British Journal of Pharmacology - Volume 165 Issue 2 (January 2012)
Showing 1 to 15 of 20 results
1. Interactions between antidepressants and P‐glycoprotein at the blood–brain barrier: clinical significance of in vitro and in vivo findings
Date: Dec 16, 2011, Pages: 289-312
The drug efflux pump P‐glycoprotein (P‐gp) plays an important role in the function of the blood–brain barrier by selectively extruding certain endogenous and exogenous molecules, thus limiting the ability of its substrates to reach the brain. Emerging evidence suggests that P‐gp may restrict the uptake of several antidepressants into the brain, thus contributing to the poor success rate of current antidepressant therapies. Despite some...
2. Adiponectin receptor signalling in the brain
Date: Dec 16, 2011, Pages: 313-327
Adiponectin is an important adipocyte‐derived hormone that regulates metabolism of lipids and glucose, and its receptors (AdipoR1, AdipoR2, T‐cadherin) appear to exert actions in peripheral tissues by activating the AMP‐activated protein kinase, p38‐MAPK, PPARα and NF‐kappa B. Adiponectin has been shown to exert a wide range of biological functions that could elicit different effects, depending on the target organ and the biological...
3. Translational approaches targeting the p53 pathway for anti‐cancer therapy
Date: Dec 16, 2011, Pages: 328-344
The p53 tumour suppressor blocks cancer development by triggering apoptosis or cellular senescence in response to oncogenic stress or DNA damage. Consequently, the p53 signalling pathway is virtually always inactivated in human cancer cells. This unifying feature has commenced tremendous efforts to develop p53‐based anti‐cancer therapies. Different strategies exist that are adapted to the mechanisms of p53 inactivation. In p53‐mutated...
4. Interaction of innovative small molecule drugs used for cancer therapy with drug transporters
Date: Dec 16, 2011, Pages: 345-362
Multiple new small molecules such as tyrosine kinase, mammalian target of rapamycin (mTOR) and proteasome inhibitors have been approved in the last decade and are a considerable progress for cancer therapy. Drug transporters are important determinants of drug concentrations in the systemic circulation. Moreover, expression of drug transporters in blood–tissue barriers (e.g. blood–brain barrier) can limit access of small molecules to the...
5. New anticoagulants – promising and failed developments
Date: Dec 16, 2011, Pages: 363-372
New direct and indirect acting factor Xa (FXa) and thrombin inhibitors are being developed to overcome the downsides of the conventional anticoagulants – unfractionated and low molecular weight heparins and vitamin K antagonists. Ximelagatran and idraparinux failed to demonstrate an acceptable safety profile. Rivaroxaban and dabigatran are approved for the post‐operative prevention of thromboembolic complications after elective hip or...
6. Interplay between statins and PPARs in improving cardiovascular outcomes: a double‐edged sword?
Date: Dec 16, 2011, Pages: 373-379
Statins are best‐selling medications in the management of high cholesterol and associated cardiovascular complications. They inhibit 3‐hydroxy‐3‐methylglutaryl‐coenzyme A (HMG‐CoA)‐reductase in order to prevent disproportionate cholesterol synthesis. Statins slow the progression of atherosclerosis, prevent the secondary cardiovascular events and improve the cardiovascular outcomes in patients with elevated cholesterol levels. The...
7. Cardiac dysfunction in adipose triglyceride lipase deficiency: treatment with a PPARα agonist
Date: Dec 16, 2011, Pages: 380-389
BACKGROUND AND PURPOSE Adipose triglyceride lipase (ATGL) has been identified as a rate‐limiting enzyme of mammalian triglyceride catabolism. Deletion of the ATGL gene in mice results in severe lipid accumulation in a variety of tissues including the heart. In the present study we investigated cardiac function in ATGL‐deficient mice and the potential therapeutic effects of the PPARα and γ agonists Wy14,643...
8. Molecular basis of selective antagonism of the P2X1 receptor for ATP by NF449 and suramin: contribution of basic amino acids in the cysteine‐rich loop
Date: Dec 16, 2011, Pages: 390-400
BACKGROUND AND PURPOSE The cysteine‐rich head region, which is adjacent to the proposed ATP‐binding pocket in the extracellular ligand‐binding loop of P2X receptors for ATP, is absent in the antagonist‐insensitive Dictyostelium receptors. In this study we have determined the contribution of the head region to the antagonist action of NF449 and suramin at the human P2X1 receptor. EXPERIMENTAL APPROACH Chimeras and...
9. Prostaglandin E 2 induces spontaneous rhythmic activity in mouse urinary bladder independently of efferent nerves
Date: Dec 16, 2011, Pages: 401-413
BACKGROUND AND PURPOSE The acute effects of PGE2 on bladder smooth muscle and nerves were examined to determine the origin of PGE2‐induced spontaneous rhythmic contractions. EXPERIMENTAL APPROACH Contraction studies, confocal Ca2+ imaging and electrophysiological recordings in strips of mouse urinary bladder were used to differentiate the effects of PGE2 on bladder smooth muscle and efferent nerves. ...
10. Molecular mechanisms underlying bile acid‐stimulated glucagon‐like peptide‐1 secretion
Date: Dec 16, 2011, Pages: 414-423
BACKGROUND AND PURPOSE The glucagon‐like peptides GLP‐1 and GLP‐2 are secreted from enteroendocrine L‐cells following nutrient ingestion. Drugs that increase activity of the GLP‐1 axis are highly successful therapies for type 2 diabetes, and boosting L‐cell secretion is a potential strategy for future diabetes treatment. The aim of the present study was to further our understanding of the bile acid receptor GPBA (TGR5), an L‐cell target...
11. Involvement of neuropeptide FF receptors in neuroadaptive responses to acute and chronic opiate treatments
Date: Dec 16, 2011, Pages: 424-435
BACKGROUND AND PURPOSE Opiates remain the most effective compounds for alleviating severe pain across a wide range of conditions. However, their use is associated with significant side effects. Neuropeptide FF (NPFF) receptors have been implicated in several opiate‐induced neuroadaptive changes including the development of tolerance. In this study, we investigated the consequences of NPFF receptor blockade on acute and chronic stimulation...
12. Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non‐competitive allosteric inhibitor
Date: Dec 16, 2011, Pages: 436-454
BACKGROUND AND PURPOSE DF 2156A is a new dual inhibitor of IL‐8 receptors CXCR1 and CXCR2 with an optimal pharmacokinetic profile. We characterized its binding mode, molecular mechanism of action and selectivity, and evaluated its therapeutic potential. EXPERIMENTAL APPROACH The binding mode, molecular mechanism of action and selectivity were investigated using chemotaxis of L1.2 transfectants and human leucocytes, in...
13. Amplified NO/cGMP‐mediated relaxation and ryanodine receptor‐to‐BK Ca channel signalling in corpus cavernosum smooth muscle from phospholamban knockout mice
Date: Dec 16, 2011, Pages: 455-466
BACKGROUND AND PURPOSE Relaxation of corpus cavernosum smooth muscle (CCSM) is induced by NO. NO promotes the formation of cGMP, which activates cGMP‐dependent protein kinase I (PKGI). The large conductance calcium‐activated potassium (BKCa) channel is regarded as a major target of NO/cGMP signalling; however, the mechanism of BKCa activation remains unclear. The aim of the present study was to determine whether sarcoplasmic reticulum (SR) Ca2+ load and Ca2+...
14. Comparison of the I Kr blockers moxifloxacin, dofetilide and E‐4031 in five screening models of pro‐arrhythmia reveals lack of specificity of isolated cardiomyocytes
Date: Dec 16, 2011, Pages: 467-478
BACKGROUND AND PURPOSE Drug development requires the testing of new chemical entities for adverse effects. For cardiac safety screening, improved assays are urgently needed. Isolated adult cardiomyocytes (CM) and human embryonic stem cell‐derived cardiomyocytes (hESC‐CM) could be used to identify pro‐arrhythmic compounds. In the present study, five assays were employed to investigate their sensitivity and...
15. Recombinant viral protein promotes apoptosis and suppresses invasion of ovarian adenocarcinoma cells by targeting α5β1 integrin to down‐regulate Akt and MMP‐2
Date: Dec 16, 2011, Pages: 479-493
BACKGROUND AND PURPOSE As prognosis for patients with metastatic ovarian cancer is generally poor, advances in treatment are needed. Here, we studied the mechanism of action of a recombinant viral capsid protein (rVP1) and explored its effect against ovarian tumour growth and metastasis in vivo. EXPERIMENTAL APPROACH The human ovarian cancer cell line SKOV3 and BALB/cAnN‐Foxn1 female nude mice were used. Effects of...
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