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CHEMISTRY (593 journals)                  1 2 3 | Last

Showing 1 - 200 of 735 Journals sorted alphabetically
2D Materials     Hybrid Journal   (Followers: 8)
Accreditation and Quality Assurance: Journal for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 26)
ACS Catalysis     Full-text available via subscription   (Followers: 34)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 18)
ACS Combinatorial Science     Full-text available via subscription   (Followers: 23)
ACS Macro Letters     Full-text available via subscription   (Followers: 23)
ACS Medicinal Chemistry Letters     Full-text available via subscription   (Followers: 39)
ACS Nano     Full-text available via subscription   (Followers: 233)
ACS Photonics     Full-text available via subscription   (Followers: 11)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 21)
Acta Chemica Iasi     Open Access   (Followers: 2)
Acta Chimica Sinica     Full-text available via subscription   (Followers: 1)
Acta Chimica Slovaca     Open Access   (Followers: 1)
Acta Chromatographica     Full-text available via subscription   (Followers: 9)
Acta Facultatis Medicae Naissensis     Open Access  
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 5)
Acta Scientifica Naturalis     Open Access   (Followers: 2)
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 5)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 7)
Adsorption Science & Technology     Full-text available via subscription   (Followers: 5)
Advanced Functional Materials     Hybrid Journal   (Followers: 50)
Advanced Science Focus     Free   (Followers: 3)
Advances in Chemical Engineering and Science     Open Access   (Followers: 55)
Advances in Chemical Science     Open Access   (Followers: 13)
Advances in Chemistry     Open Access   (Followers: 14)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 18)
Advances in Drug Research     Full-text available via subscription   (Followers: 22)
Advances in Enzyme Research     Open Access   (Followers: 9)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 15)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8)
Advances in Materials Physics and Chemistry     Open Access   (Followers: 19)
Advances in Nanoparticles     Open Access   (Followers: 15)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15)
Advances in Polymer Science     Hybrid Journal   (Followers: 41)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 19)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Science and Technology     Full-text available via subscription   (Followers: 12)
African Journal of Bacteriology Research     Open Access  
African Journal of Chemical Education     Open Access   (Followers: 2)
African Journal of Pure and Applied Chemistry     Open Access   (Followers: 7)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 68)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 14)
American Journal of Chemistry     Open Access   (Followers: 26)
American Journal of Plant Physiology     Open Access   (Followers: 14)
American Mineralogist     Hybrid Journal   (Followers: 14)
Analyst     Full-text available via subscription   (Followers: 40)
Angewandte Chemie     Hybrid Journal   (Followers: 222)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 213)
Annales UMCS, Chemia     Open Access   (Followers: 1)
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 3)
Annual Reports in Computational Chemistry     Full-text available via subscription   (Followers: 3)
Annual Reports Section A (Inorganic Chemistry)     Full-text available via subscription   (Followers: 4)
Annual Reports Section B (Organic Chemistry)     Full-text available via subscription   (Followers: 8)
Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 12)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 15)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antiviral Chemistry and Chemotherapy     Hybrid Journal  
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 7)
Applied Spectroscopy     Full-text available via subscription   (Followers: 23)
Applied Surface Science     Hybrid Journal   (Followers: 28)
Arabian Journal of Chemistry     Open Access   (Followers: 6)
ARKIVOC     Open Access   (Followers: 2)
Asian Journal of Biochemistry     Open Access   (Followers: 1)
Atomization and Sprays     Full-text available via subscription   (Followers: 4)
Australian Journal of Chemistry     Hybrid Journal   (Followers: 7)
Autophagy     Hybrid Journal   (Followers: 2)
Avances en Quimica     Open Access   (Followers: 1)
Biochemical Pharmacology     Hybrid Journal   (Followers: 10)
Biochemistry     Full-text available via subscription   (Followers: 295)
Biochemistry Insights     Open Access   (Followers: 6)
Biochemistry Research International     Open Access   (Followers: 6)
BioChip Journal     Hybrid Journal  
Bioinorganic Chemistry and Applications     Open Access   (Followers: 9)
Bioinspired Materials     Open Access   (Followers: 5)
Biointerface Research in Applied Chemistry     Open Access   (Followers: 2)
Biointerphases     Open Access   (Followers: 1)
Biology, Medicine, & Natural Product Chemistry     Open Access   (Followers: 1)
Biomacromolecules     Full-text available via subscription   (Followers: 19)
Biomass Conversion and Biorefinery     Partially Free   (Followers: 10)
Biomedical Chromatography     Hybrid Journal   (Followers: 6)
Biomolecular NMR Assignments     Hybrid Journal   (Followers: 3)
BioNanoScience     Partially Free   (Followers: 4)
Bioorganic & Medicinal Chemistry     Hybrid Journal   (Followers: 121)
Bioorganic & Medicinal Chemistry Letters     Hybrid Journal   (Followers: 98)
Bioorganic Chemistry     Hybrid Journal   (Followers: 10)
Biopolymers     Hybrid Journal   (Followers: 18)
Biosensors     Open Access   (Followers: 2)
Biotechnic and Histochemistry     Hybrid Journal   (Followers: 1)
Bitácora Digital     Open Access  
Boletin de la Sociedad Chilena de Quimica     Open Access  
Bulletin of the Chemical Society of Ethiopia     Open Access   (Followers: 2)
Bulletin of the Chemical Society of Japan     Full-text available via subscription   (Followers: 24)
Bulletin of the Korean Chemical Society     Hybrid Journal   (Followers: 1)
C - Journal of Carbon Research     Open Access   (Followers: 3)
Cakra Kimia (Indonesian E-Journal of Applied Chemistry)     Open Access  
Canadian Association of Radiologists Journal     Full-text available via subscription   (Followers: 3)
Canadian Journal of Chemistry     Hybrid Journal   (Followers: 10)
Canadian Mineralogist     Full-text available via subscription   (Followers: 3)
Carbohydrate Research     Hybrid Journal   (Followers: 26)
Carbon     Hybrid Journal   (Followers: 66)
Catalysis for Sustainable Energy     Open Access   (Followers: 7)
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: 8)
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: 13)
Chemical Bulletin of Kazakh National University     Open Access  
Chemical Communications     Full-text available via subscription   (Followers: 70)
Chemical Engineering Research and Design     Hybrid Journal   (Followers: 23)
Chemical Research in Chinese Universities     Hybrid Journal   (Followers: 3)
Chemical Research in Toxicology     Full-text available via subscription   (Followers: 19)
Chemical Reviews     Full-text available via subscription   (Followers: 176)
Chemical Science     Open Access   (Followers: 22)
Chemical Technology     Open Access   (Followers: 16)
Chemical Vapor Deposition     Hybrid Journal   (Followers: 5)
Chemical Week     Full-text available via subscription   (Followers: 8)
Chemie in Unserer Zeit     Hybrid Journal   (Followers: 57)
Chemie-Ingenieur-Technik (Cit)     Hybrid Journal   (Followers: 26)
ChemInform     Hybrid Journal   (Followers: 8)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 6)
Chemistry & Biology     Full-text available via subscription   (Followers: 30)
Chemistry & Industry     Hybrid Journal   (Followers: 5)
Chemistry - A European Journal     Hybrid Journal   (Followers: 142)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 15)
Chemistry and Materials Research     Open Access   (Followers: 18)
Chemistry Central Journal     Open Access   (Followers: 4)
Chemistry Education Research and Practice     Free   (Followers: 5)
Chemistry in Education     Open Access   (Followers: 9)
Chemistry International     Hybrid Journal   (Followers: 2)
Chemistry Letters     Full-text available via subscription   (Followers: 44)
Chemistry of Materials     Full-text available via subscription   (Followers: 258)
Chemistry of Natural Compounds     Hybrid Journal   (Followers: 9)
Chemistry World     Full-text available via subscription   (Followers: 22)
Chemistry-Didactics-Ecology-Metrology     Open Access   (Followers: 1)
ChemistryOpen     Open Access   (Followers: 2)
Chemkon - Chemie Konkret, Forum Fuer Unterricht Und Didaktik     Hybrid Journal  
Chemoecology     Hybrid Journal   (Followers: 3)
Chemometrics and Intelligent Laboratory Systems     Hybrid Journal   (Followers: 15)
Chemosensors     Open Access  
ChemPhysChem     Hybrid Journal   (Followers: 9)
ChemPlusChem     Hybrid Journal   (Followers: 2)
ChemTexts     Hybrid Journal  
CHIMIA International Journal for Chemistry     Full-text available via subscription   (Followers: 2)
Chinese Journal of Chemistry     Hybrid Journal   (Followers: 6)
Chinese Journal of Polymer Science     Hybrid Journal   (Followers: 10)
Chromatographia     Hybrid Journal   (Followers: 24)
Clay Minerals     Full-text available via subscription   (Followers: 10)
Cogent Chemistry     Open Access  
Colloid and Interface Science Communications     Open Access  
Colloid and Polymer Science     Hybrid Journal   (Followers: 10)
Colloids and Surfaces B: Biointerfaces     Hybrid Journal   (Followers: 7)
Combinatorial Chemistry & High Throughput Screening     Hybrid Journal   (Followers: 4)
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   (Followers: 1)
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: 12)
Current Catalysis     Hybrid Journal   (Followers: 2)
Current Metabolomics     Hybrid Journal   (Followers: 5)
Current Opinion in Colloid & Interface Science     Hybrid Journal   (Followers: 9)
Current Research in Chemistry     Open Access   (Followers: 8)
Current Science     Open Access   (Followers: 58)
Dalton Transactions     Full-text available via subscription   (Followers: 22)
Detection     Open Access   (Followers: 2)
Developments in Geochemistry     Full-text available via subscription   (Followers: 2)
Diamond and Related Materials     Hybrid Journal   (Followers: 12)
Dislocations in Solids     Full-text available via subscription  
Doklady Chemistry     Hybrid Journal  
Drying Technology: An International Journal     Hybrid Journal   (Followers: 4)
Eclética Química     Open Access   (Followers: 1)
Ecological Chemistry and Engineering S     Open Access   (Followers: 4)
Ecotoxicology and Environmental Contamination     Open Access  
Educación Química     Open Access   (Followers: 1)
Education for Chemical Engineers     Hybrid Journal   (Followers: 5)
EJNMMI Radiopharmacy and Chemistry     Open Access  
Elements     Full-text available via subscription   (Followers: 2)
Environmental Chemistry     Hybrid Journal   (Followers: 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: 17)

        1 2 3 | Last

Journal Cover Biochemical Pharmacology
  [SJR: 2.263]   [H-I: 160]   [10 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0006-2952
   Published by Elsevier Homepage  [3044 journals]
  • Spatial encryption of G protein-coupled receptor signaling in endosomes;
           Mechanisms and applications
    • Authors: Silvia Sposini; Aylin C. Hanyaloglu
      Pages: 1 - 9
      Abstract: Publication date: 1 November 2017
      Source:Biochemical Pharmacology, Volume 143
      Author(s): Silvia Sposini, Aylin C. Hanyaloglu
      Within any cellular signaling system membrane trafficking is a critical mechanism for cells to translate complex networks into specific downstream responses, including the signal pathways activated by the superfamily of G protein-coupled receptors (GPCRs). Classically, membrane trafficking is viewed as a mechanism to regulate ligand sensitivity of a target tissue by controlling the level of surface receptors. Recent studies, however, have not only highlighted that GPCR trafficking is a tightly regulated process critical for spatio-temporal control of signaling, but that heterotrimeric G protein signaling can also be reactivated or continue to signal from distinct endocytic compartments, and even endosomal microdomains. The significance of spatio-temporal control will be discussed, not only with respect to how these novel molecular pathways impact our basic understanding of cellular regulation, but also our view of how aberrant signaling can result in disease. Furthermore, these mechanisms offer the potential application for novel therapeutic strategies to identify GPCR compounds with high specificity in their actions.
      Graphical abstract image

      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.04.028
      Issue No: Vol. 143 (2017)
  • Challenges and opportunities for the development of new antipsychotic
    • Authors: Carlos Forray; Raimund Buller
      Pages: 10 - 24
      Abstract: Publication date: 1 November 2017
      Source:Biochemical Pharmacology, Volume 143
      Author(s): Carlos Forray, Raimund Buller
      In spite of the significant impact that the serendipitous discovery of drugs with antipsychotic properties had on the care of patients with psychotic disorders, there are significant challenges when aiming at therapeutic goals such as remission, recovery, improved health-related quality of life and functioning. The efficacy and effectiveness of existing antipsychotic drugs fail to address the full spectrum of symptoms and functional deficits that currently prevent patients with psychotic disorders from achieving fulfilling lives. The study of the pharmacological mechanism of action has increased our knowledge on molecular targets and brain circuits related to the antipsychotic properties of this drug class. However, our understanding of how these molecular targets and brain circuits relate to other aspects of disease pathophysiology like cognitive impairment and negative symptoms is incomplete although these are significant clinical unmet needs. Currently, there is still an important knowledge gap between psychopathology and pathophysiology in schizophrenia research. This may have contributed to some recent costly failures of large clinical development programs for drugs targeted at glutamatergic function and nicotinic receptors. The lack of success of these pharmacological approaches to achieve clinical validation raises important questions concerning the underlying hypothesis that guided the choice of molecular targets, and about the predictive validity of translational models that supported the rationale for testing these drugs in clinical studies. From a clinical perspective there is a need to more strongly consider the disease heterogeneity linked to the use of the current diagnostic classification of subjects and to the validity of the psychopathological constructs and assessments that are used to assess clinical outcomes. A paradigm shift in the development of drugs for schizophrenia is needed. This will require among other addressing: the shortcomings of a single diagnostic entity; the needs for in depth clinical phenotyping to leverage the findings of schizophrenia genetics and advance the understanding of the disease biology; the symptom domains that are the major sources of disability in order to improve functional outcomes beyond current treatment options. In spite of the progress achieved during the last century the task ahead is still daunting and will require the efforts of scientists and clinicians through inclusive public-private partnerships and consortia to create the scientific basis for new therapeutic approaches to schizophrenia.
      Graphical abstract image

      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.05.009
      Issue No: Vol. 143 (2017)
  • Characterization of potent and selective iodonium-class inhibitors of
           NADPH oxidases
    • Authors: Jiamo Lu; Prabhakar Risbood; Charles T. Kane; Md Tafazzal Hossain; Larry Anderson; Kimberly Hill; Anne Monks; Yongzhong Wu; Smitha Antony; Agnes Juhasz; Han Liu; Guojian Jiang; Erik Harris; Krishnendu Roy; Jennifer L. Meitzler; Mariam Konaté; James H. Doroshow
      Pages: 25 - 38
      Abstract: Publication date: 1 November 2017
      Source:Biochemical Pharmacology, Volume 143
      Author(s): Jiamo Lu, Prabhakar Risbood, Charles T. Kane, Md Tafazzal Hossain, Larry Anderson, Kimberly Hill, Anne Monks, Yongzhong Wu, Smitha Antony, Agnes Juhasz, Han Liu, Guojian Jiang, Erik Harris, Krishnendu Roy, Jennifer L. Meitzler, Mariam Konaté, James H. Doroshow
      The NADPH oxidases (NOXs) play a recognized role in the development and progression of inflammation-associated disorders, as well as cancer. To date, several NOX inhibitors have been developed, through either high throughput screening or targeted disruption of NOX interaction partners, although only a few have reached clinical trials. To improve the efficacy and bioavailability of the iodonium class NOX inhibitor diphenylene iodonium (DPI), we synthesized 36 analogs of DPI, focusing on improved solubility and functionalization. The inhibitory activity of the analogs was interrogated through cell viability and clonogenic studies with a colon cancer cell line (HT-29) that depends on NOX for its proliferative potential. Lack of altered cellular respiration at relevant iodonium analog concentrations was also demonstrated. Additionally, inhibition of ROS generation was evaluated with a luminescence assay for superoxide, or by Amplex Red® assay for H2O2 production, in cell models expressing specific NOX isoforms. DPI and four analogs (NSCs 740104, 751140, 734428, 737392) strongly inhibited HT-29 cell growth and ROS production with nanomolar potency in a concentration-dependent manner. NSC 737392 and 734428, which both feature nitro functional groups at the meta position, had >10-fold higher activity against ROS production by cells that overexpress dual oxidase 2 (DUOX2) than the other compounds examined (IC50 ≈200–400nM). Based on these results, we synthesized and tested NSC 780521 with optimized potency against DUOX2. Iodonium analogs with anticancer activity, including the first generation of targeted agents with improved specificity against DUOX2, may provide a novel therapeutic approach to NOX-driven tumors.
      Graphical abstract image

      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.007
      Issue No: Vol. 143 (2017)
  • Potent inhibitors of human LAT1 (SLC7A5) transporter based on dithiazole
           and dithiazine compounds for development of anticancer drugs
    • Authors: Lara Napolitano; Mariafrancesca Scalise; Maria Koyioni; Panayiotis Koutentis; Marco Catto; Ivano Eberini; Chiara Parravicini; Luca Palazzolo; Leonardo Pisani; Michele Galluccio; Lara Console; Angelo Carotti; Cesare Indiveri
      Pages: 39 - 52
      Abstract: Publication date: 1 November 2017
      Source:Biochemical Pharmacology, Volume 143
      Author(s): Lara Napolitano, Mariafrancesca Scalise, Maria Koyioni, Panayiotis Koutentis, Marco Catto, Ivano Eberini, Chiara Parravicini, Luca Palazzolo, Leonardo Pisani, Michele Galluccio, Lara Console, Angelo Carotti, Cesare Indiveri
      The LAT1 transporter is acknowledged as a pharmacological target of tumours since it is strongly overexpressed in many human cancers. The purpose of this work was to find novel compounds exhibiting potent and prolonged inhibition of the transporter. To this aim, compounds based on dithiazole and dithiazine scaffold have been screened in the proteoliposome experimental model. Inhibition was tested on the antiport catalysed by hLAT1 as transport of extraliposomal [3H]histidine in exchange with intraliposomal histidine. Out of 59 compounds tested, 8 compounds, showing an inhibition higher than 90% at 100µM concentration, were subjected to dose-response analysis. Two of them exhibited IC50 lower than 1µM. Inhibition kinetics, performed on the two best inhibitors, indicated a mixed type of inhibition with respect to the substrate. Furthermore, inhibition of the transporter was still present after removal of the compounds from the reaction mixture, but was reversed on addition of dithioerythritol, a S-S reducing agent, indicating the formation of disulfide(s) between the compounds and the protein. Molecular docking of the two best inhibitors on the hLAT1 homology structural model, highlighted interaction with the substrate binding site and formation of a covalent bond with the residue C407. Indeed, the inhibition was impaired in the hLAT1 mutant C407A confirming the involvement of that Cys residue. Treatment of SiHa cells expressing hLAT1 at relatively high level, with the two most potent inhibitors led to cell death which was not observed after treatment with a compound exhibiting very poor inhibitory effect.
      Graphical abstract image

      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.006
      Issue No: Vol. 143 (2017)
  • Global alteration of the drug-binding pocket of human P-glycoprotein
           (ABCB1) by substitution of fifteen conserved residues reveals a negative
           correlation between substrate size and transport efficiency
    • Authors: Shahrooz Vahedi; Eduardo E. Chufan; Suresh V. Ambudkar
      Pages: 53 - 64
      Abstract: Publication date: 1 November 2017
      Source:Biochemical Pharmacology, Volume 143
      Author(s): Shahrooz Vahedi, Eduardo E. Chufan, Suresh V. Ambudkar
      P-glycoprotein (P-gp), an ATP-dependent efflux pump, is linked to the development of multidrug resistance in cancer cells. However, the drug-binding sites and translocation pathways of this transporter are not yet well-characterized. We recently demonstrated the important role of tyrosine residues in regulating P-gp ATP hydrolysis via hydrogen bond formations with high affinity modulators. Since tyrosine is both a hydrogen bond donor and acceptor, and non-covalent interactions are key in drug transport, in this study we investigated the global effect of enrichment of tyrosine residues in the drug-binding pocket on the drug binding and transport function of P-gp. By employing computational analysis, 15 conserved residues in the drug-binding pocket of human P-gp that interact with substrates were identified and then substituted with tyrosine, including 11 phenylalanine (F72, F303, F314, F336, F732, F759, F770, F938, F942, F983, F994), two leucine (L339, L975), one isoleucine (I306), and one methionine (M949). Characterization of the tyrosine-rich P-gp mutant in HeLa cells demonstrated that this major alteration in the drug-binding pocket by introducing fifteen additional tyrosine residues is well tolerated and has no measurable effect on total or cell surface expression of this mutant. Although the tyrosine-enriched mutant P-gp could transport small to moderate size (<1000 Daltons) fluorescent substrates, its ability to transport large (>1000 Daltons) substrates such as NBD-cyclosporine A, Bodipy-paclitaxel and Bodipy-vinblastine was significantly decreased. This was further supported by the physico-chemical characterization of seventeen tested substrates, which revealed a negative correlation between drug transport and molecular size for the tyrosine-enriched P-gp mutant.
      Graphical abstract image

      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.014
      Issue No: Vol. 143 (2017)
  • Antibacterial activity of chensinin-1b, a peptide with a random coil
           conformation, against multiple-drug-resistant Pseudomonas aeruginosa
    • Authors: Dejing Shang; Xin Meng; Dongdong Zhang; Zhiru Kou
      Pages: 65 - 78
      Abstract: Publication date: 1 November 2017
      Source:Biochemical Pharmacology, Volume 143
      Author(s): Dejing Shang, Xin Meng, Dongdong Zhang, Zhiru Kou
      Nosocomial infections caused by Pseudomonas aeruginosa are difficult to treat due to the low permeability of its outer membrane as well as to its remarkable ability to acquire further resistance to antibiotics. Chensinin-1b exhibited antibacterial activity against the tested multiple-drug-resistant bacteria with a MIC ranging between 1.56 and 50μM, except E. cloacae strain 0320 (MREC0320), P. fluorescens strain 0322 (MRPF0322) and E. aerogenes strain 0320 (MREA0320). However, the MIC (25μM) of chensinin-1b to multiple-drug-resistant P. aeruginosa strain (MRPA 0108) was 16-fold higher than that observed to P. aeruginosa susceptible strain CGMCC 1.860 (PA1860). Chensinin-1b was able to disturb the integration of the cytoplasmic membrane of PA1860 and MRPA0108 cells similarly, but the outer membrane permeability of MRPA0108 cells was significantly lower. This low permeability was associated with increased expression of lipopolysaccharide (LPS) in the outer membrane and a decrease in negatively charged phospholipids in the outer membrane leaflet. In addition, the biofilm of MRPA0108 was responsible for the reduced susceptibility to chensinin-1b. A higher concentration of chensinin-1b (12.5µM) was required to maximally inhibit the formation of MRPA0108 biofilm. Notably, chensinin-1b inhibited the formation of MRPA0108 biofilm at concentrations below its MIC value by down-regulating the level of PelA, algD, and PslA gene transcription. Importantly, chensinin-1b had a significant antibacterial effect against MRPA0108 in vivo. Administration of chensinin-1b to mice infected with MRPA 0108 significantly increased survival by 50–70%. Moreover, chensinin-1b reduced the production of pro-inflammatory mediators and correspondingly reduced lung and liver tissue damage in the mouse model of septic shock induced by MRPA 0108. Collectively, these results suggest that chensinin-1b could be an effective antibiotic against multiple-drug-resistant bacterial strains.
      Graphical abstract image

      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.017
      Issue No: Vol. 143 (2017)
  • Activation of ALDH1A1 in MDA-MB-468 breast cancer cells that over-express
           CYP2J2 protects against paclitaxel-dependent cell death mediated by
           reactive oxygen species
    • Authors: Sarah E. Allison; Yongjuan Chen; Nenad Petrovic; Jian Zhang; Kirsi Bourget; Peter I. Mackenzie; Michael Murray
      Pages: 79 - 89
      Abstract: Publication date: 1 November 2017
      Source:Biochemical Pharmacology, Volume 143
      Author(s): Sarah E. Allison, Yongjuan Chen, Nenad Petrovic, Jian Zhang, Kirsi Bourget, Peter I. Mackenzie, Michael Murray
      Cytochrome P450 2J2 (CYP2J2) expression is elevated in breast and other tumours, and is known to be protective against cytotoxic agents that may be used in cancer chemotherapy. This study evaluated the mechanisms by which MDA-MB-468 breast cancer cells that stably expressed CYP2J2 (MDA-2J2 cells) were protected against killing by the anti-cancer agent paclitaxel. Compared to control cells caspase-3/7 activation by paclitaxel was lower in MDA-2J2 cells, while cell proliferation and colony formation following paclitaxel treatment were increased. Basal lipid peroxidation was lower in MDA-2J2 cells than in control cells, and the paclitaxel-mediated increase in peroxidation was attenuated. The mitochondrial complex III inhibitor antimycin A modulated basal and paclitaxel-activated reactive oxygen species (ROS) formation in control cells; paclitaxel-activated ROS production was also modulated by the NADPH oxidase inhibitor diphenyleneiodonium. Paclitaxel increased the formation of protein adducts by the reactive aldehyde 4-hydroxynonenal that is produced by lipid peroxidation; adduct formation was attenuated in MDA-2J2 cells. ALDH1A1 expression and activity was strongly upregulated in MDA-2J2 cells that was attributed to CYP2J2-derived 14,15-epoxyeicosatrienoic acid (14,15-EET); the 8,9- and 11,12-EET regioisomers did not activate ALDH1A1 expression. Silencing of ALDH1A1 restored the sensitivity of MDA-2J2 cells to paclitaxel, as indicated by a more pronounced decrease in proliferation, and greater increases in caspase activity and formation of ROS to levels comparable with control cells. Similar findings were observed with doxorubicin, sorafenib and staurosporine, that also promoted ROS-mediated cell death that was attenuated in MDA-2J2 cells and reversed by ALDH1A1 gene silencing. These findings implicate ALDH1A1 as an important gene that is activated in MDA-MB-468-derived cells that contain high levels of CYP2J2. ALDH1A1 modulates the production of ROS by anti-cancer agents such as paclitaxel and diminishes their efficacy. Future approaches could adapt this information to facilitate the targeting of ALDH1A1 to promote the efficacy of ROS-generating cytotoxic agents and enhance the treatment of breast cancer.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.020
      Issue No: Vol. 143 (2017)
  • Downregulation of TIGAR sensitizes the antitumor effect of physapubenolide
           through increasing intracellular ROS levels to trigger apoptosis and
           autophagosome formation in human breast carcinoma cells
    • Authors: Ting Ma; Yi Zhang; Chao Zhang; Jian-Guang Luo; Ling-Yi Kong
      Pages: 90 - 106
      Abstract: Publication date: 1 November 2017
      Source:Biochemical Pharmacology, Volume 143
      Author(s): Ting Ma, Yi Zhang, Chao Zhang, Jian-Guang Luo, Ling-Yi Kong
      Physapubenolide (PB) is a cytotoxic withanolide isolated from Physalis angulata that was used as a traditional Chinese medicine. In this study, we investigated the role of TIGAR and ROS in PB-induced apoptosis and autophagosome formation in human breast carcinoma MDA-MB-231 and MCF-7 cells. PB induced apoptosis by decreasing mitochondrial membrane potential and elevating the Bax/Bcl-2 protein expression ratio in MDA-MB-231 and MCF-7 cells. Caspase inhibitor Z-VAD-FMK treatment partly blocked PB induced cytotoxicity, suggesting that apoptosis serves as an important role in the anti-proliferative effect of PB. Meanwhile, PB induced autophagosome formation, as characterized by increased acridine orange-stained positive cells, accumulation of punctate LC3B fluorescence and a greater number of autophagic vacuoles under electron microscopy. Furthermore, PB inhibited autophagic flux as reflected by the overlapping of mCherry and GFP fluorescence when MDA-MB-231 cells were transfected with GFP-mCherry-LC3 plasmid. Depletion of LC3B, ATG5 or ATG7 reduced PB-induced cytotoxicity, indicating that autophagosome associated cell death participated in the anti-cancer effect of PB. Moreover, PB-induced apoptosis and autophagosome formation were linked to the generation of intracellular ROS, and pre-treatment with the antioxidant NAC obviously mitigated the effects. Interestingly, PB treatment slightly increased TIGAR expression at low concentrations but decreased TIGAR expression drastically at high concentrations. Downregulation of TIGAR by small interfering RNA augmented low concentrations of PB-induced apoptosis and autophagosome formation, which contributed to the observed anti-cancer effect of PB and were reversed by NAC pre-treatment. Consistently, in MDA-MB-231 or MCF-7 xenograft mouse model, PB suppressed tumor growth through ROS induced apoptosis and autophagosome associated cell death accompanied with the downregulation of TIGAR. Taken together, these results indicate that downregulation of TIGAR increased PB-induced apoptosis and autophagosomes associated cell death through promoting ROS generation in MDA-MB-231 and MCF-7 cells.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.018
      Issue No: Vol. 143 (2017)
  • Pyrrolidine dithiocarbamate (PDTC) inhibits inflammatory signaling via
           expression of regulator of calcineurin activity 1 (RCAN1)
    • Authors: Eun Hye Lee; Seon Sook Kim; Su Ryeon Seo
      Pages: 107 - 117
      Abstract: Publication date: 1 November 2017
      Source:Biochemical Pharmacology, Volume 143
      Author(s): Eun Hye Lee, Seon Sook Kim, Su Ryeon Seo
      Pyrrolidine dithiocarbamate (PDTC) is a thiol compound that elicits anti-inflammatory effects by inhibiting NF-κB signaling. In this study, we report that regulator of calcineurin activity 1 (RCAN1) expression is induced by PDTC treatment and that increased RCAN1 expression is dependent on the generation of reactive oxygen species (ROS) and activation of p38 MAPK and JNK signaling. We also report that the ability of PDTC to induce RCAN1 is mediated by activator protein-1 (AP-1)-dependent gene transcription, and identified a functional AP-1 binding site in the RCAN1 promoter by producing mutations and conducting chromatin immunoprecipitation (ChIP) analyses. Moreover, we show that the PDTC-mediated inhibitory effect on NF-κB signaling is significantly perturbed by knocking out RCAN1. Our data provide the first evidence that PDTC prevents in vivo expression of pro-inflammatory cytokines by inducing RCAN1 expression.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.011
      Issue No: Vol. 143 (2017)
  • Functional characterization of 21 allelic variants of dihydropyrimidinase
    • Authors: Eiji Hishinuma; Fumika Akai; Yoko Narita; Masamitsu Maekawa; Hiroaki Yamaguchi; Nariyasu Mano; Akifumi Oda; Noriyasu Hirasawa; Masahiro Hiratsuka
      Pages: 118 - 128
      Abstract: Publication date: 1 November 2017
      Source:Biochemical Pharmacology, Volume 143
      Author(s): Eiji Hishinuma, Fumika Akai, Yoko Narita, Masamitsu Maekawa, Hiroaki Yamaguchi, Nariyasu Mano, Akifumi Oda, Noriyasu Hirasawa, Masahiro Hiratsuka
      Dihydropyrimidinase (DHP, EC, encoded by the gene DPYS, is the second enzyme in the catabolic pathway of pyrimidine and of fluoropyrimidine drugs such as 5-fluorouracil, which are commonly used in anticancer treatment; DHP catalyzes the hydrolytic ring opening of dihydrouracil and dihydro-5-fluorouracil. DPYS mutations are known to contribute to interindividual variations in the toxicity of fluoropyrimidine drugs, but the functional characterization of DHP allelic variants remains inadequate. In this study, in vitro analysis was performed on 22 allelic variants of DHP by transiently expressing wild-type DHP and 21 DHP variants in 293FT cells and characterizing their enzymatic activities by using dihydrouracil and dihydro-5-fluorouracil as substrates. DHP expression levels and oligomeric forms were determined using immunoblotting and blue native PAGE, respectively, and the stability of the DHP variants was assessed by examining the proteins in variant-transfected cells treated with cycloheximide or bortezomib. Moreover, three kinetic parameters, Km , Vmax , and intrinsic clearance (Vmax/Km ), for the hydrolysis of dihydrouracil and dihydro-5-fluorouracil were determined. We found that 5/21 variants showed significantly decreased intrinsic clearance as compared to wild-type DHP, and that 9/21 variants were expressed at low levels and were inactive due to proteasome-mediated degradation. The band patterns observed in the immunoblotting of blue native gels corresponded to DHP activity, and, notably, 18/21 DHP variants exhibited decreased or null enzymatic activity and these variants also showed a drastically reduced ability to form large oligomers. Thus, detection of DPYS genetic polymorphisms might facilitate the prediction severe adverse effects of fluoropyrimidine-based treatments.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.06.121
      Issue No: Vol. 143 (2017)
  • Cytochrome P450 3A selectively affects the pharmacokinetic interaction
           between erlotinib and docetaxel in rats
    • Authors: Xuan Qin; Jian Lu; Peili Wang; Peipei Xu; Mingyao Liu; Xin Wang
      Pages: 129 - 139
      Abstract: Publication date: 1 November 2017
      Source:Biochemical Pharmacology, Volume 143
      Author(s): Xuan Qin, Jian Lu, Peili Wang, Peipei Xu, Mingyao Liu, Xin Wang
      Erlotinib as a first-line drug is used in non-small cell lung cancer (NSCLC) patients with sensitive EGFR mutations, while resistance to this drug will occur after several years of treatment. Therefore, the microtubule disturber docetaxel is introduced as combined regimen in clinical trials. This report investigated the potentials and mechanisms of drug-drug interaction (DDI) between erlotinib and docetaxel using wild type (WT) and Cyp3a1/2 knockout (KO) rats. The erlotinib O-demethylation and docetaxel hydroxylation reactions in the absence or the presence of another drug were analyzed in vitro via the assay of rat liver microsomes. In whole animal studies, erlotinib and docetaxel were given to WT and KO rats individually or jointly, and the pharmacokinetic profiles of these two drugs were analyzed and compared among different groups. The results showed that docetaxel not only inhibited the CYP3A-mediated biotransformation of erlotinib in vitro, but also significantly increased the maximum concentration and systemic exposure of erlotinib in vivo in WT rats. In contrast, the DDI was significantly attenuated in KO rats. On the other hand, erlotinib did not influence docetaxel either in vitro biotransformation or in vivo pharmacokinetic behaviors. These results exhibited the potentials of erlotinib-docetaxel interaction and indicated that the CYP3A played the perpetrating role of docetaxel on erlotinib in rats. A better understanding of this DDI with CYP3A may help the regulation of the use of these two drugs, avoid potential problems, and adjust dose carefully and early in clinic.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.013
      Issue No: Vol. 143 (2017)
  • Curcumin attenuates oxidative stress induced NFκB mediated inflammation
           and endoplasmic reticulum dependent apoptosis of splenocytes in diabetes
    • Authors: Kahkashan Rashid; Sayantani Chowdhury; Sumit Ghosh; Parames C. Sil
      Pages: 140 - 155
      Abstract: Publication date: 1 November 2017
      Source:Biochemical Pharmacology, Volume 143
      Author(s): Kahkashan Rashid, Sayantani Chowdhury, Sumit Ghosh, Parames C. Sil
      The present study was aimed to determine the curative role of curcumin against diabetes induced oxidative stress and its associated splenic complications. Diabetes was induced in the experimental rats via the intraperitoneal administration of a single dose of STZ (65mgkg−1 body weight). Increased blood glucose and intracellular ROS levels along with decreased body weight, the activity of cellular antioxidant enzymes and GSH/GSSG ratio were observed in the diabetic animals. Histological assessment showed white pulp depletion and damaged spleen anatomy in these animals. Oral administration of curcumin at a dose of 100mgkg−1 body weight daily for 8weeks, however, restored these alterations. Investigation of the mechanism of hyperglycemia induced oxidative stress mediated inflammation showed upregulation of inflammatory cytokines, chemokines, adhesion molecules and increased translocation of NFκB into the nucleus. Moreover, ER stress dependent cell death showed induction of eIF2α and CHOP mediated signalling pathways as well as increment in the expression of GRP78, Caspase-12, Calpain-1, phospho JNK, phospho p38 and phospho p53 in the diabetic group. Alteration of Bax/Bcl-2 ratio; disruption of mitochondrial membrane potential, release of cytochrome-C from mitochondria and upregulation of caspase 3 along with the formation of characteristic DNA ladder in the diabetic animals suggest the involvement of mitochondria dependent apoptotic pathway in the splenic cells. Treatment with curcumin could, however, protect cells from inflammatory damage and ER as well as mitochondrial apoptotic death by restoring the alterations of these parameters. Our results suggest that curcumin has the potential to act as an anti-diabetic, anti-oxidant, anti-inflammatory and anti-apoptotic therapeutic against diabetes mediated splenic damage.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.009
      Issue No: Vol. 143 (2017)
  • The impact of cellular senescence in skin ageing: A notion of mosaic and
           therapeutic strategies
    • Authors: Marie Toutfaire; Emilie Bauwens; Florence Debacq-Chainiaux
      Pages: 1 - 12
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Marie Toutfaire, Emilie Bauwens, Florence Debacq-Chainiaux
      Cellular senescence is now recognized as one of the nine hallmarks of ageing. Recent data show the involvement of senescent cells in tissue ageing and some age-related diseases. Skin represents an ideal model for the study of ageing. Indeed, skin ageing varies between individuals depending on their chronological age but also on their exposure to various exogenous factors (mainly ultraviolet rays). If senescence traits can be detected with ageing in the skin, the senescent phenotype varies among the various skin cell types. Moreover, the origin of cellular senescence in the skin is still unknown, and multiple origins are possible. This reflects the mosaic of skin ageing. Senescent cells can interfere with their microenvironment, either via the direct secretion of factors (the senescence-associated secretory phenotype) or via other methods of communication, such as extracellular vesicles. Knowledge regarding the impact of cellular senescence on skin ageing could be integrated into dermatology research, especially to limit the appearance of senescent cells after photo(chemo)therapy or in age-related skin diseases. Therapeutic approaches include the clearance of senescent cells via the use of senolytics or via the cooperation with the immune system.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.04.011
      Issue No: Vol. 142 (2017)
  • Repurposing bacterial toxins for intracellular delivery of therapeutic
    • Authors: Greg L. Beilhartz; Seiji N. Sugiman-Marangos; Roman A. Melnyk
      Pages: 13 - 20
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Greg L. Beilhartz, Seiji N. Sugiman-Marangos, Roman A. Melnyk
      Despite enormous efforts, achieving efficacious levels of proteins inside mammalian cells remains one of the greatest challenges in biologics-based drug discovery and development. The inability of proteins to readily cross biological membranes precludes access to the wealth of intracellular targets and applications that lie within mammalian cells. Existing methods of delivery commonly suffer from an inability to target specific cells and tissues, poor endosomal escape, and limited in vivo efficacy. The aim of the present commentary is to highlight the potential of certain classes of bacterial toxins, which naturally deliver a large protein into the cytosolic compartment of target cells after binding a host cell-surface receptor with high affinity, as robust protein delivery platforms. We review the progress made in recent years toward demonstrating the utility of these systems at delivering a wide variety of protein cargo, with special attention paid to three distinct toxin-based platforms. We contend that with recent advances in protein deimmunization strategies, bacterial toxins are poised to introduce biologics into the inner sanctum of cells and treat a wealth of heretofore untreatable diseases with a new generation of therapeutics.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.04.009
      Issue No: Vol. 142 (2017)
  • The overexpression of CPR and P450 3A4 in pancreatic cancer cells changes
           the metabolic profile and increases the cytotoxicity and pro-apoptotic
           activity of acridine antitumor agent, C-1748
    • Authors: Barbara Borowa-Mazgaj; Anna Mróz; Ewa Augustin; Ewa Paluszkiewicz; Zofia Mazerska
      Pages: 21 - 38
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Barbara Borowa-Mazgaj, Anna Mróz, Ewa Augustin, Ewa Paluszkiewicz, Zofia Mazerska
      Drug resistance is one of the major causes of pancreatic cancer treatment failure. Thus, it is still imperative to develop new active compounds and novel approach to improve drug efficacy. Here we present 9-amino-1-nitroacridine antitumor agent, C-1748, developed in our laboratory, as a candidate for pancreatic cancer treatment. We examined (i) the cellular response of pancreatic cancer cell lines: Panc-1, MiaPaCa-2, BxPC-3 and AsPC-1, differing in expression levels of commonly mutated genes for this cancer type, to C-1748 treatment and (ii) the role of P450 3A4 isoenzyme and cytochrome P450 reductase (CPR) in the modulation of this response. C-1748 exhibited the highest cytotoxic activity against MiaPaCa-2, while AsPC-1 cells were the most resistant (IC50: 0.015, 0.075µM, respectively). A considerable amount of apoptosis was detected in Panc-1 and MiaPaCa-2 cells but only limited apoptosis was observed in AsPC-1 and BxPC-3 cells as indicated by morphological changes and biochemical markers. Furthermore, only AsPC-1 cells underwent senescence. Since AsPC-1 cells were the most resistant to C-1748 as evidenced by the lowest P450 3A4 and CPR protein levels, this cell line was subjected to transient transfection either with P450 3A4 or CPR gene. The overexpression of P450 3A4 or CPR changed the pro-apoptotic activity of C-1748 and sensitized AsPC-1 cells to this drug compared to wild-type cells. However, metabolism was changed significantly only for CPR overexpressing cells. In conclusion, the antitumor effectiveness of C-1748 would be improved by multi-drug therapy with chemotherapeutics, that are able to induce P450 3A4 and/or CPR gene expression.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.06.124
      Issue No: Vol. 142 (2017)
  • A high throughput assay to identify substrate-selective inhibitors of the
           ERK protein kinases
    • Authors: Chad J. Miller; Yagmur Muftuoglu; Benjamin E. Turk
      Pages: 39 - 45
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Chad J. Miller, Yagmur Muftuoglu, Benjamin E. Turk
      Extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylate a variety of substrates important for survival and proliferation, and their activity is frequently deregulated in tumors. ERK pathway inhibitors have shown clinical efficacy as anti-cancer drugs, but most patients eventually relapse due to reactivation of the pathway. One factor limiting the efficacy of current therapeutics is the difficulty in reaching clinically effective inhibition of the ERK pathway in the absence of on-target toxicities. Here, we describe an assay suitable for high throughput screening to discover substrate selective ERK1/2 inhibitors, which may have a larger therapeutic window than conventional inhibitors. Specifically, we aim to target a substrate-binding pocket within the ERK1/2 catalytic domain outside of the catalytic cleft. The assay uses an AlphaScreen format to detect phosphorylation of a high-efficiency substrate harboring an essential docking site motif. Pilot screening established that the assay is suitably robust for high-throughput screening. Importantly, the assay can be conducted at high ATP concentrations, which we show reduces the discovery of conventional ATP-competitive inhibitors. These studies provide the basis for high-throughput screens to discover new classes of non-conventional ERK1/2 inhibitors.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.06.127
      Issue No: Vol. 142 (2017)
  • Geranylnaringenin (CG902) inhibits constitutive and inducible STAT3
           activation through the activation of SHP-2 tyrosine phosphatase
    • Authors: Yena Jin; Yae Jin Yoon; Yoon Jung Jeon; Jiyeon Choi; Yu-Jin Lee; Joonku Lee; Sangho Choi; Oyekanmi Nash; Dong Cho Han; Byoung-Mog Kwon
      Pages: 46 - 57
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Yena Jin, Yae Jin Yoon, Yoon Jung Jeon, Jiyeon Choi, Yu-Jin Lee, Joonku Lee, Sangho Choi, Oyekanmi Nash, Dong Cho Han, Byoung-Mog Kwon
      The roles and significance of signal transducer and activator of transcription 3 (STAT3) in human cancers have been extensively studied and STAT3 is a promising therapeutic target for cancer drug discovery. During the screening of natural products to identify STAT3 inhibitors, we identified geranylnaringenin (CG902), which decreased luciferase activity in a dose-dependent manner. CG902 specifically inhibited STAT3 phosphorylation at Tyr-705 in DU145 prostate cancer cells and decreased the expression levels of STAT3 target genes, such as cyclin D1, cyclin A, and survivin. Notably, the knockdown of the SHP-2 gene by small interfering RNA suppressed the ability of CG902 to inhibit STAT3 activation and CG902 activated the phosphatase activity of SHP-2 through direct interaction with SHP-2 and induced the phosphorylation of SHP-2. The interactions between CG902 and SHP-2 were confirmed by pull-down assay using biotinylated CG902. The interactions were also further validated by the drug affinity responsive target stability (DARTS) and cellular thermal shift assay (CETSA). The inhibitory effect of CG902 on cell growth was confirmed using the DU145 mouse xenograft model. We propose that CG902 inhibits STAT3 activity through a mechanism that involves the interactions between CG902 and SHP-2, and the phosphorylation of SHP-2, which leads to SHP-2 activation in DU145 cells. CG902 is the first compound to regulate STAT3 activity via the modulation of SHP-2 activity, and our results suggest that CG902 is a novel inhibitor of the STAT3 pathway and an activator of SHP-2, and may be a useful lead molecule for the development of a therapeutic STAT3 inhibitor.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.06.131
      Issue No: Vol. 142 (2017)
  • Eriocalyxin B, a novel autophagy inducer, exerts anti-tumor activity
           through the suppression of Akt/mTOR/p70S6K signaling pathway in breast
    • Authors: Xunian Zhou; Grace Gar-Lee Yue; Andrew Man-Lok Chan; Stephen Kwok-Wing Tsui; Kwok-Pui Fung; Handong Sun; Jianxin Pu; Clara Bik-San Lau
      Pages: 58 - 70
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Xunian Zhou, Grace Gar-Lee Yue, Andrew Man-Lok Chan, Stephen Kwok-Wing Tsui, Kwok-Pui Fung, Handong Sun, Jianxin Pu, Clara Bik-San Lau
      Eriocalyxin B (EriB), a natural ent-kaurane diterpenoid presented in the plant Isodon eriocalyx var. laxiflora, has been reported to diminish angiogenesis-dependent breast tumor growth. In the present study, the effects of EriB on human breast cancer and its underlying mechanisms were further investigated. The in vitro anti-breast cancer activity of EriB was determined using MCF-7 and MDA-MB-231 cell lines. MDA-MB-231 xenograft model of human breast cancer was also established to explore the anti-tumor effect in vivo. We found that EriB was able to induce apoptosis accompanied by the activation of autophagy, which was evidenced by the increased accumulation of autophagosomes, acidic vesicular organelles formation, the microtubule-associated protein 1A/1B-light chain 3B-II (LC3B-II) conversion from LC3B-I and p62 degradation. Meanwhile, EriB treatment time-dependently decreased the phosphorylation of Akt, mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase (p70S6K), leading to the inhibition of Akt/mTOR/p70S6K signaling pathway. Moreover, the blockage of autophagy obviously sensitized EriB-induced cell death, which suggested the cytoprotective function of autophagy in both MCF-7 and MDA-MB-231 cells. Interestingly, the autophagic features and apoptosis induction were prevented by reactive oxygen species (ROS) scavenger N-acetyl-l-cysteine, indicating that ROS played an essential role in the mediation of EriB-induced cell death. Furthermore, in MDA-MB-231 xenograft model, EriB displayed a significant anti-tumor effect via the activation of autophagy and apoptosis in breast tumor cells. Taken together, our findings firstly demonstrated that EriB suppressed breast cancer cells growth both in vitro and in vivo, and thus could be developed as a promising anti-breast tumor agent.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.06.133
      Issue No: Vol. 142 (2017)
  • Walsuronoid B induces mitochondrial and lysosomal dysfunction leading to
           apoptotic rather than autophagic cell death via ROS/p53 signaling pathways
           in liver cancer
    • Authors: Ya-di Geng; Chao Zhang; Jian-li Lei; Pei Yu; Yuan-zheng Xia; Hao Zhang; Lei Yang; Ling-yi Kong
      Pages: 71 - 86
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Ya-di Geng, Chao Zhang, Jian-li Lei, Pei Yu, Yuan-zheng Xia, Hao Zhang, Lei Yang, Ling-yi Kong
      Walsuronoid B is a limonoid compound extracted from Walsura robusta. Previous studies have shown that limonoid compounds possess anti-cancer potential, although the molecular mechanism of this activity remains elusive. In this study, we demonstrated for the first time that walsuronoid B inhibited cell proliferation in several human cancer lines. Liver cancer cells (HepG2 and Bel-7402) were chosen for their high sensitivity to walsuronoid B. Walsuronoid B induced cell death through G2/M phase arrest and apoptosis and induced the accumulation of autophagosomes through the suppression of mTOR signaling, which serves as a cell survival mechanism and prevents cell death. We further examined the molecular mechanisms and found that walsuronoid B-induced dysfunction of the mitochondria and lysosomes rather than the endoplasmic reticulum contributed to its cell death effect. Walsuronoid B enhanced the generation of hydrogen peroxide, nitric oxide and superoxide anion radical, resulting in elevated levels of reactive oxygen species (ROS). In addition, ROS induced by walsuronoid B upregulated p53 levels; conversely, p53 stimulated ROS. These results suggested that ROS and p53 reciprocally promoted each other’s production and cooperated to induce liver cancer cell death. We found that the induction of ROS and p53 significantly triggered G2/M phase arrest and mitochondrial and lysosomal apoptosis. Finally, walsuronoid B suppressed tumor growth in vivo with few side effects. In summary, our findings demonstrated that walsuronoid B caused G2/M phase arrest and induced mitochondrial and lysosomal apoptosis through the ROS/p53 signaling pathway in human liver cancer cells in vitro and in vivo.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.06.134
      Issue No: Vol. 142 (2017)
  • A TSPO ligand prevents mitochondrial sterol accumulation and dysfunction
           during myocardial ischemia-reperfusion in hypercholesterolemic rats
    • Authors: Julien Musman; Stéphanie Paradis; Mathieu Panel; Sandrine Pons; Caroline Barau; Claudio Caccia; Valerio Leoni; Bijan Ghaleh; Didier Morin
      Pages: 87 - 95
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Julien Musman, Stéphanie Paradis, Mathieu Panel, Sandrine Pons, Caroline Barau, Claudio Caccia, Valerio Leoni, Bijan Ghaleh, Didier Morin
      A major cause of cell death during myocardial ischemia-reperfusion is mitochondrial dysfunction. We previously showed that the reperfusion of an ischemic myocardium was associated with an accumulation of cholesterol into mitochondria and a concomitant strong generation of auto-oxidized oxysterols. The inhibition of mitochondrial accumulation of cholesterol abolished the formation of oxysterols and prevented mitochondrial injury at reperfusion. The aim of this study was to investigate the impact of hypercholesterolemia on sterol and oxysterol accumulation in rat cardiac cytosols and mitochondria and to analyse the effect of the translocator protein ligand 4′-chlorodiazepam on this accumulation and mitochondrial function. Hypercholesterolemic ZDF fa/fa rats or normocholesterolemic lean rats were submitted to 30min of coronary artery occlusion followed by 15min reperfusion where cardiac cytosols and mitochondria were isolated. Hypercholesterolemia increased the cellular cardiac concentrations of cholesterol, cholesterol precursors and oxysterols both in cytosol and mitochondria in non-ischemic conditions. It also amplified the accumulation of all these compounds in cardiac cells and the alteration of mitochondrial function with ischemia-reperfusion. Administration of 4′-chlorodiazepam to ZDF fa/fa rats had no effect on the enhancement of sterols and oxysterols observed in the cytosols but inhibited cholesterol transfer to the mitochondria. It also alleviated the mitochondrial accumulation of all the investigated sterols and oxysterols. This was associated with a restoration of oxidative phosphorylation and a prevention of mitochondrial transition pore opening. The inhibition of cholesterol accumulation with TSPO ligands represents an interesting strategy to protect the mitochondria during ischemia-reperfusion in hypercholesterolemic conditions.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.06.125
      Issue No: Vol. 142 (2017)
  • Receptor activity-modifying protein dependent and independent activation
           mechanisms in the coupling of calcitonin gene-related peptide and
           adrenomedullin receptors to Gs
    • Authors: Michael J. Woolley; Christopher A. Reynolds; John Simms; Christopher S. Walker; Juan Carlos Mobarec; Michael L. Garelja; Alex C. Conner; David R. Poyner; Debbie L. Hay
      Pages: 96 - 110
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Michael J. Woolley, Christopher A. Reynolds, John Simms, Christopher S. Walker, Juan Carlos Mobarec, Michael L. Garelja, Alex C. Conner, David R. Poyner, Debbie L. Hay
      Calcitonin gene-related peptide (CGRP) or adrenomedullin (AM) receptors are heteromers of the calcitonin receptor-like receptor (CLR), a class B G protein-coupled receptor, and one of three receptor activity-modifying proteins (RAMPs). How CGRP and AM activate CLR and how this process is modulated by RAMPs is unclear. We have defined how CGRP and AM induce Gs-coupling in CLR-RAMP heteromers by measuring the effect of targeted mutagenesis in the CLR transmembrane domain on cAMP production, modeling the active state conformations of CGRP and AM receptors in complex with the Gs C-terminus and conducting molecular dynamics simulations in an explicitly hydrated lipidic bilayer. The largest effects on receptor signaling were seen with H295A5.40b, I298A5.43b, L302A5.47b, N305A5.50b, L345A6.49b and E348A6.52b, F349A6.53b and H374A7.47b (class B numbering in superscript). Many of these residues are likely to form part of a group in close proximity to the peptide binding site and link to a network of hydrophilic and hydrophobic residues, which undergo rearrangements to facilitate Gs binding. Residues closer to the extracellular loops displayed more pronounced RAMP or ligand-dependent effects. Mutation of H3747.47b to alanine increased AM potency 100-fold in the CGRP receptor. The molecular dynamics simulation showed that TM5 and TM6 pivoted around TM3. The data suggest that hydrophobic interactions are more important for CLR activation than other class B GPCRs, providing new insights into the mechanisms of activation of this class of receptor. Furthermore the data may aid in the understanding of how RAMPs modulate the signaling of other class B GPCRs.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.005
      Issue No: Vol. 142 (2017)
  • Sodium butyrate regulates Th17/Treg cell balance to ameliorate uveitis via
           the Nrf2/HO-1 pathway
    • Authors: Xiaoqing Chen; Wenru Su; Taoshang Wan; Jianfeng Yu; Wenjie Zhu; Fen Tang; Guangming Liu; Nancy Olsen; Dan Liang; Song Guo Zheng
      Pages: 111 - 119
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Xiaoqing Chen, Wenru Su, Taoshang Wan, Jianfeng Yu, Wenjie Zhu, Fen Tang, Guangming Liu, Nancy Olsen, Dan Liang, Song Guo Zheng
      Autoimmune uveitis, a group of potentially blinding intraocular inflammatory diseases, remains a therapeutic challenge for ophthalmologists. Butyrates, which belong to the short-chain fatty acid family, possess immunomodulatory properties and therapeutic potential in several inflammatory disorders. However, the roles of butyrates in uveitis and their underlying immunomodulatory mechanisms remain elusive. Here, we report that treatment with sodium butyrate (NaB) significantly attenuated the ocular inflammatory response in mice with experimental autoimmune uveitis (EAU) at 14days after immunization, with significant decreases in inflammatory cell infiltration and inflammatory cytokine production in the retinas. Furthermore, NaB treatment decreased the frequency and number of Th17 cells and increased the frequency and number of T regulatory (Treg) cells in both draining lymph nodes and spleens of EAU mice. In vitro, NaB treatment directly converted the differentiation of naive T cells from Th17 cells toward Treg cells. Mechanistically, the NaB-mediated inhibition of Th17 cell differentiation may occur via inhibition of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1)/interleukin-6 receptor pathway. Moreover, the NaB-mediated inhibition on Th17 cell differentiation and uveitis were abrogated when an HO-1 inhibitor, SnPP, was used. These findings suggest that NaB inverts the differentiation of Th17 cells toward Treg cells and attenuates experimental autoimmune uveitis by modulating the Nrf2/HO-1 pathway.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.06.136
      Issue No: Vol. 142 (2017)
  • 4-Aroyl-3-hydroxy-5-phenyl-1H-pyrrol-2(5H)-ones as N-formyl peptide
           receptor 1 (FPR1) antagonists
    • Authors: Liliya N. Kirpotina; Igor A. Schepetkin; Andrei I. Khlebnikov; Olga I. Ruban; Yunjun Ge; Richard D. Ye; Douglas J. Kominsky; Mark T. Quinn
      Pages: 120 - 132
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Liliya N. Kirpotina, Igor A. Schepetkin, Andrei I. Khlebnikov, Olga I. Ruban, Yunjun Ge, Richard D. Ye, Douglas J. Kominsky, Mark T. Quinn
      Formyl peptide receptors (FPRs) are expressed on a variety of leukocytes and play important roles in inflammation. Thus, FPR antagonists may represent novel therapeutics for modulating innate immunity and treating inflammatory diseases. Previously, 1H-pyrrol-2(5H)-ones were reported to be potent and competitive FPR1 antagonists. In the present studies, 42 additional 1H-pyrrol-2(5H)-one analogs were evaluated for FPR1 antagonist activity. We identified a number of novel competitive FPR1 antagonists that inhibited N-formylmethionyl-leucyl-phenylalanine (fMLF)-induced intracellular Ca2+ mobilization in FPR1-transfected HL60 cells and effectively competed with WKYMVm-FITC for binding to FPR1 in FPR1-transfected RBL cells. The most active pyrroles inhibited human neutrophil Ca2+ flux, chemotaxis, and adhesion to human epithelial cells, with the most potent being compounds 14 (4-benzoyl-1-hexyl-3-hydroxy-5-(4-hydroxy-3-methoxyphenyl)-2,5-dihydro-1H-pyrrol-2-one) and 17 (4-benzoyl-5-(2,5-dimethoxyphenyl)-3-hydroxy-1-(2-methoxyethyl)-2,5-dihydro-1H-pyrrol-2-one). In addition, these FPR1 antagonists inhibited fMLF-induced phosphorylation of extracellular signal-regulated kinases (ERK1/2) in FPR1-RBL cells, differentiated HL-60 cells, and human neutrophils. Most of the antagonists were specific for FPR1 and did not inhibit WKYMVM/WKYMVm-induced intracellular Ca2+ mobilization in FPR2-HL60 cells, FPR3-HL60 cells, or interleukin 8-induced Ca2+ flux in human neutrophils. Moreover, molecular modeling showed that the active pyrroles had a significantly higher degree of similarity with the FPR1 antagonist pharmacophore template as compared to inactive analogs. Thus, the 4-aroyl-3-hydroxy-5-phenyl-1H-pyrrol-2(5H)-one scaffold represents an important backbone for the development of novel FPR1 antagonists and could provide important clues for understanding the molecular structural requirements of FPR1 antagonists.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.004
      Issue No: Vol. 142 (2017)
  • Suppressing mPGES-1 expression by sinomenine ameliorates inflammation and
    • Authors: Hua Zhou; Jian-Xin Liu; Jin-Fang Luo; Chun-Song Cheng; Elaine Lai-Han Leung; Ying Li; Xiao-Hui Su; Zhong-Qiu Liu; Ting-Bo Chen; Fu-Gang Duan; Yan Dong; Yi-Han Zuo; Chong Li; Chon Kit Lio; Ting Li; Pei Luo; Ying Xie; Xiao-Jun Yao; Pei-Xun Wang; Liang Liu
      Pages: 133 - 144
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Hua Zhou, Jian-Xin Liu, Jin-Fang Luo, Chun-Song Cheng, Elaine Lai-Han Leung, Ying Li, Xiao-Hui Su, Zhong-Qiu Liu, Ting-Bo Chen, Fu-Gang Duan, Yan Dong, Yi-Han Zuo, Chong Li, Chon Kit Lio, Ting Li, Pei Luo, Ying Xie, Xiao-Jun Yao, Pei-Xun Wang, Liang Liu
      Recently, microsomal prostaglandin E synthase 1 (mPGES-1) has attracted much attention from pharmacologists as a promising strategy and an attractive target for treating various types of diseases including rheumatoid arthritis (RA), which could preserve the anti-inflammatory effect while reducing the adverse effects often occur during administration of non-steroidal anti-inflammatory drugs (NSAIDs). Here, we report that sinomenine (SIN) decreased prostaglandin (PG)E2 levels without affecting prostacyclin (PG)I2 and thromboxane (TX)A2 synthesis via selective inhibiting mPGES-1 expression, a possible reason of low risk of cardiovascular event compared with NSAIDs. In addition, mPGES-1 protein expression was down-regulated by SIN treatment in the inflamed paw tissues both in carrageenan-induced edema model in rats and the collagen-II induced arthritis (CIA) model in DBA mice. More interestingly, SIN suppressed the last step of mPGES-1 gene expression by decreasing the DNA binding ability of NF-κB, paving a new way for drug discovery.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.010
      Issue No: Vol. 142 (2017)
  • Sulodexide prevents activation of the PLA2/COX-2/VEGF inflammatory pathway
           in human retinal endothelial cells by blocking the effect of AGE/RAGE
    • Authors: Giovanni Giurdanella; Francesca Lazzara; Nunzia Caporarello; Gabriella Lupo; Carmelina Daniela Anfuso; Chiara M. Eandi; Gian Marco Leggio; Filippo Drago; Claudio Bucolo; Salvatore Salomone
      Pages: 145 - 154
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Giovanni Giurdanella, Francesca Lazzara, Nunzia Caporarello, Gabriella Lupo, Carmelina Daniela Anfuso, Chiara M. Eandi, Gian Marco Leggio, Filippo Drago, Claudio Bucolo, Salvatore Salomone
      Diabetic retinopathy is characterized by the breakdown of endothelial blood-retinal barrier. We tested the hypothesis that sulodexide (SDX), a highly purified glycosaminoglycan composed of 80% iduronylglycosaminoglycan sulfate and 20% dermatan sulfate, protects human retinal endothelial cells (HREC) from high glucose (HG)-induced damage, through the suppression of inflammatory ERK/cPLA2/COX-2/PGE2 pathway, by blocking the effect of advanced glycation end-products (AGEs). HREC were treated with HG (25mM) or AGEs (glycated-BSA, 2mg/ml) for 48h, with or without SDX (60μg/ml) or aflibercept (AFL, 40μg/ml), a VEGF-trap. SDX protected HREC from HG-induced damage (MTT and LDH release) and preserved their blood-retinal barrier-like properties (Trans Endothelial Electrical Resistance and junction proteins, claudin-5, VE-cadherin and occludin, immunofluorescence and immunoblot) as well as their angiogenic potential (Tube Formation Assay). Both HG and AGEs increased phosphoERK and phospho-cPLA2, an effect counteracted by SDX and, less efficiently, by AFL. Both HG and exogenous VEGF (80ng/ml) increased PGE2 release, an effect partially reverted by SDX for HG and by AFL for VEGF. Analysis of NFκB activity revealed that HG increased the abundance of p65 in the nuclear fraction (nuclear translocation), an effect entirely reverted by SDX, but only partially by AFL. SDX, AFL and SDX+AFL protected HREC even when added 24h after HG. These data show that SDX protects HREC from HG damage and suggest that it counteracts the activation of ERK/cPLA2/COX-2/PGE2 pathway by reducing AGE-related signaling and downstream NFκB activity. This mechanism, partially distinct from VEGF blockade, may contribute to the therapeutic effect of SDX.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.06.130
      Issue No: Vol. 142 (2017)
  • Xenopus GLP-1-inspired discovery of novel GLP-1 receptor agonists as
           long-acting hypoglycemic and insulinotropic agents with significant
           therapeutic potential
    • Authors: Jing Han; Xinyu Chen; Yiyun Wang; Yingying Fei; Feng Zhou; Ying Zhang; Lin Liu; Pengbin Si; Junjie Fu
      Pages: 155 - 167
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Jing Han, Xinyu Chen, Yiyun Wang, Yingying Fei, Feng Zhou, Ying Zhang, Lin Liu, Pengbin Si, Junjie Fu
      We here report the discovery and therapeutic efficacy of a novel series of glucagon-like peptide-1 (GLP-1) receptor agonists derived from Xenopus GLP-1. First, five amino acid-mutated Xenopus GLP-1s were synthesized, and xGLP-3 with the best acute and long-acting hypoglycemic activity was selected for further modification. Next, PEGylation of xGLP-3 was performed at specific sites, which were determined using cysteine mutagenesis scanning. Twelve PEGylated conjugates tethered with Mal-PEGs of 1, 2, and 5kDa were synthesized. Conjugates 7b and 7c, which exhibited comparable hypoglycemic and insulinotropic effects to Gly8-GLP-1, were selected for in-depth evaluation. It was found that 7b and 7c exhibited prolonged in vivo half-life and improved pharmacokinetic behaviors. The long-term hypoglycemic effects of 7b and 7c were further confirmed by pre-OGTT and multiple OGTT. Importantly, long-term administration of 7b or 7c in db/db mice achieved beneficial effects on body weight loss, food intake and HbA1c reduction, and glucose tolerance normalization. These preclinical studies indicate the promising role of 7b and 7c as long-acting type 2 diabetes therapeutics. In addition, our research demonstrated the feasibility of developing novel antidiabetic agents based on Xenopus GLP-1.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.06.132
      Issue No: Vol. 142 (2017)
  • Study of new interactions of glitazone’s stereoisomers and the
           endogenous ligand 15d-PGJ2 on six different PPAR gamma proteins
    • Authors: Samuel Álvarez-Almazán; Martiniano Bello; Feliciano Tamay-Cach; Marlet Martínez-Archundia; Diana Alemán-González-Duhart; José Correa-Basurto; Jessica Elena Mendieta-Wejebe
      Pages: 168 - 193
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Samuel Álvarez-Almazán, Martiniano Bello, Feliciano Tamay-Cach, Marlet Martínez-Archundia, Diana Alemán-González-Duhart, José Correa-Basurto, Jessica Elena Mendieta-Wejebe
      Diabetes mellitus is a chronic disease characterized by hyperglycemia, insulin resistance and hyperlipidemia. Glitazones or thiazolidinediones (TZD) are drugs that act as insulin-sensitizing agents whose molecular target is the peroxisome proliferator-activated receptor gamma (PPARγ). The euglycemic action of TZD has been linked with the induction of type 4 glucose transporter. However, it has been shown that the effect of TZD depends on the specific stereoisomer that interacts with PPARγ. Therefore, this work is focused on exploring the interactions and geometry adopted by glitazone's stereoisomers and one endogenous ligand on different conformations of the six crystals of the PPARγ protein using molecular docking and molecular dynamics (MD) simulations accompanied by the MMGBSA approach. Specifically, the 2,4-thiazolidinedione ring, pioglitazone (PIO), rosiglitazone (ROSI) and troglitazone (TRO) stereoisomers (exogenous ligands), as well as the endogenous ligand 15d-PGJ2, were evaluated. The six crystallographic structures of PPARγ are available at Protein Data Bank as the PDB entries 2PRG, 4PRG, 3T03, 1I7I, 1FM6, and 4EMA. According to the results, a boomerang shape and a particular location of ligands were found with low variations according to the protein conformations. The 15d-PGJ2, TZD, PIO, ROSI and (S,S)-TRO enantiomers were mostly stabilized by twenty hydrophobic residues: Phe226, Pro227, Leu228, Ile281, Phe282, Cys285, Ala292, Ile296, Ile326, Tyr327, Met329, Leu330, Leu333, Met334, Val339, Ile341, Met348, Leu353, Phe363 and Met364. Most hydrogen bond interactions were found between the polar groups of ligands with Arg288, Ser289, Lys367, Gln286, His323, Glu343 and His449 residues. An energetic analysis revealed binding free energy trends that supported known experimental findings of other authors describing better binding properties for PIO, ROSI and (S,S)-TRO than for 15d-PGJ2 and the TZD ring.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.012
      Issue No: Vol. 142 (2017)
  • Pregnane X receptor (PXR) deficiency improves high fat diet-induced
           obesity via induction of fibroblast growth factor 15 (FGF15) expression
    • Authors: Li-Yang Zhao; Jia-Yi Xu; Zhe Shi; Neal A. Englert; Shu-Yun Zhang
      Pages: 194 - 203
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Li-Yang Zhao, Jia-Yi Xu, Zhe Shi, Neal A. Englert, Shu-Yun Zhang
      Obesity has become a significant global health problem, and is a high risk factor for a variety of metabolic diseases. Fibroblast growth factor (FGF) 15 plays an important role in the regulation of metabolism. Xenobiotic-sensing nuclear receptors pregnane X receptor (PXR/NR1I2) and constitutive androstane receptor (CAR/NR1I3) play important roles in xenobiotic detoxification and metabolism, and also are involved in the regulation of energy metabolism. However, the effects that PXR and CAR have on the regulation of FGF15 are unknown. Here, we found that body weight, hepatic triglyceride levels, liver steatosis, and hepatic mRNA expression levels of cholesterol 7α-hydroxylase (CYP7A1) and sterol 12α-hydroxylase (CYP8B1), the key enzymes in the bile acid classical synthesis pathway, were significantly decreased in high fat diet (HFD)-fed PXR knockout (KO) mice compared to HFD-fed wild-type mice. Interestingly, intestinal FGF15 expression levels were significantly elevated in HFD-fed PXR KO mice compared with HFD-fed wild-type mice. Additionally, serum total bile acid levels were significantly decreased in PXR KO mice than those in wild-type mice when fed a control diet or HFD. Total lipids in feces were significantly increased in HFD-fed PXR KO mice compared to HFD-fed wild-type mice. However, these alterations were not found in HFD-fed CAR KO mice. These results indicate that PXR deficiency improves HFD-induced obesity via induction of FGF15 expression, resulting in suppression of bile acid synthesis and reduction of lipid absorption, hepatic lipid accumulation and liver triglyceride levels. Our findings suggest that PXR may negatively regulate FGF15 expression and represent a potential therapeutic target for the treatment for metabolic disorders such as obesity.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.019
      Issue No: Vol. 142 (2017)
  • Inhibitor mechanisms in the S1 binding site of the dopamine transporter
           defined by multi-site molecular tethering of photoactive cocaine analogs
    • Authors: Danielle Krout; Akula Bala Pramod; Rejwi Acharya Dahal; Michael J. Tomlinson; Babita Sharma; James D. Foster; Mu-Fa Zou; Comfort Boatang; Amy Hauck Newman; John R. Lever; Roxanne A. Vaughan; L. Keith Henry
      Pages: 204 - 215
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Danielle Krout, Akula Bala Pramod, Rejwi Acharya Dahal, Michael J. Tomlinson, Babita Sharma, James D. Foster, Mu-Fa Zou, Comfort Boatang, Amy Hauck Newman, John R. Lever, Roxanne A. Vaughan, L. Keith Henry
      Dopamine transporter (DAT) blockers like cocaine and many other abused and therapeutic drugs bind and stabilize an inactive form of the transporter inhibiting reuptake of extracellular dopamine (DA). The resulting increases in DA lead to the ability of these drugs to induce psychomotor alterations and addiction, but paradoxical findings in animal models indicate that not all DAT antagonists induce cocaine-like behavioral outcomes. How this occurs is not known, but one possibility is that uptake inhibitors may bind at multiple locations or in different poses to stabilize distinct conformational transporter states associated with differential neurochemical endpoints. Understanding the molecular mechanisms governing the pharmacological inhibition of DAT is therefore key for understanding the requisite interactions for behavioral modulation and addiction. Previously, we leveraged complementary computational docking, mutagenesis, peptide mapping, and substituted cysteine accessibility strategies to identify the specific adduction site and binding pose for the crosslinkable, photoactive cocaine analog, RTI 82, which contains a photoactive azide attached at the 2β position of the tropane pharmacophore. Here, we utilize similar methodology with a different cocaine analog N-[4-(4-azido-3-I-iodophenyl)-butyl]-2-carbomethoxy-3-(4-chlorophenyl)tropane, MFZ 2–24, where the photoactive azide is attached to the tropane nitrogen. In contrast to RTI 82, which crosslinked into residue Phe319 of transmembrane domain (TM) 6, our findings show that MFZ 2–24 adducts to Leu80 in TM1 with modeling and biochemical data indicating that MFZ 2–24, like RTI 82, occupies the central S1 binding pocket with the (+)-charged tropane ring nitrogen coordinating with the (−)-charged carboxyl side chain of Asp79. The superimposition of the tropane ring in the three-dimensional binding poses of these two distinct ligands provides strong experimental evidence for cocaine binding to DAT in the S1 site and the importance of the tropane moiety in competitive mechanisms of DA uptake inhibition. These findings set a structure-function baseline for comparison of typical and atypical DAT inhibitors and how their interactions with DAT could lead to the loss of cocaine-like behaviors.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.07.015
      Issue No: Vol. 142 (2017)
  • Differential changes in the pharmacokinetics of statins in
           collagen-induced arthritis rats
    • Authors: Chun-Han Lin; Ke-Wei Hsu; Chia-Hao Chen; Yow-Shieng Uang; Chun-Jung Lin
      Pages: 216 - 228
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Chun-Han Lin, Ke-Wei Hsu, Chia-Hao Chen, Yow-Shieng Uang, Chun-Jung Lin
      The elevated systemic levels of cytokines in rheumatoid arthritis (RA) can change the expression of metabolic enzymes and transporters. Given that statins are lipid-lowering agents frequently used in RA patients with concurrent cardiovascular diseases, the objective of the present study was to investigate the impacts of RA on the pharmacokinetics of statins of different disposition properties in rats with collagen-induced arthritis (CIA). The expression of metabolic enzymes and transporters in tissues of CIA rats were analyzed by RT-qPCR. Statins were given to CIA rats and controls through different routes, respectively. Blood samples were collected and analyzed by UPLC/MS/MS. Isolated microsomes and hepatocytes were used to determine the metabolic and uptake clearance of statins. The results showed that, compared with controls, the mRNA levels of intestinal Cyp3a1 and hepatic Cyp2c6, Cyp2c7, Cyp3a1, Oatp1a1, Oatp1b2, Oatp1a4, and Mrp2 were markedly decreased in the CIA rats. The maximal metabolic activities of Cyp2c and Cyp3a were reduced in liver microsomes of CIA rats. When given orally or injected through hepatic portal vein, the systemic levels of fluvastatin, simvastatin, and atorvastatin, but not of rosuvastatin and pravastatin, were increased in CIA rats. The metabolic clearance of simvastatin and hepatic uptake clearance of fluvastatin and atorvastatin were decreased in CIA rats. These findings suggest that the changes in the expression of enzymes and/or transporters in CIA rats differentially affect the pharmacokinetics of statins.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.06.118
      Issue No: Vol. 142 (2017)
  • The neurotoxicant PCB-95 by increasing the neuronal transcriptional
           repressor REST down-regulates caspase-8 and increases Ripk1, Ripk3 and
           MLKL expression determining necroptotic neuronal death
    • Authors: Natascia Guida; Giusy Laudati; Angelo Serani; Luigi Mascolo; Pasquale Molinaro; Paolo Montuori; Gianfranco Di Renzo; Lorella M.T. Canzoniero; Luigi Formisano
      Pages: 229 - 241
      Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142
      Author(s): Natascia Guida, Giusy Laudati, Angelo Serani, Luigi Mascolo, Pasquale Molinaro, Paolo Montuori, Gianfranco Di Renzo, Lorella M.T. Canzoniero, Luigi Formisano
      Our previous study showed that the environmental neurotoxicant non-dioxin-like polychlorinated biphenyl (PCB)-95 increases RE1-silencing transcription factor (REST) expression, which is related to necrosis, but not apoptosis, of neurons. Meanwhile, necroptosis is a type of a programmed necrosis that is positively regulated by receptor interacting protein kinase 1 (RIPK1), RIPK3 and mixed lineage kinase domain-like (MLKL) and negatively regulated by caspase-8. Here we evaluated whether necroptosis contributes to PCB-95-induced neuronal death through REST up-regulation. Our results demonstrated that in cortical neurons PCB-95 increased RIPK1, RIPK3, and MLKL expression and decreased caspase-8 at the gene and protein level. Furthermore, the RIPK1 inhibitor necrostatin-1 or siRNA-mediated RIPK1, RIPK3 and MLKL expression knockdown significantly reduced PCB-95-induced neuronal death. Intriguingly, PCB-95-induced increases in RIPK1, RIPK3, MLKL expression and decreases in caspase-8 expression were reversed by knockdown of REST expression with a REST-specific siRNA (siREST). Notably, in silico analysis of the rat genome identified a REST consensus sequence in the caspase-8 gene promoter (Casp8-RE1), but not the RIPK1, RIPK3 and MLKL promoters. Interestingly, in PCB-95-treated neurons, REST binding to the Casp8-RE1 sequence increased in parallel with a reduction in its promoter activity, whereas under the same experimental conditions, transfection of siREST or mutation of the Casp8-RE1 sequence blocked PCB-95-induced caspase-8 reduction. Since RIPK1, RIPK3 and MLKL rat genes showed no putative REST binding site, we assessed whether the transcription factor cAMP Responsive Element Binding Protein (CREB), which has a consensus sequence in all three genes, affected neuronal death. In neurons treated with PCB-95, CREB protein expression decreased in parallel with a reduction in binding to the RIPK1, RIPK3 and MLKL gene promoter sequence. Furthermore, CREB overexpression was associated with reduced promoter activity of the RIPK1, RIPK3 and MLKL genes. Collectively, these results indicate that PCB-95 was associated with REST-induced necroptotic cell death by increasing RIPK1, RIPK3 and MLKL expression and reducing caspase-8 levels. In addition, since REST is involved in several neurological disorders, therapies that block REST-induced necroptosis could be a new strategy to revert the neurodetrimental effects associated to its overexpression.
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      PubDate: 2017-09-21T12:54:46Z
      DOI: 10.1016/j.bcp.2017.06.135
      Issue No: Vol. 142 (2017)
  • The pharmacology of neurogenesis: Conceptual advances and remaining
    • Authors: Marta Boccazzi; Stefania Ceruti
      Pages: 1 - 3
      Abstract: Publication date: 1 October 2017
      Source:Biochemical Pharmacology, Volume 141
      Author(s): Marta Boccazzi, Stefania Ceruti

      PubDate: 2017-09-16T12:51:10Z
      DOI: 10.1016/j.bcp.2017.08.006
      Issue No: Vol. 141 (2017)
  • New neurons in adult brain: distribution, molecular mechanisms and
    • Authors: Annachiara Pino; Guido Fumagalli; Francesco Bifari; Ilaria Decimo
      Pages: 4 - 22
      Abstract: Publication date: 1 October 2017
      Source:Biochemical Pharmacology, Volume 141
      Author(s): Annachiara Pino, Guido Fumagalli, Francesco Bifari, Ilaria Decimo
      “Are new neurons added in the adult mammalian brain?” “Do neural stem cells activate following CNS diseases?” “How can we modulate their activation to promote recovery?” Recent findings in the field provide novel insights for addressing these questions from a new perspective. In this review, we will summarize the current knowledge about adult neurogenesis and neural stem cell niches in healthy and pathological conditions. We will first overview the milestones that have led to the discovery of the classical ventricular and hippocampal neural stem cell niches. In adult brain, new neurons originate from proliferating neural precursors located in the subventricular zone of the lateral ventricles and in the subgranular zone of the hippocampus. However, recent findings suggest that new neuronal cells can be added to the adult brain by direct differentiation (e.g., without cell proliferation) from either quiescent neural precursors or non-neuronal cells undergoing conversion or reprogramming to neuronal fate. Accordingly, in this review we will also address critical aspects of the newly described mechanisms of quiescence and direct conversion as well as the more canonical activation of the neurogenic niches and neuroblast reservoirs in pathological conditions. Finally, we will outline the critical elements involved in neural progenitor proliferation, neuroblast migration and differentiation and discuss their potential as targets for the development of novel therapeutic drugs for neurodegenerative diseases.
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      PubDate: 2017-09-16T12:51:10Z
      DOI: 10.1016/j.bcp.2017.07.003
      Issue No: Vol. 141 (2017)
  • Emerging pharmacological approaches to promote neurogenesis from
           endogenous glial cells
    • Authors: Enrica Boda; Giulia Nato; Annalisa Buffo
      Pages: 23 - 41
      Abstract: Publication date: 1 October 2017
      Source:Biochemical Pharmacology, Volume 141
      Author(s): Enrica Boda, Giulia Nato, Annalisa Buffo
      Neurodegenerative disorders are emerging as leading contributors to the global disease burden. While some drug-based approaches have been designed to limit or prevent neuronal loss following acute damage or chronic neurodegeneration, regeneration of functional neurons in the adult Central Nervous System (CNS) still remains an unmet need. In this context, the exploitation of endogenous cell sources has recently gained an unprecedented attention, thanks to the demonstration that, in some CNS regions or under specific circumstances, glial cells can activate spontaneous neurogenesis or can be instructed to produce neurons in the adult mammalian CNS parenchyma. This field of research has greatly advanced in the last years and identified interesting molecular and cellular mechanisms guiding the neurogenic activation/conversion of glia. In this review, we summarize the evolution of the research devoted to understand how resident glia can be directed to produce neurons. We paid particular attention to pharmacologically-relevant approaches exploiting the modulation of niche-associated factors and the application of selected small molecules.
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      PubDate: 2017-09-16T12:51:10Z
      DOI: 10.1016/j.bcp.2017.06.129
      Issue No: Vol. 141 (2017)
  • Multipotency and therapeutic potential of NG2 cells
    • Authors: Martin Valny; Pavel Honsa; Jan Kriska; Miroslava Anderova
      Pages: 42 - 55
      Abstract: Publication date: 1 October 2017
      Source:Biochemical Pharmacology, Volume 141
      Author(s): Martin Valny, Pavel Honsa, Jan Kriska, Miroslava Anderova
      NG2 cells represent one of the most proliferative glial cell populations in the intact mammalian central nervous system (CNS). They are well-known for their ability to renew themselves or to generate new oligodendrocytes during development as well as in adulthood, therefore also being termed oligodendrocyte progenitor cells. Following CNS injuries, such as demyelination, trauma or ischemia, the proliferative capacity of NG2 cells rapidly increases and moreover, their differentiation potential broadens, as documented by numerous reports also describing their differentiation into astrocytes or even neurons. Here, we summarize the current knowledge about NG2 cells proliferation, their fate plasticity during embryogenesis as well as in postnatal CNS under physiological and pathological conditions, with the main emphasis on the role of various signaling molecules, growth factors, hormones or even neurotransmitters on the fate potential of NG2 cells.
      Graphical abstract image

      PubDate: 2017-09-16T12:51:10Z
      DOI: 10.1016/j.bcp.2017.05.008
      Issue No: Vol. 141 (2017)
  • Sex steroids and neurogenesis
    • Authors: Christine Heberden
      Pages: 56 - 62
      Abstract: Publication date: 1 October 2017
      Source:Biochemical Pharmacology, Volume 141
      Author(s): Christine Heberden
      The brain has long been known as a dimorphic organ and as a target of sex steroids. It is also a site for their synthesis. Sex steroids in numerous ways can modify cerebral physiology, and along with many processes adult neurogenesis is also modulated by sex steroids. This review will focus on the effects of the main steroids, estrogens, androgens and progestogens, and unveil some aspects of their partly disclosed mechanisms of actions. Gonadal steroids act on different steps of neurogenesis: cell proliferation seems to be increased by estrogens only, while androgens and progestogens favor neuronal renewal by increasing cell survival; differentiation is a common target. Aging is characterized by a cognitive deficiency, paralleled by a decrease in the rate of neuronal renewal and in the levels of circulating gonadal hormones. Therefore, the effects of gonadal hormones on the aging brain are important to consider. The review will also be expanded to related molecules which are agonists to the nuclear receptors. Sex steroids can modify adult neuronal renewal and the extensive knowledge of their actions on neurogenesis is essential, as it can be a leading pathway to therapeutic perspectives.
      Graphical abstract image

      PubDate: 2017-09-16T12:51:10Z
      DOI: 10.1016/j.bcp.2017.05.019
      Issue No: Vol. 141 (2017)
  • Nutrients, neurogenesis and brain ageing: From disease mechanisms to
           therapeutic opportunities
    • Authors: Marco Fidaleo; Virve Cavallucci; Giovambattista Pani
      Pages: 63 - 76
      Abstract: Publication date: 1 October 2017
      Source:Biochemical Pharmacology, Volume 141
      Author(s): Marco Fidaleo, Virve Cavallucci, Giovambattista Pani
      Appreciation of the physiological relevance of mammalian adult neurogenesis has in recent years rapidly expanded from a phenomenon of homeostatic cell replacement and brain repair to the current view of a complex process involved in high order cognitive functions. In parallel, an array of endogenous or exogenous triggers of neurogenesis has also been identified, among which metabolic and nutritional cues have drawn significant attention. Converging evidence from animal and in vitro studies points to nutrient sensing and energy metabolism as major physiological determinants of neural stem cell fate, and modulators of the whole neurogenic process. While the cellular and molecular circuitries underlying metabolic regulation of neurogenesis are still incompletely understood, the key role of mitochondrial activity and dynamics, and the importance of autophagy have begun to be fully appreciated; moreover, nutrient-sensitive pathways and transducers such as the insulin-IGF cascade, the AMPK/mTOR axis and the transcription regulators CREB and Sirt-1 have been included, beside more established “developmental” signals like Notch and Wnt, in the molecular networks that dictate neural-stem-cell self-renewal, migration and differentiation in response to local and systemic inputs. Many of these nutrient-related cascades are deregulated in the contest of metabolic diseases and in ageing, and may contribute to impaired neurogenesis and thus to cognition defects observed in these conditions. Importantly, accumulating knowledge on the metabolic control of neurogenesis provides a theoretical framework for the trial of new or repurposed drugs capable of interfering with nutrient sensing as enhancers of neurogenesis in the context of neurodegeneration and brain senescence.
      Graphical abstract image

      PubDate: 2017-09-16T12:51:10Z
      DOI: 10.1016/j.bcp.2017.05.016
      Issue No: Vol. 141 (2017)
  • Neurogenesis in the aging brain
    • Authors: Deana M. Apple; Rene Solano-Fonseca; Erzsebet Kokovay
      Pages: 77 - 85
      Abstract: Publication date: 1 October 2017
      Source:Biochemical Pharmacology, Volume 141
      Author(s): Deana M. Apple, Rene Solano-Fonseca, Erzsebet Kokovay
      Adult neurogenesis is the process of producing new neurons from neural stem cells (NSCs) for integration into the brain circuitry. Neurogenesis occurs throughout life in the ventricular-subventricular zone (V-SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the hippocampal dentate gyrus. However, during aging, NSCs and their progenitors exhibit reduced proliferation and neuron production, which is thought to contribute to age-related cognitive impairment and reduced plasticity that is necessary for some types of brain repair. In this review, we describe NSCs and their niches during tissue homeostasis and how they undergo age-associated remodeling and dysfunction. We also discuss some of the functional ramifications in the brain from NSC aging. Finally, we discuss some recent insights from interventions in NSC aging that could eventually translate into therapies for healthy brain aging.
      Graphical abstract image

      PubDate: 2017-09-16T12:51:10Z
      DOI: 10.1016/j.bcp.2017.06.116
      Issue No: Vol. 141 (2017)
  • Adult hippocampal neurogenesis: Is it the alpha and omega of
           antidepressant action'
    • Authors: Hoda Eliwa; Catherine Belzung; Alexandre Surget
      Pages: 86 - 99
      Abstract: Publication date: 1 October 2017
      Source:Biochemical Pharmacology, Volume 141
      Author(s): Hoda Eliwa, Catherine Belzung, Alexandre Surget
      It is now well established that all clinically available antidepressants share a common aptitude: they increase the production of adult-generated neurons in the dentate gyrus of the hippocampus. This was first observed in animal models and subsequently in human populations, highlighting the clinical relevance of this finding. Later, it was suggested that hippocampal neurogenesis was not an epiphenomenal correlate of antidepressant action but was causally involved. Indeed, when neurogenesis is suppressed, antidepressant compounds can no longer achieve remission. This action of adult-born neurons seems necessary to achieve remission, but less evidence exists to show that it is sufficient alone. In the following decades, a new generation of putative antidepressants that act through different non-monoaminergic mechanisms were proposed in preclinical research as potential therapies. Interestingly, these treatments all increased neurogenesis in animal models of pathological states: this was observed with drugs acting through peptidergic or glutamatergic mechanisms and with neurostimulation strategies not targeting the hippocampus. However, the involvement of neurogenesis was not always causal. To advance further in this field, an understanding of how adult-generated neurons induce therapeutic effects and how this is related to the pathophysiology of depression are required.
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      PubDate: 2017-09-16T12:51:10Z
      DOI: 10.1016/j.bcp.2017.08.005
      Issue No: Vol. 141 (2017)
  • The impact of cocaine on adult hippocampal neurogenesis: Potential
           neurobiological mechanisms and contributions to maladaptive cognition in
           cocaine addiction disorder
    • Authors: Estela Castilla-Ortega; David Ladrón de Guevara-Miranda; Antonia Serrano; Francisco J. Pavón; Juan Suárez; Fernando Rodríguez de Fonseca; Luis J. Santín
      Pages: 100 - 117
      Abstract: Publication date: 1 October 2017
      Source:Biochemical Pharmacology, Volume 141
      Author(s): Estela Castilla-Ortega, David Ladrón de Guevara-Miranda, Antonia Serrano, Francisco J. Pavón, Juan Suárez, Fernando Rodríguez de Fonseca, Luis J. Santín
      After discovering that addictive drugs alter adult neurogenesis, the potential role of adult-born hippocampal neurons in drug addiction has become a promising research field, in which cocaine is the most frequently investigated drug. Although a substantial amount of pre-clinical evidence has accumulated, additional studies are required to reveal the mechanisms by which cocaine modulates adult hippocampal neurogenesis (AHN) and determine whether these adult-born neurons have a role in cocaine-related behaviors, such as cocaine-mediated cognitive symptoms. First, this review will summarize the cocaine-induced alterations in a number of neurobiological factors (neurotransmitters, neurotrophins, glucocorticoids, inflammatory mediators) that likely regulate both hippocampal-dependent learning and adult hippocampal neurogenesis after cocaine exposure. A separate section will provide a detailed review of the available literature that challenges the common view that cocaine reduces adult hippocampal neurogenesis. In fact, cocaine has a short-term anti-proliferative role, but the young adult-born neurons are apparently spared, or even enhanced, following certain cocaine protocols. Thus, we will try to reconcile this evidence with the hippocampal-dependent cognitive symptoms that are typically observed in cocaine addicts, and we will propose new directions for future studies to test the relevant hypothesis. Based on the evidence presented here, the regulation of adult hippocampal neurogenesis might be one of the many mechanisms by which cocaine sculpts hippocampus-dependent learning.
      Graphical abstract image

      PubDate: 2017-09-16T12:51:10Z
      DOI: 10.1016/j.bcp.2017.05.003
      Issue No: Vol. 141 (2017)
  • MicroRNA: Basic concepts and implications for regeneration and repair of
           neurodegenerative diseases
    • Authors: Cláudia Saraiva; Marta Esteves; Liliana Bernardino
      Pages: 118 - 131
      Abstract: Publication date: 1 October 2017
      Source:Biochemical Pharmacology, Volume 141
      Author(s): Cláudia Saraiva, Marta Esteves, Liliana Bernardino
      MicroRNAs (miRNA) are small non-coding molecules that revolutionized our knowledge about the regulation of gene expression. Capable to target a large number of mRNA, miRNA are thought to regulate around 30% of the entire human genome. Therefore, these molecules are able to regulate several biological processes, including neuronal survival, differentiation and regeneration. Additionally, miRNA might act as valuable clinical agents in brain pathological conditions. Their specific expression patterns in the brain parenchyma and/or in circulating fluids have been highlighted as potential biomarkers, while the modulation of their activity may have therapeutic value for several neurodegenerative diseases. In this review, we describe miRNA biogenesis, signaling and regulation as well as the role of miR-9, miR-124, miR-132 and miR-137 in both adult neurogenesis and neurodegeneration, namely in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis. The relationship between miRNA, neurodegeneration and neurogenesis will be highlighted. Moreover, the benefits, outcomes and limitations of therapies using miRNA technology for neurodegenerative disorders will also be discussed.
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      PubDate: 2017-09-16T12:51:10Z
      DOI: 10.1016/j.bcp.2017.07.008
      Issue No: Vol. 141 (2017)
  • Modulation of neurogenesis via neurotrophic factors in acupuncture
           treatments for neurological diseases
    • Authors: Hwa Kyoung Shin; Sae-Won Lee; Byung Tae Choi
      Pages: 132 - 142
      Abstract: Publication date: 1 October 2017
      Source:Biochemical Pharmacology, Volume 141
      Author(s): Hwa Kyoung Shin, Sae-Won Lee, Byung Tae Choi
      Acupuncture is one of the main healing arts in Oriental medicine. It has long been used in East Asian countries, including Korea and China, and is thought to be an effective alternative treatment for various neurological diseases. The therapeutic effects of acupuncture come from inserting a needle at specific acupoints on the body surface, with subsequent delivery of stimulation via manual rotation or electric pulses (electroacupuncture, EA). In various neurological disease models, peripheral nerve stimulation using acupuncture or EA may have protective effects on neural tissues by increasing expression of neurotrophic factors (NTFs), such as brain-derived neurotrophic factor and glial-derived neurotrophic factor, in the central nervous system, especially the brain. In addition, acupuncture may contribute to recovery from functional impairments following brain damage by encouraging neural stem cell proliferation, which is active at the initial stage of injury, and by further facilitating differentiation. Hence, acupuncture may act as a stimulator activating peripheral nerves at specific acupoints and inducing the expression of various NTFs in the brain. Subsequently, NTFs induced by this treatment trigger autocrine or paracrine signaling, which stimulates adult neurogenesis, thereby exerting therapeutic effects on functional impairments in neurological diseases. Acupuncture may offer an alternative treatment that promotes adult neurogenesis through the expression of NTFs in the brain. It may also have synergistic effects when combined with pharmacological interventions, again facilitating neurogenesis. This review examines recent studies concerning the effects of acupuncture and EA on adult neurogenesis associated with NTF expression in neurological diseases, in particular stroke, Alzheimer’s disease, and Parkinson’s disease.
      Graphical abstract image

      PubDate: 2017-09-16T12:51:10Z
      DOI: 10.1016/j.bcp.2017.04.029
      Issue No: Vol. 141 (2017)
  • Chinese herbal medicine for Alzheimer’s disease: Clinical evidence and
           possible mechanism of neurogenesis
    • Authors: Wen-ting Yang; Xia-wei Zheng; Shuang Chen; Chun-shuo Shan; Qing-qing Xu; Jia-Zhen Zhu; Xiao-Yi Bao; Yan Lin; Guo-qing Zheng; Yan Wang
      Pages: 143 - 155
      Abstract: Publication date: 1 October 2017
      Source:Biochemical Pharmacology, Volume 141
      Author(s): Wen-ting Yang, Xia-wei Zheng, Shuang Chen, Chun-shuo Shan, Qing-qing Xu, Jia-Zhen Zhu, Xiao-Yi Bao, Yan Lin, Guo-qing Zheng, Yan Wang
      Currently, there is lack of cure or disease-modifying treatment for Alzheimer’s disease (AD). Chinese herbal medicine (CHM) is purported to ameliorate AD progression, perhaps by promoting hippocampal neurogenesis. Here, we conducted an updated systematic review to investigate the efficacy and safety of CHM for AD based on high-quality randomized controlled trials (RCTs) and reviewed its possible mechanisms of neurogenesis according to animal-based researches. Twenty eligible studies with 1767 subjects were identified in eight database searches from inception to February 2017. The studies investigated the CHM versus placebo (n=3), CHM versus donepezil (n=9 with 10 comparisons), CHM plus donepezil versus donepezil (n=3), CHM versus a basic treatment (n=3), and CHM plus basic treatment versus basic treatment (n=2). Adverse events were reported in 11 studies, analyzed but not observed in 3 studies, and not analyzed in 6 studies. The main findings of present study are that CHM as adjuvant therapy exerted an additive anti-AD benefit, whereas the efficacy of CHM as a monotherapy was inconclusive. Additionally, CHMs were generally safe and well tolerated in AD patients. Active molecules in frequent constituents of CHMs can alter multiple critical signaling pathways regulating neurogenesis. Thus, the present evidence supports, to a limited extent, the conclusion that CHM can be recommended for routine use in AD patients and its possible mechanism enhances adult hippocampal neurogenesis through activating the multi-signal pathways.
      Graphical abstract image

      PubDate: 2017-09-16T12:51:10Z
      DOI: 10.1016/j.bcp.2017.07.002
      Issue No: Vol. 141 (2017)
  • Steroid receptor coactivators present a unique opportunity for drug
           development in hormone-dependent cancers
    • Authors: Aarti D. Rohira; David M. Lonard
      Pages: 1 - 7
      Abstract: Publication date: 15 September 2017
      Source:Biochemical Pharmacology, Volume 140
      Author(s): Aarti D. Rohira, David M. Lonard
      Steroid receptor coactivators (SRCs) are essential regulators of nuclear hormone receptor function. SRCs coactivate transcription mediated by hormone stimulation of nuclear receptors and other transcription factors and have essential functions in human physiology and health. The SRCs are over expressed in a number of cancers such as breast, prostate, endometrial and pancreatic cancers where they promote tumor growth, invasion, metastasis and chemo-resistance. With their multiple roles in cancer, the SRCs are promising targets for the development of small molecule agents that can interfere with their function. For instance, perturbing SRC function with small molecule inhibitors and stimulators has been shown to be effective in reducing tumor growth in vivo. These early studies demonstrate that targeting the SRCs might prove effective for cancer treatment and more effort should be made to realize the untapped potential of developing drugs designed to target these coactivators.
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      PubDate: 2017-08-13T15:44:12Z
      DOI: 10.1016/j.bcp.2017.04.005
      Issue No: Vol. 140 (2017)
  • Proprotein convertase inhibition: Paralyzing the cell’s master
    • Authors: Andres J. Klein-Szanto; Daniel E. Bassi
      Pages: 8 - 15
      Abstract: Publication date: 15 September 2017
      Source:Biochemical Pharmacology, Volume 140
      Author(s): Andres J. Klein-Szanto, Daniel E. Bassi
      Proprotein convertases are serine proteases responsible for the cleavage and subsequent activation of protein substrates, many of them relevant for the development of an ample variety of diseases. Seven of the PCs, including furin and PACE4, recognize and hydrolyze the C-terminal end of the general sequence RXRR/KXR, whereas PCSK-9 recognizes a series of non-basic amino acids. In some systems, PC-mediated substrate activation results in the development of pathological processes, such as cancer, endocrinopathies, and cardiovascular and infectious diseases. After establishing PCs as relevant contributors to disease processes, research efforts were directed towards the development of inhibition strategies, including small and large molecules, anti-sense therapies, and antibody-based therapies. Most of these inhibitors mimic the consensus sequence of PCs, blocking the active site in a competitive manner. The most promising inhibitors were designed as bioengineered proteins; however, some non-protein and peptidomimetic agents have also proved to be effective. These efforts led to the design of pre-clinical studies and clinical trials utilizing inhibitors to PCs. Although the initial studies were performed using non-selective PCs inhibitors, such as CMK, the search for more specific, and compartmentalized selective inhibitors resulted in specific activities ascribed to some, but not all of the PCs. For instance, PACE4 inhibitors were effective in decreasing prostate cancer cell proliferation, and neovascularization. Decreased metastatic ovarian cancer utilizing furin inhibitors represents one of the major endeavors, currently in a phase II trial stage. Antibodies targeting PCSK-9 decreased significantly the levels of HDL-cholesterol, in a phase III trial. The study of Proprotein convertases has reached a stage of maturity. New strategies based on the alteration of their activity at the cellular and clinical level represent a promising experimental pharmacology field. The development of allosteric inhibitors, or specific agents directed against individual PCs is one of the challenges to be unraveled in the future.
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      PubDate: 2017-08-13T15:44:12Z
      DOI: 10.1016/j.bcp.2017.04.027
      Issue No: Vol. 140 (2017)
  • OP16, a novel ent-kaurene diterpenoid, potentiates the antitumor effect of
           rapamycin by inhibiting rapamycin-induced feedback activation of Akt
           signaling in esophageal squamous cell carcinoma
    • Authors: Ke-Zheng Peng; Yu Ke; Qi Zhao; Fei Tian; Hong-Min Liu; Guiqin Hou; Zhaoming Lu
      Pages: 16 - 27
      Abstract: Publication date: 15 September 2017
      Source:Biochemical Pharmacology, Volume 140
      Author(s): Ke-Zheng Peng, Yu Ke, Qi Zhao, Fei Tian, Hong-Min Liu, Guiqin Hou, Zhaoming Lu
      Hyperactivation of mTOR signaling pathway has been viewed as a significant molecular pathogenesis of cancer. However, inhibition of mTOR by rapamycin and its analogs could induce numerous negative feedback loops to attenuate their therapeutic efficacy. As a traditional Chinese herbal medicine, Rabdosia rubescens has been used to treat esophageal squamous cell carcinoma (ESCC) for hundreds of years, and its major effective component is oridonin. Here we reported that OP16, a novel analog of oridonin, showed potent inhibition of cell proliferation and Akt phosphorylation in ESCC cells. The combination of OP16 and rapamycin possesses synergistic anti-proliferative and pro-apoptotic effects both in ESCC cells and ESCC xenografts, and no obvious adverse effect was observed in vivo. Mechanistic analysis revealed that OP16 could inhibit rapamycin-induced Akt activation through the p70S6K-mediated negative feedback loops, and the combination of OP16 and rapamycin was more effective in activating caspase-dependent apoptotic signaling cascade. This study supports the combined use of OP16 with rapamycin as a feasible and effective therapeutic approach for future treatment of ESCC.
      Graphical abstract image

      PubDate: 2017-08-13T15:44:12Z
      DOI: 10.1016/j.bcp.2017.05.013
      Issue No: Vol. 140 (2017)
  • Editorial Advisory Board
    • Abstract: Publication date: 1 November 2017
      Source:Biochemical Pharmacology, Volume 143

      PubDate: 2017-09-21T12:54:46Z
  • Editorial Advisory Board
    • Abstract: Publication date: 15 October 2017
      Source:Biochemical Pharmacology, Volume 142

      PubDate: 2017-09-21T12:54:46Z
  • Editorial Advisory Board
    • Abstract: Publication date: 1 October 2017
      Source:Biochemical Pharmacology, Volume 141

      PubDate: 2017-09-16T12:51:10Z
  • Editorial Advisory Board
    • Abstract: Publication date: 15 September 2017
      Source:Biochemical Pharmacology, Volume 140

      PubDate: 2017-08-13T15:44:12Z
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