MedWorm.com provides a medical RSS filtering service. Over 6000 RSS medical sources are combined and output via different filters. This feed contains the latest items from the 'Current Opinion in Pharmacology' source. Wed, 08 Feb 2012 14:04:08 +0100 http://www.medworm.com/index.php?rid=5643186&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22285392%26dopt%3DAbstract Authors: Suvorava T, Dao VT, Bas M, Kojda G Abstract The post surgery success of coronary artery bypass grafting (CABG) is counteracted by thrombosis and de-endothelialization, intimal hyperplasia and, over the long term, atherosclerosis. There are many reasons to assume that in CABG patients vascular bioavailability of NO generated by the endothelium plays an important role for graft function. This holds true for factors such as graft type, harvesting and storage, the type of surgery, non-pharmacologic prevention of risk factors, for example, regular physical activity (if feasible), and drug therapy. Although the precise role of graft endothelial NO bioavailability for graft patency and clinical endpoints is still uncertain, current data rather speak in favor of NO indicating that... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5643186 Fri, 27 Jan 2012 05:00:00 +0100 5643186 http://www.medworm.com/index.php?rid=5643185&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22285393%26dopt%3DAbstract Authors: Nutt D PMID: 22285393 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5643185 Fri, 27 Jan 2012 05:00:00 +0100 5643185 http://www.medworm.com/index.php?rid=5643187&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22285216%26dopt%3DAbstract Authors: Head SJ, Bogers AJ, Kappetein AP Abstract Percutaneous coronary intervention (PCI) with bare-metal stents (BMS) has been performed increasingly ever since its introduction in the late 1970s. BMS have been replaced by drug-eluting stents (DES), and many interventional cardiologists consider this as a breakthrough therapy that might compete with coronary artery bypass grafting (CABG) as the standard treatment for coronary artery disease. Several DES are currently used and elute different agents. This review described what these agents are and provides an overview regarding the outcomes and associated adverse events. More importantly, this review compares outcomes of PCI with DES to CABG for patients with left anterior descending coronary artery involvement, left main involve... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5643187 Wed, 25 Jan 2012 05:00:00 +0100 5643187 http://www.medworm.com/index.php?rid=5643188&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22281067%26dopt%3DAbstract Authors: Thomas AC Abstract Vein grafts have been extensively used to bypass blockages in arteries, but are themselves subject to early closure by thrombosis or later obstruction by vein graft disease (neointimal hyperplasia and remodelling). Animal models are a crucial means of testing potential therapeutic and surgical interventions to prevent graft stenosis and occlusion. This review outlines many of the animal models of vein grafting. Recent studies include targeted gene therapy to prevent acute vein graft thrombosis and the use of folic acid to limit graft failure in diabetic pigs. PMID: 22281067 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5643188 Tue, 24 Jan 2012 05:00:00 +0100 5643188 http://www.medworm.com/index.php?rid=5537484&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22188874%26dopt%3DAbstract Authors: Dolly JO, O'Connell MA Abstract There is a pressing unmet need for long-acting and effective therapeutics to alleviate symptoms of the varied forms of chronic pain. As many sufferers do not respond satisfactorily to non-addictive anti-nociceptives, a new treatment has emerged using inhibitors for the release of pain mediators from peripheral sensory nerves to give prolonged benefit. This strategy relies on proteolytically inactivating intra-neuronal SNARE (soluble N-ethylmaleimide-sensitive-factor attachment protein receptors) proteins which are essential for regulated exocytosis of transmitters, peptides and other pain signalling molecules. Success has been achieved with botulinum neurotoxin A (BoNT/A) which targets neuronal acceptors via its heavy chain, becomes endocyto... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5537484 Mon, 19 Dec 2011 05:00:00 +0100 5537484 http://www.medworm.com/index.php?rid=5537485&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22178186%26dopt%3DAbstract Authors: Costigan M, Latremoliere A, Woolf CJ Abstract Physiological control of the co-factor tetrahydrobiopterin (BH4) is tight in normal circumstances but levels increase pathologically in the injured somatosensory system. BH4 is an essential co-factor in the production of serotonin, dopamine, epinephrine, norepinephrine and nitric oxide. Excess BH4 levels cause pain, likely through excess production of one or more of these neurotransmitters or signaling molecules. The rate limiting step for BH4 production is GTP Cyclohydrolase 1 (GCH1). A human GCH1 gene haplotype exists that leads to less GCH1 transcription, translation, and therefore enzyme activity, following cellular stress. Carriers of this haplotype produce less BH4 and therefore feel less pain, especially following nerve ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5537485 Thu, 15 Dec 2011 05:00:00 +0100 5537485 http://www.medworm.com/index.php?rid=5537486&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22172234%26dopt%3DAbstract Authors: Bagetta G, Sakurada S PMID: 22172234 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5537486 Tue, 13 Dec 2011 05:00:00 +0100 5537486 http://www.medworm.com/index.php?rid=5477915&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22136937%26dopt%3DAbstract Authors: Negri L, Lattanzi R Abstract Mammalian Bv8 (also called prokineticin 2) is a secreted protein that regulates diverse biological processes including pain perception. It belongs to a new family of chemokines, which activate two G-protein linked receptors (prokineticin receptor 1 and 2, PKR1 and PKR2) expressed in regions of the nervous system associated with pain and in cells participating to immuno-inflammatory responses. Primary sensitive neurons co-express PKRs and the transient potential receptor vanilloid 1, cooperating in nociceptor sensitization. Bv8, strongly upregulated in neutrophils and other inflammatory cells, is a main pronociceptive mediator in inflamed tissues, where it sensitizes peripheral nociceptors, stimulates neutrophil chemotaxis and modulates the rele... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5477915 Wed, 30 Nov 2011 05:00:00 +0100 5477915 http://www.medworm.com/index.php?rid=5477917&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22104468%26dopt%3DAbstract Authors: Palazzo E, Luongo L, de Novellis V, Rossi F, Marabese I, Maione S Abstract Transient receptor potential vanilloid type 1 (TRPV1), a ligand-gated cation channel, is a polymodal nocitransducer widely expressed within pain transmitting/modulating areas of the peripheral and central nervous system. TRPV1 is both activated and sensitized by inflammatory endogenous mediators during inflammatory pain conditions and appears to be up regulated in neuropathic pain conditions. Owing to its role as pain integrator, its widespread expression in pain neuraxis and its involvement in pain development TRPV1 offers an exciting opportunity for therapeutic interventions in pain management. In particular, its supraspinal expression within the antinociceptive descending pathway, which includes ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5477917 Sat, 19 Nov 2011 05:00:00 +0100 5477917 http://www.medworm.com/index.php?rid=5477916&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22104733%26dopt%3DAbstract Authors: Mizoguchi H, Watanabe C, Sakurada T, Sakurada S Abstract The μ-opioid receptors mainly contribute to the control of pain transmission, while a number of splice variants may have different physiological roles. In fact, some μ-opioid receptor agonists show distinct antinociceptive properties probably mediated via splice variants insensitive to traditional μ-opioid receptor agonists. These atypical μ-opioid receptor agonists are extremely effective against morphine-resistant interactive pain and lack the psychological dependence liability. μ-Opioid receptor splice variants specific for these atypical agonists may be the target for better analgesics effective against morphine-resistant interactive pain and lacking psychological dependence liability. PMID: 22104733 [Pu... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5477916 Fri, 18 Nov 2011 05:00:00 +0100 5477916 http://www.medworm.com/index.php?rid=5426744&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22088890%26dopt%3DAbstract Authors: Berliocchi L, Russo R, Tassorelli C, Morrone LA, Bagetta G, Corasaniti MT Abstract A complex network operates in the spinal dorsal horn to integrate peripheral nociceptive inputs with local and descending control mechanisms, and to cross-talk with higher brain areas. Injury to peripheral sensory nerves can trigger a cascade of events within this relay which, in some cases, may turn into abnormal responses outlasting the initial detrimental stimulus and leading to chronic pain. In the spinal dorsal horn, evidence has been provided both in support and against the occurrence of neuronal loss following peripheral nerve injury, leaving this issue still unresolved. Only new conceptual and technical approaches will determine the relevance of spinal neurodegenerative mechanisms to... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5426744 Mon, 14 Nov 2011 05:00:00 +0100 5426744 http://www.medworm.com/index.php?rid=5426745&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22079477%26dopt%3DAbstract Authors: Manganiello V PMID: 22079477 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5426745 Thu, 10 Nov 2011 05:00:00 +0100 5426745 http://www.medworm.com/index.php?rid=5426746&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22078436%26dopt%3DAbstract Authors: Sandkühler J, Gruber-Schoffnegger D Abstract Long-term potentiation of synaptic strength (LTP) in nociceptive pathways shares principle features with hyperalgesia including induction protocols, pharmacological profile, neuronal and glial cell types involved and means for prevention. LTP at synapses of nociceptive nerve fibres constitutes a contemporary cellular model for pain amplification following trauma, inflammation, nerve injury or withdrawal from opioids. It provides a novel target for pain therapy. This review summarizes recent progress which has been made in unravelling the properties and functions of LTP in the nociceptive system and in identifying means for its prevention and reversal. PMID: 22078436 [PubMed - as supplied by publisher] (Source: Current Opini... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5426746 Wed, 09 Nov 2011 05:00:00 +0100 5426746 http://www.medworm.com/index.php?rid=5426749&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22056025%26dopt%3DAbstract Authors: Wood JN, Eijkelkamp N Abstract Drugs that block mechanically-evoked pain would be useful for many common pain conditions, but appropriate drug development targets have yet to be defined. There is increasing evidence that both peripheral sensory neuron wiring patterns as well as the expression of transducing molecules are important for modality specific pain sensations. Progress in identifying the cell types, candidate transducing molecules and wiring patterns involved in mechanosensation has been dramatic over the past few years. Here we focus on potential mechano-transducing channels, and the relevant cell types and wiring patterns that provide clues for new analgesic drug development strategies. PMID: 22056025 [PubMed - as supplied by publisher] (Source: Current Opin... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5426749 Thu, 03 Nov 2011 04:00:00 +0100 5426749 http://www.medworm.com/index.php?rid=5426747&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22056114%26dopt%3DAbstract Authors: Hotta R, Natarajan D, Burns AJ, Thapar N Abstract Currently available therapies for gastrointestinal motility conditions are often inadequate. Recent scientific advances, however, have facilitated the identification of neural stem cells as novel tools for cellular replenishment. Such cells can be generated from a number of tissue sources including the gut itself. Neural stem cells can readily be harvested from postnatal human gut including by conventional endoscopy, and in experimental transplantation studies appear capable of generating a neo-Enteric Nervous System. Current initiatives are addressing pre-clinical proof of concept studies in vivo utilising animal models of disease. Although definitive cell replenishment therapies for gut motility disorders appear to be an ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5426747 Thu, 03 Nov 2011 04:00:00 +0100 5426747 http://www.medworm.com/index.php?rid=5426750&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22056024%26dopt%3DAbstract Authors: Old EA, Malcangio M Abstract Treatment of neuropathic pain is problematic; response to current pharmacological interventions is often poor and associated with undesirable side-effects, thus the identification of new targets for treating this condition is needed. Here we collect evidence demonstrating the potential of chemokines as mediators of neuron-glia communication and contributors to pain signalling. The expression of chemokines such as CX3CL1, CCL2 and CCL21 and their receptors CX3CR1, CCR2 and CXCR3 is altered in the spinal cord under neuropathic pain conditions and chemokine receptor antagonists attenuate neuropathic pain behaviour. By understanding the mechanisms of chemokine-mediated communication we may expose glial targets as a novel approach for the treatment ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5426750 Wed, 02 Nov 2011 04:00:00 +0100 5426750 http://www.medworm.com/index.php?rid=5426748&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22056026%26dopt%3DAbstract This article reviews the early evidence suggesting that epigenetic mechanisms are engaged after injury and in chronic pain states, and that drugs used clinically to target the epigenetic machinery for the treatment of cancer might be useful for the management of chronic pain. PMID: 22056026 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5426748 Wed, 02 Nov 2011 04:00:00 +0100 5426748 http://www.medworm.com/index.php?rid=5382702&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22051884%26dopt%3DAbstract Authors: Begum N, Shen W, Manganiello V Abstract Phosphodiesterase-3 (PDE3) is a major cAMP-hydrolyzing PDE in vascular smooth muscle cells (VSMCs) and oocytes. The exact role and contribution of the two PDE3 isoforms, PDE3A and PDE3B, in VSMC growth regulation and oocyte maturation was examined using PDE3A (3A) and PDE3B (3B) knockout (KO) mouse models. PDE3A-deficient VSMCs exhibit marked reduction in mitogen-induced cell growth due to cell cycle arrest at G(0)-G(1) phase, which resulted from dysregulation of cAMP/protein kinase A (PKA)-activated and mitogen-activated protein kinase (MAPK)-signaling pathways, as well as from alterations in key cell cycle regulatory proteins. Similarly, PDE3A-deficient oocytes exhibit cell cycle arrest at G(2)/M phase because increased cAMP/PKA si... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5382702 Tue, 01 Nov 2011 04:00:00 +0100 5382702 http://www.medworm.com/index.php?rid=5382704&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22047791%26dopt%3DAbstract Authors: Levy I, Horvath A, Azevedo M, de Alexandre RB, Stratakis CA Abstract Phosphodiesterases (PDEs) are enzymes that regulate the intracellular levels of cyclic adenosine monophosphate and cyclic guanosine monophosphate, and, consequently, exhibit a central role in multiple cellular functions. The pharmacological exploitation of the ability of PDEs to regulate specific pathways has led to the discovery of drugs with selective action against specific PDE isoforms. Considerable attention has been given to the development of selective PDE inhibitors, especially after the therapeutic success of PDE5 inhibitors in the treatment of erectile dysfunction. Several associations between PDE genes and genetic diseases have been described, and more recently PDE11A and PDE8B have been implic... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5382704 Mon, 31 Oct 2011 04:00:00 +0100 5382704 http://www.medworm.com/index.php?rid=5382703&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22047792%26dopt%3DAbstract Authors: Beca S, Aschars-Sobbi R, Panama BK, Backx PH Abstract Cyclic nucleotide phosphodiesterases (PDEs) encompass a large group of enzymes that regulate intracellular levels of two-second messengers, cAMP and cGMP, by controlling the rates of their degradation. More than 60 isoforms, subdivided into 11 gene families (PDE1-11), exist in mammals with at least six families (PDE1-5 and PDE8) identified in mammalian hearts. The two predominant families implicated in regulating contraction strength of the heart are PDE3 and PDE4. Studies using transgenic models in combination with family-specific PDE inhibitors have demonstrated that PDE3A, PDE4B, and PDE4D isoforms regulate cardiac contractility by modulating cAMP levels in various subcellular compartments. These studies have further... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5382703 Mon, 31 Oct 2011 04:00:00 +0100 5382703 http://www.medworm.com/index.php?rid=5382705&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22040745%26dopt%3DAbstract Authors: Chiechio S, Nicoletti F Abstract Over the past two decades metabotropic glutamate (mGlu) receptor ligands have been investigated for their potential therapeutic effects in different disorders of the central nervous system (CNS), including anxiety, depression, schizophrenia, and neurodegenerative diseases. In addition, it has been widely demonstrated that mGlu receptors are able to modulate pain transmission both in inflammatory and neuropathic pain models. A large number of preclinical studies combining the use of selective ligands with the knockout strategy have revealed more details about the role of the different mGlu receptor subtypes in the modulation of pain information. This review will address the role of mGlu receptors in pain sensitivity focusing on different str... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5382705 Sat, 29 Oct 2011 04:00:00 +0100 5382705 http://www.medworm.com/index.php?rid=5382706&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22036885%26dopt%3DAbstract Authors: Burnstock G Abstract Experimental evidence is presented to support the hypothesis that purinergic mechanosensory transduction can initiate visceral pain in urinary bladder, ureter, gut and uterus. In general, physiological reflexes are mediated via P2X3 and P2X2/3 receptors on low threshold sensory fibres, while these receptors on high threshold sensory fibres mediate pain. Potential therapeutic strategies are considered for the treatment of visceral pain in such conditions as renal colic, interstitial cystitis and inflammatory bowel disease by purinergic agents, including P2X3 and P2X2/3 receptor antagonists that are orally bioavailable and stable in vivo and agents that modulate ATP release and breakdown. PMID: 22036885 [PubMed - as supplied by publisher] (Source: Cu... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5382706 Fri, 28 Oct 2011 04:00:00 +0100 5382706 http://www.medworm.com/index.php?rid=5382709&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22036168%26dopt%3DAbstract Authors: Boeckxstaens GE, Denison H, Jensen JM, Lehmann A, Ruth M Abstract The development of the novel γ-aminobutyric acid type-B receptor (GABA(B)) agonist lesogaberan is presented as an example of a partly successful translational strategy in the field of gastroenterology. Data on transient lower esophageal sphincter relaxations (TLESRs) and gastroesophageal reflux inhibition from preclinical models translated well to clinical studies in healthy volunteers and patients with gastroesophageal reflux disease (GERD). Animal models have also been used successfully to predict the effect of other target mechanisms on TLESRs in humans. However, while translation of physiology to symptomatology in patients with GERD was achieved, the effect size was too small to be of clinical significa... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5382709 Thu, 27 Oct 2011 04:00:00 +0100 5382709 http://www.medworm.com/index.php?rid=5382708&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22036169%26dopt%3DAbstract Authors: Maurice DH Abstract When lecturing on the topic of cellular signaling I have had occasion to ask the class for examples of cellular processes NOT impacted by cyclic AMP (cAMP) and am struck by how few examples exist. Indeed, studies spanning the past 60 years have detailed how this ubiquitous second messenger impacts virtually all cellular processes, including intermediary metabolism, contractility, motility, proliferation, and gene expression in most mammalian cells. Since the hydrophobic cAMP could in principle diffuse rapidly throughout the cell once formed, the remarkable spatial and temporal specificity of its numerous actions in cells is truly impressive. Herein I introduce the main players involved in coordinating actions of cAMP in vascular endothelial cells (VECs)... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5382708 Thu, 27 Oct 2011 04:00:00 +0100 5382708 http://www.medworm.com/index.php?rid=5382707&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22036170%26dopt%3DAbstract This article highlights recent advances that further increase our understanding of the mechanisms by which microglial purinergic receptors contribute to the pathogenesis of neuropathic pain. PMID: 22036170 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5382707 Thu, 27 Oct 2011 04:00:00 +0100 5382707 http://www.medworm.com/index.php?rid=5382710&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22033338%26dopt%3DAbstract Authors: Obara I, Géranton SM, Hunt SP Abstract Research on the role of axonal protein synthesis in the regulation of nociceptive mechanisms has grown significantly over the past four years. Recent advances include evidence that local translation of mRNA can occur in adult primary afferents under the control of the mammalian target of rapamycin (mTOR) and the extracellular signal-regulated kinase (ERK) signaling pathways. Studies investigating the effect of mTOR and ERK pathway inhibitors in a number of pain models suggest that these signaling pathways may act independently, depending on the type of sensory afferents studied. The evidence that nociception can be regulated at the level of mRNA translation in nociceptors has important implications for the understanding of the mechan... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5382710 Tue, 25 Oct 2011 04:00:00 +0100 5382710 http://www.medworm.com/index.php?rid=5382714&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22019564%26dopt%3DAbstract Authors: Conti M Abstract The function of the mammalian follicle is regulated by circulating gonadotropins and a myriad of local paracrine regulations functioning within the ovary. Cyclic nucleotide signaling plays an essential role in mediating both these endocrine and paracrine regulations. Given their role in controlling cyclic nucleotide levels, cyclic nucleotide phosphodiesterases (PDEs) are critical for ovarian function. PDEs modulate gonadotropin responses in the somatic compartment of the ovarian follicle. Specific PDEs are also essential for the oocyte entry and exit from the meiotic cell cycle. This review summarizes the function and regulation of PDEs in the somatic compartment and in the oocyte, and highlights the potential of PDEs as targets to improve assisted reprodu... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5382714 Fri, 21 Oct 2011 04:00:00 +0100 5382714 http://www.medworm.com/index.php?rid=5382713&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22019565%26dopt%3DAbstract Authors: Zac-Varghese S, De Silva A, Bloom SR Abstract The obesity epidemic has a direct impact on every aspect of health. Current strategies to treat obesity are limited and there is a need to pioneer novel solutions. Anorectic gut hormones, physiologically secreted post-prandially to mediate satiety, have recently emerged as potential therapeutic targets in obesity. Peptide tyrosine tyrosine (PYY) is one such anorectic gut hormone, secreted from entero-endocrine L cells, which acts on neuropeptide Y (NPY) receptors within the central appetite circuit. Since the first intravenous administration of PYY to man nearly a decade ago, a number of translational studies and clinical trials have ensued with a view to developing this peptide as a treatment for obesity. This review reports o... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5382713 Fri, 21 Oct 2011 04:00:00 +0100 5382713 http://www.medworm.com/index.php?rid=5382712&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22019566%26dopt%3DAbstract Authors: Kiguchi N, Kobayashi Y, Kishioka S Abstract There has been recent evidence showing the correlation between neuroinflammation owing to the chemokine-cytokine network and neuropathic pain. Chemokines and cytokines are derived from several types of cells in the peripheral and central nervous systems following nerve injury, and are largely involved in the pathogenesis of neuropathic pain. The roles of typical inflammatory cytokines such as interleukin-1β have become the recent center of attention. There is growing evidence that inflammatory chemokines (CCL2, CCL3, and fractalkine) play pivotal roles in neuropathic pain. Further investigations concerning the functions of the chemokine-cytokine network-mediated regulation of neuroinflammation may lead to novel therapeutic strat... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5382712 Fri, 21 Oct 2011 04:00:00 +0100 5382712 http://www.medworm.com/index.php?rid=5382711&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22019567%26dopt%3DAbstract Authors: Dinning P, Scott S Abstract Colonic motor abnormalities are implicated in several gastrointestinal disorders including constipation, irritable bowel syndrome and functional diarrhoea. Defining the colonic abnormalities is difficult and several novel techniques including, high-resolution fibre optic manometry, wireless motility capsules, ultrasound and magnetic resonance imaging have emerged to help in the diagnosis of these conditions. Coupled with the developing techniques are the novel treatments that look to restore normal colonic motility. These treatments include pharmacological agents (pharmabiotics, serotonin agonist, secretagogues) and medical devices (sacral nerve stimulation, transcutaneous electrical stimulation and biofeedback). This review summarizes the novel... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5382711 Fri, 21 Oct 2011 04:00:00 +0100 5382711 http://www.medworm.com/index.php?rid=5382715&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22018840%26dopt%3DAbstract Authors: Lugnier C Abstract About one third of people in the world suffer from metabolic syndrome (MetS), with symptoms such as hypertension and elevated blood cholesterol, and with increased risk of developing additional diseases such as diabetes mellitus and heart disease. The progression of this multifactorial pathology, which targets various tissues and organs, might necessitate a renewal in therapeutic approaches. Since cyclic nucleotide phosphodiesterases (PDEs), enzymes which hydrolyze cyclic AMP and cyclic GMP, play a crucial role in regulating endocrine and cardiovascular functions, inflammation, oxidative stress, and cell proliferation, all of which contribute to MetS, we wonder whether PDE inhibitors might represent new therapeutic approaches for preventing and treating ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5382715 Wed, 19 Oct 2011 04:00:00 +0100 5382715 http://www.medworm.com/index.php?rid=5382716&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22001403%26dopt%3DAbstract This article highlights the complexity involved in the regulation of PDE3B by hormones, and in the regulation of downstream metabolic effects by PDE3B in several interacting tissues. PMID: 22001403 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5382716 Fri, 14 Oct 2011 04:00:00 +0100 5382716 http://www.medworm.com/index.php?rid=5382721&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22000603%26dopt%3DAbstract Authors: Zaccolo M Abstract The cyclic adenosine 3',5'-monophosphate signalling pathway is now recognised to transduce signals in a compartmentalised manner such that individual stimuli only engage a subset of the pathway components that are physically constrained within defined subcellular locales, thus resulting in a precise functional outcome. As we are starting to appreciate the complexity of the spatial organisation and of the temporal regulation of this pathway, it is becoming clear that disruption of local signalling may lead to pathology and that local manipulation of cAMP signals may offer alternative approaches to treat disease. PMID: 22000603 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5382721 Thu, 13 Oct 2011 04:00:00 +0100 5382721 http://www.medworm.com/index.php?rid=5382720&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22000604%26dopt%3DAbstract Authors: Spiller R, Lam C Abstract Recent data developing from the study of postinfectious IBS has challenged the belief that IBS is a purely psychological disorder. Distinct abnormalities of the gut mucosa have been reported including immune activation and increased release of inflammatory mediators with some overlap with IBD. New studies show that genetic factors which predispose to IBD are also associated with IBS. A common feature is impaired gut barrier function which appears to precede the development of IBD while in IBS it may be the result of either a preceding infection or psychosocial stress. Stress can activate mast cells which are a feature in most but not all IBS series. Anti-inflammatory treatments targeting activated mast cells may benefit IBS patients but currently ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5382720 Thu, 13 Oct 2011 04:00:00 +0100 5382720 http://www.medworm.com/index.php?rid=5382719&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22000605%26dopt%3DAbstract Authors: Bulmer DC, Grundy D Abstract The failure of drugs to modify pain end points in clinical trials for irritable bowel syndrome (IBS) highlights the knowledge gap that exists in the translation of efficacy in animal models of visceral pain into the clinic. Recent progress has been made towards improving the translation of visceral pain, particularly with regard to the activation of the sensory nerves which relay pain from the gut to the brain. This review will focus on studies which have identified the presence of an altered gastrointestinal and immune environment in IBS patients. The development of human gastrointestinal visceral afferent recordings has allowed direct comparison between sensory nerve studies in animals and human, as well as important advances in our understan... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5382719 Thu, 13 Oct 2011 04:00:00 +0100 5382719 http://www.medworm.com/index.php?rid=5382718&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22000933%26dopt%3DAbstract Authors: Monteleone G, Pallone F, Macdonald TT Abstract Crohn's disease (CD) and ulcerative colitis (UC) are the major forms of inflammatory bowel diseases (IBD) in man. They are caused by damage to the lining of the intestine and deeper layers, due to an excessive immune response directed against components of the gut microflora and poorly controlled by counter-regulatory mechanisms. CD and UC are however immunologically distinct. CD-related inflammation is characterized by a marked mucosal infiltration of T lymphocytes secreting T helper type (Th) 1 and Th17 cytokines. In UC, the local immune response is less polarized but may show enhanced production of IL-5, IL-13 and Th17 cytokines. Downstream however CD and UC share important end-stage effector pathways of intestinal injury, ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5382718 Wed, 12 Oct 2011 04:00:00 +0100 5382718 http://www.medworm.com/index.php?rid=5382717&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D22000934%26dopt%3DAbstract Authors: Blackshaw LA, Aziz Q PMID: 22000934 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5382717 Wed, 12 Oct 2011 04:00:00 +0100 5382717 http://www.medworm.com/index.php?rid=5382723&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21996283%26dopt%3DAbstract Authors: Quigley EM Abstract Thanks to rapid progress in the development and application of molecular techniques to the assessment of the human gut microbiome, the true nature, diversity and metabolic potential of this 'hidden organ' are being revealed. Simultaneously, the complex physiological, immunological and metabolic interactions between host and microbiome are being untangled. By contrast, the probiotic concept has been with us for decades and, while supported more by fad and folklore in the past, is now gaining support, not only from experimental work in animal models, but also by well-designed studies in human diseases, most notably infectious diarrheas, inflammatory bowel disease and the irritable bowel syndrome. PMID: 21996283 [PubMed - as supplied by publisher] (Sou... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5382723 Tue, 11 Oct 2011 04:00:00 +0100 5382723 http://www.medworm.com/index.php?rid=5382722&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21996284%26dopt%3DAbstract Authors: Brierley SM, Kelber O Abstract Altered motility, discomfort and pain are common debilitating symptoms of patients with functional gastrointestinal disorders. However, these conditions represent a significant and unmet need for mainstream medical treatment, particularly after high profile therapeutic drug withdrawals due to safety concerns. As such an increasing number of sufferers are turning to alternative medicines in an effort to seek relief from their symptoms. Alternative medicines have traditionally been looked at by mainstream medicine with cynicism. However, new evidence demonstrates that the active components in natural products have actions on specific ion channels and receptors, many of which are located in sensory systems distributed throughout the body. These ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5382722 Tue, 11 Oct 2011 04:00:00 +0100 5382722 http://www.medworm.com/index.php?rid=5382724&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21992930%26dopt%3DAbstract Authors: David S, Meltzer SJ Abstract MicroRNAs (miRs) have recently emerged as a novel class of gene expression regulators. The number of studies documenting an altered miR expression pattern in cancer continues to expand rapidly. Critical information is continuously gained regarding how aberrantly expressed miRs contribute to carcinogenesis. Current studies provide evidence that analyses of miR expression patterns have potential clinical applications toward developing tumor biomarkers to identify the presence and dissemination of esophageal cancer, as well as to assess tumor chemosensitivity or radiosensitivity. The incidence of esophageal cancer is on the rise, and this disease continues to portend a poor prognosis. The current review addresses ways in which altered miR expressi... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5382724 Mon, 10 Oct 2011 04:00:00 +0100 5382724 http://www.medworm.com/index.php?rid=5382725&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21983454%26dopt%3DAbstract Authors: Sandle GI Abstract There have been significant advances in unravelling the cellular mechanisms of diarrhoea in common gut infections and colonic inflammation, as well as in the identification of targets for potential antidiarrhoeal drugs. Infective diarrhoea reflects activation of electrogenic Cl(-) secretion, inhibition of electroneutral NaCl absorption and in some cases, downregulation of tight junctional proteins and increased apoptosis. In colonic inflammation, diarrhoea mainly reflects impairment of colonic Na(+) and Cl(-) absorption by inflammatory cytokines, leading to decreased water absorption. Stimulation of endogenous opiate-dependent pathways, manipulation of epithelial ion (Na(+), K(+) and Cl(-)) channels and suppression of proinflammatory cytokine production ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5382725 Fri, 07 Oct 2011 04:00:00 +0100 5382725 http://www.medworm.com/index.php?rid=5283250&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21962439%26dopt%3DAbstract Authors: Chan S, Yan C Abstract Pathological vascular remodeling is a hallmark of most vascular disorders such as atherosclerosis, postangioplasty restenosis, allograft vasculopathy, and pulmonary hypertension. Pathological vascular remodeling is a multi-cell-dependent process leading to detrimental changes of vessel structure and eventual vessel occlusion. Cyclic nucleotide signaling regulates a variety of vascular functions ranging from cell contractility to cell growth. Cyclic nucleotide phosphodiesterases (PDEs), a large family of structurally and functionally distinct isozymes, regulate cyclic nucleotide levels and compartmentalization through catalyzing their degradation reaction. Increasing evidence has suggested that one of the important mechanisms for specific cyclic nucle... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5283250 Thu, 29 Sep 2011 04:00:00 +0100 5283250 http://www.medworm.com/index.php?rid=5283249&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21962440%26dopt%3DAbstract Authors: Tsai LC, Beavo JA Abstract The second messenger, cAMP, is one of the most important regulatory signals for control of steroidogenesis. This review focuses on current knowledge about regulation of cyclic nucleotides by phosphodiesterases (PDEs) in steroidogenic tissues. The first PDE known to directly regulate steroidogenesis was PDE2, the cGMP-stimulated PDE. PDE2 mediates ANP/cGMP-induced decreases in aldosterone production. Recently, the PDE8 family has been shown to control steroidogenesis in two tissues. Specifically, PDE8A regulates testosterone production by itself and in concert with additional IBMX-sensitive PDEs. PDE8B modulates basal corticosterone synthesis via acute and chronic mechanisms. In addition to cAMP-dependent pathways, cGMP signaling also can promote ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5283249 Thu, 29 Sep 2011 04:00:00 +0100 5283249 http://www.medworm.com/index.php?rid=5283248&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21962613%26dopt%3DAbstract Authors: Movsesian M, Wever-Pinzon O, Vandeput F Abstract In dilated cardiomyopathy, a condition characterized by chamber enlargement and reduced myocardial contractility, decreases in β-adrenergic receptor density and increases in Gαi and β-adrenergic receptor kinase activities attenuate the stimulation of adenylyl cyclase in response to catecholamines. PDE3 inhibitors have been used to 'overcome' the reduction in cAMP generation by blocking cAMP hydrolysis. These drugs increase contractility in the short-term, but long-term administration leads to an increase in mortality that correlates with an increase in sudden cardiac death. Whether separate mechanisms account for these beneficial and harmful effects, and, if so, whether PDE3 can be targeted so as to increase contractility... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5283248 Wed, 28 Sep 2011 04:00:00 +0100 5283248 http://www.medworm.com/index.php?rid=5234696&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21924956%26dopt%3DAbstract Authors: Francis SH, Corbin JD Abstract Erectile dysfunction (ED) is strongly linked to cardiovascular disease (CVD), especially in diabetics. ED is associated with deleterious changes in the overall vasculature and is recognized as an indicator of higher risk for adverse cardiovascular events. Endothelial dysfunction, vascular smooth muscle changes and increased fibrosis are indicated as major players in both ED and CVD. ED in diabetics is more refractory to acute treatment with phosphodiesterase-5 (PDE5) inhibitors (Viagra, Cialis, Levitra, Zydena) than in non-diabetics, but recent studies indicate that chronic administration of these drugs improves endothelial function, preserves vascular smooth muscle and decreases fibrotic changes. Use of PDE5 inhibitors in pre-diabetic and di... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5234696 Thu, 15 Sep 2011 04:00:00 +0100 5234696 http://www.medworm.com/index.php?rid=5221184&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21903474%26dopt%3DAbstract Authors: Theuretzbacher U, Mouton JW PMID: 21903474 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5221184 Tue, 06 Sep 2011 04:00:00 +0100 5221184 http://www.medworm.com/index.php?rid=5221185&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21893430%26dopt%3DAbstract Authors: Muglia P Abstract Neuropsychiatric disorders as schizophrenia, autism and mood disorders represent one of the leading causes of disability. The cost of bringing a drug to the market is increasing and becoming more risky. Pharmaceutical investments in neuroscience are decreasing. At the same time we are facing an unprecedented rate of discovery in human genetics. Genes predisposing for common diseases including psychiatric disorders are being identified. The knowledge derived from the identification of genes relevant for psychiatric disorders holds the promise of providing truly innovative therapeutic interventions. The process of approving new psychiatric drugs, is however complex, lengthy and requires a well orchestrated and funded effort of multiple disciplines. In this ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5221185 Sat, 03 Sep 2011 04:00:00 +0100 5221185 http://www.medworm.com/index.php?rid=5221186&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21889911%26dopt%3DAbstract Authors: Seyedmousavi S, Melchers WJ, Verweij PE, Mouton JW Abstract Experimental models of invasive aspergillosis (IA) have been used to explore pharmacokinetic and pharmacodynamic (PK/PD) properties of antifungal agents. Survival is still considered the golden standard effect measure but has the disadvantage that a large number of animals are needed to determine the dose-response relationships and PK/PD of antifungals. The feasibility of using fungal load by real-time quantitative PCR (qPCR) as an effect measure has been explored recently. The majority of studies reported convincingly demonstrate a larger dynamic range for qPCR compared to conventional assays. However interpretation and translating the results to guidance in clinical decision making need further study. It is expe... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5221186 Thu, 01 Sep 2011 04:00:00 +0100 5221186 http://www.medworm.com/index.php?rid=5180153&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21868287%26dopt%3DAbstract Authors: Singh R, Tam VH Abstract The widespread emergence of resistance to antimicrobial agents has taken mammoth dimension and warrants immediate steps to minimize it. Pharmacokinetics/pharmacodynamics of antimicrobial agents, differences among bacterial species, and time-dependent changes in the bacterial population are important factors involved in the development of drug resistance. The key to minimizing resistance lies in understanding how these factors affect resistance emergence and incorporating them in dosing regimen design. In vitro models have proven to be a valuable tool to study these factors and their contribution in resistance emergence. This review summarizes the key factors implicated in resistance development and the lessons learnt from in vitro studies optimizin... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5180153 Mon, 22 Aug 2011 23:00:00 +0100 5180153 http://www.medworm.com/index.php?rid=5160152&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21862408%26dopt%3DAbstract Authors: Theuretzbacher U Abstract New resistance challenges continue to evolve and spread worldwide. In an otherwise mature field, antibacterial drug development is primarily driven by resistance trends with a focus on development of new analogs of known scaffolds to strengthen them against class-specific resistance mechanisms. Currently new analogs of cephalosporins (with or without beta-lactamase inhibitors), oxazolidinones, glycopeptides, quinolones, aminoglycosides, tetracyclines, and ketolides are in clinical studies. While showing some benefit, these new analogs only partially address the clinical crisis of multidrug-resistant pathogens; this is especially the case for Gram-negative bacteria. The medical community faces grim reality-general solutions to the treatment of rapi... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5160152 Thu, 18 Aug 2011 23:00:00 +0100 5160152 http://www.medworm.com/index.php?rid=5160151&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21862409%26dopt%3DAbstract Authors: Macgowan A Abstract Pre-clinical pharmacokinetic-pharmacodynamic assessments indicate Beta-lactam antibiotics have time-dependent killing, variable persistent antibiotic effects and that free drug T>MIC is the dominant pharmacodynamic index. Prolonged or continuous infusion therapy has improved microbiological responses in pathogens with MICs at or 2-4 fold higher than existing EUCAST clinical breakpoints in pre-clinical studies. Human population pharmacokinetic modelling combined with Monte Carlo Simulation indicates improved pharmacodynamic target attainment rates and hence predicts improved clinical responses for those pathogens with raised MICs. However, the majority of human clinical trials comparing prolonged or continuous infusion to intermittent injection have f... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5160151 Thu, 18 Aug 2011 23:00:00 +0100 5160151 http://www.medworm.com/index.php?rid=5142511&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21840259%26dopt%3DAbstract Authors: Cantón R, Ruiz-Garbajosa P Abstract Co-resistance involves transfer of several genes into the same bacteria and/or the acquisition of mutations in different genetic loci affecting different antimicrobials whereas pleiotropic resistance implies the same genetic event affecting several antimicrobials. There is an increasing prevalence of isolates with co-resistance which are over-represented within the so-called high-risk clones. Compensatory events avoid fitness cost of co-resistance, even in the absence of antimicrobials. Nevertheless, they might be selected by different antimicrobials and a single agent might select co-resistant isolates. This process, named as co-selection, is not avoided with cycling or mixing strategies of antimicrobial use. Co-resistance and co-selec... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5142511 Wed, 10 Aug 2011 23:00:00 +0100 5142511 http://www.medworm.com/index.php?rid=5142513&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21835694%26dopt%3DAbstract Authors: Bergen PJ, Li J, Nation RL Abstract The increasing prevalence of multidrug-resistant Gram-negative bacteria worldwide has led to a re-evaluation of the previously discarded antibiotic, colistin. Despite its important role as salvage therapy for otherwise untreatable infections, dosage guidelines for the prodrug colistin methanesulfonate (CMS) are not scientifically based and have led to treatment failure and increased colistin resistance. In this review we summarise the recent progress made in the understanding of the pharmacokinetics of CMS and formed colistin with an emphasis on critically ill patients. The pharmacodynamics of colistin is also reviewed, with special attention given to the relationship between pharmacokinetics and pharmacodynamics and how the emerging dat... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5142513 Mon, 08 Aug 2011 23:00:00 +0100 5142513 http://www.medworm.com/index.php?rid=5142512&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21835695%26dopt%3DAbstract Authors: Martínez JL, Baquero F, Andersson DI Abstract Market launching of a new antibiotic requires knowing in advance its benefits and possible risks, and among them how rapidly resistance will emerge and spread among bacterial pathogens. This information is not only useful from a public health point of view, but also for pharmaceutical industry, in order to reduce potential waste of resources in the development of a compound that might be discontinued at the short term because of resistance development. Most assays currently used for predicting the emergence of resistance are based on culturing the target bacteria by serial passages in the presence of increasing concentrations of antibiotics. Whereas these assays may be valuable for identifying mutations that might cause resist... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5142512 Mon, 08 Aug 2011 23:00:00 +0100 5142512 http://www.medworm.com/index.php?rid=5108378&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21807559%26dopt%3DAbstract Authors: Pasipanodya JG, Gumbo T The current understanding of the mechanism of anti-tuberculosis drug resistance has been shaped by the history of development of anti-tuberculosis drugs in the past 60 years and was arrived at as part of inductive generalization. Recently, these standard beliefs have been tested in controlled hollow fiber systems experiments. Drug resistance in Mycobacterium tuberculosis was shown to be related to pharmacokinetic-pharmacodynamic (PK/PD) factors, and factors such as pharmacokinetic variability. Poor PK/PD exposures owing to our current non-optimized dosing regimens initiate a chain of evolution driven events, starting with induction of multi-drug efflux pumps, followed by the development of chromosomal mutations in time, which together lead to high level... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5108378 Fri, 29 Jul 2011 23:00:00 +0100 5108378 http://www.medworm.com/index.php?rid=5108381&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21803654%26dopt%3DAbstract Authors: Blackburn EA, Walkinshaw MD The FK506 binding protein (FKBP) family of proteins provide an interesting series of drug targets since different isoforms modulate diverse cellular pathways. There are therapeutic opportunities in the fields of cancer therapy, neurodegenerative conditions and psychiatric disorders. X-ray crystallographic or NMR data are available for eight of fourteen human FKBPs covering ten of the twenty-two different FKBP domains. We have made a detailed sequence and structural comparison of human FKBP domains. These data show that the chemical scaffolds common to the immunosuppressive inhibitors FK506 and rapamycin bind to the most conserved region of the binding site. This observation opens the way to the design of isoform specific inhibitors. PMID: 218036... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5108381 Thu, 28 Jul 2011 23:00:00 +0100 5108381 http://www.medworm.com/index.php?rid=5108380&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21803655%26dopt%3DAbstract Authors: John Curnow S, Wallace GR PMID: 21803655 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5108380 Thu, 28 Jul 2011 23:00:00 +0100 5108380 http://www.medworm.com/index.php?rid=5108379&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21803656%26dopt%3DAbstract Authors: Rosenzweig HL, Planck S, Rosenbaum J Innate immune receptors such as the nucleotide-binding domain, leucine-rich repeat-containing (NBD-LRR) receptors, referred to as NLRs, are known to serve as a critical component of host defense. However, their participation in inflammatory responses within immune privileged sites such as the brain and eye is less understood. The potential importance of NLRs in regulation of inflammation within these particular sites is further underscored by their association with autoinflammatory disorders, wherein localized inflammation can occur within the brain or eye as neuroinflammation or uveitis, respectively. Many NLRs are expressed within the brain and eye and in this review, we discuss their roles in the inflammation of the central nervous syste... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5108379 Thu, 28 Jul 2011 23:00:00 +0100 5108379 http://www.medworm.com/index.php?rid=5108382&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21783419%26dopt%3DAbstract Authors: Merlo Pich E The discovery of novel drugs is a complex and highly regulated process organized around a critical moment, that is, when the novel compound is tested in humans. This process encompasses a series of clinical studies, identified as Phase I and Phase II, whose composite outcome should deliver the data needed for an informed decision about progressing or not the compound in full development (Phase III). Over the last 10 years the global delivery of novel treatments from the pharmaceutical industry has plunged to the level of the '70ies in spite of a 10-fold larger investment, the differential mostly due to failures in Phase III. There is the need to improve the decision making at the early clinical stage by using innovation and the high-profile achievements of basic s... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5108382 Wed, 20 Jul 2011 23:00:00 +0100 5108382 http://www.medworm.com/index.php?rid=5108383&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21775205%26dopt%3DAbstract Authors: Stewardson AJ, Huttner B, Harbarth S This review presents recent evidence regarding the adverse effects of antibiotic therapy mediated by collateral damage to commensal flora. Two major drivers have characterized recent research in this field: new perspectives into human microbiota afforded by next-generation DNA sequencing techniques and ongoing attention to antimicrobial resistance. New molecular techniques have illustrated that antibiotic therapy can disturb human microbiota, and that these changes are associated with infection. Concurrently, epidemiologic studies using patient-level data offer new insights into the role of antibiotics in the emergence, selection and spread of antimicrobial resistance, and Clostridium difficile infection (CDI). PMID: 21775205 [PubMed - ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5108383 Sun, 17 Jul 2011 23:00:00 +0100 5108383 http://www.medworm.com/index.php?rid=5108384&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21763200%26dopt%3DAbstract Authors: Humby T, Wilkinson LS Inhibition is a fundamental property of behaviour required for flexible responding and humans have evolved executive brain systems that can engage inhibitory processes in order to reduce interference from irrelevant distracting stimuli, block unwanted memories and emotions and suppress inappropriate choices and actions. Without the efficient operation of these inhibitory mechanisms behaviour can become maladaptive, as seen in a large range of disorders where subjects exhibit impulsive responding, such as ADHD, mania, chronic substance abuse and schizophrenia. Animal models are making an increasing contribution to our understanding of the psychology and underlying neurobiology of behavioural inhibition and impulsivity. Here, in this short article we summar... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5108384 Tue, 12 Jul 2011 23:00:00 +0100 5108384 http://www.medworm.com/index.php?rid=5108385&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21752712%26dopt%3DAbstract Authors: Bates S Monitoring gene expression through the dual approaches of transcriptomics (RNA profiling) and proteomics (protein profiling) has become a key component in our efforts to understand complex biological processes. From the molecular stratification of disease states and the selection of potential drug targets, to patient selection and the confirmation of engagement of pharmacology in clinical studies, we are seeing the impact of gene expression profiling across all phases of the drug discovery process. Ongoing technological advances have driven an expansion in the use of these techniques, demonstrated utility in preclinical and clinical settings and increased regulatory and clinical acceptance. As technologies continue to advance apace, gene expression profiling is likely ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5108385 Sun, 10 Jul 2011 23:00:00 +0100 5108385 http://www.medworm.com/index.php?rid=5108386&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21741310%26dopt%3DAbstract Authors: Prince LR, Whyte MK, Sabroe I, Parker LC Neutrophils are key innate immune effector cells that are rapidly recruited to sites of infection and inflammation to provide early defence against invading microorganisms. This function is facilitated by the expression of Toll-like receptor (TLR) family members by neutrophils, allowing the recognition of an extensive repertoire of pathogen-associated molecular patterns (PAMPs) and thus triggering the response to invading pathogens. TLR activation leads to important cellular processes including reactive oxygen species (ROS) generation, cytokine production and increased survival, all of which can contribute to the pathogenesis of chronic inflammation when signalling becomes dysregulated. In turn, inflammation and tissue injury results in... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5108386 Tue, 05 Jul 2011 23:00:00 +0100 5108386 http://www.medworm.com/index.php?rid=5012092&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21737346%26dopt%3DAbstract Authors: Nathan PJ, Cobb SR, Lu B, Bullmore ET, Davies CH Synaptic plasticity is the ability of synaptic connections between neurons to be strengthened or weakened; a process that is central to the information processing within the brain and which plays a particularly important role in enabling higher cognitive processes [1,2]. Its role in disease is becoming increasingly clear across a wide spectrum of CNS disorders. Thus, for example, dysfunctional synaptic plasticity has been reported in neurodegenerative disorders such as Alzheimer's Disease (AD) as well as in schizophrenia and in a range of disorders associated with learning disabilities [3]. Moreover, maladaptive plasticity processes in response to specific external challenges are believed to underlie disorders such as addiction ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5012092 Mon, 04 Jul 2011 23:00:00 +0100 5012092 http://www.medworm.com/index.php?rid=5012093&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21723195%26dopt%3DAbstract Authors: Tobe BT, Snyder EY, Nye JS Identifying the molecular and cellular basis of complex neuropsychiatric disorders (cNPDs) has been limited by the inaccessibility of central neurons, variability within broad diagnostic classifications, and the interplay of genetic and environmental factors. Recent work utilizing neuronally differentiated human induced pluripotent stem cells (hiPSCs) from Mendelian and polygenic cNPDs is beginning to illuminate neuritic, synaptic or cell body variations accompanied by specific gene or protein expression alterations largely mimicking known pathology. In some cases, phenotypes have only emerged after application of cellular stress or long duration of differentiation. Pathological and cellular expression features are fully or partially responsive to ph... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5012093 Tue, 28 Jun 2011 23:00:00 +0100 5012093 http://www.medworm.com/index.php?rid=5012095&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21704559%26dopt%3DAbstract Authors: Trist DG Scientific method in drug discovery has centered on generating a hypothesis (target identification) and hypothesis testing (target validation). Traditionally, both processes were performed using animal data, with the basic pharmacologist being pivotal. Many therapeutic areas that rely on human data to validate targets as animal models are seen as poorly predictive. Failures of molecules in Phase III for poor efficacy raise questions about target identification and validation. The clinical pharmacologist, working with the basic pharmacologist can play a major role in aiding target identification and by developing trial designs using small patient populations, mitigating the need for full Phase III studies to test the hypothesis. Technologies such as genomics, non-invas... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5012095 Wed, 22 Jun 2011 23:00:00 +0100 5012095 http://www.medworm.com/index.php?rid=5012094&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21704560%26dopt%3DAbstract Authors: Trist DG, Davies CH PMID: 21704560 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=5012094 Wed, 22 Jun 2011 23:00:00 +0100 5012094 http://www.medworm.com/index.php?rid=4969080&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21664870%26dopt%3DAbstract Authors: Mazzone SB, McGovern AE, Cole LJ, Farrell MJ For many years the idea of a cough center in the brain dominated discussions in the field without any substantial progress in defining what this cough center is or how it functions. Substantial progress has now been made and many of the central neural elements involved in coughing are being described. Furthermore, hypothesis driven research into the function of these neural elements is providing exciting new leads for possible therapeutic targets. The concept of a specific, centrally acting drug for cough suppression is fast becoming a reality. This review summarizes the key findings from the past few years and provides a perspective on future directions for the development of novel antitussives. PMID: 21664870 [PubMed - as supp... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4969080 Wed, 08 Jun 2011 23:00:00 +0100 4969080 http://www.medworm.com/index.php?rid=4922326&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21652263%26dopt%3DAbstract Authors: Rossi T, Braggio S The constant decline in drug discovery productivity despite the continuous growth in R&D investments has been on the table for many years and is driving changes in the current business model. We have focused our attention on what appears to be by far the major cause of attrition, the intrinsic quality of drug candidates; with the assumption that candidate quality can be designed and assessed at a rather early stage in drug discovery we have developed tools such as CNS chemical space mapping through PLS analysis, Drug Efficiency (DRUG(eff)) and the mechanistic PK/PD hypothesis. We also introduced best practices that were found extremely valuable which will be discussed in this article. PMID: 21652263 [PubMed - as supplied by publisher] (Source: Curren... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4922326 Sun, 05 Jun 2011 23:00:00 +0100 4922326 http://www.medworm.com/index.php?rid=4922328&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21646047%26dopt%3DAbstract Authors: Romano MF PMID: 21646047 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4922328 Fri, 03 Jun 2011 23:00:00 +0100 4922328 http://www.medworm.com/index.php?rid=4922327&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21646048%26dopt%3DAbstract Authors: Pignataro G, Capone D, Polichetti G, Vinciguerra A, Gentile A, Di Renzo G, Annunziato L The acronym mTOR defines a family of serine-threonine protein kinase called mammalian target of rapamycin. The major role of these kinases in the cell is to merge extracellular instructions with information about cellular metabolic resources and to control the rate of anabolic and catabolic processes accordingly. In mammalian cells mTOR is present in two distinct heteromeric protein complexes commonly referred to as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), involved in the control of a wide variety of cellular processes. It has been recently reported that compounds acting modulating mTOR activity, beside mediating the well recognized processes exploited in the anticancer and immu... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4922327 Fri, 03 Jun 2011 23:00:00 +0100 4922327 http://www.medworm.com/index.php?rid=4922329&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21628105%26dopt%3DAbstract Authors: Fisher JT, Canning BJ PMID: 21628105 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4922329 Sat, 28 May 2011 23:00:00 +0100 4922329 http://www.medworm.com/index.php?rid=4876540&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21571591%26dopt%3DAbstract Authors: Choi BH, Yoon HS FKBP38, a noncanonical member of the immunosuppressive drug FK506 binding protein (FKBP) family members, possesses an inducible rotamase. FKBP38 interacts with several proteins and regulates multiple signaling pathways such as cell survival, apoptosis, proliferation, and metastasis. Deregulation of apoptosis is associated with chemoresistance and tumor relapse. The antiapoptotic protein Bcl-2 is a key player for increasing the apoptotic threshold in response to various cytotoxic drugs. The molecular interaction of Bcl-2 with FKBP38 potentiates the biological function of Bcl-2 and contributes to tumorigenesis and chemoresistance. Here, we discuss recent advances in the role of FKBP38 in connection with Bcl-2 and its possible link to chemotherapeutic resistance.... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4876540 Thu, 12 May 2011 23:00:00 +0100 4876540 http://www.medworm.com/index.php?rid=4876541&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21570913%26dopt%3DAbstract Authors: Matthews PM, Rabiner I, Gunn R Clinical imaging offers a range of methods for the support of drug development that are able to address major questions related to target validation and molecule biodistribution, target interactions and pharmacodynamics. Here we review recent innovative applications of positron emission tomography (PET) and magnetic resonance imaging (MRI). New approaches to human target validation exploring MRI or PET biomarker changes related to allelic variation at candidate target loci can contribute to human target validation. PET molecular imaging can define molecule biodistribution directly and, if an appropriate, target-specific radioligand is available, be employed in small experimental medicine studies to provide plasma pharmacokinetic-target occupancy ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4876541 Wed, 11 May 2011 23:00:00 +0100 4876541 http://www.medworm.com/index.php?rid=4823505&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21565551%26dopt%3DAbstract Authors: Turcotte SE, Lougheed MD Asthma is one of the most common causes of chronic cough, and cough may be the sole or predominant symptom of asthma. The mechanisms of cough in asthma are complex and presumbably multi-factorial. In particular, the pathophysiologic basis of cough variant versus classic asthma is poorly understood. Recent research utilizing various inhalation challenge tests suggests that preservation of the bronchodilating and bronchoprotective effects of deep inspirations is a distinguishing feature of cough variant asthma. This review outlines the tussive agents used in cough research (including tussive and direct, indirect and combined bronchoconstrictive stimuli), their mechanisms of action, the receptors involved in eliciting cough, and characteristic responses i... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823505 Mon, 09 May 2011 23:00:00 +0100 4823505 http://www.medworm.com/index.php?rid=4823504&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21565552%26dopt%3DAbstract Authors: Stechschulte LA, Sanchez ER FK506-binding protein 51 (FKBP51) is gaining increased recognition for its essential roles in cell biology. Originally discovered as a component of steroid receptor complexes, it is now known to regulate a diverse set of transcription factors, enzymes and structural proteins. Its cellular properties suggest numerous possible functions for FKBP51 in physiology, and the best clue to its potential importance may be the following: FKBP51 is a glucocorticoid-induced negative regulator of the glucocorticoid receptor. Thus, FKBP51 is intricately involved in regulation of the most pleiotropic hormone known to biology. In contrast to glucocorticoid receptor, FKBP51 is a positive regulator of the androgen receptor, suggesting that it functions as a reciprocal... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823504 Mon, 09 May 2011 23:00:00 +0100 4823504 http://www.medworm.com/index.php?rid=4823503&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21565553%26dopt%3DAbstract This article is an overview of the causes of aberrant NF-κB regulation in cancer and highlights recent papers that implicate FKBP51 in such deregulation. PMID: 21565553 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823503 Mon, 09 May 2011 23:00:00 +0100 4823503 http://www.medworm.com/index.php?rid=4823506&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21555247%26dopt%3DAbstract This article focuses on cognitive deficits associated with schizophrenia to illustrate: a) How non-invasive EEG biomarkers of cognitive function constitute such a 'higher level correlate' of underlying pathologies. b) How derangement of multiple, cell-specific, molecular processes can converge on such EEG-visible, correlates of disrupted cognitive function. This approach suggests that evidence-based design of multi-target therapies may take advantage of hierarchical patterns of convergence to improve both efficacy and selectivity of disease-intervention. PMID: 21555247 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823506 Fri, 06 May 2011 23:00:00 +0100 4823506 http://www.medworm.com/index.php?rid=4823507&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21543258%26dopt%3DAbstract Authors: Gu Q, Lee LY Inhalation or aspiration of acid solution evokes airway defense responses such as cough and reflex bronchoconstriction, resulting from activation of vagal bronchopulmonary C-fibers and Aδ afferents. The stimulatory effect of hydrogen ion on these sensory nerves is generated by activation of two major types of ion channels expressed in these neurons: a rapidly activating and inactivating current mediated through ASICs, and a slow sustaining current via activation of TRPV1. Recent studies have shown that these acid-evoked responses are elevated during airway inflammatory reaction, revealing the potential convergence of a wide array of inflammatory signaling on these ion channels. Since pH in the airway fluid drops substantially in patients with inflammatory airway ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823507 Sun, 01 May 2011 23:00:00 +0100 4823507 http://www.medworm.com/index.php?rid=4823508&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21531622%26dopt%3DAbstract Authors: Williams M Preclinical characterization of new chemical entities (NCEs) in terms of efficacy, safety and their pharmacokinetic (PK), pharmacodynamic and pharmaceutical properties, is key to advancing appropriate compounds to clinical trials. The use of high throughput synthetic and screening methodologies has frequently led to NCE characterization becoming highly reductionistic, to the extent that compounds are often selected without adequate characterization. Classical, null hypothesis-based approaches involving the use of concentration/dose response curves and antagonists have been replaced by more qualitative approaches that limit NCE characterization. The return to a more integrated, hierarchical and pharmacologically driven approach will aid in ensuring that the NCEs adva... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823508 Thu, 28 Apr 2011 23:00:00 +0100 4823508 http://www.medworm.com/index.php?rid=4823509&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21531172%26dopt%3DAbstract Authors: Jääskeläinen T, Makkonen H, Palvimo JJ FK506 binding protein 51 (FKBP51, FKBP5) functions as a co-chaperone for androgen, glucocorticoid, mineralocorticoid and progesterone receptors. The FKBP51 can act as an important determinant of the responses to steroids, especially to glucocorticoids in stress and mood disorders and androgens in prostate cancer, raising medical and pharmacological interests in the protein and its gene. Recent studies have revealed the molecular mechanisms by which the androgens and the glucocorticoids via their nuclear receptors elicit the robust up-regulation of the FKBP51 gene. Several polymorphisms in the FKBP51 gene have been associated with the mood disorders and differences in glucocorticoid sensitivity. The polymorphisms may contribute to the s... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823509 Wed, 27 Apr 2011 23:00:00 +0100 4823509 http://www.medworm.com/index.php?rid=4823512&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21530399%26dopt%3DAbstract Authors: Staibano S, Mascolo M, Ilardi G, Siano M, De Rosa G FKBP51 is a FK506-binding immunophilin involved in the regulation of several fundamental biological processes. A growing body of data indicates that this protein has also a role in the abnormal cell growth of cancers, and could be considered as a promising new marker of tumor progression and response to radio/chemotherapy. However, the data concerning the expression of FKBP51 in cancer are not conclusive, and partially contradictory. They delineate a very complex scenario, in which many molecular FKBP51-related pathways are variously intersected among different tumors. This review reports the available data concerning FKBP51 expression in normal tissues and human malignancies, outlining the role of the immunohistochemical ana... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823512 Tue, 26 Apr 2011 23:00:00 +0100 4823512 http://www.medworm.com/index.php?rid=4823511&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21530400%26dopt%3DAbstract This article reviews recent findings of NEB functional morphology and innervation, and postulates a role in the generation of dyspnea. This is based on their potential for transduction of dyspneic stimuli and findings of NEB cell abnormalities in a number of pulmonary disorders presenting with this symptom. PMID: 21530400 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823511 Tue, 26 Apr 2011 23:00:00 +0100 4823511 http://www.medworm.com/index.php?rid=4823510&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21530401%26dopt%3DAbstract Authors: Sheel AW, Foster GE, Romer LM Dyspnea is a subjective experience of breathing discomfort that can limit the ability and motivation to perform exercise or exertion. It is a common problem that affects specific groups of patients, such as, those suffering from chronic obstructive pulmonary disease, congestive heart failure, and interstitial lung disease, and in healthy humans during aging, pregnancy, and obesity. In this review, the current mechanistic model of exertional dyspnea is summarized and new research demonstrating how treatment strategies improve dyspnea by reducing central ventilatory drive, improving dynamic ventilatory mechanics, and improving respiratory muscle function is highlighted. Lastly, we review the effects of healthy aging and recent evidence for a male-fe... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823510 Tue, 26 Apr 2011 23:00:00 +0100 4823510 http://www.medworm.com/index.php?rid=4823513&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21514887%26dopt%3DAbstract Authors: Cioffi DL, Hubler TR, Scammell JG Best established as components of steroid hormone receptor complexes, it is now clear that the large molecular weight immunophilins, FKBP52 and FKBP51, play important regulatory roles elsewhere in the cell. This review outlines what is known about the organization of the genes, FKBP4 and FKBP5, respectively, encoding these proteins and describes their diverse actions in the nervous system, reproduction, and cancer. The organization of FKBP4 and FKBP5 is very similar among the chordates, and gene expression is influenced by both genetic and epigenetic mechanisms. Recent studies identifying roles of FKBP52 and FKBP51 in the regulation of the microtubule-associated protein tau and microtubule assembly are discussed, as is their interaction with a... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823513 Wed, 20 Apr 2011 23:00:00 +0100 4823513 http://www.medworm.com/index.php?rid=4823515&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21514221%26dopt%3DAbstract Authors: Solassol J, Mange A, Maudelonde T FK506-binding proteins (FKBPs) belong to the immunophilin family and bind immunosuppressive drugs, such as FK506 and rapamycin. These proteins, through interactions with steroid hormone receptors, kinases, or other cellular factors, play important roles in various physiological processes and, more interestingly, in pathological processes in mammals. Accumulating evidence has implicated some FKBP members in a variety of processes, such as the cell cycle and survival and apoptotic signaling pathways, particularly in cancers. After the deregulation of their expression was observed in cancer tissues, it became increasingly clear that FKBP members played an important role in tumorigenesis and the response to chemotherapies and radiotherapies and th... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823515 Tue, 19 Apr 2011 23:00:00 +0100 4823515 http://www.medworm.com/index.php?rid=4823514&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21514222%26dopt%3DAbstract Authors: Edlich F, Lücke C FKBP38 is in many ways an exceptional member of the FK506-binding proteins. The calmodulin-regulated activity of FKBP38 for instance is unique within this protein family. The activated FKBP38 participates in apoptosis signaling by inhibiting the anti-apoptotic Bcl-2. Beyond this role in programmed cell death, FKBP38 seems to be involved in very different cellular processes that do not necessarily depend on the FKBP domain. These functions involve regulation of the kinase mTOR, regulation of neural tube formation, regulation of cellular hypoxia response, but also Hepatitis C virus replication. Pharmacological targeting of FKBP38 might therefore prove a successful strategy for intervention in different FKBP38-dependent processes, including programmed cell deat... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823514 Tue, 19 Apr 2011 23:00:00 +0100 4823514 http://www.medworm.com/index.php?rid=4823516&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21511531%26dopt%3DAbstract Authors: Sivils JC, Storer CL, Galigniana MD, Cox MB The large FK506-binding protein FKBP52 has been characterized as an important positive regulator of androgen, glucocorticoid and progesterone receptor signaling pathways. FKBP52 associates with receptor-Hsp90 complexes and is proposed to have roles in both receptor hormone binding and receptor subcellular localization. Data from biochemical and cellular studies have been corroborated in whole animal models as fkbp52-deficient male and female mice display characteristics of androgen, glucocorticoid and/or progesterone insensitivity. FKBP52 receptor specificity and the specific phenotypes displayed by the fkbp52-deficient mice have firmly established FKBP52 as a promising target for the treatment of a variety of hormone-dependent disea... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823516 Mon, 18 Apr 2011 23:00:00 +0100 4823516 http://www.medworm.com/index.php?rid=4823517&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21501972%26dopt%3DAbstract Authors: Dunne A, Marshall NA, Mills KH Toll-like receptors (TLRs) play a crucial role in innate immune responses to infection. Binding of agonists to TLRs promotes maturation of antigen presenting cells, such as dendritic cells, which in turn directs the induction of adaptive immune responses. For this reason TLR agonists are being exploited as vaccine adjuvants for infectious disease or cancer and as therapeutics against tumors. However TLR agonists also promote inflammatory cytokine production and have a pathogenic role in many diseases with an inflammatory basis, including autoimmune diseases. Consequently, antibodies to TLRs and inhibitors of TLR signalling pathways have considerable potential as therapeutics for inflammatory disorders. Some have shown to be efficacious in pre-cli... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823517 Fri, 15 Apr 2011 23:00:00 +0100 4823517 http://www.medworm.com/index.php?rid=4823520&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21498116%26dopt%3DAbstract Authors: Wang L FK506 binding protein 51 (FKBP51, also called FKBP5) belongs to a family of immunophilins, FK506 binding proteins (FKBPs). FKBP family members are targets for drugs such as rapamycin. Although FKBP51 shares characteristics with other FKBPs, it also has unique features, especially the role in its regulation of important signaling pathways such as the AKT kinase/protein kinase B pathway. In this review, we will focus on the function of FKBP51 as a scaffolding protein in the regulation of AKT activation and, in turn, its role in tumorigenesis and response to chemotherapy. PMID: 21498116 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823520 Thu, 14 Apr 2011 23:00:00 +0100 4823520 http://www.medworm.com/index.php?rid=4823519&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21498117%26dopt%3DAbstract Authors: Netea MG, van de Veerdonk FL, van Deuren M, van der Meer JW Genetic defects leading to impaired recognition of invading pathogens by the innate immune system, and hence to increased susceptibility to specific classes of microorganisms have been recently recognized. To date, defects have been described in three of the major families of pattern recognition receptors (PRRs): the Toll-like receptors (TLRs), the C-type lectin receptors (CLRs), and the nucleotide binding domain leucine-rich repeat containing receptors (NLRs). By contrast, defects in the viral receptors RigI helicases have not been found. PRR defects vary greatly in severity, display a narrow susceptibility profile towards specific pathogens, and when severe in infancy and childhood, often decrease in severity therea... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823519 Thu, 14 Apr 2011 23:00:00 +0100 4823519 http://www.medworm.com/index.php?rid=4823518&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21498118%26dopt%3DAbstract Authors: Eskelinen EL Autophagy is a mechanism for the degradation of cytoplasmic material, damaged organelles and aggregate-prone proteins in lysosomes. Recent evidence indicates that autophagy is a tumor suppressor mechanism, which is connected to its role in the clearance of the scaffold protein p62/SQSTM1 and prevention of oxidative stress and genomic instability. However, since autophagy is a survival mechanism, cancer cells can also exploit it to survive nutrient limitation and hypoxia that often occur in solid tumors. Tumor cells can also upregulate autophagy as a response to cancer treatment, and recent studies show that inhibition of autophagy can enhance the killing of tumor cells after treatment. Interestingly, the FK506-binding protein 51 plays a role in the autophagy-linke... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823518 Thu, 14 Apr 2011 23:00:00 +0100 4823518 http://www.medworm.com/index.php?rid=4823522&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21497134%26dopt%3DAbstract Authors: Giordano A, Romano A The current management of the stenosis of the coronary arteries relies on the insertion of a metal mesh tube, namely stent, into the obstructed vessel. Coronary stents have been envisaged to reduce the restenosis after balloon angioplasty. Nonetheless, one of the major complications after successful revascularization is the late in-stent restenosis. Such lesion consists mainly of inflammatory reaction and neointima formation as a consequence of the mechanical injury of the vessel. In this review, we examine the molecular players underlying the in-stent restenosis, with particular reference to the role of the mTOR pathway and the intracellular receptor immunophilins. The 'limus' based drugs, which are developed or are under development in drug-eluting stent... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823522 Tue, 12 Apr 2011 23:00:00 +0100 4823522 http://www.medworm.com/index.php?rid=4823521&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21497135%26dopt%3DAbstract Authors: Theuerkorn M, Fischer G, Schiene-Fischer C It is an emerging view that in many cases cell signalling relies on slow conformational interconversions of the backbone of key proteins as exemplified by the prolyl cis/trans isomerization, and that prolyl cis/trans isomerases (PPIases), such as cyclophilins, FK506-binding proteins and the parvulin-like Pin1, serve to integrate temporally and spatially protein conformers with signalling events. The causal relationship between prolyl cis/trans isomerization catalysis, malignant transformation and tumour progression is not yet fully understood because of the pleiotropic biochemical effects characterizing these enzymes. However, recent studies on the role of cyclophilins and Pin1 indicate that PPIases utilize isomerization catalysis on ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823521 Tue, 12 Apr 2011 23:00:00 +0100 4823521 http://www.medworm.com/index.php?rid=4823523&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21489876%26dopt%3DAbstract Authors: Yao YL, Liang YC, Huang HH, Yang WM FK506-binding proteins (FKBPs) are intracellular receptors for FK506 and rapamycin, immunosuppressants that have recently been utilized as anticancer drugs. In the cytoplasm, FKBPs and these drugs modulate signal transduction pathways. However, recent reports reveal novel functions of FKBPs in the nucleus, which include regulation of transcription factors, histone chaperone activity, and modifications of chromatin structure. These activities are known to affect gene expression, DNA repair, and DNA replication. Therefore, elucidation of the nuclear functions of FKBPs will help researchers and clinicians better understand how immunosuppressants work as anticancer drugs, which might in turn lead to novel designs of cancer therapy. PMID: 214... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4823523 Sun, 10 Apr 2011 23:00:00 +0100 4823523 http://www.medworm.com/index.php?rid=4663571&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21450522%26dopt%3DAbstract Authors: Raghavan N, Webb K, Amornputtisathaporn N, O'Donnell DE Dyspnea is the most distressing symptom experienced by those suffering from advanced stages of chronic obstructive pulmonary disease (COPD). Activity-related dyspnea in COPD is multifactorial but is associated with increased central neural drive, impaired dynamic respiratory mechanics and abnormal respiratory muscle function. Each of these components can potentially be targeted for pharmacotherapy. Recent advances in the pharmacotherapy of COPD include the development of new long-acting bronchodilators which, when combined, provide sustained improvements in dyspnea. Additionally, novel applications of older therapies such as opiates, furosemide, helium-oxygen, and statins show early promise as dyspnea-relieving interventi... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4663571 Sun, 27 Mar 2011 23:00:00 +0100 4663571 http://www.medworm.com/index.php?rid=4663572&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21439906%26dopt%3DAbstract Authors: Murphy DL, Moya PR Recent major findings from studies of SLC6A4 and its corresponding protein, the serotonin (5-HT) transporter (SERT) in humans, rodents and non-human primates indicate that combinations of SLC6A4 non-coding 5', 3' UTRs and intronic regions plus coding variants acting together can change 5HT transport as much as 40-fold in vitro. In vivo, SLC6A4 variants in humans and other species lead to marked physiological changes, despite mitigating neurodevelopmental adaptations in 5-HT receptors plus compensatory alterations in 5-HT synthesis and metabolism. Polymorphisms in SLC6A4 are associated with differences in emotional, endocrine, and personality characteristics as well as many diseases. This gene, in combinations with gene×gene (G×G) and gene×environment (G×... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4663572 Wed, 23 Mar 2011 00:00:00 +0100 4663572 http://www.medworm.com/index.php?rid=4663573&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21420906%26dopt%3DAbstract Authors: Meltzer H, Massey B The main class of atypical antipsychotic drugs (APDs) in current use includes the protypical atypical APD, clozapine, as well as aripiprazole, asenapine, iloperidone, lurasidone, olanzapine, quetiapine, risperidone, and ziprasidone. At clinically effective doses, these agents produce extensive blockade of serotonin (5-HT)(2A) receptors, direct or indirect stimulation of 5-HT(1A) receptors, and to a lesser extent, reduction in dopamine (DA) D(2) receptor-mediated neurotransmission. This contrasts with typical APDs, for example haloperidol and perphenazine, which are mainly DA D(2/)D(3) receptor antagonists and have weaker, if any, potency as 5-HT(2A) receptor antagonists. Some, but not all, atypical APDs are also effective 5-HT(2C) receptor inverse agonists ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4663573 Fri, 18 Mar 2011 00:00:00 +0100 4663573 http://www.medworm.com/index.php?rid=4663574&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21420360%26dopt%3DAbstract Authors: Barnes NM PMID: 21420360 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4663574 Thu, 17 Mar 2011 00:00:00 +0100 4663574 http://www.medworm.com/index.php?rid=4604283&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21398180%26dopt%3DAbstract Authors: Spiller RC Irritable bowel syndrome, which affects 5-10% of the population includes around 25% with predominantly diarrhoea (IBS-D). Several lines of evidence suggest an increase in mucosal 5-HT availability in IBS-D including a decrease in the serotonin transporter (SERT) which is also seen following acute diverticulitis. 5-HT(3) receptor antagonists have proved effective in suppressing urgency, prolonging small and large bowel transit and relieving symptoms in IBS-D. Alosetron continues to be used under restricted availability without any serious morbidity despite ischemic colitis which occurs at a rate of <1/1000 patient year. Other agents such as ramosetron and ondansetron are still in use and have not been associated with ischemic colitis. 5-HT(3) receptor agonists sti... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4604283 Fri, 11 Mar 2011 00:00:00 +0100 4604283 http://www.medworm.com/index.php?rid=4604284&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21393060%26dopt%3DAbstract Authors: Ahern GP The classical neurotransmitter, serotonin (5-HT), plays an important role outside of the central nervous system in immune signaling. Here I review recent studies describing 5-HT uptake in dendritic cells and B lymphocytes, 5-HT synthesis in T lymphocytes, and the role of specific 5-HT receptor subtypes in innate and adaptive immune cells. Furthermore, a recent paper describing the immune phenotype of 5-HT deficient mice is discussed. PMID: 21393060 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4604284 Tue, 08 Mar 2011 00:00:00 +0100 4604284 http://www.medworm.com/index.php?rid=4604286&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21377931%26dopt%3DAbstract Authors: Andrews N, O'Neill MF The following brief overview reflects our own opinion of where the most likely advances to treating pain (unrelated to IBS and migraine) may come from with respect to ligands directly interacting with specific 5-HT receptors. It is fully appreciated, and possibly more likely, that 5-HT plays a modulatory role in the mediation of analgesic effects of certain compounds, for example tricyclic antidepressants and the newer, safer class of serotonin/noradrenaline re-uptake inhibitors, for example duloxetine and milnacipran. However, we find that recent pre-clinical findings highlight the potential of peripherally acting 5-HT(1) and 5-HT(2A) receptor agonists and centrally penetrating 5-HT(7) receptor agonists to reduce chronic pain. We encourage experimentatio... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4604286 Fri, 04 Mar 2011 00:00:00 +0100 4604286 http://www.medworm.com/index.php?rid=4604285&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21377932%26dopt%3DAbstract This article highlights recent discoveries that advance our understanding of how 5-HT-evoked changes at molecular, cellular and neuropsychological levels might interact to alleviate the symptoms of clinical depression. PMID: 21377932 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4604285 Fri, 04 Mar 2011 00:00:00 +0100 4604285 http://www.medworm.com/index.php?rid=4604287&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21371939%26dopt%3DAbstract Authors: Zucker IH, Zimmerman MC PMID: 21371939 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4604287 Tue, 01 Mar 2011 00:00:00 +0100 4604287 http://www.medworm.com/index.php?rid=4604288&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21367658%26dopt%3DAbstract Authors: Diz DI, Arnold AC, Nautiyal M, Isa K, Shaltout HA, Tallant EA Aging, hypertension, and fetal-programmed cardiovascular disease are associated with a functional deficiency of angiotensin (Ang)-(1-7) in the brain dorsomedial medulla. The resulting unrestrained activity of Ang II in brainstem regions negatively impacts resting mean arterial pressure, sympathovagal balance, and baroreflex sensitivity for control of heart rate. The differential effects of Ang II and Ang-(1-7) may be related to the cellular sources of these peptides as well as different precursor pathways. Long-term alterations of the brain renin-angiotensin system may influence signaling pathways including phosphoinositol-3-kinase and mitogen-activated protein kinase and their downstream mediators, and as a consequ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4604288 Mon, 28 Feb 2011 00:00:00 +0100 4604288 http://www.medworm.com/index.php?rid=4541715&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21345728%26dopt%3DAbstract Authors: Millan MJ In addition to transcriptional regulation, the translation of protein-coding genes is modulated by MicroRNA-binding miRNAs (miRNAs), which have emerged to fulfil important roles in the control and expression of serotonergic transmission. Thus, miR-96 and miR-510 inhibit the translation of serotonin (5-HT)(1B) receptors and 5-HT(3E) receptor subunits respectively, and their susceptibility to repression is modified by polymorphisms in the 3'-UTR (miRNA-binding) regions of their mRNAs. Contrasting susceptibility of human subjects to miRNA-induced alterations in the translation of cerebral 5-HT(1B) receptors and intestinal 5-HT(3E) receptor subunits is related to differential aggressive behaviour and incidence of irritable bowel syndrome, respectively. Fluoxetine promote... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4541715 Mon, 21 Feb 2011 00:00:00 +0100 4541715 http://www.medworm.com/index.php?rid=4541714&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21345729%26dopt%3DAbstract Authors: Niesler B Serotonin type 3 (5-HT(3)) receptors are ligand-gated ion channels built by five subunits of diverse composition. In humans, five subunits exist (5-HT3A-E) which are encoded by the genes HTR3A-E and are expressed in various isoforms. Recently, the importance of factors influencing receptor expression became clear, such as chaperones and microRNAs. Owing to their expression profile and physiological functions, 5-HT(3) receptors have been implicated in irritable bowel syndrome (IBS) and psychiatric disorders. Interestingly, HTR3 variants have now been shown to be associated with these conditions. This underlines the potential of 5-HT(3) receptors as therapeutic targets and may enable personalised therapies in the future. PMID: 21345729 [PubMed - as supplied by publ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4541714 Mon, 21 Feb 2011 00:00:00 +0100 4541714 http://www.medworm.com/index.php?rid=4541717&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21342787%26dopt%3DAbstract Authors: Bockaert J, Claeysen S, Compan V, Dumuis A 5-HT(4) receptors control brain physiological functions such as learning and memory, feeding and mood behaviour as well as gastro-intestinal transit. 5-HT(4) receptors are one of the 5-HT receptors for which the available drugs and signalling knowledge are the most advanced. Several therapeutic 5-HT(4) receptor drugs have been commercialized. Therefore, the hope that 5-HT(4) receptors could also be the target for brain diseases is reasonable. Several major devastating illnesses could benefit from 5-HT(4) receptors-directed therapy such as Alzheimer's disease, feeding-associated diseases such as anorexia and major depressive disorders. PMID: 21342787 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4541717 Sun, 20 Feb 2011 00:00:00 +0100 4541717 http://www.medworm.com/index.php?rid=4541716&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21342788%26dopt%3DAbstract Authors: Davies PA 5-Hydroxytryptamine type 3 (5-HT(3)) receptors are ligand-gated ion channels that play important roles in depression, anxiety, substance abuse, emesis, inflammatory pain, spinal nociception, gastrointestinal function, and cardiovascular reflexes. Probably the most studied modulators of 5-HT(3) receptors are the high affinity competitive 'setron' antagonists typified by ondansetron. However, there exists a broad range of compounds that modulate the 5-HT(3) receptor, not through the orthosteric site but by binding to allosteric sites. Most notable are therapeutic compounds ascribed to certain targets but that allosterically modulate 5-HT(3) receptors at clinically relevant concentrations. PMID: 21342788 [PubMed - as supplied by publisher] (Source: Current Opinion i... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4541716 Sun, 20 Feb 2011 00:00:00 +0100 4541716 http://www.medworm.com/index.php?rid=4541718&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21339086%26dopt%3DAbstract Authors: Navar LG, Prieto MC, Satou R, Kobori H The increased activity of intrarenal renin-angiotensin system (RAS) in a setting of elevated arterial pressure elicits renal vasoconstriction, increased sodium reabsorption, proliferation, fibrosis and renal injury. Increases in intrarenal and interstitial angiotensin (Ang) II levels are due to increased AT(1) receptor mediated Ang II uptake and stimulation of renal angiotensinogen (AGT) mRNA and protein expression. Augmented proximal tubule AGT production increases tubular AGT secretion and spillover of AGT into the distal nephron and urine. Increased renin formation by principal cells of the collecting ducts forms Ang I from AGT thus increasing Ang II. The catalytic actions of renin and prorenin are enhanced by prorenin receptors (PRRs)... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4541718 Sat, 19 Feb 2011 00:00:00 +0100 4541718 http://www.medworm.com/index.php?rid=4541720&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21330209%26dopt%3DAbstract Authors: Sargent BJ, Henderson AJ Serotonin is known to have anorectic properties through centrally acting mechanisms. Three serotonin receptors have been implicated in mediating these effects: 5-HT(1B), 5-HT(2C) and 5-HT(6). Hypophagic effects are elicited through agonism of the former two receptors, whereas antagonism of the 5-HT(6) receptor appears to have an anorectic effect. All three targets have been validated through extensive studies including knockout mice and selective ligand assessment. 5-HT(1B) receptor agonists have limited utility due to mechanism-based side effects, whereas 5-HT(2C) receptor agonists suffer from challenges associated with selectivity over the closely related 5-HT(2A) and 5-HT(2B) receptors. 5-HT(6) receptor antagonists appear to offer great promise, alt... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4541720 Tue, 15 Feb 2011 00:00:00 +0100 4541720 http://www.medworm.com/index.php?rid=4541719&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21330210%26dopt%3DAbstract Authors: Codony X, Vela JM, Ramírez MJ Since its discovery in 1993 and subsequent development of selective antagonists, a growing number of studies support the use of serotonin 5-HT(6) receptor antagonism as a promising mechanism for treating cognitive dysfunction. Lately, several studies with structurally different compounds have shown that not only antagonists, but also 5-HT(6) receptor agonists improve learning and memory in animal models. There is even an antagonist, SB-742457, that has completed phase II trials for the treatment of Alzheimer's disease. In addition to describe preclinical and clinical evidence of the effect of 5-HT(6) receptor compounds on cognition, this article will also focus on the purported biochemical and neurochemical mechanisms of action by which 5-HT(6) r... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4541719 Tue, 15 Feb 2011 00:00:00 +0100 4541719 http://www.medworm.com/index.php?rid=4484096&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21320797%26dopt%3DAbstract Authors: Ducy P Bone formation and bone resorption, the two processes occurring constantly and in a balanced fashion throughout the skeleton, are regulated by signals as various as local and low range growth factors, hormones, and neuronal outputs. Adding to the long list of molecules involved in these regulations, gut-derived and brain-derived serotonin were recently shown to control one or both of these processes. They do so, however, by targeting different cells, respectively acting as a hormone and as a neuromediator. Moreover, while brain serotonin positively regulates bone mass accrual peripheral serotonin is a potent inhibitor of bone formation. These findings raise the prospect that pharmacologically manipulating serotonin production could therefore become a novel strategy to t... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4484096 Sat, 12 Feb 2011 00:00:00 +0100 4484096 http://www.medworm.com/index.php?rid=4484095&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21320798%26dopt%3DAbstract Authors: Mercado CP, Ziu E, Kilic F Advances over the past decade have improved our understanding of the serotonin (5-HT) biology outside the central nervous system specifically the molecular mechanisms of serotonergic signaling in association with small GTPases. It is now recognized that the communication between 5-HT and GTPases plays important roles in peripheral tissues, vascular cells and are involved in coagulation, hypertension, inflammation, healing and protection. Furthermore, 5-HT receptors as heterotrimeric GTP-binding protein-coupled receptors act as effector protein on the small GTPases. Therefore, the antagonists or agonists of the effector proteins of small GTPases could be useful therapeutic agents for the treatment of several diseases and disorders. PMID: 21320798 ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4484095 Sat, 12 Feb 2011 00:00:00 +0100 4484095 http://www.medworm.com/index.php?rid=4484097&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21317038%26dopt%3DAbstract Authors: Lamarca B, Wallace K, Granger J Despite being one of the leading causes of maternal death and a major contributor of maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of preeclampsia are unclear. One important initiating event in preeclampsia is thought to be reduced placental perfusion leading to the production of a variety of factors that cause widespread dysfunction of the maternal vasculature. The major objective of this review is to discuss the potential role of a novel agonistic autoantibody to the angiotensin II type I receptor (AT1-AA) in mediating hypertension during pregnancy. Although animal studies suggest that increasing plasma AT1-AA concentration in pregnant rats to levels observed in preeclamptic women or placental ischemic rats ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4484097 Fri, 11 Feb 2011 00:00:00 +0100 4484097 http://www.medworm.com/index.php?rid=4484098&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21296616%26dopt%3DAbstract Authors: Roks AJ, Rodgers K, Walther T The current concept is that there are both cells that integrate into the vasculature, true endothelial progenitor cells (EPC), and cells with hematopoietic markers that support neovascularisation. As identification of the EPC is controversial and studies refer cells that might fall into either pools, we will use the term, vasculogenesis-related progenitor cells (VRPC), for this review. VRPC are considered to be an important target for the treatment of cardiovascular diseases (CVD). Angiotensin II is known to be an important player in neovascularisation and the modulation of renin angiotensin system (RAS) is one of the major pharmacotherapeutic strategies for the treatment of CVD. We will review the effects of different components of the RAS on suc... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4484098 Fri, 04 Feb 2011 00:00:00 +0100 4484098 http://www.medworm.com/index.php?rid=4416289&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21269877%26dopt%3DAbstract Authors: Allen AM Whilst crucial for behavioural and homeostatic responses to environmental challenges, chronic elevation of sympathetic nervous system activity to specific vascular beds is associated with hypertension. Indeed such elevated activity may drive the increase in blood pressure seen in some people and in some experimental models of hypertension. This review discusses the neural circuitry involved in generating and modulating sympathetic efferent nerve activity, focusing on the premotor neurons of the rostral ventrolateral medulla. Neurons in the rostral ventrolateral medulla show altered responses to angiotensin II in experimental models of hypertension, suggesting that this might be an important node for interaction between these two systems that are crucial for regulation... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4416289 Mon, 24 Jan 2011 00:00:00 +0100 4416289 http://www.medworm.com/index.php?rid=4416290&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21257347%26dopt%3DAbstract Authors: Zimmerman MC Reactive oxygen species (ROS) are important intra-neuronal signaling intermediates in angiotensin II (AngII)-related neuro-cardiovascular diseases associated with excessive sympathoexcitation, including hypertension and heart failure. ROS-sensitive effector mechanisms, such as modulation of ion channel activity, indicate that elevated levels of ROS increase neuronal activity. Nitric oxide, which may work to counter the effects of ROS, particularly superoxide, has been identified as a signaling molecule in angiotensin-1-7 (Ang-(1-7)) stimulated neurons. This review focuses on recent studies that have revealed details on the AngII-activated sources of ROS, the downstream redox-sensitive effectors, Ang-(1-7)-stimulated increase in nitric oxide, and the neuro-cardiova... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4416290 Fri, 21 Jan 2011 00:00:00 +0100 4416290 http://www.medworm.com/index.php?rid=4416291&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21242106%26dopt%3DAbstract Authors: Schultz HD The carotid body (CB) plays an important role in the control of breathing and in autonomic control of cardiovascular function. CB chemoreceptor activity is enhanced in chronic heat failure (CHF) and contributes to the sympathetic hyperactivity that exacerbates the progression of the disease. Studies in the past few years have revealed that a local angiotensin (Ang) system exists in the CB and plays an important role in altering CB function in CHF as well as other conditions, such as chronic hypoxia. This brief review highlights recent revelations that Ang I metabolites exert effects within the CB, and focuses on the influence of Ang II and Ang-(1-7) on CB function in CHF. PMID: 21242106 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4416291 Sat, 15 Jan 2011 00:00:00 +0100 4416291 http://www.medworm.com/index.php?rid=4355271&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21215698%26dopt%3DAbstract Authors: Shenoy V, Qi Y, Katovich MJ, Raizada MK Pulmonary arterial hypertension (PAH) is a chronic lung disease with poor diagnosis and limited therapeutic options. The currently available therapies are ineffective in improving the quality of life and reducing mortality rates. There exists a clear unmet medical need to treat this disease, which necessitates the discovery of novel therapeutic targets/agents for safe and successful therapy. An altered renin-angiotensin system (RAS) has been implicated as a causative factor in the pathogenesis of PAH. Angiotensin II (Ang II), a key effector peptide of the RAS, can exert deleterious effects on the pulmonary vasculature resulting in vasoconstriction, proliferation, and inflammation, all of which contribute to PAH development. Recently, a n... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4355271 Wed, 05 Jan 2011 00:00:00 +0100 4355271 http://www.medworm.com/index.php?rid=4355272&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21196131%26dopt%3DAbstract Authors: Marvar PJ, Lob H, Vinh A, Zarreen F, Harrison DG In recent years a major research effort has focused on the role of inflammation, and in particular adaptive immunity, in the genesis of hypertension. Hypertension stimulates the accumulation of inflammatory cells including macrophages and T lymphocytes in peripheral tissues important in blood pressure control, such as the kidney and vasculature. Angiotensin II modulates blood pressure via actions on the central nervous system (CNS) and the adaptive immune system. Recent work suggests that the central actions of angiotensin II via the circumventricular organs lead to activation of circulating T-cells and vascular inflammation. The neuro-immune system plays an essential role in the pathogenesis of hypertension and further understa... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4355272 Fri, 31 Dec 2010 00:00:00 +0100 4355272 http://www.medworm.com/index.php?rid=4355273&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21167778%26dopt%3DAbstract Authors: Steckelings UM, Larhed M, Hallberg A, Widdop RE, Jones ES, Wallinder C, Namsolleck P, Dahlöf B, Unger T The renin-angiotensin-system harbours two main receptor subtypes binding angiotensin II which are the AT1-receptor and the AT2-receptor. While the AT1-receptor has been a drug target in cardiovascular disease for many years, the AT2-receptor was only a subject of academic interest. This has changed with the design and synthesis of a first non-peptide, orally active AT2-receptor agonist, compound 21 (C21). First data using C21 revealed tissue protective effects and functional improvement after myocardial infarction and in hypertension-induced end organ damage, notably in a blood-pressure independent way. In all of these models, AT2-receptor mediated anti-inflammation seemed ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4355273 Wed, 15 Dec 2010 00:00:00 +0100 4355273 http://www.medworm.com/index.php?rid=4355274&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21159555%26dopt%3DAbstract Authors: Gao L, Zucker IH There is a growing consensus that the balance between Angiotensin Type 1 (AT1R) and Angiotensin Type 2 (AT2R) signaling in many tissues may determine the magnitude and, in some cases the direction, of the biological response. Sympatho-excitation in cardiovascular diseases is mediated by a variety of factors and is, in part, dependent on Angiotensin II signaling in the central nervous system. Recent data have provided evidence that the AT2R can modulate sympatho-excitation in animals with hypertension and heart failure. The evidence for this concept is reviewed and a model is put forward to support the rationale that therapeutic targeting of the central AT2R may be beneficial in the setting of chronic heart failure. PMID: 21159555 [PubMed - as supplied by p... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4355274 Mon, 13 Dec 2010 00:00:00 +0100 4355274 http://www.medworm.com/index.php?rid=4355275&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21147033%26dopt%3DAbstract Authors: Mederos Y Schnitzler M, Storch U, Gudermann T G-protein-coupled receptors are appreciated as central components of neurohormonal signaling. Recently, it turned out that they may also play a role in mechanotransduction. The angiotensin II AT(1) receptor was the first G-protein-coupled receptor claimed to be a mechanosensor. In the meantime, several other G(q/11)-coupled receptors were found to be sensitive to mechanical stimuli. Furthermore, there is first evidence to support the concept that G(i/o)-coupled receptors are susceptible to mechanical stimulation as well. Mechanical receptor activation appears to be agonist-independent and is initiated by a conformational change of the receptor protein discernible from agonist-bound conformations. Mechanically induced receptor activ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4355275 Fri, 10 Dec 2010 00:00:00 +0100 4355275 http://www.medworm.com/index.php?rid=4258405&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21130035%26dopt%3DAbstract Authors: Bernstein KE, Shen XZ, Gonzalez-Villalobos RA, Billet S, Okwan-Duodu D, Ong FS, Fuchs S Angiotensin-converting enzyme (ACE) can cleave angiotensin I, bradykinin, neurotensin and many other peptide substrates in vitro. In part, this is due to the structure of ACE, a protein composed of two independent catalytic domains. Until very recently, little was known regarding the specific in vivo role of each ACE domain, and they were commonly regarded as equivalent. This is not true, as shown by mouse models with a genetic inactivation of either the ACE N- or C-domain. In vivo, most angiotensin II is produced by the ACE C-domain. Some peptides, such as the anti-fibrotic peptide AcSDKP, are substrates only of the ACE N-domain. Knowing the in vivo role of each ACE domain has great signif... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4258405 Wed, 01 Dec 2010 00:00:00 +0100 4258405 http://www.medworm.com/index.php?rid=4140857&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D21036104%26dopt%3DAbstract Authors: Firestone GL PMID: 21036104 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4140857 Thu, 28 Oct 2010 00:00:00 +0100 4140857 http://www.medworm.com/index.php?rid=4109111&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20971683%26dopt%3DAbstract Authors: Yengo CM, Berger CL Fluorescence spectroscopy/microscopy is a versatile method for examining protein dynamics in vitro and in vivo that can be combined with other techniques to simultaneously examine complementary pharmacological parameters. The following review will highlight the advantages and challenges of using fluorescence spectroscopic methods for examining protein dynamics with a special emphasis on fluorescence resonance energy transfer and fluorescence anisotropy. Both of these methods are amenable to measurements on an ensemble of molecules as well as at the single molecule level, in live cells and in high throughput screening assays, providing a powerful set of tools to aid in the design and testing of new drugs under a variety of experimental conditions. PMID: ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4109111 Thu, 21 Oct 2010 23:00:00 +0100 4109111 http://www.medworm.com/index.php?rid=4109110&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20971684%26dopt%3DAbstract Authors: Salsbury FR Molecular dynamics simulations have become increasingly useful in studying biological systems of biomedical interest, and not just in the study of model or toy systems. In this article, the methods and principles of all-atom molecular dynamics will be elucidated with several examples provided of their utility to investigators interested on drug discovery. PMID: 20971684 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4109110 Thu, 21 Oct 2010 23:00:00 +0100 4109110 http://www.medworm.com/index.php?rid=4098803&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20965786%26dopt%3DAbstract Authors: Jacobs DJ Molecular dynamics (MD) simulation is a natural approach for studying protein dynamics, and coupled with the ideas of multiscale modeling, MD proves to be the gold standard in computational biology to investigate mechanistic details related to protein function. In principle, if MD trajectories are long enough, the ensemble of protein conformations generated allows thermodynamic and kinetic properties to be predicted. We know from experiments that proteins exhibit a high degree of fidelity in function, and that empirical kinetic models are successful in describing kinetics, suggesting that the ensemble of conformations cluster into well-defined thermodynamic states, which are frequently metastable. The experimental evidence suggest that more efficient computational mo... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4098803 Mon, 18 Oct 2010 23:00:00 +0100 4098803 http://www.medworm.com/index.php?rid=4098806&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20951642%26dopt%3DAbstract Authors: Leitman DC, Paruthiyil S, Vivar OI, Saunier EF, Herber CB, Cohen I, Tagliaferri M, Speed TP Estrogenic effects are mediated through two estrogen receptor (ER) subtypes, ERα and ERβ. Estrogens are the most commonly prescribed drugs to treat menopausal conditions, but by non-selectively triggering both ERα and ERβ pathways in different tissues they can cause serious adverse effects. The different sizes of the binding pockets and sequences of their activation function domains indicate that ERα and ERβ should have different specificities for ligands and biological responses that can be exploited for designing safer and more selective estrogens. ERα and ERβ regulate different genes by binding to different regulatory elements and recruiting different transcription and chroma... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4098806 Wed, 13 Oct 2010 23:00:00 +0100 4098806 http://www.medworm.com/index.php?rid=4098805&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20951643%26dopt%3DAbstract Authors: Livesay DR PMID: 20951643 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4098805 Wed, 13 Oct 2010 23:00:00 +0100 4098805 http://www.medworm.com/index.php?rid=4098804&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20951644%26dopt%3DAbstract Authors: Schug A, Onuchic JN Protein folding and function are inherently linked sharing a joined funneled energy landscape. In this theoretical framework, the integration of simulations, structural information, and sequence data has led to quantitatively explore, understand, and predict biomolecular binding and recognition, key processes in pharmacology, as a natural extension of the selective self-binding found in protein folding. Computer simulations based on these principles have made valuable contributions to understanding protein and RNA folding, protein-protein interactions, and protein-metabolite/RNA-metabolite interactions. PMID: 20951644 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4098804 Wed, 13 Oct 2010 23:00:00 +0100 4098804 http://www.medworm.com/index.php?rid=4066911&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20934381%26dopt%3DAbstract Authors: Zwier MC, Chong LT Molecular dynamics (MD) simulations can provide atomically detailed views of protein motions, sampling multiple timescales ranging from femtoseconds to nanoseconds on typical computing resources. The 'reach' of these computer simulations toward biologically relevant timescales (microseconds and beyond) has been improving with advances in hardware and software, as well as the development of enhanced sampling techniques. This review outlines these advances, focusing on techniques that also provide realistic, unperturbed kinetics. These longer-timescale MD simulations can provide detailed insights into the mechanisms of biological events, potentially aiding the design of pharmaceuticals. PMID: 20934381 [PubMed - as supplied by publisher] (Source: Current Op... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4066911 Wed, 06 Oct 2010 23:00:00 +0100 4066911 http://www.medworm.com/index.php?rid=4066913&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20933468%26dopt%3DAbstract Authors: Vaidehi N, Kenakin T It has been observed that some ligands cause receptors to selectively interact with subsets of signaling proteins to 'bias' their signaling; this is inconsistent with receptors forming a single active state. Here we review the concept of receptor conformation ensembles that can account for a given agonist showing varied efficacies for different signaling pathways. Data show that agonists can stabilize different receptor conformations. We provide a demonstration at the molecular level of how the various receptor conformations in the ensemble can produce functional selectivity for signaling pathways. Specifically, agonists that selectively stabilize certain receptor conformations from the ensemble can produce biased agonism towards this signaling pathway. Th... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4066913 Tue, 05 Oct 2010 23:00:00 +0100 4066913 http://www.medworm.com/index.php?rid=4066912&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20933469%26dopt%3DAbstract Authors: Sapienza PJ, Lee AL Proteins exist not as singular structures with precise coordinates, but rather as fluctuating bodies that move rapidly through an enormous number of conformational substates. These dynamics have important implications for understanding protein function and for structure-based drug design. NMR spectroscopy is particularly well suited to characterize the dynamics of proteins and other molecules in solution at atomic resolution. Here, NMR relaxation methods for characterizing thermal motions on the picosecond-nanosecond (ps-ns) timescale are reviewed. Motion on this timescale can be conveniently captured by the Lipari-Szabo order parameter, S(2), a bond-specific measure of restriction of motion. Approaches for determining order parameters are discussed, as are... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4066912 Tue, 05 Oct 2010 23:00:00 +0100 4066912 http://www.medworm.com/index.php?rid=4066914&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20926342%26dopt%3DAbstract Authors: McDonnell DP, Wardell SE Our understanding of the molecular mechanisms underlying the pharmacological actions of estrogen receptor (ER) ligands has evolved considerably in recent years. Much of this knowledge has come from a detailed dissection of the mechanism(s) of action of the Selective Estrogen Receptor Modulators (SERMs) tamoxifen and raloxifene, so called for their ability to function as ER agonists or antagonists depending on the tissue in which they operate. These mechanistic insights have had a significant impact on the discovery of second generation SERMs, some of which are in late stage clinical development for the treatment/prevention of breast cancer as well as other estrogenopathies. In addition to the SERMs, however, have emerged the Selective Estrogen Degrader... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4066914 Sun, 03 Oct 2010 23:00:00 +0100 4066914 http://www.medworm.com/index.php?rid=4030537&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20889377%26dopt%3DAbstract Authors: Dunker AK, Uversky VN Transcription factors (TFs) are very attractive but difficult drug targets. The difficulties come from several directions including the binding promiscuity of TFs and the intrinsically disordered nature of their binding sites, which often resemble 'protein clouds'. For a long time the targeting of proteins without defined structures was considered infeasible. Data have now emerged showing that selective blocking of specific interactions of intrinsically disordered TFs with their protein binding partners is possible. Initial hits have been optimized to increase their specificity and affinity. Several strategies have been elaborated for elucidating the mechanisms of blocking of intrinsic disorder-based protein-protein interactions. However, challenges remai... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4030537 Thu, 30 Sep 2010 23:00:00 +0100 4030537 http://www.medworm.com/index.php?rid=4016149&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20860919%26dopt%3DAbstract Authors: Mizoguchi A, Mizoguchi E Spontaneous development of intestinal inflammation in many different kinds of genetically engineered mice as well as the presence of numerous susceptibility genes in humans suggests that inflammatory bowel disease (IBD) is mediated by more complicated mechanisms than previously predicted. The human genetic studies implicate some major pathways in the pathogenesis of IBD, including epithelial defense against commensal microbiota, the IL-23/Th17 axis, and immune regulation. Murine IBD models, which are genetically engineered to lack some susceptibility genes, have been generated, and have provided useful insights into the therapeutic potential of targeting the susceptibility genes directly or their downstream pathways indirectly for IBD. This review summ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4016149 Thu, 30 Sep 2010 18:20:14 +0100 4016149 http://www.medworm.com/index.php?rid=4016148&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20860920%26dopt%3DAbstract Authors: Marcelin G, Chua S Obesity is a chronic disease that increases susceptibility to various diseases, particularly cardiovascular dysfunction, type 2 diabetes, and some types of cancer. In this review, we highlighted recent evidence in mouse models that support a potential benefit of increasing adipose lipid utilization through stimulating lipolysis in adipose tissue and fatty acid oxidation. Brown adipocyte development within white adipose tissue of humans suggests that mouse models may be applicable to human obesity. Consequently, new therapies should target adipose tissue to specifically reduce fat mass through controlled triglyceride utilization. PMID: 20860920 [PubMed - in process] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4016148 Thu, 30 Sep 2010 18:20:10 +0100 4016148 http://www.medworm.com/index.php?rid=4016147&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20864407%26dopt%3DAbstract Authors: Barker A, Giles KM, Epis MR, Zhang PM, Kalinowski F, Leedman PJ Recent years have seen a massive expansion in our understanding of the biology of microRNAs (miRNAs) in cancer, through the identification of miRNAs with aberrant expression in specific cancers and the functional validation of their critical target molecules and cellular effects. In parallel, targeted therapeutic agents to block signalling pathways critical to tumour growth and progression have been developed but have yielded disappointing clinical results. The discovery of miRNAs that regulate ErbB signalling in cancer cells brings new hope that in the future these oncogenic pathways can be more effectively inhibited to improve patient outcomes. PMID: 20864407 [PubMed - as supplied by publisher] (Source: Curr... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4016147 Mon, 20 Sep 2010 23:00:00 +0100 4016147 http://www.medworm.com/index.php?rid=4016150&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20833107%26dopt%3DAbstract Authors: Hwang-Verslues WW, Sladek FM Hepatocyte nuclear factor 4α (HNF4α) is a highly conserved member of the nuclear receptor superfamily of ligand-dependent transcription factors. It is best known as a master regulator of liver-specific gene expression, especially those genes involved in lipid transport and glucose metabolism. However, there is also a growing body of work that indicates the importance of HNF4α in the regulation of genes involved in xenobiotic and drug metabolism. A recent study identifying the essential fatty acid linoleic acid (LA, C18:2) as the endogenous, reversible ligand for HNF4α suggests that HNF4α may also be a potential drug target and that its activity may be regulated by diet. This review will discuss the role of HNF4α in drug metabolism... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4016150 Wed, 08 Sep 2010 23:00:00 +0100 4016150 http://www.medworm.com/index.php?rid=4016151&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20832360%26dopt%3DAbstract Authors: Ostrander JH, Daniel AR, Lange CA Breast tumor kinase (Brk), also termed PTK6, is known to function in cell-type and context-dependent processes governing normal differentiation. However, in tumors in which Brk is overexpressed, this unusual soluble tyrosine kinase is emerging as a mediator of cancer cell phenotypes, including increased proliferation, survival, and migration. Nuclear and cytoplasmic substrates phosphorylated by Brk include a collection of regulatory RNA-binding proteins, adaptor molecules that link Brk to signaling pathways generally associated with the activation of growth factor receptors, and Signal Transducers and Activators of Transcription (STAT) molecules that are direct regulators of gene expression. Understanding Brk-dependent regulation of these key ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=4016151 Tue, 07 Sep 2010 23:00:00 +0100 4016151 http://www.medworm.com/index.php?rid=3958615&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20829110%26dopt%3DAbstract Authors: Faulds MH, Zhao C, Dahlman-Wright K The metabolic syndrome constitutes a group of metabolic conditions that increase the risk of developing diseases, including cardiovascular disease (CVD) and type 2 diabetes (T2D). LXRα/β are regulators of lipogenesis, cholesterol/glucose homoeostasis and inflammatory pathways, processes that are intertwined with development of the metabolic syndrome. The employment of LXRs as pharmaceutical targets for treatment of various aspects of the metabolic syndrome has been promptly investigated but serious side effects, like hepatic steatosis, have hampered this process. Novel treatment regimes now focus on development of isoform-specific or tissue-specific LXR agonist/antagonist compounds to circumvent effects on lipid biosynthesis. Other str... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=3958615 Mon, 06 Sep 2010 23:00:00 +0100 3958615 http://www.medworm.com/index.php?rid=3958614&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20829111%26dopt%3DAbstract Authors: Pandey DP, Picard D Nuclear receptors (NRs) form one of the largest superfamilies of transcription factors in metazoans. MicroRNAs (miRNAs) are small non-coding RNAs that bind the 3' untranslated region (3'UTR) of target mRNAs to reduce their stability and/or translation. miRNAs can directly regulate the protein output of target NR mRNAs, and, conversely, the expression of miRNAs can be modulated by NRs at the transcriptional level. At least one NR also regulates the posttranscriptional maturation of miRNAs by interacting with miRNA processing factors via NR co-regulators. Moreover, miRNAs regulate NR signaling by targeting the mRNAs of NR co-regulators and target genes. This complex set of interactions also leads to an extensive network of feedback and feedforward regulatory ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=3958614 Mon, 06 Sep 2010 23:00:00 +0100 3958614 http://www.medworm.com/index.php?rid=3958616&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20822955%26dopt%3DAbstract Authors: Jahchan NS, Luo K SnoN (Ski-novel protein) was discovered as a nuclear proto-oncogene on the basis of its ability to induce transformation of chicken and quail embryonic fibroblasts. As a crucial negative regulator of transforming growth factor-beta (TGF-beta) signaling and also an activator of p53, it plays an important role in regulating cell proliferation, senescence, apoptosis, and differentiation. Recent studies of its expression patterns and functions in mouse models and mammalian cells have revealed important functions of SnoN in normal epithelial development and tumorigenesis. Evidence suggests that SnoN has both pro-oncogenic and anti-oncogenic functions by modulating multiple signaling pathways. These studies suggest that SnoN may have broad functions in the developm... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=3958616 Thu, 02 Sep 2010 23:00:00 +0100 3958616 http://www.medworm.com/index.php?rid=3958619&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20817605%26dopt%3DAbstract Authors: Hinohara K, Gotoh N Cancer stem cells (CSCs), which make up only a small proportion of heterogeneous tumor cells, may possess greater ability to maintain tumorigenesis than do other tumor cell types. Breast cancer tissue is reported to contain cancer stem-like cells. In order to eradicate tumor cells, various approaches have been taken to identify the critical molecules and signaling pathways in breast CSCs. Recent findings suggest that inflammatory signaling pathways are important for the maintenance of breast CSCs. Here, we review the current understanding of the role of inflammatory pathways in these cells and discuss future perspectives of the research on and the possibility of targeting the molecules involved in these pathways for developing treatments for breast cancer. ... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=3958619 Tue, 31 Aug 2010 23:00:00 +0100 3958619 http://www.medworm.com/index.php?rid=3958618&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20817606%26dopt%3DAbstract Authors: Le-Niculescu H, Patel SD, Niculescu AB Animal models and human studies of bipolar disorder and other psychiatric disorders are becoming increasingly integrated, prompted by recent successes. Particularly for genomics, the convergence and integration of data across species, experimental modalities and technical platforms is providing a fit-to-disease way of extracting reproducible and biologically important signal, in sharp contrast to the fit-to-cohort effect, disappointing findings to date, and limited reproducibility of human genetic analyses alone. Such work in psychiatry can provide an example of how to address other genetically complex disorders, and in turn will benefit by incorporating concepts from other areas, such as cancer biology and diabetes. PMID: 20817606 [P... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=3958618 Tue, 31 Aug 2010 23:00:00 +0100 3958618 http://www.medworm.com/index.php?rid=3958617&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20817607%26dopt%3DAbstract Authors: Wong RH, Sul HS Transcription of enzymes involved in FA and TAG synthesis is coordinately induced in lipogenic tissues by feeding and insulin treatment. The three major transcription factors involved are USF, SREBP-1c, and LXRalpha. New insights into the insulin-signaling pathway(s) that control(s) lipogenic gene transcription via these factors have recently been revealed. Dephosphorylation/activation of DNA-PK by PP1 causes phosphorylation of USF that in turn recruits P/CAF to be acetylated for transcriptional activation. SREBP-1c can be induced by mTORC1, bifurcating lipogenesis from AKT-activated gluconeogenesis. LXRalpha may serve as a glucose sensor and, along with ChREBP, may activate lipogenic genes in the fed state. Dysregulation of FA and TAG metabolism often contribu... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=3958617 Tue, 31 Aug 2010 23:00:00 +0100 3958617 http://www.medworm.com/index.php?rid=3958622&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20810315%26dopt%3DAbstract Authors: Roarty K, Rosen JM The mammary stem cell and its local microenvironment are central for the maintenance of proper tissue homeostasis during normal development. Defining the hierarchical organization of the epithelial subtypes in the mammary gland and the molecular pathways guiding their development has begun to provide a framework for understanding how cancer stem cells sustain the progression and heterogeneity of breast cancers. The Wnt pathway plays a fundamental role in multiple adult stem cells, as well as in orchestrating proper mammary gland development and maintenance. These processes are intricately guided by the influence of systemic hormones and local factors. Alterations in Wnt signaling can skew the homeostatic balance of the mammary epithelium to drive malignant p... Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=3958622 Sun, 29 Aug 2010 23:00:00 +0100 3958622 http://www.medworm.com/index.php?rid=3958621&cid=s_35496_13_f&fid=35496&url=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Ftmpl%3DNoSidebarfile%26db%3DPubMed%26cmd%3DRetrieve%26list_uids%3D20810316%26dopt%3DAbstract Authors: Dorner AJ, Schaub R PMID: 20810316 [PubMed - as supplied by publisher] (Source: Current Opinion in Pharmacology) Current Opinion in Pharmacology journals http://www.medworm.com/rss/comments.php?id=3958621 Sun, 29 Aug 2010 23:00:00 +0100 3958621