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Publisher: Elsevier   (Total: 3031 journals)

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Showing 1 - 200 of 3031 Journals sorted alphabetically
AASRI Procedia     Open Access   (Followers: 15)
Academic Pediatrics     Hybrid Journal   (Followers: 20, SJR: 1.402, h-index: 51)
Academic Radiology     Hybrid Journal   (Followers: 16, SJR: 1.008, h-index: 75)
Accident Analysis & Prevention     Partially Free   (Followers: 79, SJR: 1.109, h-index: 94)
Accounting Forum     Hybrid Journal   (Followers: 22, SJR: 0.612, h-index: 27)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 27, SJR: 2.515, h-index: 90)
Achievements in the Life Sciences     Open Access   (Followers: 4)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 5, SJR: 0.338, h-index: 19)
Acta Astronautica     Hybrid Journal   (Followers: 303, SJR: 0.726, h-index: 43)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 3)
Acta Biomaterialia     Hybrid Journal   (Followers: 25, SJR: 2.02, h-index: 104)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription  
Acta de Investigación Psicológica     Open Access   (Followers: 2)
Acta Ecologica Sinica     Open Access   (Followers: 8, SJR: 0.172, h-index: 29)
Acta Haematologica Polonica     Free   (SJR: 0.123, h-index: 8)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.604, h-index: 38)
Acta Materialia     Hybrid Journal   (Followers: 196, SJR: 3.683, h-index: 202)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 5, SJR: 0.615, h-index: 21)
Acta Mechanica Solida Sinica     Full-text available via subscription   (Followers: 9, SJR: 0.442, h-index: 21)
Acta Oecologica     Hybrid Journal   (Followers: 9, SJR: 0.915, h-index: 53)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription   (Followers: 1)
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 3, SJR: 0.311, h-index: 16)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 2)
Acta Poética     Open Access   (Followers: 4)
Acta Psychologica     Hybrid Journal   (Followers: 21, SJR: 1.365, h-index: 73)
Acta Sociológica     Open Access  
Acta Tropica     Hybrid Journal   (Followers: 5, SJR: 1.059, h-index: 77)
Acta Urológica Portuguesa     Open Access  
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 4)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 3)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 3, SJR: 0.383, h-index: 19)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 2)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 5, SJR: 0.141, h-index: 3)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 4, SJR: 0.112, h-index: 2)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 4)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.967, h-index: 57)
Addictive Behaviors     Hybrid Journal   (Followers: 15, SJR: 1.514, h-index: 92)
Addictive Behaviors Reports     Open Access   (Followers: 5)
Additive Manufacturing     Hybrid Journal   (Followers: 7, SJR: 1.039, h-index: 5)
Additives for Polymers     Full-text available via subscription   (Followers: 20)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 119, SJR: 5.2, h-index: 222)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 11, SJR: 1.265, h-index: 53)
Advanced Powder Technology     Hybrid Journal   (Followers: 16, SJR: 0.739, h-index: 33)
Advances in Accounting     Hybrid Journal   (Followers: 8, SJR: 0.299, h-index: 15)
Advances in Agronomy     Full-text available via subscription   (Followers: 15, SJR: 2.071, h-index: 82)
Advances in Anesthesia     Full-text available via subscription   (Followers: 24, SJR: 0.169, h-index: 4)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 3)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 6, SJR: 1.054, h-index: 35)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 10, SJR: 0.801, h-index: 26)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 21, SJR: 1.286, h-index: 49)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 16, SJR: 3.31, h-index: 42)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.277, h-index: 43)
Advances in Botanical Research     Full-text available via subscription   (Followers: 3, SJR: 0.619, h-index: 48)
Advances in Cancer Research     Full-text available via subscription   (Followers: 26, SJR: 2.215, h-index: 78)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9, SJR: 0.9, h-index: 30)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 2.139, h-index: 42)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 12)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 24, SJR: 0.183, h-index: 23)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 10, SJR: 0.665, h-index: 29)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 8, SJR: 1.268, h-index: 45)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 28, SJR: 0.938, h-index: 33)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 18, SJR: 2.314, h-index: 130)
Advances in Computers     Full-text available via subscription   (Followers: 16, SJR: 0.223, h-index: 22)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 11)
Advances in Digestive Medicine     Open Access   (Followers: 4)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 5)
Advances in Drug Research     Full-text available via subscription   (Followers: 22)
Advances in Ecological Research     Full-text available via subscription   (Followers: 39, SJR: 3.25, h-index: 43)
Advances in Engineering Software     Hybrid Journal   (Followers: 25, SJR: 0.486, h-index: 10)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 7)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 38, SJR: 5.465, h-index: 64)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 3)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 8)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 41, SJR: 0.674, h-index: 38)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 14)
Advances in Genetics     Full-text available via subscription   (Followers: 15, SJR: 2.558, h-index: 54)
Advances in Genome Biology     Full-text available via subscription   (Followers: 11)
Advances in Geophysics     Full-text available via subscription   (Followers: 6, SJR: 2.325, h-index: 20)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 18, SJR: 0.906, h-index: 24)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 0.497, h-index: 31)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 22)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 2, SJR: 0.396, h-index: 27)
Advances in Immunology     Full-text available via subscription   (Followers: 33, SJR: 4.152, h-index: 85)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 9, SJR: 1.132, h-index: 42)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 3, SJR: 1.274, h-index: 27)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 4)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 4)
Advances in Life Course Research     Hybrid Journal   (Followers: 7, SJR: 0.764, h-index: 15)
Advances in Lipobiology     Full-text available via subscription   (Followers: 1)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 8)
Advances in Marine Biology     Full-text available via subscription   (Followers: 16, SJR: 1.645, h-index: 45)
Advances in Mathematics     Full-text available via subscription   (Followers: 10, SJR: 3.261, h-index: 65)
Advances in Medical Sciences     Hybrid Journal   (Followers: 5, SJR: 0.489, h-index: 25)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 4, SJR: 1.44, h-index: 51)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 21)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 10)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 6, SJR: 0.324, h-index: 8)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 3)
Advances in Oncobiology     Full-text available via subscription   (Followers: 3)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 15, SJR: 2.885, h-index: 45)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 7, SJR: 0.148, h-index: 11)
Advances in Parasitology     Full-text available via subscription   (Followers: 7, SJR: 2.37, h-index: 73)
Advances in Pediatrics     Full-text available via subscription   (Followers: 20, SJR: 0.4, h-index: 28)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 14)
Advances in Pharmacology     Full-text available via subscription   (Followers: 13, SJR: 1.718, h-index: 58)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 7, SJR: 0.384, h-index: 26)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.248, h-index: 11)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 8)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 5)
Advances in Porous Media     Full-text available via subscription   (Followers: 4)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 18)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 17, SJR: 1.5, h-index: 62)
Advances in Psychology     Full-text available via subscription   (Followers: 56)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 5, SJR: 0.478, h-index: 32)
Advances in Radiation Oncology     Open Access  
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 1, SJR: 0.1, h-index: 2)
Advances in Space Research     Full-text available via subscription   (Followers: 332, SJR: 0.606, h-index: 65)
Advances in Structural Biology     Full-text available via subscription   (Followers: 7)
Advances in Surgery     Full-text available via subscription   (Followers: 6, SJR: 0.823, h-index: 27)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 28, SJR: 1.321, h-index: 56)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 14)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 12)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 1.878, h-index: 68)
Advances in Water Resources     Hybrid Journal   (Followers: 42, SJR: 2.408, h-index: 94)
Aeolian Research     Hybrid Journal   (Followers: 5, SJR: 0.973, h-index: 22)
Aerospace Science and Technology     Hybrid Journal   (Followers: 303, SJR: 0.816, h-index: 49)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.318, h-index: 36)
African J. of Emergency Medicine     Open Access   (Followers: 4, SJR: 0.344, h-index: 6)
Ageing Research Reviews     Hybrid Journal   (Followers: 7, SJR: 3.289, h-index: 78)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 388, SJR: 1.385, h-index: 72)
Agri Gene     Hybrid Journal  
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 15, SJR: 2.18, h-index: 116)
Agricultural Systems     Hybrid Journal   (Followers: 29, SJR: 1.275, h-index: 74)
Agricultural Water Management     Hybrid Journal   (Followers: 36, SJR: 1.546, h-index: 79)
Agriculture and Agricultural Science Procedia     Open Access  
Agriculture and Natural Resources     Open Access   (Followers: 1)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 48, SJR: 1.879, h-index: 120)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.434, h-index: 14)
Air Medical J.     Hybrid Journal   (Followers: 3, SJR: 0.234, h-index: 18)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.285, h-index: 3)
Alcohol     Hybrid Journal   (Followers: 9, SJR: 0.922, h-index: 66)
Alcoholism and Drug Addiction     Open Access   (Followers: 5)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 1, SJR: 0.436, h-index: 12)
Alexandria J. of Medicine     Open Access  
Algal Research     Partially Free   (Followers: 7, SJR: 2.05, h-index: 20)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.46, h-index: 29)
Allergology Intl.     Open Access   (Followers: 5, SJR: 0.776, h-index: 35)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 6, SJR: 0.158, h-index: 9)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 45, SJR: 4.289, h-index: 64)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 5)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 3)
American Heart J.     Hybrid Journal   (Followers: 45, SJR: 3.157, h-index: 153)
American J. of Cardiology     Hybrid Journal   (Followers: 47, SJR: 2.063, h-index: 186)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 34, SJR: 0.574, h-index: 65)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 6, SJR: 1.091, h-index: 45)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 14, SJR: 1.653, h-index: 93)
American J. of Human Genetics     Hybrid Journal   (Followers: 32, SJR: 8.769, h-index: 256)
American J. of Infection Control     Hybrid Journal   (Followers: 25, SJR: 1.259, h-index: 81)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 31, SJR: 2.313, h-index: 172)
American J. of Medicine     Hybrid Journal   (Followers: 48, SJR: 2.023, h-index: 189)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 173, SJR: 2.255, h-index: 171)
American J. of Ophthalmology     Hybrid Journal   (Followers: 51, SJR: 2.803, h-index: 148)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 2)
American J. of Orthodontics and Dentofacial Orthopedics     Full-text available via subscription   (Followers: 6, SJR: 1.249, h-index: 88)
American J. of Otolaryngology     Hybrid Journal   (Followers: 22, SJR: 0.59, h-index: 45)
American J. of Pathology     Hybrid Journal   (Followers: 23, SJR: 2.653, h-index: 228)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 21, SJR: 2.764, h-index: 154)
American J. of Surgery     Hybrid Journal   (Followers: 32, SJR: 1.286, h-index: 125)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 13, SJR: 0.653, h-index: 70)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 5)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.066, h-index: 51)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 52, SJR: 0.124, h-index: 9)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 3)
Anales de Cirugia Vascular     Full-text available via subscription  
Anales de Pediatría     Full-text available via subscription   (Followers: 2, SJR: 0.209, h-index: 27)
Anales de Pediatría (English Edition)     Full-text available via subscription  
Anales de Pediatría Continuada     Full-text available via subscription   (SJR: 0.104, h-index: 3)
Analytic Methods in Accident Research     Hybrid Journal   (Followers: 2, SJR: 2.577, h-index: 7)
Analytica Chimica Acta     Hybrid Journal   (Followers: 38, SJR: 1.548, h-index: 152)
Analytical Biochemistry     Hybrid Journal   (Followers: 151, SJR: 0.725, h-index: 154)
Analytical Chemistry Research     Open Access   (Followers: 7, SJR: 0.18, h-index: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 10)
Anesthésie & Réanimation     Full-text available via subscription  
Anesthesiology Clinics     Full-text available via subscription   (Followers: 21, SJR: 0.421, h-index: 40)
Angiología     Full-text available via subscription   (SJR: 0.124, h-index: 9)
Angiologia e Cirurgia Vascular     Open Access  
Animal Behaviour     Hybrid Journal   (Followers: 141, SJR: 1.907, h-index: 126)
Animal Feed Science and Technology     Hybrid Journal   (Followers: 5, SJR: 1.151, h-index: 83)
Animal Reproduction Science     Hybrid Journal   (Followers: 5, SJR: 0.711, h-index: 78)
Annales d'Endocrinologie     Full-text available via subscription   (SJR: 0.394, h-index: 30)
Annales d'Urologie     Full-text available via subscription  
Annales de Cardiologie et d'Angéiologie     Full-text available via subscription   (SJR: 0.177, h-index: 13)
Annales de Chirurgie de la Main et du Membre Supérieur     Full-text available via subscription  
Annales de Chirurgie Plastique Esthétique     Full-text available via subscription   (Followers: 2, SJR: 0.354, h-index: 22)
Annales de Chirurgie Vasculaire     Full-text available via subscription   (Followers: 1)

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Journal Cover Advances in Pharmacology
  [SJR: 1.718]   [H-I: 58]   [13 followers]  Follow
    
   Full-text available via subscription Subscription journal  (Not entitled to full-text)
   ISSN (Print) 1054-3589
   Published by Elsevier Homepage  [3031 journals]
  • Genetically Encoded Calcium Indicators as Probes to Assess the Role of
           Calcium Channels in Disease and for High-Throughput Drug Discovery
    • Authors: J.J. Bassett; G.R. Monteith
      Abstract: Publication date: Available online 6 March 2017
      Source:Advances in Pharmacology
      Author(s): J.J. Bassett, G.R. Monteith
      The calcium ion (Ca2+) is an important signaling molecule implicated in many cellular processes, and the remodeling of Ca2+ homeostasis is a feature of a variety of pathologies. Typical methods to assess Ca2+ signaling in cells often employ small molecule fluorescent dyes, which are sometimes poorly suited to certain applications such as assessment of cellular processes, which occur over long periods (hours or days) or in vivo experiments. Genetically encoded calcium indicators are a set of tools available for the measurement of Ca2+ changes in the cytosol and subcellular compartments, which circumvent some of the inherent limitations of small molecule Ca2+ probes. Recent advances in genetically encoded calcium sensors have greatly increased their ability to provide reliable monitoring of Ca2+ changes in mammalian cells. New genetically encoded calcium indicators have diverse options in terms of targeting, Ca2+ affinity and fluorescence spectra, and this will further enhance their potential use in high-throughput drug discovery and other assays. This review will outline the methods available for Ca2+ measurement in cells, with a focus on genetically encoded calcium sensors. How these sensors will improve our understanding of the deregulation of Ca2+ handling in disease and their application to high-throughput identification of drug leads will also be discussed.

      PubDate: 2017-03-07T23:01:09Z
      DOI: 10.1016/bs.apha.2017.01.001
       
  • Physiology and Pharmacology of Ryanodine Receptor Calcium Release Channels
    • Authors: A.F. Dulhunty; P.G. Board; N.A. Beard; M.G. Casarotto
      Abstract: Publication date: Available online 22 February 2017
      Source:Advances in Pharmacology
      Author(s): A.F. Dulhunty, P.G. Board, N.A. Beard, M.G. Casarotto
      Ryanodine receptor (RyR) ion channels are essential for skeletal and cardiac muscle function. Their knockout leads to perinatal death from respiratory and cardiac failure. Acquired changes or mutations in the protein cause debilitating skeletal myopathy and cardiac arrhythmia which can be deadly. Knowledge of the pharmacology of RyR channels is central to developing effective and specific treatments of these myopathies. The ion channel is a >2.2MDa homotetamer with distinct structural and functional characteristics giving rise to a myriad of regulatory sites that are potential therapeutic targets. Australian researchers have been intimately involved in the exploration of the proteins since their identification in the mid-1980s. We discuss major aspects of RyR physiology and pharmacology that have been tackled in Australian laboratories. Specific areas of interest include ultrastructural aspects and mechanisms of RyR activation in excitation–contraction (EC) coupling and related pharmacological developments, regulation of RyRs by divalent cations, by associated proteins including the FK506-binding proteins, by redox factors and phosphorylation. We consider adverse effects of anthracycline chemotherapeutic drugs on cardiac RyRs. Phenotypes associated with RyR mutations are discussed with current and developing therapeutic approaches for treating the underlying RyR dysfunction.

      PubDate: 2017-02-28T21:54:45Z
      DOI: 10.1016/bs.apha.2016.12.001
       
  • Nanojunctions of the Sarcoplasmic Reticulum Deliver Site- and
           Function-Specific Calcium Signaling in Vascular Smooth Muscles
    • Authors: A. Mark Evans
      Abstract: Publication date: Available online 2 December 2016
      Source:Advances in Pharmacology
      Author(s): A. Mark Evans
      Vasoactive agents may induce myocyte contraction, dilation, and the switch from a contractile to a migratory–proliferative phenotype(s), which requires changes in gene expression. These processes are directed, in part, by Ca2+ signals, but how different Ca2+ signals are generated to select each function is enigmatic. We have previously proposed that the strategic positioning of Ca2+ pumps and release channels at membrane–membrane junctions of the sarcoplasmic reticulum (SR) demarcates cytoplasmic nanodomains, within which site- and function-specific Ca2+ signals arise. This chapter will describe how nanojunctions of the SR may: (1) define cytoplasmic nanospaces about the plasma membrane, mitochondria, contractile myofilaments, lysosomes, and the nucleus; (2) provide for functional segregation by restricting passive diffusion and by coordinating active ion transfer within a given nanospace via resident Ca2+ pumps and release channels; (3) select for contraction, relaxation, and/or changes in gene expression; and (4) facilitate the switch in myocyte phenotype through junctional reorganization. This should serve to highlight the need for further exploration of cellular nanojunctions and the mechanisms by which they operate, that will undoubtedly open up new therapeutic horizons.

      PubDate: 2016-12-05T07:17:14Z
      DOI: 10.1016/bs.apha.2016.10.001
       
  • Rho-Mancing to Sensitize Calcium Signaling for Contraction in the
           Vasculature: Role of Rho Kinase
    • Authors: T. Szasz; R.C. Webb
      Abstract: Publication date: Available online 27 October 2016
      Source:Advances in Pharmacology
      Author(s): T. Szasz, R.C. Webb
      Vascular smooth muscle contraction is an important physiological process contributing to cardiovascular homeostasis. The principal determinant of smooth muscle contraction is the intracellular free Ca2+ concentration, and phosphorylation of myosin light chain (MLC) by activated myosin light chain kinase (MLCK) in response to increased Ca2+ is the main pathway by which vasoconstrictor stimuli induce crossbridge cycling of myosin and actin filaments. A secondary pathway for vascular smooth muscle contraction that is not directly dependent on Ca2+ concentration, but rather mediating Ca2+ sensitization, is the RhoA/Rho kinase pathway. In response to contractile stimuli, the small GTPase RhoA activates its downstream effector Rho kinase which, in turn, promotes contraction via myosin light chain phosphatase (MLCP) inhibition. RhoA/Rho kinase-mediated MLCP inhibition occurs mainly by phosphorylation and inhibition of MYPT1, the regulatory subunit of MLCP, or by CPI-17-mediated inhibition of the catalytic subunit of MLCP. In this review, we describe the molecular mechanisms underlying the pivotal role exerted by Rho kinase on vascular smooth muscle contraction and discuss the main regulatory pathways for its activity.

      PubDate: 2016-10-31T14:54:42Z
      DOI: 10.1016/bs.apha.2016.09.001
       
  • Vascular Cells in Blood Vessel Wall Development and Disease
    • Authors: R. Mazurek; J.M. Dave; R.R. Chandran; A. Misra; A.Q. Sheikh; D.M. Greif
      Abstract: Publication date: Available online 14 October 2016
      Source:Advances in Pharmacology
      Author(s): R. Mazurek, J.M. Dave, R.R. Chandran, A. Misra, A.Q. Sheikh, D.M. Greif
      The vessel wall is composed of distinct cellular layers, yet communication among individual cells within and between layers results in a dynamic and versatile structure. The morphogenesis of the normal vascular wall involves a highly regulated process of cell proliferation, migration, and differentiation. The use of modern developmental biological and genetic approaches has markedly enriched our understanding of the molecular and cellular mechanisms underlying these developmental events. Additionally, the application of similar approaches to study diverse vascular diseases has resulted in paradigm-shifting insights into pathogenesis. Further investigations into the biology of vascular cells in development and disease promise to have major ramifications on therapeutic strategies to combat pathologies of the vasculature.

      PubDate: 2016-10-16T11:15:45Z
      DOI: 10.1016/bs.apha.2016.08.001
       
  • Smooth Muscle Phenotypic Diversity: Effect on Vascular Function and Drug
           Responses
    • Authors: S.A. Fisher
      Abstract: Publication date: Available online 14 October 2016
      Source:Advances in Pharmacology
      Author(s): S.A. Fisher
      At its simplest resistance to blood flow is regulated by changes in the state of contraction of the vascular smooth muscle (VSM), a function of the competing activities of the myosin kinase and phosphatase determining the phosphorylation and activity of the myosin ATPase motor protein. In contrast, the vascular system of humans and other mammals is incredibly complex and highly regulated. Much of this complexity derives from phenotypic diversity within the smooth muscle, reflected in very differing power outputs and responses to signaling pathways that regulate vessel tone, presumably having evolved over the millennia to optimize vascular function and its control. The highly regulated nature of VSM tone, described as pharmacomechanical coupling, likely underlies the many classes of drugs in clinical use to alter vascular tone through activation or inhibition of these signaling pathways. This review will first describe the phenotypic diversity within VSM, followed by presentation of specific examples of how molecular diversity in signaling, myofilament, and calcium cycling proteins impacts arterial smooth muscle function and drug responses.

      PubDate: 2016-10-16T11:15:45Z
      DOI: 10.1016/bs.apha.2016.07.003
       
  • Calcium Channels in Vascular Smooth Muscle
    • Authors: D. Ghosh; A.U. Syed; M.P. Prada; M.A. Nystoriak; L.F. Santana; M. Nieves-Cintrón; M.F. Navedo
      Abstract: Publication date: Available online 14 October 2016
      Source:Advances in Pharmacology
      Author(s): D. Ghosh, A.U. Syed, M.P. Prada, M.A. Nystoriak, L.F. Santana, M. Nieves-Cintrón, M.F. Navedo
      Calcium (Ca2+) plays a central role in excitation, contraction, transcription, and proliferation of vascular smooth muscle cells (VSMs). Precise regulation of intracellular Ca2+ concentration ([Ca2+]i) is crucial for proper physiological VSM function. Studies over the last several decades have revealed that VSMs express a variety of Ca2+-permeable channels that orchestrate a dynamic, yet finely tuned regulation of [Ca2+]i. In this review, we discuss the major Ca2+-permeable channels expressed in VSM and their contribution to vascular physiology and pathology.

      PubDate: 2016-10-16T11:15:45Z
      DOI: 10.1016/bs.apha.2016.08.002
       
  • Ca2+/Calmodulin-Dependent Protein Kinase II in Vascular Smooth Muscle
    • Authors: F.Z. Saddouk; R. Ginnan; H.A. Singer
      Abstract: Publication date: Available online 14 October 2016
      Source:Advances in Pharmacology
      Author(s): F.Z. Saddouk, R. Ginnan, H.A. Singer
      Ca2+-dependent signaling pathways are central regulators of differentiated vascular smooth muscle (VSM) contractile function. In addition, Ca2+ signals regulate VSM gene transcription, proliferation, and migration of dedifferentiated or “synthetic” phenotype VSM cells. Synthetic phenotype VSM growth and hyperplasia are hallmarks of pervasive vascular diseases including hypertension, atherosclerosis, postangioplasty/in-stent restenosis, and vein graft failure. The serine/threonine protein kinase Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a ubiquitous mediator of intracellular Ca2+ signals. Its multifunctional nature, structural complexity, diversity of isoforms, and splice variants all characterize this protein kinase and make study of its activity and function challenging. The kinase has unique autoregulatory mechanisms, and emerging studies suggest that it can function to integrate Ca2+ and reactive oxygen/nitrogen species signaling. Differentiated VSM expresses primarily CaMKIIγ and -δ isoforms. CaMKIIγ isoform expression correlates closely with the differentiated phenotype, and some studies link its function to regulation of contractile activity and Ca2+ homeostasis. Conversely, synthetic phenotype VSM cells primarily express CaMKIIδ and substantial evidence links it to regulation of gene transcription, proliferation, and migration of VSM in vitro, and vascular hypertrophic and hyperplastic remodeling in vivo. CaMKIIδ and -γ isoforms have opposing functions at the level of cell cycle regulation, proliferation, and VSM hyperplasia in vivo. Isoform switching following vascular injury is a key step in promoting vascular remodeling. Recent availability of genetically engineered mice with smooth muscle deletion of specific isoforms and transgenics expressing an endogenous inhibitor protein (CAMK2N) has enabled a better understanding of CaMKII function in VSM and should facilitate future studies.

      PubDate: 2016-10-16T11:15:45Z
      DOI: 10.1016/bs.apha.2016.08.003
       
  • Notch Signaling in Vascular Smooth Muscle Cells
    • Authors: J.T. Baeten; B. Lilly
      Abstract: Publication date: Available online 26 August 2016
      Source:Advances in Pharmacology
      Author(s): J.T. Baeten, B. Lilly
      The Notch signaling pathway is a highly conserved pathway involved in cell fate determination in embryonic development and also functions in the regulation of physiological processes in several systems. It plays an especially important role in vascular development and physiology by influencing angiogenesis, vessel patterning, arterial/venous specification, and vascular smooth muscle biology. Aberrant or dysregulated Notch signaling is the cause of or a contributing factor to many vascular disorders, including inherited vascular diseases, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, associated with degeneration of the smooth muscle layer in cerebral arteries. Like most signaling pathways, the Notch signaling axis is influenced by complex interactions with mediators of other signaling pathways. This complexity is also compounded by different members of the Notch family having both overlapping and unique functions. Thus, it is vital to fully understand the roles and interactions of each Notch family member in order to effectively and specifically target their exact contributions to vascular disease. In this chapter, we will review the Notch signaling pathway in vascular smooth muscle cells as it relates to vascular development and human disease.

      PubDate: 2016-08-31T12:34:10Z
      DOI: 10.1016/bs.apha.2016.07.002
       
  • Potassium Channels in Regulation of Vascular Smooth Muscle Contraction and
           Growth
    • Authors: W.F. Jackson
      Abstract: Publication date: Available online 17 August 2016
      Source:Advances in Pharmacology
      Author(s): W.F. Jackson
      Potassium channels importantly contribute to the regulation of vascular smooth muscle (VSM) contraction and growth. They are the dominant ion conductance of the VSM cell membrane and importantly determine and regulate membrane potential. Membrane potential, in turn, regulates the open-state probability of voltage-gated Ca2+ channels (VGCC), Ca2+ influx through VGCC, intracellular Ca2+, and VSM contraction. Membrane potential also affects release of Ca2+ from internal stores and the Ca2+ sensitivity of the contractile machinery such that K+ channels participate in all aspects of regulation of VSM contraction. Potassium channels also regulate proliferation of VSM cells through membrane potential-dependent and membrane potential-independent mechanisms. VSM cells express multiple isoforms of at least five classes of K+ channels that contribute to the regulation of contraction and cell proliferation (growth). This review will examine the structure, expression, and function of large conductance, Ca2+-activated K+ (BKCa) channels, intermediate-conductance Ca2+-activated K+ (KCa3.1) channels, multiple isoforms of voltage-gated K+ (KV) channels, ATP-sensitive K+ (KATP) channels, and inward-rectifier K+ (KIR) channels in both contractile and proliferating VSM cells.

      PubDate: 2016-08-22T06:25:32Z
       
  • Protein Kinase C as Regulator of Vascular Smooth Muscle Function and
           Potential Target in Vascular Disorders
    • Authors: H.C. Ringvold; R.A. Khalil
      Abstract: Publication date: Available online 18 July 2016
      Source:Advances in Pharmacology
      Author(s): H.C. Ringvold, R.A. Khalil
      Vascular smooth muscle (VSM) plays an important role in maintaining vascular tone. In addition to Ca2+-dependent myosin light chain (MLC) phosphorylation, protein kinase C (PKC) is a major regulator of VSM function. PKC is a family of conventional Ca2+-dependent α, β, and γ, novel Ca2+-independent δ, ɛ, θ, and η, and atypical ξ, and ι/λ isoforms. Inactive PKC is mainly cytosolic, and upon activation it undergoes phosphorylation, maturation, and translocation to the surface membrane, the nucleus, endoplasmic reticulum, and other cell organelles; a process facilitated by scaffold proteins such as RACKs. Activated PKC phosphorylates different substrates including ion channels, pumps, and nuclear proteins. PKC also phosphorylates CPI-17 leading to inhibition of MLC phosphatase, increased MLC phosphorylation, and enhanced VSM contraction. PKC could also initiate a cascade of protein kinases leading to phosphorylation of the actin-binding proteins calponin and caldesmon, increased actin–myosin interaction, and VSM contraction. Increased PKC activity has been associated with vascular disorders including ischemia–reperfusion injury, coronary artery disease, hypertension, and diabetic vasculopathy. PKC inhibitors could test the role of PKC in different systems and could reduce PKC hyperactivity in vascular disorders. First-generation PKC inhibitors such as staurosporine and chelerythrine are not very specific. Isoform-specific PKC inhibitors such as ruboxistaurin have been tested in clinical trials. Target delivery of PKC pseudosubstrate inhibitory peptides and PKC siRNA may be useful in localized vascular disease. Further studies of PKC and its role in VSM should help design isoform-specific PKC modulators that are experimentally potent and clinically safe to target PKC in vascular disease.

      PubDate: 2016-07-27T21:39:05Z
      DOI: 10.1016/bs.apha.2016.06.002
       
  • Sodium–Calcium Exchanger in Pig Coronary Artery
    • Authors: A.K. Grover
      Abstract: Publication date: Available online 15 July 2016
      Source:Advances in Pharmacology
      Author(s): A.K. Grover
      This review focuses on the sodium–calcium exchangers (NCX) in the left anterior descending coronary artery smooth muscle. Bathing tissues in Na+-substituted solutions caused them to contract. In cultured smooth muscle cells, it increased the cytosolic Ca2+ concentration and extracellular entry of 45Ca2+. All three activities were attributed to NCX since they were inhibited by NCX inhibitors. The tissues also expressed the sarco/endoplasmic reticulum (SER) Ca2+ pump SERCA2b whose activity was much greater than that of NCX. Inhibiting SERCA2b with thapsigargin decreased the NCX-mediated 45Ca2+ accumulation by the cells. The decrease was not observed in cells loaded with the Ca2+-chelator BAPTA. The results are consistent with a limited diffusional space model with a proximity between NCX and SERCA2b. NCX molecules appear to be colocalized with the subsarcolemmal SERCA2b based on studies on membrane flotation experiments and microscopic fluorescence imaging of antibody-labeled cells. Thapsigargin inhibition of SERCA2b moved NCX even closer to SER. This provides a model for the NCX-mediated Ca2+ refilling of SER in the arterial smooth muscle. The model for the NCX-mediated refilling of the depleted SER proposed for smooth muscle did not apply to endothelium in which NCX levels were greater and SERCA levels were lower than in smooth muscle. The effect of thapsigargin on the NCX-mediated Ca2+ accumulation which was observed in smooth muscle was absent in the endothelium. We propose that the coupling between NCX and smooth muscle may be tissue dependent.

      PubDate: 2016-07-27T21:39:05Z
      DOI: 10.1016/bs.apha.2016.06.001
       
  • Chapter One The Endothelium-Dependent Nitric Oxide–cGMP Pathway
    • Authors: F.Z. Bian; Murad
      Abstract: Publication date: 2016
      Source:Advances in Pharmacology, Volume 77
      Author(s): F.Z. Mónica, K. Bian, F. Murad
      Nitric oxide (NO)–cyclic 3′-5′ guanosine monophosphate (cGMP) signaling plays a critical role on smooth muscle tone, platelet activity, cardiac contractility, renal function and fluid balance, and cell growth. Studies of the 1990s established endothelium dysfunction as one of the major causes of cardiovascular diseases. Therapeutic strategies that benefit NO bioavailability have been applied in clinical medicine extensively. Basic and clinical studies of cGMP regulation through activation of soluble guanylyl cyclase (sGC) or inhibition of cyclic nucleotide phosphodiesterase type 5 (PDE5) have resulted in effective therapies for pulmonary hypertension, erectile dysfunction, and more recently benign prostatic hyperplasia. This section reviews (1) how endothelial dysfunction and NO deficiency lead to cardiovascular diseases, (2) how soluble cGMP regulation leads to beneficial effects on disorders of the circulation system, and (3) the epigenetic regulation of NO–sGC pathway components in the cardiovascular system. In conclusion, the discovery of the NO–cGMP pathway revolutionized the comprehension of pathophysiological mechanisms involved in cardiovascular and other diseases. However, considering the expression “from bench to bedside” the therapeutic alternatives targeting NO–cGMP did not immediately follow the marked biochemical and pathophysiological revolution. Some therapeutic options have been effective and released on the market for pulmonary hypertension and erectile dysfunction such as inhaled NO, PDE5 inhibitors, and recently sGC stimulators. The therapeutic armamentarium for many other disorders is expected in the near future. There are currently numerous active basic and clinical research programs in universities and industries attempting to develop novel therapies for many diseases and medical applications.

      PubDate: 2016-07-27T21:39:05Z
       
  • Chapter Five Endothelin-1
    • Authors: Houde Desbiens
      Abstract: Publication date: 2016
      Source:Advances in Pharmacology, Volume 77
      Author(s): M. Houde, L. Desbiens, P. D’Orléans-Juste
      Endothelin-1 (ET-1) is an extremely potent vasoconstrictor peptide originally isolated from endothelial cells. Its synthesis, mainly regulated at the gene transcription level, involves processing of a precursor by a furin-type proprotein convertase to an inactive intermediate, big ET-1. The latter peptide can then be cleaved directly by an endothelin-converting enzyme (ECE) into ET-1 or reach the active metabolite through a two-step process involving chymase hydrolyzing big ET-1 to ET-1 (1–31), itself needing conversion to ET-1 by neprilysin (NEP) to exert physiological activity. ET-1 signals through two G protein-coupled receptors, endothelin receptor A (ETA) and endothelin receptor B (ETB). Both receptors induce an increase in intracellular Ca2+, mainly from the extracellular space through voltage-independent mechanisms, the receptor-operated channels and store-operated channels. ET-1 also induces signaling through epidermal growth factor receptor transactivation, oxidative stress induction, rho-kinase, and the activation (ETA) or inhibition (ETB) of the adenylate cyclase/cyclic adenosine monophosphate pathway. Arterial vasoconstriction is mediated mainly by the ETA receptor. ET-1, via endothelium-located ETB, relaxes arteries or constricts vessels following activation of the same receptor type on the smooth muscle, where it can interact with ETA. In addition, ETB-dependent vasoconstriction seems more prominent in the venous vasculature. A better understanding of how ET-1 is synthesized and how ETA and ETB receptors interact could help design better pharmacological agents in the treatment of cardiovascular diseases where targeting the ET-1 system is indicated.

      PubDate: 2016-07-27T21:39:05Z
       
  • Chapter Ten Estrogens and Coronary Artery Disease
    • Authors: M.R. Meyer; Barton
      Abstract: Publication date: 2016
      Source:Advances in Pharmacology, Volume 77
      Author(s): M.R. Meyer, M. Barton
      In premenopausal women, endogenous estrogens are associated with reduced prevalence of arterial hypertension, coronary artery disease, myocardial infarction, and stroke. Clinical trials conducted in the 1990s such as HERS, WHI, and WISDOM have shown that postmenopausal treatment with horse hormone mixtures (so-called conjugated equine estrogens) and synthetic progestins adversely affects female cardiovascular health. Our understanding of rapid (nongenomic) and chronic (genomic) estrogen signaling has since advanced considerably, including identification of a new G protein-coupled estrogen receptor (GPER), which like the “classical” receptors ERα and ERβ is highly abundant in the cardiovascular system. Here, we discuss the role of estrogen receptors in the pathogenesis of coronary artery disease and review natural and synthetic ligands of estrogen receptors as well as their effects in physiology, on cardiovascular risk factors, and atherosclerotic vascular disease. Data from preclinical and clinical studies using nonselective compounds activating GPER, which include selective estrogen receptor modulators such as tamoxifen or raloxifene, selective estrogen receptor downregulators such as Faslodex™ (fulvestrant/ICI 182,780), vitamin B3 (niacin), green tea catechins, and soy flavonoids such as genistein or resveratrol, strongly suggest that activation of GPER may afford therapeutic benefit for primary and secondary prevention in patients with or at risk for coronary artery disease. Evidence from preclinical studies suggest similar efficacy profiles for selective small molecule GPER agonists such as G-1 which are devoid of uterotrophic activity. Further clinical research in this area is warranted to provide opportunities for future cardiovascular drug development.

      PubDate: 2016-07-27T21:39:05Z
       
  • Endothelium-Dependent Contractions: Prostacyclin and Endothelin-1,
           Partners in Crime'
    • Authors: Baretella P.M.; Vanhoutte
      Abstract: Publication date: Available online 6 June 2016
      Source:Advances in Pharmacology
      Author(s): O. Baretella, P.M. Vanhoutte
      Both the lipid prostacyclin and the peptide endothelin-1 are endothelium-derived substances. Endothelin-1 is one of the most powerful endogenous vasoconstrictors, while prostacyclin is a potent antiaggregatory and vasodilator mediator upon activation of prostaglandin I2 (IP) receptors. During endothelium-dependent, prostanoid-mediated contractions/constrictions, however, prostacyclin appears to be a major endothelium-derived contracting factor (EDCF). Such cyclooxygenase-dependent responses, whether measured ex vivo or in vivo, are exacerbated by aging, obesity, diabetes, or hypertension. On the background of such cardiovascular risk factors, endothelin-1 may potentiate these contractions by promoting prostacyclin production. The latter is reduced by endothelin-A (ETA) receptor antagonists. This receptor subtype is recognized for mediating contractions of smooth muscle cells to endothelin-1. However, it is present also on endothelial cells, where its activation increases intracellular calcium concentration with subsequent initiation of phospholipase A2 that provides arachidonic acid for metabolism by cyclooxygenases. Thus, endothelin-1 favors cyclooxygenase-dependent vasoconstrictor prostanoid formation, including prostacyclin. Activation of endothelial endothelin-B (ETB) receptors promotes the release of nitric oxide, which opposes both EDCF and endothelin-1. This is less pronounced in disease promoting ETA- and smooth muscle ETB receptor-dependent as well as prostanoid-mediated contractions. In addition, the thromboxane prostanoid (TP) receptors on vascular smooth muscle cells become hyperresponsive to EDCF under pathophysiological conditions, while IP receptor responsiveness diminishes. A better understanding of the interaction between prostacyclin and endothelin-1 and the determination of the roles of the TP and IP receptors involved in prostanoid-mediated contractions in health and during disease will help to define advanced pharmacological strategies for the therapy of cardiovascular disorders.

      PubDate: 2016-06-11T00:35:04Z
       
  • Foreword
    • Authors: S.H. Snyder
      Abstract: Publication date: 2016
      Source:Advances in Pharmacology, Volume 76
      Author(s): S.H. Snyder


      PubDate: 2016-06-11T00:35:04Z
       
  • Ultimate Translation: Developing Therapeutics Targeting on
           N-Methyl-d-Aspartate Receptor
    • Authors: G.E. Tsai
      Abstract: Publication date: Available online 24 May 2016
      Source:Advances in Pharmacology
      Author(s): G.E. Tsai
      N-Methyl-d-aspartate receptors (NMDARs) are broadly distributed in the central nervous system (CNS), where they mediate excitatory signaling. NMDAR-mediated neurotransmission (NMDARMN) is the molecular engine of learning, memory and cognition, which are the basis for high cortical function. NMDARMN is also critically involved in the development and plasticity of CNS. Due to its essential and critical role, either over- or under-activation of NMDARMN can contribute substantially to the development of CNS disorders. The involvement of NMDARMN has been demonstrated in a variety of CNS disorders, including schizophrenia, depression, posttraumatic stress disorder, aging, mild cognitive impairment and Alzheimer's dementia, amyotrophic lateral sclerosis, and anti-NMDAR encephalitis. Several targets to “correct” or “reset” the NMDARMN in these CNS disorders have been identified and confirmed. With analogy to aminergic treatments, these targets include the glycine/d-serine co-agonist site, channel ionophore, glycine transporter-1, and d-amino acid oxidase. It is still early days in terms of developing novel therapeutics targeting the NMDAR. However, agents modulating NMDARMN hold promise as the next generation of CNS therapeutics.

      PubDate: 2016-05-26T20:25:37Z
       
  • Endothelial Small- and Intermediate-Conductance K Channels and
           Endothelium-Dependent Hyperpolarization as Drug Targets in Cardiovascular
           Disease
    • Authors: Wulff
      Abstract: Publication date: Available online 4 May 2016
      Source:Advances in Pharmacology
      Author(s): R. Köhler, A. Oliván-Viguera, H. Wulff
      Endothelial calcium/calmodulin-gated K channels of small (KCa2.3) and intermediate conductance (KCa3.1) produce membrane hyperpolarization and endothelium-dependent hyperpolarization (EDH)-mediated vasodilation. Dysfunctions of the two channels and ensuing EDH impairments are found in several cardiovascular pathologies such as diabetes, atherosclerosis, postangioplastic neointima formation, but also inflammatory disease, cancer, and organ fibrosis. Moreover, KCa3.1 plays an important role in endothelial barrier dysfunction, edema formation in cardiac and pulmonary disease, and in ischemic stroke. Concerning KCa2.3, genome-wide association studies revealed an association of KCa2.3 channels with atrial fibrillation in humans. Accordingly, both channels are considered potential drug targets for cardio- and cerebrovascular disease states. In this chapter, we briefly review the function of the two channels in EDH-type vasodilation and systemic circulatory regulation and then highlight their pathophysiological roles in ischemic stroke as well as in pulmonary and brain edema. Finally, the authors summarize recent advances in the pharmacology of the channels and explore potential therapeutic utilities of novel channel modulators.

      PubDate: 2016-05-07T14:24:29Z
       
  • The Long and Winding Road: From the High-Affinity Choline Uptake Site to
           Clinical Trials for Malignant Brain Tumors
    • Authors: P.R. Lowenstein; M.G. Castro
      Abstract: Publication date: Available online 23 April 2016
      Source:Advances in Pharmacology
      Author(s): P.R. Lowenstein, M.G. Castro
      Malignant brain tumors are one of the most lethal cancers. They originate from glial cells which infiltrate throughout the brain. Current standard of care involves surgical resection, radiotherapy, and chemotherapy; median survival is currently ~14–20 months postdiagnosis. Given that the brain immune system is deficient in priming systemic immune responses to glioma antigens, we proposed to reconstitute the brain immune system to achieve immunological priming from within the brain. Two adenoviral vectors are injected into the resection cavity or remaining tumor. One adenoviral vector expresses the HSV-1-derived thymidine kinase which converts ganciclovir into a compound only cytotoxic to dividing glioma cells. The second adenovirus expresses the cytokine fms-like tyrosine kinase 3 ligand (Flt3L). Flt3L differentiates precursors into dendritic cells and acts as a chemokine that attracts dendritic cells to the brain. HSV-1/ganciclovir killing of tumor cells releases tumor antigens that are taken up by dendritic cells within the brain tumor microenvironment. Tumor killing also releases HMGB1, an endogenous TLR2 agonist that activates dendritic cells. HMGB1-activated dendritic cells, loaded with glioma antigens, migrate to cervical lymph nodes to stimulate a systemic CD8+ T cells cytotoxic immune response against glioma. This immune response is specific to glioma tumors, induces immunological memory, and does neither cause brain toxicity nor autoimmune responses. An IND was granted by the FDA on 4/7/2011. A Phase I, first in person trial, to test whether reengineering the brain immune system is potentially therapeutic is ongoing.

      PubDate: 2016-04-27T04:09:54Z
       
  • Choline on the Move: Perspectives on the Molecular Physiology and
           Pharmacology of the Presynaptic Choline Transporter
    • Authors: E.A. Ennis; R.D. Blakely
      Abstract: Publication date: Available online 7 April 2016
      Source:Advances in Pharmacology
      Author(s): E.A. Ennis, R.D. Blakely
      Genetic, biochemical, physiological, and pharmacological approaches have advanced our understanding of cholinergic biology for over 100 years. High-affinity choline uptake (HACU) was one of the last features of cholinergic signaling to be defined at a molecular level, achieved through the cloning of the choline transporter (CHT, SLC5A7). In retrospect, the molecular era of CHT studies initiated with the identification of hemicholinium-3 (HC-3), a potent, competitive CHT antagonist, though it would take another 30 years before HC-3, in radiolabeled form, was used by Joseph Coyle's laboratory to identify and monitor the dynamics of CHT proteins. Though HC-3 studies provided important insights into CHT distribution and regulation, another 15 years would pass before the structure of CHT genes and proteins were identified, a full decade after the cloning of most other neurotransmitter-associated transporters. The availability of CHT gene and protein probes propelled the development of cell and animal models as well as efforts to gain insights into how human CHT gene variation affects the risk for brain and neuromuscular disorders. Most recently, our group has pursued a broadening of CHT pharmacology, elucidating novel chemical structures that may serve to advance cholinergic diagnostics and medication development. Here we provide a short review of the transformation that has occurred in HACU research and how such advances may promote the development of novel therapeutics.

      PubDate: 2016-04-08T22:59:00Z
       
  • Transcriptional Regulation of Glutamate Transporters: From Extracellular
           Signals to Transcription Factors
    • Authors: Martinez-Lozada A.M.; Guillem M.B. Robinson
      Abstract: Publication date: Available online 24 March 2016
      Source:Advances in Pharmacology
      Author(s): Z. Martinez-Lozada, A.M. Guillem, M.B. Robinson
      Glutamate is the predominant excitatory neurotransmitter in the mammalian CNS. It mediates essentially all rapid excitatory signaling. Dysfunction of glutamatergic signaling contributes to developmental, neurologic, and psychiatric diseases. Extracellular glutamate is cleared by a family of five Na+-dependent glutamate transporters. Two of these transporters (GLAST and GLT-1) are relatively selectively expressed in astrocytes. Other of these transporters (EAAC1) is expressed by neurons throughout the nervous system. Expression of the last two members of this family (EAAT4 and EAAT5) is almost exclusively restricted to specific populations of neurons in cerebellum and retina, respectively. In this review, we will discuss our current understanding of the mechanisms that control transcriptional regulation of the different members of this family. Over the last two decades, our understanding of the mechanisms that regulate expression of GLT-1 and GLAST has advanced considerably; several specific transcription factors, cis-elements, and epigenetic mechanisms have been identified. For the other members of the family, little or nothing is known about the mechanisms that control their transcription. It is assumed that by defining the mechanisms involved, we will advance our understanding of the events that result in cell-specific expression of these transporters and perhaps begin to define the mechanisms by which neurologic diseases are changing the biology of the cells that express these transporters. This approach might provide a pathway for developing new therapies for a wide range of essentially untreatable and devastating diseases that kill neurons by an excitotoxic mechanism.

      PubDate: 2016-03-26T16:40:22Z
       
  • Still NAAG’ing After All These Years: The Continuing Pursuit of
           GCPII Inhibitors
    • Authors: J.J. Vornov; K.R. Hollinger P.F. Jackson K.M. Wozniak M.H. Farah
      Abstract: Publication date: Available online 18 March 2016
      Source:Advances in Pharmacology
      Author(s): J.J. Vornov, K.R. Hollinger, P.F. Jackson, K.M. Wozniak, M.H. Farah, P. Majer, R. Rais, B.S. Slusher
      Nearly two decades ago, Joe Coyle published a single-authored review with the provocative title, The Nagging Question of the Function of N-Acetylaspartylglutamate (Coyle, 1997). In this review, Coyle documented NAAG's localization to subpopulations of glutamatergic, cholinergic, GABAergic, and noradrenergic neurons, Ca2+-dependent release, mGlu3 receptor agonist and NMDA receptor antagonist activity, and cleavage by the glial enzyme glutamate carboxypeptidase II (GCPII). However, at the time of his review, NAAG's physiological function as a neurotransmitter remained elusive. Ironically his review was published months following the discovery of the first potent and selective GCPII inhibitor, 2-(phosphonomethyl)pentanedioc acid (2-PMPA) (Jackson et al., 1996). Over the ensuing decades, over a dozen independent laboratories used 2-PMPA and other GCPII inhibitors to elucidate two distinct neurotransmitter functions for NAAG. Under basal conditions, when GCPII activity is relatively low, intact NAAG dampens synaptic activity via presynaptic mGlu3 receptor activation and NMDA receptor blockade. However, under stimulated conditions, NAAG release and GCPII activity are enhanced resulting in excess glutamate generation, activating NMDA and other glutamate receptors, often pathologically. Diverse classes of GCPII inhibitors have been synthesized and shown to increase NAAG, decrease glutamate, and provide robust efficacy in many disease models wherein abnormal glutamatergic transmission is presumed pathogenic. In addition, over the past 20 years, basic questions regarding NAAG's synthesis, packaging into vesicles, and receptor selectivity profile have been eloquently elucidated. The purpose of this chapter is to summarize these advances and the promise of regulating NAAG metabolism through GCPII inhibition as a therapeutic strategy.

      PubDate: 2016-03-22T14:23:18Z
       
  • Still NAAG’ing After All These Years: The Continuing Pursuit of
           GCPII Inhibitors
    • Authors: J.J. Vornov; K.R. Hollinger P.F. Jackson K.M. Wozniak M.H. Farah
      Abstract: Publication date: Available online 18 March 2016
      Source:Advances in Pharmacology
      Author(s): J.J. Vornov, K.R. Hollinger, P.F. Jackson, K.M. Wozniak, M.H. Farah, P. Majer, R. Rais, B.S. Slusher
      Nearly two decades ago, Joe Coyle published a single-authored review with the provocative title, The Nagging Question of the Function of N-Acetylaspartylglutamate (Coyle, 1997). In this review, Coyle documented NAAG's localization to subpopulations of glutamatergic, cholinergic, GABAergic, and noradrenergic neurons, Ca2+-dependent release, mGlu3 receptor agonist and NMDA receptor antagonist activity, and cleavage by the glial enzyme glutamate carboxypeptidase II (GCPII). However, at the time of his review, NAAG's physiological function as a neurotransmitter remained elusive. Ironically his review was published months following the discovery of the first potent and selective GCPII inhibitor, 2-(phosphonomethyl)pentanedioc acid (2-PMPA) (Jackson et al., 1996). Over the ensuing decades, over a dozen independent laboratories used 2-PMPA and other GCPII inhibitors to elucidate two distinct neurotransmitter functions for NAAG. Under basal conditions, when GCPII activity is relatively low, intact NAAG dampens synaptic activity via presynaptic mGlu3 receptor activation and NMDA receptor blockade. However, under stimulated conditions, NAAG release and GCPII activity are enhanced resulting in excess glutamate generation, activating NMDA and other glutamate receptors, often pathologically. Diverse classes of GCPII inhibitors have been synthesized and shown to increase NAAG, decrease glutamate, and provide robust efficacy in many disease models wherein abnormal glutamatergic transmission is presumed pathogenic. In addition, over the past 20 years, basic questions regarding NAAG's synthesis, packaging into vesicles, and receptor selectivity profile have been eloquently elucidated. The purpose of this chapter is to summarize these advances and the promise of regulating NAAG metabolism through GCPII inhibition as a therapeutic strategy.

      PubDate: 2016-03-22T14:23:18Z
       
  • The Therapeutic Role of d-Cycloserine in Schizophrenia
    • Authors: Goff
      Abstract: Publication date: Available online 11 March 2016
      Source:Advances in Pharmacology
      Author(s): D. Goff
      The ketamine model for schizophrenia has led to several therapeutic strategies for enhancing N-methyl d-aspartate (NMDA) receptor activity, including agonists directed at the glycine receptor site and inhibitors of glycine reuptake. Because ketamine may primarily block NMDA receptors on inhibitory interneurons, drugs that reduce glutamate release have also been investigated as a means of countering a deficit in inhibitory input. These approaches have met with some success for the treatment of negative and positive symptoms, but results have not been consistent. An emerging approach with the NMDA partial agonist, d-cycloserine (DCS), aims to enhance plasticity by intermittent treatment. Early trials have demonstrated benefit with intermittent DCS dosing for negative symptoms and memory. When combined with cognitive remediation, intermittent DCS treatment enhanced learning on a practiced auditory discrimination task and when added to cognitive behavioral therapy, DCS improved delusional severity in subjects who received DCS with the first CBT session. These studies require replication, but point toward a promising strategy for the treatment of schizophrenia and other disorders of plasticity.

      PubDate: 2016-03-14T07:33:43Z
       
  • Kynurenines and Glutamate: Multiple Links and Therapeutic Implications
    • Authors: Schwarcz
      Abstract: Publication date: Available online 11 March 2016
      Source:Advances in Pharmacology
      Author(s): R. Schwarcz
      Glutamate is firmly established as the major excitatory neurotransmitter in the mammalian brain and is actively involved in most aspects of neurophysiology. Moreover, glutamatergic impairments are associated with a wide variety of dysfunctional states, and both hypo- and hyperfunction of glutamate have been plausibly linked to the pathophysiology of neurological and psychiatric diseases. Metabolites of the kynurenine pathway (KP), the major catabolic route of the essential amino acid tryptophan, influence glutamatergic activity in several distinct ways. This includes direct effects of these “kynurenines” on ionotropic and metabotropic glutamate receptors or vesicular glutamate transport, and indirect effects, which are initiated by actions at various other recognition sites. In addition, some KP metabolites affect glutamatergic functions by generating or scavenging highly reactive free radicals. This review summarizes these phenomena and discusses implications for brain physiology and pathology.

      PubDate: 2016-03-14T07:33:43Z
       
  • The NMDA Receptor and Schizophrenia: From Pathophysiology to Treatment
    • Authors: D.T. Balu
      Abstract: Publication date: Available online 4 March 2016
      Source:Advances in Pharmacology
      Author(s): D.T. Balu
      Schizophrenia is a severe mental illness that affects almost 1% of the population worldwide. Even though the etiology of schizophrenia is uncertain, it is believed to be a neurodevelopmental disorder that results from a combination of environmental insults and genetic vulnerabilities. Over the past 20 years, there has been a confluence of evidence from many research disciplines pointing to alterations in excitatory signaling, particularly involving hypofunction of the N-methyl-d-aspartate receptor (NMDAR), as a key contributor to the schizophrenia disease process. This review describes the structure–function relationship of the NMDAR channel and how the glycine modulatory site acts as an important regulator of its activity. In addition, this review highlights the genetic, pharmacologic, and biochemical evidence supporting the hypothesis that NMDAR hypofunction contributes to the pathophysiology of schizophrenia. Finally, this chapter highlights some of the most recent and promising pharmacological strategies that are designed to either, directly or indirectly, augment NMDAR function in an effort to treat the cognitive and negative symptoms of schizophrenia that are not helped by currently available medications.

      PubDate: 2016-03-05T01:42:54Z
       
  • My Life in Clinical Neuroscience: The Beginning
    • Authors: J.T. Coyle
      Pages: 1 - 12
      Abstract: Publication date: Available online 24 March 2016
      Source:Advances in Pharmacology
      Author(s): J.T. Coyle
      This chapter recounts the author's life from childhood until he opened his research laboratory as an Assistant Professor in the Department of Pharmacology and Experimental Therapeutics at Johns Hopkins School of Medicine in 1976. It emphasizes the importance of chance opportunities and generous mentoring in the initiation of his career in neuroscience and psychiatric research.

      PubDate: 2016-03-26T16:40:22Z
      DOI: 10.1016/bs.apha.2016.02.002
       
  • Transcriptional and Posttranslational Regulation of eNOS in the
           Endothelium
    • Authors: D.J.R. Fulton
      Pages: 29 - 64
      Abstract: Publication date: Available online 18 May 2016
      Source:Advances in Pharmacology
      Author(s): D.J.R. Fulton
      Nitric oxide (NO) is a highly reactive free radical gas and these unique properties have been adapted for a surprising number of biological roles. In neurons, NO functions as a neurotransmitter; in immune cells, NO contributes to host defense; and in endothelial cells, NO is a major regulator of blood vessel homeostasis. In the vasculature, NO is synthesized on demand by a specific enzyme, endothelial nitric oxide synthase (eNOS) that is uniquely expressed in the endothelial cells that form the interface between the circulating blood and the various tissues of the body. NO regulates endothelial and blood vessel function via two distinct pathways, the activation of soluble guanylate cyclase and cGMP-dependent signaling and the S-nitrosylation of proteins with reactive thiols (S-nitrosylation). The chemical properties of NO also serve to reduce oxidation and regulate mitochondrial function. Reduced synthesis and/or compromised biological activity of NO precede the development of cardiovascular disease and this has generated a high level of interest in the mechanisms controlling the synthesis and fate of NO in the endothelium. The amount of NO produced results from the expression level of eNOS, which is regulated at the transcriptional and posttranscriptional levels as well as the acute posttranslational regulation of eNOS. The goal of this chapter is to highlight and integrate past and current knowledge of the mechanisms regulating eNOS expression in the endothelium and the posttranslational mechanisms regulating eNOS activity in both health and disease.

      PubDate: 2016-05-21T18:28:46Z
      DOI: 10.1016/bs.apha.2016.04.001
       
  • Impulsivity, Stimulant Abuse, and Dopamine Receptor Signaling
    • Authors: E.D. London
      Pages: 67 - 84
      Abstract: Publication date: Available online 2 March 2016
      Source:Advances in Pharmacology
      Author(s): E.D. London
      The nonmedical use of amphetamine-type stimulants is a worldwide problem, with substantial medical and social consequences. Nonetheless, the identification of a pharmacological treatment for amphetamine use disorder remains elusive. Stimulant users exhibit neurochemical evidence of dopamine-system dysfunction as well as impulsive behaviors that may interfere with the success of treatments for their addiction. This review focuses on the potential role of dopaminergic neurotransmission in impulsivity, both in healthy individuals and chronic stimulant users who meet criteria for methamphetamine dependence. Presented are findings related to the potential contributions of signaling through dopamine D1- and D2-type receptors to self-control impulsivity in methamphetamine- dependent users. The information available points to signaling through striatal D2-type dopamine receptors as a potential therapeutic target for stimulant use disorders, but medications that target D2-type dopamine receptors have not been successful in treating stimulant-use disorders, possibly because D2-type receptors are downregulated. Other means to augment D2-type receptor signaling are therefore under consideration, and one promising approach is the addition of exercise training as an adjunct to behavioral treatment for addiction.

      PubDate: 2016-03-05T01:42:54Z
      DOI: 10.1016/bs.apha.2016.01.002
       
  • Excitotoxicity as a Common Mechanism for Fetal Neuronal Injury with
           Hypoxia and Intrauterine Inflammation
    • Authors: I. Burd; J. Welling; G. Kannan; M.V. Johnston
      Pages: 85 - 101
      Abstract: Publication date: Available online 24 March 2016
      Source:Advances in Pharmacology
      Author(s): I. Burd, J. Welling, G. Kannan, M.V. Johnston
      Excitotoxicity is a mechanism of neuronal injury, implicated in the pathogenesis of many acute and chronic neurologic disorders, including perinatal brain injury associated with hypoxia–ischemia and exposure to intrauterine inflammation. Glutamate, the primary excitatory neurotransmitter, signals through N-methyl-d-aspartic acid (NMDA)/α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors. Proper functioning of both of these receptors, in conjunction with glutamate signaling, is crucial for normal development. However, even a small imbalance can result in perinatal neuronal injury. Therefore, a mechanistic understanding of the role of excitotoxicity and the NMDA/AMPA receptor functions is critical to establishing the pathogenesis of hypoxic–ischemic encephalopathy (HIE) and perinatal brain injury due to exposure to intrauterine inflammation. Evidence from experimental animal models and clinical studies indicates that both oxygen and glucose deficiencies play a major role in fetal neuronal injury. However, the connection between these deficiencies, excitotoxicity, and HIE is not well established. The excitotoxic mechanisms in animal models and humans have many parallels, suggesting that detailed animal studies can elicit clinically relevant discoveries. While current therapies for HIE include hypothermia and other neuroprotective measures, emphasizing prevention of acute injuries, increase of therapeutic time window, and increased neural repair, there are no effective widely used treatment modalities for fetuses and neonates exposed to intrauterine inflammation. Further studies of HIE and intrauterine inflammation (as in cases of preterm birth and chorioamnionitis) will provide a better insight into development of effective therapeutic interventions for these conditions.

      PubDate: 2016-03-26T16:40:22Z
      DOI: 10.1016/bs.apha.2016.02.003
       
  • Epoxyeicosatrienoic Acids and 20-Hydroxyeicosatetraenoic Acid on
           Endothelial and Vascular Function
    • Authors: J.D. Imig
      Pages: 105 - 141
      Abstract: Publication date: Available online 5 May 2016
      Source:Advances in Pharmacology
      Author(s): J.D. Imig
      Endothelial and vascular smooth cells generate cytochrome P450 (CYP) arachidonic acid metabolites that can impact endothelial cell function and vascular homeostasis. The objective of this review is to focus on the physiology and pharmacology of endothelial CYP metabolites. The CYP pathway produces two types of eicosanoid products: epoxyeicosatrienoic acids (EETs), formed by CYP epoxygenases, and hydroxyeicosatetraenoic acids (HETEs), formed by CYP hydroxylases. Advances in CYP enzymes, EETs, and 20-HETE by pharmacological and genetic means have led to a more complete understanding of how these eicosanoids impact on endothelial cell function. Endothelial-derived EETs were initially described as endothelial-derived hyperpolarizing factors. It is now well recognized that EETs importantly contribute to numerous endothelial cell functions. On the other hand, 20-HETE is the predominant CYP hydroxylase synthesized by vascular smooth muscle cells. Like EETs, 20-HETE acts on endothelial cells and impacts importantly on endothelial and vascular function. An important aspect for EETs and 20-HETE endothelial actions is their interactions with hormonal and paracrine factors. These include interactions with the renin–angiotensin system, adrenergic system, puringeric system, and endothelin. Alterations in CYP enzymes, 20-HETE, or EETs contribute to endothelial dysfunction and cardiovascular diseases such as ischemic injury, hypertension, and atherosclerosis. Recent advances have led to the development of potential therapeutics that target CYP enzymes, 20-HETE, or EETs. Thus, future investigation is required to obtain a more complete understanding of how CYP enzymes, 20-HETE, and EETs regulate endothelial cell function.

      PubDate: 2016-05-07T14:24:29Z
      DOI: 10.1016/bs.apha.2016.04.003
       
  • Communication Through Gap Junctions in the Endothelium
    • Authors: K. Schmidt; R. Windler; C. de Wit
      Pages: 209 - 240
      Abstract: Publication date: Available online 9 May 2016
      Source:Advances in Pharmacology
      Author(s): K. Schmidt, R. Windler, C. de Wit
      A swarm of fish displays a collective behavior (swarm behavior) and moves “en masse” despite the huge number of individual animals. In analogy, organ function is supported by a huge number of cells that act in an orchestrated fashion and this applies also to vascular cells along the vessel length. It is obvious that communication is required to achieve this vital goal. Gap junctions with their modular bricks, connexins (Cxs), provide channels that interlink the cytosol of adjacent cells by a pore sealed against the extracellular space. This allows the transfer of ions and charge and thereby the travel of membrane potential changes along the vascular wall. The endothelium provides a low-resistance pathway that depends crucially on connexin40 which is required for long-distance conduction of dilator signals in the microcirculation. The experimental evidence for membrane potential changes synchronizing vascular behavior is manifold but the functional verification of a physiologic role is still open. Other molecules may also be exchanged that possibly contribute to the synchronization (eg, Ca2+). Recent data suggest that vascular Cxs have more functions than just facilitating communication. As pharmacological tools to modulate gap junctions are lacking, Cx-deficient mice provide currently the standard to unravel their vascular functions. These include arteriolar dilation during functional hyperemia, hypoxic pulmonary vasoconstriction, vascular collateralization after ischemia, and feedback inhibition on renin secretion in the kidney.

      PubDate: 2016-05-11T14:58:58Z
      DOI: 10.1016/bs.apha.2016.04.004
       
  • Molecular Signaling Pathways Controlling Vascular Tube Morphogenesis and
           Pericyte-Induced Tube Maturation in 3D Extracellular Matrices
    • Authors: S.L.K. Bowers; P.R. Norden; G.E. Davis
      Pages: 241 - 280
      Abstract: Publication date: Available online 25 May 2016
      Source:Advances in Pharmacology
      Author(s): S.L.K. Bowers, P.R. Norden, G.E. Davis
      During capillary network formation, ECs establish interconnecting tubes with defined lumens that reside within vascular guidance tunnels (physical spaces generated during EC tubulogenesis). Pericytes are recruited to EC tubes within these tunnels and capillary basement membrane deposition occurs to facilitate tube maturation. Here, we discuss molecular mechanisms controlling EC tubulogenesis demonstrating the involvement of integrins, MT1-MMP, extracellular matrix, Cdc42, Rac1, Rac2, k-Ras, Rap1b, and key downstream effectors including Pak2, Pak4, IQGAP1, MRCKβ, and Rasip1. These molecules activate kinase cascades controlling EC tube formation, in conjunction with growth factor receptor signaling, which involve PKCɛ, Src family, Raf, Mek, and Erk kinases. These molecules and signaling cascades stimulate EC lumen and tube formation by: regulating MT-MMP-dependent lumen expansion and vascular guidance tunnel formation; generation of intracellular vacuoles/vesicles to create EC apical membranes; and establishing cytoskeletal polarity with acetylated tubulin distributed subapically (and F-actin basally) to facilitate vacuole trafficking/fusion in a polarized, perinuclear region. Using defined serum-free models, we have demonstrated that human EC tubulogenesis and EC–pericyte tube coassembly requires five exogenously applied growth factors which are SCF, IL-3, SDF-1α, FGF-2, and insulin (Factors). Also, we have demonstrated that EC-derived PDGF-BB and HB-EGF are necessary for pericytes to proliferate, recruit to tubes, and induce basement membrane assembly. Finally, we have shown that VEGF fails to directly stimulate EC tubulogenesis. In contrast, it acts as an upstream EC primer of downstream “Factor”-induced tubulogenic and EC–pericyte tube coassembly by upregulating c-Kit, IL-3Rα, and CXCR4 as well as PDGF-BB and HB-EGF expression.

      PubDate: 2016-05-26T20:25:37Z
      DOI: 10.1016/bs.apha.2016.04.005
       
  • Stress-Induced Premature Senescence of Endothelial and Endothelial
           Progenitor Cells
    • Authors: M.S. Goligorsky; K. Hirschi
      Pages: 281 - 306
      Abstract: Publication date: Available online 6 June 2016
      Source:Advances in Pharmacology
      Author(s): M.S. Goligorsky, K. Hirschi
      This brief overview of premature senescence of dysfunctional endothelial and endothelial progenitor cells provides information on endothelial cell differentiation and specialization, their ontogeny, and controversies related to endothelial stem and progenitor cells. Stressors responsible for the dysfunction of endothelial and endothelial progenitor cells, as well as cellular mechanisms and consequences of endothelial cell dysfunction are presented. Metabolic signatures of dysfunctional endothelial cells and senescence pathways are described. Emerging strategies to rejuvenate endothelial and endothelial progenitor cells conclude the review.

      PubDate: 2016-06-11T00:35:04Z
      DOI: 10.1016/bs.apha.2016.04.007
       
  • The Good and Bad Sides of NAAG
    • Authors: P. Khacho; B. Wang; R. Bergeron
      Pages: 311 - 349
      Abstract: Publication date: Available online 2 March 2016
      Source:Advances in Pharmacology
      Author(s): P. Khacho, B. Wang, R. Bergeron
      Why has such a small peptide been the source of controversy in neuroscience over the last 5 decades' Is N-acetyl-aspartyl-glutamate (NAAG) a neurotransmitter' Is NAAG located in neuronal tissue or in astrocytes' Is NAAG involved in neuropsychiatric and neurodegenerative disorders' Is NAAG therapeutically beneficial in the treatment of stroke or in initiating cascades of events leading to psychosis' After many years of intense research there is no clear consensus within the scientific community on how NAAG behaves in the brain. One of the major controversies about NAAG is its physiological action at N-methyl-d-aspartate (NMDA) receptors. While some researchers strongly argue that NAAG acts as a weak agonist at NMDA receptors, others have suggested that NAAG could behave as a potent antagonist. Published data from our laboratory demonstrate that the effect of NAAG on NMDA receptors could be influenced by a number of factors including the subcellular localization and subunit composition of NMDA receptors, as well as protons. In this chapter, we will summarize the knowledge of the literature on NAAG, however, we will place emphasis on our recently published data. More specifically, we have reported interesting findings on the effects of NAAG on NMDA receptors at synaptic and extrasynaptic sites using a pharmacological paradigm to distinguish the two populations of NMDA receptors. Additionally, we have evaluated the role of NAAG on GluN2A- and GluN2B-containing NMDA receptors using a HEK293 cell recombinant system. Finally, we have studied the effects of NAAG on GluN2A- and GluN2B-containing NMDA receptors in different extracellular pH conditions. We believe that our findings could potentially resolve some aspects of the debate regarding the role of NAAG at NMDA receptors.

      PubDate: 2016-03-05T01:42:54Z
      DOI: 10.1016/bs.apha.2016.01.003
       
  • Mechanisms of Endothelial Dysfunction in Hypertensive Pregnancy and
           Preeclampsia
    • Authors: J.S. Possomato-Vieira; R.A. Khalil
      Pages: 361 - 431
      Abstract: Publication date: Available online 14 June 2016
      Source:Advances in Pharmacology
      Author(s): J.S. Possomato-Vieira, R.A. Khalil
      Preeclampsia is a pregnancy-related disorder characterized by hypertension and could lead to maternal and fetal morbidity and mortality. Although the causative factors and pathophysiological mechanisms are unclear, endothelial dysfunction is a major hallmark of preeclampsia. Clinical tests and experimental research have suggested that generalized endotheliosis in the systemic, renal, cerebral, and hepatic circulation could decrease endothelium-derived vasodilators such as nitric oxide, prostacyclin, and hyperpolarization factor and increase vasoconstrictors such as endothelin-1 and thromboxane A2, leading to increased vasoconstriction, hypertension, and other manifestation of preeclampsia. In search for the upstream mechanisms that could cause endothelial dysfunction, certain genetic, demographic, and environmental risk factors have been suggested to cause abnormal expression of uteroplacental integrins, cytokines, and matrix metalloproteinases, leading to decreased maternal tolerance, apoptosis of invasive trophoblast cells, inadequate spiral arteries remodeling, reduced uterine perfusion pressure (RUPP), and placental ischemia/hypoxia. RUPP may cause imbalance between the antiangiogenic factors soluble fms-like tyrosine kinase-1 and soluble endoglin and the proangiogenic factors vascular endothelial growth factor and placental growth factor, or stimulate the release of other circulating bioactive factors such as inflammatory cytokines, hypoxia-inducible factor-1, reactive oxygen species, and angiotensin AT1 receptor agonistic autoantibodies. These circulating factors could then target endothelial cells and cause generalized endothelial dysfunction. Therapeutic options are currently limited, but understanding the factors involved in endothelial dysfunction could help design new approaches for prediction and management of preeclampsia.

      PubDate: 2016-06-16T18:20:37Z
      DOI: 10.1016/bs.apha.2016.04.008
       
 
 
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