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  Subjects -> CHEMISTRY (Total: 841 journals)
    - ANALYTICAL CHEMISTRY (50 journals)
    - CHEMISTRY (593 journals)
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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: 234)
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: 69)
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: 204)
Angewandte Chemie International Edition     Hybrid Journal   (Followers: 214)
Annales UMCS, Chemia     Open Access   (Followers: 1)
Annals of Clinical Chemistry and Laboratory Medicine     Open Access   (Followers: 2)
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: 293)
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: 124)
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: 71)
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: 143)
Chemistry - An Asian Journal     Hybrid Journal   (Followers: 15)
Chemistry and Materials Research     Open Access   (Followers: 18)
Chemistry Central Journal     Open Access   (Followers: 4)
Chemistry Education Research and Practice     Free   (Followers: 5)
Chemistry in Education     Open Access   (Followers: 9)
Chemistry International     Hybrid Journal   (Followers: 2)
Chemistry Letters     Full-text available via subscription   (Followers: 45)
Chemistry of Materials     Full-text available via subscription   (Followers: 260)
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: 9)
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: 18)

        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]
  • The pharmacology of neurogenesis: Conceptual advances and remaining
           challenges
    • 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
           therapies
    • 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.
      Graphical abstract image

      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.
      Graphical abstract image

      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.
      Graphical abstract image

      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.
      Graphical abstract image

      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.
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      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.
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      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
           switches
    • 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.
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      PubDate: 2017-08-13T15:44:12Z
      DOI: 10.1016/j.bcp.2017.05.013
      Issue No: Vol. 140 (2017)
       
  • The effects of curcumin on proliferation, apoptosis, invasion, and NEDD4
           expression in pancreatic cancer
    • Authors: Jingna Su; Xiuxia Zhou; Xuyuan Yin; Lixia Wang; Zhe Zhao; Yingying Hou; Nana Zheng; Jun Xia; Zhiwei Wang
      Pages: 28 - 40
      Abstract: Publication date: 15 September 2017
      Source:Biochemical Pharmacology, Volume 140
      Author(s): Jingna Su, Xiuxia Zhou, Xuyuan Yin, Lixia Wang, Zhe Zhao, Yingying Hou, Nana Zheng, Jun Xia, Zhiwei Wang
      Pancreatic cancer (PC) is one of the most fatal cancers worldwide. The incidence and death rates are still increasing for PC. Curcumin is the biologically active diarylheptanoid constituent of the spice turmeric, which exerts its anticancer properties in various human cancers including PC. In particular, accumulating evidence has proved that curcumin targets numerous therapeutically important proteins in cell signaling pathways. The neural precursor cell expressed developmentally down-regulated protein 4 (NEDD4) is an E3 HECT ubiquitin ligase and is frequently over-expressed in various cancers. It has reported that NEDD4 might facilitate tumorigenesis via targeting and degradation of multiple tumor suppressor proteins including PTEN. Hence, in the present study we explore whether curcumin inhibits NEDD4, resulting in the suppression of cell growth, migration and invasion in PC cells. We found that curcumin inhibited cell proliferation and triggered apoptosis in PC, which is associated with increased expression of PTEN and p73. These results suggested that inhibition of NEDD4 might be beneficial to the antitumor properties of curcumin on PC treatments.
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      PubDate: 2017-08-13T15:44:12Z
      DOI: 10.1016/j.bcp.2017.05.014
      Issue No: Vol. 140 (2017)
       
  • Lipoxygenase inhibitors protect acute lymphoblastic leukemia cells from
           ferroptotic cell death
    • Authors: Lukas Probst; Jasmin Dächert; Barbara Schenk; Simone Fulda
      Pages: 41 - 52
      Abstract: Publication date: 15 September 2017
      Source:Biochemical Pharmacology, Volume 140
      Author(s): Lukas Probst, Jasmin Dächert, Barbara Schenk, Simone Fulda
      Ferroptosis has recently been identified as a mode of programmed cell death. However, little is yet known about the signaling mechanism. Here, we report that lipoxygenases (LOX) contribute to the regulation of RSL3-induced ferroptosis in acute lymphoblastic leukemia (ALL) cells. We show that the glutathione (GSH) peroxidase 4 (GPX4) inhibitor RSL3 triggers lipid peroxidation, production of reactive oxygen species (ROS) and cell death in ALL cells. All these events are impeded in the presence of Ferrostatin-1 (Fer-1), a small-molecule inhibitor of lipid peroxidation. Also, lipid peroxidation and ROS production precede the induction of cell death, underscoring their contribution to cell death upon exposure to RSL3. Importantly, LOX inhibitors, including the selective 12/15-LOX inhibitor Baicalein and the pan-LOX inhibitor nordihydroguaiaretic acid (NDGA), protect ALL cells from RSL3-stimulated lipid peroxidation, ROS generation and cell death, indicating that LOX contribute to ferroptosis. RSL3 triggers lipid peroxidation and cell death also in FAS-associated Death Domain (FADD)-deficient cells which are resistant to death receptor-induced apoptosis indicating that the induction of ferroptosis may bypass apoptosis resistance. By providing new insights into the molecular regulation of ferroptosis, our study contributes to the development of novel treatment strategies to reactivate programmed cell death in ALL.
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      PubDate: 2017-08-13T15:44:12Z
      DOI: 10.1016/j.bcp.2017.06.112
      Issue No: Vol. 140 (2017)
       
  • Cav1.2 channel current block by the PKA inhibitor H-89 in rat tail artery
           myocytes via a PKA-independent mechanism: Electrophysiological,
           functional, and molecular docking studies
    • Authors: Fabio Fusi; Alfonso Trezza; Ottavia Spiga; Giampietro Sgaragli; Sergio Bova
      Pages: 53 - 63
      Abstract: Publication date: 15 September 2017
      Source:Biochemical Pharmacology, Volume 140
      Author(s): Fabio Fusi, Alfonso Trezza, Ottavia Spiga, Giampietro Sgaragli, Sergio Bova
      To characterize the role of cAMP-dependent protein kinase (PKA) in regulating vascular Ca2+ current through Cav1.2 channels [ICa1.2], we have documented a marked capacity of the isoquinoline H-89, widely used as a PKA inhibitor, to reduce current amplitude. We hypothesized that the ICa1.2 inhibitory activity of H-89 was mediated by mechanisms unrelated to PKA inhibition. To support this, an in-depth analysis of H-89 vascular effects on both ICa1.2 and contractility was undertaken by performing whole-cell patch-clamp recordings and functional experiments in rat tail main artery single myocytes and rings, respectively. H-89 inhibited ICa1.2 with a pIC50 (M) value of about 5.5, even under conditions where PKA activity was either abolished by both the PKA antagonists KT5720 and protein kinase inhibitor fragment 6–22 amide or enhanced by the PKA stimulators 6-Bnz-cAMP and 8-Br-cAMP. Inhibition of ICa1.2 by H-89 appeared almost irreversible upon washout, was charge carrier- and voltage-dependent, and antagonised by the Cav1.2 channel agonist (S)-(-)-Bay K 8644. H-89 did not alter both potency and efficacy of verapamil, did not affect current kinetics or voltage-dependent activation, while shifting to the left the 50% voltage of inactivation in a concentration-dependent manner. H-89 docked at the α1C subunit in a pocket region close to that of (S)-(-)-Bay K 8644 docking, forming a hydrogen bond with the same, key amino acid residue Tyr-1489. Finally, both high K+- and (S)-(-)-Bay K 8644-induced contractions of rings were fully reverted by H-89. In conclusion, these results indicate that H-89 inhibited vascular ICa1.2 and, consequently, the contractile function through a PKA-independent mechanism. Therefore, caution is recommended when interpreting experiments where H-89 is used to inhibit vascular smooth muscle PKA.
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      PubDate: 2017-08-13T15:44:12Z
      DOI: 10.1016/j.bcp.2017.05.020
      Issue No: Vol. 140 (2017)
       
  • Synthetic anti-endotoxin peptides inhibit cytoplasmic LPS-mediated
           responses
    • Authors: Anja Pfalzgraff; Lena Heinbockel; Qi Su; Klaus Brandenburg; Günther Weindl
      Pages: 64 - 72
      Abstract: Publication date: 15 September 2017
      Source:Biochemical Pharmacology, Volume 140
      Author(s): Anja Pfalzgraff, Lena Heinbockel, Qi Su, Klaus Brandenburg, Günther Weindl
      Toll-like receptor (TLR) 4-independent recognition of lipopolysaccharide (LPS) in the cytosol by inflammatory caspases leads to non-canonical inflammasome activation and induction of IL-1 secretion and pyroptosis. The discovery of this novel mechanism has potential implications for the development of effective drugs to treat sepsis since LPS-mediated hyperactivation of caspases is critically involved in endotoxic shock. Previously, we demonstrated that Pep19-2.5, a synthetic anti-endotoxin peptide, efficiently neutralises pathogenicity factors of Gram-negative and Gram-positive bacteria and protects against sepsis in vivo. Here, we report that Pep19-2.5 inhibits the effects of cytoplasmic LPS in human myeloid cells and keratinocytes. In THP-1 monocytes and macrophages, the peptide strongly reduced secretion of IL-1β and LDH induced by intracellular LPS. In contrast, the TLR4 signaling inhibitor TAK-242 abrogates LPS-induced TNF and IL-1β secretion, but not pyroptotic cell death. Furthermore, Pep19-2.5 suppressed LPS-induced HMGB-1 production and caspase-1 activation in THP-1 monocytes. Consistent with this observation, we found impaired IL-1β and IL-1α release in LPS-stimulated primary monocytes in the presence of Pep19-2.5 and reduced LDH release and IL-1B and IL-1A expression in LPS-transfected HaCaT keratinocytes. Additionally, Pep19-2.5 completely abolished IL-1β release induced by LPS/ATP in macrophages via canonical inflammasome activation. In conclusion, we provide evidence that anti-endotoxin peptides inhibit the inflammasome/IL-1 axis induced by cytoplasmic LPS sensing in myeloid cells and keratinocytes and activation of the classical inflammasome by LPS/ATP which may contribute to the protection against bacterial sepsis and skin infections with intracellular Gram-negative bacteria.
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      PubDate: 2017-08-13T15:44:12Z
      DOI: 10.1016/j.bcp.2017.05.015
      Issue No: Vol. 140 (2017)
       
  • Testosterone regulates 3T3-L1 pre-adipocyte differentiation and epididymal
           fat accumulation in mice through modulating macrophage polarization
    • Authors: Xiaojiao Ren; Xiaojian Fu; Xinhua Zhang; Shiqiang Chen; Shuguang Huang; Lun Yao; Guoquan Liu
      Pages: 73 - 88
      Abstract: Publication date: 15 September 2017
      Source:Biochemical Pharmacology, Volume 140
      Author(s): Xiaojiao Ren, Xiaojian Fu, Xinhua Zhang, Shiqiang Chen, Shuguang Huang, Lun Yao, Guoquan Liu
      Low testosterone levels are strongly related to obesity in males. The balance between the classically M1 and alternatively M2 polarized macrophages also plays a critical role in obesity. It is not clear whether testosterone regulates macrophage polarization and then affects adipocyte differentiation. In this report, we demonstrate that testosterone strengthens interleukin (IL) -4-induced M2 polarization and inhibits lipopolysaccharide (LPS)-induced M1 polarization, but has no direct effect on adipocyte differentiation. Cellular signaling studies indicate that testosterone regulates macrophage polarization through the inhibitory regulative G-protein (Gαi) mainly, rather than via androgen receptors, and phosphorylation of Akt. Moreover, testosterone inhibits pre-adipocyte differentiation induced by M1 macrophage medium. Lowering of serum testosterone in mice by injecting a luteinizing hormone receptor (LHR) peptide increases epididymal white adipose tissue. Testosterone supplementation reverses this effect. Therefore, our findings indicate that testosterone inhibits pre-adipocyte differentiation by switching macrophages to M2 polarization through the Gαi and Akt signaling pathways.
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      PubDate: 2017-08-13T15:44:12Z
      DOI: 10.1016/j.bcp.2017.05.022
      Issue No: Vol. 140 (2017)
       
  • Nociceptin/orphanin FQ antagonizes lipopolysaccharide-stimulated
           proliferation, migration and inflammatory signaling in human glioblastoma
           U87 cells
    • Authors: Andrea Bedini; Monica Baiula; Gabriele Vincelli; Francesco Formaggio; Sara Lombardi; Marco Caprini; Santi Spampinato
      Pages: 89 - 104
      Abstract: Publication date: 15 September 2017
      Source:Biochemical Pharmacology, Volume 140
      Author(s): Andrea Bedini, Monica Baiula, Gabriele Vincelli, Francesco Formaggio, Sara Lombardi, Marco Caprini, Santi Spampinato
      Glioblastoma is among the most aggressive brain tumors and has an exceedingly poor prognosis. Recently, the importance of the tumor microenvironment in glioblastoma cell growth and progression has been emphasized. Toll-like receptor 4 (TLR4) recognizes bacterial lipopolysaccharide (LPS) and endogenous ligands originating from dying cells or the extracellular matrix involved in host defense and in inflammation. G-protein coupled receptors (GPCRs) have gained interest in anti-tumor drug discovery due to the role that they directly or indirectly play by transactivating other receptors, causing cell migration and proliferation. A proteomic analysis showed that the nociceptin receptor (NOPr) is among the GPCRs significantly expressed in glioblastoma cells, including U87 cells. We describe a novel role of the peptide nociceptin (N/OFQ), the endogenous ligand of the NOPr that counteracts cell migration, proliferation and increase in IL-1β mRNA elicited by LPS via TLR4 in U87 glioblastoma cells. Signaling pathways through which N/OFQ inhibits LPS-mediated cell migration and elevation of [Ca2+]i require β-arrestin 2 and are sensitive to TNFR-associated factor 6, c-Src and protein kinase C (PKC). LPS-induced cell proliferation and increase in IL-1β mRNA are counteracted by N/OFQ via β-arrestin 2, PKC and extracellular signal-regulated kinase 1/2; furthermore, the contributions of the transcription factors NF-kB and AP-1 were investigated. Independent of LPS, N/OFQ induces a significant increase in cell apoptosis. Contrary to what was observed in other cell models, a prolonged exposure to this endotoxin did not promote any tolerance of the cellular effects above described, including NOPr down-regulation while N/OFQ loses its inhibitory role.
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      PubDate: 2017-08-13T15:44:12Z
      DOI: 10.1016/j.bcp.2017.05.021
      Issue No: Vol. 140 (2017)
       
  • Rho kinase-dependent desensitization of GPR39; a unique mechanism of GPCR
           downregulation
    • Authors: Yuji Shimizu; Ryokichi Koyama; Tomohiro Kawamoto
      Pages: 105 - 114
      Abstract: Publication date: 15 September 2017
      Source:Biochemical Pharmacology, Volume 140
      Author(s): Yuji Shimizu, Ryokichi Koyama, Tomohiro Kawamoto
      GPR39, a G-protein-coupled receptor activated by zinc, reportedly activates multiple intracellular signaling pathways via Gs, Gq, G12/13, and β-arrestin, but little is known about downregulation of the receptor upon its activation. To our knowledge, this is the first report on the mechanism of feedback regulation of GPR39 function determined in GPR39-expressing HEK293 cells (HEK293-GPR39) as a model cell system. In HEK293-GPR39 cells, GPR39-C3, which is a positive allosteric modulator, activated cAMP production (downstream of Gs), IP1 accumulation (downstream of Gq), SRF-RE-dependent transcription (downstream of G12/13), and β-arrestin recruitment. GPR39-C3 induced dose- and time-dependent loss of response in cAMP production by second challenge of the compound. This functional desensitization was blocked by the Rho kinase (ROCK) inhibitor, Y-27632, but not by Gq or Gs-pathway inhibitors or inhibition of β-arrestin recruitment. In the receptor localization assay, GPR39-C3 induced internalization of GFP-tagged GPR39. This internalization was also inhibited by Y-27632, which suggested that ROCK activation is critical for internalization and desensitization of GPR39. A novel biased GPR39 positive allosteric modulator, 5-[2-[(2,4-dichlorophenyl)methoxy]phenyl]-2,2-dimethyl-1,3,5,6-tetrahydrobenzo[a]phenanthridin-4-one (GSB-118), which activated cAMP responses and β-arrestin recruitment but showed no effect on SRF-RE–dependent transcription, did not induce desensitization. These results revealed a unique mechanism of desensitization of GPR39.
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      PubDate: 2017-08-13T15:44:12Z
      DOI: 10.1016/j.bcp.2017.06.115
      Issue No: Vol. 140 (2017)
       
  • Wnt/β-catenin signaling plays an essential role in α7 nicotinic
           receptor-mediated neuroprotection of dopaminergic neurons in a mouse
           Parkinson’s disease model
    • Authors: Yuan Liu; Shuai Hao; Beibei Yang; Yi Fan; Xiaodong Qin; Yun Chen; Jun Hu
      Pages: 115 - 123
      Abstract: Publication date: 15 September 2017
      Source:Biochemical Pharmacology, Volume 140
      Author(s): Yuan Liu, Shuai Hao, Beibei Yang, Yi Fan, Xiaodong Qin, Yun Chen, Jun Hu
      Parkinson’s disease (PD) is a neurodegenerative disorder with an incidence second only to Alzheimer’s disease. The main pathological feature of PD is the death of dopaminergic neurons in the substantia nigra pars compacta. Nicotinic receptor agonists are neuroprotective in several PD models and there is considerable evidence that α7 nicotinic acetylcholine receptors (α7-nAChRs) are important therapeutic targets for neurodegenerative diseases. However, the involvement of α7-nAChRs and underlying signaling mechanisms in PD pathogenesis are unclear. The objective of the present study was to explore the potential functions of α7-nAChRs in PD pathology, and to determine whether these effects are exerted via Wnt/β-catenin signaling in a mouse PD model. In the in vivo study, α7-nAChR knockout (α7-KO) reversed the beneficial effects of nicotine on motor deficits, dopaminergic neuron loss, astrocyte and microglia activation, and reduced striatal dopamine release induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Injury to SH-SY5Y cells by 1-methyl-4-phenylpyridinium treatment was also ameliorated by nicotine, and this effect was abolished by methyllycaconitine (MLA), a selective α7-nAChR antagonist, or by siRNA-mediated α7-nAChR knockdown. Furthermore, nicotine increased expression levels of Wnt/β-catenin signaling proteins in the PD mouse model or in the SH-SY5Y cells treated by 1-methyl-4-phenylpyridinium, and these effects were also reversed by MLA or α7-siRNA treatment in vivo or in vitro. These results suggest that endogenous α7-nAChR mechanisms play a crucial role in a mouse PD model via regulation of Wnt/β-catenin signaling.
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      PubDate: 2017-08-13T15:44:12Z
      DOI: 10.1016/j.bcp.2017.05.017
      Issue No: Vol. 140 (2017)
       
  • Single nucleotide polymorphisms of ABCC2 modulate renal secretion of
           endogenous organic anions
    • Authors: Kienana Muhrez; Bérenger Largeau; Patrick Emond; Frédéric Montigny; Jean-Michel Halimi; Patrick Trouillas; Chantal Barin-Le Guellec
      Pages: 124 - 138
      Abstract: Publication date: 15 September 2017
      Source:Biochemical Pharmacology, Volume 140
      Author(s): Kienana Muhrez, Bérenger Largeau, Patrick Emond, Frédéric Montigny, Jean-Michel Halimi, Patrick Trouillas, Chantal Barin-Le Guellec
      The ATP-binding cassette family transporter MRP2 (multidrug resistance-associated protein 2), encoded by the ABCC2 gene, is involved in the renal excretion of numerous xenobiotics and it is likely that it also transports many endogenous molecules arising from not only normal essential metabolic processes but also from environmental toxins or food intake. We used a targeted gas chromatography-mass spectrometry metabolomics analysis to study whether endogenous organic anions are differentially excreted in urines of healthy volunteers according to their genotype for three functional single nucleotide polymorphisms (SNPs) in ABCC2. This was the case for 35 of the 108 metabolites analyzed. Eight of them are most likely substrates of MRP2 since they are the most contributive to the difference between carriers of a decreasing function allele vs those carrying an increasing function one. Seven out of 8 metabolites are fatty acids (dodecanoic acid; 3-hydroxypropanoic acid) or metabolites of polyphenols (caffeine; resorcinol; caffeic acid; 2-(3,4-dihydroxyphenyl) acetic acid; and 4-hydroxyhippuric acid). Most of them were structurally similar to a series of substances previously shown to interact with MRP2 function in vitro. Interestingly, coproporphyrin isomer I, a prototypical substrate of MRP2, also belonged to our final list although it was not significantly discriminant on its own. This suggests that the simultaneous measurement of a set of endogenous metabolites in urine, rather than that of unique metabolites, has the potential to provide a phenotypic measure of MRP2 function in vivo. This would represent an innovative tool to study the variability of the transport activity of MRP2 under a physiological or pathological condition, especially in pharmacokinetic studies of its substrates.
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      PubDate: 2017-08-13T15:44:12Z
      DOI: 10.1016/j.bcp.2017.05.012
      Issue No: Vol. 140 (2017)
       
  • MicroRNA hsa-miR-370-3p suppresses the expression and induction of CYP2D6
           by facilitating mRNA degradation
    • Authors: Linjuan Zeng; Yinting Chen; Yong Wang; Li-Rong Yu; Bridgett Knox; Jiwei Chen; Tieliu Shi; Si Chen; Zhen Ren; Lei Guo; Yuanfeng Wu; David Liu; Kaihong Huang; Weida Tong; Dianke Yu; Baitang Ning
      Pages: 139 - 149
      Abstract: Publication date: 15 September 2017
      Source:Biochemical Pharmacology, Volume 140
      Author(s): Linjuan Zeng, Yinting Chen, Yong Wang, Li-Rong Yu, Bridgett Knox, Jiwei Chen, Tieliu Shi, Si Chen, Zhen Ren, Lei Guo, Yuanfeng Wu, David Liu, Kaihong Huang, Weida Tong, Dianke Yu, Baitang Ning
      Cytochrome P450 2D6 (CYP2D6) participates in the metabolism of approximately 20–25% of prescribed drugs. Genetic polymorphisms influence the expression and/or activity of CYP2D6, and inter-individual differences in drug activation and elimination caused by CYP2D6 genetic variants were reported. However, little is known about the potential modulation of CYP2D6 expression by microRNAs (miRNAs). In the current study, by using in silico prediction of the stabilities of miRNA/mRNA complexes, we screened 38 miRNA candidates that may interact with the transcript of CYP2D6. An inverse correlation between the expression of miRNA hsa-miR-370-3p and the expression of CYP2D6 was observed in human liver tissue samples. Electrophoretic mobility shift assays confirmed that hsa-miR-370-3p was able to directly bind to its cognate target within the coding region of the CYP2D6 transcript. The transfection of hsa-miR-370-3p mimics into the HepG2CYP2D6 cell line, a genetically modified cell line that overexpresses exogenous CYP2D6, was able to suppress the expression of CYP2D6 significantly at both mRNA and protein levels. The transfection of hsa-miR-370-3p mimics was also able to inhibit endogenous mRNA expression and/or protein production of CYP2D6 in HepaRG cells. Furthermore, in HepaRG, HepG2, and Huh7 cells, dexamethasone-induced expression of CYP2D6 was inhibited by hsa-miR-370-3p mimics. To investigate whether the miRNA mediated suppression is caused by inhibiting protein translation or promoting mRNA degradation, an actinomycin D assay was used to measure the stability of CYP2D6 transcripts. The results indicated that hsa-miR-370-3p mimics facilitated significantly the degradation of CYP2D6 mRNA. In addition, proteomics analyses of proteins isolated from the miRNA/mRNA/protein complex suggested that a group of multifunctional proteins facilitated the interaction between hsa-miR-370-3p and CYP2D6, thereby promoting mRNA degradation.
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      PubDate: 2017-08-13T15:44:12Z
      DOI: 10.1016/j.bcp.2017.05.018
      Issue No: Vol. 140 (2017)
       
  • Identification of enzymes responsible for nitrazepam metabolism and
           toxicity in human
    • Authors: Keigo Konishi; Tatsuki Fukami; Saki Gotoh; Miki Nakajima
      Pages: 150 - 160
      Abstract: Publication date: 15 September 2017
      Source:Biochemical Pharmacology, Volume 140
      Author(s): Keigo Konishi, Tatsuki Fukami, Saki Gotoh, Miki Nakajima
      Nitrazepam (NZP) is a hypnotic agent that rarely causes liver injuries in humans and teratogenicity in rodents. In humans, NZP is primarily metabolized to 7-aminonitrazepam (ANZP) by reduction and subsequently to 7-acetylamino nitrazepam (AANZP) by acetylation. ANZP can be regenerated from AANZP by hydrolysis in rodents, but it is still unclear whether this reaction occurs in humans. In rodents, AANZP may be associated with teratogenicity, while in humans, it is known that drug-induced liver injuries may be caused by NZP reactive metabolite(s). In this study, we attempted to identify the enzymes responsible for NZP metabolism to obtain a basic understanding of this process and the associated metabolite toxicities. We found that the NZP reductase activity in human liver cytosol (HLC) was higher than that in human liver microsomes (HLM). We purified the responsible enzyme(s) from HLC and found that the NZP reductase was aldehyde oxidase 1 (AOX1). The role of AOX1 was confirmed by an observed increase in the NZP reductase activity upon addition of N 1-methylnicotinamide, an electron donor of AOX1, as well as inhibition of this activity in HLC in the presence of AOX1 inhibitors. ANZP was acetylated to form AANZP by N-acetyltransferase (NAT) 2. An experiment using recombinant esterases in an inhibition study using HLM revealed that AANZP is hydrolyzed by arylacetamide deacetylase (AADAC) in the human liver. N-Hydroxylamino NZP, which is suspected to be a reactive metabolite, was detected as a conjugate with N-acetyl-l-cysteine through NZP reduction and ANZP hydroxylation reactions. In the latter reaction, the conjugate was readily formed by recombinant CYP3A4 among the various P450 isoforms tested. In sum, we found that AOX1, NAT2, AADAC, and CYP3A4 are the determinants for the pharmacokinetics of NZP and that they confer interindividual variability in sensitivity to NZP side effects.
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      PubDate: 2017-08-13T15:44:12Z
      DOI: 10.1016/j.bcp.2017.06.114
      Issue No: Vol. 140 (2017)
       
  • Joint ICMAN and IUPHAR natural products section meeting. Aberdeen UK
           27-29th September 2017
    • Authors: Yongxiang Zhang; Michael Spedding; Cherry Wainwright; Valérie Schini-Kerth; Giovanna Bermano
      Pages: 1 - 2
      Abstract: Publication date: 1 September 2017
      Source:Biochemical Pharmacology, Volume 139
      Author(s): Yongxiang Zhang, Michael Spedding, Cherry Wainwright, Valérie Schini-Kerth, Giovanna Bermano
      This special issue of Biochemical Pharmacology contains proceedings of a joint conference sponsored by the Natural Products Section of the International Union of Basic and Clinical Pharmacology (IUPHAR) and the International Conference on the Mechanism of Action of Nutraceuticals (ICMAN), an organization dedicated to defining actions and clinical benefits of pharmaceuticals and nutraceuticals. Entitled “From Nutraceuticals to Pharmaceuticals: Common Challenges and Approaches”, the conference was held in Aberdeen UK in September 2017. The aim of this gathering was to identify the challenges that must be overcome to identify and characterize novel therapeutics from natural products. Contained in this issue are reviews prepared by conference participants as well as abstracts describing oral and poster presentations.

      PubDate: 2017-08-03T15:21:41Z
      DOI: 10.1016/j.bcp.2017.06.126
      Issue No: Vol. 139 (2017)
       
  • Sponging off nature for new drug leads
    • Authors: Raymond J. Andersen
      Pages: 3 - 14
      Abstract: Publication date: 1 September 2017
      Source:Biochemical Pharmacology, Volume 139
      Author(s): Raymond J. Andersen
      Marine sponges have consistently been the richest source of new marine natural products with unprecedented chemical scaffolds and potent biological activities that have been reported in the chemical literature since the early 1970s. During the last 40years, chemists in the Andersen laboratory at UBC, in collaboration with biologists, have discovered many novel bioactive sponge natural products. Four experimental drug candidates for treatment of inflammation and cancer, that were inspired by members of this sponge natural product collection, have progressed to phase I/II/III clinical trials. This review recounts the scientific stories behind the discovery and development of these four drug candidates; IPL576,092, HTI-286 (Taltobulin), EPI-506 (Ralaniten acetate), and AQX-1125.
      Graphical abstract image

      PubDate: 2017-08-03T15:21:41Z
      DOI: 10.1016/j.bcp.2017.04.012
      Issue No: Vol. 139 (2017)
       
  • I1 Sponging off nature for new drug leads
    • Authors: Raymond J. Andersen
      Pages: 3 - 14
      Abstract: Publication date: 1 September 2017
      Source:Biochemical Pharmacology, Volume 139
      Author(s): Raymond Andersen
      The secondary metabolites found in marine organisms represent an extremely rich source of novel chemical diversity for academic drug discovery and chemical biology programs. Among the marine invertebrates, marine sponges have historically been one of the most prolific sources of new natural products. Our group at UBC has amassed a sizable library of crude extracts from marine sponges, other marine invertebrates, and cultured marine microorganisms collected in many of the world’s oceans. In collaboration with biologists, this crude extract library has been screened for activity in cell-based and pure enzyme assays designed to identify promising marine natural product lead compounds for the development of drugs. Bioassay-guided fractionation of crude extracts and extensive spectroscopic analysis has been used to identify the structures of pure natural products active in the assays. Biology-oriented chemical synthesis has been undertaken to probe the SAR for new natural product pharmacophores that we have discovered and to provide material for in vivo testing in animal models. Several new drug candidates for the treatment of cancer, inflammation, cystic fibrosis, and infectious diseases have emerged from this research program. Three of them have progressed to phase II/III clinical trials in humans and others are in preclinical evaluation/development. The lecture will present some highlights from our academic ‘Drugs from the Sea’ and chemical biology research.

      PubDate: 2017-08-03T15:21:41Z
      DOI: 10.1016/j.bcp.2017.04.012
      Issue No: Vol. 139 (2017)
       
  • Factors modulating bioavailability of quercetin-related flavonoids and the
           consequences of their vascular function
    • Authors: Junji Terao
      Pages: 15 - 23
      Abstract: Publication date: 1 September 2017
      Source:Biochemical Pharmacology, Volume 139
      Author(s): Junji Terao
      Nowadays dietary flavonoids attract much attention in the prevention of chronic diseases. Epidemiological and intervention studies strongly suggest that flavonoid intake has beneficial effects on vascular health. It is unlikely that flavonoids act as direct antioxidants, although oxidative stress profoundly contributes to vascular impairment leading to cardiovascular diseases. Instead, flavonoids may exert their function by tuning the cellular redox state to an adaptive response or tolerable stress. However, the optimum intake of flavonoids from supplements or diet has not been clarified yet, because a number of exogenous and endogenous factors modulating their bioavailability affect their vascular function. This review will focus on the current knowledge of the bioavailability and vascular function of quercetin as a representative of antioxidative flavonoids. Current intervention studies imply that intake of quercetin-rich onion improves vascular health. Onion may be superior to quercetin supplement from the viewpoint of quercetin bioavailability, probably because the food matrix enhances the intestinal absorption of quercetin. α-Glucosylation increases its bioavailability by elevating the accessibility to the absorptive cells. Prenylation may enhance bioaccumulation at the target site by increasing the cellular uptake. However, these chemical modifications do not guarantee health benefits to the vascular system. Dietary quercetin is exclusively present as their conjugated form in the blood stream. Quercetin may exert its vascular function as an aglycone within macrophage cells after inflammation-induced deconjugation and as conjugated metabolites by targeting endothelial cells. The relationship between the bioavailability and bio-efficacy should be clarified, to evaluate the vascular function of a wide variety of dietary flavonoids.
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      PubDate: 2017-08-03T15:21:41Z
      DOI: 10.1016/j.bcp.2017.03.021
      Issue No: Vol. 139 (2017)
       
  • Role of the small intestine, colon and microbiota in determining the
           metabolic fate of polyphenols
    • Authors: Gary Williamson; Michael N. Clifford
      Pages: 24 - 39
      Abstract: Publication date: 1 September 2017
      Source:Biochemical Pharmacology, Volume 139
      Author(s): Gary Williamson, Michael N. Clifford
      (Poly)phenols are a large group of compounds, found in food, beverages, dietary supplements and herbal medicines. Owing to interest in their biological activities, absorption and metabolism of the most abundant compounds in humans are well understood. Both the chemical structure of the phenolic moiety and any attached chemical groups define whether the polyphenol is absorbed in the small intestine, or reaches the colon and is subject to extensive catabolism by colonic microbiota. Untransformed substrates may be absorbed, appearing in plasma primarily as methylated, sulfated and glucuronidated derivatives, with in some cases the unchanged substrate. Many of the catabolites are well absorbed from the colon and appear in the plasma either similarly conjugated, or as glycine conjugates, or in some cases unchanged. Although many (poly)phenol catabolites have been identified in human plasma and/or urine, the exact pathways from substrate to final microbial catabolite, and the species of bacteria and enzymes involved, are still scarcely reported. While it is clear that the composition of the human gut microbiota can be modulated in vivo by supplementation with some (poly)phenol-rich commodities, such modulation is definitely not an inevitable consequence of supplementation; it depends on the treatment, length of time and on the individual metabotype, and it is not clear whether the modulation is sustained when supplementation ceases. Some catabolites have been recorded in plasma of volunteers at concentrations similar to those shown to be effective in in vitro studies suggesting that some benefit may be achieved in vivo by diets yielding such catabolites.
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      PubDate: 2017-08-03T15:21:41Z
      DOI: 10.1016/j.bcp.2017.03.012
      Issue No: Vol. 139 (2017)
       
  • Natural product-based amyloid inhibitors
    • Authors: Paul Velander; Ling Wu; Frances Henderson; Shijun Zhang; David R. Bevan; Bin Xu
      Pages: 40 - 55
      Abstract: Publication date: 1 September 2017
      Source:Biochemical Pharmacology, Volume 139
      Author(s): Paul Velander, Ling Wu, Frances Henderson, Shijun Zhang, David R. Bevan, Bin Xu
      Many chronic human diseases, including multiple neurodegenerative diseases, are associated with deleterious protein aggregates, also called protein amyloids. One common therapeutic strategy is to develop protein aggregation inhibitors that can slow down, prevent, or remodel toxic amyloids. Natural products are a major class of amyloid inhibitors, and several dozens of natural product-based amyloid inhibitors have been identified and characterized in recent years. These plant- or microorganism-extracted compounds have shown significant therapeutic potential from in vitro studies as well as in vivo animal tests. Despite the technical challenges of intrinsic disordered or partially unfolded amyloid proteins that are less amenable to characterizations by structural biology, a significant amount of research has been performed, yielding biochemical and pharmacological insights into how inhibitors function. This review aims to summarize recent progress in natural product-based amyloid inhibitors and to analyze their mechanisms of inhibition in vitro. Major classes of natural product inhibitors and how they were identified are described. Our analyses comprehensively address the molecular interactions between the inhibitors and relevant amyloidogenic proteins. These interactions are delineated at molecular and atomic levels, which include covalent, non-covalent, and metal-mediated mechanisms. In vivo animal studies and clinical trials have been summarized as an extension. To enhance natural product bioavailability in vivo, emerging work using nanocarriers for delivery has also been described. Finally, issues and challenges as well as future development of such inhibitors are envisioned.
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      PubDate: 2017-08-03T15:21:41Z
      DOI: 10.1016/j.bcp.2017.04.004
      Issue No: Vol. 139 (2017)
       
  • Is there a future for andrographolide to be an anti-inflammatory drug'
           Deciphering its major mechanisms of action
    • Authors: W.S. Daniel Tan; Wupeng Liao; Shuo Zhou; W.S. Fred Wong
      Pages: 71 - 81
      Abstract: Publication date: 1 September 2017
      Source:Biochemical Pharmacology, Volume 139
      Author(s): W.S. Daniel Tan, Wupeng Liao, Shuo Zhou, W.S. Fred Wong
      Andrographis paniculata has long been part of the traditional herbal medicine system in Asia and in Scandinavia. Andrographolide was isolated as a major bioactive constituent of A. paniculata in 1951, and since 1984, andrographolide and its analogs have been scrutinized with modern drug discovery approach for anti-inflammatory properties. With this accumulated wealth of pre-clinical data, it is imperative to review and consolidate different sources of information, to decipher the major anti-inflammatory mechanisms of action in inflammatory diseases, and to provide direction for future studies. Andrographolide and its analogs have been shown to provide anti-inflammatory benefits in a variety of inflammatory disease models. Among the diverse signaling pathways investigated, inhibition of NF-κB activity is the prevailing anti-inflammatory mechanism elicited by andrographolide. There is also increasing evidence supporting endogenous antioxidant defense enhancement by andrographolide through Nrf2 activation. However, the exact pathway leading to NF-κB and Nrf2 activation by andrographolide has yet to be elucidated. Validation and consensus on the major mechanistic actions of andrographolide in different inflammatory conditions are required before translating current findings into clinical settings. There are a few clinical trials conducted using andrographolide in fixed combination formulation which have shown anti-inflammatory benefits and good safety profile. A concerted effort is definitely needed to identify potent andrographolide lead compounds with improved pharmacokinetics and toxicological properties. Taken together, andrographolide and its analogs have great potential to be the next new class of anti-inflammatory agents, and more andrographolide molecules are likely moving towards clinical study stage in the near future.
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      PubDate: 2017-08-03T15:21:41Z
      DOI: 10.1016/j.bcp.2017.03.024
      Issue No: Vol. 139 (2017)
       
  • The gut microbiota: A key factor in the therapeutic effects of
           (poly)phenols
    • Authors: Juan Carlos Espín; Antonio González-Sarrías; Francisco A. Tomás-Barberán
      Pages: 82 - 93
      Abstract: Publication date: 1 September 2017
      Source:Biochemical Pharmacology, Volume 139
      Author(s): Juan Carlos Espín, Antonio González-Sarrías, Francisco A. Tomás-Barberán
      (Poly)phenols (PPs) constitute a large family of phytochemicals with high chemical diversity that are known to be active principles of plant-derived nutraceuticals and herbal medicinal products. Their pharmacological activity, however, is difficult to demonstrate due to their mild physiological effects, and to the large inter-individual variability observed. Many PPs have little bioavailability and reach the colon almost unaltered. There they encounter the gut microbes resulting in a two-way interaction in which PPs modulate the gut microbiota composition, and the intestinal microbes catabolize the ingested PPs to release metabolites that are often more active and better absorbed than the native phenolic compounds. The type and quantity of the PP metabolites produced in humans depend on the gut microbiota composition and function, and different metabotypes have been identified. However, not all the metabolites have the same biological activity, and therefore the final health effects of dietary PPs depend on the gut microbiota composition. Stratification in clinical trials according to individuals’ metabotypes is necessary to fully understand the health effects of PPs. In this review, we present and discuss the most significant and updated knowledge regarding the reciprocal interrelation of the gut microbiota with dietary PPs as a key factor that modulates the health effects of these compounds. The review will focus in those PPs that are known to be metabolized by gut microbiota resulting in bioactive metabolites.
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      PubDate: 2017-08-03T15:21:41Z
      DOI: 10.1016/j.bcp.2017.04.033
      Issue No: Vol. 139 (2017)
       
  • Major achievements of evidence-based traditional Chinese medicine in
           treating major diseases
    • Authors: Jung Chao; Yuntao Dai; Robert Verpoorte; Wing Lam; Yung-Chi Cheng; Li-Heng Pao; Wei Zhang; Shilin Chen
      Pages: 94 - 104
      Abstract: Publication date: 1 September 2017
      Source:Biochemical Pharmacology, Volume 139
      Author(s): Jung Chao, Yuntao Dai, Robert Verpoorte, Wing Lam, Yung-Chi Cheng, Li-Heng Pao, Wei Zhang, Shilin Chen
      A long history of use and extensive documentation of the clinical practices of traditional Chinese medicine resulted in a considerable number of classical preparations, which are still widely used. This heritage of our ancestors provides a unique resource for drug discovery. Already, a number of important drugs have been developed from traditional medicines, which in fact form the core of Western pharmacotherapy. Therefore, this article discusses the differences in drug development between traditional medicine and Western medicine. Moreover, the article uses the discovery of artemisinin as an example that illustrates the “bedside–bench–bedside” approach to drug discovery to explain that the middle way for drug development is to take advantage of the best features of these two distinct systems and compensate for certain weaknesses in each. This article also summarizes evidence-based traditional medicines and discusses quality control and quality assessment, the crucial steps in botanical drug development. Herbgenomics may provide effective tools to clarify the molecular mechanism of traditional medicines in the botanical drug development. The totality-of-the-evidence approach used by the U.S. Food and Drug Administration for botanical products provides the directions on how to perform quality control from the field throughout the entire production process.
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      PubDate: 2017-08-03T15:21:41Z
      DOI: 10.1016/j.bcp.2017.06.123
      Issue No: Vol. 139 (2017)
       
  • I2 Nutraceuticals retrieved from food processing waste
    • Authors: Charis M. Galanakis
      First page: 105
      Abstract: Publication date: 1 September 2017
      Source:Biochemical Pharmacology, Volume 139
      Author(s): Charis M. Galanakis
      The prospect of recovering high added-value compounds from the non-consumed materials of food processing is a story started a few decades ago. The first successful efforts dealt with the recovery of oil from olive kernel, the production of essential oils, flavonoids, sugars and pectin from citrus peel, as well as the recapture of protein concentrates and lactose from cheese whey. These commercially available applications inspired the scientific community to intensify its efforts for the valorization of all kind of food by-products for recovery purposes. Nowadays, many relevant projects progress around the world and across different disciplines, whereas the existence of numerous scientific articles, patents, congresses and commercialization efforts have emerged a wealth of literature in the field. However, despite this plethora of information and the developed technologies that promise the recovery, recycling and sustainability of valuable compounds inside the food chain, the respective shelf products remain rather limited. This is happening because the industrial implementation of recovery processes meets several implementation problems that require careful consideration of different aspects. For instance, a commercially feasible product can be manufactured only if a certain degree of flexibility and alternative choices can be adapted in the developing methodology. The current presentation highlights the most important assets that cause stifling of innovation in the field. Finally, solutions are provided in order to help progress and reveal relevant innovations with an ultimate goal to fulfil market and consumers’ needs.

      PubDate: 2017-08-03T15:21:41Z
      DOI: 10.1016/j.bcp.2017.06.050
      Issue No: Vol. 139 (2017)
       
  • I4 Factors affecting bioavailability of plant polyphenols
    • Authors: Junji Terao
      Pages: 105 - 106
      Abstract: Publication date: 1 September 2017
      Source:Biochemical Pharmacology, Volume 139
      Author(s): Junji Terao
      Nowadays plant polyphenols attract much attention in the prevention of chronic diseases. Epidemiological and intervention studies strongly suggest that polyphenol intake has beneficial effects on vascular health. It is unlikely that polyphenols act as direct antioxidants, although oxidative stress profoundly contributes to vascular impairment leading to cardiovascular diseases. Polyphenols, in particular, low-molecular weight flavonoids may exert their function by tuning the cellular redox state to an adaptive response or tolerable stress. However, the optimum intake of flavonoids from supplements or diet has not been clarified yet, because a number of exogenous and endogenous factors modulating their bioavailability affect their vascular function. This lecture will focus on the current knowledge of the bioavailability and its consequence on vascular function of an antioxidative flavonoid quercetin. Current intervention studies imply that intake of quercetin-rich onion improves vascular health. Onion may be superior to quercetin supplement from the viewpoint of quercetin bioavailability, probably because the food matrix enhances the intestinal absorption of quercetin. a-Glucosylation increases its bioavailability by elevating the accessibility to the absorptive cells. Prenylaton may enhance bioaccumulation at the target site by increasing the cellular uptake. However, these chemical modifications do not guarantee health benefits to the vascular system. Although dietary quercetin is exclusively present as their conjugated form in the blood stream, its vascular function seems to be mediated by inflammation-dependent deconjugation reaction. Finally, bioavailability of non-absorptive polyphenols to microbiota in the gut should be pointed out, as the colonic microbiota is regarded as a separate organ within the human host.

      PubDate: 2017-08-03T15:21:41Z
      DOI: 10.1016/j.bcp.2017.06.051
      Issue No: Vol. 139 (2017)
       
  • I5 Bioavailability and anti-diabetic action of naturally-occurring
           flavonoids and phenolic acids
    • Authors: Gary Williamson
      First page: 106
      Abstract: Publication date: 1 September 2017
      Source:Biochemical Pharmacology, Volume 139
      Author(s): Gary Williamson
      Flavonoids and phenolic acids (polyphenols) are naturally-occurring bioactive compounds from plants, often found in high amounts in many foods and beverages. They are also present in many plant based dietary supplements, at levels up to pharmaceutical doses. The pathways of absorption and metabolism of the most common dietary polyphenols are now mostly understood. The enzymes involved, their site of action, essential transporters and exact conjugating enzymes have been characterised, and in vitro mechanistic experiments have been supported by numerous studies, using healthy volunteers, ileostomists, intestinal perfusion, and animal models. Since the types of metabolites in blood have been identified and some synthesised, we can more carefully design in vitro experiments and translate the findings into human intervention studies. The long-term health risks of excess dietary sugar consumption remains a controversial topic in nutrition. Some of the deleterious effects of dietary sugar have been linked to high blood glucose “spikes” following a meal or beverage, which are more extreme and uncontrollable in subjects with metabolic syndrome. Certain dietary polyphenols attenuate blood glucose after a high carbohydrate meal, and in addition, the absorbed polyphenols also help to repair or prevent the damage cause by high glucose. The combination of effects is essential for the overall action of dietary polyphenols where the consequence is maintenance of normal body metabolism and reduction in the risk of developing type 2 diabetes.

      PubDate: 2017-08-03T15:21:41Z
      DOI: 10.1016/j.bcp.2017.06.052
      Issue No: Vol. 139 (2017)
       
  • Editorial Advisory Board
    • Abstract: Publication date: 1 October 2017
      Source:Biochemical Pharmacology, Volume 141


      PubDate: 2017-09-16T12:51:10Z
       
  • The cAMP effectors PKA and Epac activate endothelial NO synthase through
           PI3K/Akt pathway in human endothelial cells
    • Authors: Verónica García-Morales; María Luaces-Regueira; Manuel Campos-Toimil
      Abstract: Publication date: Available online 11 September 2017
      Source:Biochemical Pharmacology
      Author(s): Verónica García-Morales, María Luaces-Regueira, Manuel Campos-Toimil
      3’,5’-cyclic adenosine monophosphate (cAMP) exerts an endothelium-dependent vasorelaxant action by stimulating endothelial NO synthase (eNOS) activity, and the subsequent NO release, through cAMP protein kinase (PKA) and exchange protein directly activated by cAMP (Epac) activation in endothelial cells. We have here investigated the mechanism by which the cAMP-Epac/PKA pathway activates eNOS. cAMP-elevating agents (forskolin and dibutyryl-cAMP) and the joint activation of PKA (6-Bnz-cAMP) and Epac (8-pCPT-2’-O-Me-cAMP) increased cytoplasmic Ca2+ concentration ([Ca2+]c) in ≤ 30% of fura-2-loaded isolated human umbilical vein endothelial cells (HUVEC). However, these drugs did not modify [Ca2+]c in fluo-4-loaded HUVEC monolayers. In DAF-2-loaded HUVEC monolayers, forskolin, PKA and Epac activators significantly increased NO release, and the forskolin effect was reduced by inhibition of PKA (Rp-cAMPs), Epac (ESI-09), eNOS (L-NAME) or posphoinositide 3-kinase (PI3K; LY-294,002). On the other hand, inhibition of CaMKII (KN-93), AMPK (Compound C), or total absence of Ca2+, were without effect. In Western blot experiments, Serine 1177 phosphorylated-eNOS was significantly increased in HUVEC by cAMP-elevating agents and PKA or Epac activators. In isolated rat aortic rings LY-294,002, but not KN-93 or Compound C, significantly reduced the vasorelaxant effects of forskolin in the presence of endothelium. Our results suggest that Epac and PKA activate eNOS via Ser 1177 phosphorylation by activating the PI3K/Akt pathway, and independently of AMPK or CaMKII activation or [Ca2+]c increase. This action explains, in part, the endothelium-dependent vasorelaxant effect of cAMP.
      Graphical abstract image

      PubDate: 2017-09-16T12:51:10Z
      DOI: 10.1016/j.bcp.2017.09.004
       
  • Farnesoid X Receptor regulates SULT1E1 expression through inhibition of
           PGC1α binding to HNF4α
    • Authors: Shuai Wang; Xue Yuan; Danyi Lu; Lianxia Guo; Baojian Wu
      Abstract: Publication date: Available online 11 September 2017
      Source:Biochemical Pharmacology
      Author(s): Shuai Wang, Xue Yuan, Danyi Lu, Lianxia Guo, Baojian Wu
      Sulfotransferase 1E1 (SULT1E1, also known as estrogen sulfotransferase) plays an important role in metabolism and detoxification of many endogenous and exogenous compounds (e.g., estrogens and flavonoids). Here we aimed to assess the effects of farnesoid X receptor (FXR) activation on SULT1E1 expression, and to determine the mechanism thereof. Treatment with specific FXR agonists (i.e., GW4064 and CDCA) significantly decreased both mRNA and protein levels of SULT1E1 in HepG2 cells. This was accompanied by a decrease in the enzymatic activity. The inhibitory effect was potentiated by FXR overexpression but attenuated by FXR knockdown, confirming FXR-dependent regulation of SULT1E1. Surprisingly, direct regulation of SULT1E1 by FXR was unlikely because FXR did not bind to SULT1E1 promoter or enhancer as revealed by chromatin immunoprecipitation (ChIP). Interestingly, SULT1E1 regulation was abolished when HNF4α (hepatocyte nuclear factor 4α, a known activator of SULT1E1) was silenced, supporting a critical role for HNF4α in FXR regulation of SULT1E1. Furthermore, a combination of ChIP, luciferase reporter and co-immunoprecipitation assays showed that FXR inhibited HNF4α transactivation of SULT1E1 by suppressed binding of the co-activator PGC1α (peroxisome proliferator-activated receptor-γ coactivator 1α) to HNF4α. In conclusion, FXR transcriptionally regulates SULT1E1 through inhibition of PGC1α binding to HNF4α. Targeting the FXR-SULT1E1 axis may represent a promising approach for management of estrogen-related diseases.
      Graphical abstract image

      PubDate: 2017-09-16T12:51:10Z
      DOI: 10.1016/j.bcp.2017.08.023
       
  • Angiogenic Imbalance and Diminished Matrix Metalloproteinase-2 and -9
           Underlie Regional Decreases in Uteroplacental Vascularization and
           Feto-placental Growth in Hypertensive Pregnancy
    • Authors: Carlos A. Dias-Junior; Juanjuan Chen; Ning Cui; Charles L. Chiang; Minglin Zhu; Zongli Ren; Jose S. Possomato-Vieira; Raouf A. Khalil
      Abstract: Publication date: Available online 11 September 2017
      Source:Biochemical Pharmacology
      Author(s): Carlos A. Dias-Junior, Juanjuan Chen, Ning Cui, Charles L. Chiang, Minglin Zhu, Zongli Ren, Jose S. Possomato-Vieira, Raouf A. Khalil
      Preeclampsia is a form of hypertension-in-pregnancy (HTN-Preg) with unclear mechanism. Generalized reduction of uterine perfusion pressure (RUPP) could be an initiating event leading to uteroplacental ischemia, angiogenic imbalance, and HTN-Preg. Additional regional differences in uteroplacental blood flow could further affect the pregnancy outcome and increase the risk of preeclampsia in twin or multiple pregnancy, but the mechanisms involved are unclear. To test the hypothesis that regional differences in angiogenic balance and matrix metalloproteinases (MMPs) underlie regional uteroplacental vascularization and feto-placental development, we compared fetal and placental growth, and placental and myoendometrial vascularization in the proximal, middle and distal regions of the uterus (in relation to the iliac bifurcation) in normal pregnant (Preg) and RUPP rats. Maternal blood pressure and plasma anti-angiogenic soluble fms-like tyrosine kinase-1 (sFlt-1)/placenta growth factor (PIGF) ratio were higher, and average placentae number, placenta weight, litter size, and pup weight were less in RUPP than Preg rats. The placenta and pup number and weight were reduced, while the number and diameter of placental and adjacent myoendometrial arteries, and MMP-2 and MMP-9 levels/activity were increased, and sFlt-1/PlGF ratio was decreased in distal vs proximal uterus of Preg rats. In RUPP rats, the placenta and pup number and weight, the number and diameter of placental and myoendometrial arteries, and MMP-2 and -9 levels/activity were decreased, and sFlt-1/PlGF ratio was increased in distal vs proximal uterus. Treatment with sFlt-1 or RUPP placenta extract decreased MMP-2 and MMP-9 in distal segments of Preg uterus, and treatment with PIGF or Preg placenta extract restored MMP levels in distal segments of RUPP uterus. Thus, in addition to the general reduction in placental and fetal growth during uteroplacental ischemia, localized angiogenic imbalance and diminished MMP-2 and MMP-9 could cause further decrease in placental and myoendometrial vascularization and placental and fetal growth in distal vs proximal uterus of HTN-Preg rats. Regional differences in uteroplacental perfusion, angiogenic balance and MMPs could be a factor in the incidence of preeclampsia in multiple pregnancy.
      Graphical abstract image

      PubDate: 2017-09-16T12:51:10Z
      DOI: 10.1016/j.bcp.2017.09.005
       
  • Therapeutic Potential of Carbohydrates as Regulators of Macrophage
           Activation
    • Authors: Mimmi L.E. Lundahl; Eoin M. Scanlan; Ed C. Lavelle
      Abstract: Publication date: Available online 8 September 2017
      Source:Biochemical Pharmacology
      Author(s): Mimmi L.E. Lundahl, Eoin M. Scanlan, Ed C. Lavelle
      It is well established for a broad range of disease states, including cancer and Mycobacterium tuberculosis infection, that pathogenesis is bolstered by polarisation of macrophages towards an anti-inflammatory phenotype, known as M2. As these innate immune cells are relatively long-lived, their re-polarisation to pro-inflammatory, phagocytic and bactericidal “classically activated” M1 macrophages is an attractive therapeutic approach. On the other hand, there are scenarios where the resolving inflammation, wound healing and tissue remodelling properties of M2 macrophages are beneficial – for example the successful introduction of biomedical implants. Although there are numerous endogenous and exogenous factors that have an impact on the macrophage polarisation spectrum, this review will focus specifically on prominent macrophage-modulating carbohydrate motifs with a view towards highlighting structure-function relationships and therapeutic potential.
      Graphical abstract image

      PubDate: 2017-09-10T05:40:06Z
      DOI: 10.1016/j.bcp.2017.09.003
       
  • Drug repurposing strategy against Trypanosoma cruzi infection: In vitro
           and in vivo assessment of the activity of metronidazole in mono- and
           combined therapy
    • Authors: M.R. Simões-Silva; J.S. De Araújo; G.M. Oliveira; K.C. Demarque; R.B. Peres; I. D'Almeida-Melo; D.G.J. Batista; C.F. Da Silva; C. Cardoso-Santos; P.B. Da Silva; M.M. Batista; M.T. Bahia; M.N.C. Soeiro
      Abstract: Publication date: Available online 7 September 2017
      Source:Biochemical Pharmacology
      Author(s): M.R. Simões-Silva, J.S. De Araújo, G.M. Oliveira, K.C. Demarque, R.B. Peres, I. D'Almeida-Melo, D.G.J. Batista, C.F. Da Silva, C. Cardoso-Santos, P.B. Da Silva, M.M. Batista, M.T. Bahia, M.N.C. Soeiro
      Metronidazole (Mtz) is a commercial broad-spectrum nitroimidazolic derivative with relevant antimicrobial activity and relative safety profile. Therefore, it is fair to consider Mtz a candidate for drug repurposing for other neglected conditions such as Chagas disease (CD), a parasitic pathology caused by Trypanosoma cruzi. CD is treated only with benznidazole (Bz) and nifurtimox, both introduced in clinics decades ago despite important limitations, including low efficacy on the later disease stage (chronic form) and severe side effects. New cheap and fast alternative treatments for CD are needed, thus the repurposing of Mtz was assessed in vitro and in vivo in mono- and combined therapy. In vitro assays demonstrated EC50 >200µM for Mtz, while for Bz the values ranged from 2.51µM (intracellular forms) to 11.5µM (bloodstream trypomastigotes). When both drugs were combined in fixed-ratio proportions, Mtz promoted Bz potency (lower EC50 values). In vivo toxicity assays for Mtz in mice showed no adverse effects neither histopathological alterations up to 2000mg/kg. Regarding experimental T. cruzi infection, Bz 100mg/kg suppressed parasitemia while Mtz (up to 1000mg/kg) in monotherapy did not, but prolonged animal survival at 250 and 500 regimen doses. The combination of both drugs (Bz 10+Mtz 250) prevented mortality (70%) besides protected against electric cardiac alterations triggered by the parasite infection. Although not able to reduce parasite load, the combination therapy prevented animal mortality; this was possibly due to a protection of the electric cardiac physiology that is normally altered in experimental infection of T. cruzi. It also suggested that the interaction with Mtz could have improved the pharmacokinetics of Bz. Our study emphasizes the importance of drug repurposing and combined therapy for CD to contribute to alternative therapies for this neglected and silent pathology.
      Graphical abstract image

      PubDate: 2017-09-10T05:40:06Z
      DOI: 10.1016/j.bcp.2017.08.025
       
  • Deficiency of N-Acetyltransferase Increases the Interactions of Isoniazid
           with Endobiotics in mouse Liver
    • Authors: Pengcheng Wang; Amina I. Shehu; Jie Lu; Rujuta H. Joshi; Raman Venkataramanan; Kim S. Sugamori; Denis M. Grant; Xiao-bo Zhong; Xiaochao Ma
      Abstract: Publication date: Available online 6 September 2017
      Source:Biochemical Pharmacology
      Author(s): Pengcheng Wang, Amina I. Shehu, Jie Lu, Rujuta H. Joshi, Raman Venkataramanan, Kim S. Sugamori, Denis M. Grant, Xiao-bo Zhong, Xiaochao Ma
      Acetylation is the major metabolic pathway of isoniazid (INH) mediated by N-acetyltransferases (NATs). Previous reports suggest that slow acetylators have higher risks of INH hepatotoxicity than rapid acetylators, but the detailed mechanisms remain elusive. The current study used Nat1/2(-/-) mice to mimic NAT slow metabolizers and to investigate INH metabolism in the liver. We found that INH acetylation is abolished in the liver of Nat1/2(-/-) mice, suggesting that INH acetylation is fully dependent on NAT1/2. In addition to the acetylation pathway, INH can be hydrolyzed to form hydrazine (Hz) and isonicotinic acid (INA). We found that INA level was not altered in the liver of Nat1/2(-/-) mice, indicating that deficiency of NAT1/2 has no effect on INH hydrolysis. Because INH acetylation was abolished and INH hydrolysis was not altered in Nat1/2(-/-) mice, we expected an extremely high level of INH in the liver. However, we only observed a modest accumulation of INH in the liver of Nat1/2(-/-) mice, suggesting that there are alternative pathways in INH metabolism in NAT1/2 deficient condition. Our further studies revealed that the conjugated metabolites of INH with endobiotics, including fatty acids and vitamin B6, were significantly increased in the liver of Nat1/2(-/-) mice. In summary, this study illustrated that deficiency of NAT1/2 decreases INH acetylation, but increases the interactions of INH with endobiotics in the liver. These findings can be used to guide future studies on the mechanisms of INH hepatotoxicity in NAT slow metabolizers.
      Graphical abstract image

      PubDate: 2017-09-10T05:40:06Z
      DOI: 10.1016/j.bcp.2017.09.001
       
  • The two faces of aldehyde oxidase: oxidative and reductive transformations
           of 5-nitroquinoline
    • Authors: Erickson M. Paragas; Sara C. Humphreys; Joshua Min; Carolyn A. Joswig-Jones; Jeffrey P. Jones
      Abstract: Publication date: Available online 6 September 2017
      Source:Biochemical Pharmacology
      Author(s): Erickson M. Paragas, Sara C. Humphreys, Joshua Min, Carolyn A. Joswig-Jones, Jeffrey P. Jones
      Aldehyde oxidase (AOX) is a cytosolic enzyme responsible for the metabolism of some drugs and drug candidates. AOX catalyzes the oxidative hydroxylation of substrates including several aliphatic and aromatic aldehydes, and nitrogen-containing heterocyclic compounds. AOX is also reported to catalyze the reductive metabolism of nitro-compounds, N-oxides, sulfoxides, isoxazoles, isothiazoles, nitrite and hydroxamic acids. These reductive transformations are not well understood and are generally believed to only occur at low oxygen concentrations. In this study, we used 5-nitroquinoline (5NQ) as a substrate to further understand both the oxidative and the reductive transformations catalyzed by AOX. In vitro reaction of 5NQ with AOX under aerobic conditions generated the oxidized (2-oxo-5-nitroquinoline, 2-oxo-5NQ), the reduced (5-aminoquinoline, 5AQ) and the oxidized/reduced (2-oxo-5-aminoquinoline, 2-oxo-5AQ) metabolites. Interestingly, in human liver cytosol, co-incubation of 5NQ and known AOX oxidative substrates DACA and phthalazine significantly increased the yield of the reduced metabolite, while oxidized metabolites production were lowered. This data indicates that 5NQ can be reduced at atmospheric oxygen concentrations and that the reductive transformation occurs at a second site that is kinetically distinct from the oxidative site.
      Graphical abstract image

      PubDate: 2017-09-10T05:40:06Z
      DOI: 10.1016/j.bcp.2017.09.002
       
  • Editorial Advisory Board
    • Abstract: Publication date: 15 September 2017
      Source:Biochemical Pharmacology, Volume 140


      PubDate: 2017-08-13T15:44:12Z
       
  • Editorial Advisory Board
    • Abstract: Publication date: 1 September 2017
      Source:Biochemical Pharmacology, Volume 139


      PubDate: 2017-08-03T15:21:41Z
       
  • I6 Natural product-based protein amyloid inhibitors
    • Authors: Bin
      Abstract: Publication date: 1 September 2017
      Source:Biochemical Pharmacology, Volume 139
      Author(s): Bin Xu
      Toxic protein amyloid formation has been implicated in more than a dozen protein misfolding diseases such as Alzheimer’s disease, Parkinson’s disease, and type 2 diabetes. Currently there are no effective disease-modifying drugs available. One common therapeutic strategy is to discover and develop protein amyloid inhibitors that can slow down, prevent, or remodel toxic amyloids. Natural products are a major class of amyloid inhibitors, and several dozens of natural product-based amyloid inhibitors have been identified and characterized in recent years. Using amyloidogenic proteins amylin, amyloid beta-peptide, and tau as model systems, we screened libraries of natural compounds used in Complementary and Alternative Medicine. We identified multiple potent inhibitors, including rosmarinic acid and baicalein (200nM and 1μM respectively in apparent IC 50 ) [1]. These compounds disaggregate amyloidogenic protein fibrils, significantly reduce protein amyloid-induced cytotoxicity and toxic amyloid oligomers in circulating sera and/or cerebrospinal fluid from diseased animal models. Dissecting the functional groups of these compounds, we demonstrated, for the first time to our knowledge, that the vicinal hydroxyl groups of the catechol groups played key functional roles in amyloid inhibition in more than two dozen catechol-containing compounds, including many plant- and fruit-derived flavonoids and other phenolic compounds [2]. Compounds with multiple catechol groups, such as rosmarinic acid, exhibited additive effects. We provided further mass spectrometric evidence that incubating several of these catechol-containing inhibitors with amyloidogenic proteins leads to covalent adducts consistent with Schiff base conjugation mechanism to interfere with toxic amyloid formation. Consistent with forming covalent adducts via the mechanism of quinone intermediates, we demonstrated that many catechol-containing natural products significantly increase amyloid inhibition effects under autooxidation or oxidizing conditions. Lastly, I will discuss our approach to enhance certain natural product solubility/bioavailability by engineering natural compound-incorporating nanoparticles [3]. Acknowledgement This work is in part supported by Virginia Tech new faculty start-up funds, Commonwealth Health Research Board (CHRB), Alzheimer’s and Related Diseases Research Award Fund (ARDRAF) from Virginia Center on Aging, Diabetes Action Research and Education Foundation (DAREF), and Virginia Tech Center for Drug Discovery (VTCDD).

      PubDate: 2017-08-03T15:21:41Z
       
 
 
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