British Journal of Pharmacology Impact Factor & Information

Publisher: British Pharmacological Society, Wiley

Journal description

All aspects of experimental pharmacology including: Cellular and molecular pharmacology Biochemical pharmacology Neuroscience All aspects of general pharmacology Special Reports for rapid publication of important new results of special pharmacological significance The British Journal of Pharmacology is the leading 'original papers' publication in the field of general pharmacology.

Current impact factor: 4.99

Impact Factor Rankings

2015 Impact Factor Available summer 2015
2013 / 2014 Impact Factor 4.99
2012 Impact Factor 5.067
2011 Impact Factor 4.409
2010 Impact Factor 4.925
2009 Impact Factor 5.204
2008 Impact Factor 4.902
2007 Impact Factor 3.767
2006 Impact Factor 3.825
2005 Impact Factor 3.41
2004 Impact Factor 3.325
2003 Impact Factor 3.611
2002 Impact Factor 3.45
2001 Impact Factor 3.502
2000 Impact Factor 3.689
1999 Impact Factor 3.722
1998 Impact Factor 3.704
1997 Impact Factor 3.619
1996 Impact Factor 4.075
1995 Impact Factor 4.739
1994 Impact Factor 4.695
1993 Impact Factor 5.27
1992 Impact Factor 5.094

Impact factor over time

Impact factor

Additional details

5-year impact 4.90
Cited half-life 7.70
Immediacy index 1.29
Eigenfactor 0.05
Article influence 1.37
Website British Journal of Pharmacology website
Other titles British journal of pharmacology (Online), BJP
ISSN 1476-5381
OCLC 39502220
Material type Document, Periodical, Internet resource
Document type Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details


  • Pre-print
    • Author can archive a pre-print version
  • Post-print
    • Author cannot archive a post-print version
  • Restrictions
    • 12 months embargo
  • Conditions
    • Some journals have separate policies, please check with each journal directly
    • On author's personal website, institutional repositories, arXiv, AgEcon, PhilPapers, PubMed Central, RePEc or Social Science Research Network
    • Author's pre-print may not be updated with Publisher's Version/PDF
    • Author's pre-print must acknowledge acceptance for publication
    • On a non-profit server
    • Publisher's version/PDF cannot be used
    • Publisher source must be acknowledged with citation
    • Must link to publisher version with set statement (see policy)
    • If OnlineOpen is available, BBSRC, EPSRC, MRC, NERC and STFC authors, may self-archive after 12 months
    • If OnlineOpen is available, AHRC and ESRC authors, may self-archive after 24 months
    • Publisher last contacted on 07/08/2014
    • This policy is an exception to the default policies of 'Wiley'
  • Classification
    ​ yellow

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: BJP is changing its procedures for the submission of articles so that authors can optimize transparency and experimental design. This relates to current moves to strengthen the robustness of the basic research that underpins drug discovery and therapeutics. To this end we are publishing new Instructions to Authors (ITA). Some are already in place and take immediate effect while others will be introduced over the next few months. Emphasis is placed on gathering essential information that authors often forget to include; this will also facilitate peer-review by hard-pressed reviewers. We have been in discussion with the Editors of other Pharmacology journals and plan that similar changes will be taking place across the sector. This will ensure that the various generic guidelines are more clearly specified for pharmacology. The major changes will be supported by three editorials: In order to link published work to the growing network of databases we are introducing hyperlinks to drug targets and key drugs in the authoritative Guide to PHARMACOLOGY database of the International Union of Basic and Clinical Pharmacology, which is now produced with the support of BPS. This is then further linked to other biological and chemical databases, placing the work first in a pharmacological then in a broader scientific context. (McGrath et al., 2015a). We have assessed the implementation of the 2010 ARRIVE guidelines for reporting experiments involving animals and respond by significantly strengthening our requirements, especially relating to disclosure of information, rather than urging compliance with respect to every conceivable issue (McGrath & Lilley, 2015). As an international journal we believe that this must be done on a worldwide basis, taking account of differing practices but adhering to one ethical standard (McGrath et al., 2015b). Inadequacy of experimental design and statistical validity of analysis of drug-related research that underpins the discovery of new medicines has attracted recent criticism. We will publish new guidance for reporting statistical analysis and experimental design (Curtis et al., 2015). This Editorial is part of a series. To view the other Editorials in this series, visit: and © 2015 The British Pharmacological Society.
    British Journal of Pharmacology 06/2015; 172(11):2671-2674. DOI:10.1111/bph.12954
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    ABSTRACT: Recent advances in the understanding of gene regulation have shown there to be much more regulation of the genome than first thought, through epigenetic mechanisms. These epigenetic mechanisms are systems that have evolved to either switch off gene activity altogether, or fine-tune any existing genetic activation. Such systems are present in all genes and include chromatin modifications and remodelling, DNA methylation (such as CpG island methylation rates) and histone covalent modifications (e.g. acetylation, methylation), RNA interference by short interfering RNAs (siRNAs) and long non-coding RNAs (ncRNAs). These systems regulate genomic activity 'beyond' simple transcriptional factor inducer or repressor function of genes to generate mRNA. Epigenetic regulation of gene activity has been shown to be important in maintaining normal phenotypic activity of cells, as well as having a role in development and diseases such as cancer and neurodegenerative disorders such as Alzheimer's. Newer classes of drugs regulate epigenetic mechanisms to counteract disease states in humans. The reports in this issue describe some advances in epigenetic understanding that relate to human disease, and our ability to control these mechanisms by pharmacological means. Increasingly the importance of epigenetics is being uncovered - it is pharmacology that will have to keep pace. This article is part of a themed section on Epigenetics and Therapy. To view the other articles in this section visit © 2015 The British Pharmacological Society.
    British Journal of Pharmacology 06/2015; 172(11):2701-2704. DOI:10.1111/bph.13136
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    ABSTRACT: cyclic Adenosine monophosphate (cAMP) plays an important role in the transduction of signaling pathways involved in neuroprotection and immune regulation. Control of the levels of this nucleotide by inhibition of cAMP specific phosphodiesterases (PDEs) such as PDE7 may affect the pathological processes of neuroinflammatory diseases like multiple sclerosis (MS). In the present study we evaluated the therapeutic potential of the selective PDE7 inhibitor, named TC3.6 in a model of primary progressive multiple sclerosis (PPMS), a rare and severe variant of MS. TMEV-induced demyelinated disease (TMEV-IDD) is one of the models used to validate the therapeutic efficacy of new drugs in MS. As recent studies have analyzed the effect of PDE7 inhibitors in the EAE model of MS, here the TMEV-IDD model is used to test the efficacy in a progressive variant of MS. Mice were subjected to two protocols of TC3.6 administration: on the presymptomatic phase and once the disease was established. Treatment with TC3.6 ameliorated the disease course and improved motor deficits of infected mice. This was associated with down-regulation of microglial activation and reduced cellular infiltrates. Decreased expression of proinflammatory mediators such as COX-2 and the cytokines, IL-1β, TNFα, IFNγ and IL-6 in the spinal cord of TMEV-infected mice was also observed after TC3.6 administration. These findings support the interest of PDE7 inhibitors, and specifically TC3.6, as a novel class of agents with therapeutic potential for PPMS raising the possibility to develop regulatory preclinical studies to reach the clinic. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 05/2015; DOI:10.1111/bph.13192
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    ABSTRACT: Few neuropharmacological model systems are based on human neurons. Moreover, available test systems rarely reflect functional roles of co-cultured glial cells. The generation of a human in vitro counterpart of the widely-used 1-methyl-4-phenyl-tetrahydropyridine (MPTP) mouse model has therefore remained a challenge in drug discovery technology. We addressed this by successfully growing an intricate network of human dopaminergic (DA) neurons on top of a dense layer of astrocytes. In these co-cultures, MPTP was metabolized to 1-methyl-4-phenyl-pyridinium (MPP(+) ) by the glial cells, and the toxic metabolite was taken up through the dopamine transporter into neurons. For initial model characterization, we studied the activation of poly-(ADP-ribose)-polymerase (PARP). Similar to mouse models, MPTP exposure lead to (poly-ADP-ribose) synthesis, and neurodegeneration was blocked by PARP inhibitors. A panel of different putative neuroprotectants was then compared in monocultures and co-cultures. Rho kinase inhibitors worked in both models; CEP1347, ascorbic acid or a caspase inhibitor protected in monocultures form MPP(+) toxicity, but did not show any protection in co-cultures, when used alone or in combinations. Application of oxidized glutathione (GSSG) prevented degeneration in co-cultures, but not in monocultures. The surprisingly different pharmacological profiles of the models suggest that the presence of glial cells, and the in vivo-like generation of the toxic metabolite MPP(+) within the layered cultures played an important role for predictions of neuroprotection. The novel model system is closer to the situation in human brain tissue than conventional cultures, and its use for screening of candidate neuroprotectants may increase the predictiveness of a test battery. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 05/2015; DOI:10.1111/bph.13193
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    ABSTRACT: This Editorial is part of a series. To view the other Editorials in this series, visit:; and © 2015 The British Pharmacological Society.
    British Journal of Pharmacology 05/2015; DOI:10.1111/bph.13112
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    ABSTRACT: The ARRIVE guidelines have been implemented in BJP for 4 years with the aim of increasing transparency in reporting experiments involving animals. BJP has assessed our success in implementing them and concluded that we could do better. This editorial discusses the issues and explains how we are changing our requirements for authors to report their findings in experiments involving animals. This is one of a series of editorials discussing updates to the BJP Instructions to Authors LINKED EDITORIALS: This Editorial is part of a series. To view the other Editorials in this series, visit:; and © 2015 The British Pharmacological Society.
    British Journal of Pharmacology 05/2015; DOI:10.1111/bph.12955
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    ABSTRACT: Chemokines, and their receptors, are essential regulators of in vivo leukocyte migration and, some years ago, a systematic nomenclature system was developed for the chemokine receptor family. Chemokine receptor biology and biochemistry was recently extensively reviewed (Bachelerie et al., 2014). In this review we also highlighted a new component to the nomenclature system that incorporates receptors previously known as 'scavenging', or 'decoy', chemokine receptors on the basis of their lack of classical signaling responses to ligand binding and their general ability to scavenge, or sequester, their cognate chemokine ligands. These molecules are now collectively referred to as 'atypical chemokine receptors', or ACKRs, and play fundamental roles in regulating in vivo responses to chemokines. This commentary highlights this new addition to the chemokine receptor nomenclature system and provides brief information on the four receptors currently covered by this nomenclature. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 05/2015; DOI:10.1111/bph.13182
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    ABSTRACT: Dimethyl fumarate (DMF) was a newly approved drug for the treatment of relapsing forms of multiple sclerosis and relapsing-remitting multiple sclerosis. Here, we investigated the effects of DMF and its metabolites mono-methylfumarate (MMF) on different gastrointestinal cancer cell lines and the underlying molecular mechanisms. Cell viability was measured by MTT assay or CCK8 assay. The protein expressions were measured by western blot analysis. The lactate dehydrogenase (LDH) release, live- and dead-cell staining, intracellular glutathione (GSH) level, and mitochondrial membrane potential were examined by using commercial kits. DMF but not MMF induced cell necroptosis as demonstrated by the pharmacological tool necrostatin-1, transmission electron microscopy,lactate dehydrogenase (LDH) and HMGB1 release in CT26 cells. DMF-induced decrease of cellular GSH level as well as cell viability and increase of reactive oxygen species (ROS) were inhibited by co-treatment with glutathione (GSH) and N-acetylcysteine (NAC) in CT26 cells. DMF activated JNK, P38, and ERK MAPKs in CT26 cells. JNK, P38, and ERK inhibitors partially reversed DMF-induced decrease of cell viability. GSH or NAC treatment inhibited DMF-induced JNK, P38, and ERK activation in CT26 cells. DMF but not MMF induced increased autophagy responses in SGC-7901, HCT116, HT29, and CT26 cancer cells, but autophagy inhibition did not prevent DMF-induced decrease of cell viability. DMF but not its metabolite MMF induces necroptosis in colon cancer cells and the mechanism is through GSH depletion/ROS increase/MAPKs activation pathway. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 05/2015; DOI:10.1111/bph.13184
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    ABSTRACT: The activation of M3 muscarinic acetylcholine receptors (M3 -mAChRs) by choline reduces cardiovascular risk, but it is unclear whether these receptors can regulate ischaemia/reperfusion (I/R)-induced vascular injury. Thus, the primary goal of the present study was to explore the effects of choline on the function of mesenteric arteries following I/R, with a major focus on Ca(2+) /calmodulin-dependent protein kinase II (CaMKII) regulation. Rats were administered choline (10 mg kg(-1) , intravenous [i.v.]), and then subjected to a 60 min period of ischaemia induced by occlusion of the superior mesenteric artery followed by 90 min of reperfusion. 4-DAMP (0.12 μg kg(-1) , i.v.), a M3 -mAChR antagonist, was injected 5 min prior to choline treatment. Vascular function was examined after the reperfusion procedure. Vascular superoxide anion production, CaMKII, and the levels of Ca(2+) -cycling proteins were also assessed. Choline treatment attenuated I/R-induced vascular dysfunction, blocked elevations in the levels of reactive oxygen species (ROS), and decreased the upregulated expression of oxidised CaMKII and phosphorylated CaMKII. In addition, choline reversed the abnormal expression of Ca(2+) -cycling proteins, including Na(+) /Ca(2+) exchanger, inositol 1,4,5-trisphosphate receptor, sarcoplasmic reticulum Ca(2+) -ATPase and phospholamban. All of these cholinergic effects of choline were abolished by 4-DAMP. Our data suggest that inhibition of the ROS-mediated CaMKII pathway and modulation of Ca(2+) -cycling proteins may be a novel mechanism underlying choline-induced vascular protection. These results represent a significant addition to the understanding of the pharmacological roles of M3 -mAChRs in the vasculature, providing new therapeutic strategy for I/R-induced vascular injury. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 05/2015; DOI:10.1111/bph.13183
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    ABSTRACT: The epithelial sodium channel (ENaC) is expressed in vascular endothelial cells and is a negative modulator of vasodilation. However, the role of endothelial ENaC in salt-sensitive hypertension remains unclear. We would investigate how endothelial ENaC responds to high-salt (HS) challenge in Sprague-Dawley (SD) rat. The blood pressure (BP) and plasma aldosterone levels were measured. We used patch-clamp technique to record ENaC, for the first time, in split-open mesenteric arteries (MAs). Western blot and Griess assay were used to detect expression of α-ENaC, eNOS and nitric oxide (NO). Vasodilatation in 2(nd) -order MAs was measured with wire myograph assays. Functional ENaC was observed in endothelial cells, and its activity was significantly decreased one week after HS diet. Three weeks after HS diet, ENaC expression was also reduced. When either ENaC activity or expression was reduced, endothelium-dependent relaxation (EDR) of MAs was enhanced, as tested by acetylcholine (ACh), and this enhancement of EDR was mimicked by amiloride, an ENaC blocker. On the other hand, HS diet significantly increased contractility of MAs, due to the decreased eNOS activity and NO levels; however, ACh-induced percent increment of NO was much higher in MAs isolated from HS rats compared to that from NS rats. HS intake significantly increased the BP of SD rats, but simultaneously enhanced EDR by reducing ENaC activity and expression due to the feedback inhibition. Therefore, ENaC may play an important role in endothelial cells for vasculature to adapt to HS challenge. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 05/2015; DOI:10.1111/bph.13185
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    ABSTRACT: The processes underpinning post-developmental neurogenesis in the mammalian brain continue to be defined. Such processes involve the proliferation of neural stem cells (NSCs) and neural progenitor cells (NPCs), neuronal migration, differentiation and integration into a network of functional synapses within the brain. Both intrinsic (cell signalling cascades) and extrinsic (neurotrophins, neurotransmitters, cytokines, hormones) signalling molecules are intimately associated with adult neurogenesis and largely dictate the proliferative activity and differentiation capacity of neural cells. Cannabinoids are a unique class of chemical compounds incorporating plant-derived cannabinoids (the active components of Cannabis sativa), the endogenous cannabinoids and synthetic cannabinoid ligands, and these compounds are becoming increasingly recognized for their roles in neural developmental processes. Indeed, cannabinoids have clear modulatory roles in adult neurogenesis, likely through activation of both CB1 and CB2 receptors. In recent years a large body of literature has deciphered the signalling networks involved in cannabinoid-mediated regulation of neurogenesis. This timely review summarises the evidence that the cannabinoid system is intricately associated with neuronal differentiation and maturation of NPCs, and highlights intrinsic/extrinsic signalling mechanisms that are cannabinoid targets. Overall these findings identify the central role of the cannabinoid system in adult neurogenesis in the hippocampus and the lateral ventricles, and hence provide insight into the processes underlying post-developmental neurogenesis in the mammalian brain. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 05/2015; DOI:10.1111/bph.13186
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    ABSTRACT: This review concerns how the primary inflammation preceding the generation of certain key damage-associated molecular patterns (DAMPs) arises in Alzheimer's disease (AD). In doing so it places soluble amyloid beta (Aβ) in a novel perspective. We argue here that increased soluble Aβ is one of the proinflammatory cytokine-induced DAMPs recognized by at least one of the Toll-like receptors (TLRs) on and in various cell types. Moreover, Aβ is best regarded as belonging to a class of DAMPs, as do the S100 proteins and HMBG1, that further exacerbate production of these same proinflammatory cytokines, which are already enhanced, and induced them further. Moreover, variation in levels of other DAMPs of this same class in AD may explain why normal aged patients can exhibit high Aβ plaque levels, and why removing Aβ or its plaque does not retard disease progression. It may also explain why mouse transgenic models, having been designed to generate high Aβ, can be treated successfully by this approach. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 05/2015; DOI:10.1111/bph.13181
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    ABSTRACT: Traumatic brain injury (TBI) has been linked to dementia and chronic neurodegeneration. Described initially in boxers and currently recognized across high contact sports, the association between repeated concussion (mild TBI) and progressive neuropsychiatric abnormalities has recently received widespread attention, and has been termed chronic traumatic encephalopathy (CTE). Less well appreciated are cognitive changes associated with neurodegeneration in the brain after isolated spinal cord injury (SCI). Also under-recognized is the role of sustained neuroinflammation after brain or spinal cord trauma, even though this relationship has been known since the 1950's and is supported by more recent pre-clinical and clinical studies. These pathological mechanisms, manifested by extensive microglial and astroglial activation and appropriately termed chronic traumatic brain inflammation (CTBI) or chronic traumatic inflammatory encephalopathy (CTIE), may be among the most important causes of posttraumatic neurodegeneration in terms of prevalence. Importantly, emerging experimental work demonstrates that persistent neuroinflammation can cause progressive neurodegeneration that may be treatable even weeks after traumatic injury. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 05/2015; DOI:10.1111/bph.13179
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    ABSTRACT: Background and purposeT16Ainh-A01, CaCCinh-A01, and MONNA are identified as selective inhibitors of the TMEM16A calcium-activated chloride channel (CaCC). The aim of this study was to examine the chloride-specificity of these compounds on isolated resistance arteries in the presence and absence (±) of extracellular chloride.Experimental approachIsolated resistance arteries were maintained in a myograph and tension recording in some instances combined with microelectrode impalement for membrane potential measurements or intracellular calcium monitoring using fura-2. Voltage-dependent calcium currents (VDCC) were measured in A7r5 cells with voltage-clamp electrophysiology using barium as charge carrier.Key resultsRodent arteries pre-constricted with noradrenaline or U46619 were concentration-dependently relaxed by T16Ainh-A01 (0.1–10μM): IC50 and maximum relaxation were equivalent ±chloride (30 minute aspartate substitution) and the T16Ainh-A01-induced vasorelaxation ±chloride was accompanied by membrane hyperpolarization and lowering of intracellular calcium. However, agonist concentration–response curves ±chloride, with 10μM T16Ainh-A01 present, achieved similar maximum constrictions though agonist-sensitivity decreased. Contractions induced by elevated extracellular potassium were concentration-dependently relaxed by T16Ainh-A01 ±chloride. Moreover, T16Ainh-A01 inhibited VDCC in A7r5 cells in a concentration-dependent manner. CaCCinh-A01 and MONNA (0.1–10μM) induced vasorelaxation ±chloride and both compounds lowered maximum contractility. 10μM MONNA induced substantial membrane hyperpolarization under resting conditions.Conclusions and implicationsT16Ainh-A01, CaCCinh-A01, and MONNA concentration-dependently relax rodent resistance arteries but an equivalent vasorelaxation occurs when the transmembrane chloride gradient is abolished with an impermeant anion. These compounds therefore display poor selectivity for TMEM16A and inhibition of CaCC in vascular tissue in the concentration range that inhibits the isolated conductance.
    British Journal of Pharmacology 05/2015; DOI:10.1111/bph.13201
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    ABSTRACT: The discovery that flavonoids are capable of inhibiting platelet function has led to their investigation as potential antithrombotic agents. However, despite the range of studies on the antiplatelet properties of flavonoids, little is known about the mechanisms by which flavonoids inhibit platelet function. In this study, we aimed to explore the pharmacological effects of a polymethoxy flavonoid, nobiletin in the modulation of platelet function. The ability of nobiletin to modulate platelet function was explored by using a range of in vitro and in vivo experimental approaches. Aggregation, dense granule secretion and spreading assays were performed using washed platelets. The fibrinogen binding, α-granule secretion and calcium mobilisation assays were performed using platelet-rich plasma and whole blood was used in impedance aggregometry and thrombus formation experiments. The effect of nobiletin in vivo was assessed by measuring tail bleeding time using C57BL/6 mice. Nobiletin was shown to supress a range of well-established activatory mechanisms, including platelet aggregation, granule secretion, integrin modulation, calcium mobilisation and thrombus formation. Nobiletin was shown to extend bleeding time in mice and reduce the phosphorylation of Akt and PLCγ2 within the collagen receptor (GPVI) - stimulated pathway, in addition to increasing the levels of cGMP and phosphorylation of VASP, a protein whose activity is associated with inhibitory cyclic nucleotide signalling. This study provides insight into the underlying molecular mechanisms through which nobiletin modulates haemostasis and thrombus formation. Therefore nobiletin may represent a potential antithrombotic agent of dietary origins. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 05/2015; DOI:10.1111/bph.13191
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    ABSTRACT: Small molecule inhibitors of prolyl hydroxylase enzymes (PHD) are a novel target for the treatment of anaemia and functional iron deficiency (FID). Other than being orally bio-available the differentiation of PHD inhibitors from recombinant human erythropoietin (rhEPO) has not been demonstrated. JNJ-42905343 was identified and characterized as a novel inhibitor of PHD and its action compared to rhEPO in healthy rats and in a rat model of inflammation induced-anaemia and FID (peptidoglycan-polysaccharide (PGPS) model). Oral administration of JNJ-42905343 to healthy rats increased the gene expression of cytochrome b (DcytB) and divalent metal-ion transporter 1 (DMT1) in the duodenum, increased plasma EPO and repeated administration of JNJ-42905343 for 28 days increased blood haemoglobin, mean corpuscular haemoglobin (MCH) and mean corpuscular volume (MCV). Serum iron concentration was increased with low doses (0.3 mg kg(-1) ) but reduced at high doses (6 mg kg(-1) ). In PGPS-treated rats, administration of JNJ-42905343 for 28 days corrected FID and anaemia as reflected by increased blood haemoglobin, MCH and MCV. Increased expression of DcytB and DMT1 genes in the duodenum resulting in increased iron availability was defined as the mechanism for these effects. rhEPO did not affect DcytB and DMT1 and was not effective in PGPS treated rats. PHD inhibition has a beneficial impact on iron metabolism in addition to stimulating the release of EPO. Small molecule inhibitors of PHD such as JNJ-42905343 represent a mechanism distinct from rhEPO to treat anaemia and FID. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 05/2015; DOI:10.1111/bph.13188
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    ABSTRACT: Highly vascularized ovarian carcinoma secretes the putative endocannabinoid and G-protein coupled receptor 55 (GPR55) ligand L-α-lysophosphatidylinositol (LPI) into the circulation. We aimed to elucidate the involvement of LPI/GPR55 in ovarian cancer angiogenesis. Secretion of LPI by three ovary cancer cell lines (OVCAR-3, OVCAR-5 and COV-362) was tested by mass spectrometery. Involvement of cancer cell-derived LPI on angiogenesis was tested in the in vivo chicken chorioallantoic membrane (CAM) assay along with the assessment of the effect of LPI on proliferation, network-formation, migration of neonatal and adult human endothelial colony-forming cells (ECFCs). Engagement of GPR55 was verified by using its pharmacological inhibitor CID16020046 and diminution of GPR55 expression by four respective target-specific siRNAs. To study underlying signal transduction Western blot analysis were performed. Ovarian carcinoma cell-derived LPI stimulated angiogenesis in the CAM assay. Applied LPI stimulated proliferation, network-formation, migration of neonatal and ECFCs in vitro and angiogenesis in the in vivo CAM. The pharmacological GPR55-inhibitor CID16020046 inhibited LPI-stimulated ECFC proliferation, network-formation and migration in vitro as well as ovarian carcinoma cells- and LPI-induced angiogenesis in vivo. Four target-specific siRNAs against GPR55 prevented the effect of LPI on angiogenesis. These pro-angiogenic effects of LPI where induced by GPR55-dependent phosphorylation of ERK1/2 and p38 kinase. We conclude that inhibiting the pro-angiogenic LPI/GPR55-pathway appears a promising target against angiogenesis in ovarian carcinoma. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 05/2015; DOI:10.1111/bph.13196
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    ABSTRACT: Background and purposeNF-κB driven inflammation is negatively regulated by the zinc finger protein, A20. Gibberellic acid (GA3) is a plant-derived diterpenoid with documented anti-inflammatory activity, which is reported to induce A20-like zinc finger proteins in plants. Here, we sought to investigate the anti-inflammatory effect of GA3 in airway epithelial cells and determine if the anti-inflammatory action relates to A20 induction.Experimental approachPrimary nasal epithelial cells (n=7), and a human bronchial epithelial cell line (16HBE14o-) were used. Cells were pre-incubated with GA3 (30μM, 1h), stimulated with Pseudomonas aeruginosa LPS (10μg/ml), IL-6 and IL-8 release, A20, NF-κB and IκBα expression determined. To determine if any observed anti-inflammatory effect occurred via an A20-dependent mechanism, A20 was silenced using siRNA.Key resultsGA3 pre-incubation significantly induced A20 mRNA (4h) and protein (24h), resulting in a significant reduction in IL-6 and IL-8 release. This effect was mediated via reduced IκBα degradation and reduced NF-κB (p65) expression. Furthermore, the anti-inflammatory action of GA3 was abrogated in A20-silenced cells.Conclusions and implicationsHere we show that A20 induction by GA3 attenuates inflammation in airway epithelial cells, at least in part through its effect on NF-κB and IκBα. GA3 or gibberellin-derived derivatives could potentially be developed into anti-inflammatory drugs for the treatment of chronic inflammatory diseases associated with A20 dysfunction.
    British Journal of Pharmacology 05/2015; DOI:10.1111/bph.13200