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Publisher: Elsevier   (Total: 2812 journals)

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Soil Dynamics and Earthquake Engineering     Hybrid Journal   (Followers: 8, SJR: 1.482, h-index: 45)
Soils and foundations     Full-text available via subscription   (SJR: 1.669, h-index: 39)
Solar Energy     Hybrid Journal   (Followers: 17, SJR: 2.291, h-index: 85)
Solar Energy Materials and Solar Cells     Hybrid Journal   (Followers: 26, SJR: 2.331, h-index: 107)
Solid State Communications     Hybrid Journal   (Followers: 7, SJR: 0.874, h-index: 93)
Solid State Ionics     Hybrid Journal   (Followers: 5, SJR: 0.938, h-index: 132)
Solid State Nuclear Magnetic Resonance     Hybrid Journal   (Followers: 3, SJR: 1.107, h-index: 43)
Solid State Physics     Full-text available via subscription   (SJR: 0.272, h-index: 18)
Solid State Sciences     Hybrid Journal   (Followers: 6, SJR: 0.717, h-index: 54)
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: 17, 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: 4)
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: 17, 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 Organic Chemistry     Full-text available via subscription   (Followers: 5)
Studies in Physical and Theoretical Chemistry     Full-text available via subscription   (Followers: 5)
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: 2)
Sugar Series     Full-text available via subscription   (Followers: 1)
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: 33, SJR: 1.178, h-index: 109)
Surface Science     Hybrid Journal   (Followers: 18, 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: 5, 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: 10, 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: 33, 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 Protein Chemistry     Full-text available via subscription   (Followers: 2)
Techniques in Regional Anesthesia and Pain Management     Hybrid Journal   (Followers: 12, SJR: 0.134, h-index: 10)
Techniques in Vascular and Interventional Radiology     Full-text available via subscription   (Followers: 3, 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)

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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  [2812 journals]
  • A historical overview of protein kinases and their targeted small molecule
           inhibitors
    • Abstract: Publication date: Available online 21 July 2015
      Source:Pharmacological Research
      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.
      Graphical abstract image

      PubDate: 2015-07-22T22:01:15Z
       
  • Mycophenolic mofetil optimized pharmacokinetic modelling, and
           exposure-effect associations in adult heart transplant recipients
    • Abstract: Publication date: Available online 17 July 2015
      Source:Pharmacological Research
      Author(s): Jean-Baptiste Woillard, Franck Saint-Marcoux, Caroline Monchaud, Rym Youdarene, Lucie Pouche, Pierre Marquet
      Mycophenolic acid (MPA) area under the curve (AUC) has been associated with graft outcome. The aims of our study were: (1) to develop pharmacokinetic tools to optimize MPA inter-dose AUC estimation in heart transplant patients; and (2) to investigate the relationships between acute allograft rejection and MPA AUC, trough level (C0) or mycophenolate mofetil (MMF) dose. Two independent modeling approaches (parametric and non parametric) were used to fit 56 rich MPA pharmacokinetic (PK) profiles collected from 40 adult heart transplant recipients enrolled in the PIGREC study, receiving MMF and a calcineurin inhibitor (CNI), in the first year post-transplantation. In addition, associations between drug exposure (MPA C0, AUC and MMF dose) and acute rejection or MMF adverse events were investigated using time-dependent Cox models with stratification on the type of calcineurin inhibitor. Exposure threshold values were investigated using ROC curve analysis. The 2 models developed fit adequately the data and the use of their combination yielded 100% consistency with the measured AUC in terms of strategy of dose adjustment (maintain, increase or decrease). MPA measured AUC adjusted on CNI exposure was significantly associated with rejection (per unit increase: HR [95% CI]=0.97 [0.95–0.99], p =0.0122), while no effect was shown for adverse events attributable to MMF. An AUC threshold of 50mg×h/L was proposed (sensitivity=77%, specificity=25%) beyond which the risk of rejection was significantly increased (low vs. high: HR=3.48 [1.21–10.0], p =0.0204). The tools developed have already been made available to the heart transplant community on our ISBA website (https://pharmaco.chu-limoges.fr).
      Graphical abstract image

      PubDate: 2015-07-18T22:00:04Z
       
  • From Pathogenesis to Therapy - Perspective on treatment strategies in
           fibrotic diseases
    • Abstract: Publication date: Available online 16 July 2015
      Source:Pharmacological Research
      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.
      Graphical abstract image

      PubDate: 2015-07-18T22:00:04Z
       
  • Use of Mometasone furoate in prolonged treatment of experimental spinal
           cord injury in mice: A comparative study of three different
           glucocorticoids
    • Abstract: Publication date: Available online 17 July 2015
      Source:Pharmacological Research
      Author(s): Maria Galuppo, Antonietta Rossi, Sabrina Giacoppo, Simona Pace, Placido Bramanti, Lidia Sautebin, Emanuela Mazzon
      Traumatic spinal cord injury (SCI) represents one of the most disabling injuries of the human body causing temporary or permanent sensory and/or motor system deficit, particularly hind limb locomotor function impairment. At present, steroidal inflammatory drugs, in particular methylprednisolone sodium succinate (MPSS) are the first line choice treatment of acute SCI. Despite progress in pharmacological, surgical and rehabilitative treatment approaches, SCI still remains a very complex medical and psychological challenge, with no curative therapy available. The aim of the present study was to compare the efficacy of MPSS in respect to other GCs such as dexamethasone (Dex) and mometasone furoate (MF) in an in vitro suitable model of LPS-induced inflammation in J774 cells as well as in an in vivo experimental mouse SCI (compression model). In both the in vitro and in vivo experiments, MF resulted surprisingly more potent than Dex and MPSS. In detail, mice sacrificed seven days after induction of SCI trauma resulted not only in tissue damage, cellular infiltration, fibrosis, astrocyte activation, iNOS expression, extracellular signal regulated kinase 1/2 phosphorylation in injured tissue, poly (ADP-ribose) polymerase 1 (PARP-1) activation but also apoptosis (Bax and Bcl-2 expression). All three GCs demonstrated the ability to modulate inflammatory, oxidative as well as apoptotic pathways, but MF demonstrated the best efficacy, while Dex and MPSS showed alternative potency with a different degree of protection. Therefore, we can conclude that MF is the best candidate for post-traumatic chronic treatment, since it ameliorates different molecular pathways involved in the damage's propagation to the surrounding areas of the injured spinal cord.
      Graphical abstract image

      PubDate: 2015-07-18T22:00:04Z
       
  • Inhibitory effect of positively charged triazine antagonists of
           prokinecitin receptors on the transient receptor vanilloid type-1 (TRPV1)
           channel
    • Abstract: Publication date: Available online 17 July 2015
      Source:Pharmacological Research
      Author(s): Luciano De Petrocellis, Aniello Schiano Moriello, Joon Seok Byun, Joo Mi Sohn, Jae Yeol Lee, Ana Vázquez-Romero, Maria Garrido, Angel Messeguer, Fang-Xiong Zhang, Gerald W. Zamponi, Alessandro Deplano, Cenzo Congiu, Valentina Onnis, Gianfranco Balboni, Vincenzo Di Marzo
      Four positively charged compounds, previously shown to produce analgesic activity by interacting with prokinecitin receptor or T-type calcium channels, were tested for their ability to inhibit capsaicin-induced elevation of intracellular Ca2+ elevation in HEK-293 cells stably transfected with the human recombinant TRPV1, with the goal of identifying novel TRPV1 open-pore inhibitors. KYS-05090 showed the highest potency as a TRPV1 antagonist, even higher than that of the open-pore triazine 8aA inhibitor. The latter showed quite remarkable agonist/desensitizer activity at the rat recombinant TRPM8 channel. The activity of KYS-05090 and the other compounds was selective because none of these compounds was able to modulate the rat TRPA1 channel. Open-pore inhibitors of TRPV1 may be a new class of multi-target analgesics with lesser side effects, such as loss of acute pain sensitivity and hyperthermia, than most TRPV1 antagonists developed so far.
      Graphical abstract image

      PubDate: 2015-07-18T22:00:04Z
       
  • “How and when Chilean Pharmacology started to be experimental and
           became a science”
    • Abstract: Publication date: Available online 17 July 2015
      Source:Pharmacological Research
      Author(s): Gonzalo Bustos, Georgina M. Renard, Viviana Noriega, Ramón Sotomayor-Zárate
      Pharmacology in Chile has about 75 years of history and from its beginning until today has grown exponentially. Today, pharmacology is taught in the biomedical careers of the main Chilean universities and research centers in pharmacology are in the north, central and south of Chile. This editorial offers an overview of the main milestones that have led to the consolidation of Chilean pharmacology in Latin America and the world.


      PubDate: 2015-07-18T22:00:04Z
       
  • Statin Therapy and Plasma Coenzyme Q10Concentrations - A Systematic Review
           and Meta-Analysis of Placebo-Controlled Trials
    • Abstract: Publication date: Available online 17 July 2015
      Source:Pharmacological Research
      Author(s): Maciej Banach, Corina Serban, Sorin Ursoniu, Jacek Rysz, Paul Muntner, Peter P. Toth, Steven R. Jones, Manfredi Rizzo, Stephen P. Glasser, Gerald F. Watts, Roger S. Blumenthal, Gregory Y.H. Lip, Dimitri P. Mikhailidis, Amirhossein Sahebkar
      Statin therapy may lower plasma coenzyme Q10 (CoQ10) concentrations, but the evidence as to the significance of this effect is unclear. We assessed the impact of statin therapy on plasma CoQ10 concentrations through the meta-analysis of available RCTs. The literature search included selected databases up to April 30, 2015. The meta-analysis was performed using either a fixed-effects or random-effect model according to I2 statistic. Effect sizes were expressed as weighted mean difference (WMD) and 95% confidence interval (CI). The data from 8 placebo-controlled treatment arms suggested a significant reduction in plasma CoQ10 concentrations following treatment with statins (WMD: −0.44μmol/L, 95%CI: −0.52, −0.37, p <0.001). The pooled effect size was robust and remained significant in the leave-one-out sensitivity analysis. Subgroup analysis suggested that the impact of statins on plasma CoQ10 concentrations is significant for all 4 types of statins studied i.e. atorvastatin (WMD: −0.41μmol/L, 95%CI: −0.53, −0.29, p <0.001), simvastatin (WMD: −0.47μmol/L, 95% CI: −0.61, −0.33, p <0.001), rosuvastatin (WMD: −0.49μmol/L, 95%CI: −0.67, −0.31, p <0.001) and pravastatin (WMD: −0.43μmol/L, 95%CI: −0.69, −0.16, p =0.001). Likewise, there was no differential effect of lipophilic (WMD: −0.43μmol/L, 95%CI: −0.53, −0.34, p <0.001) and hydrophilic statins (WMD: −0.47μmol/L, 95%CI: −0.62, −0.32, p <0.001). With respect to treatment duration, a significant effect was observed in both subsets of trials lasting <12 weeks (WMD: −0.51μmol/L, 95%CI: −0.64, −0.39, p <0.001) and ≥12 weeks (WMD: −0.40μmol/L, 95%CI: −0.50, −0.30, p <0.001). The meta-analysis showed a significant reduction in plasma CoQ10 concentrations following treatment with statins. Further well-designed trials are required to confirm our findings and elucidate their clinical relevance.
      Graphical abstract image

      PubDate: 2015-07-18T22:00:04Z
       
  • 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: Available online 18 July 2015
      Source:Pharmacological Research
      Author(s): Alan Diot, Alex Hinks-Roberts, Tiffany Lodge, Chunyan Liao, Eszter Dombi, Karl Morten, Stefen Brady, Carl Fratter, Janet Carver, Rebecca Muir, Ryan Davies, Charlotte J Green, Iain Johnston, David Hilton-Jones, Carolyn Sue, Heather Mo rtiboys, 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.
      Graphical abstract image

      PubDate: 2015-07-18T22:00:04Z
       
  • 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.
      Graphical abstract image

      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.
      Graphical abstract image

      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
       
  • Editorial Board
    • Abstract: Publication date: August 2015
      Source:Pharmacological Research, Volume 98




      PubDate: 2015-06-26T14:26:48Z
       
  • Novel therapies for T1D on the horizon
    • Abstract: Publication date: August 2015
      Source:Pharmacological Research, Volume 98
      Author(s): Moufida Ben Nasr , Paolo Fiorina



      PubDate: 2015-06-26T14:26:48Z
       
  • Disease modifying therapies in type 1 diabetes: Where have we been, and
           where are we going?
    • Abstract: Publication date: August 2015
      Source:Pharmacological Research, Volume 98
      Author(s): Sandra Lord , Carla J. Greenbaum
      With more than four decades of clinical research and 25 years of clinical trials, much is known about the natural history of T1D before and after clinical diagnosis. We know that autoimmunity occurs early in life, that islet autoimmunity inevitably leads to clinically overt disease, and that some immune therapies can alter the disease course. In the future, we will likely conduct trials to more deeply explore mechanisms of disease and response to therapy, employ combinations of agents including those aimed at supporting beta cells, consider the use of chronic, intermittent therapy, focus studies on preventing progression from islet autoimmunity, and consider the potential benefits of studying children independently from adults. Much of this work will depend upon clinical trial networks such as Diabetes TrialNet. Such networks not only have the expertise to conduct studies but their sharing of data and samples also allows for discovery work by multiple investigators, laying the groundwork for the future. Working with patients, families, funders and industry, such collaborative networks can accelerate the translation of science to clinical practice to improve the lives of those living with T1D.


      PubDate: 2015-06-26T14:26:48Z
       
  • 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
       
  • Type 1 diabetes and gut microbiota: Friend or foe?
    • Abstract: Publication date: August 2015
      Source:Pharmacological Research, Volume 98
      Author(s): Changyun Hu , F. Susan Wong , Li Wen
      Type 1 diabetes is a T cell-mediated autoimmune disease. Environmental factors play an important role in the initiation of the disease in genetically predisposed individuals. With the improved control of infectious disease, the incidence of autoimmune diseases, particularly type 1 diabetes, has dramatically increased in developed countries. Increasing evidence suggests that gut microbiota are involved in the pathogenesis of type 1 diabetes. Here we focus on recent advances in this field and provide a rationale for novel therapeutic strategies targeting gut microbiota for the prevention of type 1 diabetes.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Modern clinical management helps reducing the impact of type 1 diabetes in
           children
    • Abstract: Publication date: August 2015
      Source:Pharmacological Research, Volume 98
      Author(s): Andrea E. Scaramuzza , Gian Vincenzo Zuccotti
      Type 1 diabetes care may be very costly not only in terms of money but also in terms of psychological and therapeutic acceptance and compliance. Recently, a lot of new technologies have been introduced in the care of patients with type 1 diabetes that should allow them to achieve an improvement in glycemic control, quality of life and above all prevent long-term complications. Combining continuous glucose monitoring (CGM) and continuous subcutaneous insulin infusion (CSII) provides a more useful tool for patients with type 1 diabetes, the sensor-augmented pump (SAP). The aim of the present review is to explore SAP efficacy and safety in young patients with type 1 diabetes. SAP demonstrated increased efficacy in lowering glycated hemoglobin when compared either to multiple daily injections or CSII alone. Its efficacy is positively associated with CGM use, baseline HbA1c and patients’ age. According to currently available evidence, SAP seems sufficiently safe, effective and beneficial in improving glycemic control in pediatric patients with type 1 diabetes. Moreover, encouraging results using semi-closed loop systems are emerging, paving the way toward a fully automated artificial pancreas. As pediatric diabetologists we have the duty to offer our patients the best therapeutic option currently available, supported by evidence, to help them gain the best results with the fewest adverse effects (hypoglycemia and/or diabetic ketoacidosis), better if chomping a little piece of dark chocolate.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Type 1 diabetes and T regulatory cells
    • Abstract: Publication date: August 2015
      Source:Pharmacological Research, Volume 98
      Author(s): Basset ElEssawy , Xian C. Li
      T-regulatory cells (Tregs) play a fundamental role in the creation and maintenance of peripheral tolerance. Deficits in the numbers and/or function of Tregs may be an underlying cause of human autoimmune diseases including type 1 Diabetes Mellitus (T1D), whereas an over-abundance of Tregs can hinder immunity against cancer or pathogens. The importance of Tregs in the control of autoimmunity is well established in a variety of experimental animal models. In mice, manipulating the numbers and/or function of Tregs can decrease pathology in a wide range of contexts, including autoimmunity and it is widely assumed that similar approaches will be possible in humans. T1D, the most prevalent human autoimmune disease, has been a focus of interventions either through direct and indirect in vivo proliferations or through adoptive transfer of the in vitro generated antigen specific and non specific Treg. Some challenges still need to be addressed, including a more specific phenotype marker for Tregs; the reproducibility of satisfactory animal results in human and the reconcile of discrepancies between in vitro and in vivo studies. In this article, we will highlight the role of Tregs in autoimmune disease in general with a special focus on T1D, highlighting progress made and challenges ahead in developing Treg-based therapies.
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      PubDate: 2015-06-26T14:26:48Z
       
  • The rise, fall, and resurgence of immunotherapy in type 1 diabetes
    • Abstract: Publication date: August 2015
      Source:Pharmacological Research, Volume 98
      Author(s): Moufida Ben Nasr , Francesca D’Addio , Vera Usuelli , Sara Tezza , Reza Abdi , Paolo Fiorina
      Despite considerable effort to halt or delay destruction of β-cells in autoimmune type 1 diabetes (T1D), success remains elusive. Over the last decade, we have seen a proliferation of knowledge on the pathogenesis of T1D that emerged from studies performed in non-obese diabetic (NOD) mice. However, while results of these preclinical studies appeared to hold great promise and boosted patients’ hopes, none of these approaches, once tested in clinical settings, induced remission of autoimmune diabetes in individuals with T1D. The primary obstacles to translation reside in the differences between the human and murine autoimmune responses and in the contribution of many environmental factors associated with the onset of disease. Moreover, inaccurate dosing as well as inappropriate timing and uncertain length of drug exposure have played a central role in the negative outcomes of such therapeutic interventions. In this review, we summarize the most important approaches tested thus far in T1D, beginning with the most successful preclinical studies in NOD mice and ending with the latest disappointing clinical trials in humans. Finally, we highlight recent stem cell-based trials, for which expectations in the scientific community and among individuals with T1D are high.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Novel therapeutic approaches for diabetic nephropathy and retinopathy
    • Abstract: Publication date: August 2015
      Source:Pharmacological Research, Volume 98
      Author(s): Vera Usuelli , Ennio La Rocca
      Diabetes mellitus is a chronic disease that in the long-term increases the microvascular and macrovascular degenerative complications thus being responsible for a large part of death associated with diabetes. During the years, while preventive care for diabetic patients has improved, the increase in the prevalence of diabetes worldwide is continuous. The detrimental effects of diabetes mellitus result in microvascular diseases, which recognize hyperglycemia as major determinant. A significant number of potential therapeutic targets for the treatment of diabetic microvascular complications have been proposed, but the encouraging results obtained in preclinical studies, have largely failed in clinical trials. Currently, the most successful strategy to prevent microvascular complications of diabetes is the intensive treatment of hyperglycemia or the normalization of glycometabolic control achieved with pancreatic and islet transplantation. In this review, we focus on the novel therapeutic targets to prevent the development and progression of diabetic nephropathy and retinopathy microvascular complications.
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      PubDate: 2015-06-26T14:26:48Z
       
  • The current challenges for pancreas transplantation for diabetes mellitus
    • Abstract: Publication date: August 2015
      Source:Pharmacological Research, Volume 98
      Author(s): Christopher J.E. Watson
      Pancreas transplantation is an accepted treatment for a subset of patients with diabetes mellitus, in particular those with renal failure who also require a kidney transplant and those with life-threatening hypoglycaemic unawareness. As results have improved and demand has risen, attention has focused on increasing the availability of pancreas transplantation by utilising pancreases from less than ideal donors, as well as addressing factors that limit the longevity of graft survival. The development of islet transplantation has posed additional demands on donor pancreas availability, as well as posing new challenges for donor organ allocation. This review focuses upon some of the current areas of interest in pancreatic transplantation.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Hepatic steatosis after islet transplantation: Can ultrasound predict the
           clinical outcome? A longitudinal study in 108 patients
    • Abstract: Publication date: August 2015
      Source:Pharmacological Research, Volume 98
      Author(s): Massimo Venturini , Paola Maffi , Giulia Querques , Giulia Agostini , Lorenzo Piemonti , Sandro Sironi , Francesco De Cobelli , Paolo Fiorina , Antonio Secchi , Alessandro Del Maschio
      Percutaneous intra-portal islet transplantation (PIPIT) is a less invasive, safer, and repeatable therapeutic option for brittle type 1 diabetes, compared to surgical pancreas transplantation. Hepatic steatosis is a consequence of the islet engraftment but it is curiously present in a limited number of patients and its meaning is controversial. The aims of this study were to assess hepatic steatosis at ultrasound (US) after PIPIT investigating its relationship with graft function and its role in predicting the clinical outcome. From 1996 to 2012, 108 patients underwent PIPIT: 83 type-1 diabetic patients underwent allo-transplantation, 25 auto-transplantation. US was performed at baseline, 6, 12, and 24 months, recording steatosis prevalence, first detection, duration, and distribution. Contemporaneously, steatotic and non-steatotic patients were compared for the following parameters: infused islet mass, insulin independence rate, β-score, C-peptide, glycated hemoglobin, exogenous insulin requirement, and fasting plasma glucose. Steatosis at US was detected in 21/108 patients, 20/83 allo-transplanted and 1/25 auto-transplanted, mostly at 6 and 12 months. Infused islet mass was significantly higher in steatotic than non-steatotic patients (IE/kg: S =10.822; NS=6138; p =0.001). Metabolically, steatotic patients had worse basal conditions, but better islet function when steatosis was first detected, after which progressive islet exhaustion, along with steatosis disappearance, was observed. Conversely, in non-steatotic patients these parameters remained stable in time. Number of re-transplantations was significantly higher in steatotic than in non-steatotic patients (1.8 vs 1.1; p =0.001). Steatosis at US seems to be related to the islet mass and local overworking activity. It precedes metabolic alterations and can predict graft dysfunction addressing to therapeutic decisions before islet exhaustion. If steatosis does not appear, no conclusion can be drawn.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Immunogenicity of β-cells for autologous transplantation in type 1
           diabetes
    • Abstract: Publication date: August 2015
      Source:Pharmacological Research, Volume 98
      Author(s): Christian Schuetz , James F. Markmann
      The success of clinical islet transplantation calls for a broader application of this curative treatment for type 1 diabetes mellitus. The toxicity of immunosuppression, limited organ donor supply and high procedural costs are deterrents to expand this therapy to patients with uncomplicated diabetes. The use of pancreatic β-cell like cells derived from the patient's own induced pluripotent cells (iPSC) holds potential to overcome these barriers. In this review, we discuss the practicality of this regenerative medicine approach and existing evidence regarding the true immunogenicity of iPSC derived cells.


      PubDate: 2015-06-26T14:26:48Z
       
  • Novel immunological strategies for islet transplantation
    • Abstract: Publication date: August 2015
      Source:Pharmacological Research, Volume 98
      Author(s): Sara Tezza , Moufida Ben Nasr , Andrea Vergani , Alessandro Valderrama Vasquez , Anna Maestroni , Reza Abdi , Antonio Secchi , Paolo Fiorina
      Islet transplantation has been demonstrated to improve glycometabolic control, to reduce hypoglycemic episodes and to halt the progression of diabetic complications. However, the exhaustion of islet function and the side effects related to chronic immunosuppression limit the spread of this technique. Consequently, new immunoregulatory protocols have been developed, with the aim to avoid the use of a life-time immunosuppression. Several approaches have been tested in preclinical models, and some are now under clinical evaluation. The development of new small molecules and new monoclonal or polyclonal antibodies is continuous and raises the possibility of targeting new costimulatory pathways or depleting particular cell types. The use of stem cells and regulatory T cells is underway to take advantage of their immunological properties and to induce tolerance. Xenograft islet transplantation, although having severe problems in terms of immunological compatibility, could theoretically provide an unlimited source of donors; using pigs carrying human immune antigens has showed indeed promising results. A completely different approach, the use of encapsulated islets, has been developed; synthetic structures are used to hide islet alloantigen from the immune system, thus preserving islet endocrine function. Once one of these strategies is demonstrated safe and effective, it will be possible to establish clinical islet transplantation as a treatment for patients with type 1 diabetes long before the onset of diabetic-related complications.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Re-engineering islet cell transplantation
    • Abstract: Publication date: August 2015
      Source:Pharmacological Research, Volume 98
      Author(s): Nicoletta Fotino , Carmen Fotino , Antonello Pileggi
      We are living exciting times in the field of beta cell replacement therapies for the treatment of diabetes. While steady progress has been recorded thus far in clinical islet transplantation, novel approaches are needed to make cell-based therapies more reproducible and leading to long-lasting success. The multiple facets of diabetes impose the need for a transdisciplinary approach to attain this goal, by targeting immunity, promoting engraftment and sustained functional potency. We discuss herein the emerging technologies applied to this rapidly evolving field.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Clinical results of islet transplantation
    • Abstract: Publication date: August 2015
      Source:Pharmacological Research, Volume 98
      Author(s): Paola Maffi , Antonio Secchi
      Islet transplantation is considered an advanced therapy in the treatment of type-1 diabetes, with a progressive improvement of clinical results as seen in the Collaborative Islet Transplant Registry (CITR) report. It is an accepted method for the stabilization of frequent hypoglycemia, or severe glycemic lability, in patients with hypoglycemic unawareness, poor diabetic control, or a resistance to intensive insulin-based therapies. Worldwide data confirm a positive trend in this field, with the integrated management of pivotal factors: adequate islet mass, immunosuppressive protocols, additional anti-inflammatory therapy, and pre-transplant allo-immunity assessment. Insulin independence has been observed in several clinical trials with different rate, ranging 100–65% of patients; the maintenance of this condition during the follow-up progressively decreased, actually arranged on 44% 3 years after the last infusion, according to data reported from the CITR. Successful duration is progressively increasing, with ≥13 years being the longest reported insulin-free condition on record. The immediate results of functioning islet transplantation are an improvement in hypoglycemic awareness and a reduction in the glycated hemoglobin level. Furthermore, many studies have shown its influence on the chronic complications of diabetes, such as peripheral neuropathy, retinopathy, and macroangiopathy. Pre-transplant nephropathy remains an exclusion criterion as immunosuppressive therapy can exacerbate kidney-function deterioration. The problems linked to immunosuppression following islet transplantation for the treatment of type-1 diabetes need to be considered in order to achieve the correct risk/benefit ratio for each patient.
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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.
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      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.
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      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.
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      PubDate: 2015-06-26T14:26:48Z
       
 
 
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