British Journal of Pharmacology (Br J Pharmacol )

Publisher: British Pharmacological Society, Blackwell Publishing

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: 5.07

Impact Factor Rankings

2015 Impact Factor Available summer 2015
2011 Impact Factor 4.409

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

Blackwell Publishing

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    • Articles in some journals can be made Open Access on payment of additional charge
    • 'Blackwell Publishing' is an imprint of 'Wiley'
  • Classification
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Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Linked ArticlesThis article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-6
    British Journal of Pharmacology 03/2015; 172(6).
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    ABSTRACT: Andrographolide is the most active constituent of the medicinal plant Andrographis paniculata. Previously, we synthesized a novel andrographolide derivative AL-1, conjugating andrographolide with lipoic acid. Although the antioxidative and/or anti-inflammatory activity of AL-1 contributes to its cytoprotective effects, whether AL-1 can improve insulin resistance and the underlying mechanisms remain largely unknown. We investigated the anti-hyperlipidemic and anti-hyperglycemic effects of AL-1 on high fat diet-fed/STZ-induced animal diabetic model. In addition, we investigated the effect of AL-1 on NF-κB signaling pathway in RIN-m cells with a focus on the link between ROS-associated inflammation and insulin resistance. AL-1 had significant hypoglycemic effect at the doses of 40 and 80 mg/kg, and which could significantly reduced the level of cholesterol and increased high-density lipoprotein. AL-1 reduced homeostasis model assessment of insulin resistance (HOMA-IR) and enhanced insulin sensitivity. In addition, AL-1 improved the morphology of pancreatic islet and their function. Furthermore, AL-1 suppressed high glucose-induced phosphorylation of the p65 and IκBα in RIN-m cells. AL-1 had the hypoglycemic effect and improved insulin resistance in type 2 diabetic rats. It prevented islet from high glucose-induced oxidative damage via the down-regulation of NF-κB signaling pathway. Further investigation of AL-1 as a promising new agent for treatment and/or prevention of diabetes are warranted. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 02/2015;
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    ABSTRACT: Background and Purpose Targeted modulation of autophagy induced by myocardial ischemia/reperfusion has been the subject of intensive investigation, but there are controversies on whether autophagy is beneficial or harmful. This study is to evaluate the effects of pharmacological manipulation of autophagy on the survival of cardiomyocyte in different time windows of ischemia/reperfusion. Experimental Approach We examined the autophagy and apoptosis in cardiomyocytes subjected to different durations of anoxia/reoxygenation or ischemia/reperfusion, and evaluated the effects of autophagic enhancer rapamycin and inhibitor wortmannin on cell survival. Key Results In neonatal rat cardiomyocytes (NRCs) or murine hearts, autophagy was increased in response to anoxia/reoxygenation or ischemia/reperfusion in a time-dependent manner. Rapamycin-enhanced autophagy in NRCs led to higher cell viability and less apoptosis when anoxia was sustained for ≦6h. However, when anoxia was prolonged to 12 h, rapamycin did not increase cell viability, induced less apoptosis and more autophagic cell death. When anoxia was prolonged to 24h, rapamycin increased autophagic cell death, while wortmannin reduced autophagic cell death and apoptosis. Similar results were obtained in mice subjected to ischemia/reperfusion. Rapamycin inhibited the opening of mitochondrial transition pore in NRCs exposed to 6h anoxia/4h reoxygenation but did not exert any effect when anoxia was extended to 24h. Similarly, rapamycin reduced the myocardial expression of Bax in mice subjected to short-time ischemia, but this effect disappeared when ischemia was extended to 24h. Conclusions and Implications The cardioprotection of autophagy is context-dependent and therapies involving autophagy perturbation should be determined according to the time phase of ischemia/reperfusion.
    British Journal of Pharmacology 02/2015;
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    ABSTRACT: Functional Kv7 channels' existence in thalamocortical relay (TC) neurons and impact of M-type K+-current (IM) on thalamic signal processing have long been debated. Immunocytochemical evidence suggests their presence in this brain region. Therefore we aimed to verify their existence, pharmacological properties and function in regulating activity in neurons of the ventrobasal thalamus (VB). Characterisation of Kv7 channels was performed by combining in vitro, in vivo and in silico techniques with a pharmacological approach. Retigabine (30 μM) and XE991 (20 μM), a specific Kv7 channel enhancer and blocker, respectively, were applied in acute brain slices during electrophysiological recordings. Consequences of intrathalamic injection of retigabine (3 mM, 300 nl) and/or XE991 (2 mM, 300 nl) were investigated in freely behaving animals during hot-plate tests by behavioural observation and recording of neuronal activity. Kv7.2 and Kv7.3 subunits are abundantly expressed in TC neurons of mouse VB. A slow K+-current with properties of IM was activated by retigabine and inhibited by XE991. Kv7 channel activation resulted in membrane hyperpolarisation, reduction of tonic action potential firing, and increased burst-firing in vitro and in computational models. Single-unit recordings and pharmacological intervention demonstrated a specific burst-firing increase upon IM activation in vivo. A Kv7 channel-mediated increase in pain threshold was associated with fewer VB units responding to noxious stimuli, and increased burst firing in responsive neurons. These results show that Kv7 channel enhancement alters somatosensory activity and may reflect an anti-nociceptive mechanism during acute pain-processing. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 02/2015;
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    ABSTRACT: Background and PurposeLysophosphatidylinositol (LPI), a lipid signalling molecule, activates GPR55 and elevates intracellular Ca2+. Here we examine the actions of LPI in the rat resistance mesenteric artery and Ca2+ responses in endothelial cells isolated from the artery.Experimental ApproachVascular responses were studied using a wire myograph. Single-cell fluorescence imaging was performed using a MetaFluor system. The hypotensive effect of LPI was assessed using a Biopac system.Key ResultsIn isolated arteries, LPI-induced vasorelaxation was concentration- and endothelium-dependent and inhibited by CID 16020046, a GPR55 antagonist. The CB1 receptor antagonist AM 251 had no effect, whereas rimonabant and O-1918, significantly potentiated LPI responses. Vasorelaxation was reduced by charybdotoxin and iberiotoxin, alone or combined. LPI decreased systemic arterial pressure. GPR55 is expressed in rat mesenteric artery. LPI caused biphasic elevations of intracellular Ca2+. Pretreatment with thapsigargin or 2-APB abolished both phases. The PLC inhibitor U73122 attenuated the initial phase and enhanced the second, whereas the ROCK inhibitor Y-27632 failed to inhibit the early phase but abolished the late phase.Conclusions and ImplicationsLPI is an endothelium-dependent vasodilator in the rat small mesenteric artery and hypotensive agent. The vascular response involves activation of Ca2+-sensitive K+ channels, and is not mediated by CB1 receptors, but unexpectedly enhanced by antagonists of the “endothelial anandamide” receptor. In endothelial cells, LPI utilizes PLC-IP3 and perhaps ROCK-RhoA pathways to elevate intracellular Ca2+. Overall, these findings support the existence of an endothelial site where LPI mediates its action and suggest a possible role for GPR55 in vasculature.
    British Journal of Pharmacology 02/2015;
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    ABSTRACT: Receptor tyrosine kinase inhibitors (RTKIs) targeted at vascular endothelial growth factor receptor 2 (VEGFR2) have proved to be attractive approaches to cancer therapy based on their ability to reduce angiogenesis. Here we have undertaken a quantitative analysis of the interaction of RTKIs and two VEGF splice variants, VEGF165 a and VEGF165 b, with VEGFR2 by studying nuclear factor of activated T cells (NFAT) reporter gene activity in living HEK 293 cells. HEK-293 cells expressing the human VEGFR2 and a firefly luciferase reporter gene regulated by an NFAT response element were used for quantitative analysis of the impact of RTKIs on VEGF165 a - and VEGF165 b - stimulated luciferase gene expression. VEGF165 a produced a concentration-dependent activation of the NFAT-luciferase reporter gene in living cells that was inhibited in a non-competitive fashion by four different RTKIs (cediranib, pazopanib, sorafenib and vandetanib). The potency obtained for each RTKI from this analysis was similar to those obtained in binding studies using purified VEGFR2 kinase domains. VEGF165 b was a lower efficacy agonist of the NFAT-luciferase response when compared to VEGF165 a. Analysis of the concentration-response data using the operational model of agonism indicated that both VEGF165 isoforms had similar affinity for VEGFR2. Quantitative pharmacological analysis of the interaction of VEGF165 isoforms and RTKIs with VEGFR2 in intact living cells has provided important insights into the relative affinity and efficacy of VEGF165 a and VEGF165 b for activation of the calcineurin- NFAT signalling pathway by this tyrosine kinase receptor. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 02/2015;
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    ABSTRACT: Background and purposeLeptin, an adipokine synthesized by the placenta during pregnancy, has been proposed for the management of preterm labor (PTL), since it is able to prevent in vitro uterine contractility and remodeling associated with labor onset. Another common feature of labor onset is the phenotypic switch of myometrial smooth muscle cells from a proliferative to a hypertrophic state. As proliferative effects have been demonstrated for leptin in other tissues, we aimed to investigate its ability to induce myometrial proliferation and thus to maintain uterine quiescence.Experimental approachWe stimulated human primary myometrial smooth muscle cells with leptin in the presence or absence of receptors antagonists or signaling pathways inhibitors.Key resultsWe found that leptin induces myometrial cell proliferation in a biphasic way. At 6.25ng/ml, leptin-induced proliferation is mediated by leptin receptor (OB-R) and requires an early Erk1/2 activation. Then, we demonstrated that at a concentration above 25ng/ml, leptin induces a direct non-specific IL-6R stimulation leading to NFκB activation and exerts anti-proliferative effects. However, at 50ng/ml, leptin re-induces proliferation via IL-6R stimulation that requires STAT3 and delayed Erk1/2 activation.Conclusions and implicationsThese data bring new insights into leptin signaling-induced myometrial proliferation and its interrelationship with the IL-6/IL-6R axis. In light of our previous work, the present study emphasizes the potential value of leptin in the pharmacological management of preterm labor and it also strengthens the hypothesis that leptin might be a contributory factor in parturition-related disorders observed in obese women.
    British Journal of Pharmacology 02/2015;
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    ABSTRACT: Class A1 scavenger receptor (SR-A1) is a membrane glycoprotein that can form homotrimers. It was originally defined by its ability to mediate the accumulation of lipids in macrophages. Subsequent studies reveal that SR-A1 plays critical roles in innate immunity, cell apoptosis and proliferation. This review highlights recent advances in understanding the structure, receptor pathway and regulation of SR-A1. Although its role in atherosclerosis is disputable, recent discoveries suggest that SR-A1 function in anti-inflammatory responses by promoting a M2 macrophage phenotype in cardiovascular diseases. Therefore, SR-A1 may be a potential target for therapeutic intervention of cardiovascular diseases.
    British Journal of Pharmacology 02/2015;
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    ABSTRACT: Background and purposeEndocannabinoids are a family of lipid mediators that are involved in the regulation of gastrointestinal (GI) motility. The expression, localization and function of their biosynthetic enzymes in the GI tract are not well understood. Here we examined the expression, localization and function of the enzyme diacylglycerol lipase (DAGLα), involved in the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG).Experimental approachCannabinoid (CB)1-deficient, wildtype control and C3H/HeJ mice, a genetically constipated model, were used. The distribution of DAGLα in the enteric nervous system was examined by immunohistochemistry. The effects of the DAGL inhibitors, Orlistat and OMDM-188 on pharmacologically induced GI hypomotility were assessed by measuring intestinal contractility in vitro and whole gut transit or fecal output in vivo. EC levels were measured by mass spectrometry.Key resultsDAGLα was expressed throughout the GI tract. In the intestine, unlike DAGLβ, DAGLα immunoreactivity was prominently expressed in the enteric nervous system; in the myenteric plexus, it was co-localized with the vesicular acetylcholine transporter in cholinergic nerves. In normal mice, inhibiting DAGL significantly reversed both pharmacologically reduced intestinal contractility and pharmacologically prolonged whole gut transit. Moreover, inhibiting DAGL normalized fecal output in constipated C3H/HeJ mice. In the colon incubated with scopolamine, 2-AG was elevated while inhibiting DAGL normalized 2-AG levels.Conclusions and ImplicationsDAGLα is expressed in the enteric nervous system and its inhibition reverses slowed GI motility, intestinal contractility and constipation through 2-AG and CB1 receptor mediated mechanisms. Our data suggest that DAGLα inhibitors may be promising candidates for the treatment of constipation.
    British Journal of Pharmacology 02/2015;
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    ABSTRACT: Background and purposeCalcitonin gene-related peptide (CGRP) plays an important role in the pathology of migraine and recent clinical trials suggest the inhibition of CGRP-mediated processes as a new therapeutic option in migraine. In this study we describe the generation of NOX-L41, a CGRP-neutralizing mirror-image (l-)aptamer (Spiegelmer) and investigate its in vitro and in vivo function.Experimental approachA CGRP-binding Spiegelmer was identified by in vitro selection. Binding studies were performed using surface plasmon resonance (SPR) and the inhibitory activity was determined in cell-based assays. The pharmacokinetic profile comparing intravenous and subcutaneous dosing was analyzed in rats. Intravital two-photon microscopy was employed to follow extravasation from meningeal vessels. Finally, in vivo efficacy was tested in a model of electrically evoked meningeal plasma protein extravasation (PPE) in rats.Key resultsWe identified NOX-L41, a novel CGRP-neutralizing Spiegelmer. SPR studies show that NOX-L41 binds to human and rat/mouse CGRP with sub-nanomolar affinities and is highly selective against related peptides such as amylin. In vitro, NOX-L41 effectively inhibits CGRP-induced cAMP formation in SK-N-MC cells. In rats, NOX-L41 has a plasma half-life of 8 hours. Pharmacodynamic studies show that NOX-L41 extravasates from blood vessels in the dura mater and inhibits neurogenic meningeal PPE for at least 18 hours after single dosing.Conclusions and implicationsThis is the first description of the CGRP-neutralizing Spiegelmer NOX-L41. Pre-clinical studies confirm a role of CGRP in neurogenic PPE and provide proof-of-concept for the potential use of this new drug candidate for the treatment or prevention of migraine.
    British Journal of Pharmacology 02/2015;
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    ABSTRACT: Background and PurposeKaempferol, a plant flavonoid present in the normal human diet, can modulate vasomotor tone. The present study aimed to elucidate the signaling pathway through which this flavonoid enhances relaxation of vascular smooth muscle.Experimental ApproachThe effect of kaempferol on the relaxation of porcine coronary arteries to endothelium-dependent (bradykinin) and -independent (sodium nitroprusside) relaxing agents was studied in an in vitro organ chamber setup. The whole-cell patch clamp technique was used to determine the effect of kaempferol on potassium channels in porcine coronary artery smooth muscle cells (PCASMCs).Key ResultsAt a concentration without direct effect on vascular tone, kaempferol (3 × 10-6 M) enhanced relaxations produced by bradykinin and sodium nitroprusside. The potentiation by kaempferol of the bradykinin-induced relaxation was not affected by Nω-nitro-L-arginine methyl ester (nitric oxide synthases inhibitor, 10-4 M) or TRAM-34 plus UCL 1684 (inhibitors of intermediate- and small-conductance calcium-activated potassium channels, respectively, 10-6 M each), but was abolished by tetraethylammonium chloride (non-selective inhibitor of calcium-activated potassium channels; 10-3 M) and iberiotoxin [selective inhibitor of large-conductance calcium-activated potassium channel (KCa1.1); 10-7 M]. Iberiotoxin also inhibited the potentiation by kaempferol of sodium nitroprusside-induced relaxations. Kaempferol stimulated an outward-rectifying current in PCASMCs; this outward current was abolished by iberiotoxin.Conclusions and ImplicationsThe present results suggest that, in smooth muscle cells of the porcine coronary artery, kaempferol enhances relaxations caused by endothelium-derived and exogenous nitric oxide as well as those due to endothelium-dependent hyperpolarization. This vascular effect of kaempferol involves the activation of KCa1.1 channels.
    British Journal of Pharmacology 02/2015;
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    ABSTRACT: We aimed to characterise the pharmacology and electrophysiology of N-[3-(1H-benzimidazol-2-yl)-4-chloro-phenyl]pyridine-3-carboxamide (AZSMO-23), an activator of the human ether-a-go-go-related gene (hERG)-encoded potassium channel (Kv11.1). Automated electrophysiology was used to study the pharmacology of AZSMO-23 on wild-type (WT), Y652A, F656T or G628C/S631C hERG, and on other cardiac ion channels. Conventional electrophysiology was used to characterise its mechanism of action. AZSMO-23 activated WT hERG pre-pulse and tail current with EC50 values of 28.6 μM and 11.2 μM, respectively. At 100 μM, pre-pulse current at +40 mV was increased by 952 ± 41% and tail current at -30 mV by 238 ± 13% compared with vehicle values. The primary mechanism for this effect was a 74.5 mV depolarising shift in the voltage dependence of inactivation, but there was no shift the voltage dependence of activation. Structure-activity relationships for this effect were remarkably subtle, with close analogues of AZSMO-23 behaving instead as hERG inhibitors. Versus hERG Y652A, AZSMO-23 behaved as a blocker but its activator activity was enhanced against hERG F656T. It inhibited activity of the G628C/S631C non-inactivating hERG mutant. AZSMO-23 was not hERG-selective: it blocked hKv4.3-hKChIP2.2, hCav3.2 and hKv1.5 and activated hCav1.2/β2/α2δ. The activity of AZSMO-23 and that of its close analogues suggest these compounds may be of value to further probe the mechanism of type 2 hERG activators to better understand the pharmacology of this area from both a safety perspective and in relation to treatment of congenital Long QT syndrome. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 02/2015;
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    ABSTRACT: Abstract Background & Purpose GoSlo-SR compounds are efficacious BK channel openers, but little is known about their mechanism of action or effect on bladder contractility. We examined the effects of two closely related compounds on BK currents and bladder contractions. Experimental approach A combination of electrophysiology, molecular biology and synthetic chemistry was used to examine the effects of two novel channel agonists on BK channels from bladder smooth muscle cells and in HEK cells expressing BKα alone or in combination with either β1 or β4 subunits. Key Results GoSlo-SR-5-6 shifted the voltage required for half maximal activation (V1/2) of BK channels ∼-100 mV, irrespective of the presence of regulatory β subunits. The deaminated derivative, GoSlo-SR-5-130, also shifted the activation V1/2 in smooth muscle cells by ∼-100 mV, however this was reduced by ∼80% in HEK cells expressing only BKα subunits. When β1 or β4 subunits were co-expressed with BKα, efficacy was restored. GoSlo-SR-5-130 caused a concentration dependent reduction in spontaneous bladder contraction amplitude and this was abolished by iberiotoxin, consistent with an effect on BK channels. Conclusions & implications GoSlo-SR-5-130 required β1 or β4 subunits to mediate its full effects, whereas GoSlo-SR-5-6 worked equally well in the absence or presence of β subunits. GoSlo-SR-5-130 inhibited spontaneous bladder contractions by activating BK channels. Significance The novel BK channel opener, GoSlo-SR-5-130, is ∼5 fold more efficacious on BK channels with regulatory β subunits and may be a useful scaffold in the development of drugs to treat diseases such as overactive bladder.
    British Journal of Pharmacology 01/2015;
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    ABSTRACT: Background and PurposeAbdominal aortic aneurysm (AAA) is a degenerative vascular disease associated to angiogenesis. Bexarotene is a Retinoid X Receptor (RXR) ligand with anti-angiogenic activity. Statins also exert anti-angiogenic activity and activate PPARs. Since RXR ligands form permissive heterodimers with PPARs and a single anti-angiogenic drug may not be sufficient to combat the wide array of angiogenic factors produced during AAA, we have evaluated the effect of combined low doses of bexarotene and rosuvastatin in a mouse model of AAAExperimental ApproachThe effect of the combined treatment was investigated in a murine model of Ang-II-induced AAA in apoE-/- mice. This combination therapy was also evaluated in vivo (matrigel plug assay) and in vitro (endothelial cell diferentiation assay) models of angiogenesis as well as the underlying mechanisms involved.Key resultsCo-treatment with bexarotene plus rosuvastatin reduced aneurysm formation, inflammation and neovascularisation compared to each single treatment. In HUVEC, the combination of suboptimal concentrations of bexarotene and rosuvastatin inhibited Ang-II-induced morphogenesis, proliferation and migration. These effects were accompanied by diminished production of proangiogenic chemokines (CXCL1, CCL2 or CCL5) and VEGF, and seemed to be mediated by RXRα/PPARα and RXRα/PPARγ activation. This combined therapy reduced the activation of members of the downstream PI3K pathway (AKT/mTOR and p70S6K1) in vivo and in vitroConclusions and ImplicationsCombination of RXR agonists with statins at low doses synergistically interferes with the signalling pathways that modulate inflammation and angiogenesis and may constitute a new and safer therapeutic tool for the control of AAA.
    British Journal of Pharmacology 01/2015;
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    ABSTRACT: DNA hypomethylation was previously implicated in metastasis. In these studies we have examined whether methyl supplementation with the universal methyl donor S-adenosylmethionine (SAM) would inhibit prostate cancer associated skeletal metastasis. Highly invasive human prostate cancer cells PC-3 and DU-145 were treated with vehicle alone, S-adenosylhomocysteine (SAH), or SAM to monitor the effect on tumor cell proliferation, invasion, migration and colony formation. For in vivo studies, control (SAH) and SAM treated PC-3 cells were injected into the tibia of Fox chase SCID mice and skeletal lesions were determined by X-ray and μCT. To understand possible mechanisms involved we delineated the effect of SAM on the genome-wide methylation profile of PC-3 cells. Treatment with SAM resulted in a dose-dependent inhibition of tumor cell proliferation, invasion, cell migration, colony formation and cell cycle characteristics. Animals injected with 250μM SAM treated cells developed significantly smaller skeletal lesions which were associated with increases in bone volume to tumor volume (BV/TV) ratio and connectivity density as well as decreased trabecular spacing. Genome-wide methylation analysis showed differential methylation in several key signaling pathways implicated in prostate cancer including the Signal Transducer and Activator of Transcription 3 (STAT3) pathway. A selective STAT3 inhibitor decreased tumor cell invasion, effects which were less pronounced as compared to SAM. These studies provide a possible mechanism for the role of DNA demethylation in the development of skeletal metastasis and a rationale for the use of hypermethylation pharmacological agents to impede the development and progression of skeletal metastasis. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 01/2015;
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    ABSTRACT: Background and purposeHydrogen sulfide (H2S), an endogenous volatile mediator with pleiotropic functions, promotes vasorelaxation, exerts anti-inflammatory actions and governs angiogenesis. Previously, the SH-containing angiotensin converting enzyme inhibitor (ACEI) zofenopril, has been identified as effective in preserving endothelial function and inducing angiogenesis among ACEI. Based on H2S donor property of the active metabolite zofenoprilat, the objective of this study was to evaluate whether zofenoprilat-induced angiogenesis was due to increased H2S availability.Experimental approachHuman umbilical vein endothelial cells (HUVECs) were used for in vitro studies of angiogenesis, while the Matrigel plug assay was used for in vivo assessment.Key resultsHUVECs exposed to zofenoprilat showed an increase in all functional features of the angiogenic process in vitro. As zofenoprilat induced the expression of CSE (cystathionine-γ-lyase) and the continuous production of H2S, CSE inhibition or silencing blocked zofenoprilat to induce angiogenesis, both in vitro and in vivo. The molecular mechanisms underlying H2S/zofenoprilat induced angiogenesis were dependent on Akt, eNOS and ERK1/2 cascades. ATP-sensitive potassium (KATP) channels, the molecular target described to mediate part of the vascular functions of H2S, were involved in the upstream activation of Akt, and ERK1/2. Moreover, FGF-2 upregulation was dependent on CSE derived H2S response to H2S and KATP activation.Conclusions and ImplicationsIn conclusion, zofenoprilat induced a constant H2S production that stimulates the angiogenic process through a KATP channel/Akt/eNOS/ERK1/2 pathways. Thus, zofenopril can be considered as a proangiogenic drug acting through H2S release and production, useful in cardiovascular pathologies where vascular functions need to be reestablished and functional angiogenesis induced.
    British Journal of Pharmacology 01/2015;
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    ABSTRACT: Many human malignancies are associated with aberrant regulation of protein or lipid kinases due to mutations, chromosomal rearrangements and/or gene amplification. Protein and lipid kinases, represent an important target class for treating human disorders. This review focus on "the 10 things you should know about protein kinases and their inhibitors" including a short introduction on the history on protein kinases and inhibitor and ending with a perspective in kinase drug discovery. Although the "10 things" have been, to a certain extent, chosen arbitrarily, they cover in a comprehensive way the past and present efforts in kinase drug discovery and summarize the "status quo" of the current kinase inhibitors as well as knowledge about kinase structure and binding modes. Besides describing the potentials of protein kinase inhibitors as drugs this review also focus on their limitations, in particular on how to circumvent emerging resistance against kinase inhibitors in oncological indications. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 01/2015;
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    ABSTRACT: Background and PurposeMedical therapy of lower urinary tract symptoms (LUTS) suggestive of benign prostate hyperplasia (BPH) targets smooth muscle contraction in the prostate, or prostate growth. However, current therapeutic options are insufficient. Here, we investigated the role of Rac for the control of smooth muscle tone in the human prostate and growth of prostate stromal cells.Experimental ApproachExperiments were performed using human prostate tissues from radical prostatectomy and cultured stromal cells (WPMY-1). Expression of Rac was examined by Western blot and fluorescence staining. Effects of Rac inhibitors (NSC23677, EHT1864) on contractility were assessed in the organ bath. Rac activity was assessed by pull-down, cytotoxicity using a cell counting kit, cytoskeletal organization by phalloidin staining, and cell growth using an EdU assay.Key ResultsExpression of Rac1-3 was observed in prostate samples from each patient. Immunoreactivity for Rac1-3 was observed in the stroma, where it colocalized with the smooth muscle marker, calponin. NSC23766 and EHT1864 significantly reduced contractions of prostate strips induced by noradrenaline, phenylephrine, or electric field stimulation. NSC23766 and EHT1864 inhibited Rac activity in WPMY-1 cells. Survival of WPMY-1 cells ranged between 64-81 % after incubation with NSC23766 (50 or 100 μM) or EHT1864 (25 μM) for 24 h. NSC23766 and EHT1864 induced cytoskeletal deorganization in WPMY-1 cells. Both inhibitors impaired growth of WPMY-1 cells.Conclusions & ImplicationsRac may be a link, connecting the control of prostate smooth muscle tone with proliferation of smooth muscle cells. Improvement of LUTS suggestive of BPH by Rac inhibitors appears possible.
    British Journal of Pharmacology 01/2015;