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Publisher: Elsevier   (Total: 2812 journals)

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Soil Dynamics and Earthquake Engineering     Hybrid Journal   (Followers: 8, SJR: 1.482, h-index: 45)
Soils and foundations     Full-text available via subscription   (SJR: 1.669, h-index: 39)
Solar Energy     Hybrid Journal   (Followers: 17, SJR: 2.291, h-index: 85)
Solar Energy Materials and Solar Cells     Hybrid Journal   (Followers: 26, SJR: 2.331, h-index: 107)
Solid State Communications     Hybrid Journal   (Followers: 7, SJR: 0.874, h-index: 93)
Solid State Ionics     Hybrid Journal   (Followers: 5, SJR: 0.938, h-index: 132)
Solid State Nuclear Magnetic Resonance     Hybrid Journal   (Followers: 3, SJR: 1.107, h-index: 43)
Solid State Physics     Full-text available via subscription   (SJR: 0.272, h-index: 18)
Solid State Sciences     Hybrid Journal   (Followers: 6, SJR: 0.717, h-index: 54)
Solid-State Electronics     Hybrid Journal   (Followers: 5, SJR: 0.819, h-index: 66)
South African J. of Botany     Hybrid Journal   (Followers: 4, SJR: 0.531, h-index: 29)
Space Policy     Hybrid Journal   (Followers: 16, SJR: 0.256, h-index: 14)
Space Research Today     Full-text available via subscription   (Followers: 27, SJR: 0.123, h-index: 2)
Spanish Review of Financial Economics, The     Full-text available via subscription   (Followers: 1, SJR: 0.115, h-index: 1)
Spatial and Spatio-temporal Epidemiology     Hybrid Journal   (Followers: 3, SJR: 0.721, h-index: 8)
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy     Hybrid Journal   (Followers: 7, SJR: 0.628, h-index: 64)
Spectrochimica Acta Part B: Atomic Spectroscopy     Hybrid Journal   (Followers: 7, SJR: 1.125, h-index: 79)
Speech Communication     Hybrid Journal   (Followers: 12, SJR: 0.701, h-index: 63)
Spine Deformity     Full-text available via subscription   (Followers: 2)
Sport Management Review     Hybrid Journal   (Followers: 5, SJR: 0.754, h-index: 20)
Sport-Orthopädie - Sport-Traumatologie - Sports Orthopaedics and Traumatology     Full-text available via subscription   (Followers: 3, SJR: 0.124, h-index: 5)
Statistical Methodology     Hybrid Journal   (Followers: 9, SJR: 0.642, h-index: 15)
Statistics & Probability Letters     Hybrid Journal   (Followers: 7, SJR: 0.771, h-index: 38)
Stem Cell Reports     Open Access   (Followers: 4)
Stem Cell Research     Open Access   (Followers: 12, SJR: 1.898, h-index: 27)
Steroids     Hybrid Journal   (Followers: 1, SJR: 0.98, h-index: 77)
Stochastic Processes and their Applications     Hybrid Journal   (Followers: 3, SJR: 1.444, h-index: 46)
Strategies and Tactics in Organic Synthesis     Full-text available via subscription   (Followers: 5, SJR: 0.164, h-index: 6)
Structural Change and Economic Dynamics     Hybrid Journal   (Followers: 3, SJR: 0.334, h-index: 26)
Structural Safety     Hybrid Journal   (Followers: 7, SJR: 2.84, h-index: 49)
Structure     Full-text available via subscription   (Followers: 17, SJR: 5.17, h-index: 138)
Structures     Hybrid Journal  
Studies in Applied Mechanics     Full-text available via subscription   (Followers: 1)
Studies in Computational Mathematics     Full-text available via subscription  
Studies in Computer Science and Artificial Intelligence     Full-text available via subscription   (Followers: 5)
Studies in Educational Evaluation     Hybrid Journal   (Followers: 7, SJR: 0.626, h-index: 19)
Studies in Environmental Science     Full-text available via subscription   (Followers: 7)
Studies in History and Philosophy of Science Part A     Hybrid Journal   (Followers: 3, SJR: 0.567, h-index: 21)
Studies in History and Philosophy of Science Part B: Studies in History and Philosophy of Modern Physics     Hybrid Journal   (Followers: 7)
Studies in History and Philosophy of Science Part C: Studies in History and Philosophy of Biological and Biomedical Sciences     Hybrid Journal   (Followers: 9, SJR: 0.308, h-index: 21)
Studies in Inorganic Chemistry     Full-text available via subscription  
Studies in Interface Science     Full-text available via subscription   (Followers: 1, SJR: 0.1, h-index: 10)
Studies in Logic and Practical Reasoning     Full-text available via subscription  
Studies in Logic and the Foundations of Mathematics     Full-text available via subscription  
Studies in Mathematical Physics     Full-text available via subscription  
Studies in Mathematics and Its Applications     Full-text available via subscription  
Studies in Multidisciplinarity     Full-text available via subscription   (Followers: 5)
Studies in Mycology     Open Access  
Studies in Natural Products Chemistry     Full-text available via subscription   (Followers: 3, SJR: 0.221, h-index: 22)
Studies in Organic Chemistry     Full-text available via subscription   (Followers: 5)
Studies in Physical and Theoretical Chemistry     Full-text available via subscription   (Followers: 5)
Studies in Plant Science     Full-text available via subscription   (Followers: 2)
Studies in Surface Science and Catalysis     Full-text available via subscription   (Followers: 1, SJR: 0.282, h-index: 41)
Studies in the History and Philosophy of Mathematics     Full-text available via subscription   (Followers: 4)
Studies in Visual Information Processing     Full-text available via subscription   (Followers: 2)
Sugar Series     Full-text available via subscription   (Followers: 1)
Suma de Negocios     Open Access  
Superlattices and Microstructures     Hybrid Journal   (Followers: 2, SJR: 0.745, h-index: 44)
Supplements to Clinical Neurophysiology     Full-text available via subscription   (Followers: 1, SJR: 0.123, h-index: 29)
Surface and Coatings Technology     Hybrid Journal   (Followers: 33, SJR: 1.178, h-index: 109)
Surface Science     Hybrid Journal   (Followers: 18, SJR: 0.853, h-index: 105)
Surface Science Reports     Full-text available via subscription   (Followers: 14, SJR: 8.627, h-index: 81)
Surgery     Hybrid Journal   (Followers: 10, SJR: 1.691, h-index: 118)
Surgery (Oxford)     Full-text available via subscription   (Followers: 4, SJR: 0.132, h-index: 14)
Surgery for Obesity and Related Diseases     Full-text available via subscription   (Followers: 5, SJR: 1.918, h-index: 46)
Surgical Clinics     Full-text available via subscription   (Followers: 2, SJR: 0.978, h-index: 68)
Surgical Oncology     Hybrid Journal   (Followers: 2, SJR: 0.86, h-index: 41)
Surgical Oncology Clinics of North America     Full-text available via subscription   (Followers: 4, SJR: 0.726, h-index: 41)
Surgical Pathology Clinics     Full-text available via subscription   (Followers: 4, SJR: 0.146, h-index: 3)
Survey of Ophthalmology     Full-text available via subscription   (Followers: 10, SJR: 1.842, h-index: 92)
Sustainability of Water Quality and Ecology     Hybrid Journal  
Sustainability Science and Engineering     Full-text available via subscription   (Followers: 6, SJR: 0.581, h-index: 4)
Sustainable Cities and Society     Hybrid Journal   (Followers: 26, SJR: 0.677, h-index: 7)
Sustainable Energy Technologies and Assessments     Full-text available via subscription  
Sustainable Energy, Grids and Networks     Hybrid Journal  
Sustainable Management of Sediment Resources     Full-text available via subscription  
Sustainable Materials and Technologies     Open Access  
Swarm and Evolutionary Computation     Hybrid Journal   (SJR: 5.631, h-index: 13)
Synergy     Full-text available via subscription  
Synthetic Metals     Hybrid Journal   (Followers: 3, SJR: 0.762, h-index: 102)
System     Hybrid Journal   (Followers: 9, SJR: 0.774, h-index: 33)
Systematic and Applied Microbiology     Hybrid Journal   (Followers: 1, SJR: 1.41, h-index: 64)
Systems & Control Letters     Hybrid Journal   (Followers: 3, SJR: 1.67, h-index: 85)
Systems Engineering Procedia     Open Access  
Taiwanese J. of Obstetrics and Gynecology     Full-text available via subscription   (Followers: 1, SJR: 0.424, h-index: 18)
Talanta     Hybrid Journal   (Followers: 9, SJR: 1.235, h-index: 103)
Tanta Dental J.     Open Access  
Teaching and Learning in Nursing     Full-text available via subscription   (Followers: 7, SJR: 0.313, h-index: 8)
Teaching and Teacher Education     Hybrid Journal   (Followers: 32, SJR: 1.792, h-index: 58)
Techniques and Instrumentation in Analytical Chemistry     Full-text available via subscription   (Followers: 6, SJR: 0.107, h-index: 5)
Techniques in Gastrointestinal Endoscopy     Hybrid Journal   (Followers: 3, SJR: 0.344, h-index: 9)
Techniques in Protein Chemistry     Full-text available via subscription   (Followers: 2)
Techniques in Regional Anesthesia and Pain Management     Hybrid Journal   (Followers: 12, SJR: 0.134, h-index: 10)
Techniques in Vascular and Interventional Radiology     Full-text available via subscription   (Followers: 3, SJR: 0.422, h-index: 22)
Technological Forecasting and Social Change     Hybrid Journal   (Followers: 10, SJR: 1.265, h-index: 52)
Technology in Society     Hybrid Journal   (Followers: 4, SJR: 0.271, h-index: 27)
Technovation     Hybrid Journal   (Followers: 9, SJR: 2.027, h-index: 62)
Tectonophysics     Hybrid Journal   (Followers: 15, SJR: 1.817, h-index: 107)
Tékhne : Review of Applied Management Studies     Full-text available via subscription  
Telecommunications Policy     Hybrid Journal   (Followers: 6, SJR: 0.627, h-index: 40)

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Journal Cover   Pharmacological Research
  [SJR: 1.693]   [H-I: 84]   [3 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1043-6618 - ISSN (Online) 1096-1186
   Published by Elsevier Homepage  [2812 journals]
  • Modulation of the neuronal network activity by P2X receptors and their
           involvement in neurological disorders
    • Abstract: Publication date: Available online 26 June 2015
      Source:Pharmacological Research
      Author(s): F. Sáez-Orellana , P.A. Godoy , T. Silva-Grecchi , K.M. Barra , J. Fuentealba
      ATP is a key energetic molecule, fundamental to cell function, which also has an important role in the extracellular milieu as a signaling molecule, acting as a chemoattractant for immune cells and as a neuro- and gliotransmitter. The ionotropic P2X receptors are members of an ATP-gated ion channels family. These ionotropic receptors are widely expressed through the body, with 7 subunits described in mammals, which are arranged in a trimeric configuration with a central pore permeable mainly to Ca2+ and Na+. All 7 subunits are expressed in different brain areas, being present in neurons and glia. ATP, through these ionotropic receptors, can act as a neuromodulator, facilitating the Ca2+-dependent release of neurotransmitters, inducing the cross-inhibition between P2XR and GABA receptors, and exercising by this way a modulation of synaptic plasticity. Growing evidence shows that P2XR play an important role in neuronal disorders and neurodegenerative diseases, like Parkinson's and Alzheimer's disease; this role involves changes on P2XR expression levels, activation of key pathways like GSK3β, APP processing, oxidative stress and inflammatory response. This review is focused on the neuromodulatory function of P2XR on pathophysiological conditions of the brain; the recent evidence could open a window to a new therapeutic target.
      Graphical abstract image

      PubDate: 2015-07-01T21:37:36Z
       
  • Editorial Board
    • Abstract: Publication date: August 2015
      Source:Pharmacological Research, Volume 98




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



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


      PubDate: 2015-06-26T14:26:48Z
       
  • Molecular mechanism matters: Benefits of mechanistic computational models
           for drug development
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Lindsay E. Clegg , Feilim Mac Gabhann
      Making drug development a more efficient and cost-effective process will have a transformative effect on human health. A key, yet underutilized, tool to aid in this transformation is mechanistic computational modeling. By incorporating decades of hard-won prior knowledge of molecular interactions, cellular signaling, and cellular behavior, mechanistic models can achieve a level of predictiveness that is not feasible using solely empirical characterization of drug pharmacodynamics. These models can integrate diverse types of data from cell culture and animal experiments, including high-throughput systems biology experiments, and translate the results into the context of human disease. This provides a framework for identification of new drug targets, measurable biomarkers for drug action in target tissues, and patient populations for which a drug is likely to be effective or ineffective. Additionally, mechanistic models are valuable in virtual screening of new therapeutic strategies, such as gene or cell therapy and tissue regeneration, identifying the key requirements for these approaches to succeed in a heterogeneous patient population. These capabilities, which are distinct from and complementary to those of existing drug development strategies, demonstrate the opportunity to improve success rates in the drug development pipeline through the use of mechanistic computational models.
      Graphical abstract image

      PubDate: 2015-06-26T14:26:48Z
       
  • A novel inhaled Syk inhibitor blocks mast cell degranulation and early
           asthmatic response
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Isabel Ramis , Raquel Otal , Cristina Carreño , Anna Domènech , Peter Eichhorn , Adelina Orellana , Mónica Maldonado , Jorge De Alba , Neus Prats , Joan-Carles Fernández , Bernat Vidal , Montserrat Miralpeix
      Spleen tyrosine kinase (Syk) is essential for signal transduction of immunoreceptors. Inhibition of Syk abrogates mast cell degranulation and B cell responses. We hypothesized that Syk inhibition in the lung by inhaled route could block airway mast cells degranulation and the early asthmatic response without the need of systemic exposure. We discovered LAS189386, a novel Syk inhibitor with suitable properties for inhaled administration. The aim of this study was to characterize the in vitro and in vivo profile of LAS189386. The compound was profiled in Syk enzymatic assay, against a panel of selected kinases and in Syk-dependent cellular assays in mast cells and B cells. Pharmacokinetics and in vivo efficacy was assessed by intratracheal route. Airway resistance and mast cell degranulation after OVA challenge was evaluated in an ovalbumin-sensitized Brown Norway rat model. LAS189386 potently inhibits Syk enzymatic activity (IC50 7.2nM), Syk phosphorylation (IC50 41nM), LAD2 cells degranulation (IC50 56nM), and B cell activation (IC50 22nM). LAS189386 inhibits early asthmatic response and airway mast cell degranulation without affecting systemic mast cells. The present results support the hypothesis that topical inhibition of Syk in the lung, without systemic exposure, is sufficient to inhibit EAR in rats. Syk inhibition by inhaled route constitutes a promising therapeutic option for asthma.
      Graphical abstract image

      PubDate: 2015-06-26T14:26:48Z
       
  • Retinoic acid ameliorates blood–brain barrier disruption following
           ischemic stroke in rats
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Liang Kong , Yue Wang , Xiao-Jing Wang , Xiao-Tong Wang , Yan Zhao , Li-Mei Wang , Zhe-Yu Chen
      The intact blood–brain barrier (BBB) is essential in maintaining a stabilized milieu for synaptic and neuronal functions. Disruptions of the BBB have been observed following ischemia and reperfusion, both in patients and in animal models. Retinoic acid (RA), which plays crucial roles during vertebrate organogenesis, has been reported to participate in BBB development. However, it remains unclear whether RA could prevent BBB disruption in ischemic stroke. In this study, we determined that the injection of RA for 4 consecutive days resulted in increases in zonula occludens-1 (ZO-1) and vascular endothelial cadherin (VE-cadherin) expression, which are crucial components of the BBB structure. We demonstrated that RA pretreatment could alleviate the ischemic stroke-induced enlargement of vascular permeability, which is related to the up-regulated expression of ZO-1 and VE-cadherin proteins in rat models of middle cerebral artery occlusion (MCAO). Our findings further corroborated that the RA protective effect on BBB is dependent on RA receptor α in vitro oxygen–glucose deprivation (OGD) treatment. Significantly, RA administration immediately after MCAO reduced tissue plasminogen activator (tPA)-induced intracerebral hemorrhage (ICH) and ameliorated neurological deficits 24h after ischemic stroke. Taken together, our results suggest that RA may become a new therapeutic approach to prevent BBB dysfunction and tPA-induced ICH in ischemic stroke.
      Graphical abstract image

      PubDate: 2015-06-26T14:26:48Z
       
  • Nephrotoxicity of ibandronate and zoledronate in Wistar rats with normal
           renal function and after unilateral nephrectomy
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): R. Bergner , B. Siegrist , N. Gretz , G. Pohlmeyer-Esch , B. Kränzlin
      A previous animal study compared the nephrotoxic effect of ibandronate (IBN) and zoledronate (ZOL), but interpretation of these study results was limited because of the model of minimal nephrotoxic dosage with a dosage ratio of 1:3. The present study investigated the nephrotoxicity of ibandronate and zoledronate in a 1.5:1 dose ratio, as used in clinical practice and compared the nephrotoxicity in rats with normal and with mildly to moderately impaired renal function. We compared rats with normal renal function (SHAM) and with impaired renal function after unilateral nephrectomy (UNX), treated either with ibandronate 1.5mg/kg, zoledronate 1mg/kg or placebo once (1×) or nine (9×) times. Renal function and markers of tubular toxicity were measured over a 27 week period. After last bisphosphonate treatment the rats were sacrificed and kidneys examined histologically. All bisphosphonate treated animals showed a significant tubular toxicity, which was temporary except in the ZOL-UNX-9×-group. Also the renal function was only transiently reduced except in the ZOL-UNX-9×-group. Histologically, bisphosphonate treatment led to cortical tubuloepithelial degeneration/necrosis and medullary tubuloepithelial swelling which were slightly more pronounced in ibandronate treated animals, when compared to zoledronate treated animals, especially with impaired renal function. In contrast to the previous study we found a similar nephrotoxicity of ibandronate and zoledronate in rats with normal renal function. In rats with impaired renal function the peak of toxicity had not even been fully reached until end of experiment in the zoledronate treated animals. The peak of toxicity seems to be more severe and delayed in rats with impaired renal function compared with rats with normal renal function.
      Graphical abstract image

      PubDate: 2015-06-26T14:26:48Z
       
  • Ilexgenin A inhibits endoplasmic reticulum stress and ameliorates
           endothelial dysfunction via suppression of TXNIP/NLRP3 inflammasome
           activation in an AMPK dependent manner
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Yi Li , Jie Yang , Mei-Hong Chen , Qiang Wang , Min-Jian Qin , Tong Zhang , Xiao-Qing Chen , Bao-Lin Liu , Xiao-Dong Wen
      Ilexgenin A is a natural triterpenoid with beneficial effects on lipid disorders. This study aimed to investigate the effects of ilexgenin A on endothelial homeostasis and its mechanisms. Palmitate (PA) stimulation induced endoplasmic reticulum stress (ER stress) and subsequent thioredoxin-interacting protein (TXNIP)/NLRP3 inflammasome activation in endothelial cells, leading to endothelial dysfunction. Ilexgenin A enhanced LKB1-dependent AMPK activity and improved ER stress by suppression of ROS-associated TXNIP induction. However, these effects were blocked by knockdown of AMPKα, indicating AMPK is essential for its action in suppression of ER stress. Meanwhile, ilexgenin A inhibited NLRP3 inflammasome activation by down-regulation of NLRP3 and cleaved caspase-1 induction, and thereby reduced IL-1β secretion. It also inhibited inflammation and apoptosis exposed to PA insult. Consistent with these results in endothelial cells, ilexgenin A attenuated ER stress and restored the loss of eNOS activity in vascular endothelium, and thereby improved endothelium-dependent vasodilation in rat aorta. A further analysis in high-fat fed mice showed that oral administration of ilexgenin A blocked ER stress/NLRP3 activation with reduced ROS generation and increased NO production in vascular endothelium, well confirming the beneficial effect of ilexgenin A on endothelial homeostasis in vivo. Taken together, these results show ER stress-associated TXNIP/NLRP3 inflammasome activation was responsible for endothelial dysfunction and ilexgenin A ameliorated endothelial dysfunction by suppressing ER-stress and TXNIP/NLRP3 inflammasome activation with a regulation of AMPK. This finding suggests that the application of ilexgenin A is useful in the management of cardiovascular diseases in obesity.
      Graphical abstract image

      PubDate: 2015-06-26T14:26:48Z
       
  • Novel frontiers in calcium signaling: A possible target for chemotherapy
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Massimo Bonora , Carlotta Giorgi , Paolo Pinton
      Intracellular calcium (Ca2+) is largely known as a second messenger that is able to drive effects ranging from vesicle formation to muscle contraction, energy production and much more. In spite of its physiological regulation, Ca2+ is a strategic tool for regulating apoptosis, especially during transmission between the endoplasmic reticulum and the mitochondria. Contact sites between these organelles are well-defined as signaling platforms where oncogenes and oncosuppressors can exert anti/pro-apoptotic activities. Recent advances from in vivo investigations into these regions highlight the role of the master oncosuppressor p53 in regulating Ca2+ transmission and apoptosis, and we propose that Ca2+ signals are relevant targets when developing new therapeutic approaches.
      Graphical abstract image

      PubDate: 2015-06-26T14:26:48Z
       
  • Dihydromyricetin improves glucose and lipid metabolism and exerts
           anti-inflammatory effects in nonalcoholic fatty liver disease: A
           randomized controlled trial
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Shihui Chen , Xiaolan Zhao , Jing Wan , Li Ran , Yu Qin , Xiaofang Wang , Yanxiang Gao , Furong Shu , Yong Zhang , Peng Liu , Qianyong Zhang , Jundong Zhu , Mantian Mi
      Ampelopsis grossedentata, a medicinal and edible plant, has been widely used in China for hundreds of years, and dihydromyricetin is the main active ingredient responsible for its various biological actions. We investigated the effects of dihydromyricetin on glucose and lipid metabolism, inflammatory mediators and several biomarkers in nonalcoholic fatty liver disease. In a double-blind clinical trial, sixty adult nonalcoholic fatty liver disease patients were randomly assigned to receive either two dihydromyricetin or two placebo capsules (150mg) twice daily for three months. The serum levels of alanine, aspartate aminotransferase, γ-glutamyl transpeptidase, glucose, low-density lipoprotein-cholesterol and apolipoprotein B, and the homeostasis model assessment of insulin resistance (HOMA-IR) index were significantly decreased in the dihydromyricetin group compared with the placebo group. In the dihydromyricetin group, the serum levels of tumor necrosis factor-alpha, cytokeratin-18 fragment and fibroblast growth factor 21 were decreased, whereas the levels of serum adiponectin were increased at the end of the study. We conclude that dihydromyricetin supplementation improves glucose and lipid metabolism as well as various biochemical parameters in patients with nonalcoholic fatty liver disease, and the therapeutic effects of dihydromyricetin are likely attributable to improved insulin resistance and decreases in the serum levels of tumor necrosis factor-alpha, cytokeratin-18, and fibroblast growth factor 21.
      Graphical abstract image

      PubDate: 2015-06-26T14:26:48Z
       
  • Thymoquinone prevents RANKL-induced osteoclastogenesis activation and
           osteolysis in an in vivo model of inflammation by suppressing NF-KB and
           MAPK Signalling
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Dinesh Thummuri , Manish Kumar Jeengar , Shweta Shrivastava , Harishankar Nemani , Ravindar Naik Ramavat , Pradip Chaudhari , V.G.M. Naidu
      Osteoclasts are multinuclear giant cells responsible for bone resorption in inflammatory bone diseases such as osteoporosis, rheumatoid arthritis and periodontitis. Because of deleterious side effects with currently available drugs the search continues for novel effective and safe therapies. Thymoquinone (TQ), the major bioactive component of Nigella sativa has been investigated for its anti-inflammatory, antioxidant and anticancer activities. However, its effects in osteoclastogenesis have not been reported. In the present study we show for the first time that TQ inhibits nuclear factor-KB ligand (RANKL) induced osteoclastogenesis in RAW 264.7 and primary bone marrow derived macrophages (BMMs) cells. RANKL induced osteoclastogenesis is associated with increased expression of multiple transcription factors via activation of NF-KB, MAPKs signalling and reactive oxygen species (ROS). Mechanistically TQ blocked the RANKL induced NF-KB activation by attenuating the phosphorylation of IkB kinase (IKKα/β). Interestingly, in RAW 264.7 cells TQ inhibited the RANKL induced phosphorylation of MAPKs and mRNA expression of osteoclastic specific genes such as TRAP, DC-STAMP, NFATc1 and c-Fos. In addition, TQ also decreased the RANKL stimulated ROS generation in macropahges (RAW 264.7) and H2O2 induced ROS generation in osteoblasts (MC-3T3-E1). Consistent with in vitro results, TQ inhibited lipopolysaccharide (LPS) induced bone resorption by suppressing the osteoclastogenesis. Indeed, micro-CT analysis showed that bone mineral density (BMD) and bone architecture parameters were positively modulated by TQ. Taken together our data demonstrate that TQ has antiosteoclastogenic effect by inhibiting inflammation induced activation of MAPKs, NF-KB and ROS generation followed by suppressing the gene expression of c-Fos and NFATc1 in osteoclast precursors.
      Graphical abstract image

      PubDate: 2015-06-26T14:26:48Z
       
  • The exacerbating roles of CCAAT/enhancer-binding protein homologous
           protein (CHOP) in the development of bleomycin-induced pulmonary fibrosis
           and the preventive effects of tauroursodeoxycholic acid (TUDCA) against
           pulmonary fibrosis in mice
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Yuta Tanaka , Yoichi Ishitsuka , Marina Hayasaka , Yusei Yamada , Keishi Miyata , Motoyoshi Endo , Yuki Kondo , Hiroshi Moriuchi , Mitsuru Irikura , Ken-ichiro Tanaka , Tohru Mizushima , Yuichi Oike , Tetsumi Irie
      The purpose of this study was to evaluate the role of CCAAT/enhancer-binding protein homologous protein (CHOP), an important transcription factor that regulates the inflammatory reaction during the endoplasmic reticulum (ER) stress response, in the development of pulmonary fibrosis induced by bleomycin (BLM) in mice. An intratracheal injection of BLM transiently increased the expression of CHOP mRNA and protein in an early phase (days 1 and 3) in mice lungs. BLM-induced pulmonary fibrosis was significantly attenuated in Chop gene deficient (Chop KO) mice, compared with wild-type (WT) mice. Furthermore, the inflammatory reactions evaluated by protein concentration, the total number of leucocytes and neutrophils in the bronchoalveolar lavage fluid (BALF), the mRNA expression of interleukin 1b and caspase 11, and the apoptotic cell death were suppressed in Chop KO mice compared with those in WT mice. In addition, administration of tauroursodeoxycholic acid (TUDCA), a pharmacological agent that can inhibit CHOP expression, inhibited the BLM-induced pulmonary fibrosis and inflammation, and the increase in Chop mRNA expression in WT mice in a dose-dependent manner. These results suggest that the ER stress-induced transcription factor, CHOP, at least in part, plays an important role in the development of BLM-induced pulmonary fibrosis in mice, and that the inhibition of CHOP expression by a pharmacological agent, such as TUDCA, may be a promising strategy for the prevention of pulmonary fibrosis.
      Graphical abstract image

      PubDate: 2015-06-26T14:26:48Z
       
  • Targeting matrix metalloproteinases with intravenous doxycycline in severe
           sepsis – A randomised placebo-controlled pilot trial
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Eija Nukarinen , Taina Tervahartiala , Miia Valkonen , Marja Hynninen , Elina Kolho , Ville Pettilä , Timo Sorsa , Janne Backman , Johanna Hästbacka
      An overwhelming inflammatory process is the hallmark of severe sepsis and septic shock. Matrix metalloproteinases (MMPs)-8 and -9 are released from neutrophils and activated in sepsis to participate in inflammation in several ways. High levels of MMP-8 may associate with increased ICU mortality. The activity of MMP-8 and -9 is regulated by a natural inhibitor, tissue inhibitor of metalloproteinases-1 (TIMP-1). Moreover, MMPs are chemically inhibited by tetracycline-group antibiotics, such as doxycycline. We therefore aimed to study plasma concentration and MMP inhibition after intravenous doxycycline in critically ill patients with severe sepsis and septic shock in a prospective, randomised, placebo-controlled double-blinded pilot trial. Twenty-four patients with severe sepsis or septic shock were randomised in 3 groups. Group 1 received 200, 100 and 100mg, group 2 100, 50 and 50mg of intravenous doxycycline and group 3 placebo on three consecutive days. We measured doxycycline concentrations from baseline up to day 5. MMPs and TIMP-1 concentrations were measured from baseline up to day 10 of study and we compared their changes over time from baseline to 72h and from baseline to 120h. Data from 23 patients were analysed. At 72h all patients in group 1 showed doxycycline concentrations >1mg/l, whereas none in group 2 did. No serious adverse effects of the drug were recorded. We observed no differences over time up to 72 or up to 120h in the concentrations or activities of MMP-8, -9 or TIMP-1 in any of the groups. We found intravenous doxycycline 100, 50 and 50mg to be adequate to achieve a sub-antimicrobial concentration in patients with severe sepsis or septic shock but having no impact on MMP-8, -9 or TIMP-1 concentrations or activities.
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      PubDate: 2015-06-26T14:26:48Z
       
  • The MITF family of transcription factors: Role in endolysosomal
           biogenesis, Wnt signaling, and oncogenesis
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Diego Ploper , Edward M. De Robertis
      Canonical Wnt signaling influences cellular fate and proliferation through inhibition of Glycogen Synthase Kinase (GSK3) and the subsequent stabilization of its many substrates, most notably β-Catenin, a transcriptional co-activator. MITF, a melanoma oncogene member of the microphthalmia family of transcription factors (MiT), was recently found to contain novel GSK3 phosphorylation sites and to be stabilized by Wnt. Other MiT members, TFEB and TFE3, are known to play important roles in cellular clearance pathways by transcriptionally regulating the biogenesis of lysosomes and autophagosomes via activation of CLEAR elements in gene promoters of target genes. Recent studies suggest that MITF can also upregulate many lysosomal genes. MiT family members are dysregulated in cancer and are considered oncogenes, but the underlying oncogenic mechanisms remain unclear. Here we review the role of MiT members, including MITF, in lysosomal biogenesis, and how cancers overexpressing MITF, TFEB or TFE3 could rewire the lysosomal pathway, inhibit cellular senescence, and activate Wnt signaling by increasing sequestration of negative regulators of Wnt signaling in multivesicular bodies (MVBs). Microarray studies suggest that MITF expression inhibits macroautophagy. In melanoma the MITF-driven increase in MVBs generates a positive feedback loop between MITF, Wnt, and MVBs.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Exploring the various aspects of the pathological role of vascular
           endothelial growth factor (VEGF) in diabetic retinopathy
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Tapan Behl , Anita Kotwani
      Diabetic retinopathy, a sight-threatening microvascular complication of diabetes mellitus, is initiated by retinal endothelial dysfunction and succeeded by various pathological events, eventually resulting in vision-loss. These events are regulated by numerous mediators, including vascular endothelial growth factor (VEGF), which induces the progression of various events characterizing diabetic retinopathy, such as neovascularization and macular edema. VEGF is physiologically required for regulating proliferation and assembling of endothelial cells, during vasculogenesis, as well as for their maintenance and survival throughout the lifetime of blood vessels. However, various pathological conditions are induced in the body during diabetes (such as ischemia, oxidative stress and overactivation of protein kinase C), which upregulate the expression of VEGF, thereby deviating it from its physiological role and leading to various pathological demonstrations such as angiogenesis, increased permeability of endothelium, decreased inhibition of pro-apoptotic proteins and activation of various other inflammatory mediators. Such events disrupt vascular homeostasis and play key roles in the pathophysiology of diabetic retinopathy. Hence, acknowledging various VEGF-mediated pathways helps in understanding the deeper aspects related to progression of this disorder. Targeting and inhibiting VEGF-mediated disease progression might provide an effective alternative therapy and hence prove beneficial in the treatment of diabetic retinopathy.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Calumenin and fibulin-1 on tumor metastasis: Implications for pharmacology
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Pengli Zheng , Qiao Wang , Junlin Teng , Jianguo Chen
      Tumor metastasis is a key cause of cancer mortality, and inhibiting migration of cancer cells is one of the major directions of anti-metastatic drug development. Calumenin and fibulin-1 are two extracellular proteins that synergistically inhibit cell migration and tumor metastasis, and could potentially be served as targets for pharmacological research of anti-metastatic drugs. This review briefly introduces the multi-function of these two proteins, and discusses the mechanism of how they regulate cell migration and tumor metastasis.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Skeletal muscle atrophy: Potential therapeutic agents and their mechanisms
           of action
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Vikas Dutt , Sanjeev Gupta , Rajesh Dabur , Elisha Injeti , Ashwani Mittal
      Over the last two decades, new insights into the etiology of skeletal muscle wasting/atrophy under diverse clinical settings including denervation, AIDS, cancer, diabetes, and chronic heart failure have been reported in the literature. However, the treatment of skeletal muscle wasting remains an unresolved challenge to this day. About nineteen potential drugs that can regulate loss of muscle mass have been reported in the literature. This paper reviews the mechanisms of action of all these drugs by broadly classifying them into six different categories. Mechanistic data of these drugs illustrate that they regulate skeletal muscle loss either by down-regulating myostatin, cyclooxygenase2, pro-inflammatory cytokines mediated catabolic wasting or by up-regulating cyclic AMP, peroxisome proliferator-activated receptor gamma coactivator-1α, growth hormone/insulin-like growth factor1, phosphatidylinositide 3-kinases/protein kinase B(Akt) mediated anabolic pathways. So far, five major proteolytic systems that regulate loss of muscle mass have been identified, but the majority of these drugs control only two or three proteolytic systems. In addition to their beneficial effect on restoring the muscle loss, many of these drugs show some level of toxicity and unwanted side effects such as dizziness, hypertension, and constipation. Therefore, further research is needed to understand and develop treatment strategies for muscle wasting. For successful management of skeletal muscle wasting either therapeutic agent which regulates all five known proteolytic systems or new molecular targets/proteolytic systems must be identified.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Kaempferol and inflammation: From chemistry to medicine
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): Kasi Pandima Devi , Dicson Sheeja Malar , Seyed Fazel Nabavi , Antoni Sureda , Jianbo Xiao , Seyed Mohammad Nabavi , Maria Daglia
      Inflammation is an important process of human healing response, wherein the tissues respond to injuries induced by many agents including pathogens. It is characterized by pain, redness and heat in the injured tissues. Chronic inflammation seems to be associated with different types of diseases such as arthritis, allergies, atherosclerosis, and even cancer. In recent years natural product based drugs are considered as the novel therapeutic strategy for prevention and treatment of inflammatory diseases. Among the different types of phyto-constituents present in natural products, flavonoids which occur in many vegetable foods and herbal medicines are considered as the most active constituent, which has the potency to ameliorate inflammation under both in vitro and in vivo conditions. Kaempferol is a natural flavonol present in different plant species, which has been described to possess potent anti-inflammatory properties. Despite the voluminous literature on the anti-inflammatory effects of kaempferol, only very limited review articles has been published on this topic. Hence the present review is aimed to provide a critical overview on the anti-inflammatory effects and the mechanisms of action of kaempferol, based on the current scientific literature. In addition, emphasis is also given on the chemistry, natural sources, bioavailability and toxicity of kaempferol.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Ketamine and suicidal ideation in depression: Jumping the gun?
    • Abstract: Publication date: September 2015
      Source:Pharmacological Research, Volume 99
      Author(s): R. Rajkumar , J. Fam , E.Y.M. Yeo , G.S. Dawe
      Depression and suicide are known to be intricately entwined but the neurobiological basis underlying this association is yet to be understood. Ketamine is an N-methyl d-aspartate (NMDA) receptor antagonist used for induction and maintenance of general anaesthesia but paradoxically its euphoric effects lead to its classification under drugs of abuse. The serendipitous finding of rapid-onset antidepressant action of subanaesthetic dosing with ketamine by intravenous infusion has sparked many preclinical and clinical investigations. A remarkable suppression of suicidal ideation was also reported in depressed patients. This review focuses on the clinical trials on ketamine that reported remedial effects in suicidal ideation in depression and addresses also the molecular mechanisms underlying the antidepressant and psychotomimetic actions of ketamine. The neuropsychiatric profile of subanaesthetic doses of ketamine encourages its use in the management of suicidal ideation that could avert emergent self-harm or suicide. Finally, the need for neuroimaging studies in suicidal patients to identify the brain region specific and temporal effects of ketamine, and the possibility of employing ketamine as an experimental tool in rodent-based studies to study the mechanisms underlying suicidal behaviour are highlighted.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Type 1 diabetes and gut microbiota: Friend or foe?
    • Abstract: Publication date: August 2015
      Source:Pharmacological Research, Volume 98
      Author(s): Changyun Hu , F. Susan Wong , Li Wen
      Type 1 diabetes is a T cell-mediated autoimmune disease. Environmental factors play an important role in the initiation of the disease in genetically predisposed individuals. With the improved control of infectious disease, the incidence of autoimmune diseases, particularly type 1 diabetes, has dramatically increased in developed countries. Increasing evidence suggests that gut microbiota are involved in the pathogenesis of type 1 diabetes. Here we focus on recent advances in this field and provide a rationale for novel therapeutic strategies targeting gut microbiota for the prevention of type 1 diabetes.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Modern clinical management helps reducing the impact of type 1 diabetes in
           children
    • Abstract: Publication date: August 2015
      Source:Pharmacological Research, Volume 98
      Author(s): Andrea E. Scaramuzza , Gian Vincenzo Zuccotti
      Type 1 diabetes care may be very costly not only in terms of money but also in terms of psychological and therapeutic acceptance and compliance. Recently, a lot of new technologies have been introduced in the care of patients with type 1 diabetes that should allow them to achieve an improvement in glycemic control, quality of life and above all prevent long-term complications. Combining continuous glucose monitoring (CGM) and continuous subcutaneous insulin infusion (CSII) provides a more useful tool for patients with type 1 diabetes, the sensor-augmented pump (SAP). The aim of the present review is to explore SAP efficacy and safety in young patients with type 1 diabetes. SAP demonstrated increased efficacy in lowering glycated hemoglobin when compared either to multiple daily injections or CSII alone. Its efficacy is positively associated with CGM use, baseline HbA1c and patients’ age. According to currently available evidence, SAP seems sufficiently safe, effective and beneficial in improving glycemic control in pediatric patients with type 1 diabetes. Moreover, encouraging results using semi-closed loop systems are emerging, paving the way toward a fully automated artificial pancreas. As pediatric diabetologists we have the duty to offer our patients the best therapeutic option currently available, supported by evidence, to help them gain the best results with the fewest adverse effects (hypoglycemia and/or diabetic ketoacidosis), better if chomping a little piece of dark chocolate.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Type 1 diabetes and T regulatory cells
    • Abstract: Publication date: August 2015
      Source:Pharmacological Research, Volume 98
      Author(s): Basset ElEssawy , Xian C. Li
      T-regulatory cells (Tregs) play a fundamental role in the creation and maintenance of peripheral tolerance. Deficits in the numbers and/or function of Tregs may be an underlying cause of human autoimmune diseases including type 1 Diabetes Mellitus (T1D), whereas an over-abundance of Tregs can hinder immunity against cancer or pathogens. The importance of Tregs in the control of autoimmunity is well established in a variety of experimental animal models. In mice, manipulating the numbers and/or function of Tregs can decrease pathology in a wide range of contexts, including autoimmunity and it is widely assumed that similar approaches will be possible in humans. T1D, the most prevalent human autoimmune disease, has been a focus of interventions either through direct and indirect in vivo proliferations or through adoptive transfer of the in vitro generated antigen specific and non specific Treg. Some challenges still need to be addressed, including a more specific phenotype marker for Tregs; the reproducibility of satisfactory animal results in human and the reconcile of discrepancies between in vitro and in vivo studies. In this article, we will highlight the role of Tregs in autoimmune disease in general with a special focus on T1D, highlighting progress made and challenges ahead in developing Treg-based therapies.
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      PubDate: 2015-06-26T14:26:48Z
       
  • The rise, fall, and resurgence of immunotherapy in type 1 diabetes
    • Abstract: Publication date: August 2015
      Source:Pharmacological Research, Volume 98
      Author(s): Moufida Ben Nasr , Francesca D’Addio , Vera Usuelli , Sara Tezza , Reza Abdi , Paolo Fiorina
      Despite considerable effort to halt or delay destruction of β-cells in autoimmune type 1 diabetes (T1D), success remains elusive. Over the last decade, we have seen a proliferation of knowledge on the pathogenesis of T1D that emerged from studies performed in non-obese diabetic (NOD) mice. However, while results of these preclinical studies appeared to hold great promise and boosted patients’ hopes, none of these approaches, once tested in clinical settings, induced remission of autoimmune diabetes in individuals with T1D. The primary obstacles to translation reside in the differences between the human and murine autoimmune responses and in the contribution of many environmental factors associated with the onset of disease. Moreover, inaccurate dosing as well as inappropriate timing and uncertain length of drug exposure have played a central role in the negative outcomes of such therapeutic interventions. In this review, we summarize the most important approaches tested thus far in T1D, beginning with the most successful preclinical studies in NOD mice and ending with the latest disappointing clinical trials in humans. Finally, we highlight recent stem cell-based trials, for which expectations in the scientific community and among individuals with T1D are high.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Novel therapeutic approaches for diabetic nephropathy and retinopathy
    • Abstract: Publication date: August 2015
      Source:Pharmacological Research, Volume 98
      Author(s): Vera Usuelli , Ennio La Rocca
      Diabetes mellitus is a chronic disease that in the long-term increases the microvascular and macrovascular degenerative complications thus being responsible for a large part of death associated with diabetes. During the years, while preventive care for diabetic patients has improved, the increase in the prevalence of diabetes worldwide is continuous. The detrimental effects of diabetes mellitus result in microvascular diseases, which recognize hyperglycemia as major determinant. A significant number of potential therapeutic targets for the treatment of diabetic microvascular complications have been proposed, but the encouraging results obtained in preclinical studies, have largely failed in clinical trials. Currently, the most successful strategy to prevent microvascular complications of diabetes is the intensive treatment of hyperglycemia or the normalization of glycometabolic control achieved with pancreatic and islet transplantation. In this review, we focus on the novel therapeutic targets to prevent the development and progression of diabetic nephropathy and retinopathy microvascular complications.
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      PubDate: 2015-06-26T14:26:48Z
       
  • The current challenges for pancreas transplantation for diabetes mellitus
    • Abstract: Publication date: August 2015
      Source:Pharmacological Research, Volume 98
      Author(s): Christopher J.E. Watson
      Pancreas transplantation is an accepted treatment for a subset of patients with diabetes mellitus, in particular those with renal failure who also require a kidney transplant and those with life-threatening hypoglycaemic unawareness. As results have improved and demand has risen, attention has focused on increasing the availability of pancreas transplantation by utilising pancreases from less than ideal donors, as well as addressing factors that limit the longevity of graft survival. The development of islet transplantation has posed additional demands on donor pancreas availability, as well as posing new challenges for donor organ allocation. This review focuses upon some of the current areas of interest in pancreatic transplantation.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Hepatic steatosis after islet transplantation: Can ultrasound predict the
           clinical outcome? A longitudinal study in 108 patients
    • Abstract: Publication date: August 2015
      Source:Pharmacological Research, Volume 98
      Author(s): Massimo Venturini , Paola Maffi , Giulia Querques , Giulia Agostini , Lorenzo Piemonti , Sandro Sironi , Francesco De Cobelli , Paolo Fiorina , Antonio Secchi , Alessandro Del Maschio
      Percutaneous intra-portal islet transplantation (PIPIT) is a less invasive, safer, and repeatable therapeutic option for brittle type 1 diabetes, compared to surgical pancreas transplantation. Hepatic steatosis is a consequence of the islet engraftment but it is curiously present in a limited number of patients and its meaning is controversial. The aims of this study were to assess hepatic steatosis at ultrasound (US) after PIPIT investigating its relationship with graft function and its role in predicting the clinical outcome. From 1996 to 2012, 108 patients underwent PIPIT: 83 type-1 diabetic patients underwent allo-transplantation, 25 auto-transplantation. US was performed at baseline, 6, 12, and 24 months, recording steatosis prevalence, first detection, duration, and distribution. Contemporaneously, steatotic and non-steatotic patients were compared for the following parameters: infused islet mass, insulin independence rate, β-score, C-peptide, glycated hemoglobin, exogenous insulin requirement, and fasting plasma glucose. Steatosis at US was detected in 21/108 patients, 20/83 allo-transplanted and 1/25 auto-transplanted, mostly at 6 and 12 months. Infused islet mass was significantly higher in steatotic than non-steatotic patients (IE/kg: S =10.822; NS=6138; p =0.001). Metabolically, steatotic patients had worse basal conditions, but better islet function when steatosis was first detected, after which progressive islet exhaustion, along with steatosis disappearance, was observed. Conversely, in non-steatotic patients these parameters remained stable in time. Number of re-transplantations was significantly higher in steatotic than in non-steatotic patients (1.8 vs 1.1; p =0.001). Steatosis at US seems to be related to the islet mass and local overworking activity. It precedes metabolic alterations and can predict graft dysfunction addressing to therapeutic decisions before islet exhaustion. If steatosis does not appear, no conclusion can be drawn.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Immunogenicity of β-cells for autologous transplantation in type 1
           diabetes
    • Abstract: Publication date: August 2015
      Source:Pharmacological Research, Volume 98
      Author(s): Christian Schuetz , James F. Markmann
      The success of clinical islet transplantation calls for a broader application of this curative treatment for type 1 diabetes mellitus. The toxicity of immunosuppression, limited organ donor supply and high procedural costs are deterrents to expand this therapy to patients with uncomplicated diabetes. The use of pancreatic β-cell like cells derived from the patient's own induced pluripotent cells (iPSC) holds potential to overcome these barriers. In this review, we discuss the practicality of this regenerative medicine approach and existing evidence regarding the true immunogenicity of iPSC derived cells.


      PubDate: 2015-06-26T14:26:48Z
       
  • Novel immunological strategies for islet transplantation
    • Abstract: Publication date: August 2015
      Source:Pharmacological Research, Volume 98
      Author(s): Sara Tezza , Moufida Ben Nasr , Andrea Vergani , Alessandro Valderrama Vasquez , Anna Maestroni , Reza Abdi , Antonio Secchi , Paolo Fiorina
      Islet transplantation has been demonstrated to improve glycometabolic control, to reduce hypoglycemic episodes and to halt the progression of diabetic complications. However, the exhaustion of islet function and the side effects related to chronic immunosuppression limit the spread of this technique. Consequently, new immunoregulatory protocols have been developed, with the aim to avoid the use of a life-time immunosuppression. Several approaches have been tested in preclinical models, and some are now under clinical evaluation. The development of new small molecules and new monoclonal or polyclonal antibodies is continuous and raises the possibility of targeting new costimulatory pathways or depleting particular cell types. The use of stem cells and regulatory T cells is underway to take advantage of their immunological properties and to induce tolerance. Xenograft islet transplantation, although having severe problems in terms of immunological compatibility, could theoretically provide an unlimited source of donors; using pigs carrying human immune antigens has showed indeed promising results. A completely different approach, the use of encapsulated islets, has been developed; synthetic structures are used to hide islet alloantigen from the immune system, thus preserving islet endocrine function. Once one of these strategies is demonstrated safe and effective, it will be possible to establish clinical islet transplantation as a treatment for patients with type 1 diabetes long before the onset of diabetic-related complications.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Re-engineering islet cell transplantation
    • Abstract: Publication date: August 2015
      Source:Pharmacological Research, Volume 98
      Author(s): Nicoletta Fotino , Carmen Fotino , Antonello Pileggi
      We are living exciting times in the field of beta cell replacement therapies for the treatment of diabetes. While steady progress has been recorded thus far in clinical islet transplantation, novel approaches are needed to make cell-based therapies more reproducible and leading to long-lasting success. The multiple facets of diabetes impose the need for a transdisciplinary approach to attain this goal, by targeting immunity, promoting engraftment and sustained functional potency. We discuss herein the emerging technologies applied to this rapidly evolving field.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Clinical results of islet transplantation
    • Abstract: Publication date: August 2015
      Source:Pharmacological Research, Volume 98
      Author(s): Paola Maffi , Antonio Secchi
      Islet transplantation is considered an advanced therapy in the treatment of type-1 diabetes, with a progressive improvement of clinical results as seen in the Collaborative Islet Transplant Registry (CITR) report. It is an accepted method for the stabilization of frequent hypoglycemia, or severe glycemic lability, in patients with hypoglycemic unawareness, poor diabetic control, or a resistance to intensive insulin-based therapies. Worldwide data confirm a positive trend in this field, with the integrated management of pivotal factors: adequate islet mass, immunosuppressive protocols, additional anti-inflammatory therapy, and pre-transplant allo-immunity assessment. Insulin independence has been observed in several clinical trials with different rate, ranging 100–65% of patients; the maintenance of this condition during the follow-up progressively decreased, actually arranged on 44% 3 years after the last infusion, according to data reported from the CITR. Successful duration is progressively increasing, with ≥13 years being the longest reported insulin-free condition on record. The immediate results of functioning islet transplantation are an improvement in hypoglycemic awareness and a reduction in the glycated hemoglobin level. Furthermore, many studies have shown its influence on the chronic complications of diabetes, such as peripheral neuropathy, retinopathy, and macroangiopathy. Pre-transplant nephropathy remains an exclusion criterion as immunosuppressive therapy can exacerbate kidney-function deterioration. The problems linked to immunosuppression following islet transplantation for the treatment of type-1 diabetes need to be considered in order to achieve the correct risk/benefit ratio for each patient.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Editorial Board
    • Abstract: Publication date: July 2015
      Source:Pharmacological Research, Volume 97




      PubDate: 2015-06-26T14:26:48Z
       
  • Glycogen synthase kinase-3 beta (GSK-3β) signaling: Implications for
           Parkinson's disease
    • Abstract: Publication date: July 2015
      Source:Pharmacological Research, Volume 97
      Author(s): Mojtaba Golpich , Elham Amini , Fatemeh Hemmati , Norlinah Mohamed Ibrahim , Behrouz Rahmani , Zahurin Mohamed , Azman Ali Raymond , Leila Dargahi , Rasoul Ghasemi , Abolhassan Ahmadiani
      Glycogen synthase kinase 3 (GSK-3) dysregulation plays an important role in the pathogenesis of numerous disorders, affecting the central nervous system (CNS) encompassing both neuroinflammation and neurodegenerative diseases. Several lines of evidence have illustrated a key role of the GSK-3 and its cellular and molecular signaling cascades in the control of neuroinflammation. Glycogen synthase kinase 3 beta (GSK-3β), one of the GSK-3 isomers, plays a major role in neuronal apoptosis and its inhibition decreases expression of alpha-Synuclein (α-Synuclein), which make this kinase an attractive therapeutic target for neurodegenerative disorders. Parkinson's disease (PD) is a chronic neurodegenerative movement disorder characterized by the progressive and massive loss of dopaminergic neurons by neuronal apoptosis in the substantia nigra pars compacta and depletion of dopamine in the striatum, which lead to pathological and clinical abnormalities. Thus, understanding the role of GSK-3β in PD will enhance our knowledge of the basic mechanisms underlying the pathogenesis of this disorder and facilitate the identification of new therapeutic avenues. In recent years, GSK-3β has been shown to play essential roles in modulating a variety of cellular functions, which have prompted efforts to develop GSK-3β inhibitors as therapeutics. In this review, we summarize GSK-3 signaling pathways and its association with neuroinflammation. Moreover, we highlight the interaction between GSK-3β and several cellular processes involved in the pathogenesis of PD, including the accumulation of α-Synuclein aggregates, oxidative stress and mitochondrial dysfunction. Finally, we discuss about GSK-3β inhibitors as a potential therapeutic strategy in PD.


      PubDate: 2015-06-26T14:26:48Z
       
  • Ellagic acid: Pharmacological activities and molecular mechanisms involved
           in liver protection
    • Abstract: Publication date: July 2015
      Source:Pharmacological Research, Volume 97
      Author(s): Wylly Ramsés García-Niño , Cecilia Zazueta
      Traditional drugs or therapies rarely have effects on regression of chronic liver diseases, which result in many cases from sustained oxidative stress. In recent years, ellagic acid (EA) has gained attention due to its multiple biological activities and several molecular targets. This is the first review focused on the pharmacological properties and on the molecular mechanisms activated by EA in terms of liver protection. EA possesses antioxidant, antihepatotoxic, antisteatosic, anticholestatic, antifibrogenic, antihepatocarcinogenic and antiviral properties that improves the hepatic architectural and functions against toxic and pathological conditions. The molecular mechanisms that EA activates include the scavenging of free radicals, regulation of phase I and II enzymes, modulation of proinflammatory and profibrotic cytokines synthesis, the regulation of biochemical pathways involved in the synthesis and degradation of lipids as well as the maintenance of essential trace elements levels. EA also inhibits hepatic stellate cells and mast cells activation, the proliferation of transformed cells, as well as viral replication by increasing antioxidant response, induction of apoptosis, downregulation of genes involved in cell cycle and angiogenesis, and stimulation of cellular immune response. Despite the enormous therapeutic potential of EA as an innovative pharmacological strategy, the number of phase I and II trials in patients is scarce, precluding its clinical application. In these sense, the use of new delivery systems that enhances EA bioavailability would improve the results already obtained. Also it remains to be determined if treatment with urolithins instead of EA would represent a better strategy in hepatic disease treatment.
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      PubDate: 2015-06-26T14:26:48Z
       
  • MicroRNA-based therapy and breast cancer: A comprehensive review of novel
           therapeutic strategies from diagnosis to treatment
    • Abstract: Publication date: July 2015
      Source:Pharmacological Research, Volume 97
      Author(s): Parham Jabbarzadeh Kaboli , Asmah Rahmat , Patimah Ismail , King-Hwa Ling
      MicroRNAs (miRNA) are 21–23 nucleotide molecules not translated into proteins that bind and target the 3′ untranslated regions of mRNA. These characteristics make them a possible tool for inhibiting protein translation. Different cellular pathways involved in cancer development, such as cellular proliferation, apoptosis, and migration, are regulated by miRNAs. The objective of this review is to discuss various miRNAs involved in breast cancer in detail as well as different therapeutic strategies from the clinic to industry. A comprehensive discussion is provided on various miRNAs involved in breast cancer development, progression, and metastasis as well as the roles, targets, and related therapeutic strategies of different miRNAs associated with breast cancer. miRNAs known to be clinically useful for the diagnosis and prognosis of breast cancer are also discussed. Different strategies and challenges, including nucleic acid-based (miRNA mimics, antagomiRs, and miRNA sponges) and drug-based (drug resistance, drugs/miRNA interaction, nanodelivery, and sensing systems) approaches to suppress specific oncogenes and/or activate target tumor suppressors are discussed. In contrast to other articles written on the same topic, this review focuses on the therapeutic and clinical value of miRNAs as well as their corresponding targets in order to explore how these strategies can overcome breast cancer, which is the second most frequent type of cancer worldwide. This review focuses on promising and validated miRNAs involved in breast cancer. In particular, two miRNAs, miR-21 and miR-34, are discussed as the most promising targets for RNA-based therapy in non-invasive and invasive breast cancer, respectively. Finally, relevant and commercialized therapeutic strategies are highlighted.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Bleomycin in the setting of lung fibrosis induction: From biological
           mechanisms to counteractions
    • Abstract: Publication date: July 2015
      Source:Pharmacological Research, Volume 97
      Author(s): Veronica Della Latta , A. Cecchettini , S. Del Ry , M.A. Morales
      Bleomycin (BLM) is a drug used to treat different types of neoplasms. BLM's most severe adverse effect is lung toxicity, which induces remodeling of lung architecture and loss of pulmonary function, rapidly leading to death. While its clinical role as an anticancer agent is limited, its use in experimental settings is widespread since BLM is one of the most widely used drugs for inducing lung fibrosis in animals, due to its ability to provoke a histologic lung pattern similar to that described in patients undergoing chemotherapy. This pattern is characterized by patchy parenchymal inflammation, epithelial cell injury with reactive hyperplasia, epithelial–mesenchymal transition, activation and differentiation of fibroblasts to myofibroblasts, basement membrane and alveolar epithelium injuries. Several studies have demonstrated that BLM damage is mediated by DNA strand scission producing single- or double-strand breaks that lead to increased production of free radicals. Up to now, the mechanisms involved in the development of pulmonary fibrosis have not been fully understood; several studies have analyzed various potential biological molecular factors, such as transforming growth factor beta 1, tumor necrosis factor alpha, components of the extracellular matrix, chaperones, interleukins and chemokines. The aim of this paper is to review the specific characteristics of BLM-induced lung fibrosis in different animal models and to summarize modalities and timing of in vivo drug administration. Understanding the mechanisms of BLM-induced lung fibrosis and of commonly used therapies for counteracting fibrosis provides an opportunity for translating potential molecular targets from animal models to the clinical arena.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Platelet aggregation values in patients with cardiovascular risk factors
           are reduced by verbascoside treatment. A randomized study
    • Abstract: Publication date: July 2015
      Source:Pharmacological Research, Volume 97
      Author(s): Gianluca Campo , Rita Pavasini , Simone Biscaglia , Alessandra Ferri , Elisa Andrenacci , Matteo Tebaldi , Roberto Ferrari
      Verbascoside, a phenolic compound, showed several favorable biological activities, including an antiplatelet activity. No in vivo studies tested its efficacy and safety in subjects with cardiovascular (CV) factors. The aim of this randomized, single-center, double-blind, phase II study was to assess the efficacy and tolerability of verbascoside intake for the modulation of platelet aggregation (PA) values in subjects with cardiovascular (CV) risk factors. One-hundred subjects with at least one CV risk factor (age >65 years, diabetes mellitus, hypertension, current cigarettes use, hyperlidemia, waist circumference >102cm in male or >88cm in female) were enrolled and randomly assigned to receive placebo or verbascoside 50mg or verbascoside 100mg. PA was measured at baseline and after 2 weeks of study drug assumption, with light transmittance aggregometry (arachidonic acid, AA, 1μM and adenosine diphosphate, ADP, 5μM). Two weeks of treatment with placebo or verbascoside 50mg did not modify PA values (both after AA and ADP stimuli). On the contrary, after 2 weeks of verbascoside 100mg, PA values decreased significantly (from 51±13% to 39±15%, p <0.01 after AA; from 60±12% to 49±15%, p =0.01 after ADP). No serious adverse events were reported during the study, and no subjects discontinued the study because of adverse events. We conclude that long-term intake of verbascoside 100mg significantly reduces PA values in subjects with CV risk factors.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Peripheral FAAH and soluble epoxide hydrolase inhibitors are
           synergistically antinociceptive
    • Abstract: Publication date: July 2015
      Source:Pharmacological Research, Volume 97
      Author(s): Oscar Sasso , Karen Wagner , Christophe Morisseau , Bora Inceoglu , Bruce D. Hammock , Daniele Piomelli
      We need better medicines to control acute and chronic pain. Fatty acid amide hydrolase (FAAH) and soluble epoxide hydrolase (sEH) catalyze the deactivating hydrolysis of two classes of bioactive lipid mediators – fatty acid ethanolamides (FAEs) and epoxidized fatty acids (EpFAs), respectively – which are biogenetically distinct but share the ability to attenuate pain responses and inflammation. In these experiments, we evaluated the antihyperalgesic activity of small-molecule inhibitors of FAAH and sEH, administered alone or in combination, in two pain models: carrageenan-induced hyperalgesia in mice and streptozocin-induced allodynia in rats. When administered separately, the sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea (TPPU) and the peripherally restricted FAAH inhibitor URB937 were highly active in the two models. The combination TPPU plus URB937 was markedly synergistic, as assessed using isobolographic analyses. The results of these experiments reveal the existence of a possible functional crosstalk between FAEs and EpFAs in regulating pain responses. Additionally, the results suggest that combinations of sEH and FAAH inhibitors might be exploited therapeutically to achieve greater analgesic efficacy.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Enduring effects of tacrine on cocaine-reinforced behavior: Analysis by
           conditioned-place preference, temporal separation from drug reward, and
           reinstatement
    • Abstract: Publication date: July 2015
      Source:Pharmacological Research, Volume 97
      Author(s): Kenneth Grasing , Yungao Yang , Shuangteng He
      Previous work by our laboratory has shown that tacrine can produce long-lasting reductions in cocaine-reinforced behavior, when administered to rats as daily intravenous infusions over four days. Tacrine causes dose-related liver toxicity in different species, and its manufacture for human use was recently discontinued. This study was conducted to further characterize its actions on cocaine reward. Cocaine-experienced animals that had no contact with drug over one week resumed self-administration at levels similar to their initial baseline. When tacrine was administered over four days which were preceded and followed by washout periods to allow elimination of cocaine and tacrine respectively, subsequent cocaine self-administration was attenuated by more than one-half. Tacrine administered at 10mg/kg-day as a chronic infusion by osmotic pump did not modify cocaine-induced increases in locomotor activity or conditioned-place preference. In rats that exhibited persistent attenuation of cocaine-self-administration after receiving tacrine, cocaine-induced reinstatement was also attenuated. No changes in plasma measures of renal or hepatic function were observed in rats receiving tacrine. In conclusion, pretreatment with tacrine can decrease cocaine-motivated behavior measured by self-administration or reinstatement, but not conditioned-place preference. Reductions in cocaine self-administration following pretreatment with tacrine do not require direct interaction with cocaine and are not secondary to either liver or kidney toxicity.
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      PubDate: 2015-06-26T14:26:48Z
       
  • A new therapeutic association to manage relapsing experimental colitis:
           Doxycycline plus Saccharomyces boulardii
    • Abstract: Publication date: July 2015
      Source:Pharmacological Research, Volume 97
      Author(s): José Garrido-Mesa , Francesca Algieri , Alba Rodriguez-Nogales , Mª Pilar Utrilla , Mª Elena Rodriguez-Cabezas , Antonio Zarzuelo , Mª Angeles Ocete , Natividad Garrido-Mesa , Julio Galvez
      Immunomodulatory antibiotics have been proposed for the treatment of multifactorial conditions such as inflammatory bowel disease. Probiotics are able to attenuate intestinal inflammation, being considered as safe when chronically administered. The aim of the study was to evaluate the anti-inflammatory effects of doxycycline, a tetracycline with immunomodulatory properties, alone and in association with the probiotic Saccharomyces boulardii CNCMI-745. Doxycycline was assayed both in vitro (Caco-2 epithelial cells and RAW 264.7 macrophages) and in vivo, in the trinitrobenzenesulfonic acid (TNBS) model of rat colitis and the dextran sodium sulfate (DSS) model of mouse colitis. In addition, the anti-inflammatory effect of the association of doxycycline and the probiotic was evaluated in vitro and in vivo in a DSS model of reactivated colitis in mice. Doxycycline displayed immunomodulatory activity in vitro, reducing IL-8 production by intestinal epithelial cells and nitric oxide by macrophages. Doxycycline administration to TNBS-colitic rats (5, 10 and 25mg/kg) ameliorated the intestinal inflammatory process, being its efficacy comparable to that previously showed by minocycline. Doxycycline treatment was also effective in reducing acute intestinal inflammation in the DSS model of mouse colitis. The association of doxycycline and S. boulardii helped managing colitis in a reactivated model of colitis, by reducing intestinal inflammation and accelerating the recovery and attenuating the relapse. This was evidenced by a reduced disease activity index, colonic tissue damage and expression of inflammatory mediators. This study confirms the intestinal anti-inflammatory activity of doxycycline and supports the potential use of its therapeutic association with S. boulardii for the treatment of inflammatory bowel diseases, in which doxycycline is used to induce remission and long term probiotic administration helps to prevent the relapses.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Ventricular arrhythmia incidence in the rat is reduced by naloxone
    • Abstract: Publication date: July 2015
      Source:Pharmacological Research, Volume 97
      Author(s): M.K. Pugsley , E.S. Hayes , W.Q. Wang , M.J.A. Walker
      This study characterized the antiarrhythmic effects of the opioid receptor antagonist naloxone in rats subject to electrically induced and ischemic arrhythmias. Naloxone (2, 8 and 32μmol/kg/min) was examined on heart rate, blood pressure, and the electrocardiogram (EKG) as well as for effectiveness against arrhythmias produced by occlusion of the left anterior descending coronary artery or electrical stimulation of the left ventricle. Naloxone reduced blood pressure at the highest dose tested while heart rate was dose-dependently reduced. Naloxone dose-dependently prolonged the P–R and QRS intervals and increased the RSh amplitude indicative of effects on cardiac sodium (Na) channels. Naloxone prolonged the Q–T interval suggesting a delay in repolarization. Naloxone effects were comparable to the comparator quinidine. Naloxone (32μmol/kg/min) reduced ventricular fibrillation (VF) incidence to 38% (from 100% in controls). This same dose significantly increased the threshold for induction of ventricular fibrillation (VFt), prolonged the effective refractory period (ERP) and reduced the maximal following frequency (MFF). The patterns of ECG changes, reduction in ischemic arrhythmia (VF) incidence and changes in electrically induced arrhythmia parameters at high doses of naloxone suggest that it directly blocks cardiac Na and potassium (K) ion channels.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Ginkgo biloba extract promotes osteogenic differentiation of human bone
           marrow mesenchymal stem cells in a pathway involving Wnt/β-catenin
           signaling
    • Abstract: Publication date: July 2015
      Source:Pharmacological Research, Volume 97
      Author(s): Qiuhan Gu , Chen Chen , Zhengping Zhang , Zhigang Wu , Xiangli Fan , Zhenyu Zhang , Wuweilong Di , Lei Shi
      Human bone marrow derived mesenchymal stem cells (BM-MSCs) are a novel cell source used in stem cell therapy to treat bone diseases owing to their high potential to differentiate into osteoblasts. Effective induction of osteogenic differentiation from human BM-MSCs is critical to fulfill their therapeutic potential. In this study, Ginkgo biloba extract (GBE), a traditional herbal medicine, was used to stimulate the proliferation and osteogenic differentiation of human BM-MSCs. The present study revealed that GBE improved the proliferation and osteogenesis of human BM-MSCs in a dose-dependent manner in the range 25–75mg/l, as indicated by alkaline phosphatase (ALP) activity and calcium content. However, such effect was decreased or inhibited at 100mg/l or higher. The dose-dependent improvement in osteogenesis of human BM-MSCs by GBE was further confirmed by the dose-dependent upregulation of marker genes, osteopontin (OPN) and Collagen I. The increased osteoprotegerin (OPG) expression and minimal expression of receptor activator of nuclear factor-κB ligand (RANKL) suggested that GBE also inhibited osteoclastogenesis of human BM-MSCs. Further mechanistic study demonstrated that the transcriptional levels of bone morphogenetic protein 4 (BMP4) and runt-related transcription factor 2 (RUNX2) in the BMP signaling, β-catenin and Cyclin D1 in the Wnt/β-catenin signaling, increased significantly during GBE-promoted osteogenesis. Meanwhile, loss-of-function assay with the signaling inhibitor(s) confirmed that the BMP and Wnt/β-catenin signaling pathways were indispensable during the GBE-promoted osteogenesis, suggesting that GBE improved osteogenesis via upregulation of the BMP and Wnt/β-catenin signaling. The present study proposed GBE to be used to upregulate the osteogenic differentiation of human BM-MSCs for new bone formation in BM-MSC-based cell therapy, which could provide an attractive and promising treatment for bone disorders.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Pidotimod for the prevention of acute respiratory infections in healthy
           children entering into daycare: A double blind randomized
           placebo-controlled study
    • Abstract: Publication date: July 2015
      Source:Pharmacological Research, Volume 97
      Author(s): Chiara Mameli , Angela Pasinato , Marina Picca , Giorgio Bedogni , Stefania Pisanelli , Gian Vincenzo Zuccotti
      Acute respiratory tract infections (ARTIs) are very common in pediatric age and reach a peak in the first 4 years of life, especially in children attending daycare. Pidotimod, a synthetic immunostimulant, may reduce the incidence of ARTIs in children with predisposing risk factors. Nevertheless studies on healthy children are presently lacking. We performed a double-blinded randomized placebo-controlled trial study to assess the efficacy of Pidotimod in a population of 3-year-old healthy children who just entered kindergarten. The main outcome was the incidence of respiratory infections in this population and the secondary outcome was the prescription of antibiotics. The study group consisted of healthy 3-year-old children who had not yet attended day-care centers. Patients were enrolled by a convenience sample of 17 family pediatricians (FP). Children were randomized to receive either Pidotimod 400mg per os or placebo twice daily for the last 10 days of each month from October 2013 to April 2014. Any time a child presented to his/her FP with fever and ARTI was diagnosed, clinical and therapeutic data were collected. A total of 800 children were pre-screened, 733 did not meet the inclusion criteria and 10 refused to participate. Of the 67 eligible subjects, 57 were successfully enrolled within the study recruitment period and randomized to receive Pidotimod (n =29) or placebo (n =28). Eight children were lost to follow-up. In the final analysis were thus included 24 children who received Pidotimod and 25 who received placebo. The incidence rate ratio for respiratory infections was 0.78 (95%CI 0.53 to 1.15, p =0.211) for Pidotimod vs. placebo. The corresponding risk ratio for antibiotic usage was 0.56 (95%CI 0.27 to 1.16, p =0.120). In our trial, Pidotimod did not prove to be statistically superior to placebo for the prevention of ARTI in a population of healthy children who entered kindergarten. However, Pidotimod showed some potential as a means for reducing antibiotic usage in these children.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Levetiracetam synergises with common analgesics in producing
           antinociception in a mouse model of painful diabetic neuropathy
    • Abstract: Publication date: July 2015
      Source:Pharmacological Research, Volume 97
      Author(s): Ana Micov , Maja Tomić , Uroš Pecikoza , Nenad Ugrešić , Radica Stepanović-Petrović
      Painful diabetic neuropathy is difficult to treat. Single analgesics often have insufficient efficacy and poor tolerability. Combination therapy may therefore be of particular benefit, because it might provide optimal analgesia with fewer adverse effects. This study aimed to examine the type of interaction between levetiracetam, a novel anticonvulsant with analgesic properties, and commonly used analgesics (ibuprofen, aspirin and paracetamol) in a mouse model of painful diabetic neuropathy. Diabetes was induced in C57BL/6 mice with a single high dose of streptozotocin, applied intraperitoneally (150mg/kg). Thermal (tail-flick test) and mechanical (electronic von Frey test) nociceptive thresholds were measured before and three weeks after diabetes induction. The antinociceptive effects of orally administered levetiracetam, analgesics, and their combinations were examined in diabetic mice that developed thermal/mechanical hypersensitivity. In combination experiments, the drugs were co-administered in fixed-dose fractions of single drug ED50 and the type of interaction was determined by isobolographic analysis. Levetiracetam (10–100mg/kg), ibuprofen (2–50mg/kg), aspirin (5–75mg/kg), paracetamol (5–100mg/kg), and levetiracetam-analgesic combinations produced significant, dose-dependent antinociceptive effects in diabetic mice in both tests. In the tail-flick test, isobolographic analysis revealed 15-, and 19-fold reduction of doses of both drugs in the combination of levetiracetam with aspirin/ibuprofen, and paracetamol, respectively. In the von Frey test, approximately 7- and 9-fold reduction of doses of both drugs was detected in levetiracetam-ibuprofen and levetiracetam-aspirin/levetiracetam-paracetamol combinations, respectively. These results show synergism between levetiracetam and ibuprofen/aspirin/paracetamol in a model of painful diabetic neuropathy and might provide a useful approach to the treatment of patients suffering from painful diabetic neuropathy.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Novel insight into drug repositioning: Methylthiouracil as a case in point
    • Abstract: Publication date: Available online 25 June 2015
      Source:Pharmacological Research
      Author(s): Moon-Chang Baek , Byeongjin Jung , Hyejin Kang , Hyun-Shik Lee , Jong-Sup Bae
      Drug repositioning refers to the development of existing drugs for new indications. These drugs may have (I) failed to show efficacy in late stage clinical trials without safety issues; (II) stalled in the development for commercial reasons; (III) passed the point of patent expiry; or (IV) are being explored in new geographic markets. Over the past decade, pressure on the pharmaceutical industry caused by the ‘innovation gap’ owing to rising development costs and stagnant product output have become major reasons for the growing interest in drug repositioning. Companies that offer a variety of broad platforms for identifying new indications have emerged; some have been successful in building their own pipelines of candidates with reduced risks and timelines associated with further clinical development. The business models and platforms offered by these companies will be validated if they are able to generate positive proof-of-concept clinical data for their repositioned compounds. This review describes the strategy of biomarker-guided repositioning of chemotherapeutic drugs for inflammation therapy, considering the repositioning of methylthiouracil (MTU), an antithyroid drug, as a potential anti-inflammatory reagent.
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      PubDate: 2015-06-26T14:26:48Z
       
  • PU-H71, an Improvement on Nature's Solutions to Oncogenic Hsp90 Addiction
    • Abstract: Publication date: Available online 25 June 2015
      Source:Pharmacological Research
      Author(s): Matthew Trendowski
      Despite recent advances in precision medicine, many molecular-based antineoplastic agents do not potentiate sustainable long term remissions, warranting the investigation of novel therapeutic strategies. Heat shock protein 90 (Hsp90) is a molecular chaperone that not only has oncogenic properties, but has distinct expression profiles in malignant and normal cells, providing a rational strategy to attain preferential damage. Prior attempts to target Hsp90 with natural product-based compounds have been hampered by their associated off target toxicities, suggesting that novel, fully synthetic inhibitors may be required to achieve the specificity necessary for therapeutic efficacy. Therefore, this review highlights the antineoplastic potential of PU-H71 (6-amino-8-[(6-iodo-1,3-benzodioxol-5-yl)thio]-N-(1-methylethyl)-9H-purine-9-propanamine), a novel purine based analog that has shown efficacy in many preclinical models of malignancy, and is now under clinical examination. In addition, the review suggests potential concomitant therapeutic approaches that may be particularly beneficial to molecular-based, as well as traditional cytotoxic cancer chemotherapy.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Identification of key residues involved in the activation and signaling
           properties of dopamine D3 receptor
    • Abstract: Publication date: Available online 23 June 2015
      Source:Pharmacological Research
      Author(s): Kokila Kota , Eldo V. Kuzhikandathil , Milad Afrasiabi , Brett Lacy , Maria Kontoyianni , A. Michael Crider , Daniel Song
      The dopamine D3 receptor exhibits agonist-dependent tolerance and slow response termination (SRT) signaling properties that distinguish it from the closely-related D2 receptors. While amino acid residues important for D3 receptor ligand binding have been identified, the residues involved in activation of D3 receptor signaling and induction of signaling properties have not been determined. In this paper, we used cis and trans isomers of a novel D3 receptor agonist, 8-OH-PBZI, and site-directed mutagenesis to identify key residues involved in D3 receptor signaling function. Our results show that trans-8-OH-PBZI, but not cis-8-OH-PBZI, elicit the D3 receptor tolerance and SRT properties. We show that while both agonists require a subset of residues in the orthosteric binding site of D3 receptors for activation of the receptor, the ability of the two isomers to differentially induce tolerance and SRT is mediated by interactions with specific residues in the sixth transmembrane helix and third extracellular loop of the D3 receptor. We also show that unlike cis-8-OH-PBZI, which is a partial agonist at the dopamine D2S receptor and full agonist at dopamine D2L receptor, trans-8-OH-PBZI is a full agonist at both D2S and D2L receptors. The different effect of the two isomers on D3 receptor signaling properties and D2S receptor activation correlated with differential effects of the isomers on agonist-induced mouse locomotor activity. The two isomers of 8-OH-PBZI represent novel pharmacological tools for in silico D3 and D2 receptor homology modeling and for determining the role of D3 receptor tolerance and SRT properties in signaling and behavior.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Neuronal effects of a nickel-piperazine/NO donor complex in rodents
    • Abstract: Publication date: Available online 18 June 2015
      Source:Pharmacological Research
      Author(s): Maria Domenica Sanna , Martina Monti , Luigi Casella , Riccardo Roggeri , Nicoletta Galeotti , Lucia Morbidelli
      In the brain, NO is a very important molecule in the regulation of cerebral and extra cerebral cranial blood flow and arterial diameters. It is also importantly involved in many neuronal functions and innumerable roles of NO in many brain related disorders including epilepsy, schizophrenia, drug addiction, anxiety, major depression, have been postulated. The present study aimed to explore the neuronal role exerted by the metal-nonoate compound Ni(PipNONO)Cl, a novel NO donor whose vascular protective effects have been recently demonstrated. Ni(PipNONO)Cl showed antidepressant-like properties in the tail suspension test and antiamnesic activity in the passive avoidance test in the absence of any hypernociceptive response to a mechanical stimulus. These effects were related to the NO-releasing properties of the compound within the central nervous system as demonstrated by the increase of iNOS levels in the brain, spinal cord and dura mater. The modulation of neuronal functions appeared after acute and repeated treatment, showing the lack of any tolerance to neuronal effects. At the dose used (10mg/kg i.p.), Ni(PipNONO)Cl did not induce any visible sign of toxicity and experiments were performed in the absence of locomotor impairments. In addition to the NO-related neuronal activities of Ni(PipNONO)Cl, the decomposition control compound Ni(Pip)Cl2 showed anxiogenic-like and procognitive effects. The present findings showed neuronal modulatory activity of Ni(PipNONO)Cl through a NO-mediated mechanism. The activities of the decomposition compound Ni(Pip)Cl2 attributed to Ni(PipNONO)Cl the capability to modulate additional neuronal functions independently from NO releasing properties extending and improving the therapeutic perspectives of the NO donor.
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      PubDate: 2015-06-26T14:26:48Z
       
  • A2BP1 gene polymorphisms association with olanzapine-induced weight gain
    • Abstract: Publication date: Available online 17 June 2015
      Source:Pharmacological Research
      Author(s): Licai Dong , Hao Yan , Xuebing Huang , Xiaofeng Hu , Yongfeng Yang , Cuicui Ma , Bo Du , Tianlan Lu , Chao Jin , Lifang Wang , Hao Yu , Zheng Dong , Wenqiang Li , Yanyan Ruan , Hongyan Zhang , Hongxing Zhang , Weifeng Mi , Wenbin Ma , Keqing Li , Luxian Lv , Dai Zhang , Weihua Yue
      The ataxin-2 binding protein 1 (A2BP1) gene is reported to be one of the susceptibility genes in schizophrenia, autism, and obesity. The aim of this study was to explore the association of A2BP1 gene polymorphisms with antipsychotic induced weight gain (AIWG) in Chinese Han population. Three hundred and twenty-eight patients with schizophrenia were followed-up for an 8-week period of treatment with olanzapine. The fasting weights of 328 patients were measured before and after the 8-week course of treatment. Four single nucleotide polymorphisms (SNPs: rs8048076, rs1478697, rs10500331, and rs4786847) of the A2BP1 gene were genotyped by polymerase chain reaction (PCR). We analyzed putative association of A2BP1 polymorphisms with AIWG of olanzapine using linear regression analysis and found that SNP rs1478697 was significantly associated with AIWG caused by olanzapine (p =0.0012; Bonferroni corrected p =0.0048). The association was replicated in another independent sample including 208 first-episode and drug-naïve patients presenting with schizophrenia after a 4-week treatment with olanzapine (p =0.0092; Bonferroni corrected p =0.0368; meta p =5.33×10−5). To explore the biological plausibility of A2BP1 in the pathogenesis of AIWG, we made expression analyses and eQTL analyses; these analyses showed that A2BP1 was highly expressed in whole brain tissues using the HBT database, and that rs1478697 has an expression quantitative trait locus effect in human cerebellar cortex tissues using the BRAINEAC database (p =2.50E−04). In conclusion, the rs1478697 in A2BP1 may be associated with AIWG induced by 8-week treatment with olanzapine.
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      PubDate: 2015-06-26T14:26:48Z
       
  • Classical and atypical agonists activate M1 muscarinic acetylcholine
           receptors through common mechanisms
    • Abstract: Publication date: Available online 13 April 2015
      Source:Pharmacological Research
      Author(s): Alena Randáková , Eva Dolejší , Vladimír Rudajev , Pavel Zimčík , Vladimír Doležal , Esam E. El-Fakahany , Jan Jakubík
      We mutated key amino acids of the human variant of the M1 muscarinic receptor that target ligand binding, receptor activation, and receptor-G protein interaction. We compared the effects of these mutations on the action of two atypical M1 functionally preferring agonists (N-desmethylclozapine and xanomeline) and two classical non-selective orthosteric agonists (carbachol and oxotremorine). Mutations of D105 in the orthosteric binding site and mutation of D99 located out of the orthosteric binding site decreased affinity of all tested agonists that was translated as a decrease in potency in accumulation of inositol phosphates and intracellular calcium mobilization. Mutation of D105 decreased the potency of the atypical agonist xanomeline more than that of the classical agonists carbachol and oxotremorine. Mutation of the residues involved in receptor activation (D71) and coupling to G-proteins (R123) completely abolished functional responses to both classical and atypical agonists. Our data show that both classical and atypical agonists activate hM1 receptors by the same molecular switch that involves D71 in the second transmembrane helix. The principal difference among the studied agonists is rather in the way they interact with D105 in the orthosteric binding site. Furthermore, our data demonstrate a key role of D105 in xanomeline wash-resistant binding and persistent activation of hM1 by wash-resistant xanomeline.
      Graphical abstract image

      PubDate: 2015-04-17T05:15:30Z
       
 
 
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