRCA2 N372H variation is a new mechanism of paclitaxel resistance in breast cancer.
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      PubDate: 2017-07-07T02:46:43Z
      DOI: 10.1016/j.bcp.2017.04.015
      Issue No: Vol. 138 (2017)
  • A systematic evaluation of microRNAs in regulating human hepatic CYP2E1
    • Authors: Yong Wang; Dianke Yu; William H. Tolleson; Li-Rong Yu; Bridgett Green; Linjuan Zeng; Yinting Chen; Si Chen; Zhen Ren; Lei Guo; Weida Tong; Huaijin Guan; Baitang Ning
      Pages: 174 - 184
      Abstract: Publication date: 15 August 2017
      Source:Biochemical Pharmacology, Volume 138
      Author(s): Yong Wang, Dianke Yu, William H. Tolleson, Li-Rong Yu, Bridgett Green, Linjuan Zeng, Yinting Chen, Si Chen, Zhen Ren, Lei Guo, Weida Tong, Huaijin Guan, Baitang Ning
      Cytochrome P450 2E1 (CYP2E1) is an important drug metabolizing enzyme for processing numerous xenobiotics in the liver, including acetaminophen and ethanol. Previous studies have shown that microRNAs (miRNAs) can suppress CYP2E1 expression by binding to the 3′-untranslated region (3′-UTR) of its transcript. However, a systematic analysis of CYP2E1 regulation by miRNAs has not been described. Here, we applied in silico, in vivo, and in vitro approaches to investigate miRNAs involved in the regulation of CYP2E1. Initially, potential miRNA binding sites in the CYP2E1 mRNA transcript were identified and screened using in silico methods. Next, inverse correlations were found in human liver samples between the expression of CYP2E1 mRNA and the levels of two miRNA species, hsa-miR-214-3p and hsa-miR-942-5p. In a HepG2-derived CYP2E1 over-expression cell model, hsa-miR-214-3p exhibited strong suppression of CYP2E1 expression by targeting the coding region of its mRNA transcript, but hsa-miR-942-5p did not inhibit CYP2E1 levels. Electrophoretic mobility shift assays confirmed that hsa-miR-214-3p recruited other cellular protein factors to form stable complexes with specific sequences present in the CYP2E1 mRNA open reading frame. Transfection of HepaRG cells with hsa-miR-214-3p mimics inhibited expression of the endogenous CYP2E1 gene. Further, hsa-miR-214-3p mimics partially blocked ethanol-dependent increases in CYP2E1 mRNA and protein levels in HepG2 cells and they reduced the release of alanine aminotransferase from CYP2E1-overexpressing HepG2 cells exposed to acetaminophen. These results substantiate the suppressing effect of hsa-miR-214-3p on CYP2E1 expression.
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      PubDate: 2017-07-07T02:46:43Z
      DOI: 10.1016/j.bcp.2017.04.020
      Issue No: Vol. 138 (2017)
  • Human carbonyl reductase 1 participating in intestinal first-pass drug
           metabolism is inhibited by fatty acids and acyl-CoAs
    • Authors: Akira Hara; Satoshi Endo; Toshiyuki Matsunaga; Ossama El-Kabbani; Takeshi Miura; Toru Nishinaka; Tomoyuki Terada
      Pages: 185 - 192
      Abstract: Publication date: 15 August 2017
      Source:Biochemical Pharmacology, Volume 138
      Author(s): Akira Hara, Satoshi Endo, Toshiyuki Matsunaga, Ossama El-Kabbani, Takeshi Miura, Toru Nishinaka, Tomoyuki Terada
      Human carbonyl reductase 1 (CBR1), a member of the short-chain dehydrogenase/reductase (SDR) superfamily, reduces a variety of carbonyl compounds including endogenous isatin, prostaglandin E2 and 4-oxo-2-nonenal. It is also a major non-cytochrome P450 enzyme in the phase I metabolism of carbonyl-containing drugs, and is highly expressed in the intestine. In this study, we found that long-chain fatty acids and their CoA ester derivatives inhibit CBR1. Among saturated fatty acids, myristic, palmitic and stearic acids were inhibitory, and stearic acid was the most potent (IC50 9µM). Unsaturated fatty acids (oleic, elaidic, γ-linolenic and docosahexaenoic acids) and acyl-CoAs (palmitoyl-, stearoyl- and oleoyl-CoAs) were more potent inhibitors (IC50 1.0–2.5µM), and showed high inhibitory selectivity to CBR1 over its isozyme CBR3 and other SDR superfamily enzymes (DCXR and DHRS4) with CBR activity. The inhibition by these fatty acids and acyl-CoAs was competitive with respect to the substrate, showing the K i values of 0.49–1.2µM. Site-directed mutagenesis of the substrate-binding residues of CBR1 suggested that the interactions between the fatty acyl chain and the enzyme’s Met141 and Trp229 are important for the inhibitory selectivity. We also examined CBR1 inhibition by oleic acid in cellular levels: The fatty acid effectively inhibited CBR1-mediated 4-oxo-2-nonenal metabolism in colon cancer DLD1 cells and increased sensitivity to doxorubicin in the drug-resistant gastric cancer MKN45 cells that highly express CBR1. The results suggest a possible new food-drug interaction through inhibition of CBR1-mediated intestinal first-pass drug metabolism by dietary fatty acids.
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      PubDate: 2017-07-07T02:46:43Z
      DOI: 10.1016/j.bcp.2017.04.023
      Issue No: Vol. 138 (2017)
  • Pinocembrin ex vivo preconditioning improves the therapeutic efficacy of
           endothelial progenitor cells in monocrotaline-induced pulmonary
           hypertension in rats
    • Authors: Lamiaa A. Ahmed; Sherine M. Rizk; Shohda A. EL-Maraghy
      Pages: 193 - 204
      Abstract: Publication date: 15 August 2017
      Source:Biochemical Pharmacology, Volume 138
      Author(s): Lamiaa A. Ahmed, Sherine M. Rizk, Shohda A. EL-Maraghy
      Pulmonary hypertension is still not curable and the available current therapies can only alleviate symptoms without hindering the progression of disease. The present study was directed to investigate the possible modulatory effect of pinocembrin on endothelial progenitor cells transplanted in monocrotaline-induced pulmonary hypertension in rats. Pulmonary hypertension was induced by a single subcutaneous injection of monocrotaline (60mg/kg). Endothelial progenitor cells were in vitro preconditioned with pinocembrin (25mg/L) for 30min before being i.v. injected into rats 2weeks after monocrotaline administration. Four weeks after monocrotaline administration, blood pressure, electrocardiography and right ventricular systolic pressure were recorded. Rats were sacrificed and serum was separated for determination of endothelin-1 and asymmetric dimethylarginine levels. Right ventricles and lungs were isolated for estimation of tumor necrosis factor-alpha and transforming growth factor-beta contents as well as caspase-3 activity. Moreover, protein expression of matrix metalloproteinase-9 and endothelial nitric oxide synthase in addition to myocardial connexin-43 was assessed. Finally, histological analysis of pulmonary arteries, cardiomyocyte cross-sectional area and right ventricular hypertrophy was performed and cryosections were done for estimation of cell homing. Preconditioning with pinocembrin provided a significant improvement in endothelial progenitor cells’ effect towards reducing monocrotaline-induced elevation of inflammatory, fibrogenic and apoptotic markers. Furthermore, preconditioned cells induced a significant amelioration of endothelial markers and cell homing and prevented monocrotaline-induced changes in right ventricular function and histological analysis compared with native cells alone. In conclusion, pinocembrin significantly improves the therapeutic efficacy of endothelial progenitor cells in monocrotaline-induced pulmonary hypertension in rats.
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      PubDate: 2017-07-07T02:46:43Z
      DOI: 10.1016/j.bcp.2017.04.024
      Issue No: Vol. 138 (2017)
  • Inositol-1,4,5-trisphosphate 3-kinase-A (ITPKA) is frequently
           over-expressed and functions as an oncogene in several tumor types
    • Authors: Sabine Windhorst; Kai Song; Adi F. Gazdar
      Pages: 1 - 9
      Abstract: Publication date: 1 August 2017
      Source:Biochemical Pharmacology, Volume 137
      Author(s): Sabine Windhorst, Kai Song, Adi F. Gazdar
      At present targeted tumor therapy is based on inhibition of proteins or protein mutants that are up-regulated in tumor but not in corresponding normal cells. The actin bundling Inositol-trisphosphate 3-kinase A (ITPKA) belongs to such molecular targets. ITPKA is expressed in a broad range of tumor types but shows limited expression in normal cells. In lung and breast cancer expression of ITPKA is stimulated by gene body methylation which increases with increasing malignancy of these tumors but is not detectable in the corresponding normal tissues. Since ITPKA gene body methylation occurs early in tumor development, it could serve as biomarker for early detection of lung cancer. Detailed mechanistic studies revealed that down-regulation of ITPKA in lung adenocarcinoma cancers reduced both, tumor growth and metastasis. It is assumed that tumor growth is stimulated by the InsP3Kinase activity of ITPKA and metastasis by its actin bundling activity. A selective inhibitor against the InsP3Kinase activity of ITPKA has been identified but compounds inhibiting the actin bundling activity are not available yet. Since no curative therapy option for metastatic lung or breast tumors exist, therapies that block activities of ITPKA may offer new options for patients with these tumors. Thus, efforts should be made to develop clinical drugs that selectively target InsP3Kinase activity as well as actin bundling activity of ITPKA.
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      PubDate: 2017-06-05T15:36:29Z
      DOI: 10.1016/j.bcp.2017.03.023
      Issue No: Vol. 137 (2017)
  • Identification of novel 1-indolyl acetate-5-nitroimidazole derivatives of
           combretastatin A-4 as potential tubulin polymerization inhibitors
    • Authors: Yong-Fang Yao; Zhong-Chang Wang; Song-Yu Wu; Qing-fang Li; Chen Yu; Xin-Yi Liang; Peng-Cheng Lv; Yong-Tao Duan; Hai-Liang Zhu
      Pages: 10 - 28
      Abstract: Publication date: 1 August 2017
      Source:Biochemical Pharmacology, Volume 137
      Author(s): Yong-Fang Yao, Zhong-Chang Wang, Song-Yu Wu, Qing-fang Li, Chen Yu, Xin-Yi Liang, Peng-Cheng Lv, Yong-Tao Duan, Hai-Liang Zhu
      Microtubules are essential for the mitotic division of cells and have become an attractive target for anti-tumour drugs due to the increased incidence of cancer and significant mitosis rate of tumour cells. In this study, a total of six indole 1-position modified 1-indolyl acetate-5-nitroimidazole derivatives were designed, synthesized, and evaluated for their ability to inhibit tubulin polymerization caused by binding to the colchicine-binding site of tubulin. Among them, compound 3 displayed the best ability to inhibit tubulin polymerization; it also exhibited better anti-proliferative activities than colchicine against a panel of human cancer cells (with IC50 values ranging from 15 to 40nM), especially HeLa cells (with IC50 values of 15nM), based on the cellular cytotoxicity assay results. Moreover, cellular mechanism studies indicated that compound 3 could induce G2/M phase arrest and apoptosis of HeLa and MCF-7 cells, which were associated with alterations in the expression of cell cycle-checkpoint related proteins (Cyclin B1, Cdc2, and P21) and a reduction in the mitochondrial membrane potential as well as alterations in the levels of apoptosis-related proteins (PARP, Caspase 9, Bcl-2, and Bax) of these cells, respectively. Importantly, in vivo studies further revealed that compound 3 could dramatically suppress HeLa cell xenograft tumour growth compared with vehicle and CA-4 phosphate (CA-4P), and no signs of toxicity were observed in these mice. Collectively, these in vitro and in vivo results indicated that compound 3 might be a promising lead compound for further development as a potential anti-cancer drug.
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      PubDate: 2017-06-05T15:36:29Z
      DOI: 10.1016/j.bcp.2017.04.026
      Issue No: Vol. 137 (2017)
  • Identification of 4-arylidene curcumin analogues as novel proteasome
           inhibitors for potential anticancer agents targeting 19S regulatory
           particle associated deubiquitinase
    • Authors: Xin Yue; Yinglin Zuo; Hongpeng Ke; Jiaming Luo; Lanlan Lou; Wenjing Qin; Youqiao Wang; Ziyi Liu; Daoyuan Chen; Haixia Sun; Weichao Zheng; Cuige Zhu; Ruimin Wang; Gesi Wen; Jun Du; Binhua Zhou; Xianzhang Bu
      Pages: 29 - 50
      Abstract: Publication date: 1 August 2017
      Source:Biochemical Pharmacology, Volume 137
      Author(s): Xin Yue, Yinglin Zuo, Hongpeng Ke, Jiaming Luo, Lanlan Lou, Wenjing Qin, Youqiao Wang, Ziyi Liu, Daoyuan Chen, Haixia Sun, Weichao Zheng, Cuige Zhu, Ruimin Wang, Gesi Wen, Jun Du, Binhua Zhou, Xianzhang Bu
      The proteasomal 19S regulatory particle (RP) associated deubiquitinases (DUBs) have attracted much attention owing to their potential as a therapeutic target for cancer therapy. Identification of new entities against 19S RP associated DUBs and illustration of the underlying mechanisms is crucial for discovery of novel proteasome blockers. In this study, a series of 4-arylidene curcumin analogues were identified as potent proteasome inhibitor by preferentially blocking deubiquitinase function of proteasomal 19S RP with moderate 20S CP inhibition. The most active compound 33 exhibited a major inhibitory effect on 19S RP-associated ubiquitin-specific proteases 14, along with a minor effect on ubiquitin C-terminal hydrolase 5, which resulted in dysfunction of proteasome, and subsequently accumulated ubiquitinated proteins (such as IκB) in several cancer cells. Remarkably, though both 19S RP and 20S CP inhibition induced significantly endoplasmic reticulum stress and triggered caspase-12/9 pathway activation to promote cancer cell apoptosis, the 19S RP inhibition by 33 avoided slow onset time, Bcl-2 overexpression, and PERK-phosphorylation, which contribute to the deficiencies of clinical drug Bortezomib. These systematic studies provided insights in the development of novel proteasome inhibitors for cancer treatment.
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      PubDate: 2017-06-05T15:36:29Z
      DOI: 10.1016/j.bcp.2017.04.032
      Issue No: Vol. 137 (2017)
  • Roscovitine attenuates intimal hyperplasia via inhibiting NF-κB and STAT3
           activation induced by TNF-α in vascular smooth muscle cells
    • Authors: Ming He; Chao Wang; Jia-huan Sun; Yu Liu; Hong Wang; Jing-shan Zhao; Yun-feng Li; Hong Chang; Jian-ming Hou; Jun-na Song; Ai-ying Li; En-sheng Ji
      Pages: 51 - 60
      Abstract: Publication date: 1 August 2017
      Source:Biochemical Pharmacology, Volume 137
      Author(s): Ming He, Chao Wang, Jia-huan Sun, Yu Liu, Hong Wang, Jing-shan Zhao, Yun-feng Li, Hong Chang, Jian-ming Hou, Jun-na Song, Ai-ying Li, En-sheng Ji
      Roscovitine is a selective CDK inhibitor originally designed as anti-cancer agent, which has also been shown to inhibit proliferation in vascular smooth muscle cells (VSMCs). However, its effect on vascular remodeling and its mechanism of action remain unknown. In our study, we created a new intimal hyperplasia model in male Sprague-Dawley rats by trypsin digestion method, which cause to vascular injury as well as the model of rat carotid balloon angioplasty. Roscovitine administration led to a significant reduction in neointimal formation and VSMCs proliferation after injury in rats. Western blot analysis revealed that, in response to vascular injury, TNF-α stimulation induced p65 and STAT3 phosphorylation and promoted translocation of these molecules into the nucleus. p65 can physically associate with STAT3 and bind to TNF-α-regulated target promoters, such as MCP-1 and ICAM-1, to initiate gene transcription. Roscovitine can interrupt activation of NF-κB and reduce expression of TNF-α-induced proinflammatory gene, thus inhibiting intimal hyperplasia. These findings provide a novel mechanism to explain the roscovitine-mediated inhibition of intimal hyperplasia induced by proinflammatory pathways.
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      PubDate: 2017-06-05T15:36:29Z
      DOI: 10.1016/j.bcp.2017.04.018
      Issue No: Vol. 137 (2017)
  • Selective inhibition of EZH2 by a small molecule inhibitor regulates
           microglial gene expression essential for inflammation
    • Authors: Sarder Arifuzzaman; Amitabh Das; Sun Hwa Kim; Taeho Yoon; Young Seek Lee; Kyoung Hwa Jung; Young Gyu Chai
      Pages: 61 - 80
      Abstract: Publication date: 1 August 2017
      Source:Biochemical Pharmacology, Volume 137
      Author(s): Sarder Arifuzzaman, Amitabh Das, Sun Hwa Kim, Taeho Yoon, Young Seek Lee, Kyoung Hwa Jung, Young Gyu Chai
      Multiple studies have documented that Enhancer of zeste homolog 2 (EZH2) could play a role in inflammation and a wide range of malignancies; however, the underlying mechanisms remain largely unaddressed. Microglial activation is a key process in the production and release of numerous pro-inflammatory mediators that play important roles in inflammation and neurodegeneration in the central nervous system (CNS). Therefore, our aim was to investigate whether inhibition of EZH2 with the selective small molecule inhibitor EPZ-6438 protects against neonatal microglial activation. First, in mouse primary microglial cells and a microglial cell line, we found that LPS can rapidly increase EZH2 mRNA level and we subsequently performed gene expression profiling and constructed networks in resting, EPZ-6438-treated, LPS-treated and LPS+EPZ-6438-treated primary microglial cells and a microglial cell line using transcriptome RNA sequencing and bioinformatics analyses. By examining the RNA sequencing, we identified EPZ-6438 target genes and co-regulated modules that were critical for inflammation. We also identified unexpected relationships between the inducible transcription factors (TFs), motif strength, and the transcription of key inflammatory mediators. Furthermore, we showed that EPZ-6438 controls important inflammatory gene targets by modulating interferon regulatory factor (IRF) 1, IRF8, and signal transducer and activator of transcription (STAT) 1 levels at their promoter sites. Our unprecedented findings demonstrate that pharmacological interventions built upon EZH2 inhibition by EPZ-6438 could be a useful therapeutic approach for the treatment of neuroinflammatory diseases associated with microglial activation.
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      PubDate: 2017-06-05T15:36:29Z
      DOI: 10.1016/j.bcp.2017.04.016
      Issue No: Vol. 137 (2017)
  • Improvements in oocyte competence in superovulated mice following
           treatment with cilostazol: Ovulation of immature oocytes with high
           developmental rates
    • Authors: Ahmed M. Taiyeb; Saeeda A. Muhsen-Alanssari; William L. Dees; Jill Hiney; Michael E. Kjelland; Duane C. Kraemer; Mundhir T. Ridha-Albarzanchi
      Pages: 81 - 92
      Abstract: Publication date: 1 August 2017
      Source:Biochemical Pharmacology, Volume 137
      Author(s): Ahmed M. Taiyeb, Saeeda A. Muhsen-Alanssari, William L. Dees, Jill Hiney, Michael E. Kjelland, Duane C. Kraemer, Mundhir T. Ridha-Albarzanchi
      Exogenous administration of superovulatory hormones negatively affects oocyte competence in mammals. Phosphodiesterase 3A inhibitors were found to improve competence of oocytes matured in vitro in several species, including humans. This study was therefore designed to define oocyte maturation synchronization and competence, in vivo, using superovulated mice treated with cilostazol, a selective phosphodiesterase 3A inhibitor. Swiss Webster mice were superovulated and treated orally with 7.5mg cilostazol once or twice to result in ovulation of immature oocytes at the metaphase I (MI) or germinal vesicle (GV) stage, respectively. Control immature oocytes were recovered from preovulatory follicles of superovulated mice not treated with cilostazol. Treated GV oocytes had significantly higher rates of synchronized and advanced chromatin configuration and cortical granule distribution than did control GV oocytes. Treated GV oocytes had a moderate increase in cAMP levels and consequently higher rates of meiotic maturation, IVF, and blastocyst formation than did control GV oocytes (P<0.0001). Treated MI oocytes had higher rates of normal spindles and chromosomes aligned at the metaphase plate than did control MI oocytes (P<0.003). Treated mice ovulating MI oocytes produced litter sizes larger than those observed in control mice ovulating mature oocytes (P<0.002). This study reveals that synchronization of oocyte maturation in superovulated mice improves oocyte development and competence. The capability of cilostazol, a clinically approved medication, to improve mouse oocyte competence suggests the potential benefit of including this compound in ovarian hyperstimulation programs to improve in vitro fertilization outcomes in infertile women.
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      PubDate: 2017-06-05T15:36:29Z
      DOI: 10.1016/j.bcp.2017.04.019
      Issue No: Vol. 137 (2017)
  • Identification and validation of microRNAs directly regulating the
           UDP-glucuronosyltransferase 1A subfamily enzymes by a functional genomics
    • Authors: Ioannis Papageorgiou; Michael H. Court
      Pages: 93 - 106
      Abstract: Publication date: 1 August 2017
      Source:Biochemical Pharmacology, Volume 137
      Author(s): Ioannis Papageorgiou, Michael H. Court
      Posttranscriptional repression of UDP-glucuronosyltransferase (UGT) 1A expression by microRNAs (miRNAs) may be an important mechanism underlying interindividual variability in drug glucuronidation. Furthermore, the UGT1A 3′-UTR shared by all UGT1A enzymes is polymorphic, containing three linked SNPs (rs10929303, rs1042640, and rs8330) that could influence miRNA binding. The aim of this study was to identify the complete complement of miRNAs that could regulate UGT1A expression through binding to the reference and/or common variant UGT1A 3′-UTR. Luciferase reporter plasmids containing either the reference or variant UGT1A 3′-UTR were screened against a 2048 human miRNA library to identify those miRNAs that decrease luciferase activity by at least 30% when co-transfected into HEK293 cells. Four novel miRNAs (miR-103b, miR-141-3p, miR-200a-3p, and miR-376b-3p) were identified that repressed both reference and variant UGT1A 3′-UTR, while two other miRNAs selectively repressed the reference (miR-1286) or variant (miR-21-3p) 3′-UTR. Deletion and mutagenesis studies confirmed the binding site location for each miRNA. rs8330 disrupted miR-1286 binding to the reference UGT1A 3′-UTR, while rs10929303 enhanced miR-21-3p binding to the variant 3′-UTR. Transfection of miR-21-3p, miR-103b, miR-141-3p, miR-200a-3p, and miR-376b-3p mimics into LS180 human intestinal cells showed repression of UGT1A1 and UGT1A6 mediated glucuronidation and mRNA without affecting UGT2B7 activity or mRNA. Furthermore, transfection of miR-21-3p, miR-141-3p, and miR-200a-3p into primary human hepatocytes, repressed UGT1A1 activity and mRNA without affecting CYP3A activity. Finally, miR-21-3p and miR-200a-3p expression were negatively correlated with UGT1A6 activity and mRNA in human liver samples. Thus, UGT1A is regulated by multiple miRNAs with some showing allele-dependent effects.
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      PubDate: 2017-06-05T15:36:29Z
      DOI: 10.1016/j.bcp.2017.04.017
      Issue No: Vol. 137 (2017)
  • Catalase increases ethanol oxidation through the purine catabolism in rat
    • Authors: Daniel Villalobos-García; Rolando Hernández-Muñoz
      Pages: 107 - 112
      Abstract: Publication date: 1 August 2017
      Source:Biochemical Pharmacology, Volume 137
      Author(s): Daniel Villalobos-García, Rolando Hernández-Muñoz
      Hepatic ethanol oxidation increases according to its concentration and is raised to near-saturation levels of alcohol dehydrogenase (ADH); therefore, re-oxidation of NADH becomes rate limiting in ethanol metabolism by the liver. Adenosine is able to increase liver ethanol oxidation in both in vivo and in vitro conditions; the enhancement being related with the capacity of the nucleoside to accelerate the transport of cytoplasmic reducing equivalents to mitochondria, by modifying the subcellular distribution of the malate-aspartate shuttle components. In the present study, we explored the putative effects of adenosine and other purines on liver ethanol oxidation mediated by non-ADH pathways. Using the model of high precision-cut rat liver slices, a pronounced increase of ethanol oxidation was found in liver slices incubated with various intermediates of the purine degradation pathway, from adenosine to uric acid (175–230%, over controls). Of these, urate had the strongest (230%), whereas xanthine had the less pronounced effect (178% over controls). The enhancement was not abolished by 4-methylpyrazole, indicating that the effect was independent of alcohol dehydrogenase. Conversely, aminotriazole, a catalase inhibitor, completely abolished the effect, pointing out that this enhanced ethanol oxidation is mediated by catalase activity. It is concluded that the H2O2 needed for catalase activity is derived from the oxidation of (hypo)xanthine by xanthine oxidase and the oxidation of urate by uricase. The present and previous data led us to propose that, depending on the metabolic conditions, adenosine might be able to stimulate the metabolism of ethanol through different pathways.
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      PubDate: 2017-06-05T15:36:29Z
      DOI: 10.1016/j.bcp.2017.05.011
      Issue No: Vol. 137 (2017)
  • Benzo[a]pyrene-induced DNA damage associated with mutagenesis in primary
           human activated T lymphocytes
    • Authors: Marie Liamin; Elisa Boutet-Robinet; Emilien L. Jamin; Morgane Fernier; Laure Khoury; Benjamin Kopp; Eric Le Ferrec; Julien Vignard; Marc Audebert; Lydie Sparfel
      Pages: 113 - 124
      Abstract: Publication date: 1 August 2017
      Source:Biochemical Pharmacology, Volume 137
      Author(s): Marie Liamin, Elisa Boutet-Robinet, Emilien L. Jamin, Morgane Fernier, Laure Khoury, Benjamin Kopp, Eric Le Ferrec, Julien Vignard, Marc Audebert, Lydie Sparfel
      Polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (B[a]P), are widely distributed environmental contaminants exerting toxic effects such as genotoxicity and carcinogenicity, mainly associated with aryl hydrocarbon receptor (AhR) activation and the subsequent induction of cytochromes P-450 (CYP) 1-metabolizing enzymes. We previously reported an up-regulation of AhR expression and activity in primary cultures of human T lymphocyte by a physiological activation. Despite the suggested link between exposure to PAHs and the risk of lymphoma, the potential of activated human T lymphocytes to metabolize AhR exogenous ligands such as B[a]P and produce DNA damage has not been investigated. In the present study, we characterized the genotoxic response of primary activated T lymphocytes to B[a]P. We demonstrated that, following T lymphocyte activation, B[a]P treatment triggers a marked increase in CYP1 expression and activity generating, upon metabolic activation, DNA adducts and double-strand breaks (DSBs) after a 48-h treatment. At this time point, B[a]P also induces a DNA damage response with ataxia telangiectasia mutated kinase activation, thus producing a p53-dependent response and T lymphocyte survival. B[a]P activates DSB repair by mobilizing homologous recombination machinery but also induces gene mutations in activated human T lymphocytes which could consequently drive a cancer process. In conclusion, primary cultures of activated human T lymphocytes represent a good model for studying genotoxic effects of environmental contaminants such as PAHs, and predicting human health issues.
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      PubDate: 2017-06-05T15:36:29Z
      DOI: 10.1016/j.bcp.2017.04.025
      Issue No: Vol. 137 (2017)
  • Targeted pharmacotherapies for defective ABC transporters
    • Authors: Virginie Vauthier; Chantal Housset; Thomas Falguières
      Pages: 1 - 11
      Abstract: Publication date: 15 July 2017
      Source:Biochemical Pharmacology, Volume 136
      Author(s): Virginie Vauthier, Chantal Housset, Thomas Falguières
      Human ABC (ATP Binding Cassette) transporters form a superfamily of forty-eight transmembrane proteins, which transport their substrates across biological membranes against important concentration gradients, in an energy-dependent manner. Gene variations in approximately half of these transporters have been identified in subjects with rare and often severe genetic diseases, highlighting the importance of their biological function. For missense variations leading to defects in ABC transporters, the current challenge is to identify new molecules with therapeutic potential able to rescue the induced molecular deficiency. In this review, we first address the progress provided by emerging pharmacotherapies in cystic fibrosis, the most frequent monogenic disease caused by variations of an ABC transporter, i.e. ABCC7/CFTR. Then, we enlarge the topic to the other ABC transporters, more notably to canalicular ABC transporters, the variations of which cause rare hepatobiliary diseases, and we discuss the first promising attempts aiming to correct molecular defects of these proteins.
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      PubDate: 2017-05-26T06:30:35Z
      DOI: 10.1016/j.bcp.2017.02.020
      Issue No: Vol. 136 (2017)
  • Multifaceted anticancer activity of BH3 mimetics: Current evidence and
           future prospects
    • Authors: Małgorzata Opydo-Chanek; Oscar Gonzalo; Isabel Marzo
      Pages: 12 - 23
      Abstract: Publication date: 15 July 2017
      Source:Biochemical Pharmacology, Volume 136
      Author(s): Małgorzata Opydo-Chanek, Oscar Gonzalo, Isabel Marzo
      BH3 mimetics are a novel class of anticancer agents designed to specifically target pro-survival proteins of the Bcl-2 family. Like endogenous BH3-only proteins, BH3 mimetics competitively bind to surface hydrophobic grooves of pro-survival Bcl-2 family members, counteracting their protective effects and thus facilitating apoptosis in cancer cells. Among the small-molecule BH3 mimetics identified, ABT-737 and its analogs, obatoclax as well as gossypol derivatives are the best characterized. The anticancer potential of these compounds applied as a single agent or in combination with chemotherapeutic drugs is currently being evaluated in preclinical studies and in clinical trials. In spite of promising results, the actual mechanisms of their anticancer action remain to be identified. Findings from preclinical studies point to additional activities of BH3 mimetics in cancer cells that are not connected with apoptosis induction. These off-target effects involve induction of autophagy and necrotic cell death as well as modulation of the cell cycle and multiple cell signaling pathways. For the optimization and clinical implementation of BH3 mimetics, a detailed understanding of their role as inhibitors of the pro-survival Bcl-2 proteins, but also of their possible additional effects is required. This review summarizes the most representative BH3 mimetic compounds with emphasis on their off-target effects. Based on the present knowledge on the multifaceted effects of BH3 mimetics on cancer cells, the commentary outlines the potential pitfalls and highlights the considerable promise for cancer treatment with BH3 mimetics.
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      PubDate: 2017-05-26T06:30:35Z
      DOI: 10.1016/j.bcp.2017.03.006
      Issue No: Vol. 136 (2017)
  • Corrector VX-809 promotes interactions between cytoplasmic loop one and
           the first nucleotide-binding domain of CFTR
    • Authors: Tip W. Loo; David M. Clarke
      Pages: 24 - 31
      Abstract: Publication date: 15 July 2017
      Source:Biochemical Pharmacology, Volume 136
      Author(s): Tip W. Loo, David M. Clarke
      A large number of correctors have been identified that can partially repair defects in folding, stability and trafficking of CFTR processing mutants that cause cystic fibrosis (CF). The best corrector, VX-809 (Lumacaftor), has shown some promise when used in combination with a potentiator (Ivacaftor). Understanding the mechanism of VX-809 is essential for development of better correctors. Here, we tested our prediction that VX-809 repairs folding and processing defects of CFTR by promoting interactions between the first cytoplasmic loop (CL1) of transmembrane domain 1 (TMD1) and the first nucleotide-binding domain (NBD1). To investigate whether VX-809 promoted CL1/NBD1 interactions, we performed cysteine mutagenesis and disulfide cross-linking analysis of Cys-less TMD1 (residues 1–436) and ΔTMD1 (residues 437–1480; NBD1-R-TMD2-NBD2) truncation mutants. It was found that VX-809, but not bithiazole correctors, promoted maturation (exited endoplasmic reticulum for addition of complex carbohydrate in the Golgi) of the ΔTMD1 truncation mutant only when it was co-expressed in the presence of TMD1. Expression in the presence of VX-809 also promoted cross-linking between R170C (in CL1 of TMD1 protein) and L475C (in NBD1 of the ΔTMD1 truncation protein). Expression of the ΔTMD1 truncation mutant in the presence of TMD1 and VX-809 also increased the half-life of the mature protein in cells. The results suggest that the mechanism by which VX-809 promotes maturation and stability of CFTR is by promoting CL1/NBD1 interactions.
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      PubDate: 2017-05-26T06:30:35Z
      DOI: 10.1016/j.bcp.2017.03.020
      Issue No: Vol. 136 (2017)
  • Hydroxyurea inhibits parvovirus B19 replication in erythroid progenitor
    • Authors: Francesca Bonvicini; Gloria Bua; Ilaria Conti; Elisabetta Manaresi; Giorgio Gallinella
      Pages: 32 - 39
      Abstract: Publication date: 15 July 2017
      Source:Biochemical Pharmacology, Volume 136
      Author(s): Francesca Bonvicini, Gloria Bua, Ilaria Conti, Elisabetta Manaresi, Giorgio Gallinella
      Parvovirus B19 (B19V) infection is restricted to erythroid progenitor cells (EPCs) of the human bone marrow, leading to transient arrest of erythropoiesis and severe complications mainly in subjects with underlying hematological disorders or with immune system deficits. Currently, there are no specific antiviral drugs for B19V treatment, but identification of compounds inhibiting B19V replication can be pursued by a drug repositioning strategy. In this frame, the present study investigates the activity of hydroxyurea (HU), the only disease-modifying therapy approved for sickle cell disease (SCD), towards B19V replication in the two relevant cellular systems, the UT7/EpoS1 cell line and EPCs. Results demonstrate that HU inhibits B19V replication with EC50 values of 96.2µM and 147.1µM in UT7/EpoS1 and EPCs, respectively, providing experimental evidence of the antiviral activity of HU towards B19V replication, and confirming the efficacy of a drug discovery process by drug repositioning strategy. The antiviral activity occurs in vitro at concentrations lower than those affecting cellular DNA replication and viability, and at levels measured in plasma samples of SCD patients undergoing HU therapy. HU might determine a dual beneficial effect on SCD patients, not only for the treatment of the disease but also towards a virus responsible for severe complications.
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      PubDate: 2017-05-26T06:30:35Z
      DOI: 10.1016/j.bcp.2017.03.022
      Issue No: Vol. 136 (2017)
  • Axl molecular targeting counteracts aggressiveness but not
           platinum-resistance of ovarian carcinoma cells
    • Authors: Cristina Corno; Laura Gatti; Noemi Arrighetti; Nives Carenini; Nadia Zaffaroni; Cinzia Lanzi; Paola Perego
      Pages: 40 - 50
      Abstract: Publication date: 15 July 2017
      Source:Biochemical Pharmacology, Volume 136
      Author(s): Cristina Corno, Laura Gatti, Noemi Arrighetti, Nives Carenini, Nadia Zaffaroni, Cinzia Lanzi, Paola Perego
      Ovarian carcinoma, the most common gynaecological cancer, is characterized by high lethality mainly due to late diagnosis and treatment failure. The efficacy of platinum drug-based therapy in the disease is limited by the occurrence of drug resistance, a phenomenon often associated with increased metastatic potential. Because the Tyr-kinase receptor Axl can be deregulated in ovarian carcinoma and plays a pro-metastatic/anti-apoptotic role, the aim of this study was to examine if Axl inhibition modulates drug resistance and aggressive features of ovarian carcinoma cells, using various pairs of cisplatin-sensitive and -resistant cell lines. We found that mRNA and protein levels of Axl were increased in the platinum-resistant IGROV-1/Pt1 and IGROV-1/OHP cell lines compared to the parental IGROV-1 cells. IGROV-1/Pt1 cells displayed increased migratory and invasive capabilities. When Axl was silenced, these cells exhibited reduced growth and invasive/migratory capabilities compared to control siRNA-transfected cells, associated with decreased p38 and STAT3 phosphorylation. In keeping with this evidence, pharmacological inhibition of p38 and STAT3 decreased IGROV-1/Pt1 invasive capability. Molecular inhibition of Axl did not sensitize IGROV-1/Pt1 cells to cisplatin, but enhanced ErbB3 activation in IGROV-1/Pt1 cells and suppressed the clonogenic capability of various ovarian carcinoma cell lines. The combination of cisplatin and AZD8931, a small molecule which inhibits ErbB3, produced a synergistic effect in IGROV-1/Pt1 cells. Thus, Axl targeting per se reduces invasive capability of drug-resistant cells, but sensitization to cisplatin requires the concomitant inhibition of additional survival pathways.
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      PubDate: 2017-05-26T06:30:35Z
      DOI: 10.1016/j.bcp.2017.04.002
      Issue No: Vol. 136 (2017)
  • Guanine α-carboxy nucleoside phosphonate (G-α-CNP) shows a different
           inhibitory kinetic profile against the DNA polymerases of human
           immunodeficiency virus (HIV) and herpes viruses
    • Authors: Jan Balzarini; Michael Menni; Kalyan Das; Lizette van Berckelaer; Alan Ford; Nuala M. Maguire; Sandra Liekens; Paul E. Boehmer; Eddy Arnold; Matthias Götte; Anita R. Maguire
      Pages: 51 - 61
      Abstract: Publication date: 15 July 2017
      Source:Biochemical Pharmacology, Volume 136
      Author(s): Jan Balzarini, Michael Menni, Kalyan Das, Lizette van Berckelaer, Alan Ford, Nuala M. Maguire, Sandra Liekens, Paul E. Boehmer, Eddy Arnold, Matthias Götte, Anita R. Maguire
      α-Carboxy nucleoside phosphonates (α-CNPs) are modified nucleotides that represent a novel class of nucleotide-competing reverse transcriptase (RT) inhibitors (NcRTIs). They were designed to act directly against HIV-1 RT without the need for prior activation (phosphorylation). In this respect, they differ from the nucleoside or nucleotide RTIs [N(t)RTIs] that require conversion to their triphosphate forms before being inhibitory to HIV-1 RT. The guanine derivative (G-α-CNP) has now been synthesized and investigated for the first time. The (L)-(+)-enantiomer of G-α-CNP directly and competitively inhibits HIV-1 RT by interacting with the substrate active site of the enzyme. The (D)-(−)-enantiomer proved inactive against HIV-1 RT. In contrast, the (+)- and (−)-enantiomers of G-α-CNP inhibited herpes (i.e. HSV-1, HCMV) DNA polymerases in a non- or uncompetitive manner, strongly indicating interaction of the (L)-(+)- and the (D)-(−)-G-α-CNPs at a location different from the polymerase substrate active site of the herpes enzymes. Such entirely different inhibition profile of viral polymerases is unprecedented for a single antiviral drug molecule. Moreover, within the class of α-CNPs, subtle differences in their sensitivity to mutant HIV-1 RT enzymes were observed depending on the nature of the nucleobase in the α-CNP molecules. The unique properties of the α-CNPs make this class of compounds, including G-α-CNP, direct acting inhibitors of multiple viral DNA polymerases.
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      PubDate: 2017-05-26T06:30:35Z
      DOI: 10.1016/j.bcp.2017.04.001
      Issue No: Vol. 136 (2017)
  • Real-time analysis of the binding of fluorescent VEGF165a to VEGFR2 in
           living cells: Effect of receptor tyrosine kinase inhibitors and fate of
           internalized agonist-receptor complexes
    • Authors: Laura E. Kilpatrick; Rachel Friedman-Ohana; Diana C. Alcobia; Kristin Riching; Chloe J. Peach; Amanda J. Wheal; Stephen J. Briddon; Matthew B. Robers; Kris Zimmerman; Thomas Machleidt; Keith V. Wood; Jeanette Woolard; Stephen J. Hill
      Pages: 62 - 75
      Abstract: Publication date: 15 July 2017
      Source:Biochemical Pharmacology, Volume 136
      Author(s): Laura E. Kilpatrick, Rachel Friedman-Ohana, Diana C. Alcobia, Kristin Riching, Chloe J. Peach, Amanda J. Wheal, Stephen J. Briddon, Matthew B. Robers, Kris Zimmerman, Thomas Machleidt, Keith V. Wood, Jeanette Woolard, Stephen J. Hill
      Vascular endothelial growth factor (VEGF) is an important mediator of angiogenesis. Here we have used a novel stoichiometric protein-labeling method to generate a fluorescent variant of VEGF (VEGF165a-TMR) labeled on a single cysteine within each protomer of the antiparallel VEGF homodimer. VEGF165a-TMR has then been used in conjunction with full length VEGFR2, tagged with the bioluminescent protein NanoLuc, to undertake a real time quantitative evaluation of VEGFR2 binding characteristics in living cells using bioluminescence resonance energy transfer (BRET). This provided quantitative information on VEGF-VEGFR2 interactions. At longer incubation times, VEGFR2 is internalized by VEGF165a-TMR into intracellular endosomes. This internalization can be prevented by the receptor tyrosine kinase inhibitors (RTKIs) cediranib, sorafenib, pazopanib or vandetanib. In the absence of RTKIs, the BRET signal is decreased over time as a consequence of the dissociation of agonist from the receptor in intracellular endosomes and recycling of VEGFR2 back to the plasma membrane.
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      PubDate: 2017-05-26T06:30:35Z
      DOI: 10.1016/j.bcp.2017.04.006
      Issue No: Vol. 136 (2017)
  • Treatment with salvianolic acid B restores endothelial function in
           angiotensin II-induced hypertensive mice
    • Authors: Wei Chih Ling; Jian Liu; Chi Wai Lau; Dharmani Devi Murugan; Mohd Rais Mustafa; Yu Huang
      Pages: 76 - 85
      Abstract: Publication date: 15 July 2017
      Source:Biochemical Pharmacology, Volume 136
      Author(s): Wei Chih Ling, Jian Liu, Chi Wai Lau, Dharmani Devi Murugan, Mohd Rais Mustafa, Yu Huang
      Salvianolic acid B (Sal B) is one of the most abundant phenolic acids derived from the root of Danshen with potent anti-oxidative properties. The present study examined the vasoprotective effect of Sal B in hypertensive mice induced by angiotensin II (Ang II). Sal B (25mg/kg/day) was administered via oral gavage for 11days to Ang II (1.2mg/kg/day)-infused C57BL/6J mice (8–10weeks old). The vascular reactivity (both endothelium-dependent relaxations and contractions) in mouse arteries was examined by wire myography. The production of reactive oxygen species (ROS), protein level and localization of angiotensin AT1 receptors and the proteins involved in ROS formation were evaluated using dihydroethidium (DHE) fluorescence, lucigenin-enhanced chemiluminescence, immunohistochemistry and Western blotting, respectively. The changes of ROS generating proteins were also assessed in vitro in human umbilical vein endothelial cells (HUVECs) exposed to Ang II with and without co-treatment with Sal B (0.1–10nM). Oral administration of Sal B reversed the Ang II-induced elevation of arterial systolic blood pressure in mice, augmented the impaired endothelium-dependent relaxations and attenuated the exaggerated endothelium-dependent contractions in both aortas and renal arteries of Ang II-infused mice. In addition, Sal B treatment normalized the elevated levels of AT1 receptors, NADPH oxidase subunits (NOx-2 and NOx-4) and nitrotyrosine in arteries of Ang II-infused mice or in Ang II-treated HUVECs. In summary, the present study provided additional evidence demonstrating that Sal B treatment for 11days reverses the impaired endothelial function and with a marked inhibition of AT1 receptor-dependent vascular oxidative stress. This vasoprotective and anti-oxidative action of Sal B most likely contributes to the anti-hypertensive action of the plant-derived compound.
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      PubDate: 2017-05-26T06:30:35Z
      DOI: 10.1016/j.bcp.2017.04.007
      Issue No: Vol. 136 (2017)
  • H2S-induced S-sulfhydration of lactate dehydrogenase a (LDHA) stimulates
           cellular bioenergetics in HCT116 colon cancer cells
    • Authors: Ashley A. Untereiner; Gabor Oláh; Katalin Módis; Mark R. Hellmich; Csaba Szabo
      Pages: 86 - 98
      Abstract: Publication date: 15 July 2017
      Source:Biochemical Pharmacology, Volume 136
      Author(s): Ashley A. Untereiner, Gabor Oláh, Katalin Módis, Mark R. Hellmich, Csaba Szabo
      Cystathionine-β-synthase (CBS) is upregulated and hydrogen sulfide (H2S) production is increased in colon cancer cells. The functional consequence of this response is stimulation of cellular bioenergetics and tumor growth and proliferation. Lactate dehydrogenase A (LDHA) is also upregulated in various colon cancer cells and has been previously implicated in tumor cell bioenergetics and proliferation. In the present study, we sought to determine the potential interaction between the H2S pathway and LDH activity in the control of bioenergetics and proliferation of colon cancer, using the colon cancer line HCT116. Low concentrations of GYY4137 (a slow-releasing H2S donor) enhanced mitochondrial function (oxygen consumption, ATP production, and spare respiratory capacity) and glycolysis in HCT116 cells. SiRNA-mediated transient silencing of LDHA attenuated the GYY4137-induced stimulation of mitochondrial respiration, but not of glycolysis. H2S induced the S-sulfhydration of Cys163 in recombinant LDHA, and stimulated LDHA activity. The H2S-induced stimulation of LDHA activity was absent in C163A LDHA. As shown in HCT116 cell whole extracts, in addition to LDHA activation, GYY4137 also stimulated LDHB activity, although to a smaller extent. Total cellular lactate and pyruvate measurements showed that in HCT116 cells LDHA catalyzes the conversion of pyruvate to lactate. Total cellular lactate levels were increased by GYY4137 in wild-type cells (but not in cells with LDHA silencing). LDHA silencing sensitized HCT116 cells to glucose oxidase (GOx)-induced oxidative stress; this was further exacerbated with GYY4137 treatment. Treatment with low concentrations of GYY4137 (0.3mM) or GOx (0.01U/ml) significantly increased the proliferation rate of HCT116 cells; the effect of GOx, but not the effect of GYY4137 was attenuated by LDHA silencing. The current report points to the involvement of LDHA in the stimulatory effect of H2S on mitochondrial respiration in colon cancer cells and characterizes some of the functional interactions between LDHA and H2S-stimulated bioenergetics under resting conditions, as well as during oxidative stress.
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      PubDate: 2017-05-26T06:30:35Z
      DOI: 10.1016/j.bcp.2017.03.025
      Issue No: Vol. 136 (2017)
  • Characterization of signal bias at the GLP-1 receptor induced by backbone
           modification of GLP-1
    • Authors: Marlies V. Hager; Lachlan Clydesdale; Samuel H. Gellman; Patrick M. Sexton; Denise Wootten
      Pages: 99 - 108
      Abstract: Publication date: 15 July 2017
      Source:Biochemical Pharmacology, Volume 136
      Author(s): Marlies V. Hager, Lachlan Clydesdale, Samuel H. Gellman, Patrick M. Sexton, Denise Wootten
      The glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor that is a major therapeutic target for the treatment of type 2 diabetes. Activation of this receptor promotes insulin secretion and blood glucose regulation. The GLP-1R can initiate signaling through several intracellular pathways upon activation by GLP-1. GLP-1R ligands that preferentially stimulate subsets among the natural signaling pathways (“biased agonists”) could be useful as tools for elucidating the consequences of specific pathways and might engender therapeutic agents with tailored effects. Using HEK-293 cells recombinantly expressing human GLP-1R, we have previously reported that backbone modification of GLP-1, via replacement of selected α-amino acid residues with β-amino acid residues, generates GLP-1 analogues with distinctive preferences for promoting G protein activation versus β-arrestin recruitment. Here, we have explored the influence of cell background across these two parameters and expanded our analysis to include affinity and other key signaling pathways (intracellular calcium mobilization and ERK phosphorylation) using recombinant human GLP-1R expressed in a CHO cell background, which has been used extensively to demonstrate biased agonism of GLP-1R ligands. The new data indicate that α/β-peptide analogues of GLP-1 exhibit a range of distinct bias profiles relative to GLP-1 and that broad assessment of signaling endpoints is required to reveal the spectrum of behavior of modified peptides. These results support the view that backbone modification via α→β amino acid replacement can enable rapid discovery of peptide hormone analogues that display substantial signal bias at a cognate GPCR.
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      PubDate: 2017-05-26T06:30:35Z
      DOI: 10.1016/j.bcp.2017.03.018
      Issue No: Vol. 136 (2017)
  • Icariin protects against glucocorticoid induced osteoporosis, increases
           the expression of the bone enhancer DEC1 and modulates the
           PI3K/Akt/GSK3β/β-catenin integrated signaling pathway
    • Authors: Jinhua Hu; Zhao Mao; Shuangcheng He; Yuanran Zhan; Rui Ning; Wei Liu; Bingfang Yan; Jian Yang
      Pages: 109 - 121
      Abstract: Publication date: 15 July 2017
      Source:Biochemical Pharmacology, Volume 136
      Author(s): Jinhua Hu, Zhao Mao, Shuangcheng He, Yuanran Zhan, Rui Ning, Wei Liu, Bingfang Yan, Jian Yang
      Osteoporosis is a serious public health concern worldwide. Herba epimedii has been used for centuries and even thousands of years to treat osteoporotic conditions. Icariin, a flavonol glycoside, is one of the major active ingredients. In this study, we have shown that icariin protected against glucocorticoid-induced osteoporotic changes in SaoS-2 cells and mice. We have also shown that dexamethasone (a glucocorticoid) suppressed and icariin induced DEC1, a structurally distinct helix-loop-helix protein. DEC1 overexpression promoted whereas DEC1 knockdown decreased osteogenic activity. Likewise, DEC1 overexpression and knockdown inversely regulated the expression of β-catenin and PIK3CA, an essential player in the Wnt/β-catenin and PI3K/Akt signaling pathways, respectively. Interestingly, DKK1, an inhibitor of Wnt/β-catenin signaling inhibitor, and LY294002, an inhibitor of PI3K/Akt signaling, abolished the induction of DEC1 by icariin. It is established that these two pathways are interconnected by the phosphorylation status of GSK3β. Dexamethasone decreased but icariin increased GSK3β phosphorylation. Finally, DEC1 deficient mice developed osteoporotic phenotypes. Taken together, it is concluded that DEC1 likely supports the action of icariin against glucocorticoid induced osteoporosis with an involvement of the PI3K/Akt/GSK3β/β-catenin integrated signaling pathway.
      Graphical abstract image

      PubDate: 2017-05-26T06:30:35Z
      DOI: 10.1016/j.bcp.2017.04.010
      Issue No: Vol. 136 (2017)
  • Ligand-dependent and -independent regulation of human hepatic
           sphingomyelin phosphodiesterase acid-like 3A expression by pregnane X
           receptor and crosstalk with liver X receptor
    • Authors: Judith Jeske; Andreas Bitter; Wolfgang E. Thasler; Thomas S. Weiss; Matthias Schwab; Oliver Burk
      Pages: 122 - 135
      Abstract: Publication date: 15 July 2017
      Source:Biochemical Pharmacology, Volume 136
      Author(s): Judith Jeske, Andreas Bitter, Wolfgang E. Thasler, Thomas S. Weiss, Matthias Schwab, Oliver Burk
      Pregnane X receptor (PXR) mainly regulates xenobiotic metabolism and detoxification. Additionally, it exerts pleiotropic effects on liver physiology, which in large parts depend on transrepression of other liver-enriched transcription factors. Based on the hypothesis that lower expression levels of PXR may reduce the extent of this inhibition, an exploratory genome-wide transcriptomic profiling was performed using HepG2 cell clones with different expression levels of PXR. This screen and confirmatory real-time RT-PCR identified sphingomyelin phosphodiesterase acid-like (SMPDL) 3A, a novel nucleotide phosphodiesterase and phosphoramidase, as being up-regulated by PXR-deficiency. Transient siRNA-mediated knock-down of PXR in HepG2 cells and primary human hepatocytes similarly induced mRNA up-regulation, which translated into increased intracellular and secreted extracellular protein levels. Interestingly, ligand-dependent PXR activation also induced SMPDL3A in HepG2 cells and primary human hepatocytes. Electrophoretic mobility shift assays and chromatin immunoprecipitation demonstrated binding of PXR to the previously identified liver X receptor (LXR)-binding DR4 motif as well as to an adjacent ER8 motif in intron 1 of SMPDL3A. Constitutive binding of the unliganded receptor to the intron 1 chromatin indicated ligand-independent repression of SMPDL3A by PXR. Transient transfection and reporter gene analysis confirmed the specific role of these motifs in PXR- and LXR-dependent activation of the SMPDL3A intronic enhancer. PXR inhibited LXR mainly by competition for binding sites. In conclusion, this study describes that a decrease in PXR expression levels and ligand-dependent activation of PXR and LXR increase hepatic SMPDL3A levels, which possibly connects these receptors to hepatic purinergic signaling and phospholipid metabolism and may result in drug-drug interactions with phosphoramidate pro-drugs.
      Graphical abstract image

      PubDate: 2017-05-26T06:30:35Z
      DOI: 10.1016/j.bcp.2017.04.013
      Issue No: Vol. 136 (2017)
  • Apigenin, a modulator of PPARγ, attenuates HFD-induced NAFLD by
           regulating hepatocyte lipid metabolism and oxidative stress via Nrf2
    • Authors: Xiujing Feng; Wen Yu; Xinda Li; Feifei Zhou; Wenlong Zhang; Qi Shen; Jianxin Li; Can Zhang; Pingping Shen
      Pages: 136 - 149
      Abstract: Publication date: 15 July 2017
      Source:Biochemical Pharmacology, Volume 136
      Author(s): Xiujing Feng, Wen Yu, Xinda Li, Feifei Zhou, Wenlong Zhang, Qi Shen, Jianxin Li, Can Zhang, Pingping Shen
      Lipid metabolic disorders and oxidative stress in the liver are key steps in the progression of nonalcoholic fatty liver disease (NAFLD), which is a major risk factor for the development of metabolic syndrome. To date, no pharmacological treatment for this condition has been approved. Our previous study has found that the food-derived compound apigenin (Api) significantly attenuates obesity-induced metabolic syndrome by acting as a peroxisome proliferator-activated receptor gamma modulator (PPARM). Herein, a high fat diet (HFD) induced NAFLD model was used to dig out whether Api had the effect on NAFLD. The results showed that Api had obvious effect in restraining NAFLD progression, including attenuating HFD induced lipid accumulation and oxidative stress in vivo. As a PPARM, although Api did significantly inhibit the expression of PPARγ target genes encoding the protein associated with lipid metabolism, it had no obvious activating effect on PPARγ. Interestingly, we found that Api promoted Nrf2 into the nucleus, thereby markedly activating Nrf2 to inhibit the lipid metabolism related genes and increase the oxidative stress related genes. Further Nrf2 knockdown/knockout and overexpression experiments showed that Api regulating PPARγ target genes was dependent on Nrf2 activation and the activation of Nrf2 counteracted the activation effect of PPARγ by Api. Importantly, we also found that Api might bind with Nrf2 via auto dock and ITC assay. Therefore, our results indicate that Api ameliorates NAFLD by a novel regulating mode of Nrf2 and PPARγ in inhibiting lipid metabolism and oxidative stress abnormity.
      Graphical abstract image

      PubDate: 2017-05-26T06:30:35Z
      DOI: 10.1016/j.bcp.2017.04.014
      Issue No: Vol. 136 (2017)
  • Cytochrome P450 3A selectively affects the pharmacokinetic interaction
           between erlotinib and docetaxel in rats
    • Authors: Xuan Qin; Jian Lu; Peili Wang; Peipei Xu; Mingyao Liu; Xin Wang
      Abstract: Publication date: Available online 15 July 2017
      Source:Biochemical Pharmacology
      Author(s): Xuan Qin, Jian Lu, Peili Wang, Peipei Xu, Mingyao Liu, Xin Wang
      Erlotinib as a first-line drug is used in non-small cell lung cancer (NSCLC) patients with sensitive EGFR mutations, while resistance to this drug will occur after several years of treatment. Therefore, the microtubule disturber docetaxel is introduced as combined regimen in clinical trials. This report investigated the potentials and mechanisms of drug-drug interaction (DDI) between erlotinib and docetaxel using wild type (WT) and Cyp3a1/2 knockout (KO) rats. The erlotinib O-demethylation and docetaxel hydroxylation reactions in the absence or the presence of another drug were analyzed in vitro via the assay of rat liver microsomes. In whole animal studies, erlotinib and docetaxel were given to WT and KO rats individually or jointly, and the pharmacokinetic profiles of these two drugs were analyzed and compared among different groups. The results showed that docetaxel not only inhibited the CYP3A-mediated biotransformation of erlotinib in vitro, but also significantly increased the maximum concentration and systemic exposure of erlotinib in vivo in WT rats. In contrast, the DDI was significantly attenuated in KO rats. On the other hand, erlotinib did not influence docetaxel either in vitro biotransformation or in vivo pharmacokinetic behaviors. These results exhibited the potentials of erlotinib-docetaxel interaction and indicated that the CYP3A played the perpetrating role of docetaxel on erlotinib in rats. A better understanding of this DDI with CYP3A may help the regulation of the use of these two drugs, avoid potential problems, and adjust dose carefully and early in clinic.
      Graphical abstract image

      PubDate: 2017-07-16T17:30:26Z
      DOI: 10.1016/j.bcp.2017.07.013
  • Study of new interactions of glitazone's stereoisomers and the endogenous
           ligand 15d-PGJ2 on six different PPAR gamma proteins
    • Authors: Samuel Álvarez-Almazán; Martiniano Bello; Feliciano Tamay-Cach; Marlet Martínez-Archundia; Diana Alemán-González-Duhart; José Correa-Basurto; Jessica Elena Mendieta-Wejebe
      Abstract: Publication date: Available online 15 July 2017
      Source:Biochemical Pharmacology
      Author(s): Samuel Álvarez-Almazán, Martiniano Bello, Feliciano Tamay-Cach, Marlet Martínez-Archundia, Diana Alemán-González-Duhart, José Correa-Basurto, Jessica Elena Mendieta-Wejebe
      Diabetes mellitus is a chronic disease characterized by hyperglycemia, insulin resistance and hyperlipidemia. Glitazones or thiazolidinediones (TZD) are drugs that act as insulin-sensitizing agents whose molecular target is the peroxisome proliferator-activated receptor gamma (PPARγ). The euglycemic action of TZD has been linked with the induction of type 4 glucose transporter. However, it has been shown that the effect of TZD depends on the specific stereoisomer that interacts with PPARγ. Therefore, this work is focused on exploring the interactions and geometry adopted by glitazone's stereoisomers and one endogenous ligand on different conformations of the six crystals of the PPARγ protein using molecular docking and molecular dynamics (MD) simulations accompanied by the MMGBSA approach. Specifically, the 2,4-thiazolidinedione ring, pioglitazone (PIO), rosiglitazone (ROSI) and troglitazone (TRO) stereoisomers (exogenous ligands), as well as the endogenous ligand 15d-PGJ2, were evaluated. The six crystallographic structures of PPARγ are available at Protein Data Bank as the PDB entries 2PRG, 4PRG, 3T03, 1I7I, 1FM6, and 4EMA. According to the results, a boomerang shape and a particular location of ligands were found with low variations according to the protein conformations. The 15d-PGJ2, TZD, PIO, ROSI and (S,S)-TRO enantiomers were mostly stabilized by twenty hydrophobic residues: Phe226, Pro227, Leu228, Ile281, Phe282, Cys285, Ala292, Ile296, Ile326, Tyr327, Met329, Leu330, Leu333, Met334, Val339, Ile341, Met348, Leu353, Phe363 and Met364. Most hydrogen bond interactions were found between the polar groups of ligands with Arg288, Ser289, Lys367, Gln286, His323, Glu343 and His449 residues. An energetic analysis revealed binding free energy trends that supported known experimental findings of other authors describing better binding properties for PIO, ROSI and (S,S)-TRO than for 15d-PGJ2 and the TZD ring.
      Graphical abstract image

      PubDate: 2017-07-16T17:30:26Z
      DOI: 10.1016/j.bcp.2017.07.012
  • Pyrrolidine dithiocarbamate (PDTC) inhibits inflammatory signaling via
           expression of regulator of calcineurin activity 1 (RCAN1)
    • Authors: Eun Hye Lee; Seon Sook Kim; Su Ryeon Seo
      Abstract: Publication date: Available online 14 July 2017
      Source:Biochemical Pharmacology
      Author(s): Eun Hye Lee, Seon Sook Kim, Su Ryeon Seo
      Pyrrolidine dithiocarbamate (PDTC) is a thiol compound that elicits anti-inflammatory effects by inhibiting NF-κB signaling. In this study, we report that regulator of calcineurin activity 1 (RCAN1) expression is induced by PDTC treatment and that increased RCAN1 expression is dependent on the generation of reactive oxygen species (ROS) and activation of p38 MAPK and JNK signaling. We also report that the ability of PDTC to induce RCAN1 is mediated by activator protein-1 (AP-1)-dependent gene transcription, and identified a functional AP-1 binding site in the RCAN1 promoter by producing mutations and conducting chromatin immunoprecipitation (ChIP) analyses. Moreover, we show that the PDTC-mediated inhibitory effect on NF-κB signaling is significantly perturbed by knocking out RCAN1. Our data provide the first evidence that PDTC prevents in vivo expression of pro-inflammatory cytokines by inducing RCAN1 expression.
      Graphical abstract image

      PubDate: 2017-07-16T17:30:26Z
      DOI: 10.1016/j.bcp.2017.07.011
  • Suppressing mPGES-1 expression by sinomenine ameliorates inflammation and
    • Authors: Hua Zhou; Jian-Xin Liu; Jin-Fang Luo; Chun-Song Cheng; Elaine Lai-Han Leung; Ying Li; Xiao-Hui Su; Zhong-Qiu Liu; Ting-Bo Chen; Fu-Gang Duan; Yan Dong; Yi-Han Zuo; Chong Li; Chon Kit Lio; Ting Li; Pei Luo; Ying Xie; Xiao-Jun Yao; Pei-Xun Wang; Liang Liu
      Abstract: Publication date: Available online 13 July 2017
      Source:Biochemical Pharmacology
      Author(s): Hua Zhou, Jian-Xin Liu, Jin-Fang Luo, Chun-Song Cheng, Elaine Lai-Han Leung, Ying Li, Xiao-Hui Su, Zhong-Qiu Liu, Ting-Bo Chen, Fu-Gang Duan, Yan Dong, Yi-Han Zuo, Chong Li, Chon Kit Lio, Ting Li, Pei Luo, Ying Xie, Xiao-Jun Yao, Pei-Xun Wang, Liang Liu
      Recently, microsomal prostaglandin E synthase 1 (mPGES-1) has attracted much attention from pharmacologists as a promising strategy and an attractive target for treating various types of diseases including rheumatoid arthritis (RA), which could preserve the anti-inflammatory effect while reducing the adverse effects often occur during administration of Non-steroidal anti-inflammatory drugs (NSAIDs). Here, we report that Sinomenine (SIN) decreased prostaglandin (PG)E2 levels without affecting prostacyclin (PG)I2 and thromboxane (TX)A2 synthesis via selective inhibiting mPGES-1 expression, a possible reason of low risk of cardiovascular event compared with NSAIDs. In addition, mPGES-1 protein expression was down-regulated by SIN treatment in the inflamed paw tissues both in carrageenan-induced edema model in rats and the collagen-II induced arthritis (CIA) model in DBA mice. More interestingly, SIN suppressed the last step of mPGES-1 gene expression by decreasing the DNA binding ability of NF-κB, paving a new way for drug discovery.
      Graphical abstract image

      PubDate: 2017-07-16T17:30:26Z
      DOI: 10.1016/j.bcp.2017.07.010
  • Curcumin attenuates oxidative stress induced NFκB mediated inflammation
           and Endoplasmic reticulum dependent apoptosis of splenocytes in diabetes
    • Authors: Kahkashan Rashid; Sayantani Chowdhury; Sumit Ghosh; Parames C. Sil
      Abstract: Publication date: Available online 13 July 2017
      Source:Biochemical Pharmacology
      Author(s): Kahkashan Rashid, Sayantani Chowdhury, Sumit Ghosh, Parames C. Sil
      The present study was aimed to determine the curative role of curcumin against diabetes induced oxidative stress and its associated splenic complications. Diabetes was induced in the experimental rats via the intraperitoneal administration of a single dose of STZ (65 mg kg-1 body weight). Increased blood glucose and intracellular ROS levels along with decreased body weight, the activity of cellular antioxidant enzymes and GSH/GSSG ratio were observed in the diabetic animals. Histological assessment showed white pulp depletion and damaged spleen anatomy in these animals. Oral administration of curcumin at a dose of 100 mg kg-1 body weight daily for 8 weeks, however, restored these alterations. Investigation on the mechanism of hyperglycemia induced oxidative stress mediated inflammation showed upregulation of inflammatory cytokines, chemokines, adhesion molecules and increased translocation of NFκB into the nucleus. Moreover, ER stress dependent cell death showed induction of eIF2α and CHOP mediated signalling pathways as well as increment in the expression of GRP78, Caspase-12, Calpain-1, phospho JNK, phospho p38 and p53 in the diabetic group. Alteration of Bax/Bcl-2 ratio; disruption of mitochondrial membrane potential, release of cytochrome-C from mitochondria and upregulation of caspase 3 along with the formation of characteristic DNA ladder in the diabetic animals suggest the involvement of mitochondria dependent apoptotic pathway in the splenic cells. Treatment with curcumin could, however, protect cells from inflammatory damage and ER as well as mitochondrial apoptotic death by restoring the alterations of these parameters. Our results suggest that curcumin has the potential to act as an anti-diabetic, anti-oxidant, anti-inflammatory and anti-apoptotic therapeutic against diabetic pathophysiology induced splenic damage.
      Graphical abstract image

      PubDate: 2017-07-16T17:30:26Z
      DOI: 10.1016/j.bcp.2017.07.009
  • Potent inhibitors of human LAT1 (SLC7A5) transporter based on dithiazole
           and dithiazine compounds for development of anticancer drugs
    • Authors: Lara Napolitano; Mariafrancesca Scalise; Maria Koyioni; Panayotis Koutentis; Marco Catto; Ivano Eberini; Chiara Parravicini; Luca Palazzolo; Leonardo Pisani; Michele Galluccio; Lara Console; Angelo Carotti; Cesare Indiveri
      Abstract: Publication date: Available online 12 July 2017
      Source:Biochemical Pharmacology
      Author(s): Lara Napolitano, Mariafrancesca Scalise, Maria Koyioni, Panayotis Koutentis, Marco Catto, Ivano Eberini, Chiara Parravicini, Luca Palazzolo, Leonardo Pisani, Michele Galluccio, Lara Console, Angelo Carotti, Cesare Indiveri
      The LAT1 transporter is acknowledged as a pharmacological target of tumours since it is strongly overexpressed in many human cancers. The purpose of this work was to find novel compounds exhibiting potent and prolonged inhibition of the transporter. To this aim, compounds based on dithiazole and dithiazine scaffold have been screened in the proteoliposome experimental model. Inhibition was tested on the antiport catalysed by hLAT1 as transport of extraliposomal [3H]histidine in exchange with intraliposomal histidine. Out of 59 compounds tested, 8 compounds, showing an inhibition higher than 90% at 100 µM concentration, were subjected to dose-response analysis. Two of them exhibited IC50 lower than 1 µM. Inhibition kinetics, performed on the two best inhibitors, indicated a mixed type of inhibition with respect to the substrate. Furthermore, inhibition of the transporter was still present after removal of the compounds from the reaction mixture, but was reversed on addition of dithioerythritol, a S-S reducing agent, indicating the formation of disulfide(s) between the compounds and the protein. Molecular docking of the two best inhibitors on the hLAT1 homology structural model, highlighted interaction with the substrate binding site and formation of a covalent bond with the residue C407. Indeed, the inhibition was impaired in the hLAT1 mutant C407A confirming the involvement of that Cys residue. Treatment of SiHa cells expressing hLAT1 at relatively high level, with the two most potent inhibitors led to cell death which was not observed after treatment with a compound exhibiting very poor inhibitory effect.
      Graphical abstract image

      PubDate: 2017-07-16T17:30:26Z
      DOI: 10.1016/j.bcp.2017.07.006
  • Editorial Advisory Board
    • Abstract: Publication date: 15 August 2017
      Source:Biochemical Pharmacology, Volume 138

      PubDate: 2017-07-07T02:46:43Z
  • Cyclooxygenase-2 promotes pulmonary intravascular macrophage accumulation
           by exacerbating BMP signaling in rat experimental hepatopulmonary syndrome
    • Authors: Chang Liu; Jing Gao; Bing Chen; Lin Chen; Karine Belguise; Weifeng Yu; Kaizhi Lu; Xiaobo Wang; Bin Yi
      Abstract: Publication date: Available online 19 June 2017
      Source:Biochemical Pharmacology
      Author(s): Chang Liu, Jing Gao, Bing Chen, Lin Chen, Karine Belguise, Weifeng Yu, Kaizhi Lu, Xiaobo Wang, Bin Yi
      Background and aims One central factor in hepatopulmonary syndrome (HPS) pathogenesis is intravascular accumulation of activated macrophages in small pulmonary arteries. However, molecular mechanism underlyingthe macrophage accumulation in HPS is unknown. In this study, we aimed to explore whether elevated COX-2 induces the Bone morphogenicprotein-2 (BMP-2)/Crossveinless-2(CV-2) imbalance and then activation of BMP signaling pathway promotes the macrophage accumulation in Common Bile Duct Ligation (CBDL) rat lung. Methods The COX-2/PGE2 signaling activation, the BMP-2/CV-2 imbalance and the activation of Smad1 were evaluated in CBDL rat lung and in cultured pulmonary microvascular endothelial cells (PMVECs) under the HPS serum stimulation. The effects of Parecoxib (COX-2 inhibitor), BMP-2 and CV-2 recombinant proteins on 4-week CBDL rat lung were determined, respectively. Results The COX-2/PGE2 signaling pathway was activated in CBDL rat lung in vivo and PMVECs in vitro, which was due to the activation of NF-κB P65. The inhibition of COX-2 by Parecoxib reduced macrophage accumulation, decreased lung angiogenesis and improved HPS. Meanwhile, the CBDL rat lung secreted more BMP-2 but less CV-2, and the imbalance between BMP-2 and CV-2 exacerbated the BMP signaling activation thus promoting the macrophage accumulation and lung angiogenesis. The BMP-2/CV-2 imbalance is dependent on the COX-2/PGE2 signaling pathway, and thus the effects of this imbalance can be reversed by adminstration of Parecoxib. Conclusion Our findings indicate that inhibition of COX-2 by parecoxib can improve the HPS through the repression of BMP signaling and macrophage accumulation.
      Graphical abstract image

      PubDate: 2017-06-27T02:32:27Z
      DOI: 10.1016/j.bcp.2017.06.117
  • ATG4B inhibitors with a benzotropolone core structure block autophagy and
           augment efficiency of chemotherapy in mice
    • Authors: Ammar Kurdi; Matthias Cleenewerck; Christel Vangestel; Sophie Lyssens; Wim Declercq; Jean-Pierre Timmermans; Sigrid Stroobants; Koen Augustyns; Guido R.Y. De Meyer; Pieter Van Der Veken; Wim Martinet
      Abstract: Publication date: Available online 19 June 2017
      Source:Biochemical Pharmacology
      Author(s): Ammar Kurdi, Matthias Cleenewerck, Christel Vangestel, Sophie Lyssens, Wim Declercq, Jean-Pierre Timmermans, Sigrid Stroobants, Koen Augustyns, Guido R.Y. De Meyer, Pieter Van Der Veken, Wim Martinet
      Autophagy is a cell survival mechanism hijacked by advanced tumors to endure a rough microenvironment. Late autophagy inhibitors such as (hydroxy)chloroquine have been used clinically to halt tumor progression with modest success. However, given the toxic nature of these compounds and their lack of specificity, novel targets should be considered. We recently identified a benzotropolone derivative that significantly inhibited the essential autophagy protein ATG4B. Therefore, we synthesized and tested additional benzotropolone compounds to identify a promising ATG4B inhibitor that impairs autophagy both in vitro and in vivo. A compound library containing 27 molecules with a benzotropolone backbone was synthesized and screened for inhibition of recombinant ATG4B. Depending on the benzotropolone compound, inhibition of recombinant ATG4B ranged from 3 to 82%. Active compounds were evaluated in cellular assays to confirm inhibition of ATG4B and suppression of autophagy. Seven compounds inhibited processing of the autophagy protein LC3 and autophagosome formation. Compound UAMC-2526 was selected for further in vivo use because of its fair plasma stability. This compound abolished autophagy both in nutrient-deprived GFP-LC3 mice and in CD1−/− Foxn1nu mice bearing HT29 colorectal tumor xenografts. Moreover, addition of UAMC-2526 to the chemotherapy drug oxaliplatin significantly improved inhibition of tumor growth. Our data indicate that suppression of autophagy via ATG4B inhibition is a feasible strategy to augment existing chemotherapy efficacy and to halt tumor progression.
      Graphical abstract image

      PubDate: 2017-06-27T02:32:27Z
      DOI: 10.1016/j.bcp.2017.06.119
  • Editorial Advisory Board
    • Abstract: Publication date: 1 August 2017
      Source:Biochemical Pharmacology, Volume 137

      PubDate: 2017-06-05T15:36:29Z
  • Editorial Advisory Board
    • Abstract: Publication date: 15 July 2017
      Source:Biochemical Pharmacology, Volume 136

      PubDate: 2017-05-26T06:30:35Z
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