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  Subjects -> CHEMISTRY (Total: 846 journals)
    - ANALYTICAL CHEMISTRY (50 journals)
    - CHEMISTRY (597 journals)
    - CRYSTALLOGRAPHY (22 journals)
    - ELECTROCHEMISTRY (25 journals)
    - INORGANIC CHEMISTRY (41 journals)
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    - PHYSICAL CHEMISTRY (66 journals)

CHEMISTRY (597 journals)                  1 2 3 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 7)
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: 31)
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: 22)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 39)
ACS Nano     Full-text available via subscription   (Followers: 217)
ACS Photonics     Full-text available via subscription   (Followers: 10)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 20)
Acta Chemica Iasi     Open Access   (Followers: 2)
Acta Chimica Sinica     Full-text available via subscription  
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: 48)
Advanced Science Focus     Free   (Followers: 3)
Advances in Chemical Engineering and Science     Open Access   (Followers: 53)
Advances in Chemical Science     Open Access   (Followers: 12)
Advances in Chemistry     Open Access   (Followers: 12)
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: 10)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 14)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 18)
Advances in Nanoparticles     Open Access   (Followers: 12)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15)
Advances in Polymer Science     Hybrid Journal   (Followers: 40)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 18)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Science and Technology     Full-text available via subscription   (Followers: 10)
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: 65)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 14)
American Journal of Chemistry     Open Access   (Followers: 25)
American Journal of Plant Physiology     Open Access   (Followers: 13)
American Mineralogist     Full-text available via subscription   (Followers: 12)
Analyst     Full-text available via subscription   (Followers: 38)
Angewandte Chemie     Hybrid Journal   (Followers: 153)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 203)
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: 7)
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: 6)
Applied Spectroscopy     Full-text available via subscription   (Followers: 22)
Applied Surface Science     Hybrid Journal   (Followers: 26)
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: 9)
Biochemistry     Full-text available via subscription   (Followers: 277)
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: 3)
Biointerface Research in Applied Chemistry     Open Access   (Followers: 2)
Biointerphases     Open Access   (Followers: 1)
Biology, Medicine, & Natural Product Chemistry     Open Access  
Biomacromolecules     Full-text available via subscription   (Followers: 18)
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: 107)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 99)
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: 2)
Canadian Association of Radiologists Journal     Full-text available via subscription   (Followers: 2)
Canadian Journal of Chemistry     Full-text available via subscription   (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: 69)
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: 165)
Chemical Science     Open Access   (Followers: 21)
Chemical Technology     Open Access   (Followers: 15)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 4)
Chemical Week     Full-text available via subscription   (Followers: 7)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 55)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 25)
ChemInform     Hybrid Journal   (Followers: 7)
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: 136)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 15)
Chemistry and Materials Research     Open Access   (Followers: 17)
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: 43)
Chemistry of Materials     Full-text available via subscription   (Followers: 189)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
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: 8)
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: 23)
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: 10)
Current Catalysis     Hybrid Journal   (Followers: 2)
Current Metabolomics     Hybrid Journal   (Followers: 4)
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 9)
Current Research in Chemistry     Open Access   (Followers: 8)
Current Science     Open Access   (Followers: 48)
Dalton Transactions     Full-text available via subscription   (Followers: 18)
Detection     Open Access   (Followers: 2)
Developments in Geochemistry     Full-text available via subscription   (Followers: 2)
Diamond and Related Materials     Hybrid Journal   (Followers: 11)
Dislocations in Solids     Full-text available via subscription  
Doklady Chemistry     Hybrid Journal  
Drying Technology: An International Journal     Hybrid Journal   (Followers: 3)
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: 8)
Environmental Chemistry Letters     Hybrid Journal   (Followers: 4)
Environmental Science & Technology Letters     Full-text available via subscription   (Followers: 5)
Environmental Science : Nano     Partially Free   (Followers: 1)
Environmental Toxicology & Chemistry     Hybrid Journal   (Followers: 19)

        1 2 3 | Last

Journal Cover Biochemical Pharmacology
  [SJR: 2.263]   [H-I: 160]   [9 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0006-2952
   Published by Elsevier Homepage  [3031 journals]
  • Potentiating SLC transporter activity: Emerging drug discovery
           opportunities
    • Authors: Marie-Laure Rives; Jonathan A. Javitch; Alan D. Wickenden
      Pages: 1 - 11
      Abstract: Publication date: 1 July 2017
      Source:Biochemical Pharmacology, Volume 135
      Author(s): Marie-Laure Rives, Jonathan A. Javitch, Alan D. Wickenden
      Maintaining the integrity of cellular membranes is critical to protecting metabolic activities and genetic information from the environment. Regulation of transport across membranes of essential chemicals, including water, nutrients, hormones and many drugs, is therefore key to cellular homeostasis and physiological processes. The two main transporter superfamilies are ATP-binding cassette (ABC) transporters that primarily function as efflux transporters, and the solute carrier (SLC) transporters. SLC transporters encompass 52 gene families with almost 400 different human transporter genes. Although long under-explored, SLC transporters are an emerging drug target class and the molecular target of several approved inhibitor drugs, such as selective serotonin reuptake inhibitors (SSRIs) for depression and sodium/glucose co-transporter (SGLT2) inhibitors for diabetes. Interestingly though, although loss-of-function mutations in numerous human SLC transporters are linked to Mendelian diseases, few reports of SLC transporter activators have appeared, and only inhibitors have been advanced to clinical studies. In this commentary, we discuss several strategies for potentiating SLC transporter function, from direct acting potentiators to modulators of transcription, translation or trafficking. We review the progress made in recent years toward the understanding of the structural and molecular basis of SLC transporter function and the pathways and mechanisms that regulate SLC expression, and describe the opportunities these new insights present for discovery of SLC transporter potentiators. Finally, we highlight the challenges associated with the various approaches and provide some thoughts on future directions that might facilitate the search for SLC potentiators with therapeutic potential.
      Graphical abstract image

      PubDate: 2017-05-21T06:14:26Z
      DOI: 10.1016/j.bcp.2017.02.010
      Issue No: Vol. 135 (2017)
       
  • Inhibition and inactivation of human CYP2J2: Implications in cardiac
           pathophysiology and opportunities in cancer therapy
    • Authors: Aneesh Karkhanis; Yanjun Hong; Eric Chun Yong Chan
      Pages: 12 - 21
      Abstract: Publication date: 1 July 2017
      Source:Biochemical Pharmacology, Volume 135
      Author(s): Aneesh Karkhanis, Yanjun Hong, Eric Chun Yong Chan
      Extrahepatic cytochrome P450 enzymes (CYP450) are pivotal in the metabolism of endogenous substrates and xenobiotics. CYP2J2 is a major cardiac CYP450 and primarily metabolizes polyunsaturated fatty acids such as arachidonic acid to cardioactive epoxyeicosatrienoic acids. Due to its role in endobiotic metabolism, CYP2J2 has been actively studied in recent years with the focus on its biological functions in cardiac pathophysiology. Additionally, CYP2J2 metabolizes a number of xenobiotics such as astemizole and terfenadine and is potently inhibited by danazol and telmisartan. Notably, CYP2J2 is found to be upregulated in multiple cancers. Hence a number of specific CYP2J2 inhibitors have been developed and their efficacy in inhibiting tumor progression has been actively studied. CYP2J2 inhibitor such as C26 (1-[4-(vinyl)phenyl]-4-[4-(diphenyl-hydroxymethyl)-piperidinyl]-butanone hydrochloride) caused marked reduction in tumor proliferation and migration as well as promoted apoptosis in cancer cells. In this review, we discuss the role of CYP2J2 in cardiac pathophysiology and cancer therapeutics. Additionally, we provide an update on the substrates, reversible inhibitors and irreversible inhibitors of CYP2J2. Finally, we discuss the current gaps and future directions in CYP2J2 research.
      Graphical abstract image

      PubDate: 2017-05-21T06:14:26Z
      DOI: 10.1016/j.bcp.2017.02.017
      Issue No: Vol. 135 (2017)
       
  • Mechanisms of colitis-accelerated colon carcinogenesis and its prevention
           with the combination of aspirin and curcumin: Transcriptomic analysis
           using RNA-seq
    • Authors: Yue Guo; Zheng-Yuan Su; Chengyue Zhang; John M. Gaspar; Rui Wang; Ronald P. Hart; Michael P. Verzi; Ah-Ng Tony Kong
      Pages: 22 - 34
      Abstract: Publication date: 1 July 2017
      Source:Biochemical Pharmacology, Volume 135
      Author(s): Yue Guo, Zheng-Yuan Su, Chengyue Zhang, John M. Gaspar, Rui Wang, Ronald P. Hart, Michael P. Verzi, Ah-Ng Tony Kong
      Colorectal cancer (CRC) remains the leading cause of cancer-related death in the world. Aspirin (ASA) and curcumin (CUR) are widely investigated chemopreventive candidates for CRC. However, the precise mechanisms of their action and their combinatorial effects have not been evaluated. The purpose of the present study was to determine the effect of ASA, CUR, and their combination in azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colitis-accelerated colorectal cancer (CAC). We also aimed to characterize the differential gene expression profiles in AOM/DSS-induced tumors as well as in tumors modulated by ASA and CUR using RNA-seq. Diets supplemented with 0.02% ASA, 2% CUR or 0.01% ASA+1% CUR were given to mice from 1week prior to the AOM injection until the experiment was terminated 22weeks after AOM initiation. Our results showed that CUR had a superior inhibitory effect in colon tumorigenesis compared to that of ASA. The combination of ASA and CUR at a lower dose exhibited similar efficacy to that of a higher dose of CUR at 2%. RNA isolated from colonic tissue from the control group and from tumor samples from the experimental groups was subjected to RNA-seq. Transcriptomic analysis suggested that the low-dose combination of ASA and CUR modulated larger gene sets than the single treatment. These differentially expressed genes were situated in several canonical pathways important in the inflammatory network and liver metastasis in CAC. We identified a small subset of genes as potential molecular targets involved in the preventive action of the combination of ASA and CUR. Taken together, the current results provide the first evidence in support of the chemopreventive effect of a low-dose combination of ASA and CUR in CAC. Moreover, the transcriptional profile obtained in our study may provide a framework for identifying the mechanisms underlying the carcinogenesis process from normal colonic tissue to tumor development as well as the cancer inhibitory effects and potential molecular targets of ASA and CUR.
      Graphical abstract image

      PubDate: 2017-05-21T06:14:26Z
      DOI: 10.1016/j.bcp.2017.02.021
      Issue No: Vol. 135 (2017)
       
  • 3-O-(Z)-coumaroyloleanolic acid overcomes Cks1b-induced chemoresistance in
           lung cancer by inhibiting Hsp90 and MEK pathways
    • Authors: He Wang; Mingna Sun; Jiayi Guo; Lei Ma; Hui Jiang; Liang Gu; Huaying Wen; Siyan Liao; Jingqi Chen; Bohang Zeng; Yongmei Li; Yueshan Li; Xiyong Yu; Yinghong Feng; Yi Zhou
      Pages: 35 - 49
      Abstract: Publication date: 1 July 2017
      Source:Biochemical Pharmacology, Volume 135
      Author(s): He Wang, Mingna Sun, Jiayi Guo, Lei Ma, Hui Jiang, Liang Gu, Huaying Wen, Siyan Liao, Jingqi Chen, Bohang Zeng, Yongmei Li, Yueshan Li, Xiyong Yu, Yinghong Feng, Yi Zhou
      Expression of CDC28 protein kinase regulatory subunit 1 (Cks1), an adaptor for cyclin-dependent kinases, is tightly regulated at transcriptional and posttranslational levels. Increased expression of Cks1 has been documented to be attributable to cancer progression, chemoresistance, and chemosensitivity. Here we report that ectopic overexpression of Cks1b in human lung cancer cells (Cks1b-OE) induces chemoresistance of the cells to cisplatin (CDDP) and doxorubicin (DOX) through mechanisms independent of its canonical Skp2-p27 pathway. Further dissection with application of shRNA and selective inhibitors reveals that Hsp90 and MEK1/2 are the critical components of the non-canonical pathways responsible for the Cks1b-induced chemoresistance. Interestingly, inhibition of either Hsp90 or MEK1/2 rendered a similar magnitude of antitumor activity by resensitization of the chemoresistant Cks1b-OE cells to CDDP and DOX, suggesting that both Hsp90 and MEK1/2 are essential to Cks1b for induction of chemoresistance. Moreover, 3-O-(Z)-coumaroyloleanolic acid (3-COA), an active ingredient of oleanolic acid in the leaves of E. oldhamii Maxim, that has been shown to have antitumor activity against A549 lung cancer cells, mimicked PU-H71, a Hsp90-specific inhibitor, in antitumor activity when used alone or in combination with CDDP or DOX in Cks1b-OE cells and recurrent primary human lung cancer cells both in vitro and in vivo, suggesting that 3-COA is a novel Hsp90 inhibitor. Our data report for the first time that Cks1b employs Hsp90 and MEK1/2 pathways in lung cancer cells to develop chemoresistance and identify 3-COA as a potential antitumor drug for clinical treatment of chemoresistant lung cancer.
      Graphical abstract image

      PubDate: 2017-05-21T06:14:26Z
      DOI: 10.1016/j.bcp.2017.03.007
      Issue No: Vol. 135 (2017)
       
  • Reversal of cisplatin resistance in human gastric cancer cells by a
           wogonin-conjugated Pt(IV) prodrug via attenuating Casein Kinase 2-mediated
           Nuclear Factor-κB pathways
    • Authors: Feihong Chen; Xiaodong Qin; Gang Xu; Shaohua Gou; Xiufeng Jin
      Pages: 50 - 68
      Abstract: Publication date: 1 July 2017
      Source:Biochemical Pharmacology, Volume 135
      Author(s): Feihong Chen, Xiaodong Qin, Gang Xu, Shaohua Gou, Xiufeng Jin
      Pt(IV) prodrugs, with two additional coordination sites in contrast to Pt(II) drugs, have been actively studied nowadays, for they can perform well in enhancing the accumulation and retention of the corresponding Pt(II) drugs in cancer cells. Our designed Pt(II) drug, DN604, was recently found to exhibit significant anticancer activity and low toxicity, while, wogonin, a naturally O-methylated flavones, has been widely investigated for its tumor therapeutic potential. Thus, two Pt(IV)-based prodrugs were derived by addition of a wogonin unit to the axial position of DN604 and its analogue DN603 via a linker group. In vitro cytotoxicity assay indicated that the resulting compound 8 not only inherited the genotoxicity of DN604 on gastric cancer cells, but also obtained the COX inhibitory property arising from wogonin. Further studies revealed that compound 8 caused the accumulation of ROS production and decreased the mitochondrial membrane potential (ΔΨm). The CK2α kinase activity assay, ChIP and luciferase assays showed that CK2 plays an important role in the blockade of compound 8 on activated NF-κB survival pathways, which were established for sensitivity of cancer cells to platinum drugs. Similarly in vivo, in nude mice with SGC-7901/cDDP xenografts, compound 8 improved the effectiveness of DN604 via reversing tumor resistance and maintaining low toxicity. Overall, compound 8 is a promising Pt(IV) prodrug, which could be used to promote the anticancer activity of its counterpart Pt(II) species and reverse drug resistance via attenuating CK2-mediated NF-κB pathways during platinum-based chemotherapies.
      Graphical abstract image

      PubDate: 2017-05-21T06:14:26Z
      DOI: 10.1016/j.bcp.2017.03.004
      Issue No: Vol. 135 (2017)
       
  • Discovery of a new Mycobacterium tuberculosis thymidylate synthase X
           inhibitor with a unique inhibition profile
    • Authors: Rania Abu El Asrar; Lia Margamuljana; Hugo Klaassen; Marnik Nijs; Arnaud Marchand; Patrick Chaltin; Hannu Myllykallio; Hubert F. Becker; Steven De Jonghe; Piet Herdewijn; Eveline Lescrinier
      Pages: 69 - 78
      Abstract: Publication date: 1 July 2017
      Source:Biochemical Pharmacology, Volume 135
      Author(s): Rania Abu El Asrar, Lia Margamuljana, Hugo Klaassen, Marnik Nijs, Arnaud Marchand, Patrick Chaltin, Hannu Myllykallio, Hubert F. Becker, Steven De Jonghe, Piet Herdewijn, Eveline Lescrinier
      Tuberculosis (TB), mainly caused by Mycobacterium tuberculosis (Mtb), is an infection that is responsible for roughly 1.5 million deaths per year. The situation is further complicated by the wide-spread resistance to the existing first- and second-line drugs. As a result of this, it is urgent to develop new drugs to combat the resistant bacteria as well as have lower side effects, which can promote adherence to the treatment regimens. Targeting the de novo synthesis of thymidylate (dTMP) is an important pathway to develop drugs for TB. Although Mtb carries genes for two families of thymidylate synthases (TS), ThyA and ThyX, only ThyX is essential for its normal growth. Both enzymes catalyze the conversion of uridylate (dUMP) to dTMP but employ a different catalytic approach and have different structures. Also, ThyA is the only TS found in humans. This is the rationale for identifying selective inhibitors against ThyX. We exploited the NADPH oxidation to NADP+ step, catalyzed by ThyX, to develop a spectrophotometric biochemical assay. Success of the assay was demonstrated by its effectiveness (average Z′=0.77) and identification of selective ThyX inhibitors. The most potent compound is a tight-binding inhibitor with an IC50 of 710nM. Its mechanism of inhibition is analyzed in relation to the latest findings of ThyX mechanism and substrate and cofactor binding order.
      Graphical abstract image

      PubDate: 2017-05-21T06:14:26Z
      DOI: 10.1016/j.bcp.2017.03.017
      Issue No: Vol. 135 (2017)
       
  • Capadenoson, a clinically trialed partial adenosine A1 receptor agonist,
           can stimulate adenosine A2B receptor biased agonism
    • Authors: Jo-Anne Baltos; Elizabeth A. Vecchio; Matthew A. Harris; Cheng Xue Qin; Rebecca H. Ritchie; Arthur Christopoulos; Paul J. White; Lauren T. May
      Pages: 79 - 89
      Abstract: Publication date: 1 July 2017
      Source:Biochemical Pharmacology, Volume 135
      Author(s): Jo-Anne Baltos, Elizabeth A. Vecchio, Matthew A. Harris, Cheng Xue Qin, Rebecca H. Ritchie, Arthur Christopoulos, Paul J. White, Lauren T. May
      The adenosine A2B receptor (A2BAR) has been identified as an important therapeutic target in cardiovascular disease, however in vitro and in vivo targeting has been limited by the paucity of pharmacological tools, particularly potent agonists. Interestingly, 2-((6-amino-3,5-dicyano-4-(4-(cyclopropylmethoxy)phenyl)-2-pyridinyl)thio)acetamide (BAY60-6583), a potent and subtype-selective A2BAR agonist, has the same core structure as 2-amino-6-[[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methylsulfanyl]-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitril (capadenoson). Capadenoson, currently classified as an adenosine A1 receptor (A1AR) partial agonist, has undergone two Phase IIa clinical trials, initially in patients with atrial fibrillation and subsequently in patients with stable angina. Capadenoson has also been shown to decrease cardiac remodeling in an animal model of advanced heart failure and a capadenoson derivative, neladenoson bialanate, recently entered clinical development for the treatment of chronic heart failure. The therapeutic effects of capadenoson are currently thought to be mediated through the A1AR. However, the ability of capadenoson to stimulate additional adenosine receptor subtypes, in particular the A2BAR, has not been rigorously assessed. In this study, we demonstrate that capadenoson does indeed have significant A2BAR activity in physiologically relevant cells, cardiac fibroblasts and cardiomyocytes, which endogenously express the A2BAR. Relative to the non-selective adenosine receptor agonist NECA, capadenoson was a biased A2BAR agonist with a preference for cAMP signal transduction over other downstream mediators in cells with recombinant and endogenous A2BAR expression. These findings suggest the reclassification of capadenoson as a dual A1AR/A2BAR agonist. Furthermore, a potential A2BAR contribution should be an important consideration for the future clinical development of capadenoson-like therapeutics, as the A2BAR can promote cardioprotection and modulate cardiac fibrosis in heart disease.
      Graphical abstract image

      PubDate: 2017-05-21T06:14:26Z
      DOI: 10.1016/j.bcp.2017.03.014
      Issue No: Vol. 135 (2017)
       
  • Regulation of the nitric oxide oxidase activity of myeloperoxidase by
           pharmacological agents
    • Authors: Sophie L. Maiocchi; Jonathan C. Morris; Martin D. Rees; Shane R. Thomas
      Pages: 90 - 115
      Abstract: Publication date: 1 July 2017
      Source:Biochemical Pharmacology, Volume 135
      Author(s): Sophie L. Maiocchi, Jonathan C. Morris, Martin D. Rees, Shane R. Thomas
      The leukocyte-derived heme enzyme myeloperoxidase (MPO) is released extracellularly during inflammation and impairs nitric oxide (NO) bioavailability by directly oxidizing NO or producing NO-consuming substrate radicals. Here, structurally diverse pharmacological agents with activities as MPO substrates/inhibitors or antioxidants were screened for their effects on MPO NO oxidase activity in human plasma and physiological model systems containing endogenous MPO substrates/antioxidants (tyrosine, urate, ascorbate). Hydrazide-based irreversible/reversible MPO inhibitors (4-ABAH, isoniazid) or the sickle cell anaemia drug, hydroxyurea, all promoted MPO NO oxidase activity. This involved the capacity of NO to antagonize MPO inhibition by hydrazide-derived radicals and/or the ability of drug-derived radicals to stimulate MPO turnover thereby increasing NO consumption by MPO redox intermediates or NO-consuming radicals. In contrast, the mechanism-based irreversible MPO inhibitor 2-thioxanthine, potently inhibited MPO turnover and NO consumption. Although the phenolics acetaminophen and resveratrol initially increased MPO turnover and NO consumption, they limited the overall extent of NO loss by rapidly depleting H2O2 and promoting the formation of ascorbyl radicals, which inefficiently consume NO. The vitamin E analogue trolox inhibited MPO NO oxidase activity in ascorbate-depleted fluids by scavenging NO-consuming tyrosyl and urate radicals. Tempol and related nitroxides decreased NO consumption in ascorbate-replete fluids by scavenging MPO-derived ascorbyl radicals. Indoles or apocynin yielded marginal effects. Kinetic analyses rationalized differences in drug activities and identified criteria for the improved inhibition of MPO NO oxidase activity. This study reveals that widely used agents have important implications for MPO NO oxidase activity under physiological conditions, highlighting new pharmacological strategies for preserving NO bioavailability during inflammation.
      Graphical abstract image

      PubDate: 2017-05-21T06:14:26Z
      DOI: 10.1016/j.bcp.2017.03.016
      Issue No: Vol. 135 (2017)
       
  • Quantitation of the rates of hepatic and intestinal cholesterol synthesis
           in lysosomal acid lipase-deficient mice before and during treatment with
           ezetimibe
    • Authors: Jen-Chieh Chuang; Adam M. Lopez; Stephen D. Turley
      Pages: 116 - 125
      Abstract: Publication date: 1 July 2017
      Source:Biochemical Pharmacology, Volume 135
      Author(s): Jen-Chieh Chuang, Adam M. Lopez, Stephen D. Turley
      Esterified cholesterol (EC) and triglycerides, contained within lipoproteins taken up by cells, are hydrolysed by lysosomal acid lipase (LAL) in the late endosomal/lysosomal (E/L) compartment. The resulting unesterified cholesterol (UC) is transported via Niemann-Pick type C2 and C1 into the cytosolic compartment where it enters a putative pool of metabolically active cholesterol that is utilized in accordance with cellular needs. Loss-of-function mutations in LIPA, the gene encoding LAL, result in dramatic increases in tissue concentrations of EC, a hallmark feature of Wolman disease and cholesteryl ester storage disease (CESD). The lysosomal sequestration of EC causes cells to respond to a perceived deficit of sterol by increasing their rate of cholesterol synthesis, particularly in the liver. A similar compensatory response occurs with treatments that disrupt the enterohepatic movement of cholesterol or bile acids. Here we measured rates of cholesterol synthesis in vivo in the liver and small intestine of a mouse model for CESD given the cholesterol absorption inhibitor ezetimibe from weaning until early adulthood. Consistent with previous findings, this treatment significantly reduced the amount of EC sequestered in the liver (from 132.43±7.35 to 70.07±6.04mg/organ) and small intestine (from 2.78±0.21 to 1.34±0.09mg/organ) in the LAL-deficient mice even though their rates of hepatic and intestinal cholesterol synthesis were either comparable to, or exceeded those in matching untreated Lal−/− mice. These data reveal the role of intestinal cholesterol absorption in driving the expansion of tissue EC content and disease progression in LAL deficiency.
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      PubDate: 2017-05-21T06:14:26Z
      DOI: 10.1016/j.bcp.2017.03.010
      Issue No: Vol. 135 (2017)
       
  • A novel pyrazole-containing indolizine derivative suppresses NF-κB
           activation and protects against TNBS-induced colitis via a
           PPAR-γ-dependent pathway
    • Authors: Yong Fu; Junting Ma; Xiafei Shi; Xiang-Yun Song; Yaping Yang; Shuke Xiao; Jiahuang Li; Wei-Jin Gu; Zhen Huang; Junfeng Zhang; Jiangning Chen
      Pages: 126 - 138
      Abstract: Publication date: 1 July 2017
      Source:Biochemical Pharmacology, Volume 135
      Author(s): Yong Fu, Junting Ma, Xiafei Shi, Xiang-Yun Song, Yaping Yang, Shuke Xiao, Jiahuang Li, Wei-Jin Gu, Zhen Huang, Junfeng Zhang, Jiangning Chen
      The nuclear factor-κB (NF-κB)-mediated activation of macrophages plays a key role in mucosal immune responses in Crohn’s disease (CD). Moreover, increasing evidence shows that the activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) exerts satisfactory anti-inflammatory effects in experimental colitis models, mostly by suppressing NF-κB-mediated macrophage activation. Therefore, exploring therapeutic strategies to activate PPAR-γ and inhibit the NF-κB pathway in colonic macrophages holds great promise for the treatment of CD. In this study, five novel pyrazole-containing indolizine derivatives (B1, B2, B3, B4 and B5) were successfully synthesized and characterized, and their anti-inflammatory activities for CD treatment were also investigated. Among the five compounds, compound B4 effectively decreased the NF-κB-mediated production of the pro-inflammatory cytokine TNF-α in LPS-stimulated peritoneal macrophages. Moreover, compound B4 significantly ameliorated 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced mouse colitis symptoms, including body weight loss, colonic pathological damage and inflammatory cell infiltration. The results of western blotting and luciferase reporter assays indicated that compound B4 activated PPAR-γ and subsequently suppressed NF-κB activation. Conversely, the addition of the PPAR-γ antagonist GW9662 abrogated the anti-inflammatory effects of compound B4 both in vitro and in vivo. In summary, compound B4 activated the PPAR-γ pathway to inhibit downstream NF-κB signaling, which alleviated experimental colitis. Thus, this compound may serve as a potential therapeutic agent for patients with CD.
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      PubDate: 2017-05-21T06:14:26Z
      DOI: 10.1016/j.bcp.2017.03.013
      Issue No: Vol. 135 (2017)
       
  • The pharmacokinetics and metabolism of lumiracoxib in chimeric humanized
           and murinized FRG mice
    • Authors: A.P. Dickie; C.E. Wilson; K. Schreiter; R. Wehr; E.M. Wilson; J. Bial; N. Scheer; I.D. Wilson; R.J. Riley
      Pages: 139 - 150
      Abstract: Publication date: 1 July 2017
      Source:Biochemical Pharmacology, Volume 135
      Author(s): A.P. Dickie, C.E. Wilson, K. Schreiter, R. Wehr, E.M. Wilson, J. Bial, N. Scheer, I.D. Wilson, R.J. Riley
      The pharmacokinetics and metabolism of lumiracoxib were studied, after administration of single 10mg/kg oral doses to chimeric liver-humanized and murinized FRG mice. In the chimeric humanized mice, lumiracoxib reached peak observed concentrations in the blood of 1.10±0.08μg/mL at 0.25–0.5h post-dose with an AUCinf of 1.74±0.52μgh/mL and an effective half-life for the drug of 1.42±0.72h (n=3). In the case of the murinized animals peak observed concentrations in the blood were determined as 1.15±0.08μg/mL at 0.25h post-dose with an AUCinf of 1.94±0.22μgh/mL and an effective half-life of 1.28±0.02h (n=3). Analysis of blood indicated only the presence of unchanged lumiracoxib. Metabolic profiling of urine, bile and faecal extracts revealed a complex pattern of metabolites for both humanized and murinized animals with, in addition to unchanged parent drug, a variety of hydroxylated and conjugated metabolites detected. The profiles obtained in humanized mice were different compared to murinized animals with e.g., a higher proportion of the dose detected in the form of acyl glucuronide metabolites and much reduced amounts of taurine conjugates. Comparison of the metabolic profiles obtained from the present study with previously published data from C57bl/6J mice and humans, revealed a greater though not complete match between chimeric humanized mice and humans, such that the liver-humanized FRG model may represent a useful approach to assessing the biotransformation of such compounds in humans.
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      PubDate: 2017-05-21T06:14:26Z
      DOI: 10.1016/j.bcp.2017.03.015
      Issue No: Vol. 135 (2017)
       
  • Endophytes as sources of antibiotics
    • Authors: Elena Martinez-Klimova; Karol Rodríguez-Peña; Sergio Sánchez
      Pages: 1 - 17
      Abstract: Publication date: 15 June 2017
      Source:Biochemical Pharmacology, Volume 134
      Author(s): Elena Martinez-Klimova, Karol Rodríguez-Peña, Sergio Sánchez
      Until a viable alternative can be accessible, the emergence of resistance to antimicrobials requires the constant development of new antibiotics. Recent scientific efforts have been aimed at the bioprospecting of microorganisms’ secondary metabolites, with special emphasis on the search for antimicrobial natural products derived from endophytes. Endophytes are microorganisms that inhabit the internal tissues of plants without causing apparent harm to the plant. The present review article compiles recent (2006–2016) literature to provide an update on endophyte research aimed at finding metabolites with antibiotic activities. We have included exclusively information on endophytes that produce metabolites capable of inhibiting the growth of bacterial, fungal and protozoan pathogens of humans, animals and plants. Where available, the identified metabolites have been listed. In this review, we have also compiled a list of the bacterial and fungal phyla that have been isolated as endophytes as well as the plant families from which the endophytes were isolated. The majority of endophytes that produce antibiotic metabolites belong to either phylum Ascomycota (kingdom Fungi) or to phylum Actinobacteria (superkingdom Bacteria). Endophytes that produce antibiotic metabolites were predominant, but certainly not exclusively, from the plant families Fabaceae, Lamiaceae, Asteraceae and Araceae, suggesting that endophytes that produce antimicrobial metabolites are not restricted to a reduced number of plant families. The locations where plants (and inhabiting endophytes) were collected from, according to the literature, have been mapped, showing that endophytes that produce bioactive compounds have been collected globally.
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      PubDate: 2017-04-29T05:32:30Z
      DOI: 10.1016/j.bcp.2016.10.010
      Issue No: Vol. 134 (2017)
       
  • The cave microbiome as a source for drug discovery: Reality or pipe
           dream?
    • Authors: Soumya Ghosh; Nomeda Kuisiene; Naowarat Cheeptham
      Pages: 18 - 34
      Abstract: Publication date: 15 June 2017
      Source:Biochemical Pharmacology, Volume 134
      Author(s): Soumya Ghosh, Nomeda Kuisiene, Naowarat Cheeptham
      This review highlights cave habitats, cave microbiomes and their potential for drug discovery. Such studies face many challenges, including access to remote and pristine caves, and sample collection and transport. Inappropriate physical and chemical growth conditions in the laboratory for the isolation and cultivation of cave microorganisms pose many complications including length of cultivation; some cave microorganisms can take weeks and even months to grow. Additionally, DNA extraction from cave environmental samples may be difficult due to the high concentration of various minerals that are natural DNA blocking agents. Once cave microorganisms are grown in the lab, other problems often arise, such as maintenance of pure culture, consistency of antimicrobial activity and fermentation conditions for antimicrobial production. In this review, we suggest that, although based on what has been done in the field, there is potential in using cave microorganisms to produce antimicrobial agents, one needs to be highly committed and prepared.
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      PubDate: 2017-04-29T05:32:30Z
      DOI: 10.1016/j.bcp.2016.11.018
      Issue No: Vol. 134 (2017)
       
  • Sources of antibiotics: Hot springs
    • Authors: Girish B. Mahajan; Lakshmi Balachandran
      Pages: 35 - 41
      Abstract: Publication date: 15 June 2017
      Source:Biochemical Pharmacology, Volume 134
      Author(s): Girish B. Mahajan, Lakshmi Balachandran
      The discovery of antibiotics heralded an era of improved health care. However, the over-prescription and misuse of antibiotics resulted in the development of resistant strains of various pathogens. Since then, there has been an incessant search for discovering novel compounds from bacteria at various locations with extreme conditions. The soil is one of the most explored locations for bioprospecting. In recent times, hypersaline environments and symbiotic associations have been investigated for novel antimicrobial compounds. Among the extreme environments, hot springs are comparatively less explored. Many researchers have reported the presence of microbial life and secretion of antimicrobial compounds by microorganisms in hot springs. A pioneering research in the corresponding author’s laboratory resulted in the identification of the antibiotic Fusaricidin B isolated from a hot spring derived eubacteria, Paenibacillus polymyxa, which has been assigned a new application for its anti-tubercular properties. The corresponding author has also reported anti-MRSA and anti-VRE activity of 73 bacterial isolates from hot springs in India.
      Graphical abstract image

      PubDate: 2017-04-29T05:32:30Z
      DOI: 10.1016/j.bcp.2016.11.021
      Issue No: Vol. 134 (2017)
       
  • Search for new compounds from Kitasato microbial library by
           physicochemical screening
    • Authors: Takuji Nakashima; Yōko Takahashi; Satoshi Ōmura
      Pages: 42 - 55
      Abstract: Publication date: 15 June 2017
      Source:Biochemical Pharmacology, Volume 134
      Author(s): Takuji Nakashima, Yōko Takahashi, Satoshi Ōmura
      The Ōmura research group of the Kitasato Institute has isolated multiple microorganisms over a period of five decades. The resulting collection comprises a broad spectrum of microbes, including strains producing novel and diverse compounds with biological activities. A bioassay-guided fractionation of microbial culture broths has been employed to screen the microbial collection for compounds with new biological activities. And numerous novel natural products have been discovered among the microbial metabolites produced by members of the collection. However, dereplication of already known compounds and their potential analogs is a vital part of the discovery process of new microbial natural products. Recently, it has become easy to acquire the ultraviolet (UV) and mass spectrometry (MS) spectra of many single components of microbial culture broths in combination with high-performance liquid chromatography. To achieve most effective utilization of our microbial library, new compounds from microbial culture broths were investigated by employing an approach based on the physico-chemical properties using spectral analyses such as UV and MS and color reaction, collectively designated as physicochemical (PC) screening. As a result of physicochemical screening, many new compounds were identified among the secondary metabolites of fresh isolated rare actinomycetes and Streptomyces spp. preserved for a long time as producer of biological compounds. In this review, we introduce the Kitasato microbial library and the new compounds discovered from the library by PC screening.
      Graphical abstract image

      PubDate: 2017-04-29T05:32:30Z
      DOI: 10.1016/j.bcp.2016.09.026
      Issue No: Vol. 134 (2017)
       
  • Enabling techniques in the search for new antibiotics: Combinatorial
           biosynthesis of sugar-containing antibiotics
    • Authors: Je Won Park; Sang-Jip Nam; Yeo Joon Yoon
      Pages: 56 - 73
      Abstract: Publication date: 15 June 2017
      Source:Biochemical Pharmacology, Volume 134
      Author(s): Je Won Park, Sang-Jip Nam, Yeo Joon Yoon
      Nature has a talent for inventing a vast number of natural products, including hybrids generated by blending different scaffolds, resulting in a myriad of bioactive chemical entities. Herein, we review the highlights and recent trends (2010–2016) in the combinatorial biosynthesis of sugar-containing antibiotics where nature’s structural diversification capabilities are exploited to enable the creation of new anti-infective and anti-proliferative drugs. In this review, we describe the modern combinatorial biosynthetic approaches for polyketide synthase-derived complex and aromatic polyketides, non-ribosomal peptide synthetase-directed lipo-/glycopeptides, aminoglycosides, nucleoside antibiotics, and alkaloids, along with their therapeutic potential. Finally, we present the feasible nexus between combinatorial biosynthesis, systems biology, and synthetic biology as a toolbox to provide new antibiotics that will be indispensable in the post-antibiotic era.
      Graphical abstract image

      PubDate: 2017-04-29T05:32:30Z
      DOI: 10.1016/j.bcp.2016.10.009
      Issue No: Vol. 134 (2017)
       
  • Using bacterial genomes and essential genes for the development of new
           antibiotics
    • Authors: Francisco R. Fields; Shaun W. Lee; Michael J. McConnell
      Pages: 74 - 86
      Abstract: Publication date: 15 June 2017
      Source:Biochemical Pharmacology, Volume 134
      Author(s): Francisco R. Fields, Shaun W. Lee, Michael J. McConnell
      The shrinking antibiotic development pipeline together with the global increase in antibiotic resistant infections requires that new molecules with antimicrobial activity are developed. Traditional empirical screening approaches of natural and non-natural compounds have identified the majority of antibiotics that are currently available, however this approach has produced relatively few new antibiotics over the last few decades. The vast amount of bacterial genome sequence information that has become available since the sequencing of the first bacterial genome more than 20years ago holds potential for contributing to the discovery of novel antimicrobial compounds. Comparative genomic approaches can identify genes that are highly conserved within and between bacterial species, and thus may represent genes that participate in key bacterial processes. Whole genome mutagenesis studies can also identify genes necessary for bacterial growth and survival under different environmental conditions, making them attractive targets for the development of novel inhibitory compounds. In addition, transcriptomic and proteomic approaches can be used to characterize RNA and protein levels on a cellular scale, providing information on bacterial physiology that can be applied to antibiotic target identification. Finally, bacterial genomes can be mined to identify biosynthetic pathways that produce many intrinsic antimicrobial compounds and peptides. In this review, we provide an overview of past and current efforts aimed at using bacterial genomic data in the discovery and development of novel antibiotics.
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      PubDate: 2017-04-29T05:32:30Z
      DOI: 10.1016/j.bcp.2016.12.002
      Issue No: Vol. 134 (2017)
       
  • New approaches to antimicrobial discovery
    • Authors: Kim Lewis
      Pages: 87 - 98
      Abstract: Publication date: 15 June 2017
      Source:Biochemical Pharmacology, Volume 134
      Author(s): Kim Lewis
      The spread of resistant organisms is producing a human health crisis, as we are witnessing the emergence of pathogens resistant to all available antibiotics. An increase in chronic infections presents an additional challenge – these diseases are difficult to treat due to antibiotic-tolerant persister cells. Overmining of soil Actinomycetes ended the golden era of antibiotic discovery in the 60s, and efforts to replace this source by screening synthetic compound libraries was not successful. Bacteria have an efficient permeability barrier, preventing penetration of most synthetic compounds. Empirically establishing rules of penetration for antimicrobials will form the knowledge base to produce libraries tailored to antibiotic discovery, and will revive rational drug design. Two untapped sources of natural products hold the promise of reviving natural product discovery. Most bacterial species, over 99%, are uncultured, and methods to grow these organisms have been developed, and the first promising compounds are in development. Genome sequencing shows that known producers harbor many more operons coding for secondary metabolites than we can account for, providing an additional rich source of antibiotics. Revival of natural product discovery will require high-throughput identification of novel compounds within a large background of known substances. This could be achieved by rapid acquisition of transcription profiles from active extracts that will point to potentially novel compounds.
      Graphical abstract image

      PubDate: 2017-04-29T05:32:30Z
      DOI: 10.1016/j.bcp.2016.11.002
      Issue No: Vol. 134 (2017)
       
  • Synthetic biology era: Improving antibiotic’s world
    • Authors: Silvia Guzmán-Trampe; Corina D. Ceapa; Monserrat Manzo-Ruiz; Sergio Sánchez
      Pages: 99 - 113
      Abstract: Publication date: 15 June 2017
      Source:Biochemical Pharmacology, Volume 134
      Author(s): Silvia Guzmán-Trampe, Corina D. Ceapa, Monserrat Manzo-Ruiz, Sergio Sánchez
      The emergence of antibiotic-resistant pathogen microorganisms is problematic in the context of the current spectrum of available medication. The poor specificity and the high toxicity of some available molecules have made imperative the search for new strategies to improve the specificity and to pursue the discovery of novel compounds with increased bioactivity. Using living cells as platforms, synthetic biology has counteracted this problem by offering novel pathways to create synthetic systems with improved and desired functions. Among many other biotechnological approaches, the advances in synthetic biology have made it possible to design and construct novel biological systems in order to look for new drugs with increased bioactivity. Advancements have also been made in the redesigning of RNA and DNA molecules in order to engineer antibiotic clusters for antibiotic overexpression. As for the production of these antibacterial compounds, yeasts and filamentous fungi as well as gene therapy are utilized to enhance protein solubility. Specific delivery is achieved by creating chimeras using plant genes into bacterial hosts. Some of these synthetic systems are currently in clinical trials, proving the proficiency of synthetic biology in terms of both pharmacological activities as well as an increase in the biosafety of treatments. It is possible that we may just be seeing the tip of the iceberg, and synthetic biology applications will overpass expectations beyond our present knowledge.
      Graphical abstract image

      PubDate: 2017-04-29T05:32:30Z
      DOI: 10.1016/j.bcp.2017.01.015
      Issue No: Vol. 134 (2017)
       
  • Antibiotic use and microbiome function
    • Authors: Manuel Ferrer; Celia Méndez-García; David Rojo; Coral Barbas; Andrés Moya
      Pages: 114 - 126
      Abstract: Publication date: 15 June 2017
      Source:Biochemical Pharmacology, Volume 134
      Author(s): Manuel Ferrer, Celia Méndez-García, David Rojo, Coral Barbas, Andrés Moya
      Our microbiome should be understood as one of the most complex components of the human body. The use of β-lactam antibiotics is one of the microbiome covariates that influence its composition. The extent to which our microbiota changes after an antibiotic intervention depends not only on the chemical nature of the antibiotic or cocktail of antibiotics used to treat specific infections, but also on the type of administration, duration and dose, as well as the level of resistance that each microbiota develops. We have begun to appreciate that not all bacteria within our microbiota are vulnerable or reactive to different antibiotic interventions, and that their influence on both microbial composition and metabolism may differ. Antibiotics are being used worldwide on a huge scale and the prescription of antibiotics is continuing to rise; however, their effects on our microbiota have been reported for only a limited number of them. This article presents a critical review of the antibiotics or antibiotic cocktails whose use in humans has been linked to changes in the composition of our microbial communities, with a particular focus on the gut, oral, respiratory, skin and vaginal microbiota, and on their molecular agents (genes, proteins and metabolites). We review the state of the art as of June 2016, and cover a total of circa 68 different antibiotics. The data herein are the first to compile information about the bacteria, fungi, archaea and viruses most influenced by the main antibiotic treatments prescribed nowadays.
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      PubDate: 2017-04-29T05:32:30Z
      DOI: 10.1016/j.bcp.2016.09.007
      Issue No: Vol. 134 (2017)
       
  • Animal venoms as antimicrobial agents
    • Authors: Ramar Perumal Samy; Bradley G. Stiles; Octavio L. Franco; Gautam Sethi; Lina H.K. Lim
      Pages: 127 - 138
      Abstract: Publication date: 15 June 2017
      Source:Biochemical Pharmacology, Volume 134
      Author(s): Ramar Perumal Samy, Bradley G. Stiles, Octavio L. Franco, Gautam Sethi, Lina H.K. Lim
      Hospitals are breeding grounds for many life-threatening bacteria worldwide. Clinically associated gram-positive bacteria such as Staphylococcus aureus/methicillin-resistant S. aureus and many others increase the risk of severe mortality and morbidity. The failure of antibiotics to kill various pathogens due to bacterial resistance highlights the urgent need to develop novel, potent, and less toxic agents from natural sources against various infectious agents. Currently, several promising classes of natural molecules from snake (terrestrial and sea), scorpion, spider, honey bee and wasp venoms hold promise as rich sources of chemotherapeutics against infectious pathogens. Interestingly, snake venom-derived synthetic peptide/snake cathelicidin not only has potent antimicrobial and wound-repair activity but is highly stable and safe. Such molecules are promising candidates for novel venom-based drugs against S. aureus infections. The structure of animal venom proteins/peptides (cysteine rich) consists of hydrophobic α-helices or β-sheets that produce lethal pores and membrane-damaging effects on bacteria. All these antimicrobial peptides are under early experimental or pre-clinical stages of development. It is therefore important to employ novel tools for the design and the development of new antibiotics from the untapped animal venoms of snake, scorpion, and spider for treating resistant pathogens. To date, snail venom toxins have shown little antibiotic potency against human pathogens.
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      PubDate: 2017-04-29T05:32:30Z
      DOI: 10.1016/j.bcp.2017.03.005
      Issue No: Vol. 134 (2017)
       
  • Antibiotic resistance: A current epilogue
    • Authors: David R. Dodds
      Pages: 139 - 146
      Abstract: Publication date: 15 June 2017
      Source:Biochemical Pharmacology, Volume 134
      Author(s): David R. Dodds
      The history of the first commercial antibiotics is briefly reviewed, together with data from the US and WHO, showing the decrease in death due to infectious diseases over the 20th century, from just under half of all deaths, to less than 10%. The second half of the 20th century saw the new use of antibiotics as growth promoters for food animals in the human diet, and the end of the 20th century and beginning of the 21st saw the beginning and rapid rise of advanced microbial resistance to antibiotics.

      PubDate: 2017-04-29T05:32:30Z
      DOI: 10.1016/j.bcp.2016.12.005
      Issue No: Vol. 134 (2017)
       
  • The amazing world of antibiotics
    • Authors: Sergio Sánchez; Arnold L. Demain
      Pages: 1 - 3
      Abstract: Publication date: 1 June 2017
      Source:Biochemical Pharmacology, Volume 133
      Author(s): Sergio Sánchez, Arnold L. Demain


      PubDate: 2017-04-29T05:32:30Z
      DOI: 10.1016/j.bcp.2017.03.008
      Issue No: Vol. 133 (2017)
       
  • History of antimicrobial drug discovery: Major classes and health impact
    • Authors: Rustam Aminov
      Pages: 4 - 19
      Abstract: Publication date: 1 June 2017
      Source:Biochemical Pharmacology, Volume 133
      Author(s): Rustam Aminov
      The introduction of antibiotics into clinical practice revolutionized the treatment and management of infectious diseases. Before the introduction of antibiotics, these diseases were the leading cause of morbidity and mortality in human populations. This review presents a brief history of discovery of the main antimicrobial classes (arsphenamines, β-lactams, sulphonamides, polypeptides, aminoglycosides, tetracyclines, amphenicols, lipopeptides, macrolides, oxazolidinones, glycopeptides, streptogramins, ansamycins, quinolones, and lincosamides) that have changed the landscape of contemporary medicine. Given within a historical timeline context, the review discusses how the introduction of certain antimicrobial classes affected the morbidity and mortality rates due to bacterial infectious diseases in human populations. Problems of resistance to antibiotics of different classes are also extensively discussed.
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      PubDate: 2017-04-29T05:32:30Z
      DOI: 10.1016/j.bcp.2016.10.001
      Issue No: Vol. 133 (2017)
       
  • Non-coding RNAs as antibiotic targets
    • Authors: Savannah Colameco; Marie A. Elliot
      Pages: 29 - 42
      Abstract: Publication date: 1 June 2017
      Source:Biochemical Pharmacology, Volume 133
      Author(s): Savannah Colameco, Marie A. Elliot
      Antibiotics inhibit a wide range of essential processes in the bacterial cell, including replication, transcription, translation and cell wall synthesis. In many instances, these antibiotics exert their effects through association with non-coding RNAs. This review highlights many classical antibiotic targets (e.g. rRNAs and the ribosome), explores a number of emerging targets (e.g. tRNAs, RNase P, riboswitches and small RNAs), and discusses the future directions and challenges associated with non-coding RNAs as antibiotic targets.
      Graphical abstract image

      PubDate: 2017-04-29T05:32:30Z
      DOI: 10.1016/j.bcp.2016.12.015
      Issue No: Vol. 133 (2017)
       
  • What is an “ideal” antibiotic? Discovery challenges and
           path forward
    • Authors: Sheo B. Singh; Katherine Young; Lynn L. Silver
      Pages: 63 - 73
      Abstract: Publication date: 1 June 2017
      Source:Biochemical Pharmacology, Volume 133
      Author(s): Sheo B. Singh, Katherine Young, Lynn L. Silver
      An ideal antibiotic is an antibacterial agent that kills or inhibits the growth of all harmful bacteria in a host, regardless of site of infection without affecting beneficial gut microbes (gut flora) or causing undue toxicity to the host. Sadly, no such antibiotics exist. What exist are many effective Gram-positive antibacterial agents as well as broad-spectrum agents that provide treatment of certain Gram-negative bacteria but not holistic treatment of all bacteria. However effectiveness of all antibacterial agents is being rapidly eroded due to resistance. This viewpoint provides an overview of today’s antibiotics, challenges and potential path forward of discovery and development of new (ideal) antibiotics.
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      PubDate: 2017-04-29T05:32:30Z
      DOI: 10.1016/j.bcp.2017.01.003
      Issue No: Vol. 133 (2017)
       
  • Glycopeptide resistance: Links with inorganic phosphate metabolism and
           cell envelope stress
    • Authors: Fernando Santos-Beneit; María Ordóñez-Robles; Juan F. Martín
      Pages: 74 - 85
      Abstract: Publication date: 1 June 2017
      Source:Biochemical Pharmacology, Volume 133
      Author(s): Fernando Santos-Beneit, María Ordóñez-Robles, Juan F. Martín
      Antimicrobial resistance is a critical health issue today. Many pathogens have become resistant to many or all available antibiotics and limited new antibiotics are in the pipeline. Glycopeptides are used as a ‘last resort’ antibiotic treatment for many bacterial infections, but worryingly, glycopeptide resistance has spread to very important pathogens such as Enterococcus faecium and Staphylococcus aureus. Bacteria confront multiple stresses in their natural environments, including nutritional starvation and the action of cell-wall stressing agents. These stresses impact bacterial susceptibility to different antimicrobials. This article aims to review the links between glycopeptide resistance and different stresses, especially those related with cell-wall biosynthesis and inorganic phosphate metabolism, and to discuss promising alternatives to classical antibiotics to avoid the problem of antimicrobial resistance.
      Graphical abstract image

      PubDate: 2017-04-29T05:32:30Z
      DOI: 10.1016/j.bcp.2016.11.017
      Issue No: Vol. 133 (2017)
       
  • Antifungals
    • Authors: Sonia Campoy; José L. Adrio
      Pages: 86 - 96
      Abstract: Publication date: 1 June 2017
      Source:Biochemical Pharmacology, Volume 133
      Author(s): Sonia Campoy, José L. Adrio
      The need for new antifungal agents is undeniable. Current therapeutic choices for the treatment of invasive fungal infections are limited to three classes of drugs. Most used antifungal agents are not completely effective due to the development of resistance, host toxicity and undesirable side effects that limit their use in medical practice. Invasive fungal infections have significantly increased over the last decades and the mortality rates remain unacceptably high. More threatening, new resistance patterns have been observed including simultaneous resistance to different antifungal classes. In the last years, deeper insights into the molecular mechanisms for fungal resistance and virulence have yielded some new potential targets for antifungal therapeutics. Chemical genomics-based screenings, high throughput screenings of natural products and repurposing of approved drugs are some of the approaches being followed for the discovery of new antifungal molecules. However, despite the emerging need for effective antifungal agents, the current pipeline contains only a few promising molecules, with novel modes of action, in early clinical development stages.
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      PubDate: 2017-04-29T05:32:30Z
      DOI: 10.1016/j.bcp.2016.11.019
      Issue No: Vol. 133 (2017)
       
  • Antivirals against animal viruses
    • Authors: T.G. Villa; L. Feijoo-Siota; J.L.R. Rama; J.M. Ageitos
      Pages: 97 - 116
      Abstract: Publication date: 1 June 2017
      Source:Biochemical Pharmacology, Volume 133
      Author(s): T.G. Villa, L. Feijoo-Siota, J.L.R. Rama, J.M. Ageitos
      Antivirals are compounds used since the 1960s that can interfere with viral development. Some of these antivirals can be isolated from a variety of sources, such as animals, plants, bacteria or fungi, while others must be obtained by chemical synthesis, either designed or random. Antivirals display a variety of mechanisms of action, and while some of them enhance the animal immune system, others block a specific enzyme or a particular step in the viral replication cycle. As viruses are mandatory intracellular parasites that use the host’s cellular machinery to survive and multiply, it is essential that antivirals do not harm the host. In addition, viruses are continually developing new antiviral resistant strains, due to their high mutation rate, which makes it mandatory to continually search for, or develop, new antiviral compounds. This review describes natural and synthetic antivirals in chronological order, with an emphasis on natural compounds, even when their mechanisms of action are not completely understood, that could serve as the basis for future development of novel and/or complementary antiviral treatments.
      Graphical abstract image

      PubDate: 2017-04-29T05:32:30Z
      DOI: 10.1016/j.bcp.2016.09.029
      Issue No: Vol. 133 (2017)
       
  • Antimicrobial peptides (AMPs): Ancient compounds that represent novel
           weapons in the fight against bacteria
    • Authors: J.M. Ageitos; A. Sánchez-Pérez; P. Calo-Mata; T.G. Villa
      Pages: 117 - 138
      Abstract: Publication date: 1 June 2017
      Source:Biochemical Pharmacology, Volume 133
      Author(s): J.M. Ageitos, A. Sánchez-Pérez, P. Calo-Mata, T.G. Villa
      Antimicrobial peptides (AMPs) are short peptidic molecules produced by most living creatures. They help unicellular organisms to successfully compete for nutrients with other organisms sharing their biological niche, while AMPs form part of the immune system of multicellular creatures. Thus, these molecules represent biological weapons that have evolved over millions of years as a result of an escalating arms race for survival among living organisms. All AMPs share common features, such as a small size, with cationic and hydrophobic sequences within a linear or cyclic structure. AMPs can inhibit or kill bacteria at micromolar concentrations, often by non-specific mechanisms; hence the appearance of resistance to these antimicrobials is rare. Moreover, AMPs can kill antibiotic-resistant bacteria, including insidious microbes such as Acinetobacter baumannii and the methicillin-resistant Staphylococcus aureus. This review gives a detailed insight into a selection of the most prominent and interesting AMPs with antibacterial activity. In the near future AMPs, due to their properties and despite their ancient origin, should represent a novel alternative to antibiotics in the struggle to control pathogenic microorganisms and maintain the current human life expectancy.
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      PubDate: 2017-04-29T05:32:30Z
      DOI: 10.1016/j.bcp.2016.09.018
      Issue No: Vol. 133 (2017)
       
  • Platensimycin and platencin: Inspirations for chemistry, biology,
           enzymology, and medicine
    • Authors: Jeffrey D. Rudolf; Liao-Bin Dong; Ben Shen
      Pages: 139 - 151
      Abstract: Publication date: 1 June 2017
      Source:Biochemical Pharmacology, Volume 133
      Author(s): Jeffrey D. Rudolf, Liao-Bin Dong, Ben Shen
      Natural products have served as the main source of drugs and drug leads, and natural products produced by microorganisms are one of the most prevalent sources of clinical antibiotics. Their unparalleled structural and chemical diversities provide a basis to investigate fundamental biological processes while providing access to a tremendous amount of chemical space. There is a pressing need for novel antibiotics with new mode of actions to combat the growing challenge of multidrug resistant pathogens. This review begins with the pioneering discovery and biological activities of platensimycin (PTM) and platencin (PTN), two antibacterial natural products isolated from Streptomyces platensis. The elucidation of their unique biochemical mode of action, structure-activity relationships, and pharmacokinetics is presented to highlight key aspects of their biological activities. It then presents an overview of how microbial genomics has impacted the field of PTM and PTN and revealed paradigm-shifting discoveries in terpenoid biosynthesis, fatty acid metabolism, and antibiotic and antidiabetic therapies. It concludes with a discussion covering the future perspectives of PTM and PTN in regard to natural products discovery, bacterial diterpenoid biosynthesis, and the pharmaceutical promise of PTM and PTN as antibiotics and for the treatment of metabolic disorders. PTM and PTN have inspired new discoveries in chemistry, biology, enzymology, and medicine and will undoubtedly continue to do so.
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      PubDate: 2017-04-29T05:32:30Z
      DOI: 10.1016/j.bcp.2016.11.013
      Issue No: Vol. 133 (2017)
       
  • Editorial Advisory Board
    • Abstract: Publication date: 15 July 2017
      Source:Biochemical Pharmacology, Volume 136


      PubDate: 2017-05-26T06:30:35Z
       
  • Targeted pharmacotherapies for defective ABC transporters
    • 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
       
  • Multifaceted anticancer activity of BH3 mimetics: Current evidence and
           future prospects
    • 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
       
  • Corrector VX-809 promotes interactions between cytoplasmic loop one and
           the first nucleotide-binding domain of CFTR
    • 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
       
  • Hydroxyurea inhibits parvovirus B19 replication in erythroid progenitor
           cells
    • 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
       
  • Axl molecular targeting counteracts aggressiveness but not
           platinum-resistance of ovarian carcinoma cells
    • 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
       
  • 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
    • 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
       
  • 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
    • 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
       
  • Treatment with salvianolic acid B restores endothelial function in
           angiotensin II-induced hypertensive mice
    • 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
       
  • H2S-induced S-sulfhydration of lactate dehydrogenase a (LDHA) stimulates
           cellular bioenergetics in HCT116 colon cancer cells
    • 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
       
  • Characterization of signal bias at the GLP-1 receptor induced by backbone
           modification of GLP-1
    • 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
       
  • 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
    • 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.
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      PubDate: 2017-05-26T06:30:35Z
       
  • Ligand-dependent and -independent regulation of human hepatic
           sphingomyelin phosphodiesterase acid-like 3A expression by pregnane X
           receptor and crosstalk with liver X receptor
    • 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.
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      PubDate: 2017-05-26T06:30:35Z
       
  • Apigenin, a modulator of PPARγ, attenuates HFD-induced NAFLD by
           regulating hepatocyte lipid metabolism and oxidative stress via Nrf2
           activation
    • 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.
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      PubDate: 2017-05-26T06:30:35Z
       
  • Editorial Advisory Board
    • Abstract: Publication date: 1 July 2017
      Source:Biochemical Pharmacology, Volume 135


      PubDate: 2017-05-21T06:14:26Z
       
  • Editorial Advisory Board
    • Abstract: Publication date: 15 June 2017
      Source:Biochemical Pharmacology, Volume 134


      PubDate: 2017-04-29T05:32:30Z
       
  • Editorial Advisory Board
    • Abstract: Publication date: 1 June 2017
      Source:Biochemical Pharmacology, Volume 133


      PubDate: 2017-04-29T05:32:30Z
       
  • Lincosamides: Chemical structure, biosynthesis, mechanism of action,
           resistance, and applications
    • Authors: Jaroslav
      Abstract: Publication date: 1 June 2017
      Source:Biochemical Pharmacology, Volume 133
      Author(s): Jaroslav Spížek, Tomáš Řezanka
      Lincomycin and its derivatives are antibiotics exhibiting biological activity against bacteria, especially Gram-positive ones, and also protozoans. Lincomycin and its semi-synthetic chlorinated derivative clindamycin are widely used in clinical practice. Both antibiotics are bacteriostatic, inhibiting protein synthesis in sensitive bacteria; however, at higher concentrations, they may be bactericidal. Clindamycin is usually much more active than lincomycin in the treatment of bacterial infections, in particular those caused by anaerobic species; it can also be used for the treatment of important protozoal diseases, e.g. malaria, most effectively in combination with other antibiotic or non-antibiotic antimicrobials (primaquine, fosfidomycin, benzoyl peroxide). Chemical structures of lincosamide antibiotics and the biosynthesis of lincomycin and its genetic control have been summarized and described. Resistance to lincomycin and clindamycin may be caused by methylation of 23S ribosomal RNA, modification of the antibiotics by specific enzymes or active efflux from the bacterial cell.
      Graphical abstract image

      PubDate: 2017-04-29T05:32:30Z
       
  • Antibiotics: Pharmacokinetics, toxicity, resistance and multidrug efflux
           pumps
    • Abstract: Publication date: 1 June 2017
      Source:Biochemical Pharmacology, Volume 133
      Author(s): Çiğdem Yılmaz, Gülay Özcengiz
      The discovery of penicillin followed by streptomycin, tetracycline, cephalosporins and other natural, semi-synthetic and synthetic antimicrobials completely revolutionized medicine by reducing human morbidity and mortality from most of the common infections. However, shortly after they were introduced to clinical practice, the development of resistance was emerged. The decreasing interest from antibiotic industry in spite of rapid global emergence of antibiotic resistance is a tough dilemma from the pointview of public health. The efficiency of antimicrobial treatment is determined by both pharmacokinetics and pharmacodynamics. In spite of their selective toxicity, antibiotics still cause severe, life-threatening adverse reactions in host body mostly due to defective drug metabolism or excessive dosing regimen. The present article aims at updating current knowledge on pharmacokinetics/pharmacodynamics concepts and models, toxicity of antibiotics as well as antibiotic resistance mechanisms, resistome analyses and search for novel antibiotic resistance determinants with special emphasis given to the-state-of-the-art regarding multidrug efflux pumps and their additional physiological functions in stress adaptation and virulence of bacteria. All these issues are highly linked to each other and not only important for most efficient and prolonged use of current antibiotics, but also for discovery and development of new antibiotics and novel inhibitors of antibiotic resistance determinants of pathogens.
      Graphical abstract image

      PubDate: 2017-04-29T05:32:30Z
       
 
 
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