for Journals by Title or ISSN
for Articles by Keywords
help

Publisher: Elsevier   (Total: 3041 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  

The end of the list has been reached or no journals were found for your choice.
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  [3041 journals]
  • The mechanistic role of chemically diverse metal ions in the induction of
           autophagy
    • Authors: Sumit Sahni; Dong-Hun Bae; Patric J. Jansson; Des R. Richardson
      Pages: 118 - 127
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Sumit Sahni, Dong-Hun Bae, Patric J. Jansson, Des R. Richardson
      Autophagy is an evolutionary conserved cellular catabolic degradation process in response to stress which involves lysosomal degradation of unnecessary or damaged organelles and misfolded proteins. This is primarily a pro-survival pathway providing the cell with essential nutrients during stressful conditions. There are number of essential metal ions, which are required for normal physiological functioning of cells. Studies have shown that autophagy can be regulated by cellular metal ion concentrations. On the other hand, autophagy is also shown to regulate intracellular levels of certain metal ions. This review discusses recent advances in the research examining the role of metal ions in the autophagic pathway.
      Graphical abstract image

      PubDate: 2017-02-12T02:13:08Z
      DOI: 10.1016/j.phrs.2017.01.009
      Issue No: Vol. 119 (2017)
       
  • Is bigger still better' Walking on the trail of cancer nanomedicine
    • Authors: Davide Prosperi; Fabio Corsi
      Pages: 149 - 152
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Davide Prosperi, Fabio Corsi


      PubDate: 2017-02-12T02:13:08Z
      DOI: 10.1016/j.phrs.2017.01.030
      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)
       
  • Sex-gender-related therapeutic approaches for cardiovascular complications
           associated with diabetes
    • Authors: Ilaria Campesi; Flavia Franconi; Giuseppe Seghieri; Marco Meloni
      Pages: 195 - 207
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Ilaria Campesi, Flavia Franconi, Giuseppe Seghieri, Marco Meloni
      Diabetes is a chronic disease associated with micro- and macrovascular complications and is a well-established risk factor for cardiovascular disease. Cardiovascular complications associated with diabetes are among the most important causes of death in diabetic patients. Interestingly, several sex-gender differences have been reported to significantly impact in the pathophysiology of diabetes. In particular, sex-gender differences have been reported to affect diabetes epidemiology, risk factors, as well as cardiovascular complications associated with diabetes. This suggests that different therapeutic approaches are needed for managing diabetes-associated cardiovascular complications in men and women. In this review, we will discuss about the sex-gender differences that are known to impact on diabetes, mainly focusing on the cardiovascular complications associated with the disease. We will then discuss the therapeutic approaches for managing diabetes-associated cardiovascular complications and how differences in sex-gender can influence the existing therapeutic approaches.
      Graphical abstract image

      PubDate: 2017-02-18T03:06:37Z
      DOI: 10.1016/j.phrs.2017.01.023
      Issue No: Vol. 119 (2017)
       
  • Effects of curcumin on HDL functionality
    • Authors: Shiva Ganjali; Christopher N. Blesso; Maciej Banach; Matteo Pirro; Muhammed Majeed; Amirhossein Sahebkar
      Pages: 208 - 218
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Shiva Ganjali, Christopher N. Blesso, Maciej Banach, Matteo Pirro, Muhammed Majeed, Amirhossein Sahebkar
      Curcumin, a bioactive polyphenol, is a yellow pigment of the Curcuma longa (turmeric) plant. Curcumin has many pharmacologic effects including antioxidant, anti-carcinogenic, anti-obesity, anti-angiogenic and anti-inflammatory properties. Recently, it has been found that curcumin affects lipid metabolism, and subsequently, may alleviate hyperlipidemia and atherosclerosis. Plasma HDL cholesterol (HDL-C) is an independent negative risk predictor of cardiovascular disease (CVD). However, numerous clinical and genetic studies have yielded disappointing results about the therapeutic benefit of raising plasma HDL-C levels. Therefore, research efforts are now focused on improving HDL functionality, independent of HDL-C levels. The quality of HDL particles can vary considerably due to heterogeneity in composition. Consistent with its complexity in composition and metabolism, a wide range of biological activities is reported for HDL, including antioxidant, anti-glycation, anti-inflammatory, anti-thrombotic, anti-apoptotic and immune modulatory activities. Protective properties of curcumin may influence HDL functionality; therefore, we reviewed the literature to determine whether curcumin can augment HDL function. In this review, we concluded that curcumin may modulate markers of HDL function, such as apo-AI, CETP, LCAT, PON1, MPO activities and levels. Curcumin may subsequently improve conditions in which HDL is dysfunctional and may have potential as a therapeutic drug in future. Further clinical trials with bioavailability-improved formulations of curcumin are warranted to examine its effects on lipid metabolism and HDL function.
      Graphical abstract image

      PubDate: 2017-02-18T03:06:37Z
      DOI: 10.1016/j.phrs.2017.02.008
      Issue No: Vol. 119 (2017)
       
  • Antibiotics, gut microbiota, environment in early life and type 1 diabetes
    • Authors: Youjia Hu; F. Susan Wong; Li Wen
      Pages: 219 - 226
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Youjia Hu, F. Susan Wong, Li Wen
      The gut microbiota interact with innate immune cells and play an important role in shaping the immune system. Many factors may influence the composition of the microbiota such as mode of birth, diet, infections and medication including antibiotics. In diseases with a multifactorial etiology, like type 1 diabetes, manipulation and alterations of the microbiota in animal models have been shown to influence the incidence and onset of disease. The microbiota are an important part of the internal environment and understanding how these bacteria interact with the innate immune cells to generate immune tolerance may open up opportunities for development of new therapeutic strategies. In this review, we discuss recent findings in relation to the microbiota, particularly in the context of type 1 diabetes.
      Graphical abstract image

      PubDate: 2017-02-18T03:06:37Z
      DOI: 10.1016/j.phrs.2017.01.034
      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)
       
  • Sulforaphane inhibits platelet-derived growth factor-induced vascular
           smooth muscle cell proliferation by targeting mTOR/p70S6kinase signaling
           independent of Nrf2 activation
    • Authors: Noha M. Shawky; Lakshman Segar
      Pages: 251 - 264
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Noha M. Shawky, Lakshman Segar
      Activation of nuclear factor erythroid 2-related factor 2 (Nrf2, a transcription factor) and/or inhibition of mammalian target of rapamycin (mTOR) are implicated in the suppression of vascular smooth muscle cell (VSMC) proliferation. The present study has examined the likely regulatory effects of sulforaphane (SFN, an antioxidant) on Nrf2 activation and platelet-derived growth factor (PDGF)-induced mTOR signaling in VSMCs. Using human aortic VSMCs, nuclear extraction and siRNA-mediated downregulation studies were performed to determine the role of Nrf2 on SFN regulation of PDGF-induced proliferative signaling. Immunoprecipitation and/or immunoblot studies were carried out to determine how SFN regulates PDGF-induced mTOR/p70S6K/S6 versus ERK and Akt signaling. Immunohistochemical analysis was performed to determine SFN regulation of S6 phosphorylation in the injured mouse femoral artery. SFN (5μM) inhibits PDGF-induced activation of mTOR without affecting mTOR association with raptor in VSMCs. While SFN inhibits PDGF-induced phosphorylation of p70S6K and 4E-BP1 (downstream targets of mTOR), it does not affect ERK or Akt phosphorylation. In addition, SFN diminishes exaggerated phosphorylation of S6 ribosomal protein (a downstream target of p70S6K) in VSMCs in vitro and in the neointimal layer of injured artery in vivo. Although SFN promotes Nrf2 accumulation to upregulate cytoprotective genes (e.g., heme oxygenase-1 and thioredoxin-1), downregulation of endogenous Nrf2 by target-specific siRNA reveals an Nrf2-independent effect for SFN-mediated inhibition of mTOR/p70S6K/S6 signaling and suppression of VSMC proliferation. Strategies that utilize local delivery of SFN at the lesion site may limit restenosis after angioplasty by targeting mTOR/p70S6K/S6 axis in VSMCs independent of Nrf2 activation.
      Graphical abstract image

      PubDate: 2017-02-25T03:12:53Z
      DOI: 10.1016/j.phrs.2017.02.010
      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)
       
  • Annexin A1 influences in breast cancer: Controversies on contributions to
           tumour, host and immunoediting processes
    • Authors: Yan Tu; Cameron N. Johnstone; Alastair G. Stewart
      Pages: 278 - 288
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Yan Tu, Cameron N. Johnstone, Alastair G. Stewart
      Annexin A1 is a multifunctional protein characterised by its actions in modulating the innate and adaptive immune response. Accumulating evidence of altered annexin A1 expression in many human tumours raises interest in its functional role in cancer biology. In breast cancer, altered annexin A1 expression levels suggest a potential influence on tumorigenic and metastatic processes. However, reports of conflicting results reveal a relationship that is much more complex than first conceptualised. In this review, we explore the diverse actions of annexin A1 on breast tumour cells and various host cell types, including stromal immune and structural cells, particularly in the context of cancer immunoediting.
      Graphical abstract image

      PubDate: 2017-03-04T03:18:14Z
      DOI: 10.1016/j.phrs.2017.02.011
      Issue No: Vol. 119 (2017)
       
  • AdipoRon, an adiponectin receptor agonist, attenuates PDGF-induced VSMC
           proliferation through inhibition of mTOR signaling independent of AMPK:
           Implications toward suppression of neointimal hyperplasia
    • Authors: Arwa Fairaq; Noha M. Shawky; Islam Osman; Prahalathan Pichavaram; Lakshman Segar
      Pages: 289 - 302
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Arwa Fairaq, Noha M. Shawky, Islam Osman, Prahalathan Pichavaram, Lakshman Segar
      Hypoadiponectinemia is associated with an increased risk of coronary artery disease. Although adiponectin replenishment mitigates neointimal hyperplasia and atherosclerosis in mouse models, adiponectin therapy has been hampered in a clinical setting due to its large molecular size. Recent studies demonstrate that AdipoRon (a small-molecule adiponectin receptor agonist) improves glycemic control in type 2 diabetic mice and attenuates postischemic cardiac injury in adiponectin-deficient mice, in part, through activation of AMP-activated protein kinase (AMPK). To date, it remains unknown as to whether AdipoRon regulates vascular smooth muscle cell (VSMC) proliferation, which plays a major role in neointima formation. In the present study, oral administration of AdipoRon (50mg/kg) in C57BL/6J mice significantly diminished arterial injury-induced neointima formation by ∼57%. Under in vitro conditions, AdipoRon treatment led to significant inhibition of platelet-derived growth factor (PDGF)-induced VSMC proliferation, DNA synthesis, and cyclin D1 expression. While AdipoRon induced a rapid and sustained activation of AMPK, it also diminished basal and PDGF-induced phosphorylation of mTOR and its downstream targets, including p70S6K/S6 and 4E-BP1. However, siRNA-mediated AMPK downregulation showed persistent inhibition of p70S6K/S6 and 4E-BP1 phosphorylation, indicating AMPK-independent effects for AdipoRon inhibition of mTOR signaling. In addition, AdipoRon treatment resulted in a sustained and transient decrease in PDGF-induced phosphorylation of Akt and ERK, respectively. Furthermore, PDGF receptor-β tyrosine phosphorylation, which controls the phosphorylation state of Akt and ERK, was diminished upon AdipoRon treatment. Together, the present findings suggest that orally-administered AdipoRon has the potential to limit restenosis after angioplasty by targeting mTOR signaling independent of AMPK activation.
      Graphical abstract image

      PubDate: 2017-03-10T03:22:18Z
      DOI: 10.1016/j.phrs.2017.02.016
      Issue No: Vol. 119 (2017)
       
  • Anti-inflammatory and antioxidant effects of polyphenols extracted from
           Antirhea borbonica medicinal plant on adipocytes exposed to Porphyromonas
           gingivalis and Escherichia coli lipopolysaccharides
    • Authors: Fanny Le Sage; Olivier Meilhac; Marie-Paule Gonthier
      Pages: 303 - 312
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Fanny Le Sage, Olivier Meilhac, Marie-Paule Gonthier
      In obesity, gut microbiota LPS may translocate into the blood stream and then contribute to adipose tissue inflammation and oxidative stress, leading to insulin resistance. A causal link between periodontal infection, obesity and type 2 diabetes has also been suggested. We evaluated the ability of polyphenols from Antirhea borbonica medicinal plant to improve the inflammatory and redox status of 3T3-L1 adipocytes exposed to LPS of Porphyromonas gingivalis periodontopathogen or Escherichia coli enterobacteria. Our results show that LPS enhanced the production of Toll-like receptor-dependent MyD88 and NFκB signaling factors as well as IL-6, MCP-1, PAI-1 and resistin. Plant polyphenols reduced LPS pro-inflammatory action. Concomitantly, polyphenols increased the production of adiponectin and PPARγ, known as key anti-inflammatory and insulin-sensitizing mediators. Moreover, both LPS increased intracellular ROS levels and the expression of genes encoding ROS-producing enzymes including NOX2, NOX4 and iNOS. Plant polyphenols reversed these effects and up-regulated MnSOD and catalase antioxidant enzyme gene expression. Noticeably, preconditioning of cells with caffeic acid, chlorogenic acid or kaempferol identified among A. borbonica major polyphenols, led to similar protective properties. Altogether, these findings demonstrate the anti-inflammatory and antioxidant effects of A. borbonica polyphenols on adipocytes, in response to P. gingivalis or E. coli LPS. It will be of major interest to assess A. borbonica polyphenol benefits against obesity-related metabolic disorders such as insulin resistance in vivo.
      Graphical abstract image

      PubDate: 2017-03-10T03:22:18Z
      DOI: 10.1016/j.phrs.2017.02.020
      Issue No: Vol. 119 (2017)
       
  • High-content screening of clinically tested anticancer drugs identifies
           novel inhibitors of human MRP1 (ABCC1)
    • Authors: Brian G. Peterson; Kee W. Tan; Bremansu Osa-Andrews; Surtaj H. Iram
      Pages: 313 - 326
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Brian G. Peterson, Kee W. Tan, Bremansu Osa-Andrews, Surtaj H. Iram
      Multidrug resistance protein 1 (MRP1/ABCC1), an integral transmembrane efflux transporter, belongs to the ATP-binding cassette (ABC) protein superfamily. MRP1 governs the absorption and disposition of a wide variety of endogenous and xenobiotic substrates including various drugs across organs and physiological barriers. Additionally, its overexpression has been implicated in multidrug resistance in chemotherapy of multiple cancers. Here, we describe the development of a high content imaging-based screening assay for MRP1 activity. This live cell-based automated microscopy assay is very robust and allows simultaneous detection of cell permeable, non-toxic and potent inhibitors. The validity of the assay was demonstrated by profiling a library of 386 anti-cancer compounds, which are under clinical trials, for interactions with MRP1. The assay identified 12 potent inhibitors including two known MRP1 inhibitors, cyclosporine A and rapamycin. On the other hand, MRP1-inhibitory activity of tipifarnib, AZD1208, deforolimus, everolimus, temsirolimus, HS-173, YM201636, ESI-09, TAK-733, and CX-6258 has not been previously reported. Inhibition of MRP1 activity was further validated using flow cytometry and confocal microscopy for the respective detection of calcein and doxorubicin in MRP1-overexpressing cells. Among the identified compounds, tipifarnib, AZD1208, rapamycin, deforolimus, everolimus, TAK-733, and temsirolimus resensitized MRP1-overexpressing H69AR cells towards vincristine, a cytotoxic chemotherapeutic agent, by 2–6-fold. Using purified HEK293 membrane vesicles overexpressing MRP1, MRP2, MRP3, and MRP4, we also demonstrated that the identified compounds exert differential and selective response on the uptake of estradiol glucuronide, an endogenous MRP substrate. In summary, we demonstrated the effectiveness of the high content imaging-based high-throughput assay for profiling compound interaction with MRP1.
      Graphical abstract image

      PubDate: 2017-03-10T03:22:18Z
      DOI: 10.1016/j.phrs.2017.02.024
      Issue No: Vol. 119 (2017)
       
  • Diet phytochemicals and cutaneous carcinoma chemoprevention: A review
    • Authors: Siliang Wang; Peiliang Shen; Jinrong Zhou; Yin Lu
      Pages: 327 - 346
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Siliang Wang, Peiliang Shen, Jinrong Zhou, Yin Lu
      Cutaneous carcinoma, which has occupied a peculiar place among worldwide populations, is commonly responsible for the considerably increasing morbidity and mortality rates. Currently available medical procedures fail to completely avoid cutaneous carcinoma development or to prevent mortality. Cancer chemoprevention, as an alternative strategy, is being considered to reduce the incidence and burden of cancers through chemical agents. Derived from dietary foods, phytochemicals have become safe and reliable compounds for the chemoprevention of cutaneous carcinoma by relieving multiple pathological processes, including oxidative damage, epigenetic alteration, chronic inflammation, angiogenesis, etc. In this review, we presented comprehensive knowledges, main molecular mechanisms for the initiation and development of cutaneous carcinoma as well as effects of various diet phytochemicals on chemoprevention.
      Graphical abstract image

      PubDate: 2017-03-10T03:22:18Z
      DOI: 10.1016/j.phrs.2017.02.021
      Issue No: Vol. 119 (2017)
       
  • ATF2, a paradigm of the multifaceted regulation of transcription factors
           in biology and disease
    • Authors: Gregory Watson; Ze’ev Ronai; Eric Lau
      Pages: 347 - 357
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Gregory Watson, Ze’ev Ronai, Eric Lau
      Stringent transcriptional regulation is crucial for normal cellular biology and organismal development. Perturbations in the proper regulation of transcription factors can result in numerous pathologies, including cancer. Thus, understanding how transcription factors are regulated and how they are dysregulated in disease states is key to the therapeutic targeting of these factors and/or the pathways that they regulate. Activating transcription factor 2 (ATF2) has been studied in a number of developmental and pathological conditions. Recent findings have shed light on the transcriptional, post-transcriptional, and post-translational regulatory mechanisms that influence ATF2 function, and thus, the transcriptional programs coordinated by ATF2. Given our current knowledge of its multiple levels of regulation and function, ATF2 represents a paradigm for the mechanistic complexity that can regulate transcription factor function. Thus, increasing our understanding of the regulation and function of ATF2 will provide insights into fundamental regulatory mechanisms that influence how cells integrate extracellular and intracellular signals into a genomic response through transcription factors. Characterization of ATF2 dysfunction in the context of pathological conditions, particularly in cancer biology and response to therapy, will be important in understanding how pathways controlled by ATF2 or other transcription factors might be therapeutically exploited. In this review, we provide an overview of the currently known upstream regulators and downstream targets of ATF2.
      Graphical abstract image

      PubDate: 2017-03-10T03:22:18Z
      DOI: 10.1016/j.phrs.2017.02.004
      Issue No: Vol. 119 (2017)
       
  • The direct actions of cannabidiol and 2-arachidonoyl glycerol at GABAA
           receptors
    • Authors: T. Bakas; P.S. van Nieuwenhuijzen; S.O. Devenish; I.S. McGregor; J.C. Arnold; M. Chebib
      Pages: 358 - 370
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): T. Bakas, P.S. van Nieuwenhuijzen, S.O. Devenish, I.S. McGregor, J.C. Arnold, M. Chebib
      Cannabidiol (CBD) is a major non-intoxicating component of cannabis and possesses anti-epileptic, anxiolytic and anti-hyperalgesic properties. The mechanism of action of CBD in producing such effects remains unclear. Despite evidence that some endogenous and synthetic cannabinoids interact with GABAA receptors, no-one has yet investigated the effects of CBD. Here we used two-electrode voltage clamp electrophysiology to compare the actions of CBD with those of the major central endocannabinoid, 2-arachidonoyl glycerol (2-AG) on human recombinant GABAA receptors (synaptic α1-6βγ2 and extrasynaptic α4β2δ) expressed on Xenopus oocytes. CBD and 2-AG were positive allosteric modulators at α1-6βγ2 receptors, with low micromolar potencies. The maximal level of enhancement seen with either CBD or 2-AG were on α2-containing GABAA receptor subtypes, with approximately a 4-fold enhancement of the GABA EC5 evoked current, more than twice the potentiation seen with other α-subunit receptor combinations. Further we observed β-subunit selectivity, whereby modulatory activity was higher at β2/β3 over β1 subunits. The β1-subunit homologous mutant β2(V436T) substantially diminished the efficacy of both drugs to a third of that obtained with wild-type β2 subunit combinations, but without changing potency. The potency of CBD increased and efficacy preserved in binary α1/α2β2 receptors indicating that their effects do not involve the classic benzodiazepine site. Exploration of extrasynaptic α4β2δ receptors revealed that both compounds enhanced GABA EC5 evoked currents at concentrations ranging from 0.01–1μM. Taken together these results reveal a mode of action of CBD on specifically configured GABAA receptors that may be relevant to the anticonvulsant and anxiolytic effects of the compound.
      Graphical abstract image

      PubDate: 2017-03-10T03:22:18Z
      DOI: 10.1016/j.phrs.2017.02.022
      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: 2017-03-13T03:24:20Z
      DOI: 10.1016/j.phrs.2017.02.025
      Issue No: Vol. 119 (2017)
       
  • Curcumin as a potential protective compound against cardiac diseases
    • Authors: Shuai Jiang; Jing Han; Tian Li; Zhenlong Xin; Zhiqiang Ma; Wencheng Di; Wei Hu; Bing Gong; Shouyin Di; Dongjin Wang; Yang Yang
      Pages: 373 - 383
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): Shuai Jiang, Jing Han, Tian Li, Zhenlong Xin, Zhiqiang Ma, Wencheng Di, Wei Hu, Bing Gong, Shouyin Di, Dongjin Wang, Yang Yang
      Curcumin, which was first used 3000 years ago as an anti-inflammatory agent, is a well-known bioactive compound derived from the active ingredient of turmeric (Curcuma longa). Previous research has demonstrated that curcumin has immense therapeutic potential in a variety of diseases via anti-oxidative, anti-apoptotic, and anti-inflammatory pathways. Cardiac diseases are the leading cause of mortality worldwide and cause considerable harm to human beings. Numerous studies have suggested that curcumin exerts a protective role in the human body whereas its actions in cardiac diseases remain elusive and poorly understood. On the basis of the current evidence, we first give a brief introduction of cardiac diseases and curcumin, especially regarding the effects of curcumin in embryonic heart development. Secondly, we analyze the basic roles of curcumin in pathways that are dysregulated in cardiac diseases, including oxidative stress, apoptosis, and inflammation. Thirdly, actions of curcumin in different cardiac diseases will be discussed, as will relevant clinical trials. Eventually, we would like to discuss the existing controversial opinions and provide a detailed analysis followed by the remaining obstacles, advancement, and further prospects of the clinical application of curcumin. The information compiled here may serve as a comprehensive reference of the protective effects of curcumin in the heart, which is significant to the further research and design of curcumin analogs as therapeutic options for cardiac diseases.
      Graphical abstract image

      PubDate: 2017-03-13T03:24:20Z
      DOI: 10.1016/j.phrs.2017.03.001
      Issue No: Vol. 119 (2017)
       
  • Asthma and gender: The female lung
    • Authors: F.S. Pignataro; M. Bonini; A. Forgione; S. Melandri; O.S. Usmani
      Pages: 384 - 390
      Abstract: Publication date: May 2017
      Source:Pharmacological Research, Volume 119
      Author(s): F.S. Pignataro, M. Bonini, A. Forgione, S. Melandri, O.S. Usmani
      Asthma is a common chronic disease that affects over 300 million people worldwide, resulting in a considerable socio-economic burden. Literature data suggest that asthma has a higher incidence in females, particularly at certain stages of pubertal development. Moreover, women seem to experience more asthma symptoms than men and to use more rescue medications, resulting in a reduced quality of life. Although several mechanisms have been proposed to explain these differences, there are not yet final data available in the literature on the role of gender in the pathogenesis of asthma and different behavior in females. Some study suggested a more prevalent hyper-responsiveness in women than in men. Nevertheless, in the literature definitive data on a possible different response to drugs used for asthma between males and females are not described. Understanding the mechanisms that underlie these gender differences in clinical history of asthma patients could give inspiration to new areas of research to obtain a more specific diagnostic and therapeutic approach gender-oriented.
      Graphical abstract image

      PubDate: 2017-03-13T03:24:20Z
      DOI: 10.1016/j.phrs.2017.02.017
      Issue No: Vol. 119 (2017)
       
  • Introductory letter to the special issue “Country in focus,
           pharmacology in France”
    • Authors: Marie-Christine Perault-Pochat; Silvy Laporte
      First page: 1
      Abstract: Publication date: April 2017
      Source:Pharmacological Research, Volume 118
      Author(s): Marie-Christine Perault-Pochat, Silvy Laporte


      PubDate: 2017-03-10T03:22:18Z
      DOI: 10.1016/j.phrs.2017.01.021
      Issue No: Vol. 118 (2017)
       
  • Potassium lowering agents: Recommendations for physician and patient
           education, treatment reappraisal, and serial monitoring of potassium in
           patients with chronic hyperkalemia
    • Authors: Bertram Pitt; Patrick Rossignol
      Pages: 2 - 4
      Abstract: Publication date: April 2017
      Source:Pharmacological Research, Volume 118
      Author(s): Bertram Pitt, Patrick Rossignol


      PubDate: 2017-03-10T03:22:18Z
      DOI: 10.1016/j.phrs.2016.07.032
      Issue No: Vol. 118 (2017)
       
  • Current knowledge on the role of P2Y receptors in cardioprotection against
           ischemia-reperfusion
    • Authors: Zoubir Djerada; Catherine Feliu; Vincent Richard; Hervé Millart
      Pages: 5 - 18
      Abstract: Publication date: April 2017
      Source:Pharmacological Research, Volume 118
      Author(s): Zoubir Djerada, Catherine Feliu, Vincent Richard, Hervé Millart
      During ischemia, numerous effective endogenous extracellular mediators have been identified, particularly, nucleosides such as adenosine as well as purinergic and pyrimidinergic nucleotides. They may play important regulatory roles within the cardiovascular system and notably as cardio-protectants. Indeed, the distribution of the P2Y receptors in mammalian heart includes several cellular constituents relevant for the pathophysiology of myocardial ischemia. Beside the well-known cardioprotective effect of adenosine, the additional protective role of P2Y receptors has emerged. However, interpretation of experimental results may be sometimes perplexing. This is due to the variability of: the experimental models, the endpoints criteria, the chemical structure of agonist and antagonist ligands and their concentrations, the sequences of drug administration with respect to the model used (before and/or during and/or after ischemia). The net effect may be in the opposite direction after a transient or a prolonged stimulation. Nevertheless, the overall reading of published data highlights the beneficial role of the P2Y2/4 receptor stimulation, the useful and synergistic role of P2Y6/11 receptor activation and even of the P2Y11 receptor alone in cardioprotection. More, the P2Y11 receptor could be involved in counter-regulation of profibrotic processes. Paradoxically, transient P2X7 receptor stimulation could contribute to the net cardioprotective effect of ATP. Recently, experimental data have shown that blocking the P2Y12 receptor after ischemia confers cardioprotection independently of platelet antiaggregatory effect. This suggests for P2Y receptors an important role in primary prevention and as a therapeutic target in myocardial protection during ischemia and reperfusion.
      Graphical abstract image

      PubDate: 2017-03-10T03:22:18Z
      DOI: 10.1016/j.phrs.2016.08.009
      Issue No: Vol. 118 (2017)
       
  • Bleeding risk under selective serotonin reuptake inhibitor (SSRI)
           antidepressants: A meta-analysis of observational studies
    • Authors: Silvy Laporte; Céline Chapelle; Pascal Caillet; Marie-Noëlle Beyens; Florelle Bellet; Xavier Delavenne; Patrick Mismetti; Laurent Bertoletti
      Pages: 19 - 32
      Abstract: Publication date: April 2017
      Source:Pharmacological Research, Volume 118
      Author(s): Silvy Laporte, Céline Chapelle, Pascal Caillet, Marie-Noëlle Beyens, Florelle Bellet, Xavier Delavenne, Patrick Mismetti, Laurent Bertoletti
      Selective serotonin reuptake inhibitors (SSRIs) have been reported to be potentially associated with an increased risk of bleeding. A meta-analysis of observational studies was conducted to quantify this risk. Case-control and cohort studies investigating bleeding risk under SSRI therapy were retrieved by searching the Medline, Pascal, Google Scholar and Scopus databases. Case-control studies were included if they reported bleeding incidents with and without the use of SSRIs and cohort studies were included if they reported the rate of bleeds among SSRI users and non-users. The main outcome was severe bleeding, whatever the site. Only data concerning SSRI belonging to the ATC class N06AB were used. For both case-control and cohort studies, we recorded the adjusted effect estimates and their 95% confidence intervals (CI). Pooled adjusted odds ratio (OR) estimates were computed for case-control and cohort studies using an inverse-variance model. Meta-analysis of the adjusted ORs of 42 observational studies showed a significant association between SSRI use and the risk of bleeding [OR 1.41 (95% CI 1.27–1.57), random effect model, p<0.0001]. The association was found for the 31 case-control studies (1,255,073 patients), with an increased risk of 41% of bleeding [OR 1.41 (95% CI 1.25–1.60)], as well as for the 11 cohort studies including 187,956 patients [OR 1.36 (95% CI 1.12–1.64)]. Subgroup analyses showed that the association remained constant whatever the characteristics of studies. This meta-analysis shows an increased risk of bleeding of at least 36% (from 12% to 64%) based on the high-level of observational studies with SSRIs use.
      Graphical abstract image

      PubDate: 2017-03-10T03:22:18Z
      DOI: 10.1016/j.phrs.2016.08.017
      Issue No: Vol. 118 (2017)
       
  • Direct oral anticoagulants: Current indications and unmet needs in the
           treatment of venous thromboembolism
    • Authors: Laurent Bertoletti; Edouard Ollier; Cécile Duvillard; Xavier Delavenne; Marie-Noëlle Beyens; Elodie De Magalhaes; Florelle Bellet; Thierry Basset; Patrick Mismetti; Silvy Laporte
      Pages: 33 - 42
      Abstract: Publication date: April 2017
      Source:Pharmacological Research, Volume 118
      Author(s): Laurent Bertoletti, Edouard Ollier, Cécile Duvillard, Xavier Delavenne, Marie-Noëlle Beyens, Elodie De Magalhaes, Florelle Bellet, Thierry Basset, Patrick Mismetti, Silvy Laporte
      The treatment of acute venous thromboembolism (VTE) is being completely modified with the development of direct oral anticoagulants (DOACs). Rivaroxaban, apixaban and edoxaban directly inhibit factor Xa, whereas dabigatran inhibits factor IIa. All these drugs are proposed orally, and share pharmacological similarities: fixed doses without any therapeutic drug monitoring, key role of the transporter proteins P-glycoprotein for all of them and metabolism mediated by CYP3A4 for the anti-Xa, short half-life with variable rate of renal elimination. More than 25 000 patients with acute VTE were included in phase-III studies. Rivaroxaban and apixaban challenged all the conventional therapy (parenteral heparins followed by anti-vitamin K antagonists) whereas edoxaban and dabigatran challenged only anti-vitamin K antagonists. All the DOACs met the non-inferiority efficacy endpoint (recurrent VTE during treatment), whereas the large non-inferiority margin was debated for dabigatran. However, they were associated with better safety and a decreased risk of major bleeding. According to indirect comparisons, there were no statistically significant differences between DOACs in terms of efficacy but some differences are not excluded in term of safety. Although DOACs allow for simplification of treatment in the majority of patients with acute VTE, their risk/benefit ratio is questioned in elderly patients, patients with mild-to-severe renal impairment, and in some clinical subgroups such as cancer or chronic thromboembolic pulmonary hypertension. Validated reversal strategies (potentially based on laboratory monitoring) are expected for patients with major bleeding, overdose or with a need for surgery.
      Graphical abstract image

      PubDate: 2017-03-10T03:22:18Z
      DOI: 10.1016/j.phrs.2016.06.023
      Issue No: Vol. 118 (2017)
       
  • Pharmacological treatments of cardiovascular diseases: Evidence from
           real-life studies
    • Authors: Francesco Salvo; Julien Bezin; Pauline Bosco-Levy; Louis Letinier; Patrick Blin; Antoine Pariente; Nicholas Moore
      Pages: 43 - 52
      Abstract: Publication date: April 2017
      Source:Pharmacological Research, Volume 118
      Author(s): Francesco Salvo, Julien Bezin, Pauline Bosco-Levy, Louis Letinier, Patrick Blin, Antoine Pariente, Nicholas Moore
      The management of chronic cardiovascular diseases has evolved greatly in the last decades. Over the last thirty years, the management of acute coronary syndrome has improved, leading to an important lowering of the mortality in the acute phase of the event. Consequently, the optimal management of the secondary prevention of acute coronary syndrome has greatly evolved. Moreover, the increased number of pharmacological alternatives for patients affected by chronic heart failure and by non-valvular atrial fibrillation reserves a number of challenges for their correct management. Moreover, these diseases are without any reasonable doubt the largest contributor to global mortality in the present and will continue to be it in the future. The aim of this study was to provide the most updated information of the real-life drug use and their effectiveness. This review was performed to assess the potential knowledge gaps in the treatments of these diseases and to indicate potential perspective of pharmaco-epidemiological research in this area.

      PubDate: 2017-03-10T03:22:18Z
      DOI: 10.1016/j.phrs.2016.08.006
      Issue No: Vol. 118 (2017)
       
  • Should blood pressure goal be individualized in hypertensive patients?
    • Authors: Alexandra Yannoutsos; Rania Kheder-Elfekih; Jean-Michel Halimi; Michel E. Safar; Jacques Blacher
      Pages: 53 - 63
      Abstract: Publication date: April 2017
      Source:Pharmacological Research, Volume 118
      Author(s): Alexandra Yannoutsos, Rania Kheder-Elfekih, Jean-Michel Halimi, Michel E. Safar, Jacques Blacher
      The aim of the present review is to consider the clinical relevance of individualized blood pressure (BP) goal under treatment in hypertensive patients according to their age, comorbidities or established cardiovascular (CV) disease. Evidence from large-scale randomized trials to support a lower BP goal, as initially recommended by guidelines in high-risk hypertensive patients, were lacking. Recently, the randomized intervention SPRINT trial studied two treatment targets for systolic BP (120mm Hg versus 140mm Hg in the intensive and standard treatment group, respectively) among high-risk hypertensive patients, without diabetes and without a history of prior stroke. The trial was stopped prematurely owing to a significantly lower rate of the primary composite outcome and all-cause mortality in the intensive treatment group. Several practical questions have to be considered. First, using an automated measurement system at an office visit during the SPRINT protocol, while the patient was seated alone after 5min of quiet rest, may likely have resulted in lower BP values than would normally be obtained with the routine BP measurement. A target systolic of 120mm Hg in SRPINT trial may be thus equated to a target systolic BP of 130mm Hg in the real-world office setting. Second, careful and repeated examinations of SPRINT participants may have led to fewer adverse events (more frequent in the intensive treatment group) than that expected in the real-world setting. The safety profile of this intensive treatment approach should therefore remain a matter of concern in clinical practice, especially in elderly patients, in diabetic patients or with established CV or renal disease. Orthostatic hypotension should alert the clinician to withhold up titration. Third, beyond the question of BP goal, choice of antihypertensive medication and effective 24-h BP control are important to consider in the context of BP-lowering strategy. In particular, ambulatory BP measurements and during nighttime should be considered for an individualized hypertension care.
      Graphical abstract image

      PubDate: 2017-03-10T03:22:18Z
      DOI: 10.1016/j.phrs.2016.11.037
      Issue No: Vol. 118 (2017)
       
  • The effect of morbid obesity on morphine glucuronidation
    • Authors: Celia Lloret-Linares; Huilong Luo; Alexandra Rouquette; Laurence Labat; Christine Poitou; Joan Tordjman; Jean-Luc Bouillot; Stéphane Mouly; Jean-Michel Scherrmann; Jean-François Bergmann; Xavier Declèves
      Pages: 64 - 70
      Abstract: Publication date: April 2017
      Source:Pharmacological Research, Volume 118
      Author(s): Celia Lloret-Linares, Huilong Luo, Alexandra Rouquette, Laurence Labat, Christine Poitou, Joan Tordjman, Jean-Luc Bouillot, Stéphane Mouly, Jean-Michel Scherrmann, Jean-François Bergmann, Xavier Declèves
      The purpose of the present work was to study the change in morphine metabolic ratio in obese subjects before and after Roux-en-Y Gastric Bypass (RYGB) and to identify clinical and/or biological factors associated with this change. The pharmacokinetics (PK) of oral morphine (30mg), morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) was performed in patients before (n=25; mean BMI=43.2 (35.4–61.9)kg/m2), 7–15days (n=16) and 6 months after RYGB (n=19; mean BMI=32.3 (25.4–46.0)kg/m2). Morphine Cmax and AUC0-inf were significantly increased and morphine Tmax significantly shortened at 6 months after RYGB compared with preoperative data, indicating an important increase in the rate and extent of morphine absorption. The morphine metabolic ratio 0-inf M3G+M6G/Morphine, decreased significantly from the preoperative to 6 months postoperative period with an average of −26% (range −74%; +21%; p=0.004), but not in the immediate post-operative period. The change in morphine metabolic ratio was associated with a change in BMI, fat mass in kg, and triglyceride levels (rho=0.5, p≤0.04). The degree of change in several markers of low-grade inflammation, or the level of liver steatosis and fibrosis before surgery, was not associated with the change in morphine metabolic ratios. Our findings indicate that RYGB-induced weight loss significantly decreases morphine metabolic ratio, arguing for an effect of morbid obesity on glucuronidation. With glucuronide exposure at 6 months similar to preoperative values, a higher morphine AUC0-inf should encourage reducing morphine dosage in patients undergoing RYGB and chronically receiving immediate-release oral morphine.
      Graphical abstract image

      PubDate: 2017-03-10T03:22:18Z
      DOI: 10.1016/j.phrs.2016.08.031
      Issue No: Vol. 118 (2017)
       
  • Pharmacological aspects of the safety of gliflozins
    • Authors: Jean-Luc Faillie
      Pages: 71 - 81
      Abstract: Publication date: April 2017
      Source:Pharmacological Research, Volume 118
      Author(s): Jean-Luc Faillie
      Sodium-glucose transporter 2 (SGLT2) inhibitors, also known as gliflozins, are a new class of orally active drugs used in the management of type 2 diabetes. By inhibiting the SGLT responsible for the reabsorption of glucose from the kidney, their use aims primarily to induce glycosuria and, as a consequence, lower glycemic levels. However, their specific mechanism of action involves other pharmacodynamic consequences including potentially harmful adverse reactions. This manuscript reviews the physiological and pharmacological background behind inhibition of SGLTs, and discusses the pharmacological aspects of the safety of gliflozins.
      Graphical abstract image

      PubDate: 2017-03-10T03:22:18Z
      DOI: 10.1016/j.phrs.2016.07.001
      Issue No: Vol. 118 (2017)
       
  • Is the clinical relevance of drug-food and drug-herb interactions limited
           to grapefruit juice and Saint-John’s Wort?
    • Authors: Stéphane Mouly; Célia Lloret-Linares; Pierre-Olivier Sellier; Damien Sene; J.-F. Bergmann
      Pages: 82 - 92
      Abstract: Publication date: April 2017
      Source:Pharmacological Research, Volume 118
      Author(s): Stéphane Mouly, Célia Lloret-Linares, Pierre-Olivier Sellier, Damien Sene, J.-F. Bergmann
      An interaction of drug with food, herbs, and dietary supplements is usually the consequence of a physical, chemical or physiologic relationship between a drug and a product consumed as food, nutritional supplement or over-the-counter medicinal plant. The current educational review aims at reminding to the prescribing physicians that the most clinically relevant drug-food interactions may not be strictly limited to those with grapefruit juice and with the Saint John’s Wort herbal extract and may be responsible for changes in drug plasma concentrations, which in turn decrease efficacy or led to sometimes life-threatening toxicity. Common situations handled in clinical practice such as aging, concomitant medications, transplant recipients, patients with cancer, malnutrition, HIV infection and those receiving enteral or parenteral feeding may be at increased risk of drug-food or drug-herb interactions. Medications with narrow therapeutic index or potential life-threatening toxicity, e.g., the non-steroidal anti-inflammatory drugs, opioid analgesics, cardiovascular medications, warfarin, anticancer drugs and immunosuppressants may be at risk of significant drug-food interactions to occur. Despite the fact that considerable effort has been achieved to increase patient’ and doctor’s information and ability to anticipate their occurrence and consequences in clinical practice, a thorough and detailed health history and dietary recall are essential for identifying potential problems in order to optimize patient prescriptions and drug dosing on an individual basis as well as to increase the treatment risk/benefit ratio.
      Graphical abstract image

      PubDate: 2017-03-10T03:22:18Z
      DOI: 10.1016/j.phrs.2016.09.038
      Issue No: Vol. 118 (2017)
       
  • Increasing spinal 5-HT2A receptor responsiveness mediates anti-allodynic
           effect and potentiates fluoxetine efficacy in neuropathic rats. Evidence
           for GABA release
    • Authors: Amandine Dupuis; Anne-Sophie Wattiez; Jérémy Pinguet; Damien Richard; Frédéric Libert; Maryse Chalus; Youssef Aissouni; Benoit Sion; Denis Ardid; Philippe Marin; Alain Eschalier; Christine Courteix
      Pages: 93 - 103
      Abstract: Publication date: April 2017
      Source:Pharmacological Research, Volume 118
      Author(s): Amandine Dupuis, Anne-Sophie Wattiez, Jérémy Pinguet, Damien Richard, Frédéric Libert, Maryse Chalus, Youssef Aissouni, Benoit Sion, Denis Ardid, Philippe Marin, Alain Eschalier, Christine Courteix
      Antidepressants are one of the first line treatments for neuropathic pain but their use is limited by the incidence and severity of side effects of tricyclics and the weak effectiveness of selective serotonin reuptake inhibitors (SSRIs). Serotonin type 2A (5-HT2A) receptors interact with PDZ proteins that regulate their functionality and SSRI efficacy to alleviate pain. We investigated whether an interfering peptide (TAT-2ASCV) disrupting the interaction between 5-HT2A receptors and associated PDZ proteins would improve the treatment of traumatic neuropathic allodynia. Tactile allodynia was assessed in spinal nerve ligation-induced neuropathic pain in rats using von Frey filaments after acute treatment with TAT-2ASCV and/or 5-HT2A receptor agonist, alone or in combination with repeated treatment with fluoxetine. In vivo microdialysis was performed in order to examine the involvement of GABA in TAT-2ASCV/fluoxetine treatment-associated analgesia. TAT-2ASCV (100ng, single i.t. injection) improved SNL-induced tactile allodynia by increasing 5-HT2A receptor responsiveness to endogenous 5-HT. Fluoxetine alone (10mg/kg, five i.p. injections) slightly increased tactile thresholds and its co-administration with TAT-2ASCV (100ng, single i.t. injection) further enhanced the anti-allodynic effect. This effect depends on the integrity of descending serotonergic bulbospinal pathways and spinal release of GABA. The anti-allodynic effect of fluoxetine can be enhanced by disrupting 5-HT2A receptor-PDZ protein interactions. This enhancement depends on 5-HT2A receptor activation, spinal GABA release and GABAA receptor activation.
      Graphical abstract image

      PubDate: 2017-03-10T03:22:18Z
      DOI: 10.1016/j.phrs.2016.09.021
      Issue No: Vol. 118 (2017)
       
  • Screening for genotypic and phenotypic variations in CYP450 activity in
           patients with therapeutic problems in a psychiatric setting, a
           retrospective study
    • Authors: Célia Lloret-Linares; Victoria Rollason; Kuntheavy Ing Lorenzini; Caroline Samer; Youssef Daali; Marianne Gex-Fabry; Jean-Michel Aubry; Jules Desmeules; Marie Besson
      Pages: 104 - 110
      Abstract: Publication date: April 2017
      Source:Pharmacological Research, Volume 118
      Author(s): Célia Lloret-Linares, Victoria Rollason, Kuntheavy Ing Lorenzini, Caroline Samer, Youssef Daali, Marianne Gex-Fabry, Jean-Michel Aubry, Jules Desmeules, Marie Besson
      Objectives This retrospective study aimed to assess to what extent an adverse drug reaction (ADR), an abnormal therapeutic drug monitoring (TDM) or a non-response, was attributable to an abnormal cytochrome P450 activity in a psychiatric setting. Method We collected the results of investigations performed in these situations related to psychotropic drugs between January 2005 and November 2014. Activities of different cytochrome P450 were assessed by genotyping and/or phenotyping. Two experienced clinical pharmacologists assessed independently the possible association between the event and the results of the investigations. Results One hundred and thirty eight clinical or biological situations had a complete assessment of all major metabolic pathways of the target drug. A majority of clinical or biological situations were observed with antidepressants (n=93, 67.4%), followed by antipsychotics (n=28, 20.3%), benzodiazepines and hypnotics (n=13, 9.4%), and psychostimulants (n=4, 2.9%). Genotype and/or phenotype determination was mainly performed because of ADRs (n=68, 49.3%) or non-response (n=46, 33.3%). Inter-rate reliability of the scoring system between the pharmacologists was excellent (kappa=0.94). The probability of an association between ADR, TDM or non-response and metabolic status was rated as intermediate to high in 34.7% of all cases, with proportions of 30.4% and 36.7%, for non-response and ADR respectively. Conclusion When indicated by clinical pharmacologists, ADR, TDM or non-response may be attributable to a variation of the metabolic status with an intermediate to high probability in 34.7% of patients, based on the congruent assessment made by two clinical pharmacologists. Further studies assessing the clinical relevance of prospective explorations and clarifying the appropriate method according to the clinical context are needed.
      Graphical abstract image

      PubDate: 2017-03-10T03:22:18Z
      DOI: 10.1016/j.phrs.2016.07.002
      Issue No: Vol. 118 (2017)
       
  • Time-dependent impact of glutamatergic modulators on the promnesiant
           effect of 5-HT6R blockade on mice recognition memory
    • Authors: Rachel Asselot; Emmanuelle Simon-O’Brien; Sophie Lebourgeois; Gérald Nee; Virgile Delaunay; Pascal Duchatelle; Valentine Bouet; François Dauphin
      Pages: 111 - 118
      Abstract: Publication date: April 2017
      Source:Pharmacological Research, Volume 118
      Author(s): Rachel Asselot, Emmanuelle Simon-O’Brien, Sophie Lebourgeois, Gérald Nee, Virgile Delaunay, Pascal Duchatelle, Valentine Bouet, François Dauphin
      Selective antagonists at serotonin 5-HT6 receptors (5-HT6R) improve memory performance in rodents and are currently under clinical investigations. If blockade of 5-HT6R is known to increase glutamate release, only two studies have so far demonstrated an interaction between 5-HT6R and glutamate transmission, but both, using the non-competitive NMDA antagonist MK-801, insensitive to variations of glutamate concentrations. In a place recognition task, we investigated here in mice the role of glutamate transmission in the beneficial effects of 5-HT6R blockade (SB-271046). Through the use of increasing intervals (2, 4 and 6h) between acquisition and retrieval, we investigated the time-dependent impact of two different glutamatergic modulators. NMDAR-dependant glutamate transmission (NMDA Receptors) was either blocked by the competitive antagonist at NMDAR, CGS 19755, or potentiated by the glycine transporter type 1 (GlyT1) inhibitor, NFPS. Results showed that neither SB-271046, nor CGS 19755, nor NFPS, alter behavioural performances after short intervals, i.e. when control mice displayed significant memory performances (2h and 4h) (respectively 10, 3, and 0.625mg.kg−1). Conversely, with the 6h-interval, a situation in which spontaneous forgetting is observed in control mice, SB-271046 improved recognition memory performances. This beneficial effect was prevented when co-administered with either CGS 19755 or NFPS, which themselves had no effect. Interestingly, a dose-dependent effect was observed with NFPS, with promnesic effect observed at lower dose (0.156mg.kg−1) when administrated alone, whereas it did no modify promnesic effect of SB-271046. These results demonstrate that promnesiant effect induced by 5-HT6R blockade is sensitive to the competitive blockade of NMDAR and underline the need of a fine adjustment of the inhibition of GlyT1. Overall, our findings support the idea of a complex crosstalk between serotonergic and glutamatergic systems in the promnesic properties of 5-HT6R antagonists.
      Graphical abstract image

      PubDate: 2017-03-10T03:22:18Z
      DOI: 10.1016/j.phrs.2016.06.009
      Issue No: Vol. 118 (2017)
       
  • Neurological and digestive bleeding with Direct Oral Anticoagulants versus
           Vitamin K Antagonists: The differences do not stop there! A
           pharmacovigilance study
    • Authors: A. Cabarrot; J.L. Montastruc; L. Chebane; V. Rousseau; E. Bondon-Guitton; F. Moulis; G. Durrieu; H. Bagheri; F. Montastruc
      Pages: 119 - 120
      Abstract: Publication date: April 2017
      Source:Pharmacological Research, Volume 118
      Author(s): A. Cabarrot, J.L. Montastruc, L. Chebane, V. Rousseau, E. Bondon-Guitton, F. Moulis, G. Durrieu, H. Bagheri, F. Montastruc


      PubDate: 2017-03-10T03:22:18Z
      DOI: 10.1016/j.phrs.2016.05.024
      Issue No: Vol. 118 (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
       
  • GENDER DIFFERENCES IN CARDIOVASCULAR PROPHYLAXIS: FOCUS ON ANTIPLATELET
           TREATMENT
    • Authors: Paolo Di Giosia; Gabriella Passacquale; Marco Petrarca; Paolo Giorgini; Alberto Maria Marra; Albert Ferro
      Abstract: Publication date: Available online 25 January 2017
      Source:Pharmacological Research
      Author(s): Paolo Di Giosia, Gabriella Passacquale, Marco Petrarca, Paolo Giorgini, Alberto Maria Marra, Albert Ferro
      Cardiovascular disease (CVD) represents the leading cause of death worldwide, and equally affects both sexes although women develop disease at an older age than men. A number of clinical evidence has identified the female sex as an independent factor for poor prognosis, with the rate of mortality and disability following an acute cardiovascular (CV) event being higher in women than men. It has been argued that the different level of platelet reactivity between sexes may account for a different responsiveness to anti-platelet therapy, with consequent important implications on clinical outcomes. However, conclusive evidence supporting the concept of a gender-dependent effectiveness of platelet inhibitors are lacking. On the contrary, sex-related dissimilarities have been evidenced in cardiovascular patients in terms of age of presentation, comorbidities such as obesity, diabetes and renal disease, and a different pharmacological approach to and effectiveness in controlling classical cardiovascular risk factors such as hypertension, glucose profile and lipid dysmetabolism. All these factors could place women at an increased level of cardiovascular risk compared to men, and may concur to an enhanced pro-thrombogenic profile. The purpose of this manuscript is to provide an overview of gender-related differences in cardiovascular treatment, in order to highlight the need to improve the pharmacological prophylaxis adopted in women through a more accurate evaluation of the overall cardiovascular risk profile with consequent establishment of a more effective and targeted anti-thrombotic strategy which is not limited to the use of anti-platelet agents.
      Graphical abstract image

      PubDate: 2017-01-29T22:51:52Z
      DOI: 10.1016/j.phrs.2017.01.025
       
  • 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
       
  • Targeted basic research to highlight the role of estrogen and estrogen
           receptors in the cardiovascular system
    • Authors: Elke Dworatzek; Shokoufeh Mahmoodzadeh
      Abstract: Publication date: Available online 21 January 2017
      Source:Pharmacological Research
      Author(s): Elke Dworatzek, Shokoufeh Mahmoodzadeh
      Epidemiological, clinical and animal studies revealed that sex differences exist in the manifestation and outcome of cardiovascular disease (CVD). The underlying molecular mechanisms implicated in these sex differences are not fully understood. The reasons for sex differences in CVD are definitely multifactorial, but major evidence points to the contribution of sex steroid hormone, 17β-estradiol (E2), and its receptors, estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). In this review, we summarize past and present studies that implicate E2 and ER as important determinants of sexual dimorphism in the physiology and pathophysiology of the heart. In particular, we give an overview of studies aimed to reveal the role of E2 and ER in the physiology of the observed sex differences in CVD using ER knock-out mice. Finally, we discuss recent findings from novel transgenic mouse models, which have provided new information on the sexual dimorphic roles of ER specifically in cardiomyocytes under pathological conditions.
      Graphical abstract image

      PubDate: 2017-01-22T22:46:48Z
      DOI: 10.1016/j.phrs.2017.01.019
       
  • 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
       
  • An update on the assessment and management of Metabolic Syndrome, a
           growing medical emergency in paediatric populations
    • Authors: Chiara Mameli; Gian Vincenzo Zuccotti; Carla Carnovale; Erica Galli; Pilar Nannini; Davide Cervia; Cristiana Perrotta
      Abstract: Publication date: Available online 19 January 2017
      Source:Pharmacological Research
      Author(s): Chiara Mameli, Gian Vincenzo Zuccotti, Carla Carnovale, Erica Galli, Pilar Nannini, Davide Cervia, Cristiana Perrotta
      In the last decades the increasing rate of obesity in children and adolescent worldwide has led to the onset in paediatric age of metabolic syndrome a disease commonly associated to adulthood. Central obesity, dyslipidaemia, hyperglycaemia, and hypertension are typical features of metabolic syndrome that seem to hesitate often in type 2 diabetes, cardiovascular disease, non-alcoholic fatty liver disease, and many other clinical conditions. Thus preventing and curing metabolic syndrome in paediatric patients is becoming an urgent need for public health. While diagnostic criteria and therapy of metabolic syndrome in adults are very well defined, there is no consensus on the definition of metabolic syndrome in children and adolescents as well as on healing approaches. The aim of this review is to describe the recent advances on the pathogenesis and clinical outcomes of paediatric metabolic syndrome. We then detail the therapeutic strategies (i.e. dietary regimens, physical exercise, nutraceuticals, and medications) employed to manage the disease. Finally, we analyse the safety profile of the drugs used in children and adolescents by performing a retrospective review of paediatric adverse reactions reported in the FDA’s Adverse Event Reporting System database.
      Graphical abstract image

      PubDate: 2017-01-22T22:46:48Z
      DOI: 10.1016/j.phrs.2017.01.017
       
  • The 35-year odyssey of beta blockers in cirrhosis: any gender difference
           in sight?
    • Authors: Maria Antonella Burza; Hanns-Ulrich Marschall; Laura Napoleone; Antonio Molinaro
      Abstract: Publication date: Available online 15 January 2017
      Source:Pharmacological Research
      Author(s): Maria Antonella Burza, Hanns-Ulrich Marschall, Laura Napoleone, Antonio Molinaro
      Cirrhosis is the end-stage of chronic liver disease and leads to the development of portal hypertension and its complications such as esophagogastric varices. Non-selective beta blockers (NSBB) are the keystone for the treatment of portal hypertension since the 1980s and, over the decades, several studies have confirmed their beneficial effect on the prevention of variceal (re)bleeding. Pharmacological studies showed effects of gender, sex hormones, oral contraceptives, and pregnancy on cytochrome P450 (CYPs) enzymes that metabolise NSBB, suggesting that gender differences might exist in the effect of NSBB. In this review, we focused on the 35-year knowledge about the use of beta blockers in cirrhosis and potential gender differences. We specifically examined the role of NSBB in pre-primary, primary and secondary prophylaxis of variceal bleeding, compared two commonly used NSBB (i.e., Propranolol and Carvedilol), and present the current controversies about the window of treatment in advanced cirrhosis with a specific focus on gender differences in NSBB effects. NSBB are not currently recommended in pre-primary prophylaxis of varices mainly because of lack of proven efficacy. On the other hand, NSBB are strongly recommended in patient with cirrhosis as primary (as alternative to endoscopic band ligation, EBL) and secondary prophylaxis (in addition to EBL) of variceal bleeding. To date, no studies have focused specifically on the effect of gender on NSBB treatment. Data extrapolated from clinical studies show that gender was neither a risk factor for the development of varices nor associated with a different response to treatment in primary or secondary prophylaxis. According to the available guidelines, no different, gender-based treatment for portal hypertension is recommended.
      Graphical abstract image

      PubDate: 2017-01-15T22:30:15Z
      DOI: 10.1016/j.phrs.2017.01.015
       
 
 
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: 54.204.122.57
 
About JournalTOCs
API
Help
News (blog, publications)
JournalTOCs on Twitter   JournalTOCs on Facebook

JournalTOCs © 2009-2016