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Journal Cover Pharmacological Research
  [SJR: 2.108]   [H-I: 99]   [1 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1043-6618 - ISSN (Online) 1096-1186
   Published by Elsevier Homepage  [3043 journals]
  • Renin-angiotensin-aldosterone: An inclusive, an invigorative, an
           interactive and an interminable system
    • Authors: Pitchai Balakumar; Madhu B. Anand-Srivastava; Gowraganahalli Jagadeesh
      Pages: 1 - 3
      Abstract: Publication date: November 2017
      Source:Pharmacological Research, Volume 125, Part A
      Author(s): Pitchai Balakumar, Madhu B. Anand-Srivastava, Gowraganahalli Jagadeesh


      PubDate: 2017-09-23T15:29:27Z
      DOI: 10.1016/j.phrs.2017.07.003
      Issue No: Vol. 125 (2017)
       
  • AT1 receptor signaling pathways in the cardiovascular system
    • Authors: Tatsuo Kawai; Steven J. Forrester; Shannon O’Brien; Ariele Baggett; Victor Rizzo; Satoru Eguchi
      Pages: 4 - 13
      Abstract: Publication date: November 2017
      Source:Pharmacological Research, Volume 125, Part A
      Author(s): Tatsuo Kawai, Steven J. Forrester, Shannon O’Brien, Ariele Baggett, Victor Rizzo, Satoru Eguchi
      The importance of the renin angiotensin aldosterone system in cardiovascular physiology and pathophysiology has been well described whereas the detailed molecular mechanisms remain elusive. The angiotensin II type 1 receptor (AT1 receptor) is one of the key players in the renin angiotensin aldosterone system. The AT1 receptor promotes various intracellular signaling pathways resulting in hypertension, endothelial dysfunction, vascular remodeling and end organ damage. Accumulating evidence shows the complex picture of AT1 receptor-mediated signaling; AT1 receptor-mediated heterotrimeric G protein-dependent signaling, transactivation of growth factor receptors, NADPH oxidase and ROS signaling, G protein-independent signaling, including the β-arrestin signals and interaction with several AT1 receptor interacting proteins. In addition, there is functional cross-talk between the AT1 receptor signaling pathway and other signaling pathways. In this review, we will summarize an up to date overview of essential AT1 receptor signaling events and their functional significances in the cardiovascular system.

      PubDate: 2017-09-23T15:29:27Z
      DOI: 10.1016/j.phrs.2017.05.008
      Issue No: Vol. 125 (2017)
       
  • Biased agonism/antagonism at the AngII-AT1 receptor: Implications for
           adrenal aldosterone production and cardiovascular therapy
    • Authors: Jennifer Maning; Shmuel Negussie; Michelle A. Clark; Anastasios Lymperopoulos
      Pages: 14 - 20
      Abstract: Publication date: November 2017
      Source:Pharmacological Research, Volume 125, Part A
      Author(s): Jennifer Maning, Shmuel Negussie, Michelle A. Clark, Anastasios Lymperopoulos
      Many of the effects of angiotensin II (AngII), including adrenocortical aldosterone release, are mediated by the AngII type 1 receptor (AT1R), a receptor with essential roles in cardiovascular homeostasis. AT1R belongs to the G protein-coupled receptor (GPCR) superfamily, mainly coupling to the Gq/11 type of G proteins. However, it also signals through βarrestins, oftentimes in parallel to eliciting G protein-dependent signaling. This has spurred infinite possibilities for cardiovascular pharmacology, since various beneficial effects are purportedly exerted by AT1R via βarrestins, unlike AT1R-induced G protein-mediated pathways that usually result in damaging cardiovascular effects, including hypertension and aldosterone elevation. Over the past decade however, a number of studies from our group and others have suggested that AT1R-induced βarrestin signaling can also be damaging for the heart, similarly to the G protein-dependent one, with regard to aldosterone regulation. Additionally, AT1R-induced βarrestin signaling in astrocytes from certain areas of the brain may also play a significant role in central regulation of blood pressure and hypertension pathogenesis. These findings have provided the impetus for testing available angiotensin receptor blockers (ARBs) in their efficacy towards blocking both routes (i.e. both G protein- and βarrestin-dependent) of AT1R signaling in vitro and in vivo and also have promoted structure-activity relationship (SAR) studies for the AngII molecule in terms of βarrestin signaling to certain cellular effects, e.g. adrenal aldosterone production. In the present review, we will recount all of these recent studies on adrenal and astrocyte AT1R-dependent βarrestin signaling while underlining their implications for cardiovascular pathophysiology and therapy.
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      PubDate: 2017-09-23T15:29:27Z
      DOI: 10.1016/j.phrs.2017.05.009
      Issue No: Vol. 125 (2017)
       
  • The vasoprotective axes of the renin-angiotensin system: Physiological
           relevance and therapeutic implications in cardiovascular, hypertensive and
           kidney diseases
    • Authors: Xiao C. Li; Jianfeng Zhang; Jia L. Zhuo
      Pages: 21 - 38
      Abstract: Publication date: November 2017
      Source:Pharmacological Research, Volume 125, Part A
      Author(s): Xiao C. Li, Jianfeng Zhang, Jia L. Zhuo
      The renin-angiotensin system (RAS) is undisputedly one of the most prominent endocrine (tissue-to-tissue), paracrine (cell-to-cell) and intracrine (intracellular/nuclear) vasoactive systems in the physiological regulation of neural, cardiovascular, blood pressure, and kidney function. The importance of the RAS in the development and pathogenesis of cardiovascular, hypertensive and kidney diseases has now been firmly established in clinical trials and practice using renin inhibitors, angiotensin-converting enzyme (ACE) inhibitors, type 1 (AT1) angiotensin II (ANG II) receptor blockers (ARBs), or aldosterone receptor antagonists as major therapeutic drugs. The major mechanisms of actions for these RAS inhibitors or receptor blockers are mediated primarily by blocking the detrimental effects of the classic angiotensinogen/renin/ACE/ANG II/AT1/aldosterone axis. However, the RAS has expanded from this classic axis to include several other complex biochemical and physiological axes, which are derived from the metabolism of this classic axis. Currently, at least five axes of the RAS have been described, with each having its key substrate, enzyme, effector peptide, receptor, and/or downstream signaling pathways. These include the classic angiotensinogen/renin/ACE/ANG II/AT1 receptor, the ANG II/APA/ANG III/AT2/NO/cGMP, the ANG I/ANG II/ACE2/ANG (1–7)/Mas receptor, the prorenin/renin/prorenin receptor (PRR or Atp6ap2)/MAP kinases ERK1/2/V-ATPase, and the ANG III/APN/ANG IV/IRAP/AT4 receptor axes. Since the roles and therapeutic implications of the classic angiotensinogen/renin/ACE/ANG II/AT1 receptor axis have been extensively reviewed, this article will focus primarily on reviewing the roles and therapeutic implications of the vasoprotective axes of the RAS in cardiovascular, hypertensive and kidney diseases.
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      PubDate: 2017-09-23T15:29:27Z
      DOI: 10.1016/j.phrs.2017.06.005
      Issue No: Vol. 125 (2017)
       
  • AT2 receptors in cardiovascular and renal diseases
    • Authors: Elena Kaschina; Pawel Namsolleck; Thomas Unger
      Pages: 39 - 47
      Abstract: Publication date: November 2017
      Source:Pharmacological Research, Volume 125, Part A
      Author(s): Elena Kaschina, Pawel Namsolleck, Thomas Unger
      The renin-angiotensin system (RAS) plays an important role in the initiation and progression of cardiovascular and renal diseases. These actions mediated by AT1 receptor (AT1R) are well established and led to development of selective AT1R blockers (ARBs). In contrast, there is scientific evidence that AT2 receptor (AT2R) mediates effects different from and often opposing those of the AT1R. Meagrely expressed in healthy tissue the AT2R is upregulated in injuries providing an endogenous protection to inflammatory, oxidative and apoptotic processes. Interestingly the beneficial effects mediated by AT2R can be further enhanced by pharmacological intervention using the recently developed AT2R agonists. This review article summarizes our current knowledge about regulation, signalling and effects mediated by AT2R in health and disease, with emphasis on cardiac and renal systems. At the end a novel concept of natural protective systems will be introduced and discussed as an attractive target in drug development.
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      PubDate: 2017-09-23T15:29:27Z
      DOI: 10.1016/j.phrs.2017.07.008
      Issue No: Vol. 125 (2017)
       
  • (Pro)renin receptor as a therapeutic target for the treatment of
           cardiovascular diseases'
    • Authors: Yuan Sun; A.H. Jan Danser; Xifeng Lu
      Pages: 48 - 56
      Abstract: Publication date: November 2017
      Source:Pharmacological Research, Volume 125, Part A
      Author(s): Yuan Sun, A.H. Jan Danser, Xifeng Lu
      The discovery of the (pro)renin receptor [(P)RR] 15years ago stimulated ideas on prorenin being more than renin’s inactive precursor. Indeed, binding of prorenin to the (P)RR induces a conformational change in the prorenin molecule, allowing it to display angiotensin-generating activity, and additionally results in intracellular signaling in an angiotensin-independent manner. However, the prorenin levels required to observe these angiotensin-dependent and −independent effects of the (P)RR are many orders above its in vivo concentrations, both under normal and pathological conditions. Given this requirement, the idea that the (P)RR has a function within the renin-angiotensin system (RAS) is now being abandoned. Instead, research is now focused on the (P)RR as an accessory protein of vacuolar H+-ATPase (V-ATPase), potentially determining its integrity. Acting as an adaptor between Frizzled co-receptor LRP6 and V-ATPase, the (P)RR appears to be indispensable for Wnt/β-catenin signaling, thus explaining why (P)RR deletion (unlike renin deletion) is lethal even when restricted to specific cells, such as cardiomyocytes, podocytes and smooth muscle cells. Furthermore, recent studies suggest that the (P)RR may play important roles in lipoprotein metabolism and overall energy metabolism. In this review, we summarize the controversial RAS-related effects of the (P)RR, and critically review the novel non-RAS-related functions of the (P)RR, ending with a discussion on the potential of targeting the (P)RR to treat cardiovascular diseases.
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      PubDate: 2017-09-23T15:29:27Z
      DOI: 10.1016/j.phrs.2017.05.016
      Issue No: Vol. 125 (2017)
       
  • Renin angiotensin aldosterone inhibition in the treatment of
           cardiovascular disease
    • Authors: Carlos M. Ferrario; Adam E. Mullick
      Pages: 57 - 71
      Abstract: Publication date: November 2017
      Source:Pharmacological Research, Volume 125, Part A
      Author(s): Carlos M. Ferrario, Adam E. Mullick
      A collective century of discoveries establishes the importance of the renin angiotensin aldosterone system in maintaining blood pressure, fluid volume and electrolyte homeostasis via autocrine, paracrine and endocrine signaling. While research continues to yield new functions of angiotensin II and angiotensin-(1–7), the gap between basic research and clinical application of these new findings is widening. As data accumulates on the efficacy of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers as drugs of fundamental importance in the treatment of cardiovascular and renal disorders, it is becoming apparent that the achieved clinical benefits is suboptimal and surprisingly no different than what can be achieved with other therapeutic interventions. We discuss this issue and summarize new pathways and mechanisms effecting the synthesis and actions of angiotensin II. The presence of renin-independent non-canonical pathways for angiotensin II production are largely unaffected by agents inhibiting renin angiotensin system activity. Hence, new efforts should be directed to develop drugs that can effectively block the synthesis and/or action of intracellular angiotensin II. Improved drug penetration into cardiac or renal sites of disease, inhibiting chymase the primary angiotensin II forming enzyme in the human heart, and/or inhibiting angiotensinogen synthesis would all be more effective strategies to inhibit the system. Additionally, given the role of angiotensin II in the maintenance of renal homeostatic mechanisms, any new inhibitor should possess greater selectivity of targeting pathogenic angiotensin II signaling processes and thereby limit inappropriate inhibition.
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      PubDate: 2017-09-23T15:29:27Z
      DOI: 10.1016/j.phrs.2017.05.020
      Issue No: Vol. 125 (2017)
       
  • Brain renin-angiotensin system in the pathophysiology of cardiovascular
           diseases
    • Authors: Gianna Huber; Franziska Schuster; Walter Raasch
      Pages: 72 - 90
      Abstract: Publication date: November 2017
      Source:Pharmacological Research, Volume 125, Part A
      Author(s): Gianna Huber, Franziska Schuster, Walter Raasch
      Cardiovascular diseases (CVD) are among the main causes of death globally and in this context hypertension represents one of the key risk factors for developing a CVD. It is well established that the peripheral renin-angiotensin system (RAS) plays an important role in regulating blood pressure (BP). All components of the classic RAS can also be found in the brain but, in contrast to the peripheral RAS, how the endogenous RAS is involved in modulating cardiovascular effects in the brain is not fully understood yet. It is a complex system that may work differently in diverse areas of the brain and is linked to the peripheral system by the circumventricular organs (CVO), which do not have a blood brain barrier (BBB). In this review, we focus on the brain angiotensin peptides, their interactions with each other, and the consequences in the central nervous system (CNS) concerning cardiovascular control. Additionally, we present potential drug targets in the brain RAS for the treatment of hypertension.
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      PubDate: 2017-09-23T15:29:27Z
      DOI: 10.1016/j.phrs.2017.06.016
      Issue No: Vol. 125 (2017)
       
  • Beneficial effects of Angiotensin II receptor blockers in brain disorders
    • Authors: J.M. Saavedra
      Pages: 91 - 103
      Abstract: Publication date: November 2017
      Source:Pharmacological Research, Volume 125, Part A
      Author(s): J.M. Saavedra
      A canonical brain Renin-Angiotensin System (RAS), like the canonical peripheral RAS, has long been proposed as a major regulator of brain function. Because of methodological limitations, however, this system is in urgent need of critical revision. The Angiotensin II AT1 receptors have been confirmed as key factors in the regulation of brain function, and AT1 receptor over activity has been established as a major and early injury factor in the development of many brain diseases. Consequently, Angiotensin Receptor Blockers (ARBs), compounds widely used to treat cardiovascular and metabolic disorders, are excellent candidates for repurposing for the treatment of brain disorders. This review will discuss some of the reasons why revisiting brain RAS is a pressing necessity, will present evidence for a participation of AT1 receptor over activity in the development of major brain disorders, and will present definite evidence of ARBs neuroprotective effects. The review will focus on the beneficial effects of ARB therapy in stroke, neurodegenerative disorders including Alzheimer’s and Parkinson’s diseases, traumatic brain injury, radiation- induced brain damage, stress and mood disorders.
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      PubDate: 2017-09-23T15:29:27Z
      DOI: 10.1016/j.phrs.2017.06.017
      Issue No: Vol. 125 (2017)
       
  • Characterization of structurally novel G protein biased CB1 agonists:
           Implications for drug development
    • Authors: Benjamin M. Ford; Lirit N. Franks; Sherrica Tai; William E. Fantegrossi; Edward L. Stahl; Michael D. Berquist; Christian V. Cabanlong; Catheryn D. Wilson; Narsimha R. Penthala; Peter A. Crooks; Paul L. Prather
      Pages: 161 - 177
      Abstract: Publication date: November 2017
      Source:Pharmacological Research, Volume 125, Part B
      Author(s): Benjamin M. Ford, Lirit N. Franks, Sherrica Tai, William E. Fantegrossi, Edward L. Stahl, Michael D. Berquist, Christian V. Cabanlong, Catheryn D. Wilson, Narsimha R. Penthala, Peter A. Crooks, Paul L. Prather
      The human cannabinoid subtype 1 receptor (hCB1R) is highly expressed in the CNS and serves as a therapeutic target for endogenous ligands as well as plant-derived and synthetic cannabinoids. Unfortunately, acute use of hCB1R agonists produces unwanted psychotropic effects and chronic administration results in development of tolerance and dependence, limiting the potential clinical use of these ligands. Studies in β-arrestin knockout mice suggest that interaction of certain GPCRs, including μ-, δ-, κ-opioid and hCB1Rs, with β-arrestins might be responsible for several adverse effects produced by agonists acting at these receptors. Indeed, agonists that bias opioid receptor activation toward G-protein, relative to β-arrestin signaling, produce less severe adverse effects. These observations indicate that therapeutic utility of agonists acting at hCB1Rs might be improved by development of G-protein biased hCB1R agonists. Our laboratory recently reported a novel class of indole quinulidinone (IQD) compounds that bind cannabinoid receptors with relatively high affinity and act with varying efficacy. The purpose of this study was to determine whether agonists in this novel cannabinoid class exhibit ligand bias at hCB1 receptors. Our studies found that a novel IQD-derived hCB1 receptor agonist PNR-4-20 elicits robust G protein-dependent signaling, with transduction ratios similar to the non-biased hCB1R agonist CP-55,940. In marked contrast to CP-55,940, PNR-4-20 produces little to no β-arrestin 2 recruitment. Quantitative calculation of bias factors indicates that PNR-4-20 exhibits from 5.4-fold to 29.5-fold bias for G protein, relative to β-arrestin 2 signaling (when compared to G protein activation or inhibition of forskolin-stimulated cAMP accumulation, respectively). Importantly, as expected due to reduced β-arrestin 2 recruitment, chronic exposure of cells to PNR-4-20 results in significantly less desensitization and down-regulation of hCB1Rs compared to similar treatment with CP-55,940. PNR-4-20 (i.p.) is active in the cannabinoid tetrad in mice and chronic treatment results in development of less persistent tolerance and no significant withdrawal signs when compared to animals repeatedly exposed to the non-biased full agoinst JWH-018 or Δ9-THC. Finally, studies of a structurally similar analog PNR- 4-02 show that it is also a G protein biased hCB1R agonist. It is predicted that cannabinoid agonists that bias hCB1R activation toward G protein, relative to β-arrestin 2 signaling, will produce fewer and less severe adverse effects both acutely and chronically.
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      PubDate: 2017-09-23T15:29:27Z
      DOI: 10.1016/j.phrs.2017.08.008
      Issue No: Vol. 125 (2017)
       
  • Animal models of pulmonary arterial hypertension: A systematic review and
           meta-analysis of data from 6126 animals
    • Authors: Katarzyna Sztuka; Magdalena Jasińska-Stroschein
      Pages: 201 - 214
      Abstract: Publication date: November 2017
      Source:Pharmacological Research, Volume 125, Part B
      Author(s): Katarzyna Sztuka, Magdalena Jasińska-Stroschein
      Numerous animal models of pulmonary hypertension are currently available. A systematic review and meta-analysis was performed of a number of experimental studies of disease induction based on several animal models. A meta-analysis was performed of 291 publications discussing the efficacy of 611 interventions to introduce disease pulmonary hypertension in 6126 animals. A meta-regression analysis was done to assess the effect of prolonged periods of disease induction on the outcomes. A random-effects meta-analysis was used to assess the impact of study characteristics and seek evidence of publication bias. A more pronounced worsening in hemodynamics or right ventricle hypertrophy was observed in animals exposed to Sugen combined with hypoxia, or left pneumonectomy followed by monocrotaline. Chronic hypoxia induced the poorest, but the most stable, response to disease induction with regard to elevated hemodynamic parameters, right ventricle hypertrophy and wall thickening. The greatest elevation of right ventricle systolic pressure was observed in animals exposed to isoflurane and the weakest to chloral hydrate. This result was true for different animal models and lengths of induction of pulmonary hypertension. Publication bias was found for all the crucial parameters. Development of pulmonary hypertension depends on the choice of animal model. Classic models, especially these related to chronic hypoxia, provoke a less severe response with regard to poorer hemodynamics and myocardial hypertrophy. The outcome of disease development can be strongly determined by the duration of induction, detailed experimental conditions and anesthesia procedure.
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      PubDate: 2017-09-23T15:29:27Z
      DOI: 10.1016/j.phrs.2017.08.003
      Issue No: Vol. 125 (2017)
       
  • Selective glucocorticoid receptor modulation inhibits cytokine responses
           in a canine model of mild endotoxemia
    • Authors: Johann Bartko; Ulla Derhaschnig; Tania Neels; Gerald H. Nabozny; Christian Harcken; Jost Leuschner; Frerich De Vries; Bernd Jilma
      Pages: 215 - 223
      Abstract: Publication date: November 2017
      Source:Pharmacological Research, Volume 125, Part B
      Author(s): Johann Bartko, Ulla Derhaschnig, Tania Neels, Gerald H. Nabozny, Christian Harcken, Jost Leuschner, Frerich De Vries, Bernd Jilma
      Selective glucocorticoid receptor modulators (GRMs) promise to reduce adverse events of glucocorticoids while maintaining anti-inflammatory potency. The present study tested the anti-inflammatory activity of two novel non-steroidal GRMs (GRM1: BI 607812 BS, GRM2: BI 653048 BS*H3PO4) in comparison to prednisolone in a canine model of low dose endotoxemia. This study compared the anti-inflammatory and pharmacokinetic profile of escalating daily oral doses of GRM1 (1, 2.5, 5 and 10mg/kg) and GRM2 (0.1, 0.25 and 1mg/kg) with prednisolone (0.25 and 0.5mg/kg) and placebo after intravenous infusion of endotoxin (0.1μg/kg) to Beagle dogs. This was followed by a 14-day evaluation study of safety and pharmacokinetics. Endotoxin challenge increased TNF-α ∼2000-fold and interleukin-6 (IL-6) 100-fold. Prednisolone and both GRMs suppressed peak TNF-α and IL-6 by 71–82% as compared with placebo. The highest doses of GRM1 and GRM2 reduced the mean body temperature increase by ∼30%. The endotoxin-induced rise in plasma cortisol was strongly suppressed in all treatment groups. Pharmacokinetics of both GRMs were non-linear. Adverse effects of endotoxemia such as vomiting were mitigated by GRM2 and prednisolone, indicating an antiemetic effect. During the 14-day treatment period, the adverse event profile of both GRMs appeared to be similar to prednisolone. Both GRMs had anti-inflammatory effects comparable to prednisolone and showed good safety profiles. Compounds targeting the glucocorticoid receptor selectively may provide an alternative to traditional glucocorticoids in the treatment of inflammatory disease.
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      PubDate: 2017-09-23T15:29:27Z
      DOI: 10.1016/j.phrs.2017.09.006
      Issue No: Vol. 125 (2017)
       
  • Sphingosine 1-phosphate (S1P) signalling: Role in bone biology and
           potential therapeutic target for bone repair
    • Authors: Ziad Sartawi; Ernestina Schipani; Katie B. Ryan; Christian Waeber
      Pages: 232 - 245
      Abstract: Publication date: November 2017
      Source:Pharmacological Research, Volume 125, Part B
      Author(s): Ziad Sartawi, Ernestina Schipani, Katie B. Ryan, Christian Waeber
      The lipid mediator sphingosine 1-phosphate (S1P) affects cellular functions in most systems. Interest in its therapeutic potential has increased following the discovery of its G protein-coupled receptors and the recent availability of agents that can be safely administered in humans. Although the role of S1P in bone biology has been the focus of much less research than its role in the nervous, cardiovascular and immune systems, it is becoming clear that this lipid influences many of the functions, pathways and cell types that play a key role in bone maintenance and repair. Indeed, S1P is implicated in many osteogenesis-related processes including stem cell recruitment and subsequent differentiation, differentiation and survival of osteoblasts, and coupling of the latter cell type with osteoclasts. In addition, S1P’s role in promoting angiogenesis is well-established. The pleiotropic effects of S1P on bone and blood vessels have significant potential therapeutic implications, as current therapeutic approaches for critical bone defects show significant limitations. Because of the complex effects of S1P on bone, the pharmacology of S1P-like agents and their physico-chemical properties, it is likely that therapeutic delivery of S1P agents will offer significant advantages compared to larger molecular weight factors. Hence, it is important to explore novel methods of utilizing S1P agents therapeutically, and improve our understanding of how S1P and its receptors modulate bone physiology and repair.
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      PubDate: 2017-09-23T15:29:27Z
      DOI: 10.1016/j.phrs.2017.08.013
      Issue No: Vol. 125 (2017)
       
  • Zebrafish: A promising in vivo model for assessing the delivery of natural
           products, fluorescence dyes and drugs across the blood-brain barrier
    • Authors: Ye Li; Tongkai Chen; Xiaoqing Miao; Xiang Yi; Xueqing Wang; Haitao Zhao; Simon Ming-Yuen Lee; Ying Zheng
      Pages: 246 - 257
      Abstract: Publication date: November 2017
      Source:Pharmacological Research, Volume 125, Part B
      Author(s): Ye Li, Tongkai Chen, Xiaoqing Miao, Xiang Yi, Xueqing Wang, Haitao Zhao, Simon Ming-Yuen Lee, Ying Zheng
      The blood brain barrier (BBB) is the network of capillaries that controls the passage of substances from the blood into the brain and other parts of the central nervous system (CNS). As this barrier is the major obstacle for drug delivery into CNS, a credible BBB model is very necessary to assess the BBB permeability of novel neuroactive compounds including thousands of bioactive compounds which have been extracted from medicinal plants and have the potential for the treatment of CNS diseases. Increasing reports indicated that zebrafish has emerged as a timely, reproducible model for BBB permeability assessment. In this review, the development and functions of the BBB in zebrafish, such as its anatomical morphology, tight junctions, drug transporters and enzyme expression, are compared with those in mammals. The studies outlined in this review describe the utilization of the zebrafish as a BBB model to investigate the permeability and distribution of fluorescent dyes and drugs. Particularly, this review focuses on the use of zebrafish to evaluate the delivery of natural products and nanosized drug delivery systems across the BBB. Due to the highly conserved nature of both the structure and function of the BBB between zebrafish and mammals, zebrafish has the potential to be developed as a model for assessing and predicting the permeability of BBB to novel compounds.
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      PubDate: 2017-09-30T16:15:05Z
      DOI: 10.1016/j.phrs.2017.08.017
      Issue No: Vol. 125 (2017)
       
  • Combination Drug Treatment in Hypertension
    • Authors: Costas Tsioufis; Costas Thomopoulos
      Pages: 266 - 271
      Abstract: Publication date: Available online 20 September 2017
      Source:Pharmacological Research
      Author(s): Costas Tsioufis, M.D. Costas Thomopoulos
      Combination treatment of hypertension has been introduced almost 50 years ago, because of the marked blood pressure (BP) elevation of recruited patients in the early randomized controlled trials of BP lowering. However, in all subsequent trials combination treatment was per protocol anticipated irrespectively of the initial randomized treatment to ensure either a desirable BP lowering or a comparable level of BP reduction among arms. Beyond clinical trials, combination treatment is mainly used in the clinical practice to reinforce ongoing single-agent treatment to achieve hypertension control. Renin-angiotensin system inhibiting drugs are the cornerstone of combination treatment of hypertension because they have been repeatedly tested in clinical trials in combination with other agents either from the beginning or during the follow-up. Effective BP lowering following combination treatment depends on the activation of complementary pathophysiological pathways but different agents can stimulate a common mode of action more effectively. The rate of adverse events following combination treatment may be reduced because effects of each agents are reciprocally counterbalanced. Nevertheless, aggressive BP lowering independently of the implemented combination is associated with increase of treatment discontinuations. In the management of resistant hypertension, a fourth-line agent used on top of the failing triple (diuretic-based) combination is effective to control hypertension only in 50% of patients. At present, it is questioned whether combination treatment of hypertension should be used alternatively to monotherapy in newly-diagnosed hypertensive patients without marked BP elevation or at low cardiovascular risk. Selection between free and fixed-dose combination treatment should be individualized depending on clinical criteria.
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      PubDate: 2017-09-23T15:29:27Z
      DOI: 10.1016/j.phrs.2017.09.011
      Issue No: Vol. 125 (2017)
       
  • Taltirelin alleviates fatigue-like behavior in mouse models of
           cancer-related fatigue
    • Authors: John P. Dougherty; Brian S. Wolff; Mary J. Cullen; Leorey N. Saligan; Marvin C. Gershengorn
      Pages: 1 - 8
      Abstract: Publication date: October 2017
      Source:Pharmacological Research, Volume 124
      Author(s): John P. Dougherty, Brian S. Wolff, Mary J. Cullen, Leorey N. Saligan, Marvin C. Gershengorn
      Fatigue affects most cancer patients and has numerous potential causes, including cancer itself and cancer treatment. Cancer-related fatigue (CRF) is not relieved by rest, can decrease quality of life, and has no FDA-approved therapy. Thyrotropin-releasing hormone (TRH) has been proposed as a potential novel treatment for CRF, but its efficacy against CRF remains largely untested. Thus, we tested the TRH analog, taltirelin (TAL), in mouse models of CRF. To model fatigue, we used a mouse model of chemotherapy, a mouse model of radiation therapy, and mice bearing colon 26 carcinoma tumors. We used the treadmill fatigue test to assess fatigue-like behavior after treatment with TAL. Additionally, we used wild-type and TRH receptor knockout mice to determine which TRH receptor was necessary for the actions of TAL. Tumor-bearing mice displayed muscle wasting and all models caused fatigue-like behavior, with mice running a shorter distance in the treadmill fatigue test than controls. TAL reversed fatigue-like behavior in all three models and the mouse TRH1 receptor was necessary for the effects of TAL. These data suggest that TAL may be useful in alleviating fatigue in all cancer patients and provide further support for evaluating TAL as a potential therapy for CRF in humans.
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      PubDate: 2017-07-23T12:40:21Z
      DOI: 10.1016/j.phrs.2017.07.012
      Issue No: Vol. 124 (2017)
       
  • Natural products with anti-inflammatory and immunomodulatory activities
           against autoimmune myocarditis
    • Authors: Behjat Javadi; Amirhossein Sahebkar
      Pages: 34 - 42
      Abstract: Publication date: October 2017
      Source:Pharmacological Research, Volume 124
      Author(s): Behjat Javadi, Amirhossein Sahebkar
      Myocarditis is an inflammatory disease of the myocardium associated with immune dysfunction which may frequently lead to the development of dilated cardiomyopathy. Experimental autoimmune myocarditis is an animal model which mimics myocarditis in order to allow assessment of the therapeutic effects of different molecules on this disease. We aimed to review the inflammatory and immunological mechanisms involved in the pathogenesis of the myocarditis and finding natural products and phytochemicals with anti-myocarditis activities based on studies of cardiac myosin-induced experimental autoimmune myocarditis in rodents. A number of natural molecules (e.g. apigenin, berberine and quercetin) along with some plant extracts were found to be effective in alleviating experimental autoimmune myocarditis. Upregulation of Th1-type cytokines and elevation of the Th2-type cytokines (IL-4 and IL-10), mitigation of oxidative stress, modulation of mitogen-activated protein kinase signaling pathways and increasing Sarco-endoplasmic reticulum Ca2+-ATPase levels are among the most important anti-myocarditis mechanisms for the retrieved molecules and extracts. Interestingly, there are structural similarities between the anti-EAM compounds, suggesting the presence of similar pharmacophore and enzymatic targets for these molecules. Naturally occurring molecules discussed in the present article are potential anti-myocarditis drugs and future additional animal studies and clinical trials would shed more light on their effectiveness in the treatment of myocarditis and prevention of dilated cardiomyopathy.
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      PubDate: 2017-09-06T14:54:11Z
      DOI: 10.1016/j.phrs.2017.07.022
      Issue No: Vol. 124 (2017)
       
  • Corrigendum to “Obesity and hypertension” [Pharmacol. Res. 122
           (2017) 1–7]
    • Authors: Gino Seravalle; Guido Grassi
      First page: 156
      Abstract: Publication date: October 2017
      Source:Pharmacological Research, Volume 124
      Author(s): Gino Seravalle, Guido Grassi


      PubDate: 2017-09-06T14:54:11Z
      DOI: 10.1016/j.phrs.2017.07.018
      Issue No: Vol. 124 (2017)
       
  • Corrigendum to “Imperatorin exerts antiallergic effects in Th2-mediated
           allergic asthma via induction of IL-10-producing regulatory T cells by
           modulating the function of dendritic cells” [Pharmacol. Res. (2016)
           111–121]
    • Authors: Chu-Lun Lin; George Hsiao; Ching-Chiung Wang; Yueh-Lun Lee
      First page: 157
      Abstract: Publication date: October 2017
      Source:Pharmacological Research, Volume 124
      Author(s): Chu-Lun Lin, George Hsiao, Ching-Chiung Wang, Yueh-Lun Lee


      PubDate: 2017-09-06T14:54:11Z
      DOI: 10.1016/j.phrs.2017.07.017
      Issue No: Vol. 124 (2017)
       
  • Statistical vs clinical significance: A matter of debate for orlistat
           treatment
    • Authors: Amirhossein Sahebkar; Luis E. Simental-Mendía; Željko Reiner; Petri T. Kovanen; Mario Simental-Mendía; Vanessa Bianconi; Matteo Pirro
      Pages: 158 - 159
      Abstract: Publication date: October 2017
      Source:Pharmacological Research, Volume 124
      Author(s): Amirhossein Sahebkar, Luis E. Simental-Mendía, Željko Reiner, Petri T. Kovanen, Mario Simental-Mendía, Vanessa Bianconi, Matteo Pirro


      PubDate: 2017-09-06T14:54:11Z
      DOI: 10.1016/j.phrs.2017.06.011
      Issue No: Vol. 124 (2017)
       
  • Value-Based pricing and the end of pharmaceutical pricing as we know
           it' A case study on sorafenib and axitinib
    • Authors: Panagiotis Petrou
      Pages: 160 - 163
      Abstract: Publication date: October 2017
      Source:Pharmacological Research, Volume 124
      Author(s): Panagiotis Petrou


      PubDate: 2017-09-06T14:54:11Z
      DOI: 10.1016/j.phrs.2017.05.012
      Issue No: Vol. 124 (2017)
       
  • Tacrolimus: Does direct glucuronidation matter' An analytical and
           pharmacological perspective
    • Authors: Camille Tron; Antoine Petitcollin; Marie-Clémence Verdier; Michel Rayar; Jean-Marie Beaurepaire; Karim Boudjema; Eric Bellissant; Florian Lemaitre
      Pages: 164 - 166
      Abstract: Publication date: October 2017
      Source:Pharmacological Research, Volume 124
      Author(s): Camille Tron, Antoine Petitcollin, Marie-Clémence Verdier, Michel Rayar, Jean-Marie Beaurepaire, Karim Boudjema, Eric Bellissant, Florian Lemaitre


      PubDate: 2017-09-06T14:54:11Z
      DOI: 10.1016/j.phrs.2017.03.027
      Issue No: Vol. 124 (2017)
       
  • Skunkworks project for Big Pharma
    • Authors: Krzysztof Palczewski
      Pages: 167 - 168
      Abstract: Publication date: October 2017
      Source:Pharmacological Research, Volume 124
      Author(s): Krzysztof Palczewski


      PubDate: 2017-09-06T14:54:11Z
      DOI: 10.1016/j.phrs.2017.03.022
      Issue No: Vol. 124 (2017)
       
  • Tanshinone I prevents atorvastatin-induced cerebral hemorrhage in
           zebrafish and stabilizes endothelial cell-cell adhesion by inhibiting
           VE-cadherin internalization and actin-myosin contractility
    • Authors: Bin Huang; Zhong-Yan Zhou Shang Xiao-Hui Huang Jing-Yi Tang Maggie
      Abstract: Publication date: Available online 7 October 2017
      Source:Pharmacological Research
      Author(s): Bin Huang, Zhong-Yan Zhou, Shang Li, Xiao-Hui Huang, Jing-Yi Tang, Maggie Pui Man Hoi, Simon Ming Yuen Lee
      Defects in vascular integrity in cerebrovasculature lead to serious pathologies including hemorrhagic stroke. The stability of cell adhesion junctions and actin-myosin contractile machinery are two major determinants for the integrity of endothelial monolayer. Here we have evaluated the protective effects of tanshinone I (Tan I), a lipophilic compound presents in Salvia miltiorrhiza, against atorvastatin-induced cerebral hemorrhage in zebrafish in vivo, and further dissected the molecular mechanisms in HUVECs. We demonstrated that Tan I protected endothelial integrity by stabilizing cell-cell adhesion junctions via the inhibition of Src-mediated VE-cadherin internalization and subsequent junction-linked actin cytoskeleton depolymerization. In addition, Tan I inhibited ROCK-associated endothelial contractile machinery by dephosphorylating cofilin and MYPT1. These findings identified Tan I as an endothelial stabilizing agent and suggested Tan I as a potential treatment for vascular leakage in hemorrhagic stroke.
      Graphical abstract image

      PubDate: 2017-10-08T17:04:42Z
       
  • New Perspectives in Cancer: Modulation of Lipid Metabolism and
           Inflammation Resolution
    • Authors: Nella Prevete; Federica Liotti; Angela Amoresano; Piero Pucci; Amato de Paulis; Rosa Marina Melillo
      Abstract: Publication date: Available online 3 October 2017
      Source:Pharmacological Research
      Author(s): Nella Prevete, Federica Liotti, Angela Amoresano, Piero Pucci, Amato de Paulis, Rosa Marina Melillo
      Inflammation is considered an enabling feature of cancer. Besides the persistence of inflammatory stimuli, also defective mechanisms of resolution can lead to chronic inflammation. Inflammation resolution is an active process controlled by lipidic specialized pro-resolving mediators (SPMs), derived from ω-3 or ω-6 essential polyunsaturated fatty acids (PUFA) through the activity of lipoxygenases (ALOX5 and 15). Thus, a lack or defect in resolution mechanisms may affect cancer development and progression by prolonging inflammation. Components of pro-resolving pathways (PUFA, enzymes, or SPMs) have been reported to modulate various cancer features by affecting both epithelial cells and cancer-associated stroma. Here, we will review the most important mechanisms by which SPMs, ω-3/6 PUFA, and ALOXs affect cancer biology, paying particular attention to their role in the inhibition of inflammation and angiogenesis, two of the most important hallmarks of cancer. The collection of these results may suggest novel perspectives in cancer management based on the modulation of lipid metabolism and the production of SPMs.
      Graphical abstract image

      PubDate: 2017-10-08T17:04:42Z
      DOI: 10.1016/j.phrs.2017.09.024
       
  • Reduced adipose tissue H2S in obesity
    • Authors: Antonia Katsouda; Csaba Szabo; Andreas Papapetropoulos
      Abstract: Publication date: Available online 2 October 2017
      Source:Pharmacological Research
      Author(s): Antonia Katsouda, Csaba Szabo, Andreas Papapetropoulos
      Hydrogen sulfide (H2S) is an endogenously produced signaling molecule synthesized by cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST). Given that H2S exerts significant effects on bioenergetics and metabolism, the goal of the current study was to determine the expression of H2S-producing enzymes in adipose tissues in models of obesity and metabolic disruption. Mice fed a western diet expressed lower mRNA levels of all three enzymes in epididymal fat (EWAT), while only CSE and 3-MST were reduced in brown adipose tissue (BAT). At the protein level 3-MST was reduced in all fat depots studied. Using db/db mice, a genetic model of obesity, we found that CSE, CBS and 3-MST mRNA were reduced in white fat, while only CSE was reduced in BAT. CBS and CSE protein levels were suppressed in all three fat depots. In a model of age-related weight gain, no reduction in the mRNA of any of the enzymes was noted. Smaller amounts of 3-MST protein were found in EWAT, while both CSE and 3-MST were reduced in BAT. Tissue levels of H2S were lower in WAT in HFD mice; both WAT and BAT contained lower H2S amounts in db/db animals. Taken together, our data suggest that obesity is associated with a decreased expression of H2S-synthesizing enzymes and reduced H2S levels in adipose tissues of mice. We propose that the reduction in H2S may contribute to the metabolic response associated with obesity. Further work is needed to determine whether restoring H2S levels during obesity may have a beneficial effect on obesity-associated metabolic alterations.
      Graphical abstract image

      PubDate: 2017-10-08T17:04:42Z
      DOI: 10.1016/j.phrs.2017.09.023
       
  • Long-lasting effects of early-life intervention in mice on adulthood
           behaviour, GABAA receptor subunit expression and synaptic clustering
    • Authors: Kelly J. Skilbeck; Graham A.R. Johnston; Tina Hinton
      Abstract: Publication date: Available online 29 September 2017
      Source:Pharmacological Research
      Author(s): Kelly J. Skilbeck, Graham A.R. Johnston, Tina Hinton
      Variations in the early postnatal environment of rodents produce long-term changes in responses to stress that may underlie neuropsychiatric diseases such as anxiety, depression and schizophrenia. GABAA receptors undergo marked changes in their subunit composition during this period, involving a regionally-dependent replacement of α2 with α1 subunits, the so-called α-subunit switch. In this study we examined the effects of early-life environment on adulthood GABAA receptor α1 and α2 subunit expression and the synaptic clustering of GABAA receptors. Male and female mice were exposed to either 15min daily handling sessions (EH) or no intervention (NH) over postnatal day (PND) 1-14. Adulthood behavioural differences in anxiety were assessed on the elevated plus-maze. Immunoperoxidase histochemistry was used to examine the density of the α1 and α2 subunit proteins. Double-labelling immunofluorescence and confocal microscopy were used to study GABAA receptor synaptic clustering. NH animals showed increased anxiety-type behaviours in the elevated plus maze relative to EH mice. NH males showed a loss of α2 subunits from the thalamus and lower layers of the somatosensory cortex, whilst NH females showed a reduction of α2 but increase in α1 protein in lower layers of the primary somatosensory cortex only. The NH condition also reduced α1 subunit expression in dentate gyrus (DG) in both males and females. Regardless of sex, NH mice showed reduced colocalisation of GABAA receptor α2 subunits with the synaptic marker gephyrin relative to the control condition. These findings suggest that early-life environment has long-lasting effects on GABAA receptors, leading to long-term changes in adulthood behaviour, and are of relevance to neurodevelopmental explanations of stress-augmented neuropsychiatric disorders.
      Graphical abstract image

      PubDate: 2017-09-30T16:15:05Z
      DOI: 10.1016/j.phrs.2017.09.021
       
  • Autophagy-mediated neuroprotection induced by octreotide in an ex vivo
           model of early diabetic retinopathy
    • Authors: Rosario Amato; Elisabetta Catalani; Massimo Dal Monte; Maurizio Cammalleri; Ilaria Di Renzo; Cristiana Perrotta; Davide Cervia; Giovanni Casini
      Abstract: Publication date: Available online 29 September 2017
      Source:Pharmacological Research
      Author(s): Rosario Amato, Elisabetta Catalani, Massimo Dal Monte, Maurizio Cammalleri, Ilaria Di Renzo, Cristiana Perrotta, Davide Cervia, Giovanni Casini
      Neuronal injury plays a major role in diabetic retinopathy (DR). Our hypothesis was that the balance between neuronal death and survival may depend on a similar equilibrium between apoptosis and autophagy and that a neuroprotectant may act by influencing this equilibrium. Ex vivo mouse retinal explants were treated with high glucose (HG) for 10days and the somatostatin analog octreotide (OCT) was used as a neuroprotectant. Chloroquine (CQ) was used as an autophagy inhibitor. Apoptotic and autophagic markers were evaluated using western blot and immunohistochemistry. HG-treated explants displayed a significant increase of apoptosis paralleled by a significant decrease of the autophagic flux, which was likely to be due to increased activity of the autophagy regulator mTOR (mammalian target of rapamycin). Treatment with OCT rescued HG-treated retinal explants from apoptosis and determined an increase of autophagic activity with concomitant mTOR inhibition. Blocking the autophagic flux with CQ completely abolished the anti-apoptotic effect of OCT. Immunohistochemical observations showed that OCT-induced autophagy is localized to populations of bipolar and amacrine cells and to ganglion cells. These observations revealed the antithetic role of apoptosis and autophagy, highlighting their equilibrium from which neuronal survival is likely to depend. These data suggest the crucial role covered by autophagy, which could be considered as a molecular target for DR neuroprotective treatment strategies.
      Graphical abstract image

      PubDate: 2017-09-30T16:15:05Z
      DOI: 10.1016/j.phrs.2017.09.022
       
  • Resveratrol and cognitive performance: selecting the evidence
    • Authors: Rachel H.X. Wong; Peter R.C. Howe
      Abstract: Publication date: Available online 29 September 2017
      Source:Pharmacological Research
      Author(s): Rachel H.X. Wong, Peter R.C. Howe


      PubDate: 2017-09-30T16:15:05Z
      DOI: 10.1016/j.phrs.2017.09.018
       
  • Imatinib mesylate-induced cardiomyopathy involves resident cardiac
           progenitors
    • Authors: Monia Savi; Caterina Frati; Stefano Cavalli; Gallia Graiani; Serena Galati; Annamaria Buschini; Denise Madeddu; Angela Falco; Lucia Prezioso; Giulia Mazzaschi; Federica Galaverna; Costanza Anna Maria Lagrasta; Emilia Corradini; Antonella De Angelis; Donato Cappetta; Liberato Berrino; Franco Aversa; Federico Quaini; Konrad Urbanek
      Abstract: Publication date: Available online 28 September 2017
      Source:Pharmacological Research
      Author(s): Monia Savi, Caterina Frati, Stefano Cavalli, Gallia Graiani, Serena Galati, Annamaria Buschini, Denise Madeddu, Angela Falco, Lucia Prezioso, Giulia Mazzaschi, Federica Galaverna, Costanza Anna Maria Lagrasta, Emilia Corradini, Antonella De Angelis, Donato Cappetta, Liberato Berrino, Franco Aversa, Federico Quaini, Konrad Urbanek
      Cardiovascular complications are included among the systemic effects of tyrosine kinase inhibitor (TKI)-based therapeutic strategies. To test the hypothesis that inhibition of Kit tyrosine kinase that promotes cardiac progenitor cell (CPC) survival and function may be one of the triggering mechanisms of imatinib mesylate (IM)-related cardiovascular effects, the anatomical, structural and ultrastructural changes in the heart of IM-treated rats were evaluated. Cardiac anatomy in IM-exposed rats showed a dose-dependent, restrictive type of remodeling and depressed hemodynamic performance in the absence of remarkable myocardial fibrosis. The effects of IM on rat and human CPCs were also assessed. IM induced rat CPC depletion, reduced growth and increased cell death. Similar effects were observed in CPCs isolated from human hearts. These results extend the notion that cardiovascular side effects are driven by multiple actions of IM. The identification of cellular mechanisms responsible for cardiovascular complications due to TKIs will enable future strategies aimed at preserving concomitantly cardiac integrity and anti-tumor activity of advanced cancer treatment.
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      PubDate: 2017-09-30T16:15:05Z
      DOI: 10.1016/j.phrs.2017.09.020
       
  • Role of tangeretin as a potential bioavailability enhancer for silybin:
           pharmacokinetic and pharmacological studies
    • Authors: Zhong-Wen Yuan; Ya-Zhuo Li; Zhong-Qiu Liu; Sen-ling Feng; Hua Zhou; Chang-Xiao Liu; Liang Liu; Ying Xie
      Abstract: Publication date: Available online 27 September 2017
      Source:Pharmacological Research
      Author(s): Zhong-Wen Yuan, Ya-Zhuo Li, Zhong-Qiu Liu, Sen-ling Feng, Hua Zhou, Chang-Xiao Liu, Liang Liu, Ying Xie
      Biological responses of a variety of naturally occurring compounds in vivo were restrained by their poor oral bioavailability. Silybin, as one of the active ingredients of silymarin, has presented promising bioactivity for the treatment of chronic liver diseases and cancer. However, its exposure in body was limited. In this study, silybin was demonstrated to be substrates of both BCRP and MRP2 by utilizing monolayer Caco-2 cell model and confirmed in MDCK cells overexpressing specific efflux transporter. Of all compounds screened, tangeretin, a potent inhibitor of efflux transporters of BCRP, MRP2 and P-gp, was able to enhance exposure of silybin by inhibiting functions of the barriers mediating transcellular transport. Moreover, study carried out in sandwich-cultured rat hepatocyte (SCH) model showed that the biliary excretion index (BEI) and in vitro biliary clearance of silybin decreased as levels of tangeretin increased, indicating efflux transporters mediating biliary excretion of silybin might be involved. Pharmacokinetic behaviors of silybin in rats were altered by co-administration of tangeretin, in terms of increased AUC and Cmax of silybin by comparing with that of silybin given alone. In addition, results coming from CCl4-induced acute liver injury rat model revealed that protection effect of silybin against liver damage in the presence of tangeretin was significantly enhanced. All these data were evident that efflux transporters play a critical role in transcellular transport of silybin and account for its low bioavailability. Enhanced bioavailability of silybin with co-administration of tangeretin by significantly inhibiting the efflux transporters further boost its bioactivity which is of particular importance in clinical use.
      Graphical abstract image

      PubDate: 2017-09-30T16:15:05Z
      DOI: 10.1016/j.phrs.2017.09.019
       
  • Resveratrol and cognitive performance
    • Authors: Mohammad Hosein Farzaei; Roja Rahimi; Shekoufeh Nikfar; Mohammad Abdollahi
      Abstract: Publication date: Available online 25 September 2017
      Source:Pharmacological Research
      Author(s): Mohammad Hosein Farzaei, Roja Rahimi, Shekoufeh Nikfar, Mohammad Abdollahi


      PubDate: 2017-09-30T16:15:05Z
      DOI: 10.1016/j.phrs.2017.09.017
       
  • Arenobufagin: A potential novel opportunity for prostate cancer treatment
           – Intriguing mechanistic data but some questions on in vivo
           translatability
    • Authors: Nuggehally R. Srinivas
      Abstract: Publication date: Available online 23 September 2017
      Source:Pharmacological Research
      Author(s): Nuggehally R. Srinivas


      PubDate: 2017-09-30T16:15:05Z
      DOI: 10.1016/j.phrs.2017.09.015
       
  • Melatonin and Periodontal tissues: molecular and clinical perspectives.
    • Authors: Agata Rita Carpentieri; María Elena Peralta Lopez; Javier Aguilar; Verónica Mariana Solá
      Abstract: Publication date: Available online 14 September 2017
      Source:Pharmacological Research
      Author(s): Agata Rita Carpentieri, María Elena Peralta Lopez, Javier Aguilar, Verónica Mariana Solá
      Periodontal disease is a frequent chronic inflammatory pathology that implies the destruction of the tissues supporting the teeth, which represents a high sanitary cost. It usually appears associated with other systemic conditions such as diabetes, metabolic syndrome, depression and Alzheimer disease among others. The presence of melatonin and its receptors in the oral cavity supports the hypothesis that this hormone could play a role in homeostasis of periodontal tissues. In the present review we will discuss the potential role of melatonin, a circadian synchronizing hormone, with proved antiinflammatory and antioxidant profile, in the pathogenesis and treatment of periodontitis. Particular emphasis will be placed on the role of the indolamine in the treatment of periodontal disease when this oral condition is comorbid with other pathologies that would also benefit from the therapeutic potential of melatonin and its analogs through diverse mechanisms.
      Graphical abstract image

      PubDate: 2017-09-17T15:25:11Z
      DOI: 10.1016/j.phrs.2017.09.003
       
  • Edited course of biomedical research: leaping forward with CRISPR
    • Authors: Patrick J. Collins; Christopher M. Hale; Han Xu
      Abstract: Publication date: Available online 14 September 2017
      Source:Pharmacological Research
      Author(s): Patrick J. Collins, Christopher M. Hale, Han Xu
      Within the short few years since the report of its application in precise genome editing, CRISPR technology has become the method of choice to modify and modulate gene expression in biomedical research and therapeutic development. Subsequently, a variety of research, diagnostic, and therapeutic tools have been developed based upon CRISPR’s mechanism of action. Such tools have helped to deepen the understanding of fundamental biology and broaden the horizon in the search for treatments for diseases that have been considered hard or impossible to cure. As CRISPR technology advances closer to clinical applications, its short comings are becoming more apparent, thus creating opportunities to improve the technology’s efficacy, specificity, and safety profile in this setting. We will summarize the current status of CRISPR technology and discuss its future impact in this review.
      Graphical abstract image

      PubDate: 2017-09-17T15:25:11Z
      DOI: 10.1016/j.phrs.2017.09.008
       
  • The emerging role of AMP-activated protein kinase in cholestatic liver
           diseases
    • Authors: Xiaojiaoyang Li; Runping Liu; Luyong Zhang; Zhenzhou Jiang
      Abstract: Publication date: Available online 7 September 2017
      Source:Pharmacological Research
      Author(s): Xiaojiaoyang Li, Runping Liu, Luyong Zhang, Zhenzhou Jiang
      AMP-activated protein kinase (AMPK), recognized as an energy sensor with three heterotrimeric subunits (α, β and γ), not only maintains basal intracellular adenosine triphosphate levels but also regulates energy-intensive pathological responses, such as neurodegenerative and metabolic diseases, through multiple signaling pathways. Recent studies open a new direction for AMPK research and demonstrate that AMPK is a critical player in the pathogenesis of cholestatic liver injury and plays paradoxical roles in the regulation of different pathological processes, including the disruption of bile acid homeostasis and the regulation of hepatic polarity, inflammation and fibrosis. In the present review, we summarize recent findings that implicate AMPK-mediated signaling pathways in the pathogenesis of cholestatic liver injury. These findings provide novel insight regarding the potential use of AMPK as a therapeutic target for the treatment of cholestatic liver injury.
      Graphical abstract image

      PubDate: 2017-09-11T15:12:29Z
      DOI: 10.1016/j.phrs.2017.09.002
       
  • Toxicogenomic and bioinformatics platforms to identify key molecular
           mechanisms of a curcumin-analogue DM-1 toxicity in melanoma cells
    • Authors: Érica Aparecida de Oliveira; Diogenes Saulo de Lima; Lucas Esteves Cardozo; Garcia Ferreira de Souza; Nayane de Souza; Debora Kristina Alves-Fernandes; Fernanda Faião-Flores; José Agustín Pablo Quincoces; Silvia Berlanga de Moraes Barros; Helder I. Nakaya; Gisele Monteiro; Silvya Stuchi Maria-Engler
      Abstract: Publication date: Available online 4 September 2017
      Source:Pharmacological Research
      Author(s): Érica Aparecida de Oliveira, Diogenes Saulo de Lima, Lucas Esteves Cardozo, Garcia Ferreira de Souza, Nayane de Souza, Debora Kristina Alves-Fernandes, Fernanda Faião-Flores, José Agustín Pablo Quincoces, Silvia Berlanga de Moraes Barros, Helder I. Nakaya, Gisele Monteiro, Silvya Stuchi Maria-Engler
      Melanoma is a highly invasive and metastatic cancer with high mortality rates and chemoresistance. Around 50% of melanomas are driven by activating mutations in BRAF that has led to the development of potent anti-BRAF inhibitors. However resistance to anti-BRAF therapy usually develops within a few months and consequently there is a need to identify alternative therapies that will bypass BRAF inhibitor resistance. The curcumin analogue DM-1 (sodium 4-[5-(4-hydroxy-3-methoxy-phenyl)-3-oxo-penta-1,4-dienyl]-2-methoxy-phenolate) has substantial anti-tumor activity in melanoma, but its mechanism of action remains unclear. Here we use a synthetic lethal genetic screen in Saccharomyces cerevisiae to identify 211 genes implicated in sensitivity to DM-1 toxicity. From these 211 genes, 74 had close human orthologues implicated in oxidative phosphorylation, insulin signaling and iron and RNA metabolism. Further analysis identified 7 target genes (ADK, ATP6V0B, PEMT, TOP1, ZFP36, ZFP36L1, ZFP36L2) with differential expression during melanoma progression implicated in regulation of tumor progression, cell differentiation, and epithelial-mesenchymal transition. Of these TOP1 and ADK were regulated by DM-1 in treatment-naïve and vemurafenib-resistant melanoma cells respectively. These data reveal that the anticancer effect of curcumin analogues is likely to be mediated via multiple targets and identify several genes that represent candidates for combinatorial targeting in melanoma.
      Graphical abstract image

      PubDate: 2017-09-06T14:54:11Z
      DOI: 10.1016/j.phrs.2017.08.018
       
  • Curcumin in Alzheimer’s disease: Can we think to new strategies and
           perspectives for this molecule'
    • Authors: Serafini Melania Maria; Catanzaro Michele; Rosini Michela; Racchi Marco; Lanni Cristina
      Abstract: Publication date: Available online 12 August 2017
      Source:Pharmacological Research
      Author(s): Serafini Melania Maria, Catanzaro Michele, Rosini Michela, Racchi Marco, Lanni Cristina
      Population aging is an irreversible global trend with economic and socio-political consequences. One of the most invalidating outcomes of aging in the elderly is cognitive decline, leading to dementia and often related to neurodegenerative disorders. Among these latter, Alzheimer’s disease (AD) is the major cause of dementia, affecting more than 30 million of individuals worldwide. To date, the treatment of AD remains a challenge because of an incomplete understanding of the events that lead to the selective neurodegeneration typical of Alzheimer’s brains. There is an enormous global demand for new effective therapies and researchers are investigating new fields. One promising strategy is the use of nutraceuticals as integrative, complementary and preventive therapy. Curcumin is one example of natural product with anti-AD properties, with promising potential for prevention, treatment and diagnostic. The limitations in the use of curcumin as therapeutic are represented by its pharmacokinetics profile and the low bioavailability after oral administration. However, curcumin has been the focus of intense research for new drug development. Here we analyzed some new approaches that have been applied in the attempt to improve its use, particularly new formulations, changes in the way of administration, nanotechnology-based delivery systems and the hybridization strategy.
      Graphical abstract image

      PubDate: 2017-08-19T13:49:28Z
      DOI: 10.1016/j.phrs.2017.08.004
       
  • Anti-inflammatory activity of natural stilbenoids: A review
    • Authors: Marcela Dvorakova; Premysl Landa
      Abstract: Publication date: Available online 9 August 2017
      Source:Pharmacological Research
      Author(s): Marcela Dvorakova, Premysl Landa
      Resveratrol and other natural stilbenoids, including piceatannol, pterostilbene, and gnetol, are well-known anti-inflammatory compounds with indisputable activity in vitro as well as in vivo. Their molecular targets include inducible nitric oxide synthase, cyclooxygenases, leukotrienes, nuclear factor kappa B, tumor necrosis factor α, interleukins and many more. This anti-inflammatory activity together with their antioxidant activity is believed to stand behind their other positive health effects against cancer, cardiovascular and neurodegenerative diseases or diabetes. Thus, they are nowadays commercially marketed as nutraceuticals. Naturally, they are present in wine, grapes or berries. However, there is a rigorous debate about the real effect of these compounds on human health. It is argued that the concentration of stilbenoids in food and beverages is too low to have any therapeutic potential and this concentration is further reduced by their low bioavailability and extensive metabolism. Therefore, this review focuses on in vitro, in vivo, preclinical as well as clinical data available for various natural stilbenoids and summarizes the anti-inflammatory targets on molecular level, compares the relevance of the experimental studies, discusses the metabolism of stilbenoids and the potential activity of their metabolites and relates this knowledge to human health. Moreover, the ways to augment stilbenoidś efficacy are suggested with special focus on multitargeted therapy and nanocarriers.
      Graphical abstract image

      PubDate: 2017-08-19T13:49:28Z
      DOI: 10.1016/j.phrs.2017.08.002
       
  • Antihypertensive drugs
    • Authors: Laurent
      Abstract: Publication date: Available online 2 August 2017
      Source:Pharmacological Research
      Author(s): Stéphane Laurent
      Successful treatment of hypertension is possible with limited side effects given the availability of multiple antihypertensive drug classes. This review describes the various pharmacological classes of antihypertensive drugs, under two major aspects: their mechanisms of action and side effects. The mechanism of action is analysed through a pharmacological approach, i.e. the molecular receptor targets, the various sites along the arterial system, and the extra-arterial sites of action, in order to better understand in which type of hypertension a given pharmacological class of antihypertensive drug is most indicated. In addition, side effects are described and explained through their pharmacological mechanisms, in order to better understand their mechanism of occurrence and in which patients drugs are contra-indicated. This review does not address the effectiveness of monotherapies in large randomized clinical trials and combination therapies, since these are the matters of other articles of the present issue. Five major pharmacological classes of antihypertensive drugs are detailed here: beta-blockers, diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, and calcium channel blockers. Four additional pharmacological classes are described in a shorter manner: renin inhibitors, alpha-adrenergic receptor blockers, centrally acting agents, and direct acting vasodilators.
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      PubDate: 2017-08-08T13:24:39Z
       
  • β3 adrenergic receptor activation relaxes human corpus cavernosum and
           penile artery through a hydrogen sulfide/cGMP-dependent mechanism
    • Authors: Emma Mitidieri; Teresa Tramontano; Danila Gurgone; Ciro Imbimbo; Vincenzo Mirone; Ferdinando Fusco; Giuseppe Cirino; Roberta d’Emmanuele di Villa Bianca; Raffaella Sorrentino
      Abstract: Publication date: Available online 29 July 2017
      Source:Pharmacological Research
      Author(s): Emma Mitidieri, Teresa Tramontano, Danila Gurgone, Ciro Imbimbo, Vincenzo Mirone, Ferdinando Fusco, Giuseppe Cirino, Roberta d’Emmanuele di Villa Bianca, Raffaella Sorrentino
      Erectile function is a widely accepted indicator of systemic endothelial activity since from a clinical standpoint erectile dysfunction (ED) often precedes cardiovascular events. Recently it has been described a potential role for β3 adrenoceptor in cardiovascular diseases emphasizing a possible development of new drugs. β3 adrenoceptor stimulation relaxes human corpus cavernosum (HCC) strips in cyclic guanosine monophosphate (cGMP)-dependent and endothelium/nitric oxide (NO)-independent manner. Hydrogen sulfide (H2S), along with NO, is another gaseous molecule involved in cardiovascular system and as a consequence also in penile erection. Cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE), the enzymes mainly responsible for H2S biosynthesis, are constitutively expressed in HCC. CSE rather than CBS is more abundant in human penile tissue. Herein we investigated the involvement of H2S pathway in β3 adrenoceptor-induced relaxation in HCC and penile artery. Penile artery expresses both CSE and β3 adrenoceptor. BRL37344, a β3 selective agonist, relaxed HCC strips and penile artery rings and this effect was significantly reduced by CSE inhibition. Incubation of HCC and penile artery homogenate with BRL37344 significantly increased H2S production. This effect was significantly reduced by the inhibition of either CSE or β3 adrenoceptor. Finally, the BRL37344-induced increase in cGMP was reduced by CSE inhibition in both tissues. Thus, BRL37344-induced relaxation in HCC and penile artery occurs in a H2S/cGMP-dependent manner. In conclusion, β3/H2S/cGMP pathway can act as an alternative to NO. Since about 15% of patients do not respond to phosphodiesterase-5 inhibitors, β3 agonists could represent a therapeutic alternative or a useful adjuvant therapy to treat these patients.
      Graphical abstract image

      PubDate: 2017-07-29T12:55:44Z
      DOI: 10.1016/j.phrs.2017.07.025
       
  • Terfenadine combined with epirubicin impedes the chemo-resistant human
           non-small cell lung cancer both in vitro and in vivo through EMT and Notch
           reversal
    • Authors: Li An; Dan-Dan Li; Hai-Xiao Chu; Qiao Zhang; Chang-Li Wang; Yan-Hua Fan; Qi Song; Hong-Da Ma; Fan Feng; Qing-Chun Zhao
      Abstract: Publication date: Available online 25 July 2017
      Source:Pharmacological Research
      Author(s): Li An, Dan-Dan Li, Hai-Xiao Chu, Qiao Zhang, Chang-Li Wang, Yan-Hua Fan, Qi Song, Hong-Da Ma, Fan Feng, Qing-Chun Zhao
      The acquired resistance of non-small cell lung cancer (NSCLC) to taxanes eventually leads to the recurrence and metastasis of tumours. Thus, the development of therapeutic strategies based on the mechanisms by which cells acquire resistance to prolong their survival rate in chemotherapy drug treatment failure patients are warranted. In this study, we found that the resistant cells acquired increased migratory and invasive capabilities, and this transformation was correlated with epithelial-mesenchymal transition (EMT) and Notch pathway deregulation in the resistant cells. Finally, we reported for the first time that terfenadine augmented the effect of epirubicin (EPI) better than Taxol and cisplatin (DDP) by inhibiting migration, invasion, and the EMT phenotype, and the combination therapy also reversed Notch signalling pathway and enhanced the accumulation of fluorescent P-gp substrate rhodamine 123 (Rh123). Similar activities of terfenadine on EPI were observed in xenografts. All of our results confirmed that terfenadine combined with EPI synergistically inhibits the growth and metastatic processes of resistant cells both in vitro and in vivo. Therefore, terfenadine or its derivatives are a promising approach for the clinical challenge of resistance in patients with advanced NSCLC.
      Graphical abstract image

      PubDate: 2017-07-29T12:55:44Z
      DOI: 10.1016/j.phrs.2017.07.021
       
  • Application of pharmacometrics and quantitative systems pharmacology to
           cancer therapy: The example of luminal a breast cancer
    • Authors: Brett Fleisher; Kayla Andrews; Ashley A. Brown; Sihem Ait-Oudhia
      Abstract: Publication date: Available online 19 July 2017
      Source:Pharmacological Research
      Author(s): Brett Fleisher, Kayla Andrews, Ashley A. Brown, Sihem Ait-Oudhia
      Breast cancer (BC) is the most common cancer in women, and the second most frequent cause of cancer-related deaths in women worldwide. It is a heterogeneous disease composed of multiple subtypes with distinct morphologies and clinical implications. Quantitative systems pharmacology (QSP) is an emerging discipline bridging systems biology with pharmacokinetics (PK) and pharmacodynamics (PD) leveraging the systematic understanding of drugs’ efficacy and toxicity. Despite numerous challenges in applying computational methodologies for QSP and mechanism-based PK/PD models to biological, physiological, and pharmacological data, bridging these disciplines has the potential to enhance our understanding of complex disease systems such as BC. In QSP/PK/PD models, various sources of data are combined including large, multi-scale experimental data such as −omics (i.e. genomics, transcriptomics, proteomics, and metabolomics), biomarkers (circulating and bound), PK, and PD endpoints. This offers a means for a translational application from pre-clinical mathematical models to patients, bridging the bench to bedside paradigm. Not only can these models be applied to inform and advance BC drug development, but they also could aid in optimizing combination therapies and rational dosing regimens for BC patients. Here, we review the current literature pertaining to the application of QSP and pharmacometrics-based pharmacotherapy in BC including bottom-up and top-down modeling approaches. Bottom-up modeling approaches employ mechanistic signal transduction pathways to predict the behavior of a biological system. The ones that are addressed in this review include signal transduction and homeostatic feedback modeling approaches. Alternatively, top-down modeling techniques are bioinformatics reconstruction techniques that infer static connections between molecules that make up a biological network and include (1) Bayesian networks, (2) co-expression networks, and (3) module-based approaches. This review also addresses novel techniques which utilize the principles of systems biology, synthetic lethality and tumor priming, both of which are discussed in relationship to novel drug targets and existing BC therapies. By utilizing QSP approaches, clinicians may develop a platform for improved dose individualization for subpopulation of BC patients, strengthen rationale in treatment designs, and explore mechanism elucidation for improving future treatments in BC medicine.
      Graphical abstract image

      PubDate: 2017-07-23T12:40:21Z
      DOI: 10.1016/j.phrs.2017.07.015
       
  • Potential anti-cancer activity of 7-O-pentyl quercetin: efficient,
           membrane-targeted kinase inhibition and pro-oxidant effect
    • Authors: Nicola Sassi; Andrea Mattarei; Virginia Espina; Lance Liotta; Mario Zoratti; Cristina Paradisi; Lucia Biasutto
      Abstract: Publication date: Available online 17 July 2017
      Source:Pharmacological Research
      Author(s): Nicola Sassi, Andrea Mattarei, Virginia Espina, Lance Liotta, Mario Zoratti, Cristina Paradisi, Lucia Biasutto
      Quercetin is a redox-active plant-derived flavonoid with potential anticancer effects, stemming largely from its interaction with a number of proteins, and in particular from inhibition of pro-life kinases. To improve efficacy, we reasoned that a local increase in concentration of the compound at the level of cell membranes would result in a more efficient interaction with membrane-associated signaling kinases. We report here the synthesis of all five isomeric quercetin derivatives in which an n-pentyl group was linked via an ether bond to each hydroxyl of the flavonoid kernel. This strategy proved effective in directing quercetin to cellular membranes, and revealed a remarkable dependence of the derivatives’ bioactivity on the specific site of functionalization. The isomer bearing the pentyl group in position 7, Q-7P, turned out to be the most effective and promising derivative, selectively inducing apoptosis in tumoral and fast-growing cells, while sparing slow-growing, non-tumoral ones. Cytotoxicity for tumoral cells was strongly enhanced compared to quercetin itself. Q-7P induced massive ROS production, which however accounted only partially for cell death. Alterations in the levels of various signaling phospho-proteins were observed in a proteomics screen. An important contribution seems to come from inhibition of the PI3K/Akt pathway. This work opens new perspectives in developing membrane-associating, polyphenol-based anticancer agents.
      Graphical abstract image

      PubDate: 2017-07-23T12:40:21Z
      DOI: 10.1016/j.phrs.2017.07.016
       
  • Transient receptor potential TRPM3 channels: pharmacology, signaling, and
           biological functions
    • Authors: Gerald Thiel; Sandra Rubil; Andrea Lesch; Lisbeth A. Guethlein; Oliver G. Rössler
      Abstract: Publication date: Available online 16 July 2017
      Source:Pharmacological Research
      Author(s): Gerald Thiel, Sandra Rubil, Andrea Lesch, Lisbeth A. Guethlein, Oliver G. Rössler
      The transient receptor potential melastatin-3 (TRPM3) channel belongs to the family of transient receptor potential (TRP) cation channels that are expressed in a variety of tissues and cell types, including dorsal root ganglia, cardiomyocytes and pancreatic beta-cells. Although its natural ligands are currently unknown, TRPM3 channels can be activated by the neurosteroid pregnenolone sulfate, the synthetic ligand CIM0216, and by noxious heat. TRPM3 channels are regulated by phosphoinositides, and perhaps by calmodulin. Stimulation of TRPM3 induces an intracellular signaling cascade involving a rise in intracellular Ca2+, activation of the protein kinases Raf, ERK and JNK, and the activation of the stimulus-responsive transcription factors AP-1, CREB, Egr-1, and Elk-1. Functionally, stimulation of TRPM3 channels is connected with heat sensation by somatosensory neurons, insulin secretion by pancreatic beta-cells, regulation of neurotransmitter release, iris constriction, and tumor promotion. With the development of highly specific activators and inhibitors of TRPM3 channels, we expect that additional tissue-specific functions of TRPM3 channels will be discovered, establishing TRPM3 channels as a new therapeutic target.
      Graphical abstract image

      PubDate: 2017-07-23T12:40:21Z
      DOI: 10.1016/j.phrs.2017.07.014
       
  • Drug repurposing in cancer
    • Authors: Linda Sleire; Hilde Elisabeth Førde; Inger Anne Netland; Lina Leiss; Per Øyvind Enger
      Abstract: Publication date: Available online 13 July 2017
      Source:Pharmacological Research
      Author(s): Linda Sleire, Hilde Elisabeth Førde, Inger Anne Netland, Lina Leiss, Per Øyvind Enger
      Cancer is a major health issue worldwide, and the global burden of cancer is expected to increase in the coming years. Whereas the limited success with current therapies has driven huge investments into drug development, the average number of FDA approvals per year has declined since the 1990s. This unmet need for more effective anti-cancer drugs has sparked a growing interest for drug repurposing, i.e. using drugs already approved for other indications to treat cancer. As such, data both from pre-clinical experiments, clinical trials and observational studies have demonstrated anti-tumor efficacy for compounds within a wide range of drug classes other than cancer. Whereas some of them induce cancer cell death or suppress various aspects of cancer cell behavior in established tumors, others may prevent cancer development. Here, we provide an overview of promising candidates for drug repurposing in cancer, as well as studies describing the biological mechanisms underlying their anti-neoplastic effects.
      Graphical abstract image

      PubDate: 2017-07-23T12:40:21Z
      DOI: 10.1016/j.phrs.2017.07.013
       
 
 
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