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Publisher: Elsevier   (Total: 2801 journals)

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Simulation Modelling Practice and Theory     Hybrid Journal   (Followers: 4, SJR: 0.742, h-index: 34)
Sleep Health     Full-text available via subscription  
Sleep Medicine     Hybrid Journal   (Followers: 9, SJR: 1.391, h-index: 70)
Sleep Medicine Clinics     Full-text available via subscription   (Followers: 7, SJR: 0.223, h-index: 16)
Sleep Medicine Reviews     Hybrid Journal   (Followers: 10, SJR: 3.467, h-index: 78)
Sleep Science     Open Access  
Small Ruminant Research     Hybrid Journal   (Followers: 4, SJR: 0.654, h-index: 50)
Social Networks     Hybrid Journal   (Followers: 21, SJR: 2.324, h-index: 55)
Social Science & Medicine     Hybrid Journal   (Followers: 54, SJR: 1.789, h-index: 149)
Social Science J.     Hybrid Journal   (Followers: 4, SJR: 0.255, h-index: 18)
Social Science Research     Hybrid Journal   (Followers: 15, SJR: 1.393, h-index: 43)
Socio-Economic Planning Sciences     Hybrid Journal   (Followers: 1, SJR: 0.841, h-index: 26)
Sociologie du Travail     Full-text available via subscription   (Followers: 2, SJR: 0.229, h-index: 16)
SoftwareX     Open Access  
Soil and Tillage Research     Hybrid Journal   (Followers: 6, SJR: 1.778, h-index: 76)
Soil Biology and Biochemistry     Hybrid Journal   (Followers: 9, SJR: 2.275, h-index: 123)
Soil Dynamics and Earthquake Engineering     Hybrid Journal   (Followers: 7, 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: 20, SJR: 2.291, h-index: 85)
Solar Energy Materials and Solar Cells     Hybrid Journal   (Followers: 27, 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: 16, SJR: 0.256, h-index: 14)
Space Research Today     Full-text available via subscription   (Followers: 30, SJR: 0.123, h-index: 2)
Spanish Review of Financial Economics, The     Full-text available via subscription   (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: 4, SJR: 0.124, h-index: 5)
Statistical Methodology     Hybrid Journal   (Followers: 9, SJR: 0.642, h-index: 15)
Statistics & Probability Letters     Hybrid Journal   (Followers: 12, SJR: 0.771, h-index: 38)
Stem Cell Reports     Open Access   (Followers: 6)
Stem Cell Research     Open Access   (Followers: 13, 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: 4, SJR: 0.164, h-index: 6)
Structural Change and Economic Dynamics     Hybrid Journal   (Followers: 2, 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: 23, 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: 5, SJR: 0.626, h-index: 19)
Studies in Environmental Science     Full-text available via subscription   (Followers: 6)
Studies in History and Philosophy of Science Part A     Hybrid Journal   (Followers: 4, 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: 10, 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: 3)
Studies in Mycology     Open Access  
Studies in Natural Products Chemistry     Full-text available via subscription   (Followers: 3, SJR: 0.221, h-index: 22)
Studies in Plant Science     Full-text available via subscription   (Followers: 2)
Studies in Surface Science and Catalysis     Full-text available via subscription   (Followers: 1, SJR: 0.282, h-index: 41)
Studies in the History and Philosophy of Mathematics     Full-text available via subscription   (Followers: 4)
Studies in Visual Information Processing     Full-text available via subscription   (Followers: 3)
Sugar Series     Full-text available via subscription   (Followers: 4)
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: 31, 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: 12, SJR: 1.691, h-index: 118)
Surgery (Oxford)     Full-text available via subscription   (Followers: 4, SJR: 0.132, h-index: 14)
Surgery for Obesity and Related Diseases     Full-text available via subscription   (Followers: 7, SJR: 1.918, h-index: 46)
Surgical Clinics     Full-text available via subscription   (Followers: 2, SJR: 0.978, h-index: 68)
Surgical Oncology     Hybrid Journal   (Followers: 2, SJR: 0.86, h-index: 41)
Surgical Oncology Clinics of North America     Full-text available via subscription   (Followers: 5, 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: 12, 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: 27, 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: 10, 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: 10, SJR: 1.235, h-index: 103)

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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  [2801 journals]
  • Structure, mechanism and therapeutic utility of immunosuppressive
           oligonucleotides
    • Abstract: Publication date: March 2016
      Source:Pharmacological Research, Volume 105
      Author(s): Defne Bayik, Ihsan Gursel, Dennis M. Klinman
      Synthetic oligodeoxynucleotides that can down-regulate cellular elements of the immune system have been developed and are being widely studied in preclinical models. These agents vary in sequence, mechanism of action, and cellular target(s) but share the ability to suppress a plethora of inflammatory responses. This work reviews the types of immunosuppressive oligodeoxynucleotide (Sup ODN) and compares their therapeutic activity against diseases characterized by pathologic levels of immune stimulation ranging from autoimmunity to septic shock to cancer (see graphical abstract). The mechanism(s) underlying the efficacy of Sup ODN and the influence size, sequence and nucleotide backbone on function are considered.
      Graphical abstract image

      PubDate: 2016-02-12T07:10:44Z
       
  • Pharmacological effects of meldonium: Biochemical mechanisms and
           biomarkers of cardiometabolic activity
    • Abstract: Publication date: Available online 2 February 2016
      Source:Pharmacological Research
      Author(s): Maija Dambrova, Marina Makrecka-Kuka, Reinis Vilskersts, Elina Makarova, Janis Kuka, Edgars Liepinsh
      Meldonium (mildronate; 3-(2,2,2-trimethylhydrazinium)propionate; THP; MET-88) is a clinically used cardioprotective drug, which mechanism of action is based on the regulation of energy metabolism pathways through l-carnitine lowering effect. l-Carnitine biosynthesis enzyme γ-butyrobetaine hydroxylase and carnitine/organic cation transporter type 2 (OCTN2) are the main known drug targets of meldonium, and through inhibition of these activities meldonium induces adaptive changes in the cellular energy homeostasis. Since l-carnitine is involved in the metabolism of fatty acids, the decline in its levels stimulates glucose metabolism and decreases concentrations of l-carnitine related metabolites, such as long-chain acylcarnitines and trimethylamine-N-oxide. Here, we briefly reviewed the pharmacological effects and mechanisms of meldonium in treatment of heart failure, myocardial infarction, arrhythmia, atherosclerosis and diabetes.
      Graphical abstract image

      PubDate: 2016-02-12T07:10:44Z
       
  • Glyco-nano-oncology: Novel therapeutic opportunities by combining small
           and sweet
    • Abstract: Publication date: Available online 4 February 2016
      Source:Pharmacological Research
      Author(s): Pablo F. Hockl, Alejandro Wolosiuk, Juan M. Pérez Sáez, Andrea V. Bordoni, Diego O. Croci, Yamili Toum Terrones, Galo J.A.A. Soler-Illia, Gabriel A. Rabinovich
      Recent efforts toward defining the molecular features of the tumor microenvironment have revealed dramatic changes in the expression of glycan-related genes including glycosyltransferases and glycosidases. These changes affect glycosylation of proteins and lipids not only in cancer cells themselves, but also in cancer associated-stromal, endothelial and immune cells. These glycan alterations including increased frequency of β1,6-branched N-glycans and bisecting N-glycans, overexpression of tumor-associated mucins, preferred expression of T, Tn and sialyl-Tn antigen and altered surface sialylation, may contribute to tumor progression by masking or unmasking specific ligands for endogenous lectins, including members of the C-type lectin, siglec and galectin families. Differential expression of glycans or glycan-binding proteins could be capitalized for the identification of novel biomarkers and might provide novel opportunities for therapeutic intervention. This review focuses on the biological relevance of lectin-glycan interactions in the tumor microenvironment (mainly illustrated by the immunosuppressive and pro-angiogenic activities of galectin-1) and the design of functionalized nanoparticles for pharmacological delivery of multimeric glycans, lectins or selective inhibitors of lectin-glycan interactions with antitumor activity.
      Graphical abstract image

      PubDate: 2016-02-12T07:10:44Z
       
  • Thyroid hormones and their membrane receptors as therapeutic targets for T
           cell lymphomas
    • Abstract: Publication date: Available online 4 February 2016
      Source:Pharmacological Research
      Author(s): Graciela A. Cremaschi, Florencia Cayrol, Helena Andrea Sterle, María Celeste Díaz Flaqué, María Laura Barreiro Arcos
      Thyroid hormones (THs) are important regulators of metabolism, differentiation and cell proliferation. They can modify the physiology of human and murine T cell lymphomas (TCL). These effects involve genomic mechanisms, mediated by specific nuclear receptors (TR), as well as nongenomic mechanisms, that lead to the activation of different signaling pathways through the activation of a membrane receptor, the integrin αvβ3. Therefore, THs are able to induce the survival and growth of TCL. Specifically, the signaling induced by THs through the integrin αvβ3 activates proliferative and angiogenic programs, mediated by the regulation of the vascular endothelial growth factor (VEGF). The genomic or pharmacologic inhibition of integrin αvβ3 reduces the production of VEGF and induces cell death both in vitro and in xenograft models of human TCL. Here we review the mechanisms involved in the modulation of the physiology of TCL induced by THs, the analysis of the interaction between genomic and nongenomic actions of THs and their contribution to T cell lymphomagenesis. These actions of THs suggest a novel mechanism for the endocrine modulation of the physiopathology of TCL and they provide a potential molecular target for its treatment.
      Graphical abstract image

      PubDate: 2016-02-12T07:10:44Z
       
  • C5a and pain development: An old molecule, a new target
    • Abstract: Publication date: Available online 6 February 2016
      Source:Pharmacological Research
      Author(s): Andreza U. Quadros, Thiago M. Cunha
      Pain is a distressing sensation, resulting from real or potential tissue damage. It is crucial to protect our body, but it can be so intense that it requires treatment. Furthermore, in some circumstances, pain can become persistent/chronic, such as that triggered by inflammatory disease or neuropathy. Treatments for pain are still a clinical challenge. An advance in the knowledge of the neurobiological mechanisms involved in the genesis of acute and chronic pain might be the fundamental approach for developing novel classes of analgesic drugs. In this context, there is emerging evidence indicating that C5a, a component of the complement system, and its cell membrane receptor, C5aR, play a critical role in the genesis of acute and chronic pain states. Thus, this review will describe the mechanisms by which C5a/C5aR signaling participates in the cascade of events involved in the pathophysiology of acute (postoperative), inflammatory and neuropathic pain states. Furthermore, it will also highlight the current possibilities for the development of a novel class of analgesic drugs that target C5a/C5aR signaling.
      Graphical abstract image

      PubDate: 2016-02-12T07:10:44Z
       
  • Exosomes as a potential novel therapeutic tools against neurodegenerative
           diseases
    • Abstract: Publication date: Available online 6 February 2016
      Source:Pharmacological Research
      Author(s): Akvilė Jarmalavičiūtė, Augustas Pivoriūnas
      Exosomes are extracellular vesicles that can transfer biological information over long distances affecting normal and pathological processes throughout organism. It is known that very often composition and therapeutic properties of exosomes depends on cell type and its physiological state. Thus, depending on tissue of origin and physiological context exosomes may act as promoters, or suppressors of pathological processes in CNS. From the therapeutic perspective, the most promising cellular sources of exosomes are mesenchymal stem cells, dendritic cells and inducible pluripotent stem cells. In this review, we will summarize the current state of knowledge on the molecular mechanisms underlying neuroprotective actions of exosomes derived from these cells. New therapies for the neurodegenerative disorders are often halted by the inability of drugs to cross blood–brain barrier. In this respect exosomes have a critical advantage, because they can cross blood–brain barrier. Despite the great importance, surprisingly little is known about mechanistic details of this process. Therefore we will discuss some recent findings that may explain mechanisms of exosomal entry into the brain.
      Graphical abstract image

      PubDate: 2016-02-12T07:10:44Z
       
  • The hallucinogenic diterpene salvinorin A inhibits leukotriene synthesis
           in experimental models of inflammation
    • Abstract: Publication date: Available online 6 February 2016
      Source:Pharmacological Research
      Author(s): Antonietta Rossi, Simona Pace, Federica Tedesco, Ester Pagano, Germano Guerra, Fabiana Troisi, Markus Werner, Fiorentina Roviezzo, Jordan K. Zjawiony, Oliver Werz, Angelo A. Izzo, Raffaele Capasso
      Leukotrienes (LTs) are lipid mediators derived from arachidonic acid (AA) involved in a number of autoimmune/inflammatory disorders including asthma, allergic rhinitis and cardiovascular diseases. Salvinorin A (SA), a diterpene isolated from the hallucinogenic plant Salvia divinorum, is a well-established analgesic compound, but its anti-inflammatory properties are under-researched and its effects on LT production is unknown to date. Here, we studied the possible effect of SA on LT production and verified its actions on experimental models of inflammation in which LTs play a prominent role. Peritoneal macrophages (PM) stimulated by calcium ionophore A23187 were chosen as in vitro system to evaluate the effect of SA on LT production. Zymosan-induced peritonitis in mice and carrageenan-induced pleurisy in rats were selected as LT-related models to evaluate the effect of SA on inflammation as well as on LT biosynthesis. SA inhibited, in a concentration-dependent manner, A23187-induced LTB4 biosynthesis in isolated PM. In zymosan-induced peritonitis, SA inhibited cell infiltration, myeloperoxidase activity, vascular permeability and LTC4 production in the peritoneal cavity without decreasing the production of prostaglandin E2. In carrageenan-induced pleurisy in rats, a more sophisticated model of acute inflammation related to LTs, SA significantly inhibited LTB4 production in the inflammatory exudates, along with reducing the phlogistic process in the lung. In conclusion, SA inhibited LT production and it was effective in experimental models of inflammation in which LTs play a pivotal role. SA might be considered as a lead compound for the development of drugs useful in LTs-related diseases.
      Graphical abstract image

      PubDate: 2016-02-12T07:10:44Z
       
  • E3 Ubiquitin Ligases as Novel Targets for Inflammatory Diseases
    • Abstract: Publication date: Available online 11 February 2016
      Source:Pharmacological Research
      Author(s): Santosh Kumar Goru, Anuradha Pandey, Anil Bhanudas Gaikwad
      Ubiquitination is one of the post translational modifications which decide the fate of various proteins in the cells, by either directing them towards proteasomal degradation or participation in several cell signalling pathways. Recently, the role of ubiquitination has been unravelled in pathogenesis and progression of various diseases, where inflammation is critical, like obesity, insulin resistance, atherosclerosis, angiotensin-II induced cardiac inflammation and asthma. E3 ligases are known to be instrumental in regulation of the inflammatory cascade. This review focuses on the role of different E3 ligases in the development of inflammatory diseases and thus may help us to target these E3 ligases in future drug discovery to prevent inflammation.
      Graphical abstract image

      PubDate: 2016-02-12T07:10:44Z
       
  • Nigella Sativa (Black Seed) Effects on Plasma Lipid Concentrations in
           Humans: a Systematic Review and Meta-Analysis of Randomized
           Placebo-Controlled Trials
    • Abstract: Publication date: Available online 10 February 2016
      Source:Pharmacological Research
      Author(s): Amirhossein Sahebkar, Guglielmo Beccuti, Luis E. Simental-Mendía, Valerio Nobili, Simona Bo
      The effects of Nigella Sativa (NS) on plasma lipid concentrations are controversial. A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to obtain a conclusive result in humans. PubMed-Medline, SCOPUS, Web of Science, and Google Scholar databases were searched (up to August 2015) to identify RCTs investigating the impact of NS on total cholesterol, LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), and triglycerides concentrations. A random-effects model and the generic inverse variance weighting method were used for quantitative data synthesis. Meta-regression, sensitivity analysis, and publication bias assessments were performed using standard methods. A total of 17 RCTs examining the effects of NS on plasma lipid concentrations were included. Meta-analysis suggested a significant association between NS supplementation and a reduction in total cholesterol (weighed-mean-difference [WMD]: −15.65mg/dL, 95% CI: −24.67, −6.63, p =0.001), LDL-C (WMD: −14.10mg/dL, 95% CI: −19.32, −8.88, p <0.001), and triglyceride levels (WMD: −20.64mg/dL, 95% CI: −30.29, −11.00, p <0.001). No significant effect on HDL-C concentrations (WMD: 0.28mg/dL, 95% CI: −1.96, 2.53, p =0.804) was found. A greater effect of NS seed oil versus seed powder was observed on serum total cholesterol and LDL-C levels, and an increase in HDL-C levels was found only after NS seed powder supplementation. NS has a significant impact on plasma lipid concentrations, leading to lower total cholesterol, LDL-C, and TG levels while increased HDL-C is associated with NS powder only. Further RCTs are needed to explore the NS benefits on cardiovascular outcomes.
      Graphical abstract image

      PubDate: 2016-02-12T07:10:44Z
       
  • The antineoplastic drug flavopiridol reverses memory impairment induced by
           Amyloid-ß1-42 oligomers in mice
    • Abstract: Publication date: Available online 10 February 2016
      Source:Pharmacological Research
      Author(s): Gian Marco Leggio, Maria Vincenza Catania, Daniela Puzzo, Michela Spatuzza, Rosalia Pellitteri, Walter Gulisano, Sebastiano Alfio Torrisi, Giovanni Giurdanella, Cateno Piazza, Agata Rita Impellizzeri, Lucia Gozzo, Andrea Navarria, Claudio Bucolo, Ferdinando Nicoletti, Agostino Palmeri, Salvatore Salomone, Agata Copani, Filippo Caraci, Filippo Drago
      The ectopic re-activation of cell cycle in neurons is an early event in the pathogenesis of Alzheimer’s disease (AD), which could lead to synaptic failure and ensuing cognitive deficits before frank neuronal death. Cytostatic drugs that act as cyclin-dependent kinase (CDK) inhibitors have been poorly investigated in animal models of AD. In the present study, we examined the effects of flavopiridol, an inhibitor of CDKs currently used as antineoplastic drug, against cell cycle reactivation and memory loss induced by intracerebroventricular injection of Aß1-42 oligomers in CD1 mice. Cycling neurons, scored as NeuN-positive cells expressing cyclin A, were found both in the frontal cortex and in the hippocampus of Aβ-injected mice, paralleling memory deficits. Starting from three days after Aβ injection, flavopiridol (0.5, 1 and 3mg/kg) was intraperitoneally injected daily, for eleven days. Here we show that a treatment with flavopiridol (0.5 and 1mg/kg) was able to rescue the loss of memory induced by Aβ1-42, and to prevent the occurrence of ectopic cell-cycle events in the mouse frontal cortex and hippocampus. This is the first evidence that a cytostatic drug can prevent cognitive deficits in a non-transgenic animal model of AD.
      Graphical abstract image

      PubDate: 2016-02-12T07:10:44Z
       
  • Neurobiological actions by three distinct subtypes of brain-derived
           neurotrophic factor: Multi-ligand model of growth factor signaling
    • Abstract: Publication date: March 2016
      Source:Pharmacological Research, Volume 105
      Author(s): Toshiyuki Mizui, Yasuyuki Ishikawa, Haruko Kumanogoh, Masami Kojima
      Brain-derived neurotrophic factor (BDNF) is one of the most active members of the neurotrophin family. BDNF not only regulates neuronal survival and differentiation, but also functions in activity-dependent plasticity processes such as long-term potentiation (LTP), long-term depression (LTD), learning, and memory. Like other growth factors, BDNF is produced by molecular and cellular mechanisms including transcription and translation, and functions as a bioactive molecule in the nervous system. Among these mechanisms, a particular post-translational mechanism, namely the conversion of precursor BDNF into mature BDNF by proteolytic cleavage, was not fully understood. In this review, we discuss the manner through which this post-translational mechanism alters the biological actions of BDNF protein. In addition to the initially elucidated findings on BDNF, the biological roles of precursor BDNF and the BDNF pro-peptide, especially synaptic plasticity, will be extensively discussed. Recent findings on the BDNF pro-peptide will provide new insights for understanding the mechanisms of action of the pro-peptides of growth factors.
      Graphical abstract image

      PubDate: 2016-02-02T07:04:10Z
       
  • Oxidative Stress and Proteasome Inhibitors in Multiple Myeloma
    • Abstract: Publication date: Available online 29 January 2016
      Source:Pharmacological Research
      Author(s): Brittany C. Lipchick, Emily E. Fink, Mikhail A. Nikiforov
      Multiple myeloma is a form of plasma cell neoplasm that accounts for approximately 10% of all hematological malignancies. Recently, several novel drugs have been discovered that almost doubled the overall survival of multiple myeloma patients. One of these drugs, the first-in-class proteasome inhibitor bortezomib (Velcade) has demonstrated remarkable response rates in multiple myeloma patients, and yet, currently this disease remains incurable. The major factor undermining the success of multiple myeloma treatment is a rapidly emerging resistance to the available therapy. Thus, the development of stand-alone or adjuvant anti-myeloma agents becomes of paramount importance. Overproduction of intracellular reactive oxygen species (ROS) often accompanies malignant transformation due to oncogene activation and/or enhanced metabolism in tumor cells. As a result, these cells possess higher levels of ROS and lower levels of antioxidant molecules compared to their normal counterparts. Unbalanced production of ROS leads to oxidative stress which, if left unchecked, could be toxic for the cell. In multiple myeloma cells where high rates of immunoglobulin synthesis is an additional factor contributing to overproduction of ROS, further induction of oxidative stress can be an effective strategy to cope with this disease. Here we will review the available data on the role of oxidative stress in the cytotoxicity of proteasome inhibitors and the use of ROS-inducing compounds as anti-myeloma agents.
      Graphical abstract image

      PubDate: 2016-02-02T07:04:10Z
       
  • Recent updates on GPCR biased agonism
    • Abstract: Publication date: Available online 2 February 2016
      Source:Pharmacological Research
      Author(s): André S. Pupo, Diego A. Duarte, Vanessa Lima, Larissa B. Teixeira, Lucas T. Parreiras-e-Silva, Claudio M. Costa-Neto
      G protein-coupled receptors (GPCRs) are the most important targets for drug discovery and not surprisingly ∼40% of all drugs currently in the market act on these receptors. Currently, one of the most active areas in GPCRs signaling is biased agonism, a phenomenon that occurs when a given ligand is able to preferentially activate one (or some) of the possible signaling pathways. In this review, we highlight the most recent findings about biased agonism, including an extension of this concept to intracellular signaling, allosterism, strategies for assessment and interpretation, and perspectives of therapeutic applications for biased agonists.
      Graphical abstract image

      PubDate: 2016-02-02T07:04:10Z
       
  • Supplementation with coenzyme Q10 reduces plasma lipoprotein(a)
           concentrations but not other lipid indices: a systematic review and
           meta-analysis
    • Abstract: Publication date: Available online 2 February 2016
      Source:Pharmacological Research
      Author(s): Amirhossein Sahebkar, Luis E. Simental-Mendía, Claudia Stefanutti, Matteo Pirro
      Plasma lipoprotein(a) [Lp(a)] elevations are associated with increased cardiovascular risk. Coenzyme Q10 (CoQ10) is a member of the mitochondrial respiratory chain with a prominent role as a potent gene regulator. The Lp(a)-lowering efficacy of CoQ10 has been investigated in different clinical settings with contrasting results. A systematic literature search in Medline, SCOPUS, Web of Science and Google Scholar databases was conducted to identify controlled trials investigating the efficacy of CoQ10 supplementation on plasma Lp(a) levels. Inverse variance-weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated for net changes in Lp(a) levels using a random-effects model. Random-effects meta-regression was performed to assess the effect of putative confounders on plasma Lp(a) levels. Seven randomized controlled trials with a total of 409 subjects (206 in the CoQ10 arm and 203 in the control arm) met the eligibility criteria. Overall, CoQ10 supplementation was paralleled by a slight but significant reduction of plasma Lp(a) levels (WMD: −3.54 mgl/dL, 95% CI: −5.50, −1.58; p<0.001), this effect being more robust in those trials with higher baseline Lp(a) levels (slope: −0.44; 95% CI: −0.80, −0.08; p=0.018). Reduction of plasma Lp(a) levels was consistent across different CoQ10 doses, with an inverse association between administered CoQ10 dose and Lp(a) lowering (slope: 0.04; 95% CI: 0.01, 0.07; p=0.004). Neither total cholesterol and cholesterol subfractions, nor triglyceride levels were affected by CoQ10 supplementation. In conclusion, CoQ10 supplementation, in the tested range of doses, reduces plasma Lp(a) concentrations, particularly in patients with Lp(a)≥30mg/dL. Other lipid indices were not altered by CoQ10 supplementation.
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      PubDate: 2016-02-02T07:04:10Z
       
  • Are NHE1 and inducible nitric oxide synthase involved in human ovarian
           cancer'
    • Abstract: Publication date: Available online 26 January 2016
      Source:Pharmacological Research
      Author(s): Carlos Sanhueza, Joaquín Araos, Luciano Naranjo, Eric Barros, Lilian Toledo, Mario Subiabre, Fernando Toledo, Jaime Gutiérrez, Delia I. Chiarello, Fabián Pardo, Andrea Leiva, Luis Sobrevia



      PubDate: 2016-01-28T06:56:37Z
       
  • RECOMMENDATIONS FOR TREATING CHILDREN WITH DRUG-RESISTANT TUBERCULOSIS
    • Abstract: Publication date: Available online 26 January 2016
      Source:Pharmacological Research
      Author(s): Luisa Galli, Laura Lancella, Silvia Garazzino, Marina Tadolini, Alberto Matteelli, Giovanni Battista Migliori, Nicola Principi, Alberto Villani, Susanna Esposito
      Tuberculosis (TB) is still one of the most difficult infectious diseases to treat, and the second most frequent cause of death due to infectious disease throughout the world. The number of cases of multidrug-resistant (MDR-TB) and extensively drug-resistant TB (XDR-TB), which are characterised by high mortality rates, is increasing. The therapeutic management of children with MDR- and XDR-TB is complicated by a lack of knowledge, and the fact that many potentially useful drugs are not registered for pediatric use and there are no formulations suitable for children in the first years of life. Furthermore, most of the available drugs are burdened by major adverse events that need to be taken into account, particularly in the case of prolonged therapy. This document describes the recommendations of a group of scientific societies on the therapeutic approach to pediatric MDR- and XDR-TB. On the basis of a systematic literature review and their personal clinical experience, the experts recommend that children with active TB caused by a drug-resistant strain of Mycobacterium tuberculosis should always be referred to a specialised centre because of the complexity of patient management, the paucity of pediatric data, and the high incidence of adverse events due to second-line anti-TB treatment.


      PubDate: 2016-01-28T06:56:37Z
       
  • Pharmacological inhibitors of autophagy as novel cancer therapeutic agents
    • Abstract: Publication date: Available online 28 January 2016
      Source:Pharmacological Research
      Author(s): Cheng Wang, Qidong Hu, Han-Ming Shen
      Autophagy is an evolutionarily conserved cellular degradative process in which intracellular components (cellular proteins and organelles) are engulfed in autophagosomes which then fuse with lysosomes to form autolysosome for degradation. Autophagy is closely implicated in various physio-pathological processes and human diseases. Among them, the roles of autophagy in cancer have been extensively studied. Increasing evidence has demonstrated that inhibiting autophagy is a novel and promising approach in cancer therapy, based on the notion that autophagy is a pro-survival mechanism in cancer cells under therapeutic stress, and induction of autophagy is associated with chemoresistance of cancer cells to chemotherapeutic agents. Thus, suppression of autophagy would sensitize resistance tumor cells to cancer therapeutic agents, thereby supporting the clinical application of autophagy inhibitors. In recent years, significant progress has been achieved in developing autophagy inhibitors and testing their therapeutical potential, either as standalone or as adjuvant therapeutic agents, in cell and animal models, and more importantly in clinical trials. In this review, we will discuss some of these recent advances in development of novel small molecules autophagy inhibitors and their mechanisms of action, together with their applications in clinical trials.
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      PubDate: 2016-01-28T06:56:37Z
       
  • The Endogenous Cannabinoid Anandamide Increases Human Airway Epithelial
           Cell Permeability through an Arachidonic Acid Metabolite
    • Abstract: Publication date: Available online 22 January 2016
      Source:Pharmacological Research
      Author(s): V.C.M. Shang, S.E. O’Sullivan, D.A. Kendall, R.E. Roberts
      Injury to the bronchial epithelium in respiratory diseases such as asthma and COPD results in the loss of barrier function and an elevated sensitivity to environmental insults. An increased release of the endogenous cannabinoid, anandamide in response to inhalation of allergen in asthmatic patients has been reported. The aim of this study was, therefore, to determine the effects of endocannabinoids on bronchial epithelial cell permeability and to investigate the mechanisms involved. Calu-3 human bronchial epithelial cells were cultured at air-liquid interface to allow development of tight junctions. Changes in transepithelial electrical resistance (TEER), a reflection of epithelial permeability, were measured at various time points post-treatment, and expression of the tight junction proteins, occludin and ZO-1, were determined using Western immunoblotting. Anandamide produced a significant reduction in TEER, which was unaffected by cannabinoid receptor antagonists, but attenuated by URB597, an inhibitor of fatty acid amide hydrolase, and by a combination of cyclooxygenase (COX) and lipoxygenase (LOX) blockade. The anandamide metabolite, arachidonic acid, showed similar TEER decrease that was also prevented in the presence of COX and LOX inhibitor. Expression of occludin and ZO-1 were also reduced by anandamide. These findings indicate a pro-inflammatory-like effect of anandamide on bronchial epithelial permeability, mediated by cyclooxygenase and lipoxygenase metabolites, and suggest that inhibition of anandamide degradation might provide a novel approach to treat airway inflammation.
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      PubDate: 2016-01-28T06:56:37Z
       
  • Plumbagin, a naphthaquinone derivative induces apoptosis and in BRCA 1/2
           defective castrate resistant prostate cancer cells as well as prostate
           cancer stem-like cells
    • Abstract: Publication date: Available online 22 January 2016
      Source:Pharmacological Research
      Author(s): R.S. Reshma, K.H. Sreelatha, Veena Somasundaram, S. Kumar Satheesh, Revathy, Rakesh Sathish Nair, Priya Srinivas

      Graphical abstract image

      PubDate: 2016-01-28T06:56:37Z
       
  • Melatonin's role in preventing toxin-related and sepsis-mediated hepatic
           damage: A review
    • Abstract: Publication date: Available online 22 January 2016
      Source:Pharmacological Research
      Author(s): Eduardo Esteban-Zubero, Moisés Alejandro Alatorre-Jiménez, Laura López-Pingarrón, Marcos César Reyes-Gonzales, Priscilla Almeida de Souza, Amparo Cantín-Golet, Francisco José Ruiz-Ruiz, Dun-Xian Tan, José Joaquín García-García, Russel J. Reiter
      The liver is a central organ in detoxifying molecules and would otherwise cause molecular damage throughout the organism. Numerous toxic agents including aflatoxin, heavy metals, nicotine, carbon tetrachloride, thioacetamide, and toxins derived during septic processes, generate reactive oxygen species followed by molecular damage to lipids, proteins and DNA, which culminates in hepatic cell death. As a result, the identification of protective agents capable of ameliorating the damage at the cellular level is an urgent need. Melatonin is a powerful endogenous antioxidant produced by the pineal gland and a variety of other organs and many studies confirm its benefits against oxidative stress including lipid peroxidation, protein mutilation and molecular degeneration in various organs, including the liver. Recent studies confirm the benefits of melatonin in reducing the cellular damage generated as a result of the metabolism of toxic agents. These protective effects are apparent when melatonin is given as a sole therapy or in conjunction with other potentially protective agents. This review summarizes the published reports that document melatonin's ability to protect hepatocytes from molecular damage due to a wide variety of substances (aflatoxin, heavy metals, nicotine, carbon tetrachloride, chemotherapeutics, and endotoxins involved in the septic process), and explains the potential mechanisms by which melatonin provides these benefits. Melatonin is an endogenously-produced molecule which has a very high safety profile that should find utility as a protective molecule against a host of agents that are known to cause molecular mutilation at the level of the liver.
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      PubDate: 2016-01-28T06:56:37Z
       
  • The Untapped Potential of Tyrosine-based G Protein Signaling
    • Abstract: Publication date: Available online 22 January 2016
      Source:Pharmacological Research
      Author(s): Pradipta Ghosh
      Tyrosine-based and trimeric G protein-based signaling are the two most widely studied and distinct mechanisms for signal transduction in eukaryotes. How each of them relay signals across the plasma membrane independently of each other has been extensively characterized; however, an understanding of how they work together remained obscure. Recently, a rapidly emerging paradigm has revealed that tyrosine based signals are relayed via G proteins, and that the cross-talk between the two hubs are more robustly and sophisticatedly integrated than was previously imagined. More importantly, by straddling the two signaling hubs that are most frequently targeted for their therapeutic significance, the tyrosine-based G-protein signaling pathway has its own growing list of pathophysiologic importance, both as therapeutic target in a variety of disease states, and by paving the way for personalized medicine. The fundamental principles of this emerging paradigm and its pharmacologic potential are discussed.
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      PubDate: 2016-01-28T06:56:37Z
       
  • The anti-metastatic effect of 8-MOP on hepatocellular carcinoma is
           potentiated by the down-regulation of bHLH transcription factor DEC1
    • Abstract: Publication date: Available online 22 January 2016
      Source:Pharmacological Research
      Author(s): Jing Xiong, Huan Yang, Wenjing Luo, Enfang Shan, Jie Liu, Feng Zhang, Tao Xi, Jian Yang
      Despite progress in diagnostics and treatment of hepatocellular carcinoma (HCC), its prognosis remains poor. 8-Methoxypsoralen (8-MOP), a formerly considered photosensitizing agent, has been reported to induce cell apoptosis in HepG2 cells in a modest way when used alone. In this study, it was demonstrated that 8-MOP inhibited HCC HepG2 cells and SMMC-7721 cells migratory and invasive potentiality, as well as modulated the expression of various EMT-associated genes such as enhancing E-cadherin and reducing N-cadherin, vimentin, α-SMA and MMP9 in a concentration-dependent way. Differentiated embryonic chondrocyte-expressed gene 1, DEC1 (BHLHE40/Stra13/Sharp2), is a basic helix-loop-helix (bHLH) transcription factor that regulates cell growth, differentiation, apoptosis and tumorigenesis. 8-MOP suppressed the expression of DEC1 in a concentration- and time-dependent manner. Overexpression of DEC1 endorsed the HepG2 cells a higher metastatic phenotype, while totally abolished 8-MOP-repressed metastatic capability. In the meanwhile, overexpression of DEC1 promoted EMT process by suppressing expression of epithelial protein and enhancing expression of mesenchymal proteins, while potently antagonized the regulation of EMT-associated genes by 8-MOP. In vivo experiments revealed that the treatment of 8-MOP (5 or 20mg/kg) resulted in a dose-dependent decreases in the lung metastasis of hepatoma H22-transplanted mice without any obvious toxicity to the organs, as well as increased expression of E-cadherin in lung tissues. Consistently, 8-MOP down-regulated the expression of DEC1 in the lungs of tumor-bearing mice, which further confirms that DEC1 was correlated with 8-MOP-induced anti-metastatic effect. The present findings establish a function for DEC1 in HCC metastatic progression and suggest its candidacy as a novel target for the anti-metastasis effect of 8-MOP.
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      PubDate: 2016-01-28T06:56:37Z
       
  • Evidence for an imbalance between tau O-GlcNAcylation and phosphorylation
           in the hippocampus of a mouse model of Alzheimer's disease
    • Abstract: Publication date: Available online 24 January 2016
      Source:Pharmacological Research
      Author(s): Eleonora Gatta, Tony Lefebvre, Silvana Gaetani, Marc Dos Santos, Jordan Marrocco, Anne-Marie Mir, Tommaso Cassano, Stefania Maccari, Ferdinando Nicoletti, Jérôme Mairesse
      Intracellular accumulation of hyperphosphorylated tau protein is linked to neuronal degeneration in Alzheimer's disease (AD). Mounting evidence suggests that tau phosphorylation and O-N-acetylglucosamine glycosylation (O-GlcNAcylation) are mutually exclusive post-translational modifications. O-GlcNAcylation depends on 3-5% of intracellular glucose that enters the hexosamine biosynthetic pathway. To our knowledge, the existence of an imbalance between tau phosphorylation and O-GlcNAcylation has not been reported in animal models of AD, as yet. Here, we used triple transgenic (3xTg-AD) mice at 12 months, an age at which hyperphosphorylated tau is already detected and associated with cognitive decline. In these mice, we showed that tau was hyperphosphorylated on both Ser396 and Thr205 in the hippocampus, and to a lower extent and exclusively on Thr205 in the frontal cortex. Tau O-GlcNAcylation, assessed in tau immunoprecipitates, was substantially reduced in the hippocampus of 3xTg-AD mice, with no changes in the frontal cortex or in the cerebellum. No changes in the expression of the three major enzymes involved in O-GlcNAcylation, i.e., glutamine fructose-6-phosphate amidotransferase, O-linked β-N-acetylglucosamine transferase, and O-GlcNAc hydrolase were found in the hippocampus of 3xTg-AD mice. These data demonstrate that an imbalance between tau phosphorylation and O-GlcNAcylation exists in AD mice, and strengthens the hypothesis that O-GlcNAcylation might be targeted by disease modifying drugs in AD.
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      PubDate: 2016-01-28T06:56:37Z
       
  • Jumonji Histone Demethylases as Emerging Therapeutic Targets
    • Abstract: Publication date: Available online 24 January 2016
      Source:Pharmacological Research
      Author(s): Sung Yeon Park, Jong-Wan Park, Yang-Sook Chun

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      PubDate: 2016-01-28T06:56:37Z
       
  • Acute myeloid leukaemia-derived Langerhans-like cells enhance Th1
           polarization upon TLR2 engagement
    • Abstract: Publication date: Available online 18 January 2016
      Source:Pharmacological Research
      Author(s): Stephanie Bock, Manuela S. Murgueitio, Gerhard Wolber, Günther Weindl
      Langerhans cells (LCs) represent a highly specialized subset of epidermal dendritic cells (DCs), yet not fully understood in their function of balancing skin immunity. Here, we investigated in vitro generated Langerhans-like cells obtained from the human acute myeloid leukaemia cell line MUTZ-3 (MUTZ-LCs) to study TLR- and cytokine-dependent activation of epidermal DCs. MUTZ-LCs revealed high TLR2 expression and responded robustly to TLR2 engagement, confirmed by increased CD83, CD86, PD-L1 and IDO expression, upregulated IL-6, IL-12p40 and IL-23p19 mRNA levels IL-8 release. TLR2 activation reduced CCR6 and elevated CCR7 mRNA expression and induced migration of MUTZ-LCs towards CCL21. Similar results were obtained by stimulation with pro-inflammatory cytokines TNF-α and IL-1β whereas ligands of TLR3 and TLR4 failed to induce a fully mature phenotype. Despite limited cytokine gene expression and production for TLR2-activated MUTZ-LCs, coculture with naive CD4+ T cells led to significantly increased IFN-γ and IL-22 levels indicating Th1 differentiation independent of IL-12. TLR2-mediated effects were blocked by the putative TLR2/1 antagonist CU-CPT22, however, no selectivity for either TLR2/1 or TLR2/6 was observed. Computer-aided docking studies confirmed non-selective binding of the TLR2 antagonist. Taken together, our results indicate a critical role for TLR2 signalling in MUTZ-LCs considering the leukemic origin of the generated Langerhans-like cells.
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      PubDate: 2016-01-22T06:55:28Z
       
  • Involvement of mast cells and proteinase-activated receptor 2 in
           oxaliplatin-induced mechanical allodynia in mice
    • Abstract: Publication date: Available online 21 January 2016
      Source:Pharmacological Research
      Author(s): Ayumi Sakamoto, Tsugunobu Andoh, Yasushi Kuraishi
      The chemotherapeutic agent oxaliplatin induces neuropathic pain, a dose-limiting side effect, but the underlying mechanisms are not fully understood. Here, we show the potential involvement of cutaneous mast cells in oxaliplatin-induced mechanical allodynia in mice. A single intraperitoneal injection of oxaliplatin induced mechanical allodynia, which peaked on day 10 after injection. Oxaliplatin-induced mechanical allodynia was almost completely prevented by congenital mast cell deficiency. The numbers of total and degranulated mast cells was significantly increased in the skin after oxaliplatin administration. Repetitive topical application of the mast cell stabilizer azelastine hydrochloride inhibited mechanical allodynia and the degranulation of mast cells without affecting the number of mast cells in oxaliplatin-treated mice. The serine protease inhibitor camostat mesilate and the proteinase-activated receptor 2 (PAR2) antagonist FSLLRY-NH2 significantly inhibited oxaliplatin-induced mechanical allodynia. However, it was not inhibited by the H1 histamine receptor antagonist terfenadine. Single oxaliplatin administration increased the activity of cutaneous serine proteases, which was attenuated by camostat and mast cell deficiency. Depletion of the capsaicin-sensitive primary afferents by neonatal capsaicin treatment almost completely prevented oxaliplatin-induced mechanical allodynia, the increase in the number of mast cells, and the activity of cutaneous serine proteases. These results suggest that serine protease(s) released from mast cells and PAR2 are involved in oxaliplatin-induced mechanical allodynia. Therefore, oxaliplatin may indirectly affect the functions of mast cells through its action on capsaicin-sensitive primary afferents.
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      PubDate: 2016-01-22T06:55:28Z
       
  • Betulin alleviated ethanol-induced alcoholic liver injury via SIRT1/AMPK
           signaling pathway
    • Abstract: Publication date: Available online 15 January 2016
      Source:Pharmacological Research
      Author(s): Ting Bai, Yong Yang, You-Li Yao, Peng Sun, Li-Hua Lian, Yan-Ling Wu, Ji-Xing Nan
      The present study was conducted to investigate the protective effect of betulin, a triterpene from the bark of Betula platyphylla Suk, against ethanol-induced alcoholic liver injury and its possible underlying mechanisms. In vitro, human hepatic stellate cell line, LX-2 cells were treated with betulin (6.25, 12.5 and 25μM) prior to ethanol (50mM) for 24h. Cell viability was analyzed by methyl thiazolyl tetrazolium assay, protein expressions were assessed by Western blot. In vivo, we induced alcoholic liver injury in male C57BL/6 mice, placing them on Lieber-DeCarli ethanol-containing diets for 10 days and then administering a single dose of ethanol (5g/kg body weight) via gavage. Betulin (20 and 50mg/kg) were given by gavage every day. In vitro results showed that betulin effectively decreased LX-2 cell viability, attenuated collagen-I, α-smooth muscle actin (α-SMA) levels, activated liver kinase B-1 (LKB1) and adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. Betulin suppressed the expression of sterol regulatory element-binding protein-1 (SREBP-1), and genetic deletion of AMPK blocked the effect of betulin on SREBP-1 in ethanol treated LX-2 cells. In vivo, betulin attenuated the increases in serum aminotransferase and triglyceride levels in the mice fed with chronic-binge ethanol, while significantly inhibited SREBP-1 expression and activated LKB1-AMPK phosphorylation. Additionally, betulin enhanced the sirtuin 1 (SIRT1) expression mediated by ethanol. Taken together, betulin alleviates alcoholic liver injury possibly through blocking the regulation of SREBP-1 on fatty acid synthesis and activating SIRT1-LKB1-AMPK signaling pathway.
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      PubDate: 2016-01-18T06:53:32Z
       
  • The effect of statins on microalbuminuria, proteinuria, progression of
           kidney function, and all-cause mortality in patients with non-end stage
           chronic kidney disease: A meta-analysis
    • Abstract: Publication date: Available online 15 January 2016
      Source:Pharmacological Research
      Author(s): Zhenhong Zhang, Pingsheng Wu, Jiping Zhang, Shunyin Wang, Gengxin Zhang
      Conclusive evidence regarding the effect of statins on non-end stage chronic kidney disease (CKD) has not been reported previously. This meta-analysis evaluated the association between statins and microalbuminuria, proteinuria, progression, and all-cause mortality in patients with non-end stage CKD. Databases (e.g., PubMed, Embase and the Cochrane Library) were searched for randomized controlled trials (RCTs) with data on statins, microalbuminuria, proteinuria, renal health endpoints, and all-cause mortality patients with non-end stage CKD to perform this meta-analysis. The mean difference (MD) of the urine albumin excretion ratios (UAER), 24-h urine protein excretion, and risk ratios (RR) of all-cause mortality and renal health endpoints were calculated, and the results are presented with 95% confidence intervals (CI). A total of 23 RCTs with 39,419 participants were selected. The analysis demonstrated that statins statistically reduced UAER to 26.73μg/min [95%CI (−51.04, −2.43), Z =2.16, P <0.05], 24-h urine protein excretion to 682.68mg [95%CI (−886.72, −478.63), Z =6.56, P <0.01] and decreased all-cause mortality [RR=0.78, 95%CI (0.72, 0.84), Z =6.08, P <0.01]. However, the analysis results did not indicate that statins reduced the events of renal health endpoints [RR=0.96, 95%CI (0.91,1.01), Z =1.40, P >0.05]. In summary, our study indicates that statins statistically reduced microalbuminuria, proteinuria, and clinical deaths, but statins did not effectively slow the clinical progression of non-end stage CKD.
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      PubDate: 2016-01-18T06:53:32Z
       
  • Versatile antitumor potential of isoxanthohumol: enhancement of paclitaxel
           activity in vivo
    • Abstract: Publication date: Available online 16 January 2016
      Source:Pharmacological Research
      Author(s): Tamara Krajnović, Goran N. Kaluđerović, Ludger A. Wessjohann, Sanja Mijatović, Danijela Maksimović-Ivanić
      Isoxanthohumol (IXN), a prenylated flavonoid from hops, exhibits diverse biological activities, e.g. antitumor, antiinflammatory, antioxidant and antiangiogenic. In this study, the effect of IXN is evaluated on two melanoma cell lines with dissimilar molecular background, B16 and A375. The treatment of both cell lines with IXN resulted in dose-dependent decrease of cell viability. Abolished viability was in correlation with changed morphology and loss of dividing potential indicating phenotypical alteration of both tested cell lines. While modified B16 cells underwent the process of non-classic differentiation followed by tyrosinase activity without enhancement of melanin content, inhibition of Notch 1, β-catenin and Oct-3/4 were observed in A375 cells indicating loss of their pluripotent characteristics. In parallel with this, distinct subpopulations in both cell cultures entered the process of programmed cell death - apoptosis in a caspase independent manner. The described changes in cultures upon exposure to IXN could be connected with the suppression of reactive oxygen (ROS) and nitrogen species (RNS) induced by the drug. Despite the differences in which IXN promoted modifications in the upper part of the PI3K/Akt and MEK-ERK signaling pathways between B16 and A375 cells, p70S6K and its target S6 protein in both types of melanoma cells, after transient activation, became inhibited. In addition to direct input of IXN on cell viability, this study for the first time shows that IXN strongly sensitizes melanoma cells to the treatment with paclitaxel in vivo, in concordance with data obtained in vitro on B16 cells as well as their highly invasive F10 subclone.
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      PubDate: 2016-01-18T06:53:32Z
       
  • The HNO donor Angeli’s salt offers potential haemodynamic advantages
           over NO or dobutamine in ischaemia–reperfusion injury in the rat
           heart ex vivo
    • Abstract: Publication date: February 2016
      Source:Pharmacological Research, Volume 104
      Author(s): Kai Yee Chin, Lisa Michel, Cheng Xue Qin, Nga Cao, Owen L. Woodman, Rebecca H. Ritchie
      Available inotropic pharmacotherapy for acute heart failure (HF) remains largely ineffective at ameliorating marked impairments in contractile function. Nitroxyl (HNO), the redox sibling of NO•, has recently attracted interest as a therapeutic approach for acute HF. We now compare the impact of ischaemia–reperfusion (I–R) injury on acute haemodynamic responsiveness of the HNO donor, Angeli’s salt (AS), to that of NO and dobutamine. Dose-response curves to bolus doses of AS, diethylamine NONOate (DEA/NO, both 0.001–μmol) and dobutamine (0.1–100 nmol) were performed in rat isolated hearts, following I–R or normoxic perfusion. An additional 10μmol dose of Angeli’s salt was included, to permit roughly equivalent inotropic responses to dobutamine. Changes in cardiac contraction, heart rate and coronary flow (CF) were determined. Although AS and DEA/NO elicited comparable dose-dependent increases in CF in normoxic hearts, only AS vasodilation was preserved after I–R. AS and dobutamine elicited dose-dependent inotropic responses in normoxic hearts and I–R blunted inotropic responses to both. Dobutamine however increased heart rate, which was exacerbated by I–R; this was not evident with AS. Further, AS infusion during reperfusion (1μM), in a separate cohort of rat hearts, improved recovery of cardiac contractility, with lower incidence of I–R-induced ventricular fibrillation. In conclusion, these observations suggest that HNO offers haemodynamic advantages over NO following I–R. Although I–R suppresses inotropy to both agents, residual contractile responses to AS following I–R is likely free of concomitant pro-arrhythmic events. HNO donors may thus offer haemodynamic advantages over existing pharmacotherapy in acute HF.
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      PubDate: 2016-01-18T06:53:32Z
       
  • The control of tissue fibrosis by the inflammatory molecule LIGHT (TNF
           Superfamily member 14)
    • Abstract: Publication date: February 2016
      Source:Pharmacological Research, Volume 104
      Author(s): Rana Herro, Michael Croft
      The TNF Superfamily member LIGHT (TNFSF14) has recently emerged as a potential target for therapeutic interventions aiming to halt tissue fibrosis. In this perspective, we discuss how LIGHT may influence the inflammatory and remodeling steps that characterize fibrosis, relevant for many human diseases presenting with scarring such as asthma, idiopathic pulmonary fibrosis, systemic sclerosis, and atopic dermatitis. LIGHT acts through two receptors in the TNF receptor superfamily, HVEM (TNFRSF14) and LTβR (TNFRSF3), which are broadly expressed on hematopoietic and non-hematopoietic cells. LIGHT can regulate infiltrating T cells, macrophages, and eosinophils, controlling their trafficking or retention in the inflamed tissue, their proliferation, and their ability to produce cytokines that amplify fibrotic processes. More interestingly, LIGHT can act on structural cells, namely epithelial cells, fibroblasts, smooth muscle cells, adipocytes, and endothelial cells. By signaling through either HVEM or LTβR expressed on these cells, LIGHT can contribute to their proliferation and expression of chemokines, growth factors, and metalloproteinases. This will lead to hyperplasia of epithelial cells, fibroblasts, and smooth muscle cells, deposition of extracellular matrix proteins, vascular damage, and further immune alterations that in concert constitute fibrosis. Because of its early expression by T cells, LIGHT may be an initiator of fibrotic diseases, but other sources in the immune system could also signify a role for LIGHT in maintaining or perpetuating fibrotic activity. LIGHT may then be an attractive prognostic marker as well as an appealing target for fibrosis therapies relevant to humans.
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      PubDate: 2016-01-13T06:51:59Z
       
  • The contribution of pathways initiated via the Gq\11 G-protein family to
           atrial fibrillation
    • Abstract: Publication date: Available online 7 January 2016
      Source:Pharmacological Research
      Author(s): Andrew Tinker, Malcom Finlay, Muriel Nobles, Aaisha Opel
      Atrial fibrillation is the commonest cardiac arrhythmia and leads to significant clinical morbidity and mortality. It has a complex pathophysiology but is often initiated by atrial ectopic beats and because of atrial remodelling once it occurs it can become established. Thus therapeutic interventions designed to prevent the initial occurrence of the arrhythmia are particularly needed. At the cellular level, these ectopic beats arise because of abnormal calcium release events from the sarcoplasmic reticulum leading to an inward current mediated by the sodium-calcium exchanger. There has been considerable interest in this over the last few years largely focused on the ryanodine receptor and related signalling pathways. However atrial myocytes also possess a well-developed inositol trisphosphate (IP3) dependent calcium release system and this has been less studied. In this review we focus on pathways and molecules that couple via the Gq\11 family of G-proteins including regulators of G-protein signalling that may influence IP3 mediated calcium release and atrial fibrillation.
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      PubDate: 2016-01-09T06:40:03Z
       
  • Dynamic mass redistribution reveals diverging importance of PDZ-ligands
           for G protein-coupled receptor pharmacodynamics
    • Abstract: Publication date: Available online 7 January 2016
      Source:Pharmacological Research
      Author(s): Nathan D Camp, Kyung-Soon Lee, Allison Cherry, Jennifer L Wacker-Mhyre, Timothy S Kountz, Ji-Min Park, Dorathy-Ann Harris, Marianne Estrada, Aaron Stewart, Nephi Stella, Alejandro Wolf-Yadlin, Chris Hague
      G protein-coupled receptors (GPCRs) are essential membrane proteins that facilitate cell-to-cell communication and co-ordinate physiological processes. At least 30 human GPCRs contain a Type I PSD-95/DLG/Zo-1 (PDZ) ligand in their distal C-terminal domain; this four amino acid motif of X-[S/T]-X-[φ] sequence facilitates interactions with PDZ domain-containing proteins. Because PDZ protein interactions have profound effects on GPCR ligand pharmacology, cellular localization, signal-transduction effector coupling and duration of activity, we analyzed the importance of Type I PDZ ligands for the function of 23 full-length and PDZ-ligand truncated (ΔPDZ) human GPCRs in cultured human cells. SNAP-epitope tag polyacrylamide gel electrophoresis revealed most Type I PDZ GPCRs exist as both monomers and multimers; removal of the PDZ ligand played minimal role in multimer formation. Additionally, SNAP-cell surface staining indicated removal of the PDZ ligand had minimal effects on plasma membrane localization for most GPCRs examined. Label-free dynamic mass redistribution functional responses, however, revealed diverging effects of the PDZ ligand. While no clear trend was observed across all GPCRs tested or even within receptor families, a subset of GPCRs displayed diminished agonist efficacy in the absence of a PDZ ligand (i.e. HT2RB, ADRB1), whereas others demonstrated enhanced agonist efficacies (i.e. LPAR2, SSTR5). These results demonstrate the utility of label-free functional assays to tease apart the contributions of conserved protein interaction domains for GPCR signal-transduction coupling in cultured cells.
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      PubDate: 2016-01-09T06:40:03Z
       
  • Chronic mild stress-induced alterations of clock gene expression in rat
           prefrontal cortex: modulatory effects of prolonged lurasidone treatment
    • Abstract: Publication date: February 2016
      Source:Pharmacological Research, Volume 104
      Author(s): Francesca Calabrese, Elisa Savino, Mariusz Papp, Raffaella Molteni, Marco A. Riva
      Disruptions of biological rhythms are known to be associated with depressive disorders, suggesting that abnormalities in the molecular clock may contribute to the development of these disorders. These mechanisms have been extensively characterized in the suprachiasmatic nucleus, but little is know about the role exerted by individual clock genes in brain structures that are important for depressive disorders. Using the chronic mild stress model we found a significant reduction of BMAL1 and CLOCK protein levels in the nuclear compartment of the prefrontal cortex of CMS rats, which was paralleled by a down-regulation of the expression of several target genes, including Pers and Crys but also Reverbβ and Pparα. Interestingly, chronic treatment with the multi receptor modulator lurasidone (3mg/kg for 5 weeks) was able to normalize the molecular changes induced by CMS exposure in prefrontal cortex, but it was also able to regulate some of these genes within the hippocampus. We believe that changes in clock genes expression after CMS exposure may contribute to the disturbances associated with depressive disorders and that the ability of chronic lurasidone to normalize such alterations may be relevant for its therapeutic properties in ameliorating functions that are deteriorated in patients with major depression and other stress-related disorders.
      Graphical abstract image

      PubDate: 2016-01-09T06:40:03Z
       
  • Integrated Sphingosine-1 Phosphate Signaling in the Central Nervous
           System: From Physiological Equilibrium to Pathological Damage
    • Abstract: Publication date: Available online 7 January 2016
      Source:Pharmacological Research
      Author(s): Rasoul Ghasemi, Leila Dargahi, Abolhassan Ahmadiani
      Sphingosine-1 phosphate (S1P), a bioactive sphingolipid metabolite, plays an essential role in cellular homeostasis. It is well evidenced that enzymes responsible for S1P production, as well as S1P receptors are expressed in the central nervous system (CNS), implying that S1P may contribute to CNS physiology. In current review, we will present the current knowledge about developmental and neuromodulatory functions of S1P in the brain. Considering neuroprotective effects of S1P, we also review the relation between S1P and cellular autophagy, mitochondrial function, oxidative stress and apoptosis as well as molecular pathways underlying neuroprotective effects of S1P. Given these pivotal functions, in the last section, we will summarize latest findings about possible contribution of S1P dysregulation in neurological disorders like Alzheimer's disease and Multiple sclerosis.


      PubDate: 2016-01-09T06:40:03Z
       
  • CYP1B1 inhibition attenuates Doxorubicin-induced cardiotoxicity through a
           mid-chain HETEs-dependent mechanism
    • Abstract: Publication date: Available online 6 January 2016
      Source:Pharmacological Research
      Author(s): Zaid H. Maayah, Hassan N. Althurwi, Ghada Abdelhamid, Gabriela Lesyk, Paul Jurasz, Ayman O.S. El-Kadi
      Doxorubicin (DOX) has been reported to be a very potent and effective anticancer agent. However, clinical treatment with DOX has been greatly limited due to its cardiotoxicity. Furthermore, several studies have suggested a role for cytochrome P450 1B1 (CYP1B1) and mid-chain hydroxyeicosatetraenoic acids (mid-chain HETEs) in DOX-induced cardiac toxicity. Therefore, we hypothesized that DOX induced cardiotoxicity is mediated through the induction of CYP1B1 and its associated mid-chain HETEs metabolites. To test our hypothesis, Sprague-Dawley rats and RL-14 cells were treated with DOX in the presence and absence of tetramethoxystilbene (TMS), a selective CYP1B1 inhibitor. Thereafter, cardiotoxicity parameters were determined using echocardiography, histopathology, and gene expression. Further, the level of mid-chain HETEs was quantified using liquid chromatography-electron spray ionization-mass spectrometry. Our results showed that DOX induced cardiotoxicity in vivo and in vitro as evidenced by deleterious changes in echocardiography, histopathology, and hypertrophic markers. Importantly, the TMS significantly reversed these changes. Moreover, the DOX-induced cardiotoxicity was associated with a proportional increase in the formation of cardiac mid-chain HETEs both in vivo and in our cell culture model. Interestingly, the inhibition of cardiotoxicity by TMS was associated with a dramatic decrease in the formation of cardiac mid-chain HETEs suggesting a mid-chain HETEs-dependent mechanism. Mechanistically, the protective effect of TMS against DOX-induced cardiotoxicity was mediated through the inhibition of mitogen activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB). In conclusion, our study provides the first evidence that the inhibition of CYP1B1 and mid-chain HETE formation attenuate DOX-induced cardiotoxicty.
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      PubDate: 2016-01-09T06:40:03Z
       
  • UGT genotyping in belinostat dosing
    • Abstract: Publication date: Available online 7 January 2016
      Source:Pharmacological Research
      Author(s): Andrew K.L. Goey, William D. Figg
      Certain genetic polymorphisms of UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) can reduce gene expression (*28, *60, *93) or activity (*6), thereby altering the pharmacokinetics, pharmacodynamics, and the risk of toxicities of UGT1A1 substrates, of which irinotecan is a widely-described example. This review presents an overview of the clinical effects of UGT1A1 polymorphisms on the pharmacology of UGT1A1 substrates, with a special focus on the novel histone deacetylase inhibitor belinostat. Belinostat, approved for the treatment of peripheral T-cell lymphoma, is primarily glucuronidated by UGT1A1. Recent preclinical and clinical data showed that UGT1A1*28 was associated with reduced glucuronidation in human liver microsomes, while in a retrospective analysis of a Phase I trial with patients receiving belinostat UGT1A1*60 was predominantly associated with increased belinostat plasma concentrations. Furthermore, both UGT1A1*28 and *60 variants were associated with increased incidence of thrombocytopenia and neutropenia. Using population pharmacokinetic analysis a 33% dose reduction has been proposed for patients carrying UGT1A1 variant alleles. Clinical effects of this genotype-based dosing recommendation is currently prospectively being investigated. Overall, the data suggest that UGT1A1 genotyping is useful for improving belinostat therapy.
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      PubDate: 2016-01-09T06:40:03Z
       
  • Synthesis of dihydropyrazole sulphonamide derivatives that act as
           anti-cancer agents through COX-2 inhibition
    • Abstract: Publication date: February 2016
      Source:Pharmacological Research, Volume 104
      Author(s): Han-Yue Qiu, Peng-Fei Wang, Zhen Li, Jun-Ting Ma, Xiao-Ming Wang, Yong-Hua Yang, Hai-Liang Zhu
      COX-2 has long been exploited in the treatment of inflammation and relief of pain; however, research increasingly suggests COX-2 inhibitors might possess potential benefits to thwart tumour processes. In the present study, we designed a series of novel COX-2 inhibitors based on analysis of known inhibitors combined with an in silico scaffold modification strategy. A docking simulation combined with a primary screen in vitro were performed to filter for the lead compound, which was then substituted, synthesized and evaluated by a variety of bioassays. Derivative 4d was identified as a potent COX-2 enzyme inhibitor and exerted an anticancer effect through COX-2 inhibition. Further investigation confirmed that 4d could induce A549 cell apoptosis and arrest the cell cycle at the G2/M phase. Moreover, treatment with 4d reduced A549 cell adhesive ability and COX-2 expression. The morphological variation of treated cells was also visualized by confocal microscopy. Overall, the biological profile of 4d suggests that this compound may be developed as a potential anticancer agent.
      Graphical abstract image

      PubDate: 2016-01-05T06:01:06Z
       
  • Activation of a synapse weakening pathway by human Val66 but not Met66
           pro-brain-derived neurotrophic factor (proBDNF)
    • Abstract: Publication date: February 2016
      Source:Pharmacological Research, Volume 104
      Author(s): Sumangali Kailainathan, Thomas M. Piers, Jee Hyun Yi, Seongmin Choi, Mark S. Fahey, Eva Borger, Frank J. Gunn-Moore, Laurie O’Neill, Michael Lever, Daniel J. Whitcomb, Kwangwook Cho, Shelley J. Allen
      This study describes a fundamental functional difference between the two main polymorphisms of the pro-form of brain-derived neurotrophic factor (proBDNF), providing an explanation as to why these forms have such different age-related neurological outcomes. Healthy young carriers of the Met66 form (present in ∼30% Caucasians) have reduced hippocampal volume and impaired hippocampal-dependent memory function, yet the same polymorphic population shows enhanced cognitive recovery after traumatic brain injury, delayed cognitive dysfunction during aging, and lower risk of late-onset Alzheimer’s disease (AD) compared to those with the more common Val66 polymorphism. To examine the differences between the protein polymorphisms in structure, kinetics of binding to proBDNF receptors and in vitro function, we generated purified cleavage-resistant human variants. Intriguingly, we found no statistical differences in those characteristics. As anticipated, exogenous application of proBDNF Val66 to rat hippocampal slices dysregulated synaptic plasticity, inhibiting long-term potentiation (LTP) and facilitating long-term depression (LTD). We subsequently observed that this occurred via the glycogen synthase kinase 3β (GSK3β) activation pathway. However, surprisingly, we found that Met66 had no such effects on either LTP or LTD. These novel findings suggest that, unlike Val66, the Met66 variant does not facilitate synapse weakening signaling, perhaps accounting for its protective effects with aging.
      Graphical abstract image

      PubDate: 2016-01-05T06:01:06Z
       
  • Epigallocatechin gallate and mitochondria—A story of life and death
    • Abstract: Publication date: Available online 29 December 2015
      Source:Pharmacological Research
      Author(s): Marcos Roberto de Oliveira, Seyed Fazel Nabavi, Maria Daglia, Luca Rastrelli, Seyed Mohammad Nabavi
      Epigallocatechin gallate (EGCG) is a flavonoid belonging to the chemical class of falvan-3-ols (catechins) esterified with gallic acid. It is the main catechin found in green tea (Camellia sinensis L.) accounting for about 50% of its total polyphenols. Extensive research performed in recent years has revealed that green tea demonstrates a wide range of positive biological activities against serious chronic diseases such as cardiovascular and neurodegenerative pathologies, cancer, metabolic syndrome and type 2 diabetes. These protective properties can be traced back to the potent antioxidant and anti-inflammatory activities of EGCG. Recent studies have suggested that it may exert its beneficial effects by modulating mitochondrial functions impacting mitochondrial biogenesis, bioenergetic control (ATP production and anabolism), alteration of the cell cycle, and mitochondria-related apoptosis. This review evaluates recent evidence on the ability of EGCG to exert critical influence on the above mentioned pathways.
      Graphical abstract image

      PubDate: 2016-01-01T05:30:03Z
       
  • Kinin B1 Receptor Antagonist BI113823 Reduces Allergen-Induced Airway
           Inflammation and Mucus Secretion in Mice
    • Abstract: Publication date: Available online 30 December 2015
      Source:Pharmacological Research
      Author(s): Malarvizhi Gurusamy, Saeed Nasseri, Hana Lee, Birgit Jung, Dongwon Lee, Gilson Khang, William M. Abraham, Henri Doods, Dongmei Wu
      Kinin B1 receptors are implicated in asthmatic airway inflammation. Here we tested this hypothesis by examining the anti-inflammatory effects of BI113823, a novel non-peptide orally active kinin B1 receptor antagonist in mice sensitized to ovalbumin (OVA). Male Balb-c mice were randomly assigned to four study groups: 1) Control, 2) OVA+vehicle, 3) OVA+BI113823, 4) OVA+dexamethasone. Mice were sensitized intraperitoneally with 75μg ovalbumin on days 1 and 8. On days 15 to 17, mice were challenged intranasally with 50μg of ovalbumin. Mice received vehicle, BI113823, or dexamethasone (positive control) on days 16 to 18. On day 19, bronchoalveolar lavage (BAL) and lung tissue were collected for biochemical and immuno-histological analysis. Compared to controls treatment with BI113823 significantly reduced the numbers of BAL eosinophils, macrophages, neutrophils and lymphocytes by 58.3%, 61.1%, 66.4% and 56.0%, respectively. Mice treated with dexamethasone showed similar reductions in BAL cells. Treatment with BI113823 and dexamethasone also significantly reduced total protein content, IgE, TNF-α and IL-1β in lavage fluid, reduced myeloperoxidase activity, mucus secretion in lung tissues, and reduced the expression of B1 receptors, matrix metalloproteinase (MMP)-2 and cyclooxygenase (COX)-2 compared to vehicle-treated mice. Only BI113823 reduced MMP-9 and inducible nitric oxide synthase (iNOS). BI113823 effectively reduced OVA-induced inflammatory cell, mediator and signaling pathways equal to or greater than that seen with steroids in a mouse asthma model. BI113823 might be useful in modulating inflammation in asthma.
      Graphical abstract image

      PubDate: 2016-01-01T05:30:03Z
       
  • Mfsd2a-based pharmacological strategies for drug delivery across the
           blood–brain barrier
    • Abstract: Publication date: Available online 30 December 2015
      Source:Pharmacological Research
      Author(s): Jing-Zhang Wang, Ning Xiao, Ying-Zhou Zhang, Chao-Xian Zhao, Xin-Hua Guo, Li-Min Lu
      The blood–brain barrier (BBB) keeps the central nervous system (CNS) safe from various brain diseases, while the BBB makes it difficult for effective drugs to enter the CNS. Mfsd2a is specifically expressed on the cell membrane of brain-microvascular endothelial cell (BMEC) and is implicated in the delivery of some substances across the BBB. Mfsd2a is the first inhibitor of the transcytosis and the first transporter for lysophosphatidylcholine-docosahexaenoic acid (LPC-DHA) in BMECs. The crucial dual function of Mfsd2a puts forward two kinds of Mfsd2a-based strategies for carrying drugs from blood to the CNS. First, the reversible inhibition of Mfsd2a may temporarily induce a general disinhibition of the transcytosis in BMECs to transport macromolecular drugs across the BBB (Strategy One). Second, Mfsd2a could be used for the transport of some small-molecule drugs chemically coupled to LPC across the BBB (Strategy Two), which is quite similar to the carrier-mediated transport (CMT) via the glucose transporter (GluT1) and the L-type amino acid transporter 1 (LAT1). We here analyse and discuss the clinical significance of the two Mfsd2a-based strategies, including therapeutic potential, available pharmaceuticals, side effects, administration procedures, and disease types. In summary, the regulatory role of Mfsd2a deepens our knowledge of the function of the BBB, potentially contributing to the effective drug delivery in the treatments for neurodegenerative diseases, brain tumors, and life-threatening infections in the CNS.
      Graphical abstract image

      PubDate: 2016-01-01T05:30:03Z
       
  • Higenamine Protects Ischemia/reperfusion Induced Cardiac Injury and
           Myocyte Apoptosis through Activation of β2-AR/PI3K/AKT Signaling
           Pathway
    • Abstract: Publication date: Available online 30 December 2015
      Source:Pharmacological Research
      Author(s): Mei-ping Wu, Yi-shuai Zhang, Qian-mei Zhou, Jian Xiong, Yao-rong Dong, Chen Yan
      Cardiomyocyte apoptosis contributes to ischemic cardiac injury and the development of heart failure. Higenamine is a key component of the Chinese herb aconite root that has been prescribed for treating symptoms of heart failure for thousands of years in the oriental Asian countries. It has been shown that higenamine has anti-apoptotic effects in a few cell types including cardiomyocytes. However, the pharmacological target and molecular mechanism of higenamine in the heart are still not fully illustrated. Herein, we report that higenamine protected myocyte apoptosis and ischemia/reperfusion (I/R) injury through selective activation of beta2-adrenergic receptor (β2-AR). In particular, we show that higenamine significantly reduced I/R-induced myocardial infarction in mice. In both primary neonatal rat and adult mouse ventricular myocytes, we show higenamine inhibited cell apoptosis and also reduced biochemical markers of apoptosis such as cleaved caspase 3 and 9. More importantly, we show that the anti-apoptotic effects of higenamine in cardiomyocytes were completely abolished by β2-AR but not β1-AR antagonism. Furthermore, we confirmed that higenamine attenuated I/R-induced myocardial injury and reduced cleaved caspases in a β2-AR dependent manner in intact mouse hearts. Higenamine stimulated AKT phosphorylation and required PI3K activation for the anti-apoptotic effect in cardiomyocytes. These findings together suggest that anti-apoptotic and cardiac protective effects of higenamine are mediated by the β2-AR/PI3K/AKT cascade.
      Graphical abstract image

      PubDate: 2016-01-01T05:30:03Z
       
  • Risk of gastrointestinal complications associated to NSAIDs,
           low—dose aspirin and their combinations: results of a regional
           spontaneous reporting system
    • Abstract: Publication date: Available online 29 December 2015
      Source:Pharmacological Research
      Author(s): Concetta Rafaniello, Carmen Ferrajolo, Maria Giuseppa Sullo, Maurizio Sessa, Liberata Sportiello, Antonio Balzano, Francesco Manguso, Maria Luisa Aiezza, Francesco Rossi, Carmelo Scarpignato, Annalisa Capuano
      Gastrointestinal (GI) complications are one of the most limiting cause of use of NSAIDs. Beyond others well defined factors, history of peptic ulcer, older age, Helicobacter pylori infection and use of gastrotoxic drugs may affect their GI safety profile. In particular, the risk of GI complications associated to the use of antiplatelet drugs, especially low-dose acetylsalicylic acid (LDA) should deserve much attention. However, only few studies have focused on the effect of combination LDA/NSAIDs on the GI tract compared with the monotherapy and much less studies assessed this effect with multiple NSAIDs use. We aimed to characterize the GI safety profile of NSAIDs and LDA as monotherapy or their combinations in real-life conditions by analysing spontaneous adverse drug reactions (ADRs) reporting system in a Southern Italy. We used the case/non-case method in the Italian Pharmacovigilance Network (RNF). Cases were reports of GI events in the RNF between January 2007 and December 2011. Non-cases were all other reports during the same period. The association between NSAID and suspected GI ADRs was calculated using the reporting odds ratio (ROR) with 95% confidence intervals as a measure of disproportionality while adjusting for age, and concomitant use of antineoplastic agents or drugs for cardiovascular diseases. Sub-analysis were performed within the NSAID class. Among the 2,816 adverse drug reactions recorded, we identified 374 (13.3%) cases of GI complications. Upper GI complications were the most frequently reported type of events. The highest associations were found for the combined use of NSAIDs and/or LDA, whilst the lowest associations were for their respective monotherapy. Looking at individual NSAIDs the highest association with GI events was observed for ketorolac exposure followed by nimesulide, diclofenac, aspirin, ketoprofen, and ibuprofen. This study highlights the primary role of the national spontaneous reporting system to bring out potential signals, such as the inappropriate drug use pattern, which however, have to be furtherly studied in-depth with ad hoc population-based studies.
      Graphical abstract image

      PubDate: 2016-01-01T05:30:03Z
       
  • The modulation of BDNF expression and signalling dissects the
           antidepressant from the reinforcing properties of ketamine: Effects of
           single infusion vs. chronic self-administration in rats
    • Abstract: Publication date: Available online 17 December 2015
      Source:Pharmacological Research
      Author(s): Lucia Caffino, Marzia Di Chio, Giuseppe Giannotti, Marco Venniro, Anna Mutti, Laura Padovani, David Cheung, Guido F. Fumagalli, David T. Yew, Fabio Fumagalli, Cristiano Chiamulera
      Ketamine is a drug of abuse with a unique profile, which besides its inherent mechanism of action as a non-competitive antagonist of the NMDA glutamate receptor, displays both antidepressant and reinforcing properties. The major aim of our study was to find a molecular signature of ketamine that may help in discriminating between its reinforcing and antidepressant effects. To this end, we focused our attention on BDNF, a neurotrophin that has been shown to play a role in both antidepressant and reinforcing properties of several drugs. Rats were exposed to self-administer intravenous (IV) ketamine (S/A) for 43 days or to receive a single IV ketamine 0.5mg/kg, or vehicle infusion. Although the dose we employed is lower than that reported by the literature, it however yields Cmax values that correspond to those achieved in humans after antidepressant treatment. Our results show that while the single infusion of ketamine increased the neurotrophin expression in the hippocampus while reducing it in the ventral striatum, a feature shared with other antidepressants, the repeated self-administration reduced mBDNF expression and its downstream signalling in both ventral striatum and hippocampus. Further, we here show that phosphorylation of Akt is oppositely regulated by ketamine, pointing to this pathway as central to the different actions of the drug. Taken together, we here point to BDNF and its downstream signalling pathway as a finely tuned mechanism whose modulation might subserve the different features of ketamine.
      Graphical abstract image

      PubDate: 2015-12-20T07:21:46Z
       
  • Pharmacology of Bile Acid Receptors: Evolution of Bile Acids from Simple
           Detergents to Complex Signaling Molecules
    • Abstract: Publication date: Available online 17 December 2015
      Source:Pharmacological Research
      Author(s): Bryan L. Copple, Tiangang Li
      For many years, bile acids were thought to only function as detergents which solubilize fats and facilitate the uptake of fat-soluble vitamins in the intestine. Many early observations, however, demonstrated that bile acids regulate more complex processes, such as bile acids synthesis and immune cell function through activation of signal transduction pathways. These studies were the first to suggest that receptors may exist for bile acids. Ultimately, seminal studies by many investigators led to the discovery of several bile acid-activated receptors including the farnesoid X receptor, the vitamin D receptor, the pregnane X receptor, TGR5, α5 β1 integrin, and sphingosine-1-phosphate receptor 2. Several of these receptors are expressed outside of the gastrointestinal system, indicating that bile acids may have diverse functions throughout the body. Characterization of the functions of these receptors over the last two decades has identified many important roles for these receptors in regulation of bile acid synthesis, transport, and detoxification; regulation of glucose utilization; regulation of fatty acid synthesis and oxidation; regulation of immune cell function; regulation of energy expenditure; and regulation of neural processes such as gastric motility. Through these many functions, bile acids regulate many aspects of digestion ranging from uptake of essential vitamins to proper utilization of nutrients. Accordingly, within a short time period, bile acids moved beyond simple detergents and into the realm of complex signaling molecules. Because of the important processes that bile acids regulate through activation of receptors, drugs that target these receptors are under development for the treatment of several diseases, including cholestatic liver disease and metabolic syndrome. In this review, we will describe the various bile acid receptors, the signal transduction pathways activated by these receptors, and briefly discuss the physiological processes that these receptors regulate.
      Graphical abstract image

      PubDate: 2015-12-20T07:21:46Z
       
  • New PPARγ partial agonist improves obesity-induced metabolic
           alterations and atherosclerosis in LDLr−/− mice
    • Abstract: Publication date: Available online 17 December 2015
      Source:Pharmacological Research
      Author(s): Jacqueline C. Silva, Fernanda A. César, Edson M. de Oliveira, Walter M. Turato, Gustavo L. Tripodi, Gabriela Castilho, Adriana Machado-Lima, Beatriz de las Heras, Lisardo Boscá, Marcelo M. Rabello, Marcelo Z. Hernandes, Marina G.R. Pitta, Ivan R. Pitta, Marisa Passarelli, Martina Rudnicki, Dulcineia S.P. Abdalla
      Peroxisome proliferator-activated receptor gamma (PPARγ) regulates multiple pathways involved in the pathogenesis of obesity and atherosclerosis. Here, we evaluated the therapeutic potential of GQ-177, a new thiazolidinedione, on diet-induced obesity and atherosclerosis. The intermolecular interaction between PPARγ and GQ-177 was examined by virtual docking and PPAR activation was determined by reporter gene assay identifying GQ-177 as a partial and selective PPARγ agonist. For the evaluation of biological activity of GQ-177, low-density lipoprotein receptor-deficient (LDLr−/−) C57/BL6 mice were fed either a high fat diabetogenic diet (diet-induced obesity), or a high fat atherogenic diet, and treated with vehicle, GQ-177 (20mg/kg/day), pioglitazone (20mg/kg/day, diet-induced obesity model) or rosiglitazone (15mg/kg/day, atherosclerosis model) for 28 days. In diet-induced obesity mice, GQ-177 improved insulin sensitivity and lipid profile, increased plasma adiponectin and GLUT4 mRNA in adipose tissue, without affecting body weight, food consumption, fat accumulation and bone density. Moreover, GQ-177 enhanced hepatic mRNA levels of proteins involved in lipid metabolism. In the atherosclerosis mice, GQ-177 inhibited atherosclerotic lesion progression, increased plasma HDL and mRNA levels of PPARγ and ATP-binding cassette A1 in atherosclerotic lesions. GQ-177 acts as a partial PPARγ agonist that improves obesity-associated insulin resistance and dyslipidemia with atheroprotective effects in LDLr−/− mice.
      Graphical abstract image

      PubDate: 2015-12-20T07:21:46Z
       
  • Effects of bioactive fatty acid amide derivatives in zebrafish scale model
           of bone metabolism and disease
    • Abstract: Publication date: Available online 18 December 2015
      Source:Pharmacological Research
      Author(s): M. Carnovali, R. Ottria, S. Pasqualetti, G. Banfi, P. Ciuffreda, M. Mariotti
      The endocannabinoid system (which includes fatty acid derivatives, receptors, and metabolizing enzymes) is involved in a variety of physiological processes, including bone metabolism in which it regulates the function of osteoblasts and osteoclasts, as well as differentiation of their precursors. The zebrafish (Danio rerio) provides a useful animal model for bone research since zebrafish bones develop rapidly and are anatomically similar to mammalian bones. Putative orthologues and paralogs of endocannabinoid genes have recently been identified in zebrafish, demonstrating the presence of cannabinoid type 1 (CB1) and type 2 (CB2) receptors with affinity to endocannabinoid ligands. To identify therapeutic molecules potentially useful in bone-related diseases, we evaluated the in vivo effects of exposure to long-chain fatty acid amides in adult zebrafish. Using a well-established zebrafish scale model, we found that anandamide and N-linoleoylethanolamine are able to stimulate bone formation by increasing alkaline phosphatase activity in physiological conditions. In addition, they prevent the alteration of bone markers in a prednisolone-induced osteoporosis model in adult zebrafish scales, whereas their esterified forms do not. These data suggest that long-chain fatty acid amides are involved in regulating bone metabolism in zebrafish scales and that the CB2 receptor is a key mediator in this process.
      Graphical abstract image

      PubDate: 2015-12-20T07:21:46Z
       
  • SKF-96365 blocks human ether-à-go-go-related gene potassium channels
           stably expressed in HEK 293 cells
    • Abstract: Publication date: Available online 12 December 2015
      Source:Pharmacological Research
      Author(s): Hui Liu, Lei Yang, Kui-Hao Chen, Hai-Ying Sun, Man-Wen Jin, Guo-Sheng Xiao, Yan Wang, Gui-Rong Li
      SKF-96365 is a TRPC channel antagonist commonly used to characterize the potential functions of TRPC channels in different systems, which was recently reported to induce QTc prolongation on ECG by inhibiting TRPC channels. The present study investigates whether the blockade of cardiac repolarization currents would be involved in the increase of QTc interval. Cardiac repolarization currents were recorded in HEK 293 cells stably expressing human ether-à-go-go-related gene potassium (hERG or hKv11.1) channels, hKCNQ1/hKCNE1 channels (IKs) or hKir2.1 channels and cardiac action potentials were recorded in guinea pig ventricular myocytes using a whole-cell patch voltage-clamp technique. The potential effect of SKF-96365 on QT interval was evaluated in ex vivo guinea pig hearts. It was found that SKF-96365 inhibited hERG current in a concentration-dependent manner (IC50, 3.4μM). The hERG mutants S631A in the pore helix and F656V of the S6 region reduced the inhibitory sensitivity with IC50s of 27.4μM and 11.0μM, suggesting a channel pore blocker. In addition, this compound inhibited IKs and hKir2.1currents with IC50s of 10.8 and 8.7μM. SKF-96365 (10μM) significantly prolonged ventricular APD90 in guinea pig ventricular myocytes and QTc interval in ex vivo guinea pig hearts. These results indicate that the TRPC channel antagonist SKF-96365 exerts blocking effects on hERG, IKs, and hKir2.1 channels. Prolongation of ventricular APD and QT interval is related to the inhibition of multiple repolarization potassium currents, especially hERG channels.
      Graphical abstract image

      PubDate: 2015-12-16T12:11:27Z
       
  • Gene Expression Profiling Combined with Functional Analysis Identify
           Integrin Beta1 (ITGB1) as a Potential Prognosis Biomarker in Triple
           Negative Breast Cancer
    • Abstract: Publication date: Available online 8 December 2015
      Source:Pharmacological Research
      Author(s): Sukhontip Klahan, Wan-Chen Huang, Che-Mai Chang, Henry Sung-Ching Wong, Chi-Cheng Huang, Mei-Shin Wu, Yu-Chiao Lin, Hsing-Fang Lu, Ming-Feng Hou, Wei-Chiao Chang
      Triple negative breast cancer (TNBC) accounts for approximately 15%∼20% of all types of breast cancer, and treatment is still limited. This type of breast cancer shows a high risk of recurrence, visceral metastasis, a worse prognosis, and shorter distant metastasis-free survival. Several studies have been reported that genetics factors are associated with breast cancer disease progression and patients' survival. In this study, we combined Taiwanese microarray data from the GEO database and The Cancer Genome Atlas (TCGA) database to study the role of Integrin Beta1 (ITGB1) in TNBC. Two triple negative breast cancer cell lines (MDA-MB-231; MDA-MB-468) were used to validate the functions of ITGB1. We found that a higher ITGB1 gene expression level was associated to lower survival. Silencing of ITGB1 inhibited TNBC cell migration, invasion and store-operated calcium influx. Our study provided a potential candidate biomarker for breast cancer cells migration, invasion and TNBC patients' survival.
      Graphical abstract image

      PubDate: 2015-12-08T11:47:09Z
       
 
 
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