for Journals by Title or ISSN
for Articles by Keywords
help

Publisher: Elsevier   (Total: 3175 journals)

 A  B  C  D  E  F  G  H  I  J  K  L  M  N  O  P  Q  R  S  T  U  V  W  X  Y  Z  

We no longer collect new content from this publisher because the publisher has forbidden systematic access to its RSS feeds.
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  [3175 journals]
  • Drug-induced xenogenization of tumors: A possible role in the immune
           control of malignant cell growth in the brain'
    • Authors: Ornella Franzese; Fiorenzo Battaini; Grazia Graziani; Lucio Tentori; Maria Luisa Barbaccia; Angelo Aquino; Mario Roselli; Maria Pia Fuggetta; Enzo Bonmassar; Francesco Torino
      Pages: 1 - 6
      Abstract: Publication date: May 2018
      Source:Pharmacological Research, Volume 131
      Author(s): Ornella Franzese, Fiorenzo Battaini, Grazia Graziani, Lucio Tentori, Maria Luisa Barbaccia, Angelo Aquino, Mario Roselli, Maria Pia Fuggetta, Enzo Bonmassar, Francesco Torino
      In recent years, immune checkpoint inhibitors (ICpI) have provided the ground to bring tumor immunity back to life thanks to their capacity to afford a real clinical benefit in terms of patient’s survival. Essential to ICpI success is the presence of tumor-associated neoantigens generated by non-synonymous mutations, since a direct relationship between mutation load of malignant cells and susceptibility to ICpI has been confidently established. However, it has been also suggested that high intratumor heterogeneity (ITH) associated with subclonal neoantigens could not elicit adequate immune responses. Several years ago we discovered that in vivo treatment of leukemic mice with triazene compounds (TZC) produces a marked increase of leukemia cell immunogenicity [a phenomenon termed Drug-Induced Xenogenization (DIX)] through point mutations able to generate strong tumor neoantigens (Drug-Induced Neoantigens, DIN). Immunogenic mutations are produced by TZC-dependent methylation of O6-guanine of DNA, that is suppressed by the DNA repair protein methyl-guaninemethyltransferase (MGMT). This minireview illustrates preclinical investigations conducted in animal models where DIN-positive murine leukemia cells were inoculated intracerebrally into histocompatible mice. The analysis of the literature indicates that the growth of xenogenized malignant cells is controlled by anti-DIN graft responses and by intra-cerebral or intravenous adoptive transfer of anti-DIN cytotoxic T lymphocytes. This survey reminds also that PARP inhibitors increase substantially the antitumor activity of TZC and can be administered with the intent of suppressing more efficiently tumor load and possibly reducing ITH through downsizing the polyclonality of xenogenized tumor cell population. Finally, the present report illustrates a hypothetical clinical protocol that could be considered as an example of future development of DIXbased tumor immuno-chemotherapy in brain malignancies. The protocol involves oral or intravenous administration of TZC along with loco-regional (i.e. intracerebral “wafer”) treatment with agents able to increase tumor cell sensitivity to the cytotoxic and xenogenizing effects of TZC (i.e. MGMT and PARP inhibitors) without enhancing the systemic toxicity of these DNA methylating compounds.
      Graphical abstract image

      PubDate: 2018-03-20T11:09:38Z
      DOI: 10.1016/j.phrs.2018.03.005
      Issue No: Vol. 131 (2018)
       
  • The hypotensive effect of activated apelin receptor is correlated with
           β-arrestin recruitment
    • Authors: Élie Besserer-Offroy; Patrick Bérubé; Jérôme Côté; Alexandre Murza; Jean-Michel Longpré; Robert Dumaine; Olivier Lesur; Mannix Auger-Messier; Richard Leduc; Éric Marsault; Philippe Sarret
      Pages: 7 - 16
      Abstract: Publication date: May 2018
      Source:Pharmacological Research, Volume 131
      Author(s): Élie Besserer-Offroy, Patrick Bérubé, Jérôme Côté, Alexandre Murza, Jean-Michel Longpré, Robert Dumaine, Olivier Lesur, Mannix Auger-Messier, Richard Leduc, Éric Marsault, Philippe Sarret
      The apelinergic system is an important player in the regulation of both vascular tone and cardiovascular function, making this physiological system an attractive target for drug development for hypertension, heart failure and ischemic heart disease. Indeed, apelin exerts a positive inotropic effect in humans whilst reducing peripheral vascular resistance. In this study, we investigated the signaling pathways through which apelin exerts its hypotensive action. We synthesized a series of apelin-13 analogs whereby the C-terminal Phe13 residue was replaced by natural or unnatural amino acids. In HEK293 cells expressing APJ, we evaluated the relative efficacy of these compounds to activate Gαi1 and GαoA G-proteins, recruit β-arrestins 1 and 2 (βarrs), and inhibit cAMP production. Calculating the transduction ratio for each pathway allowed us to identify several analogs with distinct signaling profiles. Furthermore, we found that these analogs delivered i.v. to Sprague-Dawley rats exerted a wide range of hypotensive responses. Indeed, two compounds lost their ability to lower blood pressure, while other analogs significantly reduced blood pressure as apelin-13. Interestingly, analogs that did not lower blood pressure were less effective at recruiting βarrs. Finally, using Spearman correlations, we established that the hypotensive response was significantly correlated with βarr recruitment but not with G protein-dependent signaling. In conclusion, our results demonstrated that the βarr recruitment potency is involved in the hypotensive efficacy of activated APJ.
      Graphical abstract image

      PubDate: 2018-03-20T11:09:38Z
      DOI: 10.1016/j.phrs.2018.02.032
      Issue No: Vol. 131 (2018)
       
  • Disruption of TFGβ-SMAD3 pathway by the nuclear receptor SHP mediates the
           antifibrotic activities of BAR704, a novel highly selective FXR ligand
    • Authors: Adriana Carino; Michele Biagioli; Silvia Marchianò; Paolo Scarpelli; Angela Zampella; Vittorio Limongelli; Stefano Fiorucci
      Pages: 17 - 31
      Abstract: Publication date: May 2018
      Source:Pharmacological Research, Volume 131
      Author(s): Adriana Carino, Michele Biagioli, Silvia Marchianò, Paolo Scarpelli, Angela Zampella, Vittorio Limongelli, Stefano Fiorucci
      Liver fibrosis, a major health concern worldwide, results from abnormal collagen deposition by activated hepatic stellate cells (HSCs) in an injured liver. The farnesoid-x-receptor (FXR) is a bile acid sensor that counteracts HSCs transdifferentiation. While targeting FXR holds promise, 6-ethyl-CDCA known as obeticholic acid, the first in class of FXR ligands, causes side effects, partially because the lack of selectivity toward GPBAR1, a putative itching receptor. Here, we describe the 3-deoxy-6-ethyl derivative of CDCA, BAR704, as a highly selective steroidal FXR agonist. Methods Liver Fibrosis was induced in mice by carbon tetrachloride (CCl4). Main results In transactivation assay BAR704 activated FXR with and EC50 of 967 nM while exerted no agonistic activity on other receptors including GPBAR1. In naïve mice, BAR704 modulated the expression of FXR target genes in the liver of wild type mice but not in FXR−/− mice. In cirrhotic mice, administration of BAR704, 15 mg/kg for 9 weeks, spared the liver biosynthetic activity (bilirubin and albumin plasma levels), reduced liver fibrosis score (Sirius red staining), expression of pro-fibrogenetic (Colα1α, TGFβ and αSMA) and inflammatory genes (IL-1β, TNFα) and portal pressure. From mechanistic stand point, we have found that exposure of LX2 cells, a human HSCs line, to BAR704 increased the transcription of the short heterodimer partner (SHP) and induced the binding of this nuclear receptor to SMAD3, thus abrogating the binding of phosho-SMAD3 to the TGFβ promoter. Conclusions and applications. BAR704 is a selective FXR agonist that reduces liver fibrosis by interfering with the TGFβ-SMAD3 pathway in HSCs. Selective FXR agonists may represent an attractive strategy for the treatment of liver fibrosis.
      Graphical abstract image

      PubDate: 2018-03-20T11:09:38Z
      DOI: 10.1016/j.phrs.2018.02.033
      Issue No: Vol. 131 (2018)
       
  • Proprotein Convertase Subtilisin-Kexin type-9 (PCSK9) and
           triglyceride-rich lipoprotein metabolism: Facts and gaps
    • Authors: Andrea Baragetti; Daniela Grejtakova; Manuela Casula; Elena Olmastroni; Gloria Saccani Jotti; Giuseppe Danilo Norata; Alberico L. Catapano; Stefano Bellosta
      Pages: 1 - 11
      Abstract: Publication date: April 2018
      Source:Pharmacological Research, Volume 130
      Author(s): Andrea Baragetti, Daniela Grejtakova, Manuela Casula, Elena Olmastroni, Gloria Saccani Jotti, Giuseppe Danilo Norata, Alberico L. Catapano, Stefano Bellosta
      After more than a decade of intense investigation, Pro-protein Convertase Subtilisin-Kexin type 9 (PCSK9) remains a hot topic of research both at experimental and clinical level. Interestingly PCSK9 is expressed in different tissues suggesting the existence of additional function(s) beyond the modulation of the Low-Density Lipoprotein (LDL) receptor in the liver. Emerging data suggest that PCSK9 might play a role in the modulation of triglyceride-rich lipoprotein (TGRL) metabolism, mainly Very Low-Density Lipoproteins (VLDL) and their remnants. In vitro, PCSK9 affects TGRLs production by intestinal cells as well as the catabolism of LDL receptor homologous and non-homologous targets such as VLDL receptor, CD36 and ApoE2R. However, the in vivo relevance of these findings is still debated. This review aims at critically discussing the role of PCSK9 on TGRLs metabolism with a major focus on the impact of its genetic and pharmacological modulation on circulating lipids and lipoproteins beyond LDL.
      Graphical abstract image

      PubDate: 2018-02-26T06:36:30Z
      DOI: 10.1016/j.phrs.2018.01.025
      Issue No: Vol. 130 (2018)
       
  • Neuregulin 1/ErbB signalling modulates hippocampal mGluRI-dependent LTD
           and object recognition memory
    • Authors: Ada Ledonne; Dalila Mango; Emanuele Claudio Latagliata; Giulia Chiacchierini; Annalisa Nobili; Robert Nisticò; Marcello D’Amelio; Stefano Puglisi-Allegra; Nicola Biagio Mercuri
      Pages: 12 - 24
      Abstract: Publication date: April 2018
      Source:Pharmacological Research, Volume 130
      Author(s): Ada Ledonne, Dalila Mango, Emanuele Claudio Latagliata, Giulia Chiacchierini, Annalisa Nobili, Robert Nisticò, Marcello D’Amelio, Stefano Puglisi-Allegra, Nicola Biagio Mercuri
      The neurotrophic factors neuregulins (NRGs) and their receptors, ErbB tyrosine kinases, regulate neurotransmission, synaptic plasticity and cognitive functions and their alterations have been associated to different neuropsychiatric disorders. Group 1 metabotropic glutamate receptors (mGluRI)-dependent mechanisms are also altered in animal models of neuropsychiatric diseases, especially mGluRI-induced glutamatergic long-term depression (mGluRI-LTD), a form of synaptic plasticity critically involved in learning and memory. Despite this evidence, a potential link between NRGs/ErbB signalling and mGluRI-LTD has never been considered. Here, we aimed to test the hypothesis that NRGs/ErbB signalling regulates mGluRI functions in the hippocampus, thus controlling CA1 pyramidal neurons excitability and synaptic plasticity as well as mGluRI-dependent behaviors. We investigated the functional interaction between NRG1/ErbB signalling and mGluRI in hippocampal CA1 pyramidal neurons, by analyzing the effect of a pharmacological modulation of NRG1/ErbB signalling on the excitation of pyramidal neurons and on the LTD at CA3-CA1 synapses induced by an mGluRI agonist. Furthermore, we verified the involvement of ErbB signalling in mGluRI-dependent learning processes, by evaluating the consequence of an intrahippocampal in vivo injection of a pan-ErbB inhibitor in the object recognition test in mice, a learning task dependent on hippocampal mGluRI. We found that NRG1 potentiates mGluRI-dependent functions on pyramidal neurons excitability and synaptic plasticity at CA3-CA1 synapses. Further, endogenous ErbB signalling per se regulates, through mGluRI, neuronal excitability and LTD in CA1 pyramidal neurons, since ErbB inhibition reduces mGluRI-induced neuronal excitation and mGluRI-LTD. In vivo intrahippocampal injection of the ErbB inhibitor, PD158780, impairs mGluRI-LTD at CA3-CA1 synapses and affects the exploratory behavior in the object recognition test. Thus, our results identify a key role for NRG1/ErbB signalling in the regulation of hippocampal mGluRI-dependent synaptic and cognitive functions, whose alteration might contribute to the pathogenesis of different brain diseases.
      Graphical abstract image

      PubDate: 2018-02-26T06:36:30Z
      DOI: 10.1016/j.phrs.2018.02.003
      Issue No: Vol. 130 (2018)
       
  • Impact of adenosine A2a receptor polymorphism rs5751876 on platelet
           reactivity in ticagrelor treated patients
    • Authors: Matteo Nardin; Monica Verdoia; Patrizia Pergolini; Roberta Rolla; Lucia Barbieri; Paolo Marino; Giorgio Bellomo; Elvin Kedhi; Harry Suryapranata; Alessandro Carriero; Giuseppe De Luca
      Pages: 27 - 33
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Matteo Nardin, Monica Verdoia, Patrizia Pergolini, Roberta Rolla, Lucia Barbieri, Paolo Marino, Giorgio Bellomo, Elvin Kedhi, Harry Suryapranata, Alessandro Carriero, Giuseppe De Luca
      Dual antiplatelet therapy constitutes a key point in the management of patients with acute coronary syndromes. In particular, ticagrelor, an ADP-antagonist, can provide a more potent and predictable platelet inhibition as compared to clopidogrel, and adenosine-mediated pathways have been involved in its beneficial effects on mortality and myocardial perfusion. However, a quote of patients still displays a suboptimal platelet inhibition on ticagrelor, and, while the role of genetics in conditioning clopidogrel resistance is well established, few data have been reported for ticagrelor. We investigated the impact of rs5751876 C > T polymorphism of adenosine A2a receptor (ADORA2a) on platelet reactivity in patients during chronic treatment with ticagrelor. We included patients treated with ASA and ticagrelor for a recent ACS or elective coronary revascularization. Platelet reactivity was assessed at 30–90 days post-discharge by multiple-electrode aggregometry. HRPR for ticagrelor was defined as ADP-test results >417 AU*min. Genetic analysis was performed to assess the presence of rs5751876 C > T polymorphism of ADORA2a receptor. We included 244 patients in our study, 174 (71.3%) patients carried the polymorphism (T allele), 51 (20.9%) of them in homozygosis (T/T). C-allele carriers (homozygotes C/C and heterozygotes C/T) showed no difference in baseline characteristics but for lower HDL-cholesterol (p = 0.01). An absolute lower rate of HRPR on ticagrelor was observed in homozygotes T/T (p = 0.03). At multivariate analysis, C allele carriage was independently associated with the rate of HRPR on ticagrelor (adjusted OR[95%CI] = 4.63[1.02–21.01], p = 0.048). Our study results showed a significant independent association between rs5751876 allele C carriage and a higher rate of high residual platelet reactivity in patients on ticagrelor after a recent ACS or PCI.
      Graphical abstract image

      PubDate: 2018-02-05T05:25:09Z
      DOI: 10.1016/j.phrs.2017.12.035
      Issue No: Vol. 129 (2018)
       
  • Emerging role of carbon monoxide in regulation of cellular pathways and in
           the maintenance of gastric mucosal integrity
    • Authors: Katarzyna Magierowska; Tomasz Brzozowski; Marcin Magierowski
      Pages: 56 - 64
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Katarzyna Magierowska, Tomasz Brzozowski, Marcin Magierowski
      Heme oxygenase (HO) catalyzes the degradation of toxic free heme to the equimolar amounts of biliverdin, Fe2+ and concurrently releases of carbon monoxide (CO). CO is nowadays increasingly recognized as an important signaling molecule throughout the body that is involved in many physiological processes and shows multidirectional biological activity. Recent evidence indicates that CO exhibits the anti-inflammatory, anti-proliferative, anti-apoptotic, anti-aggregatory and vasodilatory properties. The cellular mechanisms underlying the activity of CO involve stimulation of cGMP-dependent signaling pathway and large conductance calcium activated K+ channels, the activation of mitogen-activated protein kinases and the nuclear factor k-light chain-enhancer of activated B cells transcription factor pathway. Stimulation of endogenous CO production by HO inducers or the inhalation of CO or the delivery of this gaseous molecule by novel pharmaceutical agents have been found in experimental animal models to be promising in the future therapy of various diseases. CO appears to act as a significant component of the complex mechanism of gastrointestinal (GI) mucosal defense. This gaseous molecule plays an important role in diabetic gastroparesis, prevention of the upper GI mucosal damage, post-operative ileus and the healing of ulcerative colitis. This review focuses on the better understanding mechanisms through which CO contributes to the mechanism of protection, resistance to injury and ulcer healing. It is becoming apparent that the pleiotropic effect of this molecule may increase clinical applicability of CO donors and their implementation in many pharmacological research areas, pharmaceutical industry and health-care system.
      Graphical abstract image

      PubDate: 2018-02-05T05:25:09Z
      DOI: 10.1016/j.phrs.2018.01.008
      Issue No: Vol. 129 (2018)
       
  • Effect of resveratrol on lipid profile: An updated systematic review and
           meta-analysis on randomized clinical trials
    • Authors: Fahimeh Haghighatdoost; Mitra Hariri
      Pages: 141 - 150
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Fahimeh Haghighatdoost, Mitra Hariri
      Despite the notion that resveratrol can significantly reduce plasma lipids, the result of randomized clinical trials (RCTs) on resveratrol effect and the serum lipid profile are contradictory. Our objective was to conduct a systematic review and meta-analysis on randomized clinical trials (RCTs) and assess the effect of resveratrol on lipids. ISI web of science, Ovid, PubMed/Medline, SCOPUS, and Google Scholar data bases were searched up to Jun 2017. RCTs that assessed resveratrol effects on lipid profile among adult participants were chosen. Treatment effects were considered as weighted mean difference (WMD) and the corresponding standard error (SE) in concentrations of serum lipids. To estimate the overall summary effect, we used random-effects model. The protocol was registered with PROSPERO (No. CRD42017072365). This meta-analysis was performed on twenty-one trials. Our results indicated that resveratrol can’t significantly change total cholesterol (TC) (WMD = −0.08 mmol/l, 95% CI: −0.23, 0.08; P = .349, I2 = 87.8%), low-density lipoprotein (LDL-C) (WMD: −0.04 mmol/l, 95% CI: −0.21, 0.12; P = .620, I2 = 93.4%), and high density lipoprotein (HDL-C) (WMD: −0.01 mmol/l, 95% CI: −0.04, 0.02; P = .269, I2 = 88.6%). Its effect on triacylglycerol (TG) (WMD: 0.58 mmol/l, 95% CI: 0.34, 0.82; P < .0001, I2 = 99.8%), was significant, but after removing one study the significance was eliminated. We also found that sex, age, BMI, resveratrol dosage, and intervention duration could not change the results. We conclude that resveratrol does not change lipid profile concentration. Confirmation of this conclusion will require more studies exclusively on dyslipidemic patients in which the intake of lipid lowering agents is among the exclusion criteria.
      Graphical abstract image

      PubDate: 2018-02-26T06:36:30Z
      DOI: 10.1016/j.phrs.2017.12.033
      Issue No: Vol. 129 (2018)
       
  • Targeting bromodomain and extraterminal proteins in breast cancer
    • Authors: Jennifer M. Sahni; Ruth A. Keri
      Pages: 156 - 176
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Jennifer M. Sahni, Ruth A. Keri
      Breast cancer is a collection of distinct tumor subtypes that are driven by unique gene expression profiles. These transcriptomes are controlled by various epigenetic marks that dictate which genes are expressed and suppressed. During carcinogenesis, extensive restructuring of the epigenome occurs, including aberrant acetylation, alteration of methylation patterns, and accumulation of epigenetic readers at oncogenes. As epigenetic alterations are reversible, epigenome-modulating drugs could provide a mechanism to silence numerous oncogenes simultaneously. Here, we review the impact of inhibitors of the Bromodomain and Extraterminal (BET) family of epigenetic readers in breast cancer. These agents, including the prototypical BET inhibitor JQ1, have been shown to suppress a variety of oncogenic pathways while inducing minimal, if any, toxicity in models of several subtypes of breast cancer. BET inhibitors also synergize with multiple approved anti-cancer drugs, providing a greater response in breast cancer cell lines and mouse models than either single agent. The combined findings of the studies discussed here provide an excellent rationale for the continued investigation of the utility of BET inhibitors in breast cancer.
      Graphical abstract image

      PubDate: 2018-02-26T06:36:30Z
      DOI: 10.1016/j.phrs.2017.11.015
      Issue No: Vol. 129 (2018)
       
  • Chalcones as putative hepatoprotective agents: Preclinical evidence and
           molecular mechanisms
    • Authors: Elham Karimi-Sales; Gisou Mohaddes; Mohammad Reza Alipour
      Pages: 177 - 187
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Elham Karimi-Sales, Gisou Mohaddes, Mohammad Reza Alipour
      Chalcones form an important group of natural compounds and flavonoid precursors which are abundant in fruits, vegetables, and edible plants. These compounds have many beneficial properties including anti-inflammatory, anti-microbial, antioxidant, anti-cancer, anti-amyloid, anti-diabetic, anti-obesity, hypolipidemic, and cytoprotective. Chalcone derivatives have protective effects on the liver in nonalcoholic fatty liver disease, alcoholic fatty liver, drug- and toxicant-induced liver injury, and liver cancer through several mechanisms. Chalcones improve adipocytes function and adiponectin secretion. They inhibit triglyceride synthesis, activating factors of hepatic stellate cells and extracellular matrix deposition and also elevate fatty acid oxidation. These effects of chalcones lead to liver injury improvement. In conclusion, chalcones with antioxidant, anti-fibrotic, and anti-inflammatory properties decrease liver injury markers and histological abnormality in liver injury.
      Graphical abstract image

      PubDate: 2018-02-26T06:36:30Z
      DOI: 10.1016/j.phrs.2017.11.022
      Issue No: Vol. 129 (2018)
       
  • TPL2 kinase action and control of inflammation
    • Authors: Daqi Xu; Marissa L. Matsumoto; Brent S. McKenzie; Ali A. Zarrin
      Pages: 188 - 193
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Daqi Xu, Marissa L. Matsumoto, Brent S. McKenzie, Ali A. Zarrin
      Tumor progression locus 2 (TPL2, also known as COT or MAP3K8) is a mitogen-activated protein kinase kinase (MAP3K) activated downstream of TNFαR, IL1R, TLR, CD40, IL17R, and some GPCRs. TPL2 regulates the MEK1/2 and ERK1/2 pathways to regulate a cascade of inflammatory responses. In parallel to this, TPL2 also activates p38α and p38δ to drive the production of various inflammatory mediators in neutrophils. We discuss the implications of this finding in the context of various inflammatory diseases.
      Graphical abstract image

      PubDate: 2018-02-26T06:36:30Z
      DOI: 10.1016/j.phrs.2017.11.031
      Issue No: Vol. 129 (2018)
       
  • CAR-T cells and combination therapies: What’s next in the
           immunotherapy revolution'
    • Authors: Maria C. Ramello; Eric B. Haura; Daniel Abate-Daga
      Pages: 194 - 203
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Maria C. Ramello, Eric B. Haura, Daniel Abate-Daga
      Cancer immunotherapies are dramatically reshaping the clinical management of oncologic patients. For many of these therapies, the guidelines for administration, monitoring, and management of associated toxicities are still being established. This is especially relevant for adoptively transferred, genetically-modified T cells, which have unique pharmacokinetic properties, due to their ability to replicate and persist long-term, following a single administration. Furthermore, in the case of CAR-T cells, the use of synthetic immune receptors may impact signaling pathways involved in T cell function and survival in unexpected ways. We, herein, comment on the most salient aspects of CAR-T cell design and clinical experience in the treatment of solid tumors. In addition, we discuss different possible scenarios for combinations of CAR-T cells and other treatment modalities, with a special emphasis on kinase inhibitors, elaborating on the strategies to maximize synergism. Finally, we discuss some of the technologies that are available to explore the molecular events governing the success of these therapies. The young fields of synthetic and systems biology are likely to be major players in the advancement of CAR-T cell therapies, providing the tools and the knowledge to engineer patients’ T lymphocytes into intelligent cancer-fighting micromachines.
      Graphical abstract image

      PubDate: 2018-02-26T06:36:30Z
      DOI: 10.1016/j.phrs.2017.11.035
      Issue No: Vol. 129 (2018)
       
  • Role of toll-like receptors in inflammatory bowel disease
    • Authors: Nastaran Kordjazy; Arvin Haj-Mirzaian; Arya Haj-Mirzaian; Mohammad Mojtaba Rohani; Erwin W. Gelfand; Nima Rezaei; Amir Hossein Abdolghaffari
      Pages: 204 - 215
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Nastaran Kordjazy, Arvin Haj-Mirzaian, Arya Haj-Mirzaian, Mohammad Mojtaba Rohani, Erwin W. Gelfand, Nima Rezaei, Amir Hossein Abdolghaffari
      Inflammatory bowel disease (IBD) is the chronic inflammation of the gastrointestinal tract. Recently, studies of the interplay between the adaptive and innate immune responses have provided a better understanding of the immunopathogenesis of inflammatory disorders such as IBD, as well as identification of novel targets for more potent interventions. Toll-like receptors (TLRs) are a class of proteins that play a significant role in the innate immune system and are involved in inflammatory processes. Activation of TLR signal transduction pathways lead to the induction of numerous genes that function in host defense, including those for inflammatory cytokines, chemokines, and antigen presenting molecules. It was proposed that TLR mutations and dysregulation are major contributing factors to the predisposition and susceptibility to IBD. Thus, modulating TLRs represent an innovative immunotherapeutic approach in IBD therapy. This article outlines the role of TLRs in IBD, focusing on both animal and human studies; the role of TLR-targeted agonists or antagonists as potential therapeutic agents in the different stages of the disease is discussed.
      Graphical abstract image

      PubDate: 2018-02-26T06:36:30Z
      DOI: 10.1016/j.phrs.2017.11.017
      Issue No: Vol. 129 (2018)
       
  • Mild cognitive impairment due to Alzheimer disease: Contemporary
           approaches to diagnostics and pharmacological intervention
    • Authors: Sergey O. Bachurin; Svetlana I. Gavrilova; Anna Samsonova; George E. Barreto; Gjumrakch Aliev
      Pages: 216 - 226
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Sergey O. Bachurin, Svetlana I. Gavrilova, Anna Samsonova, George E. Barreto, Gjumrakch Aliev
      Alzheimer disease (AD) and related forms of dementia are among the main medical and social problems in the economically developed countries. It is connected with significant increase in human life span in these regions and with the absence of efficient medicines for treatment and prevention of such diseases. Lack of positive results in the developing of novel drugs for AD treatment stimulates special attention on problem of early diagnosis and drug discovery for pharmacotherapy on the very early stages of dementia, in particular, on mild cognitive impairments (MCI) due to AD. Here we review the state of art in the field of MCI diagnostics and analyze the data on the pharmacological agents developed for MCI treatment, which currently are in preclinical and clinical trials. The conclusion was made that only the agents that act on the very early pathogenetic stages of the disease, when the damage of cholinergic neurons is not observed, can be efficient for pharmacotherapeutic intervention of MCI. Therefore, the focused search and design of “disease-modifying” medicines should be accepted as the most (and may be the only) efficient strategy for treatment and prevention of MCI.
      Graphical abstract image

      PubDate: 2018-02-26T06:36:30Z
      DOI: 10.1016/j.phrs.2017.11.021
      Issue No: Vol. 129 (2018)
       
  • Phytochemical portfolio and anticancer activity of Murraya koenigii and
           its primary active component, mahanine
    • Authors: Suman Kumar Samanta; Raghuram Kandimalla; Bhaskarjyoti Gogoi; Krishna Nayani Dutta; Paramita Choudhury; Prashanta Kumar Deb; Rajlakshmi Devi; Bikas Chandra Pal; Narayan Chandra Talukdar
      Pages: 227 - 236
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Suman Kumar Samanta, Raghuram Kandimalla, Bhaskarjyoti Gogoi, Krishna Nayani Dutta, Paramita Choudhury, Prashanta Kumar Deb, Rajlakshmi Devi, Bikas Chandra Pal, Narayan Chandra Talukdar
      Murraya koenigii, a plant belonging to the Rutaceae family is widely distributed in Eastern-Asia and its medicinal properties are well documented in Ayurveda, the traditional Indian system of medicine. Through systematic research and pharmacological evaluation of different parts of the plant extracts has been shown to possess antiviral, anti-inflammatory, antioxidant, antidiabetic, antidiarrhoeal, antileishmanial, and antitumor activity. In the plant extracts, carbazole alkaloid, mahanine has been identified as the principle bioactive component among several other chemical constituents. Scientific evidence derived not only from in vitro cellular experiments but also from in vivo studies in various cancer models is accumulating for the pronounced anticancer effects of mahanine. The primary objective of this review is to summarize research data on cytotoxic chemical constituents present in different parts of Murraya koenigii and the anticancer activity of mahanine along with the recent understanding on the mechanism of its action in diverse cancer models. The information on its bioavailability and the toxicity generated from the recent studies have also been incorporated in the review.
      Graphical abstract image

      PubDate: 2018-02-26T06:36:30Z
      DOI: 10.1016/j.phrs.2017.11.024
      Issue No: Vol. 129 (2018)
       
  • Molecular adjuvants that modulate regulatory T cell function in
           vaccination: A critical appraisal
    • Authors: Alexander Batista-Duharte; Damiana Téllez-Martínez; Deivys Leandro Portuondo Fuentes; Iracilda Zeppone Carlos
      Pages: 237 - 250
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Alexander Batista-Duharte, Damiana Téllez-Martínez, Deivys Leandro Portuondo Fuentes, Iracilda Zeppone Carlos
      Adjuvants are substances used to enhance the efficacy of vaccines. They influence the magnitude and alter the quality of the adaptive immune response to vaccine antigens by amplifying or modulating different signals involved in the innate immune response. The majority of known adjuvants have been empirically identified. The limited immunogenicity of new vaccine antigens and the need for safer vaccines have increased the importance of identifying single, well-defined adjuvants with known cellular and molecular mechanisms for rational vaccine design. Depletion or functional inhibition of CD4+CD25+FoxP3+ regulatory T cells (Tregs) by molecular adjuvants has become an emergent approach in this field. Different successful results have been obtained for specific vaccines, but there are still unresolved issues such as the risk of autoimmune disease induction, the involvement of cells other than Tregs and optimization for different conditions. This work provides a comprehensive analysis of current approaches to inhibit Tregs with molecular adjuvants for vaccine improvement, highlights the progress being made, and describes ongoing challenges.
      Graphical abstract image

      PubDate: 2018-02-26T06:36:30Z
      DOI: 10.1016/j.phrs.2017.11.026
      Issue No: Vol. 129 (2018)
       
  • Cardiovascular and renal interactions between cyclosporine and NSAIDs:
           Underlying mechanisms and clinical relevance
    • Authors: Ahmed F. El-Yazbi; Ali H. Eid; Mahmoud M. El-Mas
      Pages: 251 - 261
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Ahmed F. El-Yazbi, Ali H. Eid, Mahmoud M. El-Mas
      Cyclosporine, the prototype calcineurin inhibitor, transformed immunosuppressant regimens and practices post-organ transplantation. Therapeutic uses of cyclosporine branched out to include management of different autoimmune disorders. However, multiple additional effects posed significant clinical challenges in face of the prolonged nature of cyclosporine use. Significantly, cyclosporine produced nephrotoxic, cardiotoxic and neurotoxic effects in addition to alteration of hemodynamic function. These adverse effects are shared with other drug groups further complicating the therapeutic situation to include potential exacerbation in case of drug interactions. The potential for detrimental outcomes increases with commonly used drugs such as non-steroidal anti-inflammatory drugs also notorious for their deleterious renal and cardiovascular effects. Herein, we review the available experimental and clinical evidence describing the mechanisms and the outcomes of interactions between the two drug classes. Special attention is given to the divergent toxic effects of co-administration of cyclosporine with selective vs. non-selective cyclooxygenase inhibiting non-steroidal drugs.
      Graphical abstract image

      PubDate: 2018-02-26T06:36:30Z
      DOI: 10.1016/j.phrs.2017.11.029
      Issue No: Vol. 129 (2018)
       
  • Phytochemicals as inhibitors of NF-κB for treatment of
           Alzheimer’s disease
    • Authors: Ean-Jeong Seo; Nicolas Fischer; Thomas Efferth
      Pages: 262 - 273
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Ean-Jeong Seo, Nicolas Fischer, Thomas Efferth
      Alzheimer’s disease (AD) is the most prevalent form of dementia. The exact pathophysiology of this disease remains incompletely understood and safe and effective therapies are required. AD is highly correlated with neuroinflammation and oxidative stress in brain causing neuronal loss. Nuclear factor of activated B-cells (NF-κB) is involved in physiological inflammatory processes and thus representing a promising target for inflammation-based AD therapy. Phytochemicals are able to interfere with the NF-κB pathway. They inhibit the phosphorylation or the ubiquitination of signaling molecules, and thus, inhibit the degradation of IκB. The translocation of NF-κB to the nucleus and subsequent transcription of pro-inflammatory cytokines are inhibited by the actions of phytochemicals. Additionally, natural compounds preventing the interaction of NF-κB can block NF-κB’s transcriptional activity by inhibiting its binding to target DNA. Many polyphenols including curcumin, resveratrol, pterostilbene, punicalagin, macranthoin G, salidroside, 4-O-methylhonokiol, lycopene, genistein, obovatol and gallic acid were reported as potent NF-κB inhibitors for AD treatment. Several alkaloids such as galantamine, glaucocalyxin B, tetrandrine, berberine, oridonin, anatabine have been shown anti-inflammatory effects in AD models in vitro as well as in vivo. Besides, vitamins, tanshinone IIA, artemisinin, dihydroasparagusic acid, geniposide, xanthoceraside, l-theranine, 1,8-cineole and paeoniflorin were described as promising NF-κB inhibitors. In conclusion, natural products from plants represent interesting candidates for AD treatment. They may qualify as promising compounds for the development of derivatives providing enhanced pharmacological features.

      PubDate: 2018-02-26T06:36:30Z
      DOI: 10.1016/j.phrs.2017.11.030
      Issue No: Vol. 129 (2018)
       
  • Exploring the effects of DPP-4 inhibitors on the kidney from the bench to
           clinical trials
    • Authors: Giuseppe Coppolino; Christian Leporini; Laura Rivoli; Francesco Ursini; Eugenio Donato di Paola; Valeria Cernaro; Franco Arturi; Davide Bolignano; Emilio Russo; Giovambattista De Sarro; Michele Andreucci
      Pages: 274 - 294
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Giuseppe Coppolino, Christian Leporini, Laura Rivoli, Francesco Ursini, Eugenio Donato di Paola, Valeria Cernaro, Franco Arturi, Davide Bolignano, Emilio Russo, Giovambattista De Sarro, Michele Andreucci
      Dipeptidyl-peptidase-4 (DPP-4) inhibitors are a relatively new class of non-insulin glucose-lowering agents, belonging to the incretin family, which are able to improve glycemic control with a favorable safety profile, since they are associated with a low risk of hypoglycemia, no weight gain, and good tolerability in patients with chronic renal failure. Some experimental and clinical studies suggest that these drugs may exert significant pleiotropic effects, in particular on chronic kidney disease (CKD) progression, but data from clinical trials are still controversial. In an effort to clarify the effects of DPP-4 inhibitors (DPP-4is) on diabetes-related renal damage, we performed a narrative review of available clinical trials and other experimental studies focusing on renal effects of DPP-4is. Currently, there is no conclusive evidence proving the usefulness of this drug class for improving diabetes-related renal damage. However, our literature review suggests that DPP-4is are safe and well tolerated in type 2 diabetes mellitus (T2DM) patients with CKD. More importantly, results from the reviewed studies indicate that DPP-4 inhibitor therapy may improve two major risk factors for diabetic nephropathy, such as hyperglycemia and albuminuria, resulting in potential renal benefits beyond glycemic control. Despite several limitations, the conclusions of our review corroborate previous evidence on the potential renal benefits of DPP-4is, highlighting the urgent need of future trials adequately powered and designed on hard renal outcomes to ascertain (or contradict) the therapeutic benefit of DPP-4is in T2DM and CKD patients.
      Graphical abstract image

      PubDate: 2018-02-26T06:36:30Z
      DOI: 10.1016/j.phrs.2017.12.001
      Issue No: Vol. 129 (2018)
       
  • Functional significance of O-GlcNAc modification in regulating neuronal
           properties
    • Authors: Hongik Hwang; Hyewhon Rhim
      Pages: 295 - 307
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Hongik Hwang, Hyewhon Rhim
      Post-translational modifications (PTMs) covalently modify proteins and diversify protein functions. Along with protein phosphorylation, another common PTM is the addition of O-linked β-N-acetylglucosamine (O-GlcNAc) to serine and/or threonine residues. O-GlcNAc modification is similar to phosphorylation in that it occurs to serine and threonine residues and cycles on and off with a similar time scale. However, a striking difference is that the addition and removal of the O-GlcNAc moiety on all substrates are mediated by the two enzymes regardless of proteins, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. O-GlcNAcylation can interact or potentially compete with phosphorylation on serine and threonine residues, and thus serves as an important molecular mechanism to modulate protein functions and activation. However, it has been challenging to address the role of O-GlcNAc modification in regulating protein functions at the molecular level due to the lack of convenient tools to determine the sites and degrees of O-GlcNAcylation. Studies in this field have only begun to expand significantly thanks to the recent advances in detection and manipulation methods such as quantitative proteomics and highly selective small-molecule inhibitors for OGT and OGA. Interestingly, multiple brain regions, especially hippocampus, express high levels of both OGT and OGA, and a number of neuron-specific proteins have been reported to undergo O-GlcNAcylation. This review aims to discuss the recent updates concerning the impacts of O-GlcNAc modification on neuronal functions at multiple levels ranging from intrinsic neuronal properties to synaptic plasticity and animal behaviors.
      Graphical abstract image

      PubDate: 2018-02-26T06:36:30Z
      DOI: 10.1016/j.phrs.2017.12.006
      Issue No: Vol. 129 (2018)
       
  • ES2 enhances the efficacy of chemotherapeutic agents in
           ABCB1-overexpressing cancer cells in vitro and in vivo
    • Authors: Yanfen Fang; Juanjuan Sun; Xing Zhong; Rui Hu; Jie Gao; Guanfu Duan; Changge Ji; Lijuan Chen; Wanli Zhang; Chunxiao Miao; Haji Akber Aisa; Xiongwen Zhang
      Pages: 388 - 399
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Yanfen Fang, Juanjuan Sun, Xing Zhong, Rui Hu, Jie Gao, Guanfu Duan, Changge Ji, Lijuan Chen, Wanli Zhang, Chunxiao Miao, Haji Akber Aisa, Xiongwen Zhang
      ES2 is a new type of jatrophane diterpenoid ester isolated from the fructus E. sororia, a traditional Uyghur medicine in China. Here we reported the multidrug resistance (MDR) reversal effect of ES2 in vitro and in vivo by modulating the function of ATP-binding cassette subfamily B member 1 (ABCB1). ES2 exhibited low cytotoxicity to ABCB1-overexpressing MDR cells and their parental sensitive cells, but sensitized the MDR cells and ABCB1-transfected HEK293 cells to chemotherapeutic drugs that are ABCB1 substrates. The reversal ability of ES2 was primarily due to the inhibition of the efflux function of ABCB1. Moreover, ES2 stimulated the ATPase activity of ABCB1 in a concentration-dependent manner. There was no change in the expression of ABCB1 in the presence of ES2. The molecular docking analysis indicated that ES2 bond to the drug-binding site of ABCB1 transporter. Importantly, ES2 significantly enhanced the anti-tumor effect of vinorelbine against KBv200 cell xenografts in nude mice. Overall, these findings demonstrate that ES2 inhibits the ABCB1 transporter function and consequently reverses ABCB1-mediated MDR, indicating the potential use of ES2 in combination therapy with conventional chemotherapeutic drugs for cancer treatment.
      Graphical abstract image

      PubDate: 2018-02-26T06:36:30Z
      DOI: 10.1016/j.phrs.2017.11.001
      Issue No: Vol. 129 (2018)
       
  • Quantitative and systems pharmacology 2. In silico polypharmacology of G
           protein-coupled receptor ligands via network-based approaches
    • Authors: Zengrui Wu; Weiqiang Lu; Weiwei Yu; Tianduanyi Wang; Weihua Li; Guixia Liu; Hankun Zhang; Xiufeng Pang; Jin Huang; Mingyao Liu; Feixiong Cheng; Yun Tang
      Pages: 400 - 413
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Zengrui Wu, Weiqiang Lu, Weiwei Yu, Tianduanyi Wang, Weihua Li, Guixia Liu, Hankun Zhang, Xiufeng Pang, Jin Huang, Mingyao Liu, Feixiong Cheng, Yun Tang
      G protein-coupled receptors (GPCRs) are the largest super family with more than 800 membrane receptors. Currently, over 30% of the approved drugs target human GPCRs. However, only approximately 30 human GPCRs have been resolved three-dimensional crystal structures, which limits traditional structure-based drug discovery. Recent advances in network-based systems pharmacology approaches have demonstrated powerful strategies for identifying new targets of GPCR ligands. In this study, we proposed a network-based systems pharmacology framework for comprehensive identification of new drug-target interactions on GPCRs. Specifically, we reconstructed both global and local drug-target interaction networks for human GPCRs. Network analysis on the known drug-target networks showed rational strategies for designing new GPCR ligands and evaluating side effects of the approved GPCR drugs. We further built global and local network-based models for predicting new targets of the known GPCR ligands. The area under the receiver operating characteristic curve of more than 0.96 was obtained for the best network-based models in cross validation. In case studies, we identified that several network-predicted GPCR off-targets (e.g. ADRA2A, ADRA2C and CHRM2) were associated with cardiovascular complications (e.g. bradycardia and palpitations) of the approved GPCR drugs via an integrative analysis of drug-target and off-target-adverse drug event networks. Importantly, we experimentally validated that two newly predicted compounds, AM966 and Ki16425, showed high binding affinities on prostaglandin E2 receptor EP4 subtype with IC50 =2.67μM and 6.34μM, respectively. In summary, this study offers powerful network-based tools for identifying polypharmacology of GPCR ligands in drug discovery and development.
      Graphical abstract image

      PubDate: 2018-02-26T06:36:30Z
      DOI: 10.1016/j.phrs.2017.11.005
      Issue No: Vol. 129 (2018)
       
  • P-glycoprotein (MDR1/ABCB1) and Breast Cancer Resistance Protein
           (BCRP/ABCG2) affect brain accumulation and intestinal disposition of
           encorafenib in mice
    • Authors: Jing Wang; Changpei Gan; Rolf W. Sparidans; Els Wagenaar; Stéphanie van Hoppe; Jos H. Beijnen; Alfred H. Schinkel
      Pages: 414 - 423
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Jing Wang, Changpei Gan, Rolf W. Sparidans, Els Wagenaar, Stéphanie van Hoppe, Jos H. Beijnen, Alfred H. Schinkel
      Encorafenib (LGX818) is a promising BRAFV600E inhibitor that has efficacy against metastatic melanoma. To better understand its pharmacokinetics, we studied its interactions with the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug metabolizing enzyme CYP3A. In polarized MDCK-II cells, encorafenib was efficiently transported by canine and human ABCB1 and ABCG2 and by mouse Abcg2. Upon oral administration to wild-type, Abcb1a/1b−/− , Abcg2−/− , and Abcb1a/1b;Abcg2−/− mice, encorafenib was absorbed very quickly and to very high plasma levels, but without clear changes in oral availability between the strains. Upon oral or intravenous administration, encorafenib brain accumulation was markedly increased in Abcb1a/1b;Abcg2−/− mice and to a lesser extent in Abcb1a/1b−/− mice. However, absolute brain concentrations and brain-to-plasma ratios remained very low in all strains, indicating intrinsically poor brain penetration of encorafenib. Upon intravenous administration, Abcb1a/1b;Abcg2−/− mice showed somewhat reduced plasma elimination of encorafenib compared to wild-type mice, and lower accumulation of the drug in the intestinal tract, suggesting a limited role for these transporters in intestinal elimination of the drug. In Cyp3a−/− mice plasma levels of encorafenib were not markedly increased, suggesting a limited impact of Cyp3a on encorafenib oral availability. The low brain penetration of encorafenib might limit its efficacy against malignancies positioned behind a functional blood-brain barrier, but its oral bioavailability and distribution to other tested organs (liver, kidney, spleen, testis) was high.
      Graphical abstract image

      PubDate: 2018-02-26T06:36:30Z
      DOI: 10.1016/j.phrs.2017.11.006
      Issue No: Vol. 129 (2018)
       
  • Antibacterial activity and pharmacokinetic profile of a promising
           antibacterial agent: 14-O-[(4-Amino-6-hydroxy-pyrimidine-2-yl)thioacetyl]
           mutilin
    • Authors: Ruofeng Shang; Yunpeng Yi; Chao Zhang; Yunxing Fu; Jianping Liang; Wanxia Pu
      Pages: 424 - 431
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Ruofeng Shang, Yunpeng Yi, Chao Zhang, Yunxing Fu, Jianping Liang, Wanxia Pu
      A new pleuromutilin derivative, 14-O-[(4-Amino-6-hydroxy-pyrimidine-2-yl)thioacetyl] mutilin (APTM), has been synthesized and proved most potent antibacterial agent in in vitro assays, suggesting that further development of this compound may lead to a promising antibacterial drug. In this study, we further evaluated the cytotoxicity, antibacterial efficacy and the pharmacokinetic profile of APTM. In BRL 3A cells, 50% of viability was obtained when 363μg/mL of APTM was used, while retapamulin and tiamulin fumarate needed 49 and 28μg/mL, respectively, to reach this viability. Compared to tiamulin fumarate, APTM showed higher inhibition efficacy and faster bactericidal activity against S. aureus and lower 50% effective dose (ED50) in mice after a lethal challenge with methicillin-resistant Staphylococcus aureus (MRSA). Docking experiment for APTM showed a similar binding pattern with tiamulin. Furthermore, a simple, accurate and sensitive HPLC method for the determination of APTM in rabbit plasma was developed and successfully applied to pharmacokinetic study, in which the half life (t 1/2), clearance rate (Cl) and the area under the plasma concentration–time curve (AUC0→∞) were 3.37h, 0.35L/h/kg and 70.68μg·h/m, respectively.
      Graphical abstract image

      PubDate: 2018-02-26T06:36:30Z
      DOI: 10.1016/j.phrs.2017.11.010
      Issue No: Vol. 129 (2018)
       
  • Role of p-MKK7 in myricetin-induced protection against intestinal
           ischemia/reperfusion injury
    • Authors: Yuchao Sun; Mengqiao Lian; Yuan Lin; Bin Xu; Yanli Li; Jin Wen; Dapeng Chen; Ming Xu; Marwan Almoiliqy; Li Wang
      Pages: 432 - 442
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Yuchao Sun, Mengqiao Lian, Yuan Lin, Bin Xu, Yanli Li, Jin Wen, Dapeng Chen, Ming Xu, Marwan Almoiliqy, Li Wang
      Intestinal ischemia reperfusion (I/R) may cause inflammation-, oxidative stress-, and apoptosis-related tissue injuries and facilitate bacterial infection, leading to multiple organ failure. Myricetin, a flavonoid, is found to have diverse biological effects including anti-inflammatory, anti-oxidative, and anti-bacterial effects. Based on our pre-experiment, we proposed that myricetin pretreatment (25, 50mg/kg) could ameliorate intestinal I/R injury and myricetin-induced modulation on MKK7/JNK signal pathway might play a key role in the amelioration. The present study was designed to verify the proposal by using both rat intestinal I/R model in vivo and hypoxia/reoxygenation (H/R)-injured intestinal epithelial cell line (IEC-6 cells) model in vitro. The results confirmed our proposal. Myricetin selectively ameliorated I/R- and H/R-induced injuries in vivo and in vitro respectively without significantly affecting the corresponding normal controls. Myricetin significantly alleviated I/R-induced rat intestinal injury by reducing the generation of pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6 and by reducing MPO activity. Myricetin significantly reduced oxidative stress through decreasing MDA level and increasing the levels of SOD and GSH in the intestinal tissues compared with I/R control rats. Myricetin significantly decreased apoptosis by selectively down-regulating the expression of p-MKK7 and p-JNK without affecting MKK7 and JNK, inhibiting Bax, caspase-3 protein expression, and up-regulating Bcl-2 protein expression in I/R-injured jejunum of rats. In vitro study indicated that MKK7 siRNA transfection significantly decreased both MKK7 and p-MKK7 and other apoptosis-related proteins, partially simulating myricetin-induced anti-apoptotic effects. MKK7 siRNA transfection+myricetin could not further decrease MKK7, p-MKK7, and other apoptosis-related proteins, suggesting that inhibition of MKK7/JNK pathway plays a key role in myricetin-induced protection against intestinal I/R. MKK7 overexpression by cDNA transfection abrogated myricetin-reduced apoptosis-related protein expression, confirming that the MKK7/JNK signal pathway is the key target for myricetin-induced amelioration. The present study indicated that pretreatment of myricetin induced selective protection against intestinal I/R injury without significantly affecting corresponding normal controls and p-MKK7 was the key target, suggesting that myricetin is worth further translational studies.
      Graphical abstract image

      PubDate: 2018-02-26T06:36:30Z
      DOI: 10.1016/j.phrs.2017.11.011
      Issue No: Vol. 129 (2018)
       
  • Topical administration of reversible SAHH inhibitor ameliorates
           imiquimod-induced psoriasis-like skin lesions in mice via suppression of
           TNF-α/IFN-γ-induced inflammatory response in keratinocytes and T
           cell-derived IL-17
    • Authors: Ze-Min Lin; Meng Ma; Heng Li; Qing Qi; Yu-Ting Liu; Yu-Xi Yan; Yun-Fu Shen; Xiao-Qian Yang; Feng-Hua Zhu; Shi-Jun He; Wei Tang; Jian-Ping Zuo
      Pages: 443 - 452
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Ze-Min Lin, Meng Ma, Heng Li, Qing Qi, Yu-Ting Liu, Yu-Xi Yan, Yun-Fu Shen, Xiao-Qian Yang, Feng-Hua Zhu, Shi-Jun He, Wei Tang, Jian-Ping Zuo
      DZ2002, a reversible S-adenosyl-l-homocysteine hydrolase (SAHH) inhibitor with immunosuppressive properties and potent therapeutic activity against various autoimmune diseases in mice. The present study was designed to characterize the potential therapeutic effects of DZ2002 on murine model of psoriasis and reveal the correlated mechanisms. In this report, we demonstrated that in vitro, DZ2002 significantly decreased the expression of pro-inflammatory cytokines and adhesion molecule including IL-1α, IL-1β, IL-6, IL-8, TNF-α and ICAM-1 by inhibiting the phosphorylation of p38 MAPK, ERK and JNK in TNF-α/IFN-γ-stimulated HaCaT human keratinocytes. Topical administration of DZ2002 alleviated the imiquimod (IMQ)-induced psoriasis-like skin lesions and inflammation in mice, the therapeutic effect was comparable with the Calcipotriol. Moreover, the inflammatory skin disorder was restored by DZ2002 treatment characterized by reducing both of the CD3+ T cell accumulation and the psoriasis-specific cytokines expression. Further, we found that DZ2002 improved IMQ-induced splenomegaly and decreased the frequency of splenic IL-17-producing T cells. Our finding offered the convincing evidence that SAHH inhibitor DZ2002 might attenuate psoriasis by simultaneously interfering the abnormal activation and differentiation of keratinocytes and accumulation of IL-17-producing T cells in skin lesions.
      Graphical abstract image

      PubDate: 2018-02-26T06:36:30Z
      DOI: 10.1016/j.phrs.2017.11.012
      Issue No: Vol. 129 (2018)
       
  • Resveratrol dimer trans-ε-viniferin prevents rotaviral diarrhea in mice
           by inhibition of the intestinal calcium-activated chloride channel
    • Authors: Bo Yu; Yu Jiang; Bo Zhang; Hong Yang; Tonghui Ma
      Pages: 453 - 461
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Bo Yu, Yu Jiang, Bo Zhang, Hong Yang, Tonghui Ma
      We previously identified, by a natural-product screen, resveratrol oligomers as inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Here, we report the resveratrol dimer trans-ε-viniferin (TV) and tetramer r-2-viniferin (RV) as inhibitors of the intestinal calcium-activated chloride channel (CaCC) and demonstrate their antisecretory efficacy in a neonatal mouse model of rotaviral diarrhea. Short-circuit measurements show inhibition of CaCC current in the human colonic cell line HT-29 by TV and RV with IC50 ∼1 and 20μM, respectively. TV primarily inhibited the physiologically relevant, long-term CaCC current following agonist stimulation, without effect on cytoplasmic Ca2+ signaling. TV and RV inhibited short-circuit current in mouse colon as well. In a neonatal mouse model of rotaviral secretory diarrhea produced by oral inoculation with rotavirus, 2μg TV or 11μg RV inhibited secretory diarrhea by >50%, without effect on the rotaviral infection. Our results support the antisecretory efficacy of non-toxic, natural-product resveratrol oligomers for diarrheas produced by CaCC activation. Because these compounds also inhibit the CFTR chloride channel, they may be useful for antisecretory therapy of a wide range of diarrheas.
      Graphical abstract image

      PubDate: 2018-02-26T06:36:30Z
      DOI: 10.1016/j.phrs.2017.11.016
      Issue No: Vol. 129 (2018)
       
  • Metformin promotes the proliferation and differentiation of murine
           preosteoblast by regulating the expression of sirt6 and oct4
    • Authors: Wei Mu; Zhuoran Wang; Chuanyu Ma; Yunyun Jiang; Nannan Zhang; Kaiqiang Hu; Liyuan Li; Zhao Wang
      Pages: 462 - 474
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Wei Mu, Zhuoran Wang, Chuanyu Ma, Yunyun Jiang, Nannan Zhang, Kaiqiang Hu, Liyuan Li, Zhao Wang
      Osteopenia, osteoporosis and bone salt metabolism disorder are common diseases in the aged and diabetics. From case reports of patients with T2DM, we have observed that metformin can decrease risk of bone fracture and promote bone formation. However, the underlying mechanism of metformin’s effect on bone metabolism remains unknown. In our research, we show that metformin can promote proliferation of murine preosteoblast by regulating AMPK-mTORC2 and AKT-mTORC1 signaling axis. Furthermore, we have observed that metformin can promote SIRT6 expression before and during differentiation of murine preosteoblast. The interaction between SIRT6 and NF-κB is highly important in osteoblast differentiation just as the relationship between OPG and RANKL in the process of bone formation. During differentiation, we show that SIRT6 inhibits phosphorylation of NF-κB and that OPG increases while RANKL decrease in HG groups. In addition, ablation of sirt6 in mice causes phosphorylation of NF-κB at high-levels and RANKL increases slightly in femur bone cells. However, other bone formation marker proteins such as RUNX2, OSTERIX and OPG appear at low-levels in sirt6 KO mice. It has been confirmed that downregulation of OCT4 is critical incident in the differentiation of embryonic stem cells. Fortunately, we observe that SIRT6 can suppress OCT4 expression in murine preosteoblast and the expression of OCT4 is at high-level in sirt6 KO mice. Taken together, this study’s results illuminate metformin’s effect on bone metabolism under HG condition and help to elucidate why metformin can promote bone fracture healing of patients with T2DM.
      Graphical abstract image

      PubDate: 2018-02-26T06:36:30Z
      DOI: 10.1016/j.phrs.2017.11.020
      Issue No: Vol. 129 (2018)
       
  • Enantiomer-specific positive allosteric modulation of CB1 signaling in
           autaptic hippocampal neurons
    • Authors: Jose Mitjavila; Danielle Yin; Pushkar M. Kulkarni; Chiara Zanato; Ganesh A. Thakur; Ruth Ross; Iain Greig; Ken Mackie; Alex Straiker
      Pages: 475 - 481
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Jose Mitjavila, Danielle Yin, Pushkar M. Kulkarni, Chiara Zanato, Ganesh A. Thakur, Ruth Ross, Iain Greig, Ken Mackie, Alex Straiker
      The cannabinoid signaling system is found throughout the CNS and its involvement in several pathological processes makes it an attractive therapeutic target. Because orthosteric CB1 cannabinoid receptor ligands have undesirable adverse effects there has been great interest in the development of allosteric modulators – both negative (NAMs) and positive (PAMs) – of these receptors. NAMs of CB1 appeared first on the scene, followed more recently by PAMs. Because allosteric modulation can vary depending on the orthosteric ligand it is important to study their function in a system that employs endogenous cannabinoids. We have recently surveyed first generation NAMs using cultured autaptic hippocampal neurons. These neurons express depolarization induced suppression of excitation (DSE), a form of synaptic plasticity that is mediated by CB1 and 2-arachidonoyl glycerol (2-AG); they are therefore an excellent neuronal model of endogenous cannabinoid signaling in which to test CB1 modulators. In this study we find that while two related compounds, GAT211 and ZCZ011, each show PAM-like responses in autaptic hippocampal neurons, they also exhibit complex pharmacology. Notably we were able to separate the PAM- and agonist-like responses of GAT211 by examining the enantiomers of this racemic compound: GAT228 and GAT229. We find that GAT229 exhibits PAM-like behavior while GAT228 appears to directly activate the CB1 receptor. Both GAT229 and ZCZ011 represent the first PAMs that we have found to be effective in using this 2-AG utilizing neuronal model system. Because these compounds may exhibit both probe selectivity and biased signaling it will be important to test them with anandamide as well as other signaling pathways.
      Graphical abstract image

      PubDate: 2018-02-26T06:36:30Z
      DOI: 10.1016/j.phrs.2017.11.019
      Issue No: Vol. 129 (2018)
       
  • Down regulation of pro-inflammatory pathways by tanshinone IIA and
           cryptotanshinone in a non-genetic mouse model of Alzheimer’s disease
    • Authors: Francesco Maione; Marialuisa Piccolo; Simona De Vita; Maria Giovanna Chini; Claudia Cristiano; Carmen De Caro; Pellegrino Lippiello; Maria Concetta Miniaci; Rita Santamaria; Carlo Irace; Vincenzo De Feo; Antonio Calignano; Nicola Mascolo; Giuseppe Bifulco
      Pages: 482 - 490
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Francesco Maione, Marialuisa Piccolo, Simona De Vita, Maria Giovanna Chini, Claudia Cristiano, Carmen De Caro, Pellegrino Lippiello, Maria Concetta Miniaci, Rita Santamaria, Carlo Irace, Vincenzo De Feo, Antonio Calignano, Nicola Mascolo, Giuseppe Bifulco
      Alzheimer's disease (AD) is a common form of dementia mainly characterized by the deposition of neurofibrillary tangles and β-amyloid (Aβ) peptides in the brain. Additionally, increasing evidence demonstrates that a neuro-inflammatory state plays a key role in the development of this disease. Beside synthetic drugs, the use of natural compounds represents an alternative for the development of new potential drugs for the treatment of AD. Among these, the root of Salvia miltiorhiza Bunge (also known as Danshen) used for the treatment of cardiovascular, cerebrovascular disease and CNS functional decline in Chinese traditional medicine is one of the most representative examples. We therefore evaluated the effects of tanshinone IIA (TIIA) and cryptotanshinone (CRY) (the two major lipophilic compounds of Danshen) in a non-genetic mouse model of β-amyloid (Aβ)-induced AD, which is mainly characterized by reactive gliosis and neuro-inflammation in the brain. To this aim, mice were injected intracerebroventricularly (i.c.v.) with Aβ1–42 peptide (3μg/3μl) and after with TIIA and CRY (1, 3, or 10mg/kg) intraperitoneally (i.p.) 3 times weekly for 21days following the induction of experimental AD. Spatial working memory was assessed as a measure of short-term memory in mice, whereas the level of GFAP, S100β, COX-2, iNOS and NF-kBp65 monitored by western blot and ELISA assay, were selected as markers of reactive gliosis and neuro-inflammation. Finally, by docking studies, the modulation of key pro-inflammatory enzymes and pathways involved in the AD-related neuro-inflammation were also investigated. Results indicate that TIIA and CRY alleviate memory decline in Aβ1-42-injected mice, in a dose dependent manner. Moreover, the analysis of gliosis-related and neuro-inflammatory markers in the hippocampal tissues reveal a remarkable reduction in the expression of GFAP, S100β, COX-2, iNOS and NF-kBp65 after CRY (10mg/kg) treatment. These effects were less evident, but still significant, after TIIA (10mg/kg). Finally, in silico analysis also revealed that both compounds were able to interact with the binding sites of NF-kBp65 endorsing the data from biochemical analysis. We conclude that TIIA and CRY display anti-inflammatory and neuroprotective effect in a non-genetic mouse model of AD, thus playing a role in slowing down the course and onset of AD.
      Graphical abstract image

      PubDate: 2018-02-26T06:36:30Z
      DOI: 10.1016/j.phrs.2017.11.018
      Issue No: Vol. 129 (2018)
       
  • Corrigendum to “Mild cognitive impairment due to Alzheimer disease:
           Contemporary approaches to diagnostics and pharmacological intervention”
           [Pharmacol. Res. 129 (2018) 216–226]
    • Authors: Sergey O. Bachurin; Svetlana I. Gavrilova; Anna Samsonova; George E. Barreto; Gjumrakch Aliev
      Abstract: Publication date: Available online 17 March 2018
      Source:Pharmacological Research
      Author(s): Sergey O. Bachurin, Svetlana I. Gavrilova, Anna Samsonova, George E. Barreto, Gjumrakch Aliev


      PubDate: 2018-03-20T11:09:38Z
      DOI: 10.1016/j.phrs.2018.03.006
       
  • Nutritional patterns associated with the maintenance of neurocognitive
           functions and the risk of dementia and Alzheimer’s disease: a focus on
           human studies
    • Authors: Francesca Pistollato; Ruben Calderón Iglesias; Roberto Ruiz; Silvia Aparicio; Jorge Crespo; Luis Dzul Lopez; Piera Pia Manna; Francesca Giampieri; Maurizio Battino
      Abstract: Publication date: Available online 16 March 2018
      Source:Pharmacological Research
      Author(s): Francesca Pistollato, Ruben Calderón Iglesias, Roberto Ruiz, Silvia Aparicio, Jorge Crespo, Luis Dzul Lopez, Piera Pia Manna, Francesca Giampieri, Maurizio Battino
      Ample epidemiological evidence suggests a strong correlation among diet, lifestyle factors and the onset and consolidation of dementia and Alzheimer’s disease (AD). It has been demonstrated that AD, diabetes, obesity, insulin resistance, and cardiovascular disease are strongly interconnected pathologies. Preventive strategies and nutritional interventions seem to be promising approaches to delay neurocognitive decline and reduce the risk of AD and other non-psychiatric co-morbidities. In this regard, healthy dietary patterns, characterized by high intake of plant-based foods, probiotics, antioxidants, soy beans, nuts, and omega-3 polyunsaturated fatty acids, and a low intake of saturated fats, animal-derived proteins, and refined sugars, have been shown to decrease the risk of neurocognitive impairments and eventually the onset of AD. Here we review the role of some nutrients and, in particular, of healthy dietary patterns, such as the Mediterranean diet and other emerging healthy diets, DASH (Dietary Approach to Stop Hypertension) and MIND (Mediterranean-DASH dietIntervention for Neurodegenerative Delay), for the maintenance of cognitive performance, focusing specifically on human studies. The beneficial effects associated with overall diet composition, rather than single nutrient supplementations, for the prevention or the delay of AD and dementia are discussed.
      Graphical abstract image

      PubDate: 2018-03-20T11:09:38Z
      DOI: 10.1016/j.phrs.2018.03.012
       
  • VDAC1, Mitochondrial Dysfunction, and Alzheimer's disease
    • Authors: Varda Shoshan-Barmatz; Edna Nahon-Crystal; Anna Shteinfer-Kuzmine; Rajeev Gupta
      Abstract: Publication date: Available online 15 March 2018
      Source:Pharmacological Research
      Author(s): Varda Shoshan-Barmatz, Edna Nahon-Crystal, Anna Shteinfer-Kuzmine, Rajeev Gupta
      Alzheimer's disease (AD) is an age-related neurodegenerative disorder. Although an accumulation of brain amyloid-β (Aβ) peptide and hyperphosphorylated tau protein have been implicated in the pathogenesis of AD, the etiology of the disease remains unclear. Mitochondrial dysfunction has been identified as an early event in AD pathogenesis and is reflected by reduced metabolism, disruption of Ca2+ homeostasis, and increased levels of reactive oxygen species, lipid peroxidation, and apoptosis. The focus of this review is the involvement of mitochondrial dysfunction in AD, and specifically, the role of the voltage-dependent anion channel 1 (VDAC1), which has been linked to AD pathogenesis. VDAC1 is a multi-functional protein, expressed in the mitochondria and other cell compartments, including the plasma membrane. The protein regulates the main metabolic and energetic functions of the cell, including Ca2+ homeostasis, oxidative stress, and mitochondria-mediated apoptosis. VDAC1 represents a hub protein that interacts with over 150 other proteins including phosphorylated tau, Aβ, and γ-secretase, and participates in their toxicity. The high levels of VDAC1 demonstrated post-mortem in the brains of AD patients and in amyloid precursor protein (APP) transgenic mice prompted the hypothesis that the protein may be associated with neuronal cell destruction since over-expression of VDAC1 triggers cell death. Thus, targeting mitochondrial dysfunction via VDAC1, to prevent this pro-apoptotic activity, could represent a novel strategy for inhibiting cell death. In addition, the review also discusses possible VDAC1 involvement in the link between AD and diabetes and the inverse association between cancer and AD.
      Graphical abstract image

      PubDate: 2018-03-20T11:09:38Z
      DOI: 10.1016/j.phrs.2018.03.010
       
  • Dehydroevodiamine and hortiamine, alkaloids from the traditional Chinese
           herbal drug Evodia rutaecarpa, are IKr blockers with proarrhythmic effects
           in vitro and in vivo
    • Authors: Igor Baburin; Rosanne Varkevisser; Anja Schramm; Priyanka Saxena; Stanislav Beyl; Phillip Szkokan; Tobias Linder; Anna Stary-Weinzinger; Marcel A.G. van der Heyden; Marien Houtman; Hiroki Takanari; Malin Jonsson; Jet H.D. Beekman; Matthias Hamburger; Marc A. Vos; Steffen Hering
      Abstract: Publication date: Available online 15 March 2018
      Source:Pharmacological Research
      Author(s): Igor Baburin, Rosanne Varkevisser, Anja Schramm, Priyanka Saxena, Stanislav Beyl, Phillip Szkokan, Tobias Linder, Anna Stary-Weinzinger, Marcel A.G. van der Heyden, Marien Houtman, Hiroki Takanari, Malin Jonsson, Jet H.D. Beekman, Matthias Hamburger, Marc A. Vos, Steffen Hering
      Evodiae fructus is a widely used herbal drug in traditional Chinese medicine. Evodia extract was found to inhibit hERG channels. The aim of the current study was to identify hERG inhibitors in Evodia extract and to investigate their potential proarrhythmic effects. Dehydroevodiamine (DHE) and hortiamine were identified as IKr (rapid delayed rectifier current) inhibitors in Evodia extract by HPLC-microfractionation and subsequent patch clamp studies on human embryonic kidney cells. DHE and hortiamine inhibited IKr with IC50s of 253.2 ± 26.3 nM and 144.8 ± 35.1 nM, respectively. In dog ventricular cardiomyocytes, DHE dose-dependently prolonged the action potential duration (APD). Early afterdepolarizations (EADs) were seen in 14, 67, 100, and 67% of cells after 0.01, 0.1, 1 and 10 μM DHE, respectively. The proarrhythmic potential of DHE was evaluated in 8 anesthetized rabbits and in 8 chronic atrioventricular block (cAVB) dogs. In rabbits, DHE increased the QT interval significantly by 12 ± 10% (0.05 mg/kg/5 min) and 60 ± 26% (0.5 mg/kg/5 min), and induced Torsade de Pointes arrhythmias (TdP, 0.5 mg/kg/5 min) in 2 rabbits. In cAVB dogs, 0.33 mg/kg/5 min DHE increased QT duration by 48 ± 10% (P < 0.05*) and induced TdP in 2/4 dogs. A higher dose did not induce TdP. In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), methanolic extracts of Evodia, DHE and hortiamine dose-dependently prolonged APD. At 3 μM DHE and hortiamine induced EADs. hERG inhibition at submicromolar concentrations, APD prolongation and EADs in hiPSC-CMs and dose-dependent proarrhythmic effects of DHE at micromolar plasma concentrations in cAVB dogs should increase awareness regarding proarrhythmic effects of widely used Evodia extracts.
      Graphical abstract image

      PubDate: 2018-03-20T11:09:38Z
      DOI: 10.1016/j.phrs.2018.02.024
       
  • Curcumin in heart failure: a choice for complementary therapy'
    • Authors: Amin Saeidinia; Faeze Keihanian; Alexandra E. Butler; Ramin Khameneh Bagheri; Stephen L. Atkin; Amirhossein Sahebkar
      Abstract: Publication date: Available online 14 March 2018
      Source:Pharmacological Research
      Author(s): Amin Saeidinia, Faeze Keihanian, Alexandra E. Butler, Ramin Khameneh Bagheri, Stephen L. Atkin, Amirhossein Sahebkar
      Heart failure is a major public health concern and one of the most common reasons for a cardiac hospital admission. Heart failure may be classified as having a reduced or preserved ejection fraction and its severity is based on the symptom score. Given the aging population, it is predicted that admissions with heart failure will increase. Whilst pharmacological therapy has improved the associated morbidity and mortality, there is a need for additional therapies to improve the clinical outcome as the death rate remains high. Curcumin is a natural product derived from turmeric that appears to have cardiovascular benefit through a number of mechanisms. In this review, we have assessed the mechanisms by which curcumin may exert its effects in different models of heart failure and show that it has promise as a complementary treatment in heart failure.
      Graphical abstract image

      PubDate: 2018-03-20T11:09:38Z
      DOI: 10.1016/j.phrs.2018.03.009
       
  • Molecular insight into drug exporters within the cellular membrane
    • Authors: Emad Tajkhorshid
      Abstract: Publication date: Available online 10 March 2018
      Source:Pharmacological Research
      Author(s): Emad Tajkhorshid


      PubDate: 2018-03-20T11:09:38Z
      DOI: 10.1016/j.phrs.2018.03.008
       
  • Structural patterns of the human ABCC4/MRP4 exporter in lipid bilayers
           rationalize clinically observed polymorphisms
    • Authors: B. Chantemargue; F. Di Meo; K. Berka; N. Picard; H. Arnion; M. Essig; P. Marquet; M. Otyepka; P. Trouillas
      Abstract: Publication date: Available online 10 March 2018
      Source:Pharmacological Research
      Author(s): B. Chantemargue, F. Di Meo, K. Berka, N. Picard, H. Arnion, M. Essig, P. Marquet, M. Otyepka, P. Trouillas
      The ABCC4/MRP4 exporter has a clinical impact on membrane transport of a broad range of xenobiotics. It is expressed at key locations for drug disposition or effects such as in the liver, the kidney and blood cells. Several polymorphisms and mutations (e.g., p.Gly187Trp) leading to MRP4 dysfunction are associated with an increased risk of toxicity of some drugs. So far, no human MRP4 structure has been elucidated, precluding rationalization of these dysfunctions at a molecular level. We constructed atomistic model of the wild type (WT) MRP4 and the p.Gly187Trp mutant embedded in different lipid bilayers and relaxed them for hundreds of nanoseconds by molecular dynamics simulations. The WT MRP4 molecular structure confirmed and ameliorated the general knowledge about the transmembrane helices and the two nucleotide binding domains. Moreover, our model elucidated positions of three generally unresolved domains: L1 (linker between the two halves of the exporter); L0 (N-terminal domain); and the zipper helices (between the two NBDs). Each domain was thoroughly described in view of its function. The p.Gly187Trp mutation induced a huge structural impact on MRP4, mainly affecting NBD 1 structure and flexibility. The structure of transporter enabled rationalization of known dysfunctions associated with polymorphism of MRP4. This model is available to the pharmacology community to decipher the impact of any other clinically observed polymorphism and mutation on drug transport, giving rise to in silico predictive pharmacogenetics.
      Graphical abstract image

      PubDate: 2018-03-20T11:09:38Z
      DOI: 10.1016/j.phrs.2018.02.029
       
  • The glucagon-like peptide-1 (GLP-1) analog liraglutide attenuates renal
           fibrosis
    • Authors: Ya-Kun Li; Dong-Xia Ma; Zhi-Min Wang; Xiao-Fan Hu; Shang-Lin Li; Hong-Zhe Tian; Meng-Jun Wang; Yan-Wen Shu; Jun Yang
      Abstract: Publication date: Available online 9 March 2018
      Source:Pharmacological Research
      Author(s): Ya-Kun Li, Dong-Xia Ma, Zhi-Min Wang, Xiao-Fan Hu, Shang-Lin Li, Hong-Zhe Tian, Meng-Jun Wang, Yan-Wen Shu, Jun Yang
      Renal fibrosis is recognized as the common route of all chronic kidney disease (CKD) progressing to end-stage renal disease (ESRD). Additionally, accumulating evidence suggests that epithelial-mesenchymal transition (EMT) plays a significant role in the process of renal fibrogenesis. Liraglutide is a long-acting glucagon-like peptide-1 (GLP-1) analog that has been widely used to treat type 2 diabetes. Recent studies have demonstrated that the GLP-1 analogs could also exert protective effects in cardiac fibrosis models. However, the effects of liraglutide on the progression of CKD remain largely unknown. In the present study, we investigated the effects of liraglutide on the progression to renal fibrosis induced by unilateral ureteral obstruction (UUO) and EMT of rat renal tubular epithelial cells (NRK-52E) induced with recombinant transforming growth factor-beta 1 (TGF-β1). The results indicated that UUO increased collagen deposition and the mRNA expression of fibronectin (FN) and collagen type Ⅰ alpha 1 (Col1α1) in the obstructed kidney tissues. The effects were blunted in liraglutide-treated UUO mice compared with control mice. The upregulation of Snail1 and alpha smooth muscle actin (α-SMA), and downregulation of E-cadherin revealed that EMT occurred in the UUO kidneys, and these effects were ameliorated following liraglutide treatment. Additionally, liraglutide treatment decreased the expression of TGF-β1 and its receptor (TGF-β1R) and inhibited the activation of its downstream signaling molecules (pSmad3 and pERK1/2). The in vitro results showed that the EMT and extracellular matrix (ECM) secretion of NRK-52E cells were induced by TGF-β1. In addition, the Smad3 and ERK1/2 signaling pathways were highly activated in cells cultured with TGF-β1. All these effects were attenuated by liraglutide treatment. However, the protective effects of liraglutide were abolished by co-incubation of the GLP-1 receptor (GLP-1R) antagonist exendin-3 (9-39). These results suggest that liraglutide attenuates the EMT and ECM secretion of NRK-52E cells induced by TGF-β1 and EMT and renal fibrosis induced by UUO. The potential mechanism involves liraglutide binding to and activating GLP-1R, which prevents EMT by inhibiting the activation of TGF-β1/Smad3 and ERK1/2 signaling pathways, thereby decreasing the ECM secretion and deposition. Therefore, liraglutide is a promising therapeutic agent that may halt the progression of renal fibrosis.
      Graphical abstract image

      PubDate: 2018-03-20T11:09:38Z
      DOI: 10.1016/j.phrs.2018.03.004
       
  • Personalized immunosuppression in elderly renal transplant recipients
    • Authors: L.E.J. Peeters; L.M. Andrews; D.A. Hesselink; B.C.M. de Winter; T. van Gelder
      Abstract: Publication date: Available online 6 March 2018
      Source:Pharmacological Research
      Author(s): L.E.J. Peeters, L.M. Andrews, D.A. Hesselink, B.C.M. de Winter, T. van Gelder
      The number of elderly people has increased considerably over the last decades, due to a rising life expectancy and ageing populations. As a result, an increased number of elderly with end-stage-renal-disease are diagnosed, for which the preferred treatment is renal transplantation. Over the past years the awareness of the elderly as a specific patient population has grown, which increases the importance of research in this group. Elderly patients often receive kidneys from elderly donors while younger donor kidneys are preferentially reserved for younger recipients. Although the rate of acute rejection after transplantation is lower in the elderly, these rejections may lead to graft loss more frequently, as kidneys from elderly donors have marginal reserve capacity. To prevent acute rejection, immunosuppressive therapy is needed. On the other hand, elderly patients have a higher risk to die from infectious complications, and thus less immunosuppression would be preferable. Immunosuppressive treatment in the elderly is complicated further by changes in the pharmacokinetics and pharmacodynamics, with increasing age. Adjustments in standard immunosuppressive regimes are therefore suggested for this population. An unmet need in transplantation medicine is a tool to guide a personalized approach to immunosuppression. Recently several promising biomarkers that identify injury to the graft at an early stage or predict acute rejection have been identified. Unfortunately, none of these biomarkers were tested specifically in the elderly. We believe there is an urgent need to perform clinical trials investigating novel immunosuppressive regimens in conjunction with biomarker studies in this specific population.
      Graphical abstract image

      PubDate: 2018-03-08T07:09:29Z
      DOI: 10.1016/j.phrs.2018.02.031
       
  • Microbiota metabolites: Pivotal players of cardiovascular damage in
           chronic kidney disease
    • Authors: Carmela Cosola; Maria Teresa Rocchetti; Adamasco Cupisti; Loreto Gesualdo
      Abstract: Publication date: Available online 5 March 2018
      Source:Pharmacological Research
      Author(s): Carmela Cosola, Maria Teresa Rocchetti, Adamasco Cupisti, Loreto Gesualdo
      In chronic kidney disease (CKD), cardiovascular (CV) damage is present in parallel which leads to an increased risk of CV disease. Both traditional and non-traditional risk factors contribute to CV damage in CKD. The systemic role of the microbiota as a central player in the pathophysiology of many organs is progressively emerging in the literature: the microbiota is indeed involved in a complex, bi-directional network between many organs, including the kidney and heart connection, although many of these relationships still need to be elucidated through in-depth mechanistic studies. The aim of this review is to provide evidence that microbiota metabolites influence non-traditional risk factors, such as inflammation and endothelial dysfunction in CKD-associated CV damage. Here, we report our current understanding and hypotheses on the gut-kidney and gut-heart axes and provide details on the potential mechanisms mediated by microbial metabolites. More specifically, we summarize some novel hypotheses linking the microbiota to blood pressure regulation and hypertension. We also emphasise the idea that the nutritional management of CKD should be redesigned and include the new findings from research on the intrinsic plasticity of the microbiota and its metabolites in response to food intake. The need is felt to integrate the classical salt and protein restriction approach for CKD patients with foods that enhance intestinal wellness. Finally, we discuss the new perspectives, especially the importance of taking care of the microbiota in order to prevent the risk of developing CKD and hypertension, as well as the still not tested but very promising CKD innovative treatments, such as postbiotic supplementation and bacteriotherapy. This interesting area of research offers potential complementary approaches to the management of CKD and CV damage assuming that the causal mechanisms underlying the gut-kidney and gut-heart axes are clarified. This will pave the way to the design of new personalized therapies targeting gut microbiota.
      Graphical abstract image

      PubDate: 2018-03-08T07:09:29Z
      DOI: 10.1016/j.phrs.2018.03.003
       
  • Hydrogen sulfide and autophagy: A double edged sword
    • Authors: Dongdong Wu; Honggang Wang; Tieshan Teng; Shaofeng Duan; Ailing Ji; Yanzhang Li
      Abstract: Publication date: Available online 4 March 2018
      Source:Pharmacological Research
      Author(s): Dongdong Wu, Honggang Wang, Tieshan Teng, Shaofeng Duan, Ailing Ji, Yanzhang Li
      Hydrogen sulfide (H2S) has been considered the third gaseous signaling molecule that plays important roles in a wide range of physiological and pathological conditions. However, there has been some controversy on the role of H2S in autophagy. Recent studies indicate that a number of signaling pathways are involved in the pro-autophagy effect of H2S, such as PI3 K/Akt/mTOR, AMPK/mTOR, LKB1/STRAD/MO25, and miR-30c signaling pathways. On the other hand, there are many signaling pathways that play important roles in the anti-autophagy effect of H2S, including SR-A, PI3 K/SGK1/GSK3β, PI3 K/AKT/mTOR, Nrf2-ROS-AMPK, AMPK/mTOR, and JNK1 signaling pathways. Novel H2S-releasing donors/drugs could be designed and identified in order to increase the therapeutic effects by mediating autophagy in human diseases. In this review, the H2S metabolism in mammals is summarized and the effects of signaling pathways in H2S-mediated autophagy are further discussed.
      Graphical abstract image

      PubDate: 2018-03-08T07:09:29Z
      DOI: 10.1016/j.phrs.2018.03.002
       
  • Structure-activity relationships of HDAC8 inhibitors: Non-hydroxamates as
           anticancer agents
    • Authors: Sk. Abdul Amin; Nilanjan Adhikari; Tarun Jha
      Abstract: Publication date: Available online 4 March 2018
      Source:Pharmacological Research
      Author(s): Sk. Abdul Amin, Nilanjan Adhikari, Tarun Jha
      Histone deacetylase inhibitors (HDACIs) have a paramount importance in the acetylation process of histone and non-histone proteins that are crucial players in the cellular epigenetic modifications. HDACIs exert effective antiproliferation through DNA repairing, cell cycle arrest, apoptosis induction and alteration of genetic expression. HDAC8 is one of the crucial HDACs, affects the epigenetic gene silencing process and cancer progression. Hence, HDAC8 is one of the key cancer targets among class I HDACs that may be effectively blocked as a benchmark therapy to combat malignancy. In the current review, a special emphasis has been given for the non-hydroxamate type of HDAC8 inhibitors. It may provide some fruitful structural information to design newer better active candidates to fight against target specific malignancies in future.
      Graphical abstract image

      PubDate: 2018-03-08T07:09:29Z
      DOI: 10.1016/j.phrs.2018.03.001
       
  • Long noncoding RNAs act as regulators of autophagy in cancer
    • Authors: Ting Sun
      Abstract: Publication date: March 2018
      Source:Pharmacological Research, Volume 129
      Author(s): Ting Sun
      Long noncoding RNAs (lncRNAs) have emerged as critical regulators in various cellular processes. Studies have disclosed an important function of lncRNAs in the regulation of autophagy, a crucial cellular homeostatic mechanism that plays a pro-survival or pro-death role in cancer. Deregulation of lncRNAs can contribute to tumorigenesis and cancer progression, wherein lncRNAs can act as oncogenes or tumor suppressors. In this review, we highlight the recent advances in understanding the relationship between lncRNAs and autophagy regulation in cancer. Exploiting the newly emerging knowledge of the lncRNA-autophagy-cancer axis may provide novel targets for cancer therapy.
      Graphical abstract image

      PubDate: 2018-02-26T06:36:30Z
       
  • What are the chances that resveratrol will be the drug of tomorrow'
    • Authors: Lasse Gliemann
      Abstract: Publication date: Available online 6 February 2018
      Source:Pharmacological Research
      Author(s): Lasse Gliemann


      PubDate: 2018-02-16T06:04:26Z
      DOI: 10.1016/j.phrs.2018.02.004
       
  • The tip link protein Cadherin-23: from hearing loss to cancer
    • Authors: Paridhy Vanniya. S; C.R. Srikumari Srisailapathy; Ramkumar Kunka Mohanram
      Abstract: Publication date: Available online 5 February 2018
      Source:Pharmacological Research
      Author(s): Paridhy Vanniya. S, C.R. Srikumari Srisailapathy, Ramkumar Kunka Mohanram
      Cadherin-23 is an atypical member of the cadherin superfamily, with a particularly long extracellular domain. It has been known to be a part of the tip links of the inner ear mechanosensory hair cells. Several studies have been carried out to understand the role of Cadherin-23 in the hearing mechanism and defects in the CDH23 have been associated with hearing impairment resulting from defective or absence of tip links. Recently, studies have reported the role of Cadherin-23 in several pathological conditions, including cancer, suggesting the presence of several unknown functions. Initially, it was proposed that Cadherin-23 represents a yet unspecified subtype of Cadherins; however, no other proteins with similar characteristics have been identified, till date. It has a unique cytoplasmic domain that does not bear a β-catenin binding region, but has been demonstrated to mediate cell-cell adhesions. Several protein interacting partners have been identified for Cadherin-23 and the roles of their interactions and in various cellular mechanisms are yet to be explored. This review summarizes the characteristics of Cadherin-23 and its roles in several pathologies including cancer.
      Graphical abstract image

      PubDate: 2018-02-16T06:04:26Z
      DOI: 10.1016/j.phrs.2018.01.026
       
  • The role of small molecule platelet-derived growth factor receptor (PDGFR)
           inhibitors in the treatment of neoplastic disorders
    • Authors: Robert Roskoski
      Abstract: Publication date: Available online 3 February 2018
      Source:Pharmacological Research
      Author(s): Robert Roskoski
      Platelet-derived growth factor (PDGF) was discovered as a serum-derived component necessary for the growth of smooth muscle cells, fibroblasts, and glial cells. The PDGF family is a product of four gene products and consists of five dimeric isoforms: PDGF-AA, PDGF-BB, PDGF-CC, PDGF-DD, and the PDGF-AB heterodimer. This growth factor family plays an essential role in embryonic development and in wound healing in the adult. These growth factors mediate their effects by binding to and activating their receptor protein-tyrosine kinases, which are encoded by two genes: PDGFRA and PDGFRB. The functional receptors consist of the PDGFRα/α and PDGFRβ/β homodimers and the PDGFRα/β heterodimer. Although PDGF signaling is most closely associated with mesenchymal cells, PDGFs and PDGF receptors are widely expressed in the mammalian central nervous system. The PDGF receptors contain an extracellular domain that is made up of five immunoglobulin-like domains (Ig-D1/2/3/4/5), a transmembrane segment, a juxtamembrane segment, a protein-tyrosine kinase domain that contains an insert of about 100 amino acid residues, and a carboxyterminal tail. Although uncommon, activating mutations in the genes for PDGF or PDGF receptors have been documented in various neoplasms including dermatofibrosarcoma protuberans (DFSP) and gastrointestinal stromal tumors (GIST). In most neoplastic diseases, PDGF expression and action appear to involve the tumor stroma. Moreover, this family is pro-angiogenic. More than ten PDGFRα/β multikinase antagonists have been approved by the FDA for the treatment of several neoplastic disorders and interstitial pulmonary fibrosis (www.brimr.org/PKI/PKIs.htm). Type I protein kinase inhibitors interact with the active enzyme form with DFG-D of the proximal activation segment directed inward toward the active site (DFG-Din). In contrast, type II inhibitors bind to their target with the DFG-D pointing away from the active site (DFG-Dout). We used the Schrödinger induced-fit docking protocol to model the interaction of several antagonists with PDGFRα including imatinib, sorafenib, and sunitinib. The results indicate that these antagonists are able to bind to the DFG-Dout conformation of the receptor and are thus classified as type II inhibitors. Owing to the multiplicity of less active protein kinase conformations when compared with the canonical more active conformation, it was hypothesized that type II drugs would be less promiscuous than type I drugs which bind to the typical active conformation. Although type II inhibitors may be more selective, most – if not all – inhibit more than one target protein kinase and the differences are a matter of degree only.
      Graphical abstract image

      PubDate: 2018-02-05T05:25:09Z
      DOI: 10.1016/j.phrs.2018.01.021
       
  • HIV Infection and its effects on the development of autoimmune disorders
    • Authors: Luis E. Vega; Luis R. Espinoza
      Abstract: Publication date: Available online 10 January 2018
      Source:Pharmacological Research
      Author(s): Luis E. Vega, Luis R. Espinoza
      More than 35 years have elapsed since the initial outbreak of the HIV/AIDS epidemic and the status of a considerable number of patients has changed from a fatal disorder to a chronic one where comorbidities including sarcoidosis and autoimmune diseases have become relevant and dominant. HIV targets the immune system leading to a state of immunodeficiency in a setting of immune activation in which CD4+ T cell depletion plays a critical role. The onset, natural history and course of HIV-associated autoimmune disease has dramatically changed according to the stage of HIV infection and since the introduction of combined anti-retroviral therapy. There are some issues that need further study regarding therapy, especially when immunosuppressive drugs and biologic agents are under consideration. Currently, biologic agents and others immunosuppressive agents are recommended when patients have CD4+ T cell counts above 200 cells/mm3 and the HIV viral activity is completely suppressed.
      Graphical abstract image

      PubDate: 2018-01-15T23:43:03Z
      DOI: 10.1016/j.phrs.2018.01.005
       
  • Understanding Melanocortin-4 Receptor Control of Neuronal Circuits: Toward
           Novel Therapeutics for Obesity Syndrome
    • Authors: Sang Hyeon Ju; Gyu-Bon Cho; Jong-Woo Sohn
      Abstract: Publication date: Available online 9 January 2018
      Source:Pharmacological Research
      Author(s): Sang Hyeon Ju, Gyu-Bon Cho, Jong-Woo Sohn
      It is well known that melanocortin-4 receptors (MC4Rs) and central melanocortin pathways regulate food intake, energy expenditure, and glucose homeostasis. Importantly, MC4R deficiency is the most common monogenic cause of human obesity. Interestingly, MC4Rs expressed by distinct central nuclei are responsible for the different physiological function of MC4R stimulation. In addition, MC4Rs activate multiple intracellular and/or synaptic signaling molecules for the regulation of neuronal circuits. Therefore, MC4Rs and the downstream signal molecules are plausible targets for development of novel therapeutics against obesity and obesity-related metabolic disorders. In this review, we discuss recent findings on the neuronal circuits and signaling molecules that are responsible for MC4R control energy balance and autonomic function. Further, we review status of MC4R agonists as novel therapeutics for obesity syndrome. We believe that comprehensive understanding of signaling molecules involved in MC4R control of neuronal circuits will help to design MC4R agonists as safe and effective anti-obesity drugs.
      Graphical abstract image

      PubDate: 2018-01-15T23:43:03Z
      DOI: 10.1016/j.phrs.2018.01.004
       
  • Ischemia/reperfusion-associated tubular cells injury in renal
           transplantation: Can metabolomics inform about mechanisms and help
           identify new therapeutic targets'
    • Authors: Chantal Barin-Le Guellec; Bérenger Largeau; Delphine Bon; Pierre Marquet; Thierry Hauet
      Abstract: Publication date: Available online 6 January 2018
      Source:Pharmacological Research
      Author(s): Chantal Barin-Le Guellec, Bérenger Largeau, Delphine Bon, Pierre Marquet, Thierry Hauet
      Tubular cells are central targets of ischemia-reperfusion (I/R) injury in kidney transplantation. Inflammation and metabolic disturbances occurring within these cells are deleterious by themselves but also favor secondary events, such as activation of immune response. It is critical to have an in depth understanding of the mechanisms governing tubular cells response to I/R if one wants to define pertinent biomarkers or to elaborate targeted therapeutic interventions. As oxidative damage was shown to be central in the patho-physiological mechanisms, the impact of I/R on proximal tubular cells metabolism has been widely studied, contrary to its effects on expression and activity of membrane transporters of the proximal tubular cells. Yet, temporal modulation of transporters over ischemia and reperfusion periods appears to play a central role, not only in the induction of cells injury but also in graft function recovery. Metabolomics in cell models or diverse biofluids has the potential to provide large pictures of biochemical consequences of I/R. Metabolomic studies conducted in experimental models of I/R or in transplanted patients indeed retrieved metabolites belonging to the pathways known to be particularly affected. Interestingly, they also revealed that metabolic disturbances and transporters activities are in very close mutual interplay. As well as helping to select diagnostic biomarkers, such analyses could also contribute to identify new pharmacological targets and to set up innovative nephroprotective strategies for the future. Even if various therapeutic approaches have been evaluated for a long time to prevent or treat I/R injuries, metabolomics has helped identifying new ones, those related to membrane transporters seeming to be of particular interest. However, considering the very complex and multifactorial effects of I/R in the context of kidney transplantation, all tracks must be followed if one wants to prevent or limit its deleterious consequences.
      Graphical abstract image

      PubDate: 2018-01-15T23:43:03Z
      DOI: 10.1016/j.phrs.2017.12.032
       
 
 
JournalTOCs
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Email: journaltocs@hw.ac.uk
Tel: +00 44 (0)131 4513762
Fax: +00 44 (0)131 4513327
 
Home (Search)
Subjects A-Z
Publishers A-Z
Customise
APIs
Your IP address: 54.80.123.20
 
About JournalTOCs
API
Help
News (blog, publications)
JournalTOCs on Twitter   JournalTOCs on Facebook

JournalTOCs © 2009-