PubMed Journal Database | British journal of pharmacology 
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Showing PubMed Articles 1–25 of 251 from British journal of pharmacology
Resistance to BH3 mimetic S1 in SCLC cells that up-regulate and phosphorylate Bcl-2 through ERK1/2.
BACKGROUND AND PURPOSE: Bcl-2 is a central regulator of cell survival that is overexpressed in the majority of small cell lung cancers (SCLC) and contributes to both malignant transformation and therapeutic resistance. The purpose of this work was to study the key factors that determine the sensitivity of SCLC cells to BH3 mimetic S1 and the mechanism underlying the resistance of BH3 mimetics. EXPERIMENTAL APPROACHES: Western blot was used to evaluate the contribution of Bcl-2 family members to the cellular...
BACKGROUND AND PURPOSE: Dietary indole derivatives, indole-3-carbinol (I3C), and diindolylmethane (DIM), possess anti-cancer properties and exhibit the characteristics of aryl hydrocarbon receptor (AhR) ligands. Because AhR activation has recently been shown to regulate T cell differentiation, we tested the hypothesis that I3C and DIM may mediate anti-inflammatory properties by promoting regulatory T cell (T-regs) differentiation while inhibiting Th17 cells. EXPERIMENTAL APPROACH: We investigated the therap...
Nebulized thiocyanate improves lung infection outcomes in mice.
BACKGROUND AND PURPOSE: Nebulized saline solutions are used in the treatment of multiple pulmonary diseases including cystic fibrosis (CF), asthma and COPD. The benefits of these therapies include improved lung function, phlegm clearance and fewer lung infections. The thiocyanate anion (SCN) is a normal component of the airway epithelial lining fluid (ELF) secreted by pulmonary epithelia with antioxidant and host defense functions. We sought to test if SCN could be nebulized to combat lung infection by bols...
Pathway specific modulation of S1P1 receptor signalling in rat and human astrocytes.
BACKGROUND & PURPOSE: The sphingosine 1-phosphate receptor subtype 1 (S1P1R) is modulated by phosphorylated FTY720 (pFTY720), which causes S1P1R internalisation preventing lymphocyte migration thus limiting autoimmune response. Studies indicate that internalised S1P1Rs continue to signal, maintaining an inhibition of cAMP, thus raising question whether the effects of pFTY720 are due to transient initial agonism, functional antagonism, and/or continued signalling. To further investigate this, the current stu...
BACKGROUND AND PURPOSE: Retigabine is a recently approved anti-epileptic agent which activates Kv7.2-7.5 potassium channels. An important role for these channels in vascular regulation is emerging, but the vascular effects of retigabine in the conscious state are unknown. In the present study the regional haemodynamic responses to retigabine were assessed in conscious rats. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats were chronically instrumented with pulsed Doppler flow probes to measure regional haemo...
BACKGROUND AND PURPOSE: The 5-HT3 receptor antagonist palonosetron is an important pharmacotherapy for the treatment of emesis and nausea during cancer therapy. Its clinical efficacy is thought to result from its unique binding and clearance characteristics and receptor down-regulation mechanisms. We investigated the mechanisms by which palonosetron exerts its long-term inhibition of 5-HT3 receptors in order to better understand its clinical efficacy. EXPERIMENTAL APPROACH: Cell surface receptors (recombina...
Background and purpose: Doxorubicin is effective against breast cancer but its major side-effect is cardiotoxicity. The aim of this study was to determine whether the efficacy of doxorubicin on cancer cells could be increased in combination with PPARγ agonists or chrono-optimisation by exploiting the diurnal cycle. Experimental approach: We determined cell toxicity using MCF-7 cancer cells, neonatal rat cardiac myocytes and fibroblasts in this study. Key results: Doxorubicin damages the contractile filamen...
BACKGROUND AND PURPOSE: Synaptic vesicle protein 2A (SV2A) is the specific binding site of the anti-epileptic drug levetiracetam (LEV) and its higher affinity analogue UCB30889. Moreover, the protein has been well validated as a target for anticonvulsant therapy. Here, we report the identification of UCB1244283 acting as a SV2A positive allosteric modulator of UCB30889. EXPERIMENTAL APPROACH: UCB1244283 was characterized in vitro using radioligand binding assays with [(3) H]UCB30889 on recombinant SV2A expr...
BACKGROUND AND PURPOSE: Pulmonary hypertension is characterized by enhanced pulmonary vascular resistance, right ventricular hypertrophy, and increased right ventricular systolic pressure. Here, we investigated the effects of a N-acylhydrazone derivative, 3,4-dimethoxyphenyl-N-methyl-benzoilidrazide (LASSBio-1359), on the therapeutic treatment of monocrotaline induced pulmonary hypertension in rats. EXPERIMENTAL APPROACH: Male Wistar rats were divided into saline (control), monocrotaline, monocrotaline + ve...
BACKGROUND AND PURPOSE: Quercetin is a natural polyphenolic flavonoid that displays antidiabetic properties in vivo. Its mechanism of action on insulin secreting β-cells is poorly documented. In this work, we have analyzed in β cells the effect of quercetin both on insulin secretion and on the intracellular calcium concentration ([Ca(2+) ]i ) in the absence of any co-stimulating factor. EXPERIMENTAL APPROACH: Experiments were performed on both INS-1 cell line and rat isolated pancreatic islets. Insulin re...
Forging a Modern Generation of Polyphenol-Based Therapeutics.
The long-standing debate that polyphenol secondary metabolites from dietary plants are important nutritional components continues due to compelling evidence for their abilities to ameliorate degenerative conditions including, cancer, neurological disorders, and cardiovascular disease. The clinical use of polyphenols is not, however, main-stream as issues regarding poor selectivity, dosage, toxicity and delivery methods are unresolved. The paper by Rieder et al. (2012) suggests that the lack of selectivity,...
IL-22 in tissue protective therapy.
Interleukin (IL)-22, a member of the IL-10 cytokine family, has recently gained significant attention as protective principle in murine models of diseases driven by epithelial injury. Alike its biochemical and functional sibling IL-10, IL-22 elicits cellular activation primarily by engaging the signal transducer and activator of transcription (STAT)-3 track of cellular activation. Exclusively produced by leukocytes but targeting foremost cells of epithelial origin, IL-22 is supposed to be a specialized cyto...
BACKGROUND AND PURPOSE: Many organs suffer from ischemic injuries that reduce the ability to generate sufficient energy, which is required for functional maintenance and repair. Erythropoietin (EPO) has the potential to ameliorate ischemic tissue by pleiotropic effects. The aim of this study was to investigate a small molecule EH-201 (2,3,5,4'-tetrahydroxystilbene-2-o-beta-d-glucoside, THSG) with a potent EPO induction effect in nonhaematopoietic cells and examine the compound's therapeutic potential in isc...
BACKGROUND AND PURPOSE: Oxytocin (OT) plays a major role in the control of male sexual responses. Notably, blockade of OT receptors has been reported to inhibit ejaculation in animals. The study aimed to investigate the action of a highly selective, non-peptide OT antagonist GSK557296 in a model of pharmacologically-induced ejaculation in anaesthetised rats. The site of action was assessed by investigating different delivery routes for this compound. EXPERIMENTAL APPROACH: Urethane-anaesthetised Wistar rats...
Supra-physiological efficacy at GPCRs: superstition or super agonists?
The concept of "super agonism" has been described since the discovery of peptide hormone analogues that yielded greater functional responses than the endogenous agonists, in the early 1980s. It has remained an area of debate as to whether such compounds can really display greater efficacy than an endogenous agonist. However, recent pharmacological data, combined with crystal structures of different GPCR conformations and improved analytical methods for quantifying drug action, are starting to shed light on...
BACKGROUND AND PURPOSE: We have evaluated the influence of calcium-activated potassium channels (K(Ca) ) activation on cGMP-mediated relaxation in human penile tissues from non-diabetic and diabetic patients, and on the effects of type 5 phosphodiesterase (PDE5) inhibitors on erectile responses in control and diabetic rats. EXPERIMENTAL APPROACH: Cavernosal tissues were collected from organ donors and from patients with erectile dysfunction (ED). Relaxations of corpus cavernosum strips (HCC) and penile resi...
Arginase inhibition alleviates hypertension in the metabolic syndrome.
BACKGROUND AND PURPOSE: We have previously shown that arginase inhibition alleviates hypertension associated with in a diabetic animal model. Here we investigated the protective effect of arginase inhibition on hypertension in metabolic syndrome. EXPERIMENTAL APPROACH: Metabolic syndrome was induced in rats by administration of fructose (10% in drinking water) for 12 weeks to induce vascular dysfunction. Three arginase inhibitors (citrulline, norvaline and ornithine) were administered daily in the last 6 we...
BACKGROUND AND PURPOSE: Nasal sensory nerves play an important role in symptoms associated with rhinitis triggered by environmental stimuli. Here, we propose that TRPV1 is pivotal in nasal sensory nerve activation and assess the potential of SB-705498 as an intranasal therapy for rhinitis. EXPERIMENTAL APPROACH: The inhibitory effect of SB-705498 on capsaicin-induced currents in guinea-pig trigeminal ganglion cells innervating nasal mucosa was investigated using patch clamp electrophysiology. A guinea-pig m...
BACKGROUND AND PURPOSE: The non-psychotropic cannabinoid cannabichromene is known to activate the transient receptor potential ankyrin-type1 (TRPA1) and to inhibit endocannabinoid inactivation, both of which are involved in inflammatory processes. We examined here the effects of this phytocannabinoid on peritoneal macrophages and its efficacy in an experimental model of colitis. EXPERIMENTAL APPROACH: Murine peritoneal macrophages were activated in vitro by lipopolysaccharide (LPS). Nitrite levels were meas...
BACKGROUND AND PURPOSE: To analyse the relative contribution of β(1) -, β(2) - and β(3) -adrenoceptors (ARs) to vasodilatation in conductance and resistance vessels, assessing the role of cAMP and/or NO/cGMP signalling pathways. EXPERIMENTAL APPROACH: Rat mesenteric resistance artery (MRA) and aorta were used to analyse the β-ARs expression by RT-PCR and immunohistochemistry, and for the pharmacological characterisation of β-AR-mediated activity by wire myography and tissue nucleotide accumulation. KEY...
BACKGROUND AND PURPOSE: Estrogen receptor alpha (ERα) binds to different ligand which can function as complete / partial estrogen-agonist or antagonist. This depends on the chemical structure of the ligands which modulates the transcriptional activity of the estrogen-responsive genes by altering the conformation of the liganded-ERα complex. This study determined the molecular mechanism of estrogen-agonistic / antagonistic action of structurally similar ligands, bisphenol (BP) and bisphenol-A (BPA) on cell...
BACKGROUND AND PURPOSE: α(1) -adrenoceptor (-AR) antagonists may facilitate ureter stone passage in humans. We aimed to study effects by the α(1A) -AR selective antagonist silodosin (compared to tamsulosin and prazosin) on ureter pressures in a rat model of ureter obstruction, and on contractions of human and rat isolated ureters. EXPERIMENTAL APPROACH: After ethical approval, ureters of male rats were cannulated beneath the kidney pelvis for in vivo ureteral intraluminal recording of autonomous peristalt...
BACKGROUND AND PURPOSE: ER stress has been implicated in the pathogeneses of insulin resistance and type 2 diabetes, and extracellular signal-regulated kinase (ERK) antagonist is an insulin sensitizer that can restore muscle insulin responsiveness in both tunicamycin-treated muscle cells and type 2 diabetic mice. The present study was undertaken to determine whether the chemical or genetic inhibition ER stress pathway targeting by ERK results in metabolic benefits in muscle cells. EXPERIMENTAL APPROACH: ER...
AIMS: For four decades, 5-fluorouracil (5-FU) has been a major anticancer medicine. This drug is increasingly used with other anticancer agents such as irinotecan. Irinotecan and many others such as PPD (pentyl carbamate of p-aminobenzyl carbamate of doxazolidine) require activation by carboxylesterase-2 (CES2). 5-FU, on the other hand, reportedly induces CES2 in colorectal tumor lines. The aims of this study were to determine the molecular basis for the induction and to ascertain interactive cell-killing a...
BACKGROUND AND PURPOSE: Bone resorption induced by interleukin-1β (IL-1 β) and tumour necrosis factor (TNF-α) is synergistically potentiated by kinins, partially due to enhanced kinin receptor expression. Inflammation induced bone resorption can be impaired by IL-4 and IL-13. The aim was to investigate if expression of B(1) and B(2) kinin receptors can be affected by IL-4 and IL-13. EXPERIMENTAL APPROACH: We examined effects in a human osteoblastic cell line (MG-63), primary human gingival fibroblasts an...
