for Journals by Title or ISSN
for Articles by Keywords
help

Publisher: Elsevier   (Total: 3030 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  [3030 journals]
  • Differential activation of pregnane X receptor by carnosic acid, carnosol,
           ursolic acid, and rosmarinic acid
    • Authors: Chun Ling Seow; Aik Jiang Lau
      Abstract: Publication date: June 2017
      Source:Pharmacological Research, Volume 120
      Author(s): Chun Ling Seow, Aik Jiang Lau
      Pregnane X receptor (PXR) regulates the expression of many genes, including those involved in drug metabolism and transport, and has been linked to various diseases, including inflammatory bowel disease. In the present study, we determined whether carnosic acid and other chemicals in rosemary extract (carnosol, ursolic acid, and rosmarinic acid) are PXR activators. As assessed in dual-luciferase reporter gene assays, carnosic acid, carnosol, and ursolic acid, but not rosmarinic acid, activated human PXR (hPXR) and mouse PXR (mPXR), whereas carnosol and ursolic acid, but not carnosic acid or rosmarinic acid, activated rat PXR (rPXR). Dose-response experiments indicated that carnosic acid, carnosol, and ursolic acid activated hPXR with EC50 values of 0.79, 2.22, and 10.77μM, respectively. Carnosic acid, carnosol, and ursolic acid, but not rosmarinic acid, transactivated the ligand-binding domain of hPXR and recruited steroid receptor coactivator-1 (SRC-1), SRC-2, and SRC-3 to the ligand-binding domain of hPXR. Carnosic acid, carnosol, and ursolic acid, but not rosmarinic acid, increased hPXR target gene expression, as shown by an increase in CYP3A4, UGT1A3, and ABCB1 mRNA expression in LS180 human colon adenocarcinoma cells. Rosmarinic acid did not attenuate the extent of hPXR activation by rifampicin, suggesting it is not an antagonist of hPXR. Overall, carnosic acid, carnosol, and ursolic acid, but not rosmarinic acid, are hPXR agonists, and carnosic acid shows species-dependent activation of hPXR and mPXR, but not rPXR. The findings provide new mechanistic insight on the effects of carnosic acid, carnosol, and ursolic acid on PXR-mediated biological effects.
      Graphical abstract image

      PubDate: 2017-03-29T09:27:06Z
      DOI: 10.1016/j.dmpk.2016.10.373
      Issue No: Vol. 32, No. 1 (2017)
       
  • Short- and long-term effects of risperidone on catalepsy sensitisation and
           acquisition of conditioned avoidance response: Adolescent vs adult rats
    • Authors: Aung Aung Kywe Moe; Gregory A. Medely; Timothy Reeks; Thomas H.J. Burne; Darryl W. Eyles
      Pages: 1 - 13
      Abstract: Publication date: July 2017
      Source:Pharmacological Research, Volume 121
      Author(s): Aung Aung Kywe Moe, Gregory A. Medely, Timothy Reeks, Thomas H.J. Burne, Darryl W. Eyles
      The effects of antipsychotic drugs (APDs) on the adolescent brain are poorly understood despite a dramatic increase in prescription of these drugs in adolescents over the past twenty years. Neuronal systems continue to be remodeled during adolescence. Therefore, when given in adolescence, antipsychotic drugs (APDs) have the potential to affect this remodeling. In this study we investigated the effects of chronic 22-day risperidone treatment (1.3mg/kg/day) in both adolescent and adult rats. We examined short- and long-term changes in behaviour (catalepsy, locomotion and conditioned avoidance response (CAR)), and dopaminergic and serotonergic neurochemistry in the striatum and the nucleus accumbens. Here, we report that, both during chronic treatment and after a lengthy drug-free interval, risperidone induced a sensitised cataleptic response regardless of the age of exposure. Selectively in adolescents, risperidone-induced catalepsy was inversely correlated with striatal dopamine turnover immediately after chronic treatment. After a drug-free interval, a significant proportion of rats with prior adolescent risperidone treatment also failed to acquire CAR to a defined criterion. Our data provide evidence that the same chronic risperidone treatment regimen can induce contrasting short- and long-term neural outcomes in the adolescent and adult brains.
      Graphical abstract image

      PubDate: 2017-04-26T11:43:45Z
      DOI: 10.1016/j.phrs.2017.04.013
      Issue No: Vol. 121 (2017)
       
  • Toll-like receptor activation, vascular endothelial function, and
           hypertensive disorders of pregnancy
    • Authors: Dakshnapriya Balasubbramanian; Catalina A. Lopez Gelston; Brett M. Mitchell; Piyali Chatterjee
      Pages: 14 - 21
      Abstract: Publication date: July 2017
      Source:Pharmacological Research, Volume 121
      Author(s): Dakshnapriya Balasubbramanian, Catalina A. Lopez Gelston, Brett M. Mitchell, Piyali Chatterjee
      Aberrant innate immune system activation in the mother contributes greatly to the development of hypertension during pregnancy. Numerous groups have elicited vascular inflammation, endothelial dysfunction, and hypertension in animals during gestation by directly activating Toll-like receptors. Additionally, several experimental therapies that reduce pro-inflammatory immune cells and cytokines restore vascular endothelial function and normalize blood pressure. This review will summarize the research demonstrating that an excessive maternal innate immune response is sufficient to cause vascular inflammation and endothelial dysfunction, which contributes to the development of hypertension during pregnancy. Dampening the vascular inflammation caused by immune responses may reduce the incidence and severity of hypertensive disorders of pregnancy.
      Graphical abstract image

      PubDate: 2017-04-26T11:43:45Z
      DOI: 10.1016/j.phrs.2017.04.018
      Issue No: Vol. 121 (2017)
       
  • Cycloastragenol improves hepatic steatosis by activating farnesoid X
           receptor signalling
    • Authors: Ming Gu; Shiying Zhang; Yuanyuan Zhao; Jinwen Huang; Yahui Wang; Yin Li; Shengjie Fan; Li Yang; Guang Ji; Qingchun Tong; Cheng Huang
      Pages: 22 - 32
      Abstract: Publication date: July 2017
      Source:Pharmacological Research, Volume 121
      Author(s): Ming Gu, Shiying Zhang, Yuanyuan Zhao, Jinwen Huang, Yahui Wang, Yin Li, Shengjie Fan, Li Yang, Guang Ji, Qingchun Tong, Cheng Huang
      Non-alcoholic fatty liver disease (NAFLD) has become a global health problem. However, there is no approved therapy for NAFLD. Farnesoid X receptor (FXR) is a potential drug target for treatment of NAFLD. In an attempt to screen FXR agonists, we found that cycloastragenol (CAG), a natural occurring compound in Astragali Radix, stimulated FXR transcription activity. In animal studies, we demonstrated that CAG treatment resulted in obvious reduction of high-fat diet induced lipid accumulation in liver accompanied by lowered blood glucose, serum triglyceride levels and hepatic bile acid pool size. The stimulation of FXR signalling by CAG treatment in DIO mice was confirmed via gene expression and western blot analysis. Molecular docking data further supported the interaction of CAG and FXR. In addition, CAG alleviated hepatic steatosis in methionine and choline deficient L-amino acid diet (MCD) induced non-alcoholic steatohepatitis (NASH) mice. Our data suggest that CAG ameliorates NAFLD via the enhancement of FXR signalling.
      Graphical abstract image

      PubDate: 2017-04-26T11:43:45Z
      DOI: 10.1016/j.phrs.2017.04.021
      Issue No: Vol. 121 (2017)
       
  • p300 and C/EBPβ-regulated IKKβ expression are involved in
           thrombin-induced IL-8/CXCL8 expression in human lung epithelial cells
    • Authors: Zheng-Wei Huang; Gi-Shih Lien; Chien-Huang Lin; Chun-Ping Jiang; Bing-Chang Chen
      Pages: 33 - 41
      Abstract: Publication date: July 2017
      Source:Pharmacological Research, Volume 121
      Author(s): Zheng-Wei Huang, Gi-Shih Lien, Chien-Huang Lin, Chun-Ping Jiang, Bing-Chang Chen
      Asthma and chronic obstructive pulmonary disease (COPD) are common chronic lung inflammatory diseases. Thrombin and interleukin (IL)-8/C-X-C chemokine ligand 8 (CXCL8) play critical roles in lung inflammation. Our previous study showed that c-Src-dependent IκB kinase (IKK)/IκBα/nuclear factor (NF)-κB and mitogen-activated protein kinase kinase kinase 1 (MEKK1)/extracellular signal-regulated kinase (ERK)/ribosomal S6 protein kinase (RSK)-dependent CAAT/enhancer-binding protein β (C/EBPβ) activation are involved in thrombin-induced IL-8/CXCL8 expression in human lung epithelial cells. In this study, we aimed to investigate the roles of p300 and C/EBPβ-reliant IKKβ expression in thrombin-induced IL-8/CXCL8 expression. Thrombin-induced increases in IL-8/CXCL8-luciferase activity and IL-8/CXCL8 release were inhibited by p300 small interfering (siRNA). Thrombin-caused histone H3 acetylation was attenuated by p300 siRNA. Stimulation of cells with thrombin for 12h resulted in increases in IKKβ expression and phosphorylation in human lung epithelial cells. However, thrombin did not affect p65 expression. Moreover, 12h of thrombin stimulation produced increases in IKKβ expression and phosphorylation, and IκBα phosphorylation, which were inhibited by C/EBPβ siRNA. Finally, treatment of cells with thrombin caused increases in p300 and C/EBPβ complex formation, p65 and C/EBPβ complex formation, and recruitment of p300, p65, and C/EBPβ to the IL-8/CXCL8 promoter. These results imply that p300-dependent histone H3 acetylation and C/EBPβ-regulated IKKβ expression contribute to thrombin-induced IL-8/CXCL8 expression in human lung epithelial cells. Results of this study will help clarify C/EBPβ signaling pathways involved in thrombin-induced IL-8/CXCL8 expression in human lung epithelial cells.
      Graphical abstract image

      PubDate: 2017-04-26T11:43:45Z
      DOI: 10.1016/j.phrs.2017.04.020
      Issue No: Vol. 121 (2017)
       
  • Mechanistic and pharmacologic insights on immune checkpoint inhibitors
    • Authors: Randy F. Sweis; Jason J. Luke
      Pages: 1 - 9
      Abstract: Publication date: June 2017
      Source:Pharmacological Research, Volume 120
      Author(s): Randy F. Sweis, Jason J. Luke
      The concept of augmenting the immune system to eradicate cancer dates back at least a century. A major resurgence in cancer immunotherapy has occurred over the past decade since the identification and targeting of negative regulators with antibody therapies to augment the anti-tumor immune response. Unprecedented responses across a broad array of cancer types elevated this class of therapies to the forefront of cancer treatment. The most successful drugs to date target the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) pathways. The immune biology of these pathways was illuminated through thoughtful pre-clinical experiments over the past 20 years. The characterization of these negative immune regulators, also known as immune checkpoints, subsequently led to the successful clinical development four drugs in six different cancer types to date, and progress continues. Despite these successes, significant challenges remain including the development of predictive biomarkers, recognition and management of immune related toxicities, and elucidating and reversing mechanisms of primary and secondary resistance. Ongoing work is expected to build upon recent accomplishments and allow more patients to benefit from this class of therapies.
      Graphical abstract image

      PubDate: 2017-03-29T09:27:06Z
      DOI: 10.1016/j.phrs.2017.03.012
      Issue No: Vol. 120 (2017)
       
  • Vinpocetine reduces diclofenac-induced acute kidney injury through
           inhibition of oxidative stress, apoptosis, cytokine production, and NF-κB
           activation in mice
    • Authors: Victor Fattori; Sergio M. Borghi; Carla F.S. Guazelli; Andressa C. Giroldo; Jefferson Crespigio; Allan J.C. Bussmann; Letícia Coelho-Silva; Natasha G. Ludwig; Tânia L. Mazzuco; Rubia Casagrande; Waldiceu A. Verri
      Pages: 10 - 22
      Abstract: Publication date: June 2017
      Source:Pharmacological Research, Volume 120
      Author(s): Victor Fattori, Sergio M. Borghi, Carla F.S. Guazelli, Andressa C. Giroldo, Jefferson Crespigio, Allan J.C. Bussmann, Letícia Coelho-Silva, Natasha G. Ludwig, Tânia L. Mazzuco, Rubia Casagrande, Waldiceu A. Verri
      Acute kidney injury (AKI) represents a complex clinical condition associated with significant morbidity and mortality. Approximately, 19–33% AKI episodes in hospitalized patients are related to drug-induced nephrotoxicity. Although, considered safe, non-steroidal anti-inflammatory drugs such as diclofenac have received special attention in the past years due to the potential risk of renal damage. Vinpocetine is a nootropic drug known to have anti-inflammatory properties. In this study, we investigated the effect and mechanisms of vinpocetine in a model of diclofenac-induced AKI. We observed that diclofenac increased proteinuria and blood urea, creatinine, and oxidative stress levels 24h after its administration. In renal tissue, diclofenac also increased oxidative stress and induced morphological changes consistent with renal damage. Moreover, diclofenac induced kidney cells apoptosis, up-regulated proinflammatory cytokines, and induced the activation of NF-κB in renal tissue. On the other hand, vinpocetine reduced diclofenac-induced blood urea and creatinine. In the kidneys, vinpocetine inhibited diclofenac-induced oxidative stress, morphological changes, apoptosis, cytokine production, and NF-κB activation. To our knowledge, this is the first study demonstrating that diclofenac-induced AKI increases NF-κB activation, and that vinpocetine reduces the nephrotoxic effects of diclofenac. Therefore, vinpocetine is a promising molecule for the treatment of diclofenac-induced AKI.
      Graphical abstract image

      PubDate: 2017-03-29T09:27:06Z
      DOI: 10.1016/j.phrs.2016.12.039
      Issue No: Vol. 120 (2017)
       
  • Sex- and gender-related prevalence, cardiovascular risk and therapeutic
           approach in metabolic syndrome: A review of the literature
    • Authors: Giacomo Pucci; Riccardo Alcidi; Lisanne Tap; Francesca Battista; Francesco Mattace-Raso; Giuseppe Schillaci
      Pages: 34 - 42
      Abstract: Publication date: June 2017
      Source:Pharmacological Research, Volume 120
      Author(s): Giacomo Pucci, Riccardo Alcidi, Lisanne Tap, Francesca Battista, Francesco Mattace-Raso, Giuseppe Schillaci
      Metabolic syndrome (MS), a cluster of metabolic abnormalities linked to insulin-resistance and abdominal obesity, is associated with an increased risk of Type II diabetes mellitus (DM) and cardiovascular (CV) disease. Its prevalence is high, affecting 20%–30% of the general population, and increases with age in a sex-specific manner: in fact, while below 50 years it is slightly higher in men, it reverses after 50 years. The pronounced age-related increase in the prevalence of MS in women occurs as the result of several factors, which may be classified into sex- and gender-related factors. Sex-related factors, linked to genetical and biological pathways, are mainly driven by hyperandrogenism, insulin-resistance, and the associated increase in abdominal obesity and HDL-cholesterol reduction occurring after menopause. Gender-related factors are sensitive to social and cultural behaviors, dietary habits and psychosocial factors. Women are more prone than men to develop MS in response to work stress and low socio-economic status. Sex and gender differences in the prevalence of MS may translate in different CV risk associated. Prospective studies suggest that the CV risk in women with MS is not only equal but also superior to the CV risk of men with MS. This difference is mostly attenuated when adjusting for the presence of overt DM. Despite similar odds for CV events, the number of CV events may be higher in elderly women because of the higher prevalence of MS compared to men in this age group. Men and women may also have a differential response to treatments for MS, such as lifestyle measures and weight loss. Recent observations suggest that men are better responders than women to non-pharmaceutical therapeutic strategies aimed at reducing the prevalence of MS, although this should be confirmed in large-scale studies. The present review describes the impact of sex and gender on the prevalence, clinical presentation, prognostic significance and treatment of the MS. Attention to gender specificities should be a mandatory pre-requisite of clinical and epidemiological research on MS and CV disease, for a better knowledge and development of health strategies.
      Graphical abstract image

      PubDate: 2017-03-29T09:27:06Z
      DOI: 10.1016/j.phrs.2017.03.008
      Issue No: Vol. 120 (2017)
       
  • Breast cancer resistance protein (BCRP/ABCG2) and P-glycoprotein
           (P-gp/ABCB1) transport afatinib and restrict its oral availability and
           brain accumulation
    • Authors: Stéphanie van Hoppe; Rolf W. Sparidans; Els Wagenaar; Jos H. Beijnen; Alfred H. Schinkel
      Pages: 43 - 50
      Abstract: Publication date: June 2017
      Source:Pharmacological Research, Volume 120
      Author(s): Stéphanie van Hoppe, Rolf W. Sparidans, Els Wagenaar, Jos H. Beijnen, Alfred H. Schinkel
      Afatinib is a highly selective, irreversible inhibitor of EGFR and HER-2. It is orally administered for the treatment of patients with EGFR mutation-positive types of metastatic NSCLC. We investigated whether afatinib is a substrate for the multidrug efflux transporters ABCB1 and ABCG2 and whether these transporters influence oral availability and brain and other tissue accumulation of afatinib. We used in vitro transport assays to assess human (h)ABCB1-, hABCG2- or murine (m)Abcg2-mediated transport of afatinib. To study the single and combined roles of Abcg2 and Abcb1a/1b in oral afatinib disposition, we used appropriate knockout mouse strains. Afatinib was transported well by hABCB1, hABCG2 and mAbcg2 in vitro. Upon oral administration of afatinib, Abcg2−/−, Abcb1a/1b−/− and Abcb1a/1b−/−;Abcg2−/− mice displayed a 4.2-, 2.4- and 7-fold increased afatinib plasma AUC0-24 compared with wild-type mice. Abcg2-deficient strains also displayed decreased afatinib plasma clearance. At 2h, relative brain accumulation of afatinib was not significantly altered in the single knockout strains, but 23.8-fold increased in Abcb1a/1b−/−;Abcg2−/− mice compared to wild-type mice. Abcg2 and Abcb1a/1b restrict oral availability and brain accumulation of afatinib. Inhibition of these transporters may therefore be of clinical importance for patients with brain (micro)metastases positioned behind an intact blood-brain barrier.
      Graphical abstract image

      PubDate: 2017-03-29T09:27:06Z
      DOI: 10.1016/j.phrs.2017.01.035
      Issue No: Vol. 120 (2017)
       
  • Purinergic P2Y6 receptors: A new therapeutic target of age-dependent
           hypertension
    • Authors: Caroline Sunggip; Akiyuki Nishimura; Kakeru Shimoda; Takuro Numaga-Tomita; Makoto Tsuda; Motohiro Nishida
      Pages: 51 - 59
      Abstract: Publication date: June 2017
      Source:Pharmacological Research, Volume 120
      Author(s): Caroline Sunggip, Akiyuki Nishimura, Kakeru Shimoda, Takuro Numaga-Tomita, Makoto Tsuda, Motohiro Nishida
      Aging has a remarkable effect on cardiovascular homeostasis and it is known as the major non-modifiable risk factor in the development of hypertension. Medications targeting sympathetic nerve system and/or renin-angiotensin-aldosterone system are widely accepted as a powerful therapeutic strategy to improve hypertension, although the control rates remain unsatisfactory especially in the elder patients with hypertension. Purinergic receptors, activated by adenine, uridine nucleotides and nucleotide sugars, play pivotal roles in many biological processes, including platelet aggregation, neurotransmission and hormone release, and regulation of cardiovascular contractility. Since clopidogrel, a selective inhibitor of G protein-coupled purinergic P2Y12 receptor (P2Y12R), achieved clinical success as an anti-platelet drug, P2YRs has been attracted more attention as new therapeutic targets of cardiovascular diseases. We have revealed that UDP-responsive P2Y6R promoted angiotensin type 1 receptor (AT1R)-stimulated vascular remodeling in mice, in an age-dependent manner. Moreover, the age-related formation of heterodimer between AT1R and P2Y6R was disrupted by MRS2578, a P2Y6R-selective inhibitor. These findings suggest that P2Y6R is a therapeutic target to prevent age-related hypertension.
      Graphical abstract image

      PubDate: 2017-03-29T09:27:06Z
      DOI: 10.1016/j.phrs.2017.03.013
      Issue No: Vol. 120 (2017)
       
  • Methamphetamine: Effects on the brain, gut and immune system
    • Authors: Monica D. Prakash; Kathy Tangalakis; Juliana Antonipillai; Lily Stojanovska; Kulmira Nurgali; Vasso Apostolopoulos
      Pages: 60 - 67
      Abstract: Publication date: June 2017
      Source:Pharmacological Research, Volume 120
      Author(s): Monica D. Prakash, Kathy Tangalakis, Juliana Antonipillai, Lily Stojanovska, Kulmira Nurgali, Vasso Apostolopoulos
      Methamphetamine (METH) is a powerful central nervous system stimulant which elevates mood, alertness, energy levels and concentration in the short-term. However, chronic use and/or at higher doses METH use often results in psychosis, depression, delusions and violent behavior. METH was formerly used to treat conditions such as obesity and attention deficit hyperactivity disorder, but now is primarily used recreationally. Its addictive nature has led to METH abuse becoming a global problem. At a cellular level, METH exerts a myriad of effects on the central and peripheral nervous systems, immune system and the gastrointestinal system. Here we present how these effects might be linked and their potential contribution to the pathogenesis of neuropsychiatric disorders. In the long term, this pathway could be targeted therapeutically to protect people from the ill effects of METH use. This model of METH use may also provide insight into how gut, nervous and immune systems might break down in other conditions that may also benefit from therapeutic intervention.
      Graphical abstract image

      PubDate: 2017-03-29T09:27:06Z
      DOI: 10.1016/j.phrs.2017.03.009
      Issue No: Vol. 120 (2017)
       
  • Nanotechnological strategies for nerve growth factor delivery: Therapeutic
           implications in Alzheimer’s disease
    • Authors: Célia Faustino; Patrícia Rijo; Catarina Pinto Reis
      Pages: 68 - 87
      Abstract: Publication date: June 2017
      Source:Pharmacological Research, Volume 120
      Author(s): Célia Faustino, Patrícia Rijo, Catarina Pinto Reis
      Alzheimer’s disease (AD) is a progressive neurodegenerative disorder associated with amyloid-β peptide misfolding and aggregation. Neurotrophic factors, such as nerve growth factor (NGF), can prevent neuronal damage and rescue the cholinergic neurons that undergo cell death in AD, reverse deposition of extracellular amyloid plaques and improve cognitive deficits. However, NGF administration is hampered by the poor pharmacokinetic profile of the therapeutic protein and its inability to cross the blood-brain barrier, which requires specialised drug delivery systems (DDS) for efficient NGF delivery to the brain. This review covers the main therapeutic approaches that have been developed for NGF delivery targeting the brain, from polymeric implants to gene and cell-based therapies, focusing on the role of nanoparticulate systems for the sustained release of NGF in the brain as a neuroprotective and disease-modifying approach toward AD. Lipid- and polymer-based delivery systems, magnetic nanoparticles and quantum dots are specifically addressed as promising nanotechnological strategies to overcome the current limitations of NGF-based therapies.
      Graphical abstract image

      PubDate: 2017-04-05T09:54:22Z
      DOI: 10.1016/j.phrs.2017.03.020
      Issue No: Vol. 120 (2017)
       
  • The interplay between Angiotensin II, TLR4 and hypertension
    • Authors: Vinicia Campana Biancardi; Gisele Facholi Bomfim; Wagner Luis Reis; Sarah Al-Gassimi; Kenia Pedrosa Nunes
      Pages: 88 - 96
      Abstract: Publication date: June 2017
      Source:Pharmacological Research, Volume 120
      Author(s): Vinicia Campana Biancardi, Gisele Facholi Bomfim, Wagner Luis Reis, Sarah Al-Gassimi, Kenia Pedrosa Nunes
      Hypertension is a multifactorial disease. Although a number of different underlying mechanisms have been learned from the various experimental models of the disease, hypertension still poses challenges for treatment. Angiotensin II plays an unquestionable role in blood pressure regulation acting through central and peripheral mechanisms. During hypertension, dysregulation of the Renin-Angiotensin System is associated with increased expression of pro-inflammatory cytokines and reactive oxygen species causing kidney damage, endothelial dysfunction, and increase in sympathetic activity, among other damages, eventually leading to decline in organ function. Recent studies have shown that these effects involve both the innate and the adaptive immune response. The contribution of adaptive immune responses involving different lymphocyte populations in various models of hypertension has been extensively studied. However, the involvement of the innate immunity mediating inflammation in hypertension is still not well understood. The innate and adaptive immune systems intimately interact with one another and are essential to an effectively functioning of the immune response; hence, the importance of a better understanding of the underlying mechanisms mediating innate immune system during hypertension. In this review, we aim to discuss mechanisms linking Angiotensin II and the innate immune system, in the pathogenesis of hypertension. The newest research investigating Angiotensin II triggering toll like receptor 4 activation in the kidney, vasculature and central nervous system contributing to hypertension will be discussed. Understanding the role of the innate immune system in the development of hypertension may bring to light new insights necessary to improve hypertension management.
      Graphical abstract image

      PubDate: 2017-04-05T09:54:22Z
      DOI: 10.1016/j.phrs.2017.03.017
      Issue No: Vol. 120 (2017)
       
  • Gender differences in liver disease and the drug-dose gender gap
    • Authors: Elena Buzzetti; Pathik M. Parikh; Alessio Gerussi; Emmanuel Tsochatzis
      Pages: 97 - 108
      Abstract: Publication date: June 2017
      Source:Pharmacological Research, Volume 120
      Author(s): Elena Buzzetti, Pathik M. Parikh, Alessio Gerussi, Emmanuel Tsochatzis
      Although gender-based medicine is a relatively recent concept, it is now emerging as an important field of research, supported by the finding that many diseases manifest differently in men and women and therefore, might require a different treatment. Sex-related differences regarding the epidemiology, progression and treatment strategies of certain liver diseases have long been known, but most of the epidemiological and clinical trials still report results only about one sex, with consequent different rate of response and adverse reactions to treatment between men and women in clinical practice. This review reports the data found in the literature concerning the gender-related differences for the most representative hepatic diseases.
      Graphical abstract image

      PubDate: 2017-04-05T09:54:22Z
      DOI: 10.1016/j.phrs.2017.03.014
      Issue No: Vol. 120 (2017)
       
  • Novel adaptive and innate immunity targets in hypertension
    • Authors: Justine M. Abais-Battad; John Henry Dasinger; Daniel J. Fehrenbach; David L. Mattson
      Pages: 109 - 115
      Abstract: Publication date: June 2017
      Source:Pharmacological Research, Volume 120
      Author(s): Justine M. Abais-Battad, John Henry Dasinger, Daniel J. Fehrenbach, David L. Mattson
      Hypertension is a worldwide epidemic and global health concern as it is a major risk factor for the development of cardiovascular diseases. A relationship between the immune system and its contributing role to the pathogenesis of hypertension has been long established, but substantial advancements within the last few years have dissected specific causal molecular mechanisms. This review will briefly examine these recent studies exploring the involvement of either innate or adaptive immunity pathways. Such pathways to be discussed include innate immunity factors such as antigen presenting cells and pattern recognition receptors, adaptive immune elements including T and B lymphocytes, and more specifically, the emerging role of T regulatory cells, as well as the potential of cytokines and chemokines to serve as signaling messengers connecting innate and adaptive immunity. Together, we summarize these studies to provide new perspective for what will hopefully lead to more targeted approaches to manipulate the immune system as hypertensive therapy.
      Graphical abstract image

      PubDate: 2017-04-05T09:54:22Z
      DOI: 10.1016/j.phrs.2017.03.015
      Issue No: Vol. 120 (2017)
       
  • Vascular endothelial growth factor (VEGF) and VEGF receptor inhibitors in
           the treatment of renal cell carcinomas
    • Authors: Robert Roskoski
      Pages: 116 - 132
      Abstract: Publication date: June 2017
      Source:Pharmacological Research, Volume 120
      Author(s): Robert Roskoski
      One Von Hippel-Lindau (VHL) tumor suppressor gene is lost in most renal cell carcinomas while the nondeleted allele exhibits hypermethylation-induced inactivation or inactivating somatic mutations. As a result of these genetic modifications, there is an increased production of VEGF-A and pro-angiogenic growth factors in this disorder. The important role of angiogenesis in the pathogenesis of renal cell carcinomas and other tumors has focused the attention of investigators on the biology of VEGFs and VEGFR1–3 and to the development of inhibitors of the intricate and multifaceted angiogenic pathways. VEGFR1–3 contain an extracellular segment with seven immunoglobulin-like domains, a transmembrane segment, a juxtamembrane segment, a protein kinase domain with an insert of about 70 amino acid residues, and a C-terminal tail. VEGF-A stimulates the activation of preformed VEGFR2 dimers by the auto-phosphorylation of activation segment tyrosines followed by the phosphorylation of additional protein-tyrosines that recruit phosphotyrosine binding proteins thereby leading to signalling by the ERK1/2, AKT, Src, and p38 MAP kinase pathways. VEGFR1 modulates the activity of VEGFR2, which is the chief pathway in vasculogenesis and angiogenesis. VEGFR3 and its ligands (VEGF-C and VEGF-D) are involved primarily in lymphangiogenesis. Small molecule VEGFR1/2/3 inhibitors including axitinib, cabozantinib, lenvatinib, sorafenib, sunitinib, and pazopanib are approved by the FDA for the treatment of renal cell carcinomas. Most of these agents are type II inhibitors of VEGFR2 and inhibit the so-called DFG-Aspout inactive enzyme conformation. These drugs are steady-state competitive inhibitors with respect to ATP and like ATP they form hydrogen bonds with the hinge residues that connect the small and large protein kinase lobes. Bevacizumab, a monoclonal antibody that binds to VEGF-A, is also approved for the treatment of renal cell carcinomas. Resistance to these agents invariably occurs within one year of treatment and clinical studies are underway to determine the optimal sequence of treatment with these anti-angiogenic agents. The nivolumab immune checkpoint inhibitor is also approved for the second-line treatment of renal cell carcinomas. Owing to the resistance of renal cell carcinomas to cytotoxic drugs and radiation therapy, the development of these agents has greatly improved the therapeutic options in the treatment of these malignancies.
      Graphical abstract image

      PubDate: 2017-04-05T09:54:22Z
      DOI: 10.1016/j.phrs.2017.03.010
      Issue No: Vol. 120 (2017)
       
  • Identification of new SNPs associated with severe toxicity to capecitabine
    • Authors: Marta Pellicer; Xandra García-González; María I. García; Luis Robles; Cristina Grávalos; Pilar García-Alfonso; Vanessa Pachón; Federico Longo; Virginia Martínez; Carolina Blanco; Irene Iglesias; María Sanjurjo; Luis A. López-Fernández
      Pages: 133 - 137
      Abstract: Publication date: June 2017
      Source:Pharmacological Research, Volume 120
      Author(s): Marta Pellicer, Xandra García-González, María I. García, Luis Robles, Cristina Grávalos, Pilar García-Alfonso, Vanessa Pachón, Federico Longo, Virginia Martínez, Carolina Blanco, Irene Iglesias, María Sanjurjo, Luis A. López-Fernández
      Predicting individual risk of chemotherapy-induced severe adverse reaction is a critical issue when selecting the best treatment for cancer patients. SNPs have been identified in genes involved in the pharmacodynamics of fluoropyrimidines, and guidelines even recommend genotyping some DPYD variants in order to estimate the risk of toxicity. However, the predictive value of this approach remains insufficient, thus limiting its clinical implementation. The aim of the present study was to identify new genetic variants by selecting a group of tag SNPs in genes associated with the pharmacodynamics of fluoropyrimidines (CDA, DPYD, ENOSF1, CES1, TYMS, SLC22A7, TYMP, and UMPS). For this purpose, 23 selected SNPs were genotyped on an OpenArray™ platform in a cohort of 301 colorectal cancer patients receiving capecitabine-based chemotherapy. Univariate and multivariate statistical analysis by logistic regression revealed 10 SNPs associated with severe adverse reactions to capecitabine (P< 0.05): rs1048977, rs12726436, and rs2072671 in CDA; rs12119882 in DPYD; rs2853741 in TYMS; rs699517 in TYMS/ENOSF1; rs2270860 and rs4149178 in SLC22A7; and rs2279199 and rs4678145 in UMPS. Except for rs2072671, no association had previously been reported between these SNPs and the risk of capecitabine-induced toxicity. The use of tag SNPs to find new polymorphisms related to adverse reactions to capecitabine was successful. These new variants could increase the predictive power of currently available tests and thus prevent severe adverse reactions to capecitabine.
      Graphical abstract image

      PubDate: 2017-04-05T09:54:22Z
      DOI: 10.1016/j.phrs.2017.03.021
      Issue No: Vol. 120 (2017)
       
  • Influence of MDR1 and CYP3A5 genetic polymorphisms on trough levels and
           therapeutic response of imatinib in newly diagnosed patients with chronic
           myeloid leukemia
    • Authors: Natarajan Harivenkatesh; Lalit Kumar; Sameer Bakhshi; Atul Sharma; Madhulika Kabra; Thirumurthy Velpandian; Ajay Gogia; Shivaram S. Shastri; Nihar Ranjan Biswas; Yogendra Kumar Gupta
      Pages: 138 - 145
      Abstract: Publication date: June 2017
      Source:Pharmacological Research, Volume 120
      Author(s): Natarajan Harivenkatesh, Lalit Kumar, Sameer Bakhshi, Atul Sharma, Madhulika Kabra, Thirumurthy Velpandian, Ajay Gogia, Shivaram S. Shastri, Nihar Ranjan Biswas, Yogendra Kumar Gupta
      Polymorphisms in genes coding for imatinib transporters and metabolizing enzymes may affect imatinib pharmacokinetics and clinical response. Aim of this study was to assess the influence of polymorphisms in MDR1 and CYP3A5 genes on imatinib trough levels, cytogenetic and molecular response in patients with CML. Newly diagnosed patients with chronic-phase CML started on imatinib therapy were enrolled and followed up prospectively for 24 months. The following single nucleotide polymorphisms were genotyped; C1236T, C3435T, G2677T/A in MDR1 gene and A6986G in CYP3A5 gene. Genotyping was done using PCR-RFLP method and validated by direct gene sequencing. Trough levels of imatinib were measured using LC–MS/MS. Cytogenetic response was assessed by conventional bone-marrow cytogenetics. Molecular response was assessed by qRTPCR using international scale. A total of 173 patients were included, out of which 71 patients were imatinib responders, while 102 were non-responders. Marked inter-individual variability in trough levels of imatinib was seen. Patients with GG genotype for CYP3A5-A6986G (P =0.016) and TT genotype for MDR1-C3435T (P =0.013) polymorphisms had significantly higher trough levels of imatinib. Patients with AA genotype for CYP3A5-A6986G [RR=1.448, 95% CI (1.126, 1.860), P =0.029] and CC genotype for MDR1-C1236T [RR=1.397, 95% CI (1.066, 1.831), P =0.06] & MDR1-C3435T [RR=1.508, 95% CI (1.186, 1.917), P =0.018] polymorphisms were at high risk for failure of imatinib therapy. Patients with CGC haplotype for MDR1 polymorphisms had significantly lower imatinib trough levels and were at a higher risk of imatinib failure [RR=1.547, 95% CI (1.324, 1.808), P< 0.001]. GG vs. non-GG genotype for CYP3A5-A6986G [adjusted OR: 0.246; 95% CI (0.116, 0.519); P< 0.001] and TT vs. non-TT genotype for MDR1-C1236T [adjusted OR: 0.270; 95% CI (0.110, 0.659); P =0.004] & MDR1-C3435T [adjusted OR: 0.289; 95% CI (0.135, 0.615); P =0.001] polymorphisms were independent factors predicting imatinib response in multivariate analysis. To conclude, MDR1 and CYP3A5 genetic polymorphisms significantly influence plasma trough levels and therapeutic response of imatinib in patients with CML. Genotyping of these polymorphisms could be of value to individualize the therapy and optimize the clinical outcomes.
      Graphical abstract image

      PubDate: 2017-04-05T09:54:22Z
      DOI: 10.1016/j.phrs.2017.03.011
      Issue No: Vol. 120 (2017)
       
  • Lipocalin-2 and iron trafficking in the tumor microenvironment
    • Authors: Michaela Jung; Christina Mertens; Rebekka Bauer; Claudia Rehwald; Bernhard Brüne
      Pages: 146 - 156
      Abstract: Publication date: June 2017
      Source:Pharmacological Research, Volume 120
      Author(s): Michaela Jung, Christina Mertens, Rebekka Bauer, Claudia Rehwald, Bernhard Brüne
      Iron is an essential element for virtually all organisms. It facilitates cell proliferation and growth but also contributes to major hallmarks of cancer such as tumor initiation, growth, and metastasis. Often, iron handling of tumor cells is disturbed, with altered iron acquisition, efflux, and storage. Targeting perturbed iron metabolic pathways might open opportunities towards novel approaches in cancer treatment. It is becoming clear that cells of the tumor microenvironment such as macrophages contribute to tumor progression. Since macrophages evolved a multitude of mechanisms to sequester, transport, store, and release iron it can be speculated that tumor cells educate them to supply iron to support tumor growth. Recent evidence supports the existence of transferrin-independent iron transport mechanisms in the tumor microenvironment, which points to local iron transport proteins such as lipocalin-2 and/or low molecular weight iron-trafficking substances such as siderophores. We hypothesize that tumor cells educate immune cells, i.e. macrophages in their neighborhood to make them delivering iron for the benefit of cancer progression. In particular, we pay attention to recent developments, pointing to lipocalin-2 and siderophores as alternative iron transport molecules in the tumor microenvironment.
      Graphical abstract image

      PubDate: 2017-04-12T10:14:08Z
      DOI: 10.1016/j.phrs.2017.03.018
      Issue No: Vol. 120 (2017)
       
  • Regulation of PCSK9 by nutraceuticals
    • Authors: Amir Abbas Momtazi; Maciej Banach; Matteo Pirro; Niki Katsiki; Amirhossein Sahebkar
      Pages: 157 - 169
      Abstract: Publication date: June 2017
      Source:Pharmacological Research, Volume 120
      Author(s): Amir Abbas Momtazi, Maciej Banach, Matteo Pirro, Niki Katsiki, Amirhossein Sahebkar
      PCSK9 (proprotein convertase subtilisin kexin type 9) is a liver secretory enzyme that regulates plasma low-density lipoprotein (LDL) cholesterol (LDL-C) levels through modulation of LDL receptor (LDLR) density on the surface of hepatocytes. Inhibition of PCSK9 using monoclonal antibodies can efficiently lower plasma LDL-C, non-high-density lipoprotein cholesterol and lipoprotein (a). PCSK9 inhibition is also an effective adjunct to statin therapy; however, the cost-effectiveness of currently available PCSK9 inhibitors is under question. Nutraceuticals offer a safe and cost-effective option for PCSK9 inhibition. Several nutraceuticals have been reported to modulate PCSK9 levels and exert LDL-lowering activity. Mechanistically, those nutraceuticals that inhibit PCSK9 through a SREBP (sterol-responsive element binding protein)-independent pathway can be more effective in lowering plasma LDL-C levels compared with those inhibiting PCSK9 through the SREBP pathway. The present review aims to collect available data on the nutraceuticals with PCSK9-inhibitory effect and the underlying mechanisms.
      Graphical abstract image

      PubDate: 2017-04-12T10:14:08Z
      DOI: 10.1016/j.phrs.2017.03.023
      Issue No: Vol. 120 (2017)
       
  • Hidden targets of ubiquitin proteasome system: To prevent diabetic
           nephropathy
    • Authors: Santosh Kumar Goru; Almesh Kadakol; Anil Bhanudas Gaikwad
      Pages: 170 - 179
      Abstract: Publication date: June 2017
      Source:Pharmacological Research, Volume 120
      Author(s): Santosh Kumar Goru, Almesh Kadakol, Anil Bhanudas Gaikwad
      Diabetic nephropathy (DN) is the major cause of end stage renal failure. Although, several therapeutic targets have emerged to prevent the progression of DN, the number of people with DN still continues to rise worldwide, suggesting an urgent need of novel targets to prevent DN completely. Currently, the role of ubiquitin proteasome system (UPS) has been highlighted in the pathogenesis and progression of various diseases like obesity, insulin resistance, atherosclerosis, cancers, neurodegerative disorders and including secondary complications of diabetes. UPS mainly involves in protein homeostatis through ubiquitination (post translational modification) and proteasomal degradation of various proteins. Ubiquitination, not only involves in proteasomal degradation, but also directs the substrate proteins to participate in multitude of cell signalling pathways. However, very little is known about ubiquitination and UPS in the progression of DN. This review mainly focuses on UPS and its components including E2 conjugating enzymes, E3 ligases and deubiquitinases (DUBs) in the development of DN and thus may help us to find novel therapeutic targets with in UPS to prevent DN completely in future.
      Graphical abstract image

      PubDate: 2017-04-12T10:14:08Z
      DOI: 10.1016/j.phrs.2017.03.024
      Issue No: Vol. 120 (2017)
       
  • Role of spliceosome proteins in the regulation of glucocorticoid receptor
           isoforms by cortisol and dehydroepiandrosterone
    • Authors: Erica Buoso; Marilisa Galasso; Melania Ronfani; Melania Maria Serafini; Cristina Lanni; Emanuela Corsini; Marco Racchi
      Pages: 180 - 187
      Abstract: Publication date: June 2017
      Source:Pharmacological Research, Volume 120
      Author(s): Erica Buoso, Marilisa Galasso, Melania Ronfani, Melania Maria Serafini, Cristina Lanni, Emanuela Corsini, Marco Racchi
      Dehydroepiandrosterone (DHEA) can counteract the activity of cortisol by modulating the glucocorticoid receptor β (GRβ) expression and antagonizing the binding of GRα to the glucocorticoid responsive element (GRE) in RACK1 (Receptor for Activated C Kinase 1) promoter. These observations are important in the context of immunosenescence and can be extended to recognize a complex hormonal balance in the control of GR isoform expression and consequently in the expression of GR responsive genes. To elucidate the mechanism of DHEA on GR alternative splicing, we investigated its possible involvement in the expression of proteins such as the Serine/arginine (SR)-Rich Splicing Factors (SRSF) regulating GR splicing, specifically SRSF9 and SRSF3 also known as SRp30c and SRp20 respectively. We demonstrated that DHEA can induce the up-regulation of GR mRNA which is preferentially directed toward the β isoform. The effect is due to an increase in expression of the splicing factor SRSF9. On the other hand cortisol up-regulated SRSF3, the splicing factor promoting GRα isoform. We demonstrated that DHEA and cortisol modulate SRSF9 and SRSF3 in a different way and our data suggest that the anti-glucocorticoid effect of DHEA, among other mechanisms, is also exerted by modulating the expression of proteins involved in the splicing of the GR pre-mRNA.
      Graphical abstract image

      PubDate: 2017-04-12T10:14:08Z
      DOI: 10.1016/j.phrs.2017.03.019
      Issue No: Vol. 120 (2017)
       
  • Emerging therapeutic uses of direct-acting oral anticoagulants: An
           evidence-based perspective
    • Authors: Emanuel Raschi; Matteo Bianchin; Roberto De Ponti; Fabrizio De Ponti; Walter Ageno
      Pages: 206 - 218
      Abstract: Publication date: June 2017
      Source:Pharmacological Research, Volume 120
      Author(s): Emanuel Raschi, Matteo Bianchin, Roberto De Ponti, Fabrizio De Ponti, Walter Ageno
      Direct-acting oral anticoagulants (DOACs) were claimed to cause a potential paradigm shift in the therapeutic scenario of patients requiring short- and long-term anticoagulation, by virtue of their pharmacological properties, perceived as innovative. The evidence gathered so far (from pre-approval pivotal trials to real-world post-marketing observational data) consistently confirmed that DOACs are overall comparable to vitamin-K antagonists (VKAs) in terms of safety, efficacy and effectiveness and unequivocally documented a consistent and clinically relevant reduced risk of intracranial bleeding in the settings of non-valvular atrial fibrillation (NVAF) and venous thromboembolism (VTE). Interestingly, two parallel paths can be identified in the current research scenario: A) in the aforementioned consolidated therapeutic indications, an innovative approach is directed towards tailored treatment strategies, to identify patients most likely to benefit from one of the different anticoagulant drugs, in particular subpopulations at increased risk of adverse events (e.g., bleeding); B) in unconventional settings, DOACs are gaining interest for potential use in emerging diseases characterized by arterial and venous thromboembolic risk. In these scenarios, the risk-benefit profile of DOACs, as compared to VKAs or heparins, is less defined. The aim of this review is to critically assess the body of evidence underlying emerging therapeutic uses of DOACs (e.g., heparin-induced thrombocytopenia, anti-phospholipid antibody syndrome), including evolving issues in special populations (e.g., patients with VTE and cancer or cirrhosis). This will be achieved by analyzing the strength (i.e., systematic reviews, randomized clinical trials, observational studies, case report/series) and consistency (i.e., concordance) of both published and unpublished evidence registered in major public repositories.
      Graphical abstract image

      PubDate: 2017-04-12T10:14:08Z
      DOI: 10.1016/j.phrs.2017.03.026
      Issue No: Vol. 120 (2017)
       
  • Preventing cardiovascular heart disease: Promising nutraceutical and
           non-nutraceutical treatments for cholesterol management
    • Authors: T.P. Johnston; T.A. Korolenko; M. Pirro; A. Sahebkar
      Pages: 219 - 225
      Abstract: Publication date: June 2017
      Source:Pharmacological Research, Volume 120
      Author(s): T.P. Johnston, T.A. Korolenko, M. Pirro, A. Sahebkar
      Hypercholesterolemia is one of the major risk factors for the development of cardiovascular disease. Atherosclerosis resulting from hypercholesterolemia causes many serious cardiovascular diseases. Statins are generally accepted as a treatment of choice for lowering low-density lipoprotein (LDL) cholesterol, which reduces coronary heart disease morbidity and mortality. Since statin use can be associated with muscle problems and other adverse symptoms, non-adherence and discontinuation of statin therapy often leads to inadequate control of plasma cholesterol levels and increased cardiovascular risk. Moreover, there is compelling evidence on the presence of still considerable residual cardiovascular risk in statin-treated patients. Ezetimibe improves cholesterol-lowering efficacy and provides mild additional cardiovascular protection when combined with statin treatment. Despite a favorable safety profile compared to statins, ezetimibe-induced cholesterol-lowering is modest when used alone. Hence, there is a critical need to identity additional effective hypolipidemic agents that can be used either in combination with statins, or alone, if statins are not tolerated. Thus, hypolipidemic agents such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, apolipoprotein B-100 antisense oligonucleotides, cholesteryl ester transfer protein (CETP) inhibitors, and microsomal triglyceride transfer protein (MTTP) inhibitors, as well as yeast polysaccharides (beta-glucans and mannans) and compounds derived from natural sources (nutraceuticals) such as glucomannans, plant sterols, berberine, and red yeast rice are being used. In this review, we will discuss hypercholesterolemia, its impact on the development of cardiovascular disease (CVD), and the use of yeast polysaccharides, various nutraceuticals, and several therapeutic agents not derived from ‘natural’ sources, to treat hypercholesterolemia.
      Graphical abstract image

      PubDate: 2017-04-19T11:23:03Z
      DOI: 10.1016/j.phrs.2017.04.008
      Issue No: Vol. 120 (2017)
       
  • Targeting endothelial metaflammation to counteract diabesity
           cardiovascular risk: Current and perspective therapeutic options
    • Authors: Maria Assunta Potenza; Carmela Nacci; Maria Antonietta De Salvia; Luca Sgarra; Massimo Collino; Monica Montagnani
      Pages: 226 - 241
      Abstract: Publication date: June 2017
      Source:Pharmacological Research, Volume 120
      Author(s): Maria Assunta Potenza, Carmela Nacci, Maria Antonietta De Salvia, Luca Sgarra, Massimo Collino, Monica Montagnani
      The association of obesity and diabetes, termed “diabesity”, defines a combination of primarily metabolic disorders with insulin resistance as the underlying common pathophysiology. Cardiovascular disorders associated with diabesity represent the leading cause of morbidity and mortality in the Western world. This makes diabesity, with its rising impacts on both health and economics, one of the most challenging biomedical and social threats of present century. The emerging comprehension of the genes whose alteration confers inter-individual differences on risk factors for diabetes or obesity, together with the potential role of genetically determined variants on mechanisms controlling responsiveness, effectiveness and safety of anti-diabetic therapy underlines the need of additional knowledge on molecular mechanisms involved in the pathophysiology of diabesity. Endothelial cell dysfunction, resulting from the unbalanced production of endothelial-derived vascular mediators, is known to be present at the earliest stages of insulin resistance and obesity, and may precede the clinical diagnosis of diabetes by several years. Once considered as a mere consequence of metabolic abnormalities, it is now clear that endothelial dysfunctional activity may play a pivotal role in the progression of diabesity. In the vicious circle where vascular defects and metabolic disturbances worsen and reinforce each other, a low-grade, chronic, and ‘cold' inflammation (metaflammation) has been suggested to serve as the pathophysiological link that binds endothelial and metabolic dysfunctions. In this paradigm, it is important to consider how traditional antidiabetic treatments (specifically addressing metabolic dysregulation) may directly impact on inflammatory processes or cardiovascular function. Indeed, not all drugs currently available to treat diabetes possess the same anti-inflammatory potential, or target endothelial cell function equally. Perspective strategies pointing at reducing metaflammation or directly addressing endothelial dysfunction may disclose beneficial consequences on metabolic regulation. This review focuses on existing and potential new approaches ameliorating endothelial dysfunction and vascular inflammation in the context of diabesity.
      Graphical abstract image

      PubDate: 2017-04-19T11:23:03Z
      DOI: 10.1016/j.phrs.2017.04.009
      Issue No: Vol. 120 (2017)
       
  • YM155 induces apoptosis through proteasome-dependent degradation of MCL-1
           in primary effusion lymphoma
    • Authors: Yuki Kojima; Fumihiko Hayakawa; Takanobu Morishita; Keiki Sugimoto; Yuka Minamikawa; Mizuho Iwase; Hideyuki Yamamoto; Daiki Hirano; Naoto Imoto; Kazuyuki Shimada; Seiji Okada; Hitoshi Kiyoi
      Pages: 242 - 251
      Abstract: Publication date: June 2017
      Source:Pharmacological Research, Volume 120
      Author(s): Yuki Kojima, Fumihiko Hayakawa, Takanobu Morishita, Keiki Sugimoto, Yuka Minamikawa, Mizuho Iwase, Hideyuki Yamamoto, Daiki Hirano, Naoto Imoto, Kazuyuki Shimada, Seiji Okada, Hitoshi Kiyoi
      Primary effusion lymphoma (PEL) is a lymphoma that shows malignant effusion in body cavities without contiguous tumor masses and has a very poor prognosis. We recently developed a novel drug screening system using patient-derived xenograft (PDX) cells that maintained the primary cell phenotype better than cell lines. This screening is expected to discover anti-tumor drugs that have been overlooked by conventional screening using cell lines. We herein performed this screening to identify new therapeutic agents for PEL. We screened 3518 compounds with known pharmaceutical activities based on cytotoxic effects on PDX cells of PEL and selected YM155, a possible survivin inhibitor. It exerted strong anti-tumor effects in PDX cells and three cell lines of PEL; the GI50 of YM155 was 1.2–7.9nM. We found that YM155 reduced myeloid cell leukemia-1 (MCL-1) protein levels prior to decreasing survivin levels, and this was inhibited by a proteasome inhibitor. The knockdown of MCL-1 by siRNA induced cell death in a PEL cell line, suggesting the involvement of decreased MCL-1 levels in YM155-induced cell death. YM155 also induced the phosphorylation of ERK1/2 and MCL-1, and a MEK1 inhibitor inhibited the phosphorylation of ERK1/2, degradation of MCL-1, and YM155-induced apoptosis. These results indicate that YM155 induces the proteasome-dependent degradation of MCL-1 through its phosphorylation by ERK1/2 and causes apoptosis in PEL cells. Furthermore, a treatment with YM155 significantly inhibited the development of ascites in PEL PDX mice. These results suggest the potential of YM155 as an anti-cancer agent for PEL.
      Graphical abstract image

      PubDate: 2017-04-19T11:23:03Z
      DOI: 10.1016/j.phrs.2017.04.006
      Issue No: Vol. 120 (2017)
       
  • Anti-CD3 antibody therapy attenuates the progression of hypertension in
           female mice with systemic lupus erythematosus
    • Authors: Keisa W. Mathis; Erin B. Taylor; Michael J. Ryan
      Pages: 252 - 257
      Abstract: Publication date: June 2017
      Source:Pharmacological Research, Volume 120
      Author(s): Keisa W. Mathis, Erin B. Taylor, Michael J. Ryan
      Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disorder with prevalent hypertension that significantly contributes to the mortality in this patient population. Pre-clinical and clinical evidence suggests that anti-CD3 antibody therapy may attenuate the development of autoimmune diseases like SLE. However, it is unclear whether this treatment impacts the development of the prevalent hypertension associated with SLE. The present study was designed to determine whether anti-CD3 antibody treatment attenuates the progression of hypertension in female SLE mice with already established renal disease (albuminuria ≥100mg/dL). Female SLE (NZBWF1) and control (NZW) mice were administered either an antibody to CD3ε, a component of the T cell receptor complex expressed on all T cells, or IgG antibody (isotype control) for up to 4 weeks (intranasal; 25μg/week). Spleen weight was lower in SLE mice treated with anti-CD3 antibody than in IgG-treated SLE mice, suggesting that immune system hyperactivity is decreased. Circulating anti-dsDNA autoantibodies were increased in SLE mice compared to controls and were blunted in the anti-CD3-treated SLE mice. The development of hypertension was attenuated in anti-CD3 treated mice with SLE independently of changes in renal injury (assessed by urinary albumin). These data suggest anti-CD3 therapy during autoimmune disease may have added clinical benefit to attenuate cardiovascular risk factors like hypertension.
      Graphical abstract image

      PubDate: 2017-04-19T11:23:03Z
      DOI: 10.1016/j.phrs.2017.04.005
      Issue No: Vol. 120 (2017)
       
  • Targeting the unfolded protein response in cancer
    • Authors: Rani Ojha; Ravi K. Amaravadi
      Pages: 258 - 266
      Abstract: Publication date: June 2017
      Source:Pharmacological Research, Volume 120
      Author(s): Rani Ojha, Ravi K. Amaravadi
      Cancer cells are exposed to various intrinsic and extrinsic factors that disrupt protein homeostasis, producing endoplasmic reticulum (ER) stress. To cope with these situations, cancer cells evoke a highly conserved adaptive mechanism called the unfolded protein response (UPR) to restore the ER homeostasis. Recently, several pharmacological agents have been found to exhibit anti-tumor activity by targeting the UPR components. The development of potent and specific compounds that target the UPR components has not only shed light on the regulation of the UPR in cancer cells, but also brought the field closer to clinical drug candidates. Here we present an overview of the milestones in the field of UPR biology in cancer with a focus on new strategies for pharmacological inhibition.
      Graphical abstract image

      PubDate: 2017-04-19T11:23:03Z
      DOI: 10.1016/j.phrs.2017.04.003
      Issue No: Vol. 120 (2017)
       
  • Effects of low-dose aspirin on maternal blood pressure and vascular
           function in an experimental model of gestational hypertension
    • Authors: Oluwatobiloba Osikoya; Paresh A. Jaini; An Nguyen; Melissa Valdes; Styliani Goulopoulou
      Pages: 267 - 278
      Abstract: Publication date: June 2017
      Source:Pharmacological Research, Volume 120
      Author(s): Oluwatobiloba Osikoya, Paresh A. Jaini, An Nguyen, Melissa Valdes, Styliani Goulopoulou
      Daily intake of low-dose aspirin after 12weeks of gestation is currently recommended as a preventative intervention in pregnancies in high risk of developing preeclampsia. This recommendation is based on epidemiological evidence, whereas experimental studies investigating the exact mechanisms of aspirin action during pregnancy are lacking. We previously showed that treating pregnant rats with a synthetic mimetic of unmethylated CpG DNA (bacterial DNA) caused preeclampsia-like characteristics such as maternal hypertension and increased cyclooxygenase (COX) expression and activity. In this study, we tested the hypothesis that daily maternal treatment with low-dose aspirin would prevent the development of maternal hypertension, reduce COX activity and thromboxane A2 (TxA2) production, and improve maternal vascular function in pregnant rats exposed to CpG ODN during gestation. Pregnant rats were treated with ODN2395 (synthetic CpG DNA) or saline (vehicle) on gestational days (GD) 14, 16, 18. Daily low-dose aspirin treatment (1.5mg/kgBW) started on GD10 and continued throughout gestation. Pregnant rats treated with ODN2395 had greater systolic blood pressure compared to controls (120±4mmHg vs. 100±5mmHg, p=0.03) and aspirin did not prevent this increase (p=0.86). Aspirin prevented ODN2395-induced increases of TxB2 (TxA2 metabolite) in serum and mesenteric arteries. ODN2395 increased expression of COX-1 and COX-2 in mesenteric and uterine arteries and aspirin abolished these effects. Aspirin reduced contractile responses to phenylephrine and U46619 (TxA2 mimetic) in mesenteric arteries from control rats but not from ODN2395-treated rats. In conclusion, treatment with low-dose aspirin reduced systemic and vascular COX expression and activity but did not prevent the development of maternal hypertension induced by exposure to unmethylated CpG DNA (bacterial DNA).
      Graphical abstract image

      PubDate: 2017-04-19T11:23:03Z
      DOI: 10.1016/j.phrs.2017.04.012
      Issue No: Vol. 120 (2017)
       
  • What’s new about oral treatments in Multiple Sclerosis? Immunogenetics
           still under question
    • Authors: Cristiana Pistono; Cecilia Osera; Chiara Boiocchi; Giulia Mallucci; Mariaclara Cuccia; Roberto Bergamaschi; Alessia Pascale
      Pages: 279 - 293
      Abstract: Publication date: June 2017
      Source:Pharmacological Research, Volume 120
      Author(s): Cristiana Pistono, Cecilia Osera, Chiara Boiocchi, Giulia Mallucci, Mariaclara Cuccia, Roberto Bergamaschi, Alessia Pascale
      Multiple Sclerosis (MS) is a chronic pathology affecting the Central Nervous System characterized by inflammatory processes that lead to demyelination and neurodegeneration. In MS treatment, disease modifying therapies (DMTs) are essential to reduce disease progression by suppressing the inflammatory response responsible for promoting lesion formation. Recently, in addition to the classical injectable DMTs like Interferons and Glatiramer acetate, new orally administered drugs have been approved for MS therapy: dimethyl fumarate, teriflunomide and fingolimod. These drugs act with different mechanisms on the immune system, in order to suppress the harmful inflammatory process. An additional layer of complexity is introduced by the influence of polymorphic gene variants in the Human Leukocyte Antigen region on the risk of developing MS and its progression. To date, pharmacogenomic studies have mainly focused on the patient’s response following admission of injectable drugs. Therefore, greater consideration must be made to pharmacogenomics with a view to developing more effective and personalized therapies. This review aims to shed light on the mechanism of action of the new oral drugs dimethyl fumarate, teriflunomide and fingolimod, taking into account both the importance of immunogenetics in drug response and pharmacogenomic studies.
      Graphical abstract image

      PubDate: 2017-04-19T11:23:03Z
      DOI: 10.1016/j.phrs.2017.03.025
      Issue No: Vol. 120 (2017)
       
  • Interstitial lung disease induced by fluoxetine: Systematic review of
           literature and analysis of Vigiaccess, Eudravigilance and a national
           pharmacovigilance database
    • Authors: Arianna Deidda; Claudia Pisanu; Laura Micheletto; Alberto Bocchetta; Maria Del Zompo; Maria Erminia Stochino
      Pages: 294 - 301
      Abstract: Publication date: June 2017
      Source:Pharmacological Research, Volume 120
      Author(s): Arianna Deidda, Claudia Pisanu, Laura Micheletto, Alberto Bocchetta, Maria Del Zompo, Maria Erminia Stochino
      We investigated a pulmonary adverse drug reaction possibly induced by fluoxetine, the Interstitial Lung Disease, by performing a systematic review of published case reports on this subject, a review of the World Health Organization VigiAccess database, of the European EudraVigilance database and of a national Pharmacovigilance database (Italian Pharmacovigilance Network). The research found a total of seven cases linking fluoxetine to Interstitial Lung Disease in the literature. 36 cases of interstitial lung disease related to fluoxetine were retrieved from the VigiAccess database (updated to July 2016), and 36 reports were found in EudraVigilance database (updated to June 2016). In the Italian Pharmacovigilance database (updated to August 2016), we found only one case of Interstitial Lung Disease, codified as “pulmonary disease”. Our investigation shows that fluoxetine might be considered as a possible cause of Interstitial Lung Disease. In particular, although here we do not discuss the assessment of benefits and harms of fluoxetine, since this antidepressant is widely used, our review suggests that fluoxetine-induced Interstitial Lung Disease should be considered in patients with dyspnea, associated or not with dry cough, who are treated with this drug. An early withdrawn of fluoxetine could be useful to obtain a complete remission of this adverse drug reaction and special attention should be particularly devoted to long-term therapy, and to female and elderly patients. Although the spontaneous reporting system is affected by important limitations, drug post- marketing surveillance represents an important tool to evaluate the real world effectiveness and safety of drugs.
      Graphical abstract image

      PubDate: 2017-04-19T11:23:03Z
      DOI: 10.1016/j.phrs.2017.04.010
      Issue No: Vol. 120 (2017)
       
  • Dihydroartemisin inhibits glioma invasiveness via a ROS to P53 to
           β-catenin signaling
    • Authors: Zhongyou Que; Ping Wang; Yi Hu; Yixue Xue; Xiaobai Liu; Chengbin Qu; Jun Ma; Yunhui Liu
      Pages: 72 - 88
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Zhongyou Que, Ping Wang, Yi Hu, Yixue Xue, Xiaobai Liu, Chengbin Qu, Jun Ma, Yunhui Liu
      Dihydroartemisinin(DHA) is the active metabolic derivative of artemisinin. DHA has potential therapeutic effects on glioma but the detailed mechanism is unclear. In this study, we investigated the role and the underlying mechanisms of DHA in its inhibition of glioma cells. U87 cells are wild-type p53 glioblastoma cells and U251 cells contain mutant p53. DHA inhibited the proliferation, migration and invasion of glioma cells in a dose-dependent manner. DHA promoted reactive oxygen species production and activated p53 in two glioma cell lines, U87 and U251. In U87 cells, DHA significantly up-regulated the expression of p–β-catenin (S45) and inhibited EGFR, β-catenin, p–β-catenin (Y333) and matrix metalloprotease7/9 activity. In U251 cells, DHA significantly up-regulated p–β-catenin (S45), p–β-catenin (Y333) and EGFR, but the expression of β-cateninwas unchanged. We also found that DHA and sh–β-catenin prevented the proliferation of U87 and U251 cells in vivo. In conclusion, DHA inhibited the migration and invasion of human glioma cells with different types of p53 via different pathways.
      Graphical abstract image

      PubDate: 2017-04-19T11:23:03Z
      DOI: 10.1016/j.phrs.2017.01.014
      Issue No: Vol. 119 (2017)
       
  • Lipoprotein(a) and inflammation: A dangerous duet leading to endothelial
           loss of integrity
    • Authors: Matteo Pirro; Vanessa Bianconi; Francesco Paciullo; Massimo R. Mannarino; Francesco Bagaglia; Amirhossein Sahebkar
      Pages: 178 - 187
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Matteo Pirro, Vanessa Bianconi, Francesco Paciullo, Massimo R. Mannarino, Francesco Bagaglia, Amirhossein Sahebkar
      Lipoprotein(a) [Lp(a)] is an enigmatic lipoprotein whose ancestral useful properties have been gradually obscured by its adverse pro-atherogenic and pro-thrombotic effects, that culminate into an increased risk of ischemic cardiovascular events. Although plasma Lp(a) levels are largely determined on a genetic basis, multiple factors have been reported to interfere with its plasma levels. Inflammation is one of these factors and it is believed to promote pro-atherogenic and pro-thrombotic changes leading to increased cardiovascular disease risk. The influence of inflammation on plasma Lp(a) levels is variable, with studies reporting either increased, reduced or unchanged Lp(a) expression and plasma concentrations following exposure to pro-inflammatory stimuli. The complex association between inflammation and Lp(a) is further amplified by additional findings showing that Lp(a) may promote the expression of a plethora of pro-inflammatory cytokines and induces the endothelium to switch into an activated status which results in adhesion molecules expression and inflammatory cells invasion into the arterial wall. In this picture, it emerges that increased plasma Lp(a) levels and inflammation may coexist and their coexistence may exert a deleterious impact on endothelial integrity both at a functional and structural level. Also, the detrimental duet of inflammation and Lp(a) may interfere with the physiological endothelial repair response, thus further amplifying endothelial loss of integrity and protective functions. A fundamental understanding of the interaction between Lp(a) and inflammation is critical for our comprehension of the mechanisms leading to the derangement of endothelial homeostasis and vascular dysfunction.
      Graphical abstract image

      PubDate: 2017-02-12T02:13:08Z
      DOI: 10.1016/j.phrs.2017.02.001
      Issue No: Vol. 119 (2017)
       
  • Hormonally up-regulated neu-associated kinase: A novel target for breast
           cancer progression
    • Authors: Joelle N. Zambrano; Benjamin A. Neely; Elizabeth S. Yeh
      Pages: 188 - 194
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Joelle N. Zambrano, Benjamin A. Neely, Elizabeth S. Yeh
      Hormonally up-regulated neu-associated Kinase (Hunk) is a protein kinase that was originally identified in the murine mammary gland and has been shown to be highly expressed in Human Epidermal Growth Factor Receptor 2 positive (HER2+/ErbB2+) breast cancer cell lines as well as MMTV-neu derived mammary tumor cell lines. However, the physiological role of Hunk has been largely elusive since its identification. Though Hunk is predicted to be a Serine/Threonine (Ser/Thr) protein kinase with homology to the SNF1/AMPK family of protein kinases, there are no known Hunk substrates that have been identified to date. Recent work demonstrates a role for Hunk in HER2+/ErbB2+ breast cancer progression, including drug resistance to HER2/ErbB2 inhibitors, with Hunk potentially acting downstream of HER2/ErbB2 and the PI3K/Akt pathway. These studies have collectively shown that Hunk plays a vital role in promoting mammary tumorigenesis, as Hunk knockdown via shRNA in xenograft tumor models or crossing MMTV-neu or Pten-deficient genetically engineered mouse models into a Hunk knockout (Hunk-/-) background impairs mammary tumor growth in vivo. Because the majority of HER2+/ErbB2+ breast cancer patients acquire drug resistance to HER2/ErbB2 inhibitors, the characterization of novel drug targets like Hunk that have the potential to simultaneously suppress tumorigenesis and potentially enhance efficacy of current therapeutics is an important facet of drug development. Therefore, work aimed at uncovering specific regulatory functions for Hunk that could contribute to this protein kinase’s role in both tumorigenesis and drug resistance will be informative. This review focuses on what is currently known about this under-studied protein kinase, and how targeting Hunk may prove to be a potential therapeutic target for the treatment of breast cancer.
      Graphical abstract image

      PubDate: 2017-02-18T03:06:37Z
      DOI: 10.1016/j.phrs.2017.02.007
      Issue No: Vol. 119 (2017)
       
  • Pharmacological inhibition of MAGL attenuates experimental colon
           carcinogenesis
    • Authors: Ester Pagano; Francesca Borrelli; Pierangelo Orlando; Barbara Romano; Martina Monti; Lucia Morbidelli; Gabriella Aviello; Roberta Imperatore; Raffaele Capasso; Fabiana Piscitelli; Lorena Buono; Vincenzo Di Marzo; Angelo A. Izzo
      Pages: 227 - 236
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Ester Pagano, Francesca Borrelli, Pierangelo Orlando, Barbara Romano, Martina Monti, Lucia Morbidelli, Gabriella Aviello, Roberta Imperatore, Raffaele Capasso, Fabiana Piscitelli, Lorena Buono, Vincenzo Di Marzo, Angelo A. Izzo
      Colorectal cancer (CRC) is a major health problem in Western countries. The endocannabinoid 2-arachidonoyl-glycerol (2-AG) exerts antiproliferative actions in a number of tumoral cell lines, including CRC cells. Monoacylglycerol lipase (MAGL), a serine hydrolase that inactivates 2-AG, is highly expressed in aggressive human cancer cells. Here, we investigated the role of MAGL in experimental colon carcinogenesis. The role of MAGL was assessed in vivo by using the xenograft and the azoxymethane models of colon carcinogenesis; MAGL expression was evaluated by RT-PCR and immunohistochemistry; 2-AG levels were measured by liquid chromatography mass spectrometry; angiogenesis was evaluated in tumor tissues [by microvessel counting and by investigating the expression of vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) proteins] as well as in human umbilical vein endothelial cells (HUVEC); cyclin D1 was evaluated by RT-PCR. MAGL and 2-AG were strongly expressed in tumor tissues. The MAGL inhibitor URB602 reduced xenograft tumor volume, this effect being associated to down-regulation of VEGF and FGF-2, reduction in the number of vessels and down-regulation of cyclin D1. In HUVEC, URB602 exerted a direct antiangiogenic effect by inhibiting FGF-2 induced proliferation and migration, and by modulating pro/anti-angiogenic agents. In experiments aiming at investigating the role of MAGL in chemoprevention, URB602 attenuated azoxymethane-induced preneoplastic lesions, polyps and tumors. MAGL, possibly through modulation of angiogenesis, plays a pivotal role in experimental colon carcinogenesis. Pharmacological inhibition of MAGL could represent an innovative therapeutic approach to reduce colorectal tumor progression.
      Graphical abstract image

      PubDate: 2017-04-19T11:23:03Z
      DOI: 10.1016/j.phrs.2017.02.002
      Issue No: Vol. 119 (2017)
       
  • Long term use of metformin in idiopathic cyclic edema, report of thirteen
           cases and review of the literature
    • Authors: S. Soudet; M. Lambert; G. Lefèvre; H. Maillard; D. Huglo; P.Y. Hatron
      Pages: 237 - 239
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): S. Soudet, M. Lambert, G. Lefèvre, H. Maillard, D. Huglo, P.Y. Hatron
      Introduction Idiopathic cyclic edema (ICE) is a rare cause of edema. To date, there is no standard of care. The physiopathology of ICE could be explained by an impairment of capillary permeability. In 1995, a study demonstrated the efficacy of metformin on symptoms and capillary permeability. We evaluated ICE-patients who were treated with metformin in our department. Methods We retrospectively included patients diagnosed for ICE between January 1997 and October 2013. ICE was diagnosed in the presence of edema after excluding other etiologies. LANDIS test was used to support ICE diagnosis in all patients. The absence of edema at follow-up was considered as complete response (CR), partial decreased was considered as partial response (PR). Adverse events were recorded. Results Thirteen patients have accepted to use metformin. The median treatment duration was 28.5 months [8–167] and the median follow-up of treated patients was 40.5 months [14–167]. CR was reached in 10 patients (77%), and PR in 2 patients (15%). Two patients reported side-effects as diarrheas and one of them stopped the treatment due to mild diarrhea. Conclusion We report the interest and tolerance of the long-term use of metformin in ICE. No severe adverse events were noticed. A prospective study is needed to confirm the efficacy of metformin in ICE-patients.
      Graphical abstract image

      PubDate: 2017-02-18T03:06:37Z
      DOI: 10.1016/j.phrs.2017.02.009
      Issue No: Vol. 119 (2017)
       
  • Guidelines for preparing color figures for everyone including the
           colorblind
    • Authors: Robert Roskoski
      Pages: 240 - 241
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Robert Roskoski


      PubDate: 2017-02-18T03:06:37Z
      DOI: 10.1016/j.phrs.2017.02.005
      Issue No: Vol. 119 (2017)
       
  • Inhibition of proliferation and invasion in 2D and 3D models by
           2-methoxyestradiol in human melanoma cells
    • Authors: R.R. Massaro; F. Faião-Flores; V.W. Rebecca; S. Sandri; D.K. Alves-Fernandes; P.C. Pennacchi; K.S.M. Smalley; S.S. Maria-Engler
      Pages: 242 - 250
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): R.R. Massaro, F. Faião-Flores, V.W. Rebecca, S. Sandri, D.K. Alves-Fernandes, P.C. Pennacchi, K.S.M. Smalley, S.S. Maria-Engler
      Despite the recent advances in the clinical management of melanoma, there remains a need for new pharmacological approaches to treat this cancer. 2-methoxyestradiol (2ME) is a metabolite of estrogen that has shown anti-tumor effects in many cancer types. In this study we show that 2ME treatment leads to growth inhibition in melanoma cells, an effect associated with entry into senescence, decreased pRb and Cyclin B1 expression, increased p21/Cip1 expression and G2/M cell cycle arrest. 2ME treatment also inhibits melanoma cell growth in colony formation assay, including cell lines with acquired resistance to BRAF and BRAF+MEK inhibitors. We further show that 2ME is effective against melanoma with different BRAF and NRAS mutational status. Moreover, 2ME induced the retraction of cytoplasmic projections in a 3D spheroid model and significantly decreased cell proliferation in a 3D skin reconstruct model. Together our studies bring new insights into the mechanism of action of 2ME allowing melanoma targeted therapy to be further refined. Continued progress in this area is expected to lead to improved anti-cancer treatments and the development of new and more effective clinical analogues.
      Graphical abstract image

      PubDate: 2017-02-25T03:12:53Z
      DOI: 10.1016/j.phrs.2017.02.013
      Issue No: Vol. 119 (2017)
       
  • Biosimilars in the European Union from comparability exercise to real
           world experience: What we achieved and what we still need to achieve
    • Authors: Cristina Scavone; Liberata Sportiello; Liberato Berrino; Francesco Rossi; Annalisa Capuano
      Pages: 265 - 271
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Cristina Scavone, Liberata Sportiello, Liberato Berrino, Francesco Rossi, Annalisa Capuano


      PubDate: 2017-02-25T03:12:53Z
      DOI: 10.1016/j.phrs.2017.02.006
      Issue No: Vol. 119 (2017)
       
  • Allodynia Lowering Induced by Cannabinoids and Endocannabinoids (ALICE)
    • Authors: Livio Luongo; Katarzyna Starowicz; Sabatino Maione; Vincenzo Di Marzo
      Pages: 272 - 277
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Livio Luongo, Katarzyna Starowicz, Sabatino Maione, Vincenzo Di Marzo
      Neuropathic pain is a neurological disorder that strongly affects the quality of life of patients. The molecular and cellular mechanisms at the basis of the neuropathic pain establishment still need to be clarified. Among the neuromodulators that play a role in the pathological pain pathways, endocannabinoids could be deeply involved in both neuronal and non-neuronal mechanisms responsible for the appearance of tactile allodynia. Indeed, the function and dysfunction of this complex system in the molecular and cellular mechanisms of chronic pain induction and maintenance have been widely studied over the last two decades. In this review article, we highlighted the possible modulation of the endocannabinoid system in the neuronal, glial and microglial modulation in neuropathic pain treatment.
      Graphical abstract image

      PubDate: 2017-03-04T03:18:14Z
      DOI: 10.1016/j.phrs.2017.02.019
      Issue No: Vol. 119 (2017)
       
  • On traditional Chinese medicine regulation in China: How quality and
           safety of use are insured
    • Authors: Qingle Hu; Ramón Mª. Calduch
      Pages: 371 - 372
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Qingle Hu, Ramón Mª. Calduch


      PubDate: 2017-04-19T11:23:03Z
      DOI: 10.1016/j.phrs.2017.02.025
      Issue No: Vol. 119 (2017)
       
  • Effects of coenzyme Q10 supplementation on inflammatory markers: a
           systematic review and meta-analysis of randomized controlled trials
    • Authors: Li Fan; Yu Feng; Guo-Chong Chen; Li-Qiang Qin; Chun-ling Fu; Li-Hua Chen
      Abstract: Publication date: Available online 5 February 2017
      Source:Pharmacological Research
      Author(s): Li Fan, Yu Feng, Guo-Chong Chen, Li-Qiang Qin, Chun-ling Fu, Li-Hua Chen
      The aims of this meta-analysis were to evaluate the effects of coenzyme Q10 (CoQ10) supplementation on inflammatory mediators including C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) by analyzing published randomized controlled trials (RCTs). A systematic search in PubMed, Cochrane Library and Clinicaltrials.gov was performed to identify eligible RCTs. Data synthesis was performed using a random- or a fixed-effects model depending on the results of heterogeneity tests, and pooled data were displayed as weighed mean difference (WMD) and 95% confidence interval (CI). Seventeen RCTs were selected for the meta-analysis. CoQ10 supplementation significantly reduced the levels of circulating CRP (WMD: −0.35mg/L, 95% CI: −0.64 to −0.05, P=0.022), IL-6 (WMD: −1.61pg/mL, 95% CI: −2.64 to −0.58, P=0.002) and TNF-α (WMD: −0.49pg/mL, 95% CI: −0.93 to −0.06, P=0.027). The results of meta-regression showed that the changes of CRP were independent of baseline CRP, treatment duration, dosage, and patients characteristics. In the meta-regression analyses, a higher baseline IL-6 level was significantly associated with greater effects of CoQ10 on IL-6 levels (P for interaction=0.006). In conclusion, this meta-analysis of RCTs suggests significant lowering effects of CoQ10 on CRP, IL-6 and TNF-α. However, results should be interpreted with caution because of the evidence of heterogeneity and limited number of studies.
      Graphical abstract image

      PubDate: 2017-02-05T22:57:07Z
      DOI: 10.1016/j.phrs.2017.01.032
       
  • Pharmacological intervention of early neuropathy in neurodegenerative
           diseases
    • Authors: Min Jee Kwon; Jeong-Hoon Kim; TaeSoo Kim; Sung Bae Lee
      Abstract: Publication date: Available online 4 February 2017
      Source:Pharmacological Research
      Author(s): Min Jee Kwon, Jeong-Hoon Kim, TaeSoo Kim, Sung Bae Lee
      Extensive studies have reported the significant roles of numerous cellular features and processes in properly maintaining neuronal morphology and function throughout the lifespan of an animal. Any alterations in their homeostasis appear to be strongly associated with neuronal aging and the pathogenesis of various neurodegenerative diseases, even before the occurrence of prominent neuronal death. However, until recently, the primary focus of studies regarding many neurodegenerative diseases has been on the massive cell death occurring at the late stages of disease progression. Thus, our understanding on early neuropathy in these diseases remains relatively limited. The complicated nature of various neuropathic features manifested early in neurodegenerative diseases suggests the involvement of a system-wide transcriptional regulation and epigenetic control. Epigenetic alterations and consequent changes in the neuronal transcriptome are now begun to be extensively studied in various neurodegenerative diseases. Upon the catastrophic incident of neuronal death in disease progression, it is utterly difficult to reverse the deleterious defects by pharmacological treatments, and therefore, therapeutics targeting the system-wide transcriptional dysregulation associated with specific early neuropathy is considered a better option. Here, we review our current understanding on the system-wide transcriptional dysregulation that is likely associated with early neuropathy shown in various neurodegenerative diseases and discuss the possible future developments of pharmaceutical therapeutics.
      Graphical abstract image

      PubDate: 2017-02-05T22:57:07Z
      DOI: 10.1016/j.phrs.2017.02.003
       
  • 6-Gingerol protects intestinal barrier from ischemia/reperfusion-induced
           damage via inhibition of p38 MAPK to NF-κB signalling
    • Authors: Yanli Li; Bin Xu; Ming Xu; Dapeng Chen; Yongjian Xiong; Mengqiao Lian; Yuchao Sun; Zeyao Tang; Li Wang; Chunling Jiang; Yuan Lin
      Abstract: Publication date: Available online 4 February 2017
      Source:Pharmacological Research
      Author(s): Yanli Li, Bin Xu, Ming Xu, Dapeng Chen, Yongjian Xiong, Mengqiao Lian, Yuchao Sun, Zeyao Tang, Li Wang, Chunling Jiang, Yuan Lin
      Intestinal ischemia reperfusion (I/R) injury caused by severe trauma, intestinal obstruction, and operation is one of the tough challenges in clinic. 6-Gingerol (6G), a main active ingredient of ginger, is found to have anti-microbial, anti-inflammatory, anti-oxidative, and anti-cancer activities. The present study was designed to characterize the potential protective effects of 6G on rat intestinal I/R injury and reveal the correlated mechanisms. Rat intestinal I/R model was established with clamping the superior mesenteric artery (SMA) and 6G was intragastrically administered for three consecutive days before I/R injury. Caco-2 and IEC-6 cells were incubated under hypoxia/reoxygenation (H/R) conditions to simulate I/R injury in vitro. The results showed that 6G significantly alleviated intestinal injury in I/R injured rats by reducing the generation of oxidative stress and inhibiting p38 MAPK signaling pathway. 6G significantly reduced MDA level and increased the levels of SOD, GSH, and GSH-Px in I/R injured intestinal tissues. 6G significantly decreased the production of proinflammatory cytokines including TNF-α, IL-1β, and IL-6, and inhibited the expression of inflammatory mediators iNOS/NO in I/R injured intestinal tissues. The impaired intestinal barrier function was restored by using 6G in I/R injured rats and in both Caco-2 and IEC-6 cells characterized by inhibiting p38 MAPK phosphorylation, nuclear translocation of NF-κB, and expression of myosin light chain kinase (MLCK) protein. 6G also reduced the generation of reactive oxygen species (ROS) in both Caco-2 and IEC-6 cells. In vitro transfection of p38 MAPK siRNA mitigated the impact of 6G on NF-κB and MLCK expression, and the results further corroborated the protective effects of 6G on intestinal I/R injury by repressing p38 MAPK signaling. In conclusion, the present study suggests that 6G exerts protective effects against I/R-induced intestinal mucosa injury by inhibiting the formation of ROS and p38 MAPK activation, providing novel insights into the mechanisms of this therapeutic candidate for the treatment of intestinal injury.
      Graphical abstract image

      PubDate: 2017-02-05T22:57:07Z
      DOI: 10.1016/j.phrs.2017.01.026
       
  • Spinal or supraspinal phosphorylation deficiency at the MOR C-terminus
           does not affect morphine tolerance in vivo
    • Authors: Cherkaouia Kibaly; Hong-Yiou Lin; Horace H. Loh; Ping-Yee Law
      Abstract: Publication date: Available online 4 February 2017
      Source:Pharmacological Research
      Author(s): Cherkaouia Kibaly, Hong-Yiou Lin, Horace H. Loh, Ping-Yee Law
      The development of tolerance to morphine, one of the most potent analgesics, in the management of chronic pain is a significant clinical problem and its mechanisms are poorly understood. Morphine exerts its pharmacological effects via the μ-opioid receptor (MOR). Tolerance is highly connected to G-protein-coupled receptors (GPCR) phosphorylation and desensitization increase. Because morphine desensitization previously has been shown to be MOR phosphorylation- and ß-arrestin2-independent (in contrast to agonists such as fentanyl), we examined the contribution of phosphorylation of the entire C-terminus to the development of antinociceptive tolerance to the partial (morphine) and full (fentanyl) MOR agonists in vivo. In MOR knockout (MORKO) mice, we delivered via lentivirus the genes encoding the wild-type MOR (WTMOR) or a phosphorylation-deficient MOR (Cterm(-S/T)MOR) in which all of the serine and threonine residues were mutated to alanine into the ventrolateral periaqueductal grey matter (vlPAG) or lumbar spinal cord (SC), structures that are involved in nociception. We compared the analgesic ED50 in WTMOR- and Cterm(-S/T)MOR-expressing MORKO mice before and after morphine or fentanyl tolerance was induced. Morphine acute antinociception was partially restored in WTMOR- or Cterm(-S/T)MOR-transferred MORKO mice. Fentanyl acute antinociception was observed only in MORKO mice with the transgenes expressed in the SC. Morphine antinociceptive tolerance was not affected by expressing Cterm(-S/T)MOR in the vlPAG or SC of MORKO mice. Fentanyl-induced tolerance in MORKO mice expressing WTMOR or Cterm(-S/T)MOR, is greater than morphine-induced tolerance. Thus, MOR C-terminus phosphorylation does not appear to be critical for morphine tolerance in vivo.
      Graphical abstract image

      PubDate: 2017-02-05T22:57:07Z
      DOI: 10.1016/j.phrs.2017.01.033
       
  • Acid-sensing ion channel 1a is required for mGlu receptor dependent
           long-term depression in the hippocampus
    • Authors: D. Mango; E. Braksator; G. Battaglia; S. Marcelli; N.B. Mercuri; M. Feligioni; F. Nicoletti; Z.I. Bashir; R. Nisticò
      Abstract: Publication date: Available online 27 January 2017
      Source:Pharmacological Research
      Author(s): D. Mango, E. Braksator, G. Battaglia, S. Marcelli, N.B. Mercuri, M. Feligioni, F. Nicoletti, Z.I. Bashir, R. Nisticò
      Acid-sensing ion channels (ASICs), members of the degenerin/epithelial Na+ channel superfamily, are widely distributed in the mammalian nervous system. ASIC1a are highly permeable to Ca2+ and are thought to be important in a variety of physiological processes, including synaptic plasticity, learning and memory. To further understand the role of ASIC1a in synaptic transmission and plasticity, we investigated metabotropic glutamate (mGlu) receptor-dependent long-term depression (LTD) in the hippocampus. We found that ASIC1a channels mediate a component of LTD in P30-40 animals, since the ASIC1a selective blocker psalmotoxin-1 (PcTx1) reduced the magnitude of LTD induced by application of the group I mGlu receptor agonist (S)-3,5-Dihydroxyphenylglycine (DHPG) or induced by paired-pulse low frequency stimulation (PP-LFS). Conversely, PcTx1 did not affect LTD in P13-18 animals. We also provide evidence that ASIC1a is involved in group I mGlu receptor-induced increase in action potential firing. However, blockade of ASIC1a did not affect DHPG-induced polyphosphoinositide hydrolysis, suggesting the involvement of some other molecular partners in the functional crosstalk between ASIC1a and group I mGlu receptors. Notably, PcTx1 was able to prevent the increase in GluA1 S845 phosphorylation at the post-synaptic membrane induced by group I mGlu receptor activation. These findings suggest a novel function of ASIC1a channels in the regulation of group I mGlu receptor synaptic plasticity and intrinsic excitability.
      Graphical abstract image

      PubDate: 2017-01-29T22:51:52Z
      DOI: 10.1016/j.phrs.2017.01.028
       
  • Modulating the function of ATP-binding cassette subfamily G member 2
           (ABCG2) inhibitor cabozantinib
    • Authors: Guan-Nan Zhang; Yun-Kai Zhang; Yi-Jun Wang; Anna Maria Barbuti; Xi-Jun Zhu; Xin-Yue Yu; Ai-Wen Wen; John N.D. Wurpel; Zhe-Sheng Chen
      Abstract: Publication date: Available online 25 January 2017
      Source:Pharmacological Research
      Author(s): Guan-Nan Zhang, Yun-Kai Zhang, Yi-Jun Wang, Anna Maria Barbuti, Xi-Jun Zhu, Xin-Yue Yu, Ai-Wen Wen, John N.D. Wurpel, Zhe-Sheng Chen
      Cabozantinib (XL184) is a small molecule tyrosine kinase receptor inhibitor, which targets c-Met and VEGFR2. Cabozantinib has been approved by the Food and Drug Administration to treat advanced medullary thyroid cancer and renal cell carcinoma. In the present study, we evaluated the ability of cabozantinib to modulate the function of the ATP-binding cassette subfamily G member 2 (ABCG2) by sensitizing cells that are resistant to ABCG2 substrate antineoplastic drugs. We used a drug-selected resistant cell line H460/MX20 and three ABCG2 stable transfected cell lines ABCG2-482-R2, ABCG2-482-G2, and ABCG2-482-T7, which overexpress ABCG2. Cabozantinib, at non-toxic concentrations (3 or 5μM), sensitized the ABCG2-overexpressing cells to mitoxantrone, SN-38, and topotecan. Our results indicate that cabozantinib reverses ABCG2-mediated multidrug resistance by antagonizing the drug efflux function of the ABCG2 transporter instead of downregulating its expression. The molecular docking analysis indicates that cabozantinib binds to the drug-binding site of the ABCG2 transporter. Overall, our findings demonstrate that cabozantinib inhibits the ABCG2 transporter function and consequently enhances the effect of the antineoplastic agents that are substrates of ABCG2. Cabozantinib may be a useful agent in anticancer treatment regimens for patients who are resistant to ABCG2 substrate drugs.
      Graphical abstract image

      PubDate: 2017-01-29T22:51:52Z
      DOI: 10.1016/j.phrs.2017.01.024
       
  • Caveolin1/Protein Arginine Methyltransferase1/Sirtuin1 Axis as a Potential
           Target Against Endothelial Dysfunction
    • Authors: Soniya Charles; Vijay Raj; Jesu Arokiaraj; Kanchana Mala
      Abstract: Publication date: Available online 23 January 2017
      Source:Pharmacological Research
      Author(s): Soniya Charles, Vijay Raj, Jesu Arokiaraj, Kanchana Mala
      Endothelial dysfunction (ED), an established response to cardiovascular risk factors, is characterized by increased levels of soluble molecules secreted by endothelial cells (EC). Evidence suggest that ED is an independent predictor of cardiac events and that it is associated with a deficiency in production or bioavailability of nitric oxide (NO) and/or an imbalance in the relative contribution of endothelium-derived relaxing and contracting factors. ED can be reversed by treating cardiovascular risk factors, hence, beyond ambiguity, ED contributes to initiation and progression of atherosclerotic disease. Majority of cardiovascular risk factors act by a common pathway, oxidative stress (OS), characterized by an imbalance in bioavailability of NO and reactive oxygen species (ROS). Enhanced ROS, through several mechanisms, alters competence of EC that leads to ED, reducing its potential to maintain homeostasis and resulting in development of cardiovascular disease (CVD). Influential mechanisms that have been implicated in the development of ED include (i) presence of elevated levels of NOS inhibitor, asymmetric dimethylarginine (ADMA) due to augmented enzyme activity of protein arginine methyl transferase-1 (PRMT1); (ii) decrease in NO generation by endothelial nitric oxide synthase (eNOS) uncoupling, or by reaction of NO with free radicals and (iii) impaired post translational modification of protein (PTM) such as eNOS, caveolin-1 (cav1) and sirtuin-1 (SIRT1). However, the inter-related mechanisms that concur to developing ED is yet to be understood. The events that possibly overlay include OS-induced sequestration of SIRT1 to caveolae facilitating cav1-SIRT1 association; potential increase in lysine acetylation of enzymes such as eNOS and PRMT1 leading to enhanced ADMA formation; imbalance in acetylation-methylation ratio (AMR); diminished NO generation and ED. Here we review current literature from research showing interdependent association between cav1-PRMT1-SIRT1 to the outcomes of experimental and clinical research aiming to preserve endothelial function with gene- or pharmaco-therapy.
      Graphical abstract image

      PubDate: 2017-01-29T22:51:52Z
      DOI: 10.1016/j.phrs.2017.01.022
       
  • P-gp/ABCB1 Exerts Differential Impacts On Brain and Fetal Exposure to
           Norbuprenorphine
    • Authors: Michael Z. Liao; Chunying Gao; Laura M. Shireman; Brian Phillips; Linda J. Risler; Naveen K. Neradugomma; Prachi Choudhari; Bhagwat Prasad; Danny D. Shen; Qingcheng Mao
      Abstract: Publication date: Available online 19 January 2017
      Source:Pharmacological Research
      Author(s): Michael Z. Liao, Chunying Gao, Laura M. Shireman, Brian Phillips, Linda J. Risler, Naveen K. Neradugomma, Prachi Choudhari, Bhagwat Prasad, Danny D. Shen, Qingcheng Mao
      Norbuprenorphine is the major active metabolite of buprenorphine which is commonly used to treat opiate addiction during pregnancy. Norbuprenorphine produces marked respiratory depression and was 10 times more potent than buprenorphine. Therefore, it is important to understand the mechanism that controls fetal exposure to norbuprenorphine, as exposure to this compound may pose a significant risk to the developing fetus. P-gp/ABCB1 and BCRP/ABCG2 are two major efflux transporters regulating tissue distribution of drugs. Previous studies have shown that norbuprenorphine, but not buprenorphine, is a P-gp substrate. In this study, we systematically examined and compared the roles of P-gp and BCRP in determining maternal brain and fetal distribution of norbuprenorphine using transporter knockout mouse models. We administered 1mg/kg norbuprenorphine by retro-orbital injection to pregnant FVB wild-type, Abcb1a −/−/1b −/−, and Abcb1a −/−/1b −/−/Abcg2 −/− mice on gestation day 15. The fetal AUC of norbuprenorphine was ∼64% of the maternal plasma AUC in wild-type mice, suggesting substantial fetal exposure to norbuprenorphine. The maternal plasma AUCs of norbuprenorphine in Abcb1a −/−/1b −/− and Abcb1a −/−/1b −/−/Abcg2 −/− mice were ∼2 times greater than that in wild-type mice. Fetal AUCs in Abcb1a −/−/1b −/− and Abcb1a −/−/1b −/−/Abcg2 −/− mice were also increased compared to wild-type mice; however, the fetal-to-maternal plasma AUC ratio remained relatively unchanged by the knockout of Abcb1a/1b or Abcb1a/1b/Abcg2. In contrast, the maternal brain-to-maternal plasma AUC ratio in Abcb1a −/−/1b −/− or Abcb1a −/−/1b −/−/Abcg2 −/− mice was increased ∼30-fold compared to wild-type mice. Protein quantification by LC-MS/MS proteomics revealed significantly higher amounts of P-gp protein in the wild-type mice brain than that in the placenta. These results indicate that fetal exposure to norbuprenorphine is substantial and that P-gp has a minor impact on fetal exposure to norbuprenorphine, but plays a significant role in restricting its brain distribution. The differential impacts of P-gp on norbuprenorphine distribution into the brain and fetus are likely, at least in part, due to the differences in amounts of P-gp protein expressed in the blood-brain and blood-placental barriers. BCRP is not as important as P-gp in determining both the systemic and tissue exposure to norbuprenorphine. Finally, fetal AUCs of the metabolite norbuprenorphine-β-D-glucuronide were 3-7 times greater than maternal plasma AUCs, while the maternal brain AUCs were <50% of maternal plasma AUCs, suggesting that a reversible pool of conjugated metabolite in the fetus may contribute to the high fetal exposure to norbuprenorphine.
      Graphical abstract image

      PubDate: 2017-01-22T22:46:48Z
      DOI: 10.1016/j.phrs.2017.01.018
       
 
 
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: 54.224.204.189
 
About JournalTOCs
API
Help
News (blog, publications)
JournalTOCs on Twitter   JournalTOCs on Facebook

JournalTOCs © 2009-2016