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Publisher: Elsevier   (Total: 2800 journals)

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Solid-State Electronics     Hybrid Journal   (Followers: 5, SJR: 0.819, h-index: 66)
South African J. of Botany     Hybrid Journal   (Followers: 4, SJR: 0.531, h-index: 29)
Space Policy     Hybrid Journal   (Followers: 16, SJR: 0.256, h-index: 14)
Space Research Today     Full-text available via subscription   (Followers: 27, SJR: 0.123, h-index: 2)
Spanish Review of Financial Economics, The     Full-text available via subscription   (Followers: 1, SJR: 0.115, h-index: 1)
Spatial and Spatio-temporal Epidemiology     Hybrid Journal   (Followers: 3, SJR: 0.721, h-index: 8)
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy     Hybrid Journal   (Followers: 7, SJR: 0.628, h-index: 64)
Spectrochimica Acta Part B: Atomic Spectroscopy     Hybrid Journal   (Followers: 7, SJR: 1.125, h-index: 79)
Speech Communication     Hybrid Journal   (Followers: 13, SJR: 0.701, h-index: 63)
Spine Deformity     Full-text available via subscription   (Followers: 2)
Sport Management Review     Hybrid Journal   (Followers: 5, SJR: 0.754, h-index: 20)
Sport-Orthopädie - Sport-Traumatologie - Sports Orthopaedics and Traumatology     Full-text available via subscription   (Followers: 3, SJR: 0.124, h-index: 5)
Statistical Methodology     Hybrid Journal   (Followers: 9, SJR: 0.642, h-index: 15)
Statistics & Probability Letters     Hybrid Journal   (Followers: 8, SJR: 0.771, h-index: 38)
Stem Cell Reports     Open Access   (Followers: 5)
Stem Cell Research     Open Access   (Followers: 12, SJR: 1.898, h-index: 27)
Steroids     Hybrid Journal   (Followers: 1, SJR: 0.98, h-index: 77)
Stochastic Processes and their Applications     Hybrid Journal   (Followers: 3, SJR: 1.444, h-index: 46)
Strategies and Tactics in Organic Synthesis     Full-text available via subscription   (Followers: 5, SJR: 0.164, h-index: 6)
Structural Change and Economic Dynamics     Hybrid Journal   (Followers: 3, SJR: 0.334, h-index: 26)
Structural Safety     Hybrid Journal   (Followers: 7, SJR: 2.84, h-index: 49)
Structure     Full-text available via subscription   (Followers: 19, SJR: 5.17, h-index: 138)
Structures     Hybrid Journal  
Studies in Applied Mechanics     Full-text available via subscription   (Followers: 1)
Studies in Computational Mathematics     Full-text available via subscription  
Studies in Computer Science and Artificial Intelligence     Full-text available via subscription   (Followers: 5)
Studies in Educational Evaluation     Hybrid Journal   (Followers: 7, SJR: 0.626, h-index: 19)
Studies in Environmental Science     Full-text available via subscription   (Followers: 7)
Studies in History and Philosophy of Science Part A     Hybrid Journal   (Followers: 3, SJR: 0.567, h-index: 21)
Studies in History and Philosophy of Science Part B: Studies in History and Philosophy of Modern Physics     Hybrid Journal   (Followers: 7)
Studies in History and Philosophy of Science Part C: Studies in History and Philosophy of Biological and Biomedical Sciences     Hybrid Journal   (Followers: 9, SJR: 0.308, h-index: 21)
Studies in Inorganic Chemistry     Full-text available via subscription  
Studies in Interface Science     Full-text available via subscription   (Followers: 1, SJR: 0.1, h-index: 10)
Studies in Logic and Practical Reasoning     Full-text available via subscription  
Studies in Logic and the Foundations of Mathematics     Full-text available via subscription  
Studies in Mathematical Physics     Full-text available via subscription  
Studies in Mathematics and Its Applications     Full-text available via subscription  
Studies in Multidisciplinarity     Full-text available via subscription   (Followers: 5)
Studies in Mycology     Open Access  
Studies in Natural Products Chemistry     Full-text available via subscription   (Followers: 3, SJR: 0.221, h-index: 22)
Studies in Plant Science     Full-text available via subscription   (Followers: 2)
Studies in Surface Science and Catalysis     Full-text available via subscription   (Followers: 1, SJR: 0.282, h-index: 41)
Studies in the History and Philosophy of Mathematics     Full-text available via subscription   (Followers: 4)
Studies in Visual Information Processing     Full-text available via subscription   (Followers: 3)
Sugar Series     Full-text available via subscription   (Followers: 2)
Suma de Negocios     Open Access  
Superlattices and Microstructures     Hybrid Journal   (Followers: 2, SJR: 0.745, h-index: 44)
Supplements to Clinical Neurophysiology     Full-text available via subscription   (Followers: 1, SJR: 0.123, h-index: 29)
Surface and Coatings Technology     Hybrid Journal   (Followers: 32, SJR: 1.178, h-index: 109)
Surface Science     Hybrid Journal   (Followers: 17, SJR: 0.853, h-index: 105)
Surface Science Reports     Full-text available via subscription   (Followers: 14, SJR: 8.627, h-index: 81)
Surgery     Hybrid Journal   (Followers: 11, SJR: 1.691, h-index: 118)
Surgery (Oxford)     Full-text available via subscription   (Followers: 4, SJR: 0.132, h-index: 14)
Surgery for Obesity and Related Diseases     Full-text available via subscription   (Followers: 7, SJR: 1.918, h-index: 46)
Surgical Clinics     Full-text available via subscription   (Followers: 2, SJR: 0.978, h-index: 68)
Surgical Oncology     Hybrid Journal   (Followers: 2, SJR: 0.86, h-index: 41)
Surgical Oncology Clinics of North America     Full-text available via subscription   (Followers: 4, SJR: 0.726, h-index: 41)
Surgical Pathology Clinics     Full-text available via subscription   (Followers: 4, SJR: 0.146, h-index: 3)
Survey of Ophthalmology     Full-text available via subscription   (Followers: 11, SJR: 1.842, h-index: 92)
Sustainability of Water Quality and Ecology     Hybrid Journal  
Sustainability Science and Engineering     Full-text available via subscription   (Followers: 6, SJR: 0.581, h-index: 4)
Sustainable Cities and Society     Hybrid Journal   (Followers: 26, SJR: 0.677, h-index: 7)
Sustainable Energy Technologies and Assessments     Full-text available via subscription  
Sustainable Energy, Grids and Networks     Hybrid Journal  
Sustainable Management of Sediment Resources     Full-text available via subscription  
Sustainable Materials and Technologies     Open Access  
Swarm and Evolutionary Computation     Hybrid Journal   (SJR: 5.631, h-index: 13)
Synergy     Full-text available via subscription  
Synthetic Metals     Hybrid Journal   (Followers: 3, SJR: 0.762, h-index: 102)
System     Hybrid Journal   (Followers: 9, SJR: 0.774, h-index: 33)
Systematic and Applied Microbiology     Hybrid Journal   (Followers: 1, SJR: 1.41, h-index: 64)
Systems & Control Letters     Hybrid Journal   (Followers: 3, SJR: 1.67, h-index: 85)
Systems Engineering Procedia     Open Access  
Taiwanese J. of Obstetrics and Gynecology     Full-text available via subscription   (Followers: 1, SJR: 0.424, h-index: 18)
Talanta     Hybrid Journal   (Followers: 9, SJR: 1.235, h-index: 103)
Tanta Dental J.     Open Access  
Teaching and Learning in Nursing     Full-text available via subscription   (Followers: 7, SJR: 0.313, h-index: 8)
Teaching and Teacher Education     Hybrid Journal   (Followers: 34, SJR: 1.792, h-index: 58)
Techniques and Instrumentation in Analytical Chemistry     Full-text available via subscription   (Followers: 6, SJR: 0.107, h-index: 5)
Techniques in Gastrointestinal Endoscopy     Hybrid Journal   (Followers: 3, SJR: 0.344, h-index: 9)
Techniques in Regional Anesthesia and Pain Management     Hybrid Journal   (Followers: 13, SJR: 0.134, h-index: 10)
Techniques in Vascular and Interventional Radiology     Full-text available via subscription   (Followers: 2, SJR: 0.422, h-index: 22)
Technological Forecasting and Social Change     Hybrid Journal   (Followers: 10, SJR: 1.265, h-index: 52)
Technology in Society     Hybrid Journal   (Followers: 4, SJR: 0.271, h-index: 27)
Technovation     Hybrid Journal   (Followers: 9, SJR: 2.027, h-index: 62)
Tectonophysics     Hybrid Journal   (Followers: 15, SJR: 1.817, h-index: 107)
Tékhne : Review of Applied Management Studies     Full-text available via subscription  
Telecommunications Policy     Hybrid Journal   (Followers: 6, SJR: 0.627, h-index: 40)
Telematics and Informatics     Hybrid Journal   (Followers: 5, SJR: 0.412, h-index: 26)
Terrestrial Ecology     Full-text available via subscription   (Followers: 2)
Tetrahedron     Hybrid Journal   (Followers: 34, SJR: 1.141, h-index: 171)
Tetrahedron Letters     Hybrid Journal   (Followers: 24, SJR: 0.933, h-index: 130)
Tetrahedron Organic Chemistry Series     Full-text available via subscription   (Followers: 10)
Tetrahedron: Asymmetry     Hybrid Journal   (Followers: 7)
Textile Science and Technology     Full-text available via subscription   (Followers: 4)
The Alkaloids: Chemistry and Biology     Full-text available via subscription   (Followers: 1, SJR: 0.348, h-index: 20)
The American J. of Cardiology     Hybrid Journal   (Followers: 26, SJR: 2.315, h-index: 169)
The American J. of Emergency Medicine     Hybrid Journal   (Followers: 24)
The American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 3, SJR: 1.322, h-index: 36)
The American J. of Medicine     Hybrid Journal   (Followers: 40, SJR: 1.847, h-index: 168)

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Journal Cover   Pharmacological Research
  [SJR: 1.693]   [H-I: 84]   [3 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1043-6618 - ISSN (Online) 1096-1186
   Published by Elsevier Homepage  [2800 journals]
  • Mitochondrial ROS and cancer drug resistance: Implications for therapy
    • Abstract: Publication date: October 2015
      Source:Pharmacological Research, Volume 100
      Author(s): Imoh S. Okon, Ming-Hui Zou
      Under physiological conditions, a well-coordinated and balanced redox system exists to ensure that reactive oxygen species (ROS) are appropriately utilized to accomplish specific functions, such as signaling and protein regulation. The influence of ROS within malignant cells, whether for good or bad may depend on several factors, such as tumor and tissue type, disease stage, treatment strategy, as well as duration, specificity and levels of ROS. What then are the known roles of ROS in cancer? Firstly, ROS significantly impacts cancer phenotypes. Secondly, the oxidative ROS property responsible for killing cancer cells, also impact secondary signaling networks. Thirdly, a strong correlation exist between ROS and genetic instability which may promote mutations. Finally, emerging observations suggest a role for mitochondrial ROS in cancer drug resistance, with implications for therapy. The mitochondria is a key regulator of metabolic-redox (meta-redox) alterations within cancer cells. Like a double-edged sword, mitochondrial ROS perturbations in cancer therapy may be beneficial or detrimental. However, harnessing ROS-specific cancer-targeting benefits remain a major challenge.
      Graphical abstract image

      PubDate: 2015-08-29T12:42:25Z
       
  • Fucoxanthin increases lifespan of Drosophila melanogaster and
           Caenorhabditis elegans
    • Abstract: Publication date: October 2015
      Source:Pharmacological Research, Volume 100
      Author(s): Ekaterina Lashmanova, Ekaterina Proshkina, Svetlana Zhikrivetskaya, Oksana Shevchenko, Elena Marusich, Sergey Leonov, Alex Melerzanov, Alex Zhavoronkov, Alexey Moskalev
      The pharmacological activation of stress-defense mechanisms is one of the perspective ways to increase human lifespan. The goal of the present study was to study the effects on lifespan of Drosophila melanogaster and Caenorhabditis elegans of two carotenoids: ß-carotene and fucoxanthin, which are bioactive natural substances in human diet. In addition, the effects of carotenoids on the flies survival were studied under stress conditions, including starvation, thermal stress (35°C), oxidative stress (20mM paraquat), as well as locomotor activity, fecundity, and genes expression level. Our results demonstrated lifespan extension of flies by both carotenoids. However, the positive effects on the lifespan of C. elegans were revealed only for fucoxanthin. In presence of carotenoids decreased flies’ fecundity, increased spontaneous locomotor activity and resistance to oxidative stress were detected.
      Graphical abstract image

      PubDate: 2015-08-29T12:42:25Z
       
  • Blocking the L-type Ca2+ channel (Cav 1.2) is the key mechanism for the
           vascular relaxing effect of Pterodon spp. and its isolated diterpene
           methyl-6α-acetoxy-7β-hydroxyvouacapan-17β-oate
    • Abstract: Publication date: October 2015
      Source:Pharmacological Research, Volume 100
      Author(s): Carolina de Fátima Reis, Daniela Medeiros Lobo de Andrade, Bruno Junior Neves, Leandra de Almeida Ribeiro Oliveira, José Felippe Pinho, Leidiane Pinha da Silva, Jader Dos Santos Cruz, Maria Teresa Freitas Bara, Carolina Horta Andrade, Matheus Lavorenti Rocha
      Pterodon spp. Vogel (Fabaceae), popularly known as “sucupira”, has ethnopharmacological application which is described as having antispasmodic and relaxant effects. Hence, it was hypothesized that sucupira oil-resin (SOR) could induce smooth muscle relaxation. So, this study investigated the mechanisms involved in the vasorelaxant effect of SOR and its isolated diterpene (methyl-6α-acetoxy-7β-hydroxyvouacapan-17β-oate). Vascular reactivity experiments were performed using rat aortic rings (n =5–8) with (E+) or without endothelium (E−) in an isolated bath organ. The SOR (0–56μg/mL) relaxed phenylephrine (E+: 86.7±7.1%; E−: 92.3±4.7%) and KCl contracted rings (E−: 97.1±2.8%). In the same way, diterpene (0–48μg/mL) also relaxed phenylephrine (E+: 94.5±3.6%; E−: 92.2±3.4%) and KCl contracted rings (E−: 99.7±0.2%). The pre-incubation of arterial rings with cyclopiazonic acid (reticular Ca2+-ATPase inhibitor), tetraethylammonium (K+ channels blocker) or MDL-12,330A (adenylyl cyclesinhibitor) did not modify either SOR- or diterpeneinduced vasorelaxation. However, ODQ (guanylyl cyclase inhibitor) impaired only diterpene-induced vasorelaxation. SOR and diterpene significantly reduced CaCl2-induced contraction stimulated by Bay K8644 (1μM), phenylephrine (0.1μM) or KCl solution (40mM). Computational molecular docking studies demonstrated that the vasodilator effect of diterpene relies on blocking the Cav 1.2 channel, and patch clamp results showed that diterpene substantially decreased the ionic current through Cav 1.2 in freshly dissociated vascular smooth muscle cells. These findings suggest that SOR and its isolated diterpene induce endothelium-independent vascular relaxation by blocking the L-type Ca2+ channel (Cav 1.2).
      Graphical abstract image

      PubDate: 2015-08-29T12:42:25Z
       
  • Cardiac effects of long-term active immunization with the second
           extracellular loop of human β1- and/or β3-adrenoceptors in Lewis
           rats
    • Abstract: Publication date: October 2015
      Source:Pharmacological Research, Volume 100
      Author(s): E. Montaudon, L. Dubreil, V. Lalanne, M. Vermot Des Roches, G. Toumaniantz, M. Fusellier, J.-C. Desfontis, L. Martignat, M.Y. Mallem
      β1- and β3-adrenoceptor (AR) auto-antibodies were detected in patients with dilated cardiomyopathy. Many studies have shown that β1-AR auto-antibodies with partial agonist-like effect play an important role in the pathogenesis of this disease. Moreover, a recent study carried out in our laboratory has shown that β3-AR antibodies (β3-ABs), produced in rats, were able to reduce cardiomyocyte contractility via β3-AR activation. The aims of this study were (1) to investigate, in isolated cardiomyocytes from rabbit, the role of Gi proteins in the β3-ABs-induced cardiac negative inotropy, (2) to determine whether β3-ABs may exhibit β3-AR antagonistic property which is characteristic of partial agonists, and (3) to determine whether long-term active immunization producing both β1-ABs and/or β3-ABs leads to the development of cardiac dysfunction in Lewis rats. Lewis rats were immunized for 6 months with peptidic sequences corresponding to the second extracellular loop of human β3-AR and/or β1-AR. Agonistic effect of β3-ABs was evaluated on electrically field-stimulated isolated cardiomyocytes from adult rabbit by measuring the cell shortening. Echocardiography and ex vivo isolated perfused heart studies were conducted on immunized rats. Finally, β-AR expression was quantified by immunofluorescence and RT-qPCR. SR58611A (10nM), a preferential β3-AR agonist, and purified β3-ABs (25μg/ml) induced a decrease in cell shortening (−39.71±4.9% (n= 10) and −17.06±3.9% (n =10) respectively). This effect was significantly inhibited when the cardiomyocytes were preincubated with pertussis toxin (0.3μg/ml), a Gi protein inhibitor (p <0.05). In addition, SR58611A-mediated negative inotropic effect was decreased when cardiomyocytes were preincubated with β3-ABs (p <0.0001). Echocardiography revealed a decrease in the fractional shortening and ejection fraction in rats immunized against β1-AR and both β1- and β3-AR. However, the study on isolated heart showed a decrease of the isoproterenol-induced lusitropic and inotropic effects in the 3 groups of immunized rats. These systolic and diastolic dysfunctions are correlated with a decrease in the expression of β1-ARs and an increase of β3-ARs in rats immunized against the β1-AR and an increase of both β3-AR and β1-AR in rats immunized against the β3-AR. For the first time, these results showed that β3-ABs had a β3-AR partial agonist-like activity which might play a role in the pathogenesis of cardiac dysfunction.
      Graphical abstract image

      PubDate: 2015-08-29T12:42:25Z
       
  • Deficiency in adiponectin exaggerates cigarette smoking exposure-induced
           cardiac contractile dysfunction: Role of autophagy
    • Abstract: Publication date: October 2015
      Source:Pharmacological Research, Volume 100
      Author(s): Nan Hu, Lifang Yang, Maolong Dong, Jun Ren, Yingmei Zhang
      Second hand smoke is an independent risk factor for cardiovascular disease. Adiponectin (APN), an adipose-derived adipokine, has been shown to offer cardioprotective effect through an AMPK-dependent manner. This study was designed to evaluate the impact of adiponectin deficiency on second hand smoke-induced cardiac pathology and underlying mechanisms using a mouse model of side-stream smoke exposure. Adult wild-type (WT) and adiponectin knockout (APNKO) mice were placed in a chamber exposed to cigarette smoke for 1 hour daily for 40 days. Echocardiographic, cardiomyocyte function, and intracellular Ca2+ handling were evaluated. Autophagy and apoptosis were examined using western blot. 2′,7′-dichlorodihydrofluorescein diacetate (H2DCFDA) staining was used to evaluate reactive oxygen species (ROS) generation. Masson trichrome staining was employed to measure interstitial fibrosis. Our data revealed that adiponectin deficiency provoked smoke exposure-induced cardiomyopathy (compromised fractional shortening, disrupted cardiomyocyte function and intracellular Ca2+ homeostasis, apoptosis and ROS generation). In addition, these detrimental effects of side-stream smoke were accompanied by defective autophagolysosome formation, the effect of which was exacerbated by adiponectin deficiency. Blocking autophagolysosome formation using bafilomycin A1 (BafA1) negated the cardioprotective effect of rapamycin against smoke extract. Induction of autophagy using rapamycin and AMPKα activation using AICAR rescued against smoke extract-induced myopathic anomalies in APNKO mice. Our data suggest that adiponectin serves as an indispensable cardioprotective factor against side-stream smoke exposure-induced myopathic changes possibly through facilitating autophagolysosome formation.
      Graphical abstract image

      PubDate: 2015-08-29T12:42:25Z
       
  • Cardiovascular effects of low versus high-dose beta-carotene in a rat
           model
    • Abstract: Publication date: October 2015
      Source:Pharmacological Research, Volume 100
      Author(s): Evelin Csepanyi, Attila Czompa, David Haines, Istvan Lekli, Edina Bakondi, Gyorgy Balla, Arpad Tosaki, Istvan Bak
      β-carotene (BC), a lipid-soluble tetraterpene precursor to vitamin A, widely distributed in plants, including many used in human diet, has well-known health-enhancing properties, including reducing risk of and treatment for certain diseases. Nevertheless, BC may also act to promote disease through the activity of BC derivatives that form in the presence of external toxicants such as cigarette smoke and endogenously-produced reactive oxygen species. The present investigation evaluates the dose-dependent cardioprotective and possibly harmful properties of BC in a rat model. Adult male rats were gavage-fed BC for 4 weeks, at dosages of either 0, 30 or 150mg/kg/day. Then, hearts excised from the animals were mounted in a “working heart” apparatus and subjected to 30min of global ischemia, followed by 120min of reperfusion. A panel of cardiac functional evaluations was conducted on each heart. Infarct size and total antioxidant capacity of the myocardium were assessed. Heart tissue content of heme oxygenase-1 (HO-1) by Western blot analysis; and potential direct cytotoxic effects of BC by MTT assay were evaluated. Hearts taken from rats receiving 30mg/kg/day BC exhibited significantly improved heart function at lower reperfusion times, but lost this protection at higher BC dosage and longer reperfusion times. Myocardial HO-1 content was significantly elevated dose-responsively to both BC dosage. Finally, in vitro evaluation of BC on H9c2 cells showed that the agent significantly improved vitality of these cells in a dose range of 2.5–10μM. Although data presented here do not allow for a comprehensive mechanistic explanation for reduced cardioprotection at high dose BC, it is speculated that since Fe2+ produced as a metabolite of HO-1 activity, may determine whether BC acts as an antioxidant or prooxidant agent, the strong induction of this enzyme in response to ischemia/reperfusion-induced oxidative stress may account for the high-dose BC loss of cardioprotection.
      Graphical abstract image

      PubDate: 2015-08-29T12:42:25Z
       
  • Vaccines, adjuvants and autoimmunity
    • Abstract: Publication date: October 2015
      Source:Pharmacological Research, Volume 100
      Author(s): Luísa Eça Guimarães, Britain Baker, Carlo Perricone, Yehuda Shoenfeld
      Vaccines and autoimmunity are linked fields. Vaccine efficacy is based on whether host immune response against an antigen can elicit a memory T-cell response over time. Although the described side effects thus far have been mostly transient and acute, vaccines are able to elicit the immune system towards an autoimmune reaction. The diagnosis of a definite autoimmune disease and the occurrence of fatal outcome post-vaccination have been less frequently reported. Since vaccines are given to previously healthy hosts, who may have never developed the disease had they not been immunized, adverse events should be carefully accessed and evaluated even if they represent a limited number of occurrences. In this review of the literature, there is evidence of vaccine-induced autoimmunity and adjuvant-induced autoimmunity in both experimental models as well as human patients. Adjuvants and infectious agents may exert their immune-enhancing effects through various functional activities, encompassed by the adjuvant effect. These mechanisms are shared by different conditions triggered by adjuvants leading to the autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome). In conclusion, there are several case reports of autoimmune diseases following vaccines, however, due to the limited number of cases, the different classifications of symptoms and the long latency period of the diseases, every attempt for an epidemiological study has so far failed to deliver a connection. Despite this, efforts to unveil the connection between the triggering of the immune system by adjuvants and the development of autoimmune conditions should be undertaken. Vaccinomics is a field that may bring to light novel customized, personalized treatment approaches in the future.
      Graphical abstract image

      PubDate: 2015-08-29T12:42:25Z
       
  • Transcriptional dysregulation in Huntington’s disease: The role of
           histone deacetylases
    • Abstract: Publication date: October 2015
      Source:Pharmacological Research, Volume 100
      Author(s): Sorabh Sharma, Rajeev Taliyan
      Huntington’s disease (HD) is a progressive neurological disorder for which there are no disease-modifying treatments. Although, the exact underlying mechanism(s) leading to the neural cell death in HD still remains elusive, the transcriptional dysregulation is a major molecular feature. Recently, the transcriptional activation and repression regulated by chromatin acetylation has been found to be impaired in HD pathology. The acetylation and deacetylation of histone proteins is carried out by opposing actions of histone acetyl-transferases and histone deacetylases (HDACs), respectively. Studies carried out in cell culture, yeast, Drosophila and rodent model(s) have indicated that HDAC inhibitors (HDACIs) might provide useful class of therapeutic agents for HD. Clinical trials have also reported the beneficial effects of HDACIs in patients suffering from HD. Therefore, the development of HDACIs as therapeutics for HD has been vigorously pursued. In this review, we highlight and summarize the putative role of HDACs in HD like pathology and further discuss the potential of HDACIs as new therapeutic avenues for the treatment of HD.
      Graphical abstract image

      PubDate: 2015-08-29T12:42:25Z
       
  • Novel synthetic pyridyl analogues of CDDO-Imidazolide are useful new tools
           in cancer prevention
    • Abstract: Publication date: October 2015
      Source:Pharmacological Research, Volume 100
      Author(s): Martine Cao, Evans O. Onyango, Charlotte R. Williams, Darlene B. Royce, Gordon W. Gribble, Michael B. Sporn, Karen T. Liby
      Two new analogues of CDDO-Imidazolide (CDDO-Im), namely 1-[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]-4(-pyridin-2-yl)-1H-imidazole (“CDDO-2P-Im”) and 1-[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]-4(-pyridin-3-yl)-1H-imidazole (“CDDO-3P-Im”) have been synthesized and tested for their potential use as chemopreventive drugs. At nanomolar concentrations, they were equipotent to CDDO-Im for inducing differentiation and apoptosis in U937 leukemia cells. As inflammation and oxidative stress contribute to carcinogenesis, we also assessed their cytoprotective potential. The new compounds suppressed inducible nitric oxide synthase (iNOS) expression in RAW264.7 macrophage-like cells and significantly elevated heme oxygenase-1 (HO-1) and quinone reductase (NQO1) mRNA and protein levels in various mouse tissues in vivo. Most importantly, pharmacokinetic studies performed in vitro in human plasma and in vivo showed that each new analogue was more stable than CDDO-Im. Much higher concentrations of the new derivatives were found in mouse liver, lung, pancreas and kidney after gavage in contrast to CDDO-Im. Because of their better bioavailability and their excellent anti-inflammatory profile in vitro, CDDO-2P-Im and CDDO-3P-Im were tested for prevention in a highly relevant mouse lung cancer model, in which A/J mice develop lung carcinomas after injection of vinyl carbamate, a potent carcinogen. CDDO-2P-Im and CDDO-3P-Im were as effective as CDDO-Im for reducing the size and the severity of the lung tumors.
      Graphical abstract image

      PubDate: 2015-08-16T12:40:21Z
       
  • Sitagliptin in type 2 diabetes mellitus: Efficacy after five years of
           therapy
    • Abstract: Publication date: October 2015
      Source:Pharmacological Research, Volume 100
      Author(s): Giuseppe Derosa, Angela D’Angelo, Pamela Maffioli
      The aim of this study was to investigate whether the positive effects of sitagliptin were maintained even after five years of treatment. Starting from 2008 to today, we treated 624 patients, not well controlled by current therapy, with the addition of sitagliptin 100mg/die. Patients included 216 subjects treated with metformin, 206 treated with sulfonylureas, and 202 treated with pioglitazone. Sitagliptin was added to metformin, sulfonylureas and pioglitazone in monotherapy, respectively, and the data were compared with those of 620 patients treated with sulfonylureas+metformin, pioglitazone+metformin and pioglitazone+sulfonylureas matched for age, sex, diabetes duration. We recorded that the addition of sitagliptin to current hypoglycemic therapy led to a reduction of HbA1c similar to that obtained with sulfonylureas after two years. After five years of treatment, changes in HbA1c suggest a better glycemic control over the long term with sitagliptin compared to other treatments, particularly when compared with sulfonylureas. The other parameters evaluated as fasting plasma glucose, post-prandial plasma glucose and insulin levels, confirm the trends observed for the value of HbA1c. Regarding BMI, it increased with sulfonylureas and pioglitazone compared to sitagliptin. Patients treated with sulfonylureas had a higher incidence of hypoglycemia compared to sitagliptin. In conclusion, sitagliptin seems to maintain its positive effects on glycemia and fasting plasma insulin on the long term.
      Graphical abstract image

      PubDate: 2015-08-16T12:40:21Z
       
  • Hydrogen sulfide inhalation ameliorates allergen induced airway
           hypereactivity by modulating mast cell activation
    • Abstract: Publication date: October 2015
      Source:Pharmacological Research, Volume 100
      Author(s): Fiorentina Roviezzo, Antonio Bertolino, Rosalinda Sorrentino, Michela Terlizzi, Maria Matteis, Vincenzo Calderone, Valentina Mattera, Alma Martelli, Giuseppe Spaziano, Aldo Pinto, Bruno D’Agostino, Giuseppe Cirino
      Compelling evidence suggests that hydrogen sulfide represents an important gaseous transmitter in the mammalian respiratory system. In the present study, we have evaluated the role of mast cells in hydrogen sulfide-induced effects on airways in a mouse model of asthma. Mice were sensitized to ovalbumin and received aerosol of a hydrogen sulfide donor (NaHS; 100ppm) starting at day 7 after ovalbumin challenge. Exposure to hydrogen sulfide abrogated ovalbumin-induced bronchial hypereactivity as well as the increase in lung resistance. Concomitantly, hydrogen sulfide prevented mast cell activity as well as FGF-2 and IL-13 upregulation. Conversely, pulmonary inflammation and the increase in plasmatic IgE levels were not affected by hydrogen sulfide. A lack of hydrogen sulfide effects in mast cell deficient mice occurred. Primary fibroblasts harvested from ovalbumin-sensitized mice showed an increased proliferation rate that was inhibited by hydrogen sulfide aerosol. Furthermore, ovalbumin-induced transdifferentiation of pulmonary fibroblasts into myofibroblasts was reversed. Finally, hydrogen sulfide did abrogate in vitro the degranulation of the mast cell-like RBL-2H3 cell line. Similarly to the in vivo experiments the inhibitory effect was present only when the cells were activated by antigen exposure. In conclusion, inhaled hydrogen sulfide improves lung function and inhibits bronchial hyper-reactivity by modulating mast cells and in turn fibroblast activation.
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      PubDate: 2015-08-16T12:40:21Z
       
  • Characterization of V0162, a new long-acting antagonist at human M3
           muscarinic acetylcholine receptors
    • Abstract: Publication date: October 2015
      Source:Pharmacological Research, Volume 100
      Author(s): Peter Heusler, Didier Cussac, Emmanuel Naline, Stéphanie Tardif, Thierry Clerc, Philippe Devillier
      The anticholinergic properties of the mequitazine enantiomer V0162 make it a drug candidate for the treatment of chronic obstructive airway diseases. Here, we compared V0162’s in vitro pharmacological activity at recombinant human M3 muscarinic acetylcholine receptors (hM3Rs) with that of other anticholinergics, using (i) a radioligand binding assay, (ii) a functional reporter gene assay and (iii) a bronchoconstriction inhibition assay on human bronchial preparations. V0162 had high affinity for hM3Rs, with a pKi varying from 9.01 after a 2h incubation to 9.21 after 23h. The other mequitazine enantiomer (V0114) was less potent. V0162 displayed rapid off-kinetics and a biphasic time course of binding. V0162 was found to be an antagonist behaving as an inverse agonist for hM3R-mediated reporter gene activation, with much the same efficacy as atropine, ipratropium and tiotropium. However, in contrast to ipratropium and atropine, V0162’s inhibitory potency was only slightly affected by compound washout. V0162 antagonized acetylcholine-mediated contractions in a human bronchial preparation; the pA 2 values increased with the incubation time (up to 2h). Moreover, there was a progressive increase in V0162’s ability to inhibit electrically-induced contractions, which persisted after compound washout. In conclusion, V0162 is the most active mequitazine enantiomer at hM3Rs and shows a complex pattern of binding to the membrane compartment. These particular features may be of therapeutic value when persistent antagonism at hM3Rs is required.
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      PubDate: 2015-08-16T12:40:21Z
       
  • From pathogenesis to therapy – Perspective on treatment strategies
           in fibrotic diseases
    • Abstract: Publication date: October 2015
      Source:Pharmacological Research, Volume 100
      Author(s): Andreas Ramming, Clara Dees, Jörg H.W. Distler
      Although fibrosis is becoming increasingly recognized as a major cause of morbidity and mortality in modern societies, there are very few treatment strategies available that specifically target the pathogenesis of fibrosis. Early in disease, inflammation and vascular changes and an increase in reactive oxygen species play pivotal roles. After inflammation has subsided, fibrosis and scarring are predominant in later phases. Fibrosis is driven by a complex, not-yet fully understood interplay between inflammatory cells on one hand and endothelium and fibroblasts on the other hand. The latter are regarded as the key players due to their extensive synthesis of extracellular matrix components which results in skin and organ fibrosis. Various cytokines orchestrate altered functions of the mentioned cell types. There are promising targets with therapeutic potential that have been extensively characterized in recent years connected with the hope to translate these preclinical results into clinical practice.
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      PubDate: 2015-08-16T12:40:21Z
       
  • Evidence for the role of lipid rafts and sphingomyelin in Ca2+-gating of
           Transient Receptor Potential channels in trigeminal sensory neurons and
           peripheral nerve terminals
    • Abstract: Publication date: October 2015
      Source:Pharmacological Research, Volume 100
      Author(s): Éva Sághy, Éva Szőke, Maja Payrits, Zsuzsanna Helyes, Rita Börzsei, János Erostyák, Tibor Zoltán Jánosi, György Sétáló Jr, János Szolcsányi
      Transient Receptor Potential (TRP) cation channels, such as TRP Vanilloid 1 and TRP Ankyrin repeat domain 1 (TRPV1 and TRPA1) are nocisensors playing important role to signal pain. Two “melastatin” TRP receptors, like TRPM8 and TRPM3 are also expressed in a subgroup of primary sensory neurons. These channels serve as thermosensors with unique thermal sensitivity ranges and are activated also by several exogenous and endogenous chemical ligands inducing conformational changes from various allosteric (“multisteric”) sites. We analysed the role of plasma membrane microdomains of lipid rafts on isolated trigeminal (TRG) neurons and TRPV1-expressing CHO cell line by measuring agonist-induced Ca2+ transients with ratiometric technique. Stimulation-evoked calcitonin gene related peptide (CGRP) release from sensory nerve endings of the isolated rat trachea by radioimmunoassay was also measured. Lipid rafts were disrupted by cleaving sphingomyelin (SM) with sphingomyelinase (SMase), cholesterol depletion with methyl β-cyclodextrin (MCD) and ganglioside breakdown with myriocin. It has been revealed that intracellular Ca2+ increase responses evoked by the TRPV1 agonist capsaicin, the TRPA1 agonsits allyl isothiocyanate (AITC) and formaldehyde as well as the TRPM8 activator icilin were inhibited after SMase, MCD and myriocin incubation but the response to the TRPM3 agonist pregnenolon sulphate was not altered. Extracellular SMase treatment did not influence the thapsigargin-evoked Ca2+-release from intracellular stores. Besides the cell bodies, SMase also inhibited capsaicin- or AITC-evoked CGRP release from peripheral sensory nerve terminals, this provides the first evidence for the importance of lipid raft integrity in TRPV1 and TRPA1 gating on capsaicin-sensitive nerve terminals. SM metabolites, ceramide and sphingosine, did not influence TRPA1 and TRPV1 activation on TRG neurons, TRPV1-expressing CHO cell line, and nerve terminals. We suggest, that the hydrophobic interactions between TRP receptors and membrane lipid raft interfaces modulate the opening properties of these channels and therefore, targeting this interaction might be a promising tool for drug developmental purposes.
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      PubDate: 2015-08-16T12:40:21Z
       
  • Protein-ligand and membrane-ligand interactions in pharmacology: the case
           of the translocator protein (TSPO)
    • Abstract: Publication date: October 2015
      Source:Pharmacological Research, Volume 100
      Author(s): Claire R. Hatty, Richard B. Banati
      The targets of many small molecule drugs are membrane proteins, and traditionally the focus of pharmacology is on the interaction between such receptors and their small molecule drug ligands. However, the lipid membranes of cells and organelles are increasingly appreciated as diverse and dynamic structures that also specifically interact with small molecule drugs and peptides, causing profound changes in the properties of these membranes, and modulating the function of the membrane and the proteins within it. Drug-membrane interactions are likely to have a role in both the therapeutic and toxic activity of a variety of compounds, and their role in the overall pharmacological effect of a drug needs to be understood more clearly. This is the case for the 18 kDa translocator protein (TSPO) and its ligands, where functions that were established based on pharmacological studies are being called into question. Re-examining the putative functions of the TSPO and the effects of its ligands reveals a need to consider in more detail the interplay between protein-ligand and membrane-ligand interactions, and the modulatory relationship between TSPO and the lipid membrane.
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      PubDate: 2015-08-11T12:37:32Z
       
  • Anti-cancerous efficacy and pharmacokinetics of 6-mercaptopurine loaded
           chitosan nanoparticles
    • Abstract: Publication date: October 2015
      Source:Pharmacological Research, Volume 100
      Author(s): G. Prem Kumar, Jagadeesh S. Sanganal, A.R. Phani, C. Manohara, Syamantak M. Tripathi, H.L. Raghavendra, P.B. Janardhana, S. Amaresha, K.B. Swamy, R.G.S.V. Prasad
      6-Mercaptopurine is a cytotoxic and immunosuppressant drug. The use of this drug is limited due to its poor bioavailability and short plasma half-life. In order to nullify these drawbacks, 6-mercaptopurine-chitosan nanoparticles (6-MP-CNPs) were prepared and evaluated to study the influence of preparation conditions on the physicochemical properties by using DLS, SEM, XRD and FTIR. The in vitro drug release profile at pH 4.8 and 7.4 revealed sustained release patterns for a period of 2 days. The nanoformulations showed enhanced in vitro anti-cancer activities (MTT assay, apoptosis assay, cell cycle arrest and ROS indices) on HT-1080 and MCF-7 cells. In vivo pharmacokinetics profiles of 6-MP-CNPs showed improved bioavailability. Thus, the results of the present study revealed that, the prepared 6-MP-CNPs have a significant role in increasing anti-cancer efficacy, bioavailability and in vivo pharmacokinetics profiles.
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      PubDate: 2015-08-11T12:37:32Z
       
  • 3-Hydroxyflavone and structural analogues differentially activate pregnane
           X receptor: Implication for inflammatory bowel disease
    • Abstract: Publication date: October 2015
      Source:Pharmacological Research, Volume 100
      Author(s): Aik Jiang Lau, Thomas K.H. Chang
      Pregnane X receptor (PXR; NR1I2) is a member of the superfamily of nuclear receptors that regulates the expression of genes involved in various biological processes, including drug transport and biotransformation. In the present study, we investigated the effect of 3-hydroxyflavone and its structurally-related analogues on PXR activity. 3-Hydroxyflavone, galangin, kaempferol, querceetin, isorhamnetin, and tamarixetin, but not but not datiscetin, morin, myricetin, or syringetin, activated mouse PXR, as assessed in a cell-based reporter gene assay. By comparison, 3-hydroxyflavone activated rat PXR, whereas 3-hydroxyflavone, galangin, quercetin, isorhamnetin, and tamarixetin activated human PXR (hPXR). A time-resolved fluorescence resonance energy transfer competitive ligand-binding assay showed binding to the ligand-binding domain of hPXR by 3-hydroxyflavone, galangin, quercetin, isorhamnetin, and tamarixetin. 3-Hydroxyflavone and galangin, but not quercetin, isorhamnetin, or tamarixetin, recruited steroid receptor coactivator (SRC)-1, SRC-2, and SRC-3 to hPXR. In LS180 human colon adenocarcinoma cells, 3-hydroxyflavone, quercetin, and tamarixetin increased CYP3A4, CYP3A5, and ABCB1 mRNA expression, whereas galangin and isorhamnetin increased CYP3A4 and ABCB1 but not CYP3A5 mRNA expression. Datiscetin, kaempferol, morin, myricetin, and syringetin did not attenuate the extent of hPXR activation by rifampicin, suggesting they are not hPXR antagonists. Overall, flavonols activate PXR in an analogue-specific and species-dependent manner. Substitution at the C2′ or C5′ position of 3-hydroxyflavone with a hydroxyl or methoxy group rendered it incapable of activating hPXR. Understanding the structure-activity relationship of flavonols in hPXR activation may facilitate nutraceutical development efforts in the treatment of PXR-associated intestinal diseases, such as inflammatory bowel disease.
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      PubDate: 2015-08-11T12:37:32Z
       
  • Betahistine co-treatment ameliorates dyslipidemia induced by chronic
           olanzapine treatment in rats through modulation of hepatic
           AMPKα-SREBP-1 and PPARα-dependent pathways
    • Abstract: Publication date: October 2015
      Source:Pharmacological Research, Volume 100
      Author(s): Xuemei Liu, Jiamei Lian, Chang-Hua Hu, Chao Deng
      Second-generation antipsychotics including olanzapine are associated with weight gain, dyslipidemia and other metabolic disorders. Both animal and clinical studies have shown that co-treatment with betahistine (a histamine H1 receptor agonist/H3 receptor antagonist) is effective in controlling olanzapine-induced weight gain. In the present study, we investigate whether co-treatment with betahistine is able to prevent dyslipidemia induced by chronic olanzapine treatment and the underlying mechanisms. Female rats were orally administered with olanzapine (1mg/kg, t.i.d.) for 3.5 consecutive weeks and then a 2.5-week drug withdrawal. Then, rats were divided into 4 groups for 5 weeks treatment: (1) vehicle, (2) olanzapine-only (1mg/kg, t.i.d.), (3) betahistine-only (9.6mg/kg, t.i.d.), and (4) olanzapine and betahistine (O+B) co-treatment. After completing treatment, hepatic mRNA expression was measured by qRT-PCR, while the protein levels were detected by western blot. In our study, olanzapine-only treatment significantly increased triglyceride accumulation and non-esterified fatty acids (NEFA), and upregulated mRNA expression of sterol regulatory element binding protein 1 (SREBP-1) and its target genes, while these alterations were ameliorated by O+B co-treatment. Hepatic AMP-activated protein kinase α (AMPKα) was activated in the O+B co-treatment group, with a significant reduction in nuclear SREBP-1 protein expression but an increased expression of peroxisome proliferator-activated receptor-α (PPARα) and its-responsive molecule(CPT1A), compared with olanzapine-only treatment. In addition, olanzapine significantly increased hepatic histamine H1 receptors, while O+B co-treatment significantly reversed them to normal levels. This study provided the first evidence that betahistine could act on hepatic H1 receptors via modulation of AMPKα-SREBP-1 and PPARα-dependent pathways to ameliorate olanzapine-induced dyslipidemia in rats.
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      PubDate: 2015-08-07T12:36:52Z
       
  • Rapid NOS-1-derived nitric oxide and peroxynitrite formation act as
           signaling agents for inducible NOS-2 expression in vascular smooth muscle
           cells
    • Abstract: Publication date: Available online 4 August 2015
      Source:Pharmacological Research
      Author(s): Karin Scheschowitsch, João Alfredo de Moraes, Regina Sordi, Christina Barja- Fidalgo, Jamil Assreuy
      Septic vascular dysfunction is characterized by hypotension and hyporeactivity to vasoconstrictors and nitric oxide (NO), reactive oxygen species and peroxynitrite have a prominent role in this condition. However, the mechanism whereby the vascular dysfunction is initiated is poorly understood.Based on previous studies of our group and the literature,we hypothesize that constitutive nitric oxide synthases(c-NOS)and peroxynitrite may play a role in the development of septic vascular dysfunction. Bacterial lipopolysaccharide (LPS) and interferon-γ (IFN)were used to stimulate rat aorta smooth muscle cells (A7r5) and rat aorta slices. This stimulation led to a rapid (within minutes) production of NOand superoxide anion,which led to peroxynitrite formation.When this rapid initial burst was reduced,through the inhibition of c-NOS and NADPH oxidases (NOX) or the scavenging of NO and superoxidethe NF-κBactivation, NOS-2 expression and nitrite production were significantly attenuated.Although vascular smooth muscle cells express both c-NOS isoforms, gene knockdownrevealed that only NOS-1-dependent NO and peroxynitrite formation are important for the later NOS-2 expression. Similar findings were obtained by knockdown NOX-1 gene, one source of superoxide for peroxynitrite formation.Taking together, we show that smooth muscle cell activation by LPS/IFN leads to a rapid formation of NOS-1-derived NO and NOX-1-derived superoxide, forming peroxynitrite; and that this species act as a trigger for NOS-2 expression through NF-κBactivation. Therefore, our findings suggest a critical role for NOS-1 and NOX-1 in the initiation of the vascular dysfunction associated with sepsis and septic shock.
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      PubDate: 2015-08-07T12:36:52Z
       
  • A novel quantitative assay of mitophagy: Combining high content
           fluorescence microscopy and mitochondrial DNA load to quantify mitophagy
           and identify novel pharmacological tools against pathogenic heteroplasmic
           mtDNA
    • Abstract: Publication date: October 2015
      Source:Pharmacological Research, Volume 100
      Author(s): Alan Diot, Alex Hinks-Roberts, Tiffany Lodge, Chunyan Liao, Eszter Dombi, Karl Morten, Stefen Brady, Carl Fratter, Janet Carver, Rebecca Muir, Ryan Davis, Charlotte J Green, Iain Johnston, David Hilton-Jones, Carolyn Sue, Heather Mortiboys, Joanna Poulton
      Mitophagy is a cellular mechanism for the recycling of mitochondrial fragments. This process is able to improve mitochondrial DNA (mtDNA) quality in heteroplasmic mtDNA disease, in which mutant mtDNA co-exists with normal mtDNA. In disorders where the load of mutant mtDNA determines disease severity it is likely to be an important determinant of disease progression. Measuring mitophagy is technically demanding. We used pharmacological modulators of autophagy to validate two techniques for quantifying mitophagy. First we used the IN Cell 1000 analyzer to quantify mitochondrial co-localisation with LC3-II positive autophagosomes. Unlike conventional fluorescence and electron microscopy, this high-throughput system is sufficiently sensitive to detect transient low frequency autophagosomes. Secondly, because mitophagy preferentially removes pathogenic heteroplasmic mtDNA mutants, we developed a heteroplasmy assay based on loss of m.3243A>G mtDNA, during culture conditions requiring oxidative metabolism (“energetic stress”). The effects of the pharmacological modulators on these two measures were consistent, confirming that the high throughput imaging output (autophagosomes co-localising with mitochondria) reflects mitochondrial quality control. To further validate these methods, we performed a more detailed study using metformin, the most commonly prescribed antidiabetic drug that is still sometimes used in Maternally Inherited Diabetes and Deafness (MIDD). This confirmed our initial findings and revealed that metformin inhibits mitophagy at clinically relevant concentrations, suggesting that it may have novel therapeutic uses.
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      PubDate: 2015-08-04T03:27:15Z
       
  • A historical overview of protein kinases and their targeted small molecule
           inhibitors
    • Abstract: Publication date: October 2015
      Source:Pharmacological Research, Volume 100
      Author(s): Robert Roskoski
      Protein kinases play a predominant regulatory role in nearly every aspect of cell biology and they can modify the function of a protein in almost every conceivable way. Protein phosphorylation can increase or decrease enzyme activity and it can alter other biological activities such as transcription and translation. Moreover, some phosphorylation sites on a given protein are stimulatory while others are inhibitory. The human protein kinase gene family consists of 518 members along with 106 pseudogenes. Furthermore, about 50 of the 518 gene products lack important catalytic residues and are called protein pseudokinases. The non-catalytic allosteric interaction of protein kinases and pseudokinases with other proteins has added an important regulatory feature to the biochemistry and cell biology of the protein kinase superfamily. With rare exceptions, a divalent cation such as Mg2+ is required for the reaction. All protein kinases exist in a basal state and are activated only as necessary by divergent regulatory stimuli. The mechanisms for switching between dormant and active protein kinases can be intricate. Phosphorylase kinase was the first protein kinase to be characterized biochemically and the mechanism of its regulation led to the discovery of cAMP-dependent protein kinase (protein kinase A, or PKA), which catalyzes the phosphorylation and activation of phosphorylase kinase. This was the first protein kinase cascade or signaling module to be elucidated. The epidermal growth factor receptor-Ras-Raf-MEK-ERK signaling module contains protein-tyrosine, protein-serine/threonine, and dual specificity protein kinases. PKA has served as a prototype of this enzyme family and more is known about this enzyme than any other protein kinase. The inactive PKA holoenzyme consists of two regulatory and two catalytic subunits. After binding four molecules of cAMP, the holoenzyme dissociates into a regulatory subunit dimer (each monomer binds two cAMP) and two free and active catalytic subunits. PKA and all other protein kinase domains have a small amino-terminal lobe and large carboxyterminal lobe as determined by X-ray crystallography. The N-lobe and C-lobe form a cleft that serves as a docking site for MgATP. Nearly all active protein kinases contain a K/E/D/D signature sequence that plays important structural and catalytic roles. Protein kinases contain hydrophobic catalytic and regulatory spines and collateral shell residues that are required to assemble the active enzyme. There are two general kinds of conformational changes associated with most protein kinases. The first conformational change involves the formation of an intact regulatory spine to form an active enzyme. The second conformational change occurs in active kinases as they toggle between open and closed conformations during their catalytic cycles. Because mutations and dysregulation of protein kinases play causal roles in human disease, this family of enzymes has become one of the most important drug targets over the past two decades. Imatinib was approved by the United States FDA for the treatment of chronic myelogenous leukemia in 2001; this small molecule inhibits the BCR-Abl protein kinase oncoprotein that results from the formation of the Philadelphia chromosome. More than two dozen other orally effective mechanism-based small molecule protein kinase inhibitors have been subsequently approved by the FDA. These drugs bind to the ATP-binding site of their target enzymes and extend into nearby hydrophobic pockets. Most of these protein kinase inhibitors prolong survival in cancer patients only weeks or months longer than standard cytotoxic therapies. In contrast, the clinical effectiveness of imatinib against chronic myelogenous leukemia is vastly superior to that of any other targeted protein kinase inhibitor with overall survival lasting a decade or more. However, the near universal and expected development of drug resistance in the treatment of neoplastic disorders requires new approaches to solve this therapeutic challenge. Cancer is the predominant indication for these drugs, but disease targets are increasing. For example, we can expect the approval of new drugs inhibiting other protein kinases in the treatment of illnesses such as hypertension, Parkinson's disease, and autoimmune diseases.
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      PubDate: 2015-08-04T03:27:15Z
       
  • Chemerin: A comprehensive review elucidating the need for cardiovascular
           research
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): David J. Ferland, Stephanie W. Watts
      When chemerin was discovered in 1997, it was relegated to being a protein associated with the normal skin function contrasting the setting of psoriasis. However, with the discovery of multiple receptors for the chemerin protein and a vast collection of associations with various pathologies, chemerin has global influence capable of regulating chemotactic, adipokine, autocrine/paracrine, adipogenic, angiogenic, and reproductive functions. These individual abilities of chemerin are important for understanding its basic pharmacology and physiology, but application of these principles to human pathology relies on the ability of scientists and physicians to view this protein from a much wider, all-encompassing angle. A global participant in the action of chemerin is the cardiovascular system (CVS). Although the CVS may not have as many direct interactions (e.g. smooth muscle in endothelium) with chemerin as it does indirect (e.g. chemerin activation in the lumen by proteases), our basic understanding of the CVS and its relation to chemerin is necessary to form a proper grasp of its individual actions and make the applications to pathology. This review provides a fundamental, yet comprehensive review of chemerin that inherently identifies the CVS as a necessary link between chemerin and its associated pathologies, but also calls for basic cardiovascular research as the solution to this chasm between knowledge and application.
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      PubDate: 2015-07-30T20:51:46Z
       
  • PU-H71: An improvement on nature's solutions to oncogenic Hsp90 addiction
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Matthew Trendowski
      Despite recent advances in precision medicine, many molecular-based antineoplastic agents do not potentiate sustainable long term remissions, warranting the investigation of novel therapeutic strategies. Heat shock protein 90 (Hsp90) is a molecular chaperone that not only has oncogenic properties, but also has distinct expression profiles in malignant and normal cells, providing a rational strategy to attain preferential damage. Prior attempts to target Hsp90 with natural product-based compounds have been hampered by their associated off target toxicities, suggesting that novel, fully synthetic inhibitors may be required to achieve the specificity necessary for therapeutic efficacy. Therefore, this review highlights the antineoplastic potential of PU-H71 (8-[(6-iodo-1,3-benzodioxol-5-yl)sulfanyl]-9-[3-(propan-2-ylamino)propyl]purin-6-amine), a novel purine based analog that has shown efficacy in many preclinical models of malignancy, and is now under clinical examination. In addition, the review suggests potential concomitant therapeutic approaches that may be particularly beneficial to molecular-based, as well as traditional cytotoxic cancer chemotherapy.
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      PubDate: 2015-07-09T21:39:00Z
       
  • Imiquimod-induced psoriasis-like skin inflammation is suppressed by BET
           bromodomain inhibitor in mice through RORC/IL-17A pathway modulation
    • Abstract: Publication date: Available online 3 July 2015
      Source:Pharmacological Research
      Author(s): Ahmed Nadeem , Naif O. Al-Harbi , Mohamed M. Al-Harbi , Ahmed M. El-Sherbeeny , Sheikh F. Ahmad , Nahid Siddiqui , Mushtaq A. Ansari , Khairy M.A. Zoheir , Sabry M. Attia , Khaled A. Al-Hosaini , Shakir D. Al-Sharary
      Psoriasis is one of the most common skin disorders characterized by erythematous plaques that result from hyperproliferative keratinocytes and infiltration of inflammatory leukocytes into dermis and epidermis. Recent studies suggest that IL-23/IL-17A/IL-22 cytokine axis plays an important role in the pathogenesis of psoriasis. The small molecule bromodomain and extraterminal domain (BET) inhibitors, that disrupt interaction of BET proteins with acetylated histones have recently demonstrated efficacy in various models of inflammation through suppression of several pathways, one of them being synthesis of IL-17A/IL-22 which primarily depends on transcription factor, retinoic acid receptor-related orphan receptor C (RORC). However, the efficacy and mechanistic aspect of a BET inhibitor in mouse model of skin inflammation has not been explored previously. Therefore, this study investigated the role of BET inhibitor, JQ-1 in mouse model of psoriasis-like inflammation. Mice were topically applied imiquimod (IMQ) to develop psoriasis-like inflammation on the shaved back and ear followed by assessment of skin inflammation (myeloperoxidase activity, ear thickness, and histopathology), RORC and its signature cytokines (IL-17A/IL-22). JQ-1 suppressed IMQ-induced skin inflammation as reflected by a decrease in ear thickness/myeloperoxidase activity, and RORC/IL-17A/IL-22 expression. Additionally, a RORα/γ agonist SR1078 was utilized to investigate the role of RORC in BET-mediated skin inflammation. SR1078 reversed the protective effect of JQ-1 on skin inflammation at both histological and molecular levels in the IMQ model. The current study suggests that BET bromodomains are involved in psoriasis-like inflammation through induction of RORC/IL-17A pathway. Therefore, inhibition of BET bromodomains may provide a new therapy against skin inflammation.
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      PubDate: 2015-07-05T21:38:21Z
       
  • Adenosine Receptors and Diabetes: focus on the A2B adenosine receptor
           subtype
    • Abstract: Publication date: Available online 2 July 2015
      Source:Pharmacological Research
      Author(s): Stefania Merighi , Pier Andrea Borea , Stefania Gessi
      Over the last two decades, diabetes mellitus has become one of the most challenging health problems worldwide. Diabetes mellitus, classified as type I and II, is a pathology concerning blood glucose level in the body. The nucleoside adenosine has long been known to affect insulin secretion, glucose homeostasis and lipid metabolism, through activation of four G protein coupled adenosine receptors (ARs), named A1, A2A, A2B and A3. Currently, the novel promising subtype to develop new drugs for diabetes treatment is the A2BAR subtype. The use of selective agonists and antagonists for A2BAR subtype in various diabetic animal models allowed us to identify several effects of A2BAR signaling in cell metabolism. In particular, the focus of this review is to summarize the studies on purinergic signaling associated with diabetes through A2BARs modulation.
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      PubDate: 2015-07-05T21:38:21Z
       
  • Quercetin inhibits the mTORC1/p70S6K signaling-mediated renal tubular
           epithelial-mesenchymal transition and renal fibrosis in diabetic
           nephropathy
    • Abstract: Publication date: Available online 4 July 2015
      Source:Pharmacological Research
      Author(s): Qian Lu , Xiao-Jun Ji , Yue-Xian Zhou , Xiao-Qin Yao , Yu-Qing Liu , Fan Zhang , Xiao-Xing Yin
      Quercetin is a classic flavonoid that inhibits the epithelial-mesenchymal transition (EMT) of tumor cells. However, the effects of quercetin on the EMT of renal tubular epithelial cells, a potential mechanism of renal fibrosis and important characteristic of diabetic nephropathy (DN), remain largely unknown. In the present study, we investigated the effects of quercetin on the EMT of two lines of renal tubular proximal epithelial cells (HK-2 and NRK-52E) induced with high glucose and renal fibrosis resulting from type 1 diabetes and tried to clarify the specific mechanisms underlying these effects. The in vitro results showed that the EMT of HK-2 and NRK-52E cells was induced by high glucose, and mTORC1/p70S6K was highly activated in these two cell lines cultured under high glucose. Quercetin effectively ameliorated the high glucose-induced EMT of HK-2 and NRK-52E cells and inhibited the activation of mTORC1/p70S6K. In vivo, diabetic rats showed a significant decline in renal function and severe renal fibrosis at 14 weeks after STZ injection. Furthermore, mTORC1/p70S6K was activated in the renal cortex of diabetic rats. Treatment with quercetin alleviated the decline in renal function, and the progression of renal fibrosis and inhibited mTORC1/p70S6K activation in the diabetic renal cortex. In addition, we examined the protein and mRNA levels of four transcriptional factors (snail, slug, twist and ZEB-1), which regulate E-cadherin expression at the transcriptional level both in vivo and in vitro. The results revealed that the elevated expression of snail and twist in HK-2 and NRK-52E cells cultured under high glucose and in the renal cortex of diabetic rats was inhibited by quercetin. These results demonstrated that quercetin ameliorates the EMT of HK-2 and NRK-52E cells induced by high glucose and renal fibrosis induced by diabetes, and these effects have been associated with the inhibition of the two transcriptional factors (snail and twist) and the activation of mTORC1/p70S6K.


      PubDate: 2015-07-05T21:38:21Z
       
  • Immune therapy of non-small cell lung cancer. The future
    • Abstract: Publication date: Available online 2 July 2015
      Source:Pharmacological Research
      Author(s): Antonio Bobbio , Marco Alifano
      Surgery is still the best treatment option of lung cancer but only one third of patients are operable and prognosis remains mediocre in operated patients, with the exception of initial stages. Medical treatment is fast moving towards new frontiers. New insights in the biology of cancer development led to discovery of new drugs, which are more effective as compared to conventional platinum based chemotherapy. A new approach to immunotherapy based on immune-check point represents a remarkable innovation in lung cancer treatment. Initial trials with anti PD-1 antibodies in metastatic patients provided results never observed with previously known drug categories. Several key question need to be answered to identify patients most likely to respond to anti PD-1/anti PD-L1 treatments, to assess the role of combined treatment modalities including immune check point receptor block (associations with surgery, chemotherapy, ITKs), and to boost host immune response, possibly by lowering his systemic inflammation and improving nutritional status.
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      PubDate: 2015-07-05T21:38:21Z
       
  • 5-HT2C SEROTONIN RECEPTOR BLOCKADE PREVENTS TAU PROTEIN
           HYPERPHOSPHORYLATION AND CORRECTS THE DEFECT IN HIPPOCAMPAL SYNAPTIC
           PLASTICITY CAUSED BY A COMBINATION OF ENVIRONMENTAL STRESSORS IN MICE
    • Abstract: Publication date: Available online 2 July 2015
      Source:Pharmacological Research
      Author(s): Carla Letizia Busceti , Paola Di Pietro , Barbara Riozzi , Anna Traficante , Francesca Biagioni , Robert Nisticò , Francesco Fornai , Giuseppe Battaglia , Ferdinando Nicoletti , Valeria Bruno
      Exposure to multimodal sensory stressors is an everyday occurrence and sometimes becomes very intense, such as during rave parties or other recreational events. A growing body of evidence suggests that strong environmental stressors might cause neuronal dysfunction on their own in addition to their synergistic action with illicit drugs. Mice were exposed to a combination of physical and sensory stressors that are reminiscent of those encountered in a rave party. However, this is not a model of rave because it lacks the rewarding properties of rave. A 14-hour exposure to environmental stressors caused an impairment of hippocampal long-term potentiation (LTP) and spatial memory, and an enhanced phosphorylation of tau protein in the CA1 and CA3 regions. These effects were transient andcritically depended on the activation of 5-HT2c serotonin receptors, which are highly expressed in the CA1 region. Acute systemic injection of theselective 5-HT2C antagonist, RS-102,221 (2 mg/kg, i.p., 2 min prior the onset of stress), prevented tau hyperphosphorylation and also corrected the defects in hippocampal LTP and spatial memory.These findings suggest that passive exposure to a combination of physical and sensory stressorscausesa reversible hippocampal dysfunction, which might compromise mechanisms of synaptic plasticity and spatial memory for a few days. Drugs that block 5-HT2C receptors might protect the hippocampus against the detrimental effect of environmental stressors.
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      PubDate: 2015-07-05T21:38:21Z
       
  • Emerging molecules in the interface between skeletal system and innate
           immunity
    • Abstract: Publication date: Available online 2 July 2015
      Source:Pharmacological Research
      Author(s): Kenta Maruyama , Shizuo Akira
      Despite the improved treatment of bone destruction, significant unmet medical need remains. For example, there is a limited benefit of continued bisphosphonate therapy for osteoporotic patients, and only minor populations of rheumatoid arthritis patients obtain biologic-free remission. Therefore, the identification of a novel therapeutic target for bone destructive diseases remains an important issue in the field of skeletal biology. To date there has been little progress in identifying osteo-innate-immunological regulators that could be used for the prophylactic treatment of inflammatory bone destruction. Recently, we identified several new molecules that are critical osteo-innate-immunological regulators by using gene targeting technology. These findings may offer an invaluable opportunity to regulate bone-destructive diseases, such as osteoporosis and rheumatoid arthritis.
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      PubDate: 2015-07-05T21:38:21Z
       
  • CB2 and TRPV1 receptors oppositely modulate in vitro human osteoblast
           activity
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Francesca Rossi , Giulia Bellini , Chiara Tortora , Maria Ester Bernardo , Livio Luongo , Antonella Conforti , Nadia Starc , Iolanda Manzo , Bruno Nobili , Franco Locatelli , Sabatino Maione
      In the current study, we have investigated the effect of CB2 and TRPV1 receptor ligands on in vitro osteoblasts from bone marrow of human healthy donors. A pivotal role for the endocannabinoid/endovanilloid system in bone metabolism has been highlighted. We have demonstrated a functional cross-talk between CB2 and TRPV1 in human osteoclasts, suggesting these receptors as new pharmacological target for the treatment of bone resorption disease as osteoporosis. Moreover, we have shown the presence of these receptors on human mesenchimal stem cells, hMSCs. Osteoblasts are mononucleated cells originated from hMSCs by the essential transcription factor runt-related transcription factor 2 and involved in bone formation via the synthesis and release of macrophage colony-stimulating factor, receptor activator of nuclear factor kappa-B ligand and osteoprotegerin. For the first time, we show that CB2 and TRPV1 receptors are both expressed on human osteoblasts together with enzymes synthesizing and degrading endocannabinoids/endovanilloids, and oppositely modulate human osteoblast activity in culture in a way that the CB2 receptor stimulation improves the osteogenesis whereas TRPV1 receptor stimulation inhibits it.
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      PubDate: 2015-07-05T21:38:21Z
       
  • Molecular mechanism matters: Benefits of mechanistic computational models
           for drug development
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Lindsay E. Clegg , Feilim Mac Gabhann
      Making drug development a more efficient and cost-effective process will have a transformative effect on human health. A key, yet underutilized, tool to aid in this transformation is mechanistic computational modeling. By incorporating decades of hard-won prior knowledge of molecular interactions, cellular signaling, and cellular behavior, mechanistic models can achieve a level of predictiveness that is not feasible using solely empirical characterization of drug pharmacodynamics. These models can integrate diverse types of data from cell culture and animal experiments, including high-throughput systems biology experiments, and translate the results into the context of human disease. This provides a framework for identification of new drug targets, measurable biomarkers for drug action in target tissues, and patient populations for which a drug is likely to be effective or ineffective. Additionally, mechanistic models are valuable in virtual screening of new therapeutic strategies, such as gene or cell therapy and tissue regeneration, identifying the key requirements for these approaches to succeed in a heterogeneous patient population. These capabilities, which are distinct from and complementary to those of existing drug development strategies, demonstrate the opportunity to improve success rates in the drug development pipeline through the use of mechanistic computational models.
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      PubDate: 2015-06-26T14:26:48Z
       
  • A novel inhaled Syk inhibitor blocks mast cell degranulation and early
           asthmatic response
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Isabel Ramis , Raquel Otal , Cristina Carreño , Anna Domènech , Peter Eichhorn , Adelina Orellana , Mónica Maldonado , Jorge De Alba , Neus Prats , Joan-Carles Fernández , Bernat Vidal , Montserrat Miralpeix
      Spleen tyrosine kinase (Syk) is essential for signal transduction of immunoreceptors. Inhibition of Syk abrogates mast cell degranulation and B cell responses. We hypothesized that Syk inhibition in the lung by inhaled route could block airway mast cells degranulation and the early asthmatic response without the need of systemic exposure. We discovered LAS189386, a novel Syk inhibitor with suitable properties for inhaled administration. The aim of this study was to characterize the in vitro and in vivo profile of LAS189386. The compound was profiled in Syk enzymatic assay, against a panel of selected kinases and in Syk-dependent cellular assays in mast cells and B cells. Pharmacokinetics and in vivo efficacy was assessed by intratracheal route. Airway resistance and mast cell degranulation after OVA challenge was evaluated in an ovalbumin-sensitized Brown Norway rat model. LAS189386 potently inhibits Syk enzymatic activity (IC50 7.2nM), Syk phosphorylation (IC50 41nM), LAD2 cells degranulation (IC50 56nM), and B cell activation (IC50 22nM). LAS189386 inhibits early asthmatic response and airway mast cell degranulation without affecting systemic mast cells. The present results support the hypothesis that topical inhibition of Syk in the lung, without systemic exposure, is sufficient to inhibit EAR in rats. Syk inhibition by inhaled route constitutes a promising therapeutic option for asthma.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Retinoic acid ameliorates blood–brain barrier disruption following
           ischemic stroke in rats
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Liang Kong , Yue Wang , Xiao-Jing Wang , Xiao-Tong Wang , Yan Zhao , Li-Mei Wang , Zhe-Yu Chen
      The intact blood–brain barrier (BBB) is essential in maintaining a stabilized milieu for synaptic and neuronal functions. Disruptions of the BBB have been observed following ischemia and reperfusion, both in patients and in animal models. Retinoic acid (RA), which plays crucial roles during vertebrate organogenesis, has been reported to participate in BBB development. However, it remains unclear whether RA could prevent BBB disruption in ischemic stroke. In this study, we determined that the injection of RA for 4 consecutive days resulted in increases in zonula occludens-1 (ZO-1) and vascular endothelial cadherin (VE-cadherin) expression, which are crucial components of the BBB structure. We demonstrated that RA pretreatment could alleviate the ischemic stroke-induced enlargement of vascular permeability, which is related to the up-regulated expression of ZO-1 and VE-cadherin proteins in rat models of middle cerebral artery occlusion (MCAO). Our findings further corroborated that the RA protective effect on BBB is dependent on RA receptor α in vitro oxygen–glucose deprivation (OGD) treatment. Significantly, RA administration immediately after MCAO reduced tissue plasminogen activator (tPA)-induced intracerebral hemorrhage (ICH) and ameliorated neurological deficits 24h after ischemic stroke. Taken together, our results suggest that RA may become a new therapeutic approach to prevent BBB dysfunction and tPA-induced ICH in ischemic stroke.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Nephrotoxicity of ibandronate and zoledronate in Wistar rats with normal
           renal function and after unilateral nephrectomy
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): R. Bergner , B. Siegrist , N. Gretz , G. Pohlmeyer-Esch , B. Kränzlin
      A previous animal study compared the nephrotoxic effect of ibandronate (IBN) and zoledronate (ZOL), but interpretation of these study results was limited because of the model of minimal nephrotoxic dosage with a dosage ratio of 1:3. The present study investigated the nephrotoxicity of ibandronate and zoledronate in a 1.5:1 dose ratio, as used in clinical practice and compared the nephrotoxicity in rats with normal and with mildly to moderately impaired renal function. We compared rats with normal renal function (SHAM) and with impaired renal function after unilateral nephrectomy (UNX), treated either with ibandronate 1.5mg/kg, zoledronate 1mg/kg or placebo once (1×) or nine (9×) times. Renal function and markers of tubular toxicity were measured over a 27 week period. After last bisphosphonate treatment the rats were sacrificed and kidneys examined histologically. All bisphosphonate treated animals showed a significant tubular toxicity, which was temporary except in the ZOL-UNX-9×-group. Also the renal function was only transiently reduced except in the ZOL-UNX-9×-group. Histologically, bisphosphonate treatment led to cortical tubuloepithelial degeneration/necrosis and medullary tubuloepithelial swelling which were slightly more pronounced in ibandronate treated animals, when compared to zoledronate treated animals, especially with impaired renal function. In contrast to the previous study we found a similar nephrotoxicity of ibandronate and zoledronate in rats with normal renal function. In rats with impaired renal function the peak of toxicity had not even been fully reached until end of experiment in the zoledronate treated animals. The peak of toxicity seems to be more severe and delayed in rats with impaired renal function compared with rats with normal renal function.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Ilexgenin A inhibits endoplasmic reticulum stress and ameliorates
           endothelial dysfunction via suppression of TXNIP/NLRP3 inflammasome
           activation in an AMPK dependent manner
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Yi Li , Jie Yang , Mei-Hong Chen , Qiang Wang , Min-Jian Qin , Tong Zhang , Xiao-Qing Chen , Bao-Lin Liu , Xiao-Dong Wen
      Ilexgenin A is a natural triterpenoid with beneficial effects on lipid disorders. This study aimed to investigate the effects of ilexgenin A on endothelial homeostasis and its mechanisms. Palmitate (PA) stimulation induced endoplasmic reticulum stress (ER stress) and subsequent thioredoxin-interacting protein (TXNIP)/NLRP3 inflammasome activation in endothelial cells, leading to endothelial dysfunction. Ilexgenin A enhanced LKB1-dependent AMPK activity and improved ER stress by suppression of ROS-associated TXNIP induction. However, these effects were blocked by knockdown of AMPKα, indicating AMPK is essential for its action in suppression of ER stress. Meanwhile, ilexgenin A inhibited NLRP3 inflammasome activation by down-regulation of NLRP3 and cleaved caspase-1 induction, and thereby reduced IL-1β secretion. It also inhibited inflammation and apoptosis exposed to PA insult. Consistent with these results in endothelial cells, ilexgenin A attenuated ER stress and restored the loss of eNOS activity in vascular endothelium, and thereby improved endothelium-dependent vasodilation in rat aorta. A further analysis in high-fat fed mice showed that oral administration of ilexgenin A blocked ER stress/NLRP3 activation with reduced ROS generation and increased NO production in vascular endothelium, well confirming the beneficial effect of ilexgenin A on endothelial homeostasis in vivo. Taken together, these results show ER stress-associated TXNIP/NLRP3 inflammasome activation was responsible for endothelial dysfunction and ilexgenin A ameliorated endothelial dysfunction by suppressing ER-stress and TXNIP/NLRP3 inflammasome activation with a regulation of AMPK. This finding suggests that the application of ilexgenin A is useful in the management of cardiovascular diseases in obesity.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Novel frontiers in calcium signaling: A possible target for chemotherapy
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Massimo Bonora , Carlotta Giorgi , Paolo Pinton
      Intracellular calcium (Ca2+) is largely known as a second messenger that is able to drive effects ranging from vesicle formation to muscle contraction, energy production and much more. In spite of its physiological regulation, Ca2+ is a strategic tool for regulating apoptosis, especially during transmission between the endoplasmic reticulum and the mitochondria. Contact sites between these organelles are well-defined as signaling platforms where oncogenes and oncosuppressors can exert anti/pro-apoptotic activities. Recent advances from in vivo investigations into these regions highlight the role of the master oncosuppressor p53 in regulating Ca2+ transmission and apoptosis, and we propose that Ca2+ signals are relevant targets when developing new therapeutic approaches.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Dihydromyricetin improves glucose and lipid metabolism and exerts
           anti-inflammatory effects in nonalcoholic fatty liver disease: A
           randomized controlled trial
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Shihui Chen , Xiaolan Zhao , Jing Wan , Li Ran , Yu Qin , Xiaofang Wang , Yanxiang Gao , Furong Shu , Yong Zhang , Peng Liu , Qianyong Zhang , Jundong Zhu , Mantian Mi
      Ampelopsis grossedentata, a medicinal and edible plant, has been widely used in China for hundreds of years, and dihydromyricetin is the main active ingredient responsible for its various biological actions. We investigated the effects of dihydromyricetin on glucose and lipid metabolism, inflammatory mediators and several biomarkers in nonalcoholic fatty liver disease. In a double-blind clinical trial, sixty adult nonalcoholic fatty liver disease patients were randomly assigned to receive either two dihydromyricetin or two placebo capsules (150mg) twice daily for three months. The serum levels of alanine, aspartate aminotransferase, γ-glutamyl transpeptidase, glucose, low-density lipoprotein-cholesterol and apolipoprotein B, and the homeostasis model assessment of insulin resistance (HOMA-IR) index were significantly decreased in the dihydromyricetin group compared with the placebo group. In the dihydromyricetin group, the serum levels of tumor necrosis factor-alpha, cytokeratin-18 fragment and fibroblast growth factor 21 were decreased, whereas the levels of serum adiponectin were increased at the end of the study. We conclude that dihydromyricetin supplementation improves glucose and lipid metabolism as well as various biochemical parameters in patients with nonalcoholic fatty liver disease, and the therapeutic effects of dihydromyricetin are likely attributable to improved insulin resistance and decreases in the serum levels of tumor necrosis factor-alpha, cytokeratin-18, and fibroblast growth factor 21.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Thymoquinone prevents RANKL-induced osteoclastogenesis activation and
           osteolysis in an in vivo model of inflammation by suppressing NF-KB and
           MAPK Signalling
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Dinesh Thummuri , Manish Kumar Jeengar , Shweta Shrivastava , Harishankar Nemani , Ravindar Naik Ramavat , Pradip Chaudhari , V.G.M. Naidu
      Osteoclasts are multinuclear giant cells responsible for bone resorption in inflammatory bone diseases such as osteoporosis, rheumatoid arthritis and periodontitis. Because of deleterious side effects with currently available drugs the search continues for novel effective and safe therapies. Thymoquinone (TQ), the major bioactive component of Nigella sativa has been investigated for its anti-inflammatory, antioxidant and anticancer activities. However, its effects in osteoclastogenesis have not been reported. In the present study we show for the first time that TQ inhibits nuclear factor-KB ligand (RANKL) induced osteoclastogenesis in RAW 264.7 and primary bone marrow derived macrophages (BMMs) cells. RANKL induced osteoclastogenesis is associated with increased expression of multiple transcription factors via activation of NF-KB, MAPKs signalling and reactive oxygen species (ROS). Mechanistically TQ blocked the RANKL induced NF-KB activation by attenuating the phosphorylation of IkB kinase (IKKα/β). Interestingly, in RAW 264.7 cells TQ inhibited the RANKL induced phosphorylation of MAPKs and mRNA expression of osteoclastic specific genes such as TRAP, DC-STAMP, NFATc1 and c-Fos. In addition, TQ also decreased the RANKL stimulated ROS generation in macropahges (RAW 264.7) and H2O2 induced ROS generation in osteoblasts (MC-3T3-E1). Consistent with in vitro results, TQ inhibited lipopolysaccharide (LPS) induced bone resorption by suppressing the osteoclastogenesis. Indeed, micro-CT analysis showed that bone mineral density (BMD) and bone architecture parameters were positively modulated by TQ. Taken together our data demonstrate that TQ has antiosteoclastogenic effect by inhibiting inflammation induced activation of MAPKs, NF-KB and ROS generation followed by suppressing the gene expression of c-Fos and NFATc1 in osteoclast precursors.
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      PubDate: 2015-06-26T14:26:48Z
       
  • The exacerbating roles of CCAAT/enhancer-binding protein homologous
           protein (CHOP) in the development of bleomycin-induced pulmonary fibrosis
           and the preventive effects of tauroursodeoxycholic acid (TUDCA) against
           pulmonary fibrosis in mice
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Yuta Tanaka , Yoichi Ishitsuka , Marina Hayasaka , Yusei Yamada , Keishi Miyata , Motoyoshi Endo , Yuki Kondo , Hiroshi Moriuchi , Mitsuru Irikura , Ken-ichiro Tanaka , Tohru Mizushima , Yuichi Oike , Tetsumi Irie
      The purpose of this study was to evaluate the role of CCAAT/enhancer-binding protein homologous protein (CHOP), an important transcription factor that regulates the inflammatory reaction during the endoplasmic reticulum (ER) stress response, in the development of pulmonary fibrosis induced by bleomycin (BLM) in mice. An intratracheal injection of BLM transiently increased the expression of CHOP mRNA and protein in an early phase (days 1 and 3) in mice lungs. BLM-induced pulmonary fibrosis was significantly attenuated in Chop gene deficient (Chop KO) mice, compared with wild-type (WT) mice. Furthermore, the inflammatory reactions evaluated by protein concentration, the total number of leucocytes and neutrophils in the bronchoalveolar lavage fluid (BALF), the mRNA expression of interleukin 1b and caspase 11, and the apoptotic cell death were suppressed in Chop KO mice compared with those in WT mice. In addition, administration of tauroursodeoxycholic acid (TUDCA), a pharmacological agent that can inhibit CHOP expression, inhibited the BLM-induced pulmonary fibrosis and inflammation, and the increase in Chop mRNA expression in WT mice in a dose-dependent manner. These results suggest that the ER stress-induced transcription factor, CHOP, at least in part, plays an important role in the development of BLM-induced pulmonary fibrosis in mice, and that the inhibition of CHOP expression by a pharmacological agent, such as TUDCA, may be a promising strategy for the prevention of pulmonary fibrosis.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Targeting matrix metalloproteinases with intravenous doxycycline in severe
           sepsis – A randomised placebo-controlled pilot trial
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Eija Nukarinen , Taina Tervahartiala , Miia Valkonen , Marja Hynninen , Elina Kolho , Ville Pettilä , Timo Sorsa , Janne Backman , Johanna Hästbacka
      An overwhelming inflammatory process is the hallmark of severe sepsis and septic shock. Matrix metalloproteinases (MMPs)-8 and -9 are released from neutrophils and activated in sepsis to participate in inflammation in several ways. High levels of MMP-8 may associate with increased ICU mortality. The activity of MMP-8 and -9 is regulated by a natural inhibitor, tissue inhibitor of metalloproteinases-1 (TIMP-1). Moreover, MMPs are chemically inhibited by tetracycline-group antibiotics, such as doxycycline. We therefore aimed to study plasma concentration and MMP inhibition after intravenous doxycycline in critically ill patients with severe sepsis and septic shock in a prospective, randomised, placebo-controlled double-blinded pilot trial. Twenty-four patients with severe sepsis or septic shock were randomised in 3 groups. Group 1 received 200, 100 and 100mg, group 2 100, 50 and 50mg of intravenous doxycycline and group 3 placebo on three consecutive days. We measured doxycycline concentrations from baseline up to day 5. MMPs and TIMP-1 concentrations were measured from baseline up to day 10 of study and we compared their changes over time from baseline to 72h and from baseline to 120h. Data from 23 patients were analysed. At 72h all patients in group 1 showed doxycycline concentrations >1mg/l, whereas none in group 2 did. No serious adverse effects of the drug were recorded. We observed no differences over time up to 72 or up to 120h in the concentrations or activities of MMP-8, -9 or TIMP-1 in any of the groups. We found intravenous doxycycline 100, 50 and 50mg to be adequate to achieve a sub-antimicrobial concentration in patients with severe sepsis or septic shock but having no impact on MMP-8, -9 or TIMP-1 concentrations or activities.
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      PubDate: 2015-06-26T14:26:48Z
       
  • The MITF family of transcription factors: Role in endolysosomal
           biogenesis, Wnt signaling, and oncogenesis
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Diego Ploper , Edward M. De Robertis
      Canonical Wnt signaling influences cellular fate and proliferation through inhibition of Glycogen Synthase Kinase (GSK3) and the subsequent stabilization of its many substrates, most notably β-Catenin, a transcriptional co-activator. MITF, a melanoma oncogene member of the microphthalmia family of transcription factors (MiT), was recently found to contain novel GSK3 phosphorylation sites and to be stabilized by Wnt. Other MiT members, TFEB and TFE3, are known to play important roles in cellular clearance pathways by transcriptionally regulating the biogenesis of lysosomes and autophagosomes via activation of CLEAR elements in gene promoters of target genes. Recent studies suggest that MITF can also upregulate many lysosomal genes. MiT family members are dysregulated in cancer and are considered oncogenes, but the underlying oncogenic mechanisms remain unclear. Here we review the role of MiT members, including MITF, in lysosomal biogenesis, and how cancers overexpressing MITF, TFEB or TFE3 could rewire the lysosomal pathway, inhibit cellular senescence, and activate Wnt signaling by increasing sequestration of negative regulators of Wnt signaling in multivesicular bodies (MVBs). Microarray studies suggest that MITF expression inhibits macroautophagy. In melanoma the MITF-driven increase in MVBs generates a positive feedback loop between MITF, Wnt, and MVBs.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Exploring the various aspects of the pathological role of vascular
           endothelial growth factor (VEGF) in diabetic retinopathy
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Tapan Behl , Anita Kotwani
      Diabetic retinopathy, a sight-threatening microvascular complication of diabetes mellitus, is initiated by retinal endothelial dysfunction and succeeded by various pathological events, eventually resulting in vision-loss. These events are regulated by numerous mediators, including vascular endothelial growth factor (VEGF), which induces the progression of various events characterizing diabetic retinopathy, such as neovascularization and macular edema. VEGF is physiologically required for regulating proliferation and assembling of endothelial cells, during vasculogenesis, as well as for their maintenance and survival throughout the lifetime of blood vessels. However, various pathological conditions are induced in the body during diabetes (such as ischemia, oxidative stress and overactivation of protein kinase C), which upregulate the expression of VEGF, thereby deviating it from its physiological role and leading to various pathological demonstrations such as angiogenesis, increased permeability of endothelium, decreased inhibition of pro-apoptotic proteins and activation of various other inflammatory mediators. Such events disrupt vascular homeostasis and play key roles in the pathophysiology of diabetic retinopathy. Hence, acknowledging various VEGF-mediated pathways helps in understanding the deeper aspects related to progression of this disorder. Targeting and inhibiting VEGF-mediated disease progression might provide an effective alternative therapy and hence prove beneficial in the treatment of diabetic retinopathy.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Calumenin and fibulin-1 on tumor metastasis: Implications for pharmacology
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Pengli Zheng , Qiao Wang , Junlin Teng , Jianguo Chen
      Tumor metastasis is a key cause of cancer mortality, and inhibiting migration of cancer cells is one of the major directions of anti-metastatic drug development. Calumenin and fibulin-1 are two extracellular proteins that synergistically inhibit cell migration and tumor metastasis, and could potentially be served as targets for pharmacological research of anti-metastatic drugs. This review briefly introduces the multi-function of these two proteins, and discusses the mechanism of how they regulate cell migration and tumor metastasis.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Skeletal muscle atrophy: Potential therapeutic agents and their mechanisms
           of action
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Vikas Dutt , Sanjeev Gupta , Rajesh Dabur , Elisha Injeti , Ashwani Mittal
      Over the last two decades, new insights into the etiology of skeletal muscle wasting/atrophy under diverse clinical settings including denervation, AIDS, cancer, diabetes, and chronic heart failure have been reported in the literature. However, the treatment of skeletal muscle wasting remains an unresolved challenge to this day. About nineteen potential drugs that can regulate loss of muscle mass have been reported in the literature. This paper reviews the mechanisms of action of all these drugs by broadly classifying them into six different categories. Mechanistic data of these drugs illustrate that they regulate skeletal muscle loss either by down-regulating myostatin, cyclooxygenase2, pro-inflammatory cytokines mediated catabolic wasting or by up-regulating cyclic AMP, peroxisome proliferator-activated receptor gamma coactivator-1α, growth hormone/insulin-like growth factor1, phosphatidylinositide 3-kinases/protein kinase B(Akt) mediated anabolic pathways. So far, five major proteolytic systems that regulate loss of muscle mass have been identified, but the majority of these drugs control only two or three proteolytic systems. In addition to their beneficial effect on restoring the muscle loss, many of these drugs show some level of toxicity and unwanted side effects such as dizziness, hypertension, and constipation. Therefore, further research is needed to understand and develop treatment strategies for muscle wasting. For successful management of skeletal muscle wasting either therapeutic agent which regulates all five known proteolytic systems or new molecular targets/proteolytic systems must be identified.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Kaempferol and inflammation: From chemistry to medicine
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Kasi Pandima Devi , Dicson Sheeja Malar , Seyed Fazel Nabavi , Antoni Sureda , Jianbo Xiao , Seyed Mohammad Nabavi , Maria Daglia
      Inflammation is an important process of human healing response, wherein the tissues respond to injuries induced by many agents including pathogens. It is characterized by pain, redness and heat in the injured tissues. Chronic inflammation seems to be associated with different types of diseases such as arthritis, allergies, atherosclerosis, and even cancer. In recent years natural product based drugs are considered as the novel therapeutic strategy for prevention and treatment of inflammatory diseases. Among the different types of phyto-constituents present in natural products, flavonoids which occur in many vegetable foods and herbal medicines are considered as the most active constituent, which has the potency to ameliorate inflammation under both in vitro and in vivo conditions. Kaempferol is a natural flavonol present in different plant species, which has been described to possess potent anti-inflammatory properties. Despite the voluminous literature on the anti-inflammatory effects of kaempferol, only very limited review articles has been published on this topic. Hence the present review is aimed to provide a critical overview on the anti-inflammatory effects and the mechanisms of action of kaempferol, based on the current scientific literature. In addition, emphasis is also given on the chemistry, natural sources, bioavailability and toxicity of kaempferol.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Ketamine and suicidal ideation in depression: Jumping the gun?
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): R. Rajkumar , J. Fam , E.Y.M. Yeo , G.S. Dawe
      Depression and suicide are known to be intricately entwined but the neurobiological basis underlying this association is yet to be understood. Ketamine is an N-methyl d-aspartate (NMDA) receptor antagonist used for induction and maintenance of general anaesthesia but paradoxically its euphoric effects lead to its classification under drugs of abuse. The serendipitous finding of rapid-onset antidepressant action of subanaesthetic dosing with ketamine by intravenous infusion has sparked many preclinical and clinical investigations. A remarkable suppression of suicidal ideation was also reported in depressed patients. This review focuses on the clinical trials on ketamine that reported remedial effects in suicidal ideation in depression and addresses also the molecular mechanisms underlying the antidepressant and psychotomimetic actions of ketamine. The neuropsychiatric profile of subanaesthetic doses of ketamine encourages its use in the management of suicidal ideation that could avert emergent self-harm or suicide. Finally, the need for neuroimaging studies in suicidal patients to identify the brain region specific and temporal effects of ketamine, and the possibility of employing ketamine as an experimental tool in rodent-based studies to study the mechanisms underlying suicidal behaviour are highlighted.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Novel insight into drug repositioning: Methylthiouracil as a case in point
    • Abstract: Publication date: Available online 25 June 2015
      Source:Pharmacological Research
      Author(s): Moon-Chang Baek , Byeongjin Jung , Hyejin Kang , Hyun-Shik Lee , Jong-Sup Bae
      Drug repositioning refers to the development of existing drugs for new indications. These drugs may have (I) failed to show efficacy in late stage clinical trials without safety issues; (II) stalled in the development for commercial reasons; (III) passed the point of patent expiry; or (IV) are being explored in new geographic markets. Over the past decade, pressure on the pharmaceutical industry caused by the ‘innovation gap’ owing to rising development costs and stagnant product output have become major reasons for the growing interest in drug repositioning. Companies that offer a variety of broad platforms for identifying new indications have emerged; some have been successful in building their own pipelines of candidates with reduced risks and timelines associated with further clinical development. The business models and platforms offered by these companies will be validated if they are able to generate positive proof-of-concept clinical data for their repositioned compounds. This review describes the strategy of biomarker-guided repositioning of chemotherapeutic drugs for inflammation therapy, considering the repositioning of methylthiouracil (MTU), an antithyroid drug, as a potential anti-inflammatory reagent.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Identification of key residues involved in the activation and signaling
           properties of dopamine D3 receptor
    • Abstract: Publication date: Available online 23 June 2015
      Source:Pharmacological Research
      Author(s): Kokila Kota , Eldo V. Kuzhikandathil , Milad Afrasiabi , Brett Lacy , Maria Kontoyianni , A. Michael Crider , Daniel Song
      The dopamine D3 receptor exhibits agonist-dependent tolerance and slow response termination (SRT) signaling properties that distinguish it from the closely-related D2 receptors. While amino acid residues important for D3 receptor ligand binding have been identified, the residues involved in activation of D3 receptor signaling and induction of signaling properties have not been determined. In this paper, we used cis and trans isomers of a novel D3 receptor agonist, 8-OH-PBZI, and site-directed mutagenesis to identify key residues involved in D3 receptor signaling function. Our results show that trans-8-OH-PBZI, but not cis-8-OH-PBZI, elicit the D3 receptor tolerance and SRT properties. We show that while both agonists require a subset of residues in the orthosteric binding site of D3 receptors for activation of the receptor, the ability of the two isomers to differentially induce tolerance and SRT is mediated by interactions with specific residues in the sixth transmembrane helix and third extracellular loop of the D3 receptor. We also show that unlike cis-8-OH-PBZI, which is a partial agonist at the dopamine D2S receptor and full agonist at dopamine D2L receptor, trans-8-OH-PBZI is a full agonist at both D2S and D2L receptors. The different effect of the two isomers on D3 receptor signaling properties and D2S receptor activation correlated with differential effects of the isomers on agonist-induced mouse locomotor activity. The two isomers of 8-OH-PBZI represent novel pharmacological tools for in silico D3 and D2 receptor homology modeling and for determining the role of D3 receptor tolerance and SRT properties in signaling and behavior.
      Graphical abstract image

      PubDate: 2015-06-26T14:26:48Z
       
  • Neuronal effects of a nickel-piperazine/NO donor complex in rodents
    • Abstract: Publication date: Available online 18 June 2015
      Source:Pharmacological Research
      Author(s): Maria Domenica Sanna , Martina Monti , Luigi Casella , Riccardo Roggeri , Nicoletta Galeotti , Lucia Morbidelli
      In the brain, NO is a very important molecule in the regulation of cerebral and extra cerebral cranial blood flow and arterial diameters. It is also importantly involved in many neuronal functions and innumerable roles of NO in many brain related disorders including epilepsy, schizophrenia, drug addiction, anxiety, major depression, have been postulated. The present study aimed to explore the neuronal role exerted by the metal-nonoate compound Ni(PipNONO)Cl, a novel NO donor whose vascular protective effects have been recently demonstrated. Ni(PipNONO)Cl showed antidepressant-like properties in the tail suspension test and antiamnesic activity in the passive avoidance test in the absence of any hypernociceptive response to a mechanical stimulus. These effects were related to the NO-releasing properties of the compound within the central nervous system as demonstrated by the increase of iNOS levels in the brain, spinal cord and dura mater. The modulation of neuronal functions appeared after acute and repeated treatment, showing the lack of any tolerance to neuronal effects. At the dose used (10mg/kg i.p.), Ni(PipNONO)Cl did not induce any visible sign of toxicity and experiments were performed in the absence of locomotor impairments. In addition to the NO-related neuronal activities of Ni(PipNONO)Cl, the decomposition control compound Ni(Pip)Cl2 showed anxiogenic-like and procognitive effects. The present findings showed neuronal modulatory activity of Ni(PipNONO)Cl through a NO-mediated mechanism. The activities of the decomposition compound Ni(Pip)Cl2 attributed to Ni(PipNONO)Cl the capability to modulate additional neuronal functions independently from NO releasing properties extending and improving the therapeutic perspectives of the NO donor.
      Graphical abstract image

      PubDate: 2015-06-26T14:26:48Z
       
  • A2BP1 gene polymorphisms association with olanzapine-induced weight gain
    • Abstract: Publication date: Available online 17 June 2015
      Source:Pharmacological Research
      Author(s): Licai Dong , Hao Yan , Xuebing Huang , Xiaofeng Hu , Yongfeng Yang , Cuicui Ma , Bo Du , Tianlan Lu , Chao Jin , Lifang Wang , Hao Yu , Zheng Dong , Wenqiang Li , Yanyan Ruan , Hongyan Zhang , Hongxing Zhang , Weifeng Mi , Wenbin Ma , Keqing Li , Luxian Lv , Dai Zhang , Weihua Yue
      The ataxin-2 binding protein 1 (A2BP1) gene is reported to be one of the susceptibility genes in schizophrenia, autism, and obesity. The aim of this study was to explore the association of A2BP1 gene polymorphisms with antipsychotic induced weight gain (AIWG) in Chinese Han population. Three hundred and twenty-eight patients with schizophrenia were followed-up for an 8-week period of treatment with olanzapine. The fasting weights of 328 patients were measured before and after the 8-week course of treatment. Four single nucleotide polymorphisms (SNPs: rs8048076, rs1478697, rs10500331, and rs4786847) of the A2BP1 gene were genotyped by polymerase chain reaction (PCR). We analyzed putative association of A2BP1 polymorphisms with AIWG of olanzapine using linear regression analysis and found that SNP rs1478697 was significantly associated with AIWG caused by olanzapine (p =0.0012; Bonferroni corrected p =0.0048). The association was replicated in another independent sample including 208 first-episode and drug-naïve patients presenting with schizophrenia after a 4-week treatment with olanzapine (p =0.0092; Bonferroni corrected p =0.0368; meta p =5.33×10−5). To explore the biological plausibility of A2BP1 in the pathogenesis of AIWG, we made expression analyses and eQTL analyses; these analyses showed that A2BP1 was highly expressed in whole brain tissues using the HBT database, and that rs1478697 has an expression quantitative trait locus effect in human cerebellar cortex tissues using the BRAINEAC database (p =2.50E−04). In conclusion, the rs1478697 in A2BP1 may be associated with AIWG induced by 8-week treatment with olanzapine.
      Graphical abstract image

      PubDate: 2015-06-26T14:26:48Z
       
 
 
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