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Journal Cover Pharmacological Research
  [SJR: 2.108]   [H-I: 99]   [1 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1043-6618 - ISSN (Online) 1096-1186
   Published by Elsevier Homepage  [3040 journals]
  • Deacetylase inhibitors as a novel modality in the treatment of multiple
           myeloma
    • Authors: Paul G. Richardson; Philippe Moreau; Jacob P. Laubach; Michelle E. Maglio; Sagar Lonial; Jesus San-Miguel
      Pages: 185 - 191
      Abstract: Publication date: March 2017
      Source:Pharmacological Research, Volume 117
      Author(s): Paul G. Richardson, Philippe Moreau, Jacob P. Laubach, Michelle E. Maglio, Sagar Lonial, Jesus San-Miguel
      Deacetylase enzymes remove acetyl groups from histone and nonhistone proteins. Dysregulation of deacetylase activity is a hallmark of malignancy, including multiple myeloma (MM). Deacetylase inhibitors (DACi) cause epigenetic modification and inhibition of the aggresome pathway, resulting in death of MM cells. Panobinostat, a pan-DACi, has shown significant clinical benefit and is the first DACi approved for the treatment of MM. It is approved for use in combination with bortezomib and dexamethasone for the treatment of patients with relapsed or relapsed and refractory MM who have received ≥2 prior regimens including bortezomib and an immunomodulatory drug. Ricolinostat and ACY-241, which selectively inhibit HDAC6 and the aggresome pathway, are currently being studied in combination with dexamethasone and bortezomib or an immunomodulatory drug for the treatment of relapsed and refractory MM. In this review, we discuss the data from key clinical trials investigating deacetylase inhibitors as novel treatment options for MM.
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      PubDate: 2017-01-08T06:35:51Z
      DOI: 10.1016/j.phrs.2016.11.020
      Issue No: Vol. 117 (2017)
       
  • Artemisinin and its derivatives in treating protozoan infections beyond
           malaria
    • Authors: Cecilia Shi Ni Loo; Nelson Siu Kei Lam; Deying Yu; Xin-zhuan Su; Fangli Lu
      Pages: 192 - 217
      Abstract: Publication date: March 2017
      Source:Pharmacological Research, Volume 117
      Author(s): Cecilia Shi Ni Loo, Nelson Siu Kei Lam, Deying Yu, Xin-zhuan Su, Fangli Lu
      Parasitic protozoan diseases continue to rank among the world’s greatest global health problems, which are also common among poor populations. Currently available drugs for treatment present drawbacks, urging the need for more effective, safer, and cheaper drugs. Artemisinin (ART) and its derivatives are some of the most important classes of antimalarial agents originally derived from Artemisia annua L. However, besides the outstanding antimalarial and antischistosomal activities, ART and its derivatives also possess activities against other parasitic protozoa. In this paper we review the activities of ART and its derivatives against protozoan parasites in vitro and in vivo, including Leishmania spp., Trypanosoma spp., Toxoplasma gondii, Neospora caninum, Eimeria tenella, Acanthamoeba castellanii, Naegleria fowleri, Cryptosporidium parvum, Giardia lamblia, and Babesia spp. We conclude that ART and its derivatives may be good alternatives for treating other non-malarial protozoan infections in developing countries, although more studies are necessary before they can be applied clinically.
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      PubDate: 2017-01-08T06:35:51Z
      DOI: 10.1016/j.phrs.2016.11.012
      Issue No: Vol. 117 (2017)
       
  • Vitamin D in autoimmune rheumatic diseases: A view inside gender
           differences
    • Authors: Massimiliano Vasile; Clarissa Corinaldesi; Cristina Antinozzi; Clara Crescioli
      Pages: 228 - 241
      Abstract: Publication date: March 2017
      Source:Pharmacological Research, Volume 117
      Author(s): Massimiliano Vasile, Clarissa Corinaldesi, Cristina Antinozzi, Clara Crescioli
      A large body of evidence highlights the role for vitamin D deficiency/insufficiency in rheumatic diseases, a group of different pathologies mostly of autoimmune origin. Vitamin D and vitamin D receptor agonists exquisitely modulate the immune system against over-reactivity towards tolerance; on this basis, vitamin D could be a good therapeutic candidate to control autoimmune processes in rheumatic diseases. Similarly, to other autoimmune pathologies, rheumatic diseases show a significant female bias. This sexual dimorphism seems, in part, to rely on the different sex hormone-induced regulation on male and female immune systems. Females, in fact, retain greater immune reactivity and competence likely due to estrogens, which, at variance with androgens, are associated with a greater resilience to infections but also to a higher risk for autoimmunity. In this scenario, there is growing interest on vitamin D supplementation for prevention or therapy in rheumatic diseases in relation to gender and sexual hormones. The purpose of the review is to overview vitamin D status in rheumatic diseases, related to gender and sex hormones. In particular, the main vitamin D immunoregulatory properties are summarized with some sex hormone-driven immune activities, in females and males immune systems. Topics onto vitamin D receptor agonists as potential therapeutic agents in rheumatic disease are addressed, especially in view of the role of vitamin D inadequacy in the pathogenesis of rheumatic diseases. So far, further clinical and basic studies should be encouraged to confirm the high potential power of vitamin D receptor agonists as novel pharmacological tools in rheumatic diseases particularly in light of personalized gender-related therapeutic strategies.
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      PubDate: 2017-01-08T06:35:51Z
      DOI: 10.1016/j.phrs.2016.12.038
      Issue No: Vol. 117 (2017)
       
  • Pharmacological chaperone approaches for rescuing GPCR mutants: Current
           state, challenges, and screening strategies
    • Authors: Pieter Beerepoot; Reza Nazari; Ali Salahpour
      Pages: 242 - 251
      Abstract: Publication date: March 2017
      Source:Pharmacological Research, Volume 117
      Author(s): Pieter Beerepoot, Reza Nazari, Ali Salahpour
      A substantial number of G-protein coupled receptors (GPCRs) genetic disorders are due to mutations that cause misfolding or dysfunction of the receptor product. Pharmacological chaperoning approaches can rescue such mutant receptors by stabilizing protein conformations that behave similar to the wild type protein. For example, this can be achieved by improving folding efficiency and/or interaction with chaperone proteins. Although efficacy of pharmacological chaperones has been demonstrated in vitro for a variety of GPCRs, translation to clinical use has been limited. In this paper we discuss the history of pharmacological chaperones of GPCR’s and other membrane proteins, the challenges in translation to the clinic, and the use of different assays for pharmacological chaperone discovery.
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      PubDate: 2017-01-08T06:35:51Z
      DOI: 10.1016/j.phrs.2016.12.036
      Issue No: Vol. 117 (2017)
       
  • Melatonin as a promising agent of regulating stem cell biology and its
           application in disease therapy
    • Authors: Shuo Zhang; Simon Chen; Yuan Li; Yu Liu
      Pages: 252 - 260
      Abstract: Publication date: March 2017
      Source:Pharmacological Research, Volume 117
      Author(s): Shuo Zhang, Simon Chen, Yuan Li, Yu Liu
      Stem cells have emerged as an important approach to repair and regenerate damaged tissues or organs and show great therapeutic potential in a variety of diseases. However, the low survival of engrafted stem cells still remains a major challenge for stem cell therapy. As a major hormone from the pineal gland, melatonin has been shown to play an important role in regulating the physiological and pathological functions of stem cells, such as promoting proliferation, migration and differentiation. Thus, melatonin combined with stem cell transplantation displayed promising application potential in neurodegenerative diseases, liver cirrhosis, wound healing, myocardial infarction, kidney ischemia injury, osteoporosis, etc. It exerts its physiological and pathological functions through its anti-oxidant, anti-inflammatory, anti-apoptosis and anti-ageing properties. Here, we summarize recent advances on exploring the biological role of melatonin in stem cells, and discuss its potential applications in stem cell-based therapy.

      PubDate: 2017-01-15T22:30:15Z
      DOI: 10.1016/j.phrs.2016.12.035
      Issue No: Vol. 117 (2017)
       
  • Polymer-coated nanoparticles: Carrier platforms for hydrophobic water- and
           air-sensitive metallo-organic compounds
    • Authors: Daniel Valdeperez; Tianqiang Wang; Jens P. Eußner; Bastian Weinert; Jianyuan Hao; Wolfgang J. Parak; Stefanie Dehnen; Beatriz Pelaz
      Pages: 261 - 266
      Abstract: Publication date: March 2017
      Source:Pharmacological Research, Volume 117
      Author(s): Daniel Valdeperez, Tianqiang Wang, Jens P. Eußner, Bastian Weinert, Jianyuan Hao, Wolfgang J. Parak, Stefanie Dehnen, Beatriz Pelaz
      Many of the relevant compounds for anticancer therapy are metal-based compounds (metallodrugs), being platinum-based drugs such as cisplatin, carboplatin (Paraplatin®), and oxaliplatin (Eloxatin®) the most widely used. Despite this, their application is limited by issues such as cell-acquired platinum resistance and manifold side effects following systemic delivery. Thus, the development of new metal-based compounds is highly needed. The catalytic properties of a variety of metal-based compounds are nowadays very well known, which opens new opportunities to take advantage of them inside living cells or organisms. However, many of these compounds are hydrophobic and thus not soluble in aqueous solution, as they lack stability against water or oxygen presence. Thus, versatile platforms capable of enhancing the features of these compounds in aqueous solutions are of importance in the development of new drugs. Surface engineered nanoparticles may render metallodrugs with good colloidal stability in water and in complex media containing high salt concentration and/or proteins. Herein, polymer coated nanoparticles are proposed as a platform to link insoluble and water/oxygen sensitive drugs. The linkage of insoluble and oxygen sensitive tin clusters to nanoparticles is presented, aiming to enhance both, the solubility and the stability of these compounds in water, which may be an alternative approach in the development of metal-based drugs. The formation of the cluster-nanoparticle system was confirmed via inductively coupled plasma mass spectrometry experiments. The catalytic activity and the stability of the cluster in water were studied through the reduction of methylene blue. Results demonstrate that in fact the tin clusters could be transferred into aqueous solution and retained their catalytic activity.
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      PubDate: 2017-01-15T22:30:15Z
      DOI: 10.1016/j.phrs.2016.12.034
      Issue No: Vol. 117 (2017)
       
  • [6]-gingerol and [6]-shogaol, active ingredients of the traditional
           Japanese medicine hangeshashinto, relief oral ulcerative mucositis-induced
           pain via action on Na+ channels
    • Authors: Suzuro Hitomi; Kentaro Ono; Kiyoshi Terawaki; Chinami Matsumoto; Keita Mizuno; Kiichiro Yamaguchi; Ryota Imai; Yuji Omiya; Tomohisa Hattori; Yoshio Kase; Kiyotoshi Inenaga
      Pages: 288 - 302
      Abstract: Publication date: March 2017
      Source:Pharmacological Research, Volume 117
      Author(s): Suzuro Hitomi, Kentaro Ono, Kiyoshi Terawaki, Chinami Matsumoto, Keita Mizuno, Kiichiro Yamaguchi, Ryota Imai, Yuji Omiya, Tomohisa Hattori, Yoshio Kase, Kiyotoshi Inenaga
      The traditional Japanese herbal medicine hangeshashinto (HST) has beneficial effects for the treatment of oral ulcerative mucositis (OUM) in cancer patients. However, the ingredient-based mechanism that underlies its pain-relieving activity remains unknown. In the present study, to clarify the analgesic mechanism of HST on OUM-induced pain, we investigated putative HST ingredients showing antagonistic effects on Na+ channels in vitro and in vivo. A screen of 21 major ingredients using automated patch-clamp recordings in channel-expressing cells showed that [6]-gingerol and [6]-shogaol, two components of a Processed Ginger extract, considerably inhibited voltage-activated Na+ currents. These two ingredients inhibited the stimulant-induced release of substance P and action potential generation in cultured rat sensory neurons. A submucosal injection of a mixture of [6]-gingerol and [6]-shogaol increased the mechanical withdrawal threshold in healthy rats. In a rat OUM model, OUM-induced mechanical pain was alleviated 30min after the swab application of HST despite the absence of anti-bacterial and anti-inflammatory actions in the OUM area. A swab application of a mixture of [6]-gingerol and [6]-shogaol induced sufficient analgesia of OUM-induced mechanical or spontaneous pain when co-applied with a Ginseng extract containing abundant saponin. The Ginseng extract demonstrated an acceleration of substance permeability into the oral ulcer tissue without an analgesic effect. These findings suggest that Na+ channel blockage by gingerol/shogaol plays an essential role in HST-associated analgesia of OUM-induced pain. This pharmacological mechanism provides scientific evidence supporting the use of this herbal medicine in patients suffering from OUM-induced pain.
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      PubDate: 2017-01-15T22:30:15Z
      DOI: 10.1016/j.phrs.2016.12.026
      Issue No: Vol. 117 (2017)
       
  • Pharmacological Strategies to Target Oncogenic KRAS Signaling in
           Pancreatic Cancer
    • Authors: Hsiao-Ching Chuang; Po-Hsien Huang; Samuel K. Kulp; Ching-Shih Chen
      Abstract: Publication date: Available online 8 January 2017
      Source:Pharmacological Research
      Author(s): Hsiao-Ching Chuang, Po-Hsien Huang, Samuel K. Kulp, Ching-Shih Chen
      The clear importance of mutated KRAS as a therapeutic target has driven the investigation of multiple approaches to inhibit oncogenic KRAS signaling at different molecular levels. However, no KRAS-targeted therapy has reached the clinic to date, which underlies the intrinsic difficulty in developing effective, direct inhibitors of KRAS. Thus, this article provides an overview of the history and recent progress in the development of pharmacological strategies to target oncogenic KRAS with small molecule agents. Mechanistically, these KRAS-targeted agents can be classified into the following four categories. (1) Small-molecule RAS-binding ligands that prevent RAS activation by binding within or outside the nucleotide-binding motif. (2) Inhibitors of KRAS membrane anchorage. (3) Inhibitors that bind to RAS-binding domains of RAS-effector proteins. (4) Inhibitors of KRAS expression. The advantage and limitation of each type of these anti-KRAS agents are discussed.
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      PubDate: 2017-01-15T22:30:15Z
      DOI: 10.1016/j.phrs.2017.01.006
       
  • Anaplastic lymphoma kinase (ALK) inhibitors in the treatment of ALK-driven
           lung cancers
    • Authors: Robert Roskoski
      Abstract: Publication date: Available online 8 January 2017
      Source:Pharmacological Research
      Author(s): Robert Roskoski
      Anaplastic lymphoma kinase is expressed in two-thirds of the anaplastic large-cell lymphomas as an NPM-ALK fusion protein. Physiological ALK is a receptor protein-tyrosine kinase within the insulin receptor superfamily of proteins that participates in nervous system development. The EML4-ALK fusion protein and four other ALK-fusion proteins play a fundamental role in the development in about 5% of non-small cell lung cancers. The amino-terminal portions of the ALK fusion proteins result in dimerization and subsequent activation of the ALK protein kinase domain that plays a key role in the pathogenesis of various tumors. Downstream signaling from the ALK fusion protein leads to the activation of the Ras/Raf/MEK/ERK1/2 cell proliferation module and the JAK/STAT cell survival pathways. Moreover, nearly two dozen ALK activating mutations are involved in the pathogenesis of childhood neuroblastomas. The occurrence of oncogenic ALK-fusion proteins, particularly in non-small cell lung cancer, has fostered considerable interest in the development of ALK inhibitors. Crizotinib was the first such inhibitor approved by the US Food and Drug Administration for the treatment of ALK-positive non-small cell lung cancer in 2011. The median time for the emergence of crizotinib drug resistance is 10.5 months after the initiation of therapy. Such resistance prompted the development of second-generation drugs including ceritinib and alectinib, which are approved for the treatment of non-small cell lung cancer. Unlike the single gatekeeper mutation that occurs in drug-resistant epidermal growth factor receptor in lung cancer, nearly a dozen different mutations in the catalytic domain of ALK fusion proteins have been discovered that result in crizotinib resistance. Crizotinib, ceritinib, and alectinib form a complex within the front cleft between the small and large lobes of an inactive ALK protein-kinase domain with a compact activation segment. These drugs are classified as type I½ B inhibitors because they bind to an inactive enzyme and they do not extend past the gatekeeper into the back pocket of the drug binding site.
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      PubDate: 2017-01-15T22:30:15Z
      DOI: 10.1016/j.phrs.2017.01.007
       
  • The Mechanistic Role of Chemically Diverse Metal Ions in the Induction of
           Autophagy
    • Authors: Sumit Sahni; Dong-Hun Bae; Patric Jansson; Des Richardson
      Abstract: Publication date: Available online 10 January 2017
      Source:Pharmacological Research
      Author(s): Sumit Sahni, Dong-Hun Bae, Patric Jansson, Des Richardson
      Autophagy is an evolutionary conserved cellular catabolic degradation process in response to stress which involves lysosomal degradation of unnecessary or damaged organelles and misfolded proteins. This is primarily a pro-survival pathway providing the cell with essential nutrients during stressful conditions. There are number of essential metal ions, which are required for normal physiological functioning of cells. Studies have shown that autophagy can be regulated by cellular metal ion concentrations. On the other hand, autophagy is also shown to regulate intracellular levels of certain metal ions. This review discusses recent advances in the research examining the role of metal ions in the autophagic pathway.
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      PubDate: 2017-01-15T22:30:15Z
      DOI: 10.1016/j.phrs.2017.01.009
       
  • Hydrogen sulfide protects against endoplasmic reticulum stress and
           mitochondrial injury in nucleus pulposus cells and ameliorates
           intervertebral disc degeneration
    • Authors: Daoliang Xu; Haiming Jin; Jianxia Wen; Jiaoxiang Chen; Deheng Chen; Ningyu Cai; Yongli Wang; Jianle Wang; Yu Chen; Xiaolei Zhang; Xiangyang Wang
      Abstract: Publication date: Available online 10 January 2017
      Source:Pharmacological Research
      Author(s): Daoliang Xu, Haiming Jin, Jianxia Wen, Jiaoxiang Chen, Deheng Chen, Ningyu Cai, Yongli Wang, Jianle Wang, Yu Chen, Xiaolei Zhang, Xiangyang Wang
      It has been suggested that excessive apoptosis in intervertebral disc cells induced by inflammatory cytokines, such as interleukin (IL)-1β, is related to the process of intervertebral disc degeneration (IVDD). Hydrogen sulfide (H2S), a gaseous signaling molecule, has drawn attention for its anti-apoptosis role in various pathophysiological processes in degenerative diseases. To date, there has been no investigation of the correlation of H2S production and IVDD or of the effects of H2S on IL-1β-induced apoptosis in nucleus pulposus (NP) cells. Here, we found that the expression levels of cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE), two key enzymes in the generation of H2S, were significantly decreased in human degenerate NP tissues as well as in IL-1β-treated NP cells. NaHS (H2S donor) administration showed a protective effect by inhibiting the endoplasmic reticulum (ER) stress response and mitochondrial dysfunction induced by IL-1β stimulation in vitro, the effect was related to activation of the PI3K/Akt and ERK1/2 signaling pathways. Suppression of these pathways by specific inhibitors, LY294002 and PD98059, partially reduced the protective effect of NaHS. Moreover, in the percutaneous needle puncture disc degeneration rat tail model, disc degeneration was partially reversed by NaHS administration. Taken together, our results suggest that H2S plays a protective role in IVDD and the underlying mechanism involves PI3K/Akt and ERK1/2 signaling pathways-mediated suppression of ER stress and mitochondrial dysfunction in IL-1β-induced NP cells.
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      PubDate: 2017-01-15T22:30:15Z
      DOI: 10.1016/j.phrs.2017.01.005
       
  • An Update on the Physiological and Therapeutic Relevance of GPCR Oligomers
    • Authors: Batoul Farran
      Abstract: Publication date: Available online 11 January 2017
      Source:Pharmacological Research
      Author(s): Batoul Farran
      The traditional view on GPCRs held that they function as single monomeric units composed of identical subunits. This notion was overturned by the discovery that GPCRs can form homo- and hetero-oligomers, some of which are obligatory, and can further assemble into receptor mosaics consisting of three or more protomers. Oligomerisation exerts significant impacts on receptor function and physiology, offering a platform for the diversification of receptor signalling, pharmacology, regulation, crosstalk, internalization and trafficking. Given their involvement in the modulation of crucial physiological processes, heteromers could constitute important therapeutic targets for a wide range of diseases, including schizophrenia, Parkinson’s disease, substance abuse or obesity. This review aims at depicting the current developments in GPCR oligomerisation research, documenting various class A, B and C GPCR heteromers detected in vitro and in vivo using biochemical and biophysical approaches, as well as recently identified higher-order oligomeric complexes. It explores the current understanding of dimerization dynamics and the possible interaction interfaces that drive oligomerisation. Most importantly, it provides an inventory of the wide range of physiological processes and pathophysiological conditions to which GPCR oligomers contribute, surveying some of the oligomers that constitute potential drug targets. Finally, it delineates the efforts to develop novel classes of ligands that specifically target and tether to receptor oligomers instead of a single monomeric entity, thus ameliorating their ability to modulate GPCR function.
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      PubDate: 2017-01-15T22:30:15Z
      DOI: 10.1016/j.phrs.2017.01.008
       
  • Targeting EGFR T790M mutation in NSCLC: from biology to evaluation and
           treatment
    • Authors: Antonio Passaro; Elena Guerini-Rocco; Alessia Pochesci; Davide Vacirca; Gianluca Spitaleri; Chiara Matilde Catania; Alessandra Rappa; Massimo Barberis; Filippo de Marinis
      Abstract: Publication date: Available online 12 January 2017
      Source:Pharmacological Research
      Author(s): Antonio Passaro, Elena Guerini-Rocco, Alessia Pochesci, Davide Vacirca, Gianluca Spitaleri, Chiara Matilde Catania, Alessandra Rappa, Massimo Barberis, Filippo de Marinis
      The identification of EGFR mutations and their respectively tyrosine kinase inhibitors (TKIs), changed dramatically treatment and survival of patients with EGFR-positive lung cancer. Nowadays, different EGFR TKIs as afatinib, erlotinib and gefitinib are approved worldwide for the treatment of NSCLC harbouring EGFR mutations, in particular exon 19 deletions or exon 21 (Leu858Arg) substitution EGFR mutations. In first-line setting, when comparing with platinum-based chemotherapy, these target drugs improves progression-free survival, response rate and quality of life. Unfortunately, the development of different mechanism of resistance, limits the long term efficacy of these agents. The most clear mechanism of resistance is the development of EGFR Thr790Met mutation. Against this new target, different third-generation EGFR-mutant-selective TKIs, such as osimertinib, rociletinib and olmutinib, showed a great activity. In this review, we summarize the scientific evidences about biology, evaluation and treatment on NSCLC with EGFR T790M mutation.
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      PubDate: 2017-01-15T22:30:15Z
      DOI: 10.1016/j.phrs.2017.01.003
       
  • Resveratrol supplementation and plasma adipokines concentrations? A
           systematic review and meta-analysis of randomized controlled trials
    • Authors: Mohsen Mohammadi Sartang; Zohreh Mazloom; Zahra Sohrabi; Saeed Sherafatmanesh; Reza Barati Boldaji
      Abstract: Publication date: Available online 13 January 2017
      Source:Pharmacological Research
      Author(s): Mohsen Mohammadi Sartang, Zohreh Mazloom, Zahra Sohrabi, Saeed Sherafatmanesh, Reza Barati Boldaji
      The results of human clinical trials have revealed that the effects of resveratrol on adipokines are inconsistent. Our objective was to elucidate the role of resveratrol supplementation on adipokines through a systematic review and a meta-analysis of available randomized placebo-controlled trials (RCTs). 1 1 RCTs: randomized placebo-controlled trials. The search included PubMed-MEDLINE, SCOPUS and ISI web of sciences database till up to 6th November 2016. Weight mean differences (WMD) 2 2 WMD: weight mean difference. were calculated for net changes in adipokines using fixed-effects or random-effects models; meta-regression analysis and publication bias were conducted in accordance with standard methods. Nine RCTs with 11 treatment arms were eligible for inclusion in this systematic review and meta-analysis. Meta-analysis of data from 10 treatment arms showed a significant change in plasma adiponectin concentrations following resveratrol supplementation (WMD: 1.10μg/ml, 95%CI: 0.88, 1.33, p < 0.001); Q =11.43, I2 =21.29%, p=0.247). There was a significant greater adiponectin-reducing effect in trials with higher than or equal to 100mg/day (WMD: 1.11 ug/ml, 95%CI: 0.88, 1.34, p < 0.001), versus those with less than 100 mg/day dosage (WMD: 0.84 ug/ml, 95%CI: −0.62, 2.31, p = 0.260). Meta-analysis of data from 5 treatment arms did not find any significant change in plasma leptin concentrations following resveratrol supplementation (WMD: 3.77ng/ml, 95% CI: −2.28, 9.83, p =0.222; Q =8.00, I2 =50.01%). Resveratrol significantly improves adiponectin but does not affect leptin concentrations. Additional studies are required to further evaluate the potential benefits of resveratrol on adipokines in humans.
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      PubDate: 2017-01-15T22:30:15Z
      DOI: 10.1016/j.phrs.2017.01.012
       
  • Beta2-adrenergic signaling affects the phenotype of human cardiac
           progenitor cells through EMT modulation
    • Authors: Francesca Pagano; Francesco Angelini; Camilla Siciliano; Julia Tasciotti; Giorgio Mangino; Elena De Falco; Roberto Carnevale; Sebastiano Sciarretta; Giacomo Frati; Isotta Chimenti
      Abstract: Publication date: Available online 15 January 2017
      Source:Pharmacological Research
      Author(s): Francesca Pagano, Francesco Angelini, Camilla Siciliano, Julia Tasciotti, Giorgio Mangino, Elena De Falco, Roberto Carnevale, Sebastiano Sciarretta, Giacomo Frati, Isotta Chimenti
      Human cardiac progenitor cells (CPCs) offer great promises to cardiac cell therapy for heart failure. Many in vivo studies have shown their therapeutic benefits, paving the way for clinical translation. The 3D model of cardiospheres (CSs) represents a unique niche-like in vitro microenvironment, which includes CPCs and supporting cells. CSs have been shown to form through a process mediated by epithelial-to-mesenchymal transition (EMT). β2-adrenergic signaling significantly affects stem/progenitor cells activation and mobilization in multiple tissues, and crosstalk between β2-adrenergic signaling and EMT processes has been reported. In the present study, we aimed at investigating the biological response of CSs to β2-adrenergic stimuli, focusing on EMT modulation in the 3D culture system of CSs. We treated human CSs and CS-derived cells (CDCs) with the β2-blocker butoxamine (BUT), using either untreated or β2 agonist (clenbuterol) treated CDCs as control. BUT-treated CS-forming cells displayed increased migration capacity and a significant increase in their CS-forming ability, consistently associated with increased expression of EMT-related genes, such as Snai1. Moreover, long-term BUT-treated CDCs contained a lower percentage of CD90+ cells, and this feature has been previously correlated with higher cardiogenic and therapeutic potential of the CDCs population. In addition, long-term BUT-treated CDCs had an increased ratio of collagen-III/collagen-I gene expression levels, and showed decreased release of inflammatory cytokines, overall supporting a less fibrosis-prone phenotype. In conclusion, β2 adrenergic receptor block positively affected the stemness vs commitment balance within CSs through the modulation of type1-EMT (so called “developmental”). These results further highlight type-1 EMT to be a key process affecting the features of resident cardiac progenitor cells, and mediating their response to the microenvironment.
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      PubDate: 2017-01-15T22:30:15Z
      DOI: 10.1016/j.phrs.2017.01.016
       
  • The 35-year odyssey of beta blockers in cirrhosis: any gender difference
           in sight?
    • Authors: Maria Antonella Burza; Hanns-Ulrich Marschall; Laura Napoleone; Antonio Molinaro
      Abstract: Publication date: Available online 15 January 2017
      Source:Pharmacological Research
      Author(s): Maria Antonella Burza, Hanns-Ulrich Marschall, Laura Napoleone, Antonio Molinaro
      Cirrhosis is the end-stage of chronic liver disease and leads to the development of portal hypertension and its complications such as esophagogastric varices. Non-selective beta blockers (NSBB) are the keystone for the treatment of portal hypertension since the 1980s and, over the decades, several studies have confirmed their beneficial effect on the prevention of variceal (re)bleeding. Pharmacological studies showed effects of gender, sex hormones, oral contraceptives, and pregnancy on cytochrome P450 (CYPs) enzymes that metabolise NSBB, suggesting that gender differences might exist in the effect of NSBB. In this review, we focused on the 35-year knowledge about the use of beta blockers in cirrhosis and potential gender differences. We specifically examined the role of NSBB in pre-primary, primary and secondary prophylaxis of variceal bleeding, compared two commonly used NSBB (i.e., Propranolol and Carvedilol), and present the current controversies about the window of treatment in advanced cirrhosis with a specific focus on gender differences in NSBB effects. NSBB are not currently recommended in pre-primary prophylaxis of varices mainly because of lack of proven efficacy. On the other hand, NSBB are strongly recommended in patient with cirrhosis as primary (as alternative to endoscopic band ligation, EBL) and secondary prophylaxis (in addition to EBL) of variceal bleeding. To date, no studies have focused specifically on the effect of gender on NSBB treatment. Data extrapolated from clinical studies show that gender was neither a risk factor for the development of varices nor associated with a different response to treatment in primary or secondary prophylaxis. According to the available guidelines, no different, gender-based treatment for portal hypertension is recommended.
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      PubDate: 2017-01-15T22:30:15Z
      DOI: 10.1016/j.phrs.2017.01.015
       
  • DREAM as a novel therapeutic target for anti-thrombotic agents
    • Authors: Jaehyung Cho
      Abstract: Publication date: Available online 5 January 2017
      Source:Pharmacological Research
      Author(s): Jaehyung Cho
      Circulating platelets participate in the process of numerous diseases including thrombosis, inflammation, and cancer. Thus, it is of great importance to understand the underlying mechanisms mediating platelet activation under disease conditions. Emerging evidence indicates that despite the lack of a nucleus, platelets possess molecules involved in gene transcription occurring in nucleated cells. This review will summarize downstream regulatory element antagonist modulator (DREAM), a transcriptional repressor, and highlight recent findings suggesting its novel non-transcriptional role in hemostasis and thrombosis.
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      PubDate: 2017-01-08T06:35:51Z
      DOI: 10.1016/j.phrs.2017.01.002
       
  • Dysregulation of cytokine mediated chemotherapy induced cognitive
           impairment
    • Authors: Xiaojia Ren; Daret K.St. Clair; D.Allan Butterfield
      Abstract: Publication date: Available online 4 January 2017
      Source:Pharmacological Research
      Author(s): Xiaojia Ren, Daret K.St. Clair, D.Allan Butterfield
      One of the major complaints patients who survive cancer often make is chemotherapy induced cognitive impairment (CICI), which survivors often call “chemo brain.” CICI is a side effect of chemotherapy due to the cytotoxicity and neurotoxicity of anti-cancer drugs causing structural and functional changes in brain, even when drugs that do not cross the blood brain barrier (BBB) are used. Diminished cognitive functions including diminution of learning and memory, concentration and attention, processing speed and executive functions that reduce quality of life and ability to work are common signs and symptoms of CICI. There still is not a clarified and complete mechanism for CICI, but researchers have pointed to several biochemical candidates. Chemotherapy-induced, cytokine-mediated involvement in CICI will be mainly discussed in this review paper with emphasis on different types of cytokines, correlated with BBB and epigenetic changes. Mechanisms of ROS-generating, anti-cancer drugs and their relation to cytokine-mediated CICI will be emphasized.
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      PubDate: 2017-01-08T06:35:51Z
      DOI: 10.1016/j.phrs.2017.01.001
       
  • Balancing thromboembolic and bleeding risk with non-vitamin K antagonist
           oral anticoagulants (NOACs): a systematic review and meta-analysis on
           gender differences
    • Authors: Marco Proietti; Paola Cheli; Stefania Basili; Michal Mazurek; Gregory YH Lip
      Abstract: Publication date: Available online 7 January 2017
      Source:Pharmacological Research
      Author(s): Marco Proietti, Paola Cheli, Stefania Basili, Michal Mazurek, Gregory YH Lip
      Sex and gender differences have been reported in atrial fibrillation (AF), especially in relation to differences in thromboembolic and bleeding risks. More recently, pharmacological treatments have changed following the introduction of non-vitamin K antagonist oral anticoagulants (NOACs) progressively replacing vitamin K antagonists (VKAs). The aims of this systematic review are to summarize the available evidence on NOACs and the relationship to major adverse outcomes according to sex. Moreover, we performed a meta-analysis of data from the phase III clinical trials investigating the sex effect on stroke/systemic embolic events (SEE) and major bleeding. Our literature review found small differences in NOACs efficacy and safety between male and female patients, even if so far available literature is limited to post-hoc ancillary analyses from randomised trials and one cohort study. Meta-analysis from NOAC trials found a differential effect of NOACs, with male patients being more protected from stroke/SEE and female patients more protected from major bleeding events. Further data are needed to fully elucidate sex differences in AF patients treated with NOACs.
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      PubDate: 2017-01-08T06:35:51Z
      DOI: 10.1016/j.phrs.2017.01.004
       
  • Paradoxical sleep deprivation in rats causes a selective reduction in the
           expression of type-2 metabotropic glutamate receptors in the hippocampus
    • Authors: Isabella Panaccione; Luisa Iacovelli; Luigi di Nuzzo; Francesca Nardecchia; Gianluca Mauro; Delfina Janiri; Antonio De Blasi; Gabriele Sani; Ferdinando Nicoletti; Rosamaria Orlando
      Pages: 46 - 53
      Abstract: Publication date: March 2017
      Source:Pharmacological Research, Volume 117
      Author(s): Isabella Panaccione, Luisa Iacovelli, Luigi di Nuzzo, Francesca Nardecchia, Gianluca Mauro, Delfina Janiri, Antonio De Blasi, Gabriele Sani, Ferdinando Nicoletti, Rosamaria Orlando
      Paradoxical sleep deprivation in rats is considered as an experimental animal model of mania endowed with face, construct, and pharmacological validity. We induced paradoxical sleep deprivation by placing rats onto a small platform surrounded by water. This procedure caused the animal to fall in the water at the onset of REM phase of sleep. Control rats were either placed onto a larger platform (which allowed them to sleep) or maintained in their home cage. Sleep deprived rats showed a substantial reduction in type-2 metabotropic glutamate (mGlu2) receptors mRNA and protein levels in the hippocampus, but not in the prefrontal cortex or corpus striatum, as compared to both groups of control rats. No changes in the expression of mGlu3 receptor mRNA levels or mGlu1α and mGlu5 receptor protein levels were found with exception of an increase in mGlu1α receptor levels in the striatum of SD rats. Moving from these findings we treated SD and control rats with the selective mGlu2 receptor enhancer, BINA (30mg/kg, i.p.). SD rats were also treated with sodium valproate (300mg/kg, i.p.) as an active comparator. Both BINA and sodium valproate were effective in reversing the manic-like phenotype evaluated in an open field arena in SD rats. BINA treatment had no effect on motor activity in control rats, suggesting that our findings were not biased by a non-specific motor-lowering activity of BINA. These findings suggest that changes in the expression of mGlu2 receptors may be associated with the enhanced motor activity observed with mania.
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      PubDate: 2016-12-23T05:09:38Z
      DOI: 10.1016/j.phrs.2016.11.029
      Issue No: Vol. 117 (2016)
       
  • Sigma-2 receptor and progesterone receptor membrane component 1 (PGRMC1)
           are two different proteins: Proofs by fluorescent labeling and binding of
           sigma-2 receptor ligands to PGRMC1
    • Authors: Maria Laura Pati; Diana Groza; Chiara Riganti; Joanna Kopecka; Mauro Niso; Francesco Berardi; Sonja Hager; Petra Heffeter; Miwa Hirai; Hitoshi Tsugawa; Yasuaki Kabe; Makoto Suematsu; Carmen Abate
      Pages: 67 - 74
      Abstract: Publication date: March 2017
      Source:Pharmacological Research, Volume 117
      Author(s): Maria Laura Pati, Diana Groza, Chiara Riganti, Joanna Kopecka, Mauro Niso, Francesco Berardi, Sonja Hager, Petra Heffeter, Miwa Hirai, Hitoshi Tsugawa, Yasuaki Kabe, Makoto Suematsu, Carmen Abate
      A controversial relationship between sigma-2 and progesterone receptor membrane component 1 (PGRMC1) proteins, both representing promising targets for the therapy and diagnosis of tumors, exists since 2011, when the sigma-2 receptor was reported to be identical to PGRMC1. Because a misidentification of these proteins will lead to biased future research hampering the possible diagnostic and therapeutic exploitation of the two targets, there is the need to solve the debate on their identity. With this aim, we have herein investigated uptake and distribution of structurally different fluorescent sigma-2 receptor ligands by flow cytometry and confocal microscopy in MCF7 cells, where together with intrinsic sigma-2 receptors, PGRMC1 was constitutively present or alternatively silenced or overexpressed. HCT116 cells, with constitutive or silenced PGRMC1, were also studied. These experiments showed that the fluorescent sigma-2 ligands bind to their receptor irrespective of PGRMC1 expression. Furthermore, isothermal titration calorimetry was conducted to examine if DTG and PB28, two structurally distinct nanomolar affinity sigma-2 ligands, bind to purified PGRMC1 proteins that have recently been revealed to form both apo-monomeric and heme-mediated dimeric forms. While no binding to apo-PGRMC1 monomer was detected, a micromolar affinity to heme-mediated dimerized PGRMC1 was demonstrated in DTG but not in PB28. The current data provide evidence that sigma-2 receptor and PGRMC1 are not identical, paving the pathway for future unbiased research in which these two attractive targets are treated as different proteins while the identification of the true sigma-2 protein further needs to be pursued.
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      PubDate: 2016-12-23T05:09:38Z
      DOI: 10.1016/j.phrs.2016.12.023
      Issue No: Vol. 117 (2016)
       
  • Dysfunctional oleoylethanolamide signaling in a mouse model of
           Prader-Willi syndrome
    • Authors: Miki Igarashi; Vidya Narayanaswami; Virginia Kimonis; Pietro M. Galassetti; Fariba Oveisi; Kwang-Mook Jung; Daniele Piomelli
      Pages: 75 - 81
      Abstract: Publication date: March 2017
      Source:Pharmacological Research, Volume 117
      Author(s): Miki Igarashi, Vidya Narayanaswami, Virginia Kimonis, Pietro M. Galassetti, Fariba Oveisi, Kwang-Mook Jung, Daniele Piomelli
      Prader-Willi syndrome (PWS), the leading genetic cause of obesity, is characterized by a striking hyperphagic behavior that can lead to obesity, type-2 diabetes, cardiovascular disease and death. The molecular mechanism underlying impaired satiety in PWS is unknown. Oleoylethanolamide (OEA) is a lipid mediator involved in the control of feeding, body weight and energy metabolism. OEA produced by small-intestinal enterocytes during dietary fat digestion activates type-α peroxisome proliferator-activated receptors (PPAR-α) to trigger an afferent signal that causes satiety. Emerging evidence from genetic and human laboratory studies suggests that deficits in OEA-mediated signaling might be implicated in human obesity. In the present study, we investigated whether OEA contributes to feeding dysregulation in Magel2 m+/p− (Magel2 KO) mice, an animal model of PWS. Fasted/refed male Magel2 KO mice eat more than do their wild-type littermates and become overweight with age. Meal pattern analyses show that hyperphagia in Magel2 KO is due to increased meal size and meal duration rather than to lengthening of the intermeal interval, which is suggestive of a defect in mechanisms underlying satiation. Food-dependent OEA accumulation in jejunum and fasting OEA levels in plasma are significantly greater in Magel2 KO mice than in wild-type controls. Together, these findings indicate that deletion of the Magel2 gene is accompanied by marked changes in OEA signaling. Importantly, intraperitoneal administration of OEA (10mg/kg) significantly reduces food intake in fasted/refed Magel2 KO mice, pointing to a possible use of this natural compound to control hunger in PWS.
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      PubDate: 2016-12-23T05:09:38Z
      DOI: 10.1016/j.phrs.2016.12.024
      Issue No: Vol. 117 (2016)
       
  • Potentiation of hepatic stellate cell activation by extracellular ATP is
           dependent on P2X7R-mediated NLRP3 inflammasome activation
    • Authors: Shuang Jiang; Yu Zhang; Jin-Hua Zheng; Xia Li; You-Li Yao; Yan-Ling Wu; Shun-Zong Song; Peng Sun; Ji-Xing Nan; Li-Hua Lian
      Pages: 82 - 93
      Abstract: Publication date: March 2017
      Source:Pharmacological Research, Volume 117
      Author(s): Shuang Jiang, Yu Zhang, Jin-Hua Zheng, Xia Li, You-Li Yao, Yan-Ling Wu, Shun-Zong Song, Peng Sun, Ji-Xing Nan, Li-Hua Lian
      Purinergic receptor P2x7 (P2x7R) is a key modulator of liver inflammation and fibrosis. The present study aimed to investigate the role of P2x7R in hepatic stellate cells activation. Lipopolysaccharide (LPS) or the conditioned medium (CM) from LPS-stimulated RAW 264.7 mouse macrophages was supplemented to human hepatic stellate cells, LX-2 for 24h and P2x7R selective antagonist A438079 (10μM) was supplemented to LX-2 cells 1h before LPS or CM stimulation. In addition LX-2 cells were primed with LPS for 4h and subsequently stimulated for 30min with 3mM of adenosine 5′-triphosphate (ATP). A438079 was supplemented to LX-2 cells 10min prior to ATP. Directly treated with LPS on LX-2 cells, mRNA expressions of interleukin (IL)-1β, IL-18 and IL-6 were increased, as well as mRNA expressions of P2x7R, caspase-1, apoptosis-associated speck-like protein containing CARD (ASC) and NOD-like receptor family, pyrin domain containing 3 (NLRP3) mRNA. LPS also increased α-smooth muscle actin (α-SMA) and type I collagen mRNA expressions, as well as collagen deposition. Interestingly treatment of LX-2 cells with LPS-activated CM exhibited the greater increase of above factors than those in LX-2 cells directly treated with LPS. Pretreatment of A438079 on LX-2 cells stimulated by LPS or LPS-activated CM both suppressed IL-1β mRNA expression. LPS combined with ATP dramatically increased protein synthesis and cleavage of IL-1β and its mRNA level than those in HSC treated with LPS or ATP alone. Additionally LX-2 cells primed with LPS and subsequently stimulated for 30min with ATP greatly increased mRNA and protein expression of caspase-1, NLRP3 and P2x7R, as well as liver fibrosis markers, α-SMA and type I collagen. These events were remarkably suppressed by A438079 pretreatment. siRNA against P2x7R reduced protein expression of NLRP3 and α-SMA, and suppressed deposition and secretion of type I collagen. The involvement of P2X7R-mediated NLRP3 inflammasome activation in IL-1β production of HSC might contribute to ECM deposition and suggests that blockade of the P2x7R-NLRP3 inflammasome axis represents a potential therapeutic target to liver fibrosis.
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      PubDate: 2016-12-30T06:29:56Z
      DOI: 10.1016/j.phrs.2016.11.040
      Issue No: Vol. 117 (2016)
       
  • Passive drug permeation through membranes and cellular distribution
    • Authors: D.O. Scott; A. Ghosh; L. Di; T.S. Maurer
      Pages: 94 - 102
      Abstract: Publication date: March 2017
      Source:Pharmacological Research, Volume 117
      Author(s): D.O. Scott, A. Ghosh, L. Di, T.S. Maurer
      Although often overlooked, passive mechanisms can lead to significant accumulation or restriction of drugs to intracellular sites of drug action. These mechanisms include lipoidal diffusion of ionized species and pH partitioning according to the electrochemical potential and to pH gradients that exist across subcellular compartments, respectively. These mechanisms are increasingly being exploited in the design of safe and effective drugs for the treatment of a wide variety of diseases. In this work, the authors review these efforts and the associated passive mechanisms of cellular drug permeation. A generic mathematical model of the cell is provided and used to illustrate concepts relevant to steady-state intracellular distribution. Finally, the authors review methods for estimating determinant parameters and measuring the net effect at the level of unbound intracellular drug concentrations.
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      PubDate: 2016-12-30T06:29:56Z
      DOI: 10.1016/j.phrs.2016.11.028
      Issue No: Vol. 117 (2016)
       
  • A story of metformin-butyrate synergism to control various pathological
           conditions as a consequence of gut microbiome modification: Genesis of a
           wonder drug?
    • Authors: Kunal Maniar; Amal Moideen; Ankur Mittal; Amol Patil; Amitava Chakrabarti; Dibyajyoti Banerjee
      Pages: 103 - 128
      Abstract: Publication date: March 2017
      Source:Pharmacological Research, Volume 117
      Author(s): Kunal Maniar, Amal Moideen, Ankur Mittal, Amol Patil, Amitava Chakrabarti, Dibyajyoti Banerjee
      The most widely prescribed oral anti-diabetic agent today in the world today is a member of the biguanide class of drugs called metformin. Apart from its use in diabetes, it is currently being investigated for its potential use in many diseases such as cancer, cardiovascular diseases, Alzheimer's disease, obesity, comorbidities of diabetes such as retinopathy, nephropathy to name a few. Numerous in-vitro and in-vivo studies as well as clinical trials have been and are being conducted with a vast amount of literature being published every day. Numerous mechanisms for this drug have been proposed, but they have been unable to explain all the actions observed clinically. It is of interest that insulin has a stimulatory effect on cellular growth. Metformin sensitizes the insulin action but believed to be beneficial in cancer. Like -wise metformin is shown to have beneficial effects in opposite sets of pathological scenario looking from insulin sensitization point of view. This requires a comprehensive review of the disease conditions which are claimed to be affected by metformin therapy. Such a comprehensive review is presently lacking. In this review, we begin by examining the history of metformin before it became the most popular anti-diabetic medication today followed by a review of its relevant molecular mechanisms and important clinical trials in all areas where metformin has been studied and investigated till today. We also review novel mechanistic insight in metformin action in relation to microbiome and elaborate implications of such aspect in various disease states. Finally, we highlight the quandaries and suggest potential solutions which will help the researchers and physicians to channel their research and put this drug to better use.
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      PubDate: 2016-12-30T06:29:56Z
      DOI: 10.1016/j.phrs.2016.12.003
      Issue No: Vol. 117 (2016)
       
  • sec-Butylpropylacetamide (SPD), a new amide derivative of valproic acid
           for the treatment of neuropathic and inflammatory pain
    • Authors: Dan Kaufmann; Peter J. West; Misty D. Smith; Boris Yagen; Meir Bialer; Marshall Devor; H. Steve White; K.C. Brennan
      Pages: 129 - 139
      Abstract: Publication date: March 2017
      Source:Pharmacological Research, Volume 117
      Author(s): Dan Kaufmann, Peter J. West, Misty D. Smith, Boris Yagen, Meir Bialer, Marshall Devor, H. Steve White, K.C. Brennan
      Chronic pain is a multifactorial disease comprised of both inflammatory and neuropathic components that affect ∼20% of the world’s population. sec-Butylpropylacetamide (SPD) is a novel amide analogue of valproic acid (VPA) previously shown to possess a broad spectrum of anticonvulsant activity. In this study, we defined the pharmacokinetic parameters of SPD in rat and mouse, and then evaluated its antinociceptive potential in neuropathic and acute inflammatory pain models. In the sciatic nerve ligation (SNL) model of neuropathic pain, SPD was equipotent to gabapentin and more potent than its parent compound VPA. SPD also showed either higher or equal potency to VPA in the formalin, carrageenan, and writhing tests of inflammatory pain. SPD showed no effects on compound action potential properties in a sciatic nerve preparation, suggesting that its mechanism of action is distinct from local anesthetics and membrane stabilizing drugs. SPD’s activity in both neuropathic and inflammatory pain warrants its development as a potential broad-spectrum anti-nociceptive drug.
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      PubDate: 2016-12-30T06:29:56Z
      DOI: 10.1016/j.phrs.2016.11.030
      Issue No: Vol. 117 (2016)
       
  • Effect of lysosomotropic molecules on cellular homeostasis
    • Authors: Omer F. Kuzu; Mesut Toprak; M. Anwar Noory; Gavin P. Robertson
      Pages: 177 - 184
      Abstract: Publication date: March 2017
      Source:Pharmacological Research, Volume 117
      Author(s): Omer F. Kuzu, Mesut Toprak, M. Anwar Noory, Gavin P. Robertson
      Weak bases that readily penetrate through the lipid bilayer and accumulate inside the acidic organelles are known as lysosomotropic molecules. Many lysosomotropic compounds exhibit therapeutic activity and are commonly used as antidepressant, antipsychotic, antihistamine, or antimalarial agents. Interestingly, studies also have shown increased sensitivity of cancer cells to certain lysosomotropic agents and suggested their mechanism of action as a promising approach for selective destruction of cancer cells. However, their chemotherapeutic utility may be limited due to various side effects. Hence, understanding the homeostatic alterations mediated by lysosomotropic compounds has significant importance for revealing their true therapeutic potential as well as toxicity. In this review, after briefly introducing the concept of lysosomotropism and classifying the lysosomotropic compounds into two major groups according to their cytotoxicity on cancer cells, we focused on the subcellular alterations mediated by class-II lysosomotropic compounds. Briefly, their effect on intracellular cholesterol homeostasis, autophagy and lysosomal sphingolipid metabolism was discussed. Accordingly, class-II lysosomotropic molecules inhibit intracellular cholesterol transport, leading to the accumulation of cholesterol inside the late endosomal-lysosomal cell compartments. However, the accumulated lysosomal cholesterol is invisible to the cellular homeostatic circuits, hence class-II lysosomotropic molecules also upregulate cholesterol synthesis pathway as a downstream event. Considering the fact that Niemann-Pick disease, a lysosomal cholesterol storage disorder, also triggers similar pathologic abnormalities, this review combines the knowledge obtained from the Niemann-Pick studies and lysosomotropic compounds. Taken together, this review is aimed at allowing readers a better understanding of subcellular alterations mediated by lysosomotropic drugs, as well as their potential therapeutic and/or toxic activities.
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      PubDate: 2016-12-30T06:29:56Z
      DOI: 10.1016/j.phrs.2016.12.021
      Issue No: Vol. 117 (2016)
       
  • Protective effect of gedunin on TLR-mediated inflammation by modulation of
           inflammasome activation and cytokine production: Evidence of a multitarget
           compound
    • Authors: Perla Villani Borges; Katelim Hottz Moret; Nulgumnalli Manjunathaiah Raghavendra; Thadeu Estevam Maramaldo Costa; Ana Paula Monteiro; Alan Brito Carneiro; Patrícia Pacheco; Jairo Ramos Temerozo; Dumith Chequer Bou-Habib; Maria das Graças Henriques; Carmen Penido
      Pages: 65 - 77
      Abstract: Publication date: January 2017
      Source:Pharmacological Research, Volume 115
      Author(s): Perla Villani Borges, Katelim Hottz Moret, Nulgumnalli Manjunathaiah Raghavendra, Thadeu Estevam Maramaldo Costa, Ana Paula Monteiro, Alan Brito Carneiro, Patrícia Pacheco, Jairo Ramos Temerozo, Dumith Chequer Bou-Habib, Maria das Graças Henriques, Carmen Penido
      Activation of toll-like receptors (TLRs) by pathogen-associated molecular patterns (PAMPs) triggers an innate immune response, via cytokine production and inflammasome activation. Herein, we have investigated the modulatory effect of the natural limonoid gedunin on TLR activation in vitro and in vivo. Intraperitoneal (i.p.) pre- and post-treatments of C57BL/6 mouse with gedunin impaired the influx of mononuclear cells, eosinophils and neutrophils, as well as the production of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and nitric oxide (NO), triggered by lipopolysaccharide (LPS) in mouse pleura. Accordingly, in vitro post-treatment of immortalized murine macrophages with gedunin also impaired LPS-induced production of such mediators. Gedunin diminished LPS-induced expression of the nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) on pleural leukocytes in vivo and in immortalized macrophages in vitro. In line with this, gedunin inhibited LPS-induced caspase-1 activation and the production of IL-1β in vivo and in vitro. In addition, gedunin treatment triggered the generation of the anti-inflammatory factors IL-10 and heme oxigenase-1 (HO-1) at resting conditions or upon stimulation. We also demonstrate that gedunin effect is not restricted to TLR4-mediated response, since this compound diminished TNF-α, IL-6, NO, NLRP3 and IL-1β, as well as enhanced IL-10 and HO-1, by macrophages stimulated with the TLR2 and TLR3 agonists, palmitoyl-3-Cys-Ser-(Lys)4 (PAM3) and polyriboinosinic:polyribocytidylic acid (POLY I:C), in vitro. In silico modeling studies revealed that gedunin efficiently docked into caspase-1, TLR2, TLR3 and to the myeloid differentiation protein-2 (MD-2) component of TLR4. Overall, our data demonstrate that gedunin modulates TLR4, TLR3 and TLR2-mediated responses and reveal new molecular targets for this compound.
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      PubDate: 2016-11-24T08:01:31Z
      DOI: 10.1016/j.phrs.2016.09.015
      Issue No: Vol. 115 (2016)
       
  • Niclosamide ethanolamine inhibits artery constriction
    • Authors: Shan-Liang Li; Jie Yan; Yan-Qiu Zhang; Chang-Lin Zhen; Ming-Yu Liu; Jing Jin; Jin-Lai Gao; Xiao-Lin Xiao; Xin Shen; Yu Tai; Nan Hu; Xin-Zi Zhang; Zhi-Jie Sun; De-Li Dong
      Pages: 78 - 86
      Abstract: Publication date: January 2017
      Source:Pharmacological Research, Volume 115
      Author(s): Shan-Liang Li, Jie Yan, Yan-Qiu Zhang, Chang-Lin Zhen, Ming-Yu Liu, Jing Jin, Jin-Lai Gao, Xiao-Lin Xiao, Xin Shen, Yu Tai, Nan Hu, Xin-Zi Zhang, Zhi-Jie Sun, De-Li Dong
      We previously demonstrated that the typical mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP) inhibited artery constriction, but CCCP was used only as a pharmacological tool. Niclosamide is an anthelmintic drug approved by FDA. Niclosamide ethanolamine (NEN) is a salt form of niclosamide and has been demonstrated to uncouple mitochondrial oxidative phosphorylation. The aim of the present study was to elucidate the vasoactivity of NEN and the potential mechanisms. Isometric tension of rat mesenteric artery and thoracic aorta was recorded by using multi-wire myograph system. The protein levels were measured by using western blot techniques. Niclosamide ethanolamine (NEN) treatment relaxed phenylephrine (PE)- and high K+ (KPSS)-induced constriction, and pre-treatment with NEN inhibited PE- and KPSS-induced constriction of rat mesenteric arteries. In rat thoracic aorta, NEN also showed antagonism against PE- and KPSS-induced constriction. NEN induced increase of cellular ADP/ATP ratio in vascular smooth muscle cells (A10) and activated AMP-activated protein kinase (AMPK) in A10 cells and rat thoracic aorta. NEN-induced aorta relaxation was attenuated in AMPKα1 knockout (-/-) mice. SERCA inhibitors cyclopiazonic acid and thapsigargin, but not KATP channel blockers glibenclamide and 5-hydroxydecanoic acid, attenuated NEN-induced vasorelaxation in rat mesenteric arteries. NEN treatment increased cytosolic [Ca2+]i and depolarized mitochondrial membrane potential in vascular smooth muscle cells (A10). Niclosamide in non-salt form showed the similar vasoactivity as NEN in rat mesenteric arteries. Niclosamide ethanolamine inhibits artery constriction, indicating that it would be promising to be developed as an anti-hypertensive drug or it would induce vasodilation-related side effects when absorbed in vivo.
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      PubDate: 2016-11-24T08:01:31Z
      DOI: 10.1016/j.phrs.2016.11.008
      Issue No: Vol. 115 (2016)
       
  • Pathophysiology of hemophilic arthropathy and potential targets for
           therapy
    • Authors: Astrid E. Pulles; Simon C. Mastbergen; Roger E.G. Schutgens; Floris P.J.G. Lafeber; Lize F.D. van Vulpen
      Pages: 192 - 199
      Abstract: Publication date: January 2017
      Source:Pharmacological Research, Volume 115
      Author(s): Astrid E. Pulles, Simon C. Mastbergen, Roger E.G. Schutgens, Floris P.J.G. Lafeber, Lize F.D. van Vulpen
      Hemophilia is a congenital clotting factor deficiency characterized by spontaneous and trauma-related bleeding. Spontaneous bleeding shows a predilection for joints, and repeated hemarthroses lead to a disabling condition called hemophilic arthropathy. Treatment of this condition consists of preventing joint bleeding on the one hand and orthopedic surgery as a last resort on the other. Up till now, there is no disease modifying therapy available to fill the gap between these extremes. This review provides an overview of the pathogenesis of hemophilic arthropathy in order to identify potential targets for therapy. Joint bleeding induces synovial inflammation, cartilage degeneration and bone damage. These processes interact with each other and result in a vicious circle. Hemarthrosis promotes synovial hypertrophy and neoangiogenesis, increasing the susceptibility to mechanical damage and subsequent bleeding. The inflamed synovium affects the cartilage, while cartilage is also directly affected by blood via the release of cytokines and metalloproteinases, and via hydroxyl radical formation inducing chondrocyte apoptosis. Apart from the inflammatory pathways, iron plays a pivotal role in this process, as does the fibrinolytic system. Considering its pathogenesis, potential targets for disease modifying therapy in hemophilic arthropathy are iron, inflammation, vascular remodeling, hyperfibrinolysis, bone remodeling and cartilage regeneration. So far, iron chelators, anti-inflammatory therapy, anti-fibrinolytics and bone remodeling agents have demonstrated beneficial effects, predominantly in a preclinical setting. There is still a long way to go before these interventions will translate into clinical practice. The most important challenges are: establishing a universal outcome measure to predict efficacy in humans, and determination of the optimal route and timing to administer disease modifying therapy.
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      PubDate: 2016-12-08T10:14:50Z
      DOI: 10.1016/j.phrs.2016.11.032
      Issue No: Vol. 115 (2016)
       
  • Cellular and molecular mechanisms underlying alcohol-induced
           aggressiveness of breast cancer
    • Authors: Yongchao Wang; Mei Xu; Zun-ji Ke; Jia Luo
      Pages: 299 - 308
      Abstract: Publication date: January 2017
      Source:Pharmacological Research, Volume 115
      Author(s): Yongchao Wang, Mei Xu, Zun-ji Ke, Jia Luo
      Breast cancer is a leading cause of morbidity and mortality in women. Both Epidemiological and experimental studies indicate a positive correlation between alcohol consumption and the risk of breast cancer. While alcohol exposure may promote the carcinogenesis or onset of breast cancer, it may as well enhance the progression and aggressiveness of existing mammary tumors. Recent progress in this line of research suggests that alcohol exposure is associated with invasive breast cancer and promotes the growth and metastasis of mammary tumors. There are multiple potential mechanisms involved in alcohol-stimulated progression and aggressiveness of breast cancer. Alcohol may increase the mobility of cancer cells by inducing cytoskeleton reorganization and enhancing the cancer cell invasion by causing degradation and reconstruction of the extracellular matrix (ECM). Moreover, alcohol may promote the epithelial-mesenchymal transition (EMT), a hallmark of malignancy, and impair endothelial integrity, thereby increasing the dissemination of breast cancer cells and facilitating metastasis. Furthermore, alcohol may stimulate tumor angiogenesis through the activation of cytokines and chemokines which promotes tumor growth. Additionally, alcohol may increase the cancer stem cell population which affects neoplastic cell behavior, aggressiveness, and the therapeutic response. Alcohol can be metabolized in the mammary tissues and breast cancer cells which produces reactive oxygen species (ROS), causing oxidative stress. Recent studies suggest that the epidermal growth factor receptor (EGFR) family, particularly ErbB2 (a member of this family), is involved in alcohol-mediated tumor promotion. Breast cancer cells or mammary epithelial cells over-expressing ErbB2 are more sensitive to alcohol’s tumor promoting effects. There is considerable cross-talk between oxidative stress and EGFR/ErbB2 signaling. This review further discusses how the interaction between oxidative stress and EGFR/ErbB2 signaling contributes to the cellular and molecular events associated with breast cancer aggressiveness. We also discuss the potential therapeutic approaches for cancer patients who drink alcoholic beverages.
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      PubDate: 2016-12-14T14:01:00Z
      DOI: 10.1016/j.phrs.2016.12.005
      Issue No: Vol. 115 (2016)
       
  • Curcumin: a potentially powerful tool to reverse cisplatin-induced
           toxicity
    • Authors: Ramin Rezaee; Amir Abbas Momtazi; Alireza Monemi; Amirhossein Sahebkar
      Abstract: Publication date: Available online 29 December 2016
      Source:Pharmacological Research
      Author(s): Ramin Rezaee, Amir Abbas Momtazi, Alireza Monemi, Amirhossein Sahebkar
      Curcumin is a naturally occurring polyphenol isolated from Curcuma longa that has gained considerable interest over the last decades due to its beneficial effects for human health. Moreover, the usage of cisplatin, a platinum-based chemotherapeutic, is associated with several adverse effects affecting the quality of life of the patients. Also, cisplatin therapy is jeopardized by a great challenge of resistance which reduces the efficacy of this drug. In order to conquer these dark sides of cisplatin therapy, curcumin has been widely used to fight against cisplatin-resistant cancer cells and decrease its unwanted side effects (e.g. ototoxicity, nephrotoxicity and neurotoxicity). In this review, we provide a summary of the studies done to show the protective effects of curcumin against cisplatin failure and toxicity.
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      PubDate: 2016-12-30T06:29:56Z
      DOI: 10.1016/j.phrs.2016.12.037
       
  • Multiple Nickel-Sensitive Targets Elicit Cardiac Arrhythmia in Isolated
           Mouse Hearts after Pituitary Adenylate Cyclase-Activating
           Polypeptide-Mediated Chronotropy
    • Authors: Etienne E. Tevoufouet; Erastus N. Nembo; Fabian Distler; Felix Neumaier; Jürgen Hescheler; Filomain Nguemo; Toni Schneider
      Abstract: Publication date: Available online 19 December 2016
      Source:Pharmacological Research
      Author(s): Etienne E. Tevoufouet, Erastus N. Nembo, Fabian Distler, Felix Neumaier, Jürgen Hescheler, Filomain Nguemo, Toni Schneider
      The pituitary adenylate cyclase-activating polypeptide (PACAP)-27 modulates various biological processes, from the cellular level to function specification. However, the cardiac actions of this neuropeptide are still under intense studies. Using control (+ +) and mice lacking (− −) either R-type (Cav2.3) or T-type (Cav3.2) Ca2+ channels, we investigated the effects of PACAP-27 on cardiac activity of spontaneously beating isolated perfused hearts. Superfusion of PACAP-27 (20nM) caused a significant increase of baseline heart frequency in Cav2.3(+ +) (156.9±10.8 to 239.4±23.4 bpm; p<0.01) and Cav2.3(− −) (190.3±26.4 to 270.5±25.8 bpm; p<0.05) hearts. For Cav3.2, the heart rate was significantly increased in Cav3.2(− −) (133.1±8.5 bpm to 204.6±27.9 bpm; p<0.05) compared to Cav3.2(+ +) hearts (185.7±11.2 bpm to 209.3±22.7 bpm). While the P wave duration and QTc interval were significantly increased in Cav2.3(+ +) and Cav2.3(− −) hearts following PACAP-27 superfusion, there was no effect in Cav3.2(+ +) and Cav3.2(− −) hearts. The positive chronotropic effect observed in the four study groups, as well as the effect on P wave duration and QTc interval were abolished in the presence of Ni2+ (50μM) and PACAP-27 (20nM) in hearts from Cav2.3(+ +) and Cav2.3(− −) mice. In addition to suppressing PACAP’s response, Ni2+ also induced conduction disturbances in investigated hearts. In conclusion, the most Ni2+-sensitive Ca2+ channels (R- and T-type) may modulate the PACAP signaling cascade during cardiac excitation in isolated mouse hearts, albeit to a lesser extent than other Ni2+-sensitive targets.
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      PubDate: 2016-12-23T05:09:38Z
      DOI: 10.1016/j.phrs.2016.12.025
       
  • Resveratrol regulates gene transcription via activation of
           stimulus-responsive transcription factors
    • Authors: Gerald Thiel; Oliver G. Rössler
      Abstract: Publication date: Available online 21 December 2016
      Source:Pharmacological Research
      Author(s): Gerald Thiel, Oliver G. Rössler
      Resveratrol (trans-3,4′,5-trihydroxystilbene), a polyphenolic phytoalexin of grapes and other fruits and plants, is a common constituent of our diet and of dietary supplements. Many health-promoting benefits have been connected with resveratrol in the treatment of cardiovascular diseases, cancer, diabetes, inflammation, neurodegeneration, and diseases connected with aging. To explain the pleiotropic effects of resveratrol, the molecular targets of this compound have to be identified on the cellular level. Resveratrol induces intracellular signal transduction pathways which ultimately lead to changes in the gene expression pattern of the cells. Here, we review the effect of resveratrol on the activation of the stimulus-responsive transcription factors CREB, AP-1, Egr-1, Elk-1, and Nrf2. Following activation, these transcription factors induce transcription of delayed response genes. The gene products of these delayed response genes are ultimately responsible for the changes in the biochemistry and physiology of resveratrol-treated cells. The activation of stimulus-responsive transcription factors may explain many of the intracellular activities of resveratrol. However, results obtained in vitro may not easily be transferred to in vivo systems.
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      PubDate: 2016-12-23T05:09:38Z
      DOI: 10.1016/j.phrs.2016.12.029
       
  • Gender related differences in treatment and response to statins in primary
           and secondary cardiovascular prevention: the never-ending debate
    • Authors: Roberto Cangemi; Giulio Francesco Romiti; Giuseppe Campolongo; Eleonora Ruscio; Susanna Sciomer; Daniele Gianfrilli; Valeria Raparelli
      Abstract: Publication date: Available online 21 December 2016
      Source:Pharmacological Research
      Author(s): Roberto Cangemi, Giulio Francesco Romiti, Giuseppe Campolongo, Eleonora Ruscio, Susanna Sciomer, Daniele Gianfrilli, Valeria Raparelli
      Statins are a main curbstone in the prevention of cardiovascular disease (CVD), pandemic in 21st century. CVD displays evident sex and gender differences, not only in clinical manifestation and outcomes but also in pharmacological treatment. Whether statin therapy should be differentially prescribed according to sex is a matter of debate. Aside a different pharmacological action, statins are not proven to be less effective in one gender comparing to the other, nor to be less safe. Nevertheless, up to date evidence shows that statins have not been adequately tested in women, especially in primary prevention trials. Since data-lacking, making a treatment decision on women is potentially harmful, although female individuals represent the majority of the population and they have a greater lifetime CVD risk. Therefore, adequately powered randomized control trials with longer follow-up are warranted to establish if a benefit on CV events and mortality prevention exists in both sexes. The aim of the present review is to summarize the sex and gender differences in statin use: it raises concerns and updates perspectives towards an evidence-based and sex-tailored prevention of CVD management.
      Graphical abstract image

      PubDate: 2016-12-23T05:09:38Z
      DOI: 10.1016/j.phrs.2016.12.027
       
  • Prolonged infusion of sedatives and analgesics in adult intensive care
           patients: a systematic review of pharmacokinetic data reporting and
           quality of evidence
    • Authors: Andrew H.W. Tse; Lowell Ling; Gavin M. Joynt; Anna Lee
      Abstract: Publication date: Available online 21 December 2016
      Source:Pharmacological Research
      Author(s): Andrew H.W. Tse, Lowell Ling, Gavin M. Joynt, Anna Lee
      Although pharmacokinetic (PK) data for prolonged sedative and analgesic agents in intensive care unit (ICU) has been described, the number of publications in this important area appear relatively few, and PK data presented is not comprehensive. Known pathophysiological changes in critically ill patients result in altered drug PK when compared with non-critically ill patients. ClinPK Statement was recently developed to promote consistent reporting in PK studies, however, its applicability to ICU specific PK studies is unclear. In this systematic review, we assessed the overall ClinPK Statement compliance rate, determined the factors affecting compliance rate, graded the level of PK evidence and assessed the applicability of the ClinPK Statement to future ICU PK studies. Of the 33 included studies (n=2016), 22 (67%) were low evidence quality descriptive studies (Level 4). Included studies had a median compliance rate of 80% (IQR 66% to 86%) against the ClinPK Statement. Overall pooled compliance rate (78%, 95% CI 73% to 83%) was stable across time (P=0.38), with higher compliance rates found in studies fitting three compartments models (88%, P<0.01), two compartments models (83%, P<0.01) and one compartment models (77%, P=0.17) than studies fitting noncompartmental or unspecified models (69%) (P<0.01). Data unique to the interpretation of PK data in critically ill patients, such as illness severity (48%), organ dysfunction (36%) and renal replacement therapy use (32%), were infrequently reported. Discrepancy between the general compliance rate with ClinPK Statement and the under-reporting of ICU specific parameters suggests that the applicability of the ClinPK Statement to ICU PK studies may be limited in its current form.
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      PubDate: 2016-12-23T05:09:38Z
      DOI: 10.1016/j.phrs.2016.12.028
       
  • A2B adenosine receptors stimulate IL-6 production in primary murine
           microglia through p38 MAPK kinase pathway
    • Authors: Stefania Merighi; Serena Bencivenni; Fabrizio Vincenzi; Katia Varani; Pier Andrea Borea; Stefania Gessi
      Abstract: Publication date: Available online 11 December 2016
      Source:Pharmacological Research
      Author(s): Stefania Merighi, Serena Bencivenni, Fabrizio Vincenzi, Katia Varani, Pier Andrea Borea, Stefania Gessi
      The hallmark of neuroinflammation is the activation of microglia, the immunocompetent cells of the CNS, releasing a number of proinflammatory mediators implicated in the pathogenesis of neuronal diseases. Adenosine is an ubiquitous autacoid regulating several microglia functions through four receptor subtypes named A1, A2A, A2B and A3 (ARs), that represent good targets to suppress inflammation occurring in CNS. Here we investigated the potential role of ARs in the modulation of IL-6 secretion and cell proliferation in primary microglial cells. The A2BAR agonist 2-[[6-Amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]-2-pyridinyl]thio]-acetamide (BAY60-6583) stimulated IL-6 increase under normoxia and hypoxia, in a dose- and time-dependent way. In cells incubated with the blockers of phospholipase C (PLC), protein kinase C epsilon (PKC-ε) and PKC delta (PKC-δ) the IL-6 increase due to A2BAR activation was strongly reduced, whilst it was not affected by the inhibitor of adenylyl cyclase (AC). Investigation of cellular signalling involved in the A2BAR effect revealed that only the inhibitor of p38 mitogen activated protein kinase (MAPK) was able to block the agonist’s effect on IL-6 secretion, whilst inhibitors of pERK1/2, JNK1/2 MAPKs and Akt were not. Stimulation of p38 by BAY60-6583 was A2BAR-dependent, through a pathway affecting PLC, PKC-ε and PKC-δ but not AC, in both normoxia and hypoxia. Finally, BAY60-6583 increased microglial cell proliferation involving A2BAR, PLC, PKC-ε, PKC-δ and p38 signalling. In conclusion, A2BARs activation increased IL-6 secretion and cell proliferation in murine primary microglial cells, through PLC, PKC-ε, PKC-δ and p38 pathways, thus suggesting their involvement in microglial activation and neuroinflammation.
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      PubDate: 2016-12-14T14:01:00Z
      DOI: 10.1016/j.phrs.2016.11.024
       
  • Therapeutic Potential and Limitations of Cholinergic Anti-Inflammatory
           Pathway in Sepsis
    • Authors: Alexandre Kanashiro; Fabiane Sônego; Raphael G. Ferreira; Fernanda V.S. Castanheira; Caio A. Leite; Vanessa F. Borges; Daniele C. Nascimento; David F. Cólon; José Carlos Alves-Filho; Luis Ulloa; Fernando Q. Cunha
      Abstract: Publication date: Available online 12 December 2016
      Source:Pharmacological Research
      Author(s): Alexandre Kanashiro, Fabiane Sônego, Raphael G. Ferreira, Fernanda V.S. Castanheira, Caio A. Leite, Vanessa F. Borges, Daniele C. Nascimento, David F. Cólon, José Carlos Alves-Filho, Luis Ulloa, Fernando Q. Cunha
      Sepsis is one of the main causes of mortality in hospitalized patients. Despite the recent technical advances and the development of novel generation of antibiotics, severe sepsis remains a major clinical and scientific challenge in modern medicine. Unsuccessful efforts have been dedicated to the search of therapeutic options to treat the deleterious inflammatory components of sepsis. Recent findings on neuronal networks controlling immunity raised expectations for novel therapeutic strategies to promote the regulation of sterile inflammation, such as autoimmune diseases. Interesting studies have dissected the anatomical constituents of the so-called “cholinergic anti-inflammatory pathway”, suggesting that electrical vagus nerve stimulation and pharmacological activation of beta-2 adrenergic and alpha-7 nicotinic receptors could be alternative strategies for improving inflammatory conditions. However, the literature on infectious diseases, such as sepsis, is still controversial and, therefore, the real therapeutic potential of this neuroimmune pathway is not well defined. In this review, we will discuss the beneficial and detrimental effects of neural manipulation in sepsis, which depend on the multiple variables of the immune system and the nature of the infection. These observations suggest future critical studies to validate the clinical implications of vagal parasympathetic signaling in sepsis treatment.
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      PubDate: 2016-12-14T14:01:00Z
      DOI: 10.1016/j.phrs.2016.12.014
       
  • Allosteric MEK1/2 inhibitors including cobimetanib and trametinib in the
           treatment of cutaneous melanomas
    • Authors: Robert Roskoski
      Abstract: Publication date: Available online 9 December 2016
      Source:Pharmacological Research
      Author(s): Robert Roskoski
      The Ras-Raf-MEK-ERK (Map kinase) cellular pathway is a highly conserved eukaryotic signaling module that transduces extracellular signals from growth factors and cytokines into intracellular regulatory events that are involved in cell growth and proliferation or the contrary pathway of cell differentiation. Dysregulation of this pathway occurs in more than one-third of all malignancies, a process that has fostered the development of targeted Map kinase pathway inhibitors. Cutaneous melanomas, which arise from skin melanocytes, are the most aggressive form of skin cancer. Mutations that activate the Map kinase pathway occur in more than 90% of these melanomas. This has led to the development of the combination of dabrafenib and trametinib or vemurafenib and cobimetanib for the treatment of BRAF V600E mutant melanomas. Dabrafenib and vemurafenib target V600E/K BRAF mutants while trametinib and cobimetanib target MEK1/2. The latter two agents bind to MEK1/2 at a site that is adjacent to, but separate from, the ATP-binding site and are therefore classified as type III allosteric protein kinase inhibitors. These agents form a hydrogen bond with a conserved β3-lysine and they make numerous hydrophobic contacts with residues within the αC-helix, the β5 strand, and within the activation segment, regions of the protein kinase domain that exhibit greater diversity than those found within the ATP-binding site. One advantage of such allosteric inhibitors is that they do not have to compete with millimolar concentrations of cellular ATP, which most FDA-approved small molecule competitive inhibitors such as imatinib must do. Owing to the wide spread activation of this pathway in numerous neoplasms, trametinib and cobimetinib are being studied in combination with other targeted and cytotoxic drugs in a variety of clinical situations. Except for BRAF and NRAS mutations, there are no other biomarkers correlated with treatment responses following MEK1/2 inhibition and the discovery of such biomarkers would represent an important therapeutic breakthrough.
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      PubDate: 2016-12-14T14:01:00Z
      DOI: 10.1016/j.phrs.2016.12.009
       
  • Advanced technologies charting a new path for Traditional Chinese Medicine
           drug discovery
    • Authors: Elaine Lai-Han Leung; Emilio Clementi; W.S. Fred Wong
      Abstract: Publication date: Available online 10 December 2016
      Source:Pharmacological Research
      Author(s): Elaine Lai-Han Leung, Emilio Clementi, W.S. Fred Wong


      PubDate: 2016-12-14T14:01:00Z
      DOI: 10.1016/j.phrs.2016.12.010
       
  • Title: Re-calculating! Navigating through the osteosarcoma treatment
           roadblock
    • Authors: J.M. McGuire; T.J. Utset-Ward; D.M. Reed; C.C. Lynch
      Abstract: Publication date: Available online 7 December 2016
      Source:Pharmacological Research
      Author(s): J.M. McGuire, T.J. Utset-Ward, D.M. Reed, C.C. Lynch
      The survival rates for patients with osteosarcoma has remained almost static for the past three decades. Current standard of care therapy includes chemotherapies such as doxorubicin, cisplatin, and methotrexate along with complete surgical resection and surgery with or without ifosfamide and etoposide for relapse, though outcomes are hoped to be improved through clinical trials. Additionally, increased understanding of the genetics, signaling pathways and microenvironmental factors driving the disease has led to the identification of promising agents and potential paths towards translation of an exciting array of novel targeted therapies. Here, we review the mechanism of action of these emerging therapies and how, with clinical translation, they can potentially improve the survival rates for osteosarcoma patients in the near future.
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      PubDate: 2016-12-08T10:14:50Z
      DOI: 10.1016/j.phrs.2016.12.004
       
  • Hydroxytyrosol ameliorates metabolic, cardiovascular and liver changes in
           a rat model of diet-induced metabolic syndrome: pharmacological and
           metabolism-based investigation
    • Authors: Hemant Poudyal; Nikolaos Lemonakis; Panagiotis Efentakis; Evangelos Gikas; Maria Halabalaki; Ioanna Andreadou; Leandros Skaltsounis; Lindsay Brown
      Abstract: Publication date: Available online 8 December 2016
      Source:Pharmacological Research
      Author(s): Hemant Poudyal, Nikolaos Lemonakis, Panagiotis Efentakis, Evangelos Gikas, Maria Halabalaki, Ioanna Andreadou, Leandros Skaltsounis, Lindsay Brown
      Metabolic syndrome is a clustering of interrelated risk factors for cardiovascular disease and diabetes. The Mediterranean diet has been proposed as an important dietary pattern to confer cardioprotection by attenuating risk factors of metabolic syndrome. Hydroxytyrosol (HT) is present in olive fruit and oil, which are basic constituents of the Mediterranean diet. In this study, we have shown that treatment with HT (20mg/kg/d for 8 weeks) decreased adiposity, improved impaired glucose and insulin tolerance, improved endothelial function with lower systolic blood pressure, decreased left ventricular fibrosis and resultant diastolic stiffness and reduced markers of liver damage in a diet-induced rat model of metabolic syndrome. These results were accompanied by reduced infiltration of monocytes/macrophages into the heart and liver and reduced biomarkers of oxidative stress in heart. Furthermore, in an HRMS-based metabolism study of HT, we have identified 24 HT phase I and II metabolites, six of them being over-produced in high-starch, low-fat diet fed rats treated with HT compared to obese rats on high-fructose, high-fat diet. These results provide direct evidence for cardioprotective effects of hydroxytyrosol by attenuation of metabolic risk factors. The implications of altered metabolism of HT in high-fructose, high-fat diet fed obese rats warrant further investigation.
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      PubDate: 2016-12-08T10:14:50Z
      DOI: 10.1016/j.phrs.2016.12.002
       
  • Therapeutic Implications of Toll-like Receptors in Peripheral Neuropathic
           Pain
    • Authors: Krishan K. Thakur; Jyoti Saini; Kanika Mahajan; Dhyanendra Singh; Dinkar P. Jaiswal; Srishti Mishra; Anupam Bishyaee; Gautam Sethi; Ajaikumar B. Kunnumakkara
      Abstract: Publication date: Available online 25 November 2016
      Source:Pharmacological Research
      Author(s): Krishan K. Thakur, Jyoti Saini, Kanika Mahajan, Dhyanendra Singh, Dinkar P. Jaiswal, Srishti Mishra, Anupam Bishyaee, Gautam Sethi, Ajaikumar B. Kunnumakkara
      Neuropathic pain is a state of chronic pain arising after peripheral or central nerve injury. These injuries can be mediated through the activation of various cells (astrocytes, microglia and Schwann cells), as well as the dissolution of distal axons. Recent studies have suggested that after nerve injury, Toll-like receptors (TLRs) are involved in Wallerian degeneration and generation of neuropathic pain. Furthermore, these TLRs are responsible for the stimulation of astrocytes and microglia that can cause induction of the proinflammatory mediators and cytokines in the spinal cord, thereby leading to the generation and maintenance of neuropathic pain. Indeed considering the prevalence of neuropathic pain and the suffering of the affected patients, insights into the diverse mechanism(s) of activation of TLR signaling cascades may open novel avenues for the management of this chronic condition. Moreover, existing therapies like antidepressants, anticonvulsants, opiates and other analgesic are not sufficiently effective in reducing the pain. In this review, we present substantial evidences highlighting the diverse roles of TLRs and their signaling pathways involved in the progression of neuropathic pain. Furthermore, an elaborate discussion on various existing treatment regimens and future targets involving TLRs has also been included.
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      PubDate: 2016-12-01T09:16:25Z
      DOI: 10.1016/j.phrs.2016.11.019
       
  • CURCUMIN USE IN PULMONARY DISEASES: STATE OF THE ART AND FUTURE
           PERSPECTIVES
    • Authors: Diana Lelli; Amirhossein Sahebkar; Thomas P. Johnston; Claudio Pedone
      Abstract: Publication date: Available online 22 November 2016
      Source:Pharmacological Research
      Author(s): Diana Lelli, Amirhossein Sahebkar, Thomas P. Johnston, Claudio Pedone
      Curcumin (diferuloylmethane) is a yellow pigment present in the spice turmeric (Curcuma longa). It has been used for centuries in Ayurveda (Indian traditional medicine) for the treatment of several diseases. Over the last several decades, the therapeutic properties of curcumin have slowly been elucidated. It has been shown that curcumin has pleiotropic effects, regulating transcription factors (e.g., NF-kB), cytokines (e.g., IL6, TNF-alpha), adhesion molecules (e.g., ICAM-1), and enzymes (e.g., MMPs) that play a major role in inflammation and cancerogenesis. These effects may be relevant for several pulmonary diseases that are characterized by abnormal inflammatory responses, such as asthma or chronic obstructive pulmonary disease, acute respiratory distress syndrome, pulmonary fibrosis, and acute lung injury. Furthermore, some preliminary evidence suggests that curcumin may have a role in the treatment of lung cancer. The evidence for the use of curcumin in pulmonary disease is still sparse and has mostly been obtained using either in vitro or animal models. The most important issue with the use of curcumin in humans is its poor bioavailability, which makes it necessary to use adjuvants or curcumin nanoparticles or liposomes. The aim of this review is to summarize the available evidence on curcumin’s effectiveness in pulmonary diseases, including lung cancer, and to provide our perspective on future research with curcumin so as to improve its pharmacological effects, as well as provide additional evidence of curcumin’s efficacy in the treatment of pulmonary diseases.
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      PubDate: 2016-11-24T08:01:31Z
      DOI: 10.1016/j.phrs.2016.11.017
       
  • Effects of Pomegranate Juice on Blood Pressure: A Systematic Review and
           Meta-analysis of Randomized Controlled Trials
    • Authors: Amirhossein Sahebkar; Claudio Ferri; Paolo Giorgini; Simona Bo; Petr Nachtigal; Davide Grassi
      Abstract: Publication date: Available online 23 November 2016
      Source:Pharmacological Research
      Author(s): Amirhossein Sahebkar, Claudio Ferri, Paolo Giorgini, Simona Bo, Petr Nachtigal, Davide Grassi
      Punica granatum L. (Pomegranate) has been claimed to provide several health benefits. Pomegranate juice is a polyphenol-rich fruit juice with high antioxidant capacity. Several studies suggested that pomegranate juice can exert antiatherogenic, antioxidant, antihypertensive, and anti-inflammatory effects. Nevertheless, the potential cardioprotective benefits of pomegranate juice deserve further clinical investigation. To systematically review and meta-analyze available evidence from randomized placebo-controlled trials (RCTs) investigating the effects of pomegranate juice consumption and blood pressure (BP). A comprehensive literature search in Medline and Scopus was carried out to identify eligible RCTs. A meta-analysis of eligible studies was performed using a random-effects model. Quality assessment, sensitivity analysisand publication bias evaluations were conducted using standard methods. Quantitative data synthesis from 8 RCTs showed significant reductions in both systolic [weighed mean difference (WMD): −4.96mmHg, 95% CI: −7.67 to −2.25, p<0.001) and diastolic BP (WMD: −2.01mmHg, 95% CI: −3.71 to −0.31, p=0.021) after pomegranate juice consumption. Effects on SBP remained stable to sensitivity analyses. Pomegranate juice reduced SBP regardless of the duration (>12 wks: WMD=−4.36mmHg, 95% CI: −7.89 to −0.82, p=0.016) and <12 wks: WMD=−5.83 mmHg, 95% CI: −10.05 to −1.61, p=0.007) and dose consumed (>240cc: WMD=−3.62mmHg, 95% CI: −6.62 to −0.63, p=0.018) and <240cc: WMD=−11.01mmHg, 95% CI: −17.38 to −4.65, p=0.001, pomegranate juice per day) whereas doses >240cc provided a borderline significant effect in reducing DBP. The present meta-analysis suggests consistent benefits of pomegranate juice consumption on BP. This evidence suggests it may be prudent to include this fruit juice in a heart-healthy diet.
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      PubDate: 2016-11-24T08:01:31Z
      DOI: 10.1016/j.phrs.2016.11.018
       
  • Metabolomic profile of children with recurrent respiratory infections
    • Authors: Sara Bozzetto; Paola Pirillo; Silvia Carraro; Mariangela Berardi; Laura Cesca; Matteo Stocchero; Giuseppe Giordano; Stefania Zanconato; Eugenio Baraldi
      Abstract: Publication date: Available online 22 November 2016
      Source:Pharmacological Research
      Author(s): Sara Bozzetto, Paola Pirillo, Silvia Carraro, Mariangela Berardi, Laura Cesca, Matteo Stocchero, Giuseppe Giordano, Stefania Zanconato, Eugenio Baraldi
      Recurrent respiratory infections (RRI) represent a widespread condition which has a severe social and economic impact. Immunostimulants are used for their prevention. It is crucial to better characterize children with RRI to refine their diagnosis and identify effective personalized prevention strategies. Metabolomics is a high-dimensional biological method that can be used for hypothesis-free biomarker profiling, examining a large number of metabolites in a given sample using spectroscopic techniques. Multivariate statistical data analysis then enables us to infer which metabolic information is relevant to the biological characterization of a given physiological or pathological condition. This can lead to the emergence of new, sometimes unexpected metabolites, and hitherto unknown metabolic pathways, enabling the formulation of new pathogenetic hypotheses, and the identification of new therapeutic targets. The aim of our pilot study was to apply mass-spectrometry-based metabolomics to the analysis of urine samples from children with RRI, comparing these children’s biochemical metabolic profiles with those of healthy peers. We also compared the RRI children’s and healthy controls’ metabolomic urinary profiles after the former had received pidotimod treatment for 3 months to see whether this immunostimulant was associated with biochemical changes in the RRI children’s metabolic profile. 13 children (age range 3–6 yeas) with RRI and 15 matched per age healthy peers with no history of respiratory diseases or allergies were enrolled. Their metabolomic urine samples were compared before and after the RRI children had been treated with pidotimod for a period of 3 months. Metabolomic analyses on the urine samples were done using mass spectrometry combined with ultra-performance liquid chromatography (UPLC-MS). The resulting spectroscopic data then underwent multivariate statistical analysis and the most relevant variables characterizing the two groups were identified. Data modeling with post-transformation of PLS2-Discriminant Analysis (ptPLS2-DA) generated a robust model capable of discriminating the urine samples from children with RRI from those of healthy controls (R2 = 0.92,Q2 CV7-fold = 0.75, p-value < 0.001). The dataset included 1502 time per mass variables, and 138 of them characterized the difference between the two groups. Thirty-five of these distinctive 138 variables persisted in the profiles of the children with RRI after pidotimod treatment. Metabolomics can discriminate children with RRI from healthy controls, suggesting that the former have a dysregulated metabolic profile. Among the variables characterizing children with RRI there are metabolites that may reflect the presence of a different microbiome. After pidotimod treatment, the metabolic profile of the children with RRI was no longer very different from that of the healthy controls, except for the persistence of some microbiome-related variables. We surmise that pidotimod partially “restores” the altered metabolic profile of children with RRI, without modifying the metabolites related to the composition of the gut microbiota. In the light of these results, we hypothesize a potential synergic effect of the combined use of immunostimulants and probiotics for the purpose of prevention in children with RRI.
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      PubDate: 2016-11-24T08:01:31Z
      DOI: 10.1016/j.phrs.2016.11.007
       
  • Transmembrane TNF-alpha reverse signaling leading to TGF-beta production
           is selectively activated by TNF targeting molecules: therapeutic
           implications
    • Authors: Zsuzsa Szondy; Anna Pallai
      Abstract: Publication date: Available online 22 November 2016
      Source:Pharmacological Research
      Author(s): Zsuzsa Szondy, Anna Pallai
      Tumor necrosis factor (TNF)-α is a potent pro-inflammatory cytokine exerting pleiotropic effects on various cell types. It is synthesized in a precursor form called transmembrane TNF-α (mTNF-α) which, after being processed by metalloproteinases, is released in a soluble form to mediate its biological activities through Type 1 and 2 TNF receptors in TNF receptor expressing cells. In addition to acting in soluble form, TNF-α also acts in the transmembrane form both as a ligand by activating TNF receptors, as well as a receptor that transmits outside-to-inside (reverse) signals back into mTNF-α bearing cells. Since the discovery that TNF-α plays a determining role in the pathogenesis of several chronic inflammatory diseases, anti-TNF agents are increasingly being used in the treatment of a rapidly expanding number of rheumatic and systemic autoimmune diseases, such as rheumatoid arthritis, Crohn’s disease, psoriasis, psoriatic arthritis, ankyloting spondylitis, Wegener granulomatosis and sarcoidosis. There are 5 TNF antagonists currently available: etanercept, a soluble TNF receptor construct; infliximab, a chimeric monoclonal antibody; adalimumab and golimumab, fully human antibodies; and certolizumab pegol, an Fab’ fragment of a humanized anti-TNF-α antibody. Though each compound can efficiently neutralize TNF-α, increasing evidence suggests that they show different efficacy in the treatment of these diseases. These observations indicate that in addition to neutralizing TNF-α, other biological effects induced by TNF-α targeting molecules dictate the success of the therapy. Recently, we found that mTNF-α reverse signaling leads to transforming growth factor (TGF)-β production in macrophages and anti-TNF agents selectively trigger this pathway. In this review we will focus on the potential contribution of the activation of the mTNF-α signaling pathway to the success of the anti-TNF therapy.
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      PubDate: 2016-11-24T08:01:31Z
      DOI: 10.1016/j.phrs.2016.11.025
       
  • Transcriptome Profiling of NIH3T3 Cell Lines Expressing Opsin and the P23H
           Opsin Mutant Identifies Candidate Drugs for the Treatment of Retinitis
           Pigmentosa
    • Authors: Yuanyuan Chen; Matthew J. Brooks; Linn Gieser; Anand Swaroop; Krzysztof Palczewski
      Abstract: Publication date: Available online 9 November 2016
      Source:Pharmacological Research
      Author(s): Yuanyuan Chen, Matthew J. Brooks, Linn Gieser, Anand Swaroop, Krzysztof Palczewski
      Mammalian cells are commonly employed in screening assays to identify active compounds that could potentially affect the progression of different human diseases including retinitis pigmentosa (RP), a class of inherited diseases causing retinal degeneration with compromised vision. Using transcriptome analysis, we compared NIH3T3 cells expressing wildtype (WT) rod opsin with a retinal disease-causing single P23H mutation. Surprisingly, heterologous expression of WT opsin in NIH3T3 cells caused more than a 2-fold change in 783 out of 16,888 protein coding transcripts. The perturbed genes encoded extracellular matrix proteins, growth factors, cytoskeleton proteins, glycoproteins and metalloproteases involved in cell adhesion, morphology and migration. A different set of 347 transcripts was either up- or down-regulated when the P23H mutant opsin was expressed suggesting an altered molecular perturbation compared to WT opsin. Transcriptome perturbations elicited by drug candidates aimed at mitigating the effects of the mutant protein revealed that different drugs targeted distinct molecular pathways that resulted in a similar phenotype selected by a cell-based high-throughput screen. Thus, transcriptome profiling can provide essential information about the therapeutic potential of a candidate drug to restore normal gene expression in pathological conditions.
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      PubDate: 2016-11-11T00:29:30Z
      DOI: 10.1016/j.phrs.2016.10.031
       
  • NON-INSULIN ANTI-DIABETIC DRUGS: AN UPDATE ON PHARMACOLOGICAL INTERACTIONS
    • Authors: M. Ruscica; L. Baldessin; D. Boccia; G. Racagni; N. Mitro
      Abstract: Publication date: Available online 9 November 2016
      Source:Pharmacological Research
      Author(s): M. Ruscica, L. Baldessin, D. Boccia, G. Racagni, N. Mitro
      Nowadays, the goal in the management of type 2 diabetes mellitus (T2DM) remains personalized control of glucose. Since less than 50% of patients with T2DM achieve glycemic treatment goal and most of them take medications for comorbidities associated to T2DM, drug interactions, namely pharmacokinetic and pharmacodynamic interactions, may enhance or reduce the effect of compounds involved in hyperglycemia. Hence, clinicians should be aware of the severe complications in T2DM patients in case of a concomitant use of these medications. It is within this context that this review aims to evaluate the effect of a second drug on the pharmacokinetic of these compounds which may lead, along with several pharmacodynamic interactions, to severe clinical complications, i.e., hypoglycemia. Available drugs already approved in Europe, USA and Japan have been included.
      Graphical abstract image

      PubDate: 2016-11-11T00:29:30Z
      DOI: 10.1016/j.phrs.2016.11.005
       
 
 
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