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Therapeutic Interest (therapeutic + interest)
Selected AbstractsTranscriptional dynamics of endodermal organ formationDEVELOPMENTAL DYNAMICS, Issue 1 2009Richard I. Sherwood Abstract Although endodermal organs including the liver, pancreas, and intestine are of significant therapeutic interest, the mechanism by which the endoderm is divided into organ domains during embryogenesis is not well understood. To better understand this process, global gene expression profiling was performed on early endodermal organ domains. This global analysis was followed up by dynamic immunofluorescence analysis of key transcription factors, uncovering novel expression patterns as well as cell surface proteins that allow prospective isolation of specific endodermal organ domains. Additionally, a repressive interaction between Cdx2 and Sox2 was found to occur at the prospective stomach,intestine border, with the hepatic and pancreatic domains forming at this boundary, and Hlxb9 was revealed to have graded expression along the dorsal,ventral axis. These results contribute to understanding the mechanism of endodermal organogenesis and should assist efforts to replicate this process using pluripotent stem cells. Developmental Dynamics 238:29,42, 2009. © 2008 Wiley-Liss, Inc. [source] Comparison of the pharmacological properties of GK11 and MK801, two NMDA receptor antagonists: towards an explanation for the lack of intrinsic neurotoxicity of GK11JOURNAL OF NEUROCHEMISTRY, Issue 4 2007D. Vandame Abstract Over-stimulation of NMDA receptors (NMDARs) is involved in many neurodegenerative disorders. Thus, developing safe NMDAR antagonists is of high therapeutic interest. GK11 is a high affinity uncompetitive NMDAR antagonist with low intrinsic neurotoxicity, shown to be promising for treating CNS trauma. In the present study, we investigated the molecular basis of its interaction with NMDARs and compared this with the reference molecule MK801. We show, on primary cultures of hippocampal neurons, that GK11 exhibits neuroprotection properties similar to those of MK801, but in contrast with MK801, GK11 is not toxic to neurons. Using patch-clamp techniques, we also show that on NR1a/NR2B receptors, GK11 totally blocks the NMDA-mediated currents but has a six-fold lower IC50 than MK801. On NR1a/NR2A receptors, it displays similar affinity but fails to totally prevent the currents. As NR2A is preferentially localized at synapses and NR2B at extrasynaptic sites, we investigated, using calcium imaging and patch-clamp approaches, the effects of GK11 on either synaptic or extrasynaptic NMDA-mediated responses. Here we demonstrate that in contrast with MK801, GK11 better preserve the synaptic NMDA-mediated currents. Our study supports that the selectivity of GK11 for NR2B containing receptors accounts contributes, at least partially, for its safer pharmacological profile. [source] Wnt-3a and Wnt-3 differently stimulate proliferation and neurogenesis of spinal neural precursors and promote neurite outgrowth by canonical signalingJOURNAL OF NEUROSCIENCE RESEARCH, Issue 14 2010Monica D. David Abstract Wnt factors regulate neural stem cell development and neuronal connectivity. Here we investigated whether Wnt-3a and Wnt-3, expressed in the developing spinal cord, regulate proliferation and the neuronal differentiation of spinal cord neural precursors (SCNP). Wnt-3a promoted a sustained increase of SCNP proliferation and decreased the expression of cyclin-dependent kinase inhibitors. In contrast, Wnt-3 transiently enhanced SCNP proliferation and increased neurogenesis through ,-catenin signaling. Furthermore, both Wnt-3a and Wnt-3 stimulated neurite outgrowth in SCNP-derived neurons through ,-catenin- and TCF4-dependent transcription. Glycogen synthase kinase-3, inhibitors mimicked Wnt signaling and promoted neurite outgrowth in established cultures. We conclude that Wnt-3a and Wnt-3 factors signal through the canonical Wnt/,-catenin pathway to regulate different aspects of SCNP development. These findings may be of therapeutic interest for the treatment of neurodegenerative diseases and nerve injury. © 2010 Wiley-Liss, Inc. [source] Nonsteroidal aromatase inhibitors: Recent advancesMEDICINAL RESEARCH REVIEWS, Issue 3 2002Maurizio Recanatini Abstract Aromatase is the cytochrome P450 enzyme responsible for the last step of estrogen biosynthesis, and aromatase inhibitors constitute an important class of drugs in clinical use for the treatment of breast cancer. Nonsteroidal aromatase inhibitors (NSAIs) are competitive inhibitors of aromatase, which bind to the enzyme active site by coordinating the iron atom present in the heme group of the P450 protein. Presently, third generation NSAIs are in use, and research efforts are being carried out both to identify new molecules of therapeutic interest and to clarify the mechanism of action. In this article, we present a survey of the compounds that have been recently reported as NSAIs, to provide a broad view on the general structure,activity relationships of the class. Moreover, starting from the current knowledge of the mechanistic aspects of aromatase action and from recent theoretical work on the molecular modeling of both enzyme and inhibitors, we try to indicate a way to integrate these different studies in view of a more general understanding of the aromeatase-inhibitor system. Finally, some aspects regarding the possible future development of the field are considered briefly. © 2002 Wiley Periodicals, Inc. Med Res Rev, 22, No. 3, 282,304, 2002; Published online in wiley InterScience (www.interscience.wiley.com). DOI 10.1002/med.10010 [source] Vitamin E uncouples joint destruction and clinical inflammation in a transgenic mouse model of rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 2 2002Michel De Bandt Objective Reactive oxygen species are thought to play a role in rheumatoid arthritis (RA) in humans. We postulated that antioxidant treatment could have a beneficial effect in this disease. We therefore investigated the effects of vitamin E in the transgenic KRN/NOD mouse model of RA. Methods Mice were treated by gavage with oral vitamin E (,-tocopherol). Clinical, histologic, and biochemical parameters were assessed for 6 weeks. Results Vitamin E treatment did not modify the clinical features of the disease (date of onset or disease intensity, as measured by the articular index), but it did prevent joint destruction, as measured by qualitative and semiquantitative analyses. Redox status did not differ between treated and control mice. White blood cell chemiluminescence was higher in transgenic KRN/NOD mice than in controls, but vitamin E treatment attenuated this difference. Vitamin E treatment of the transgenic animals led to a significant decrease in the levels of interleukin-1, (IL-1,) but not tumor necrosis factor ,. Conclusion Vitamin E seems to uncouple joint inflammation and joint destruction in this model of RA, with a beneficial effect on joint destruction. Since many investigations are currently in progress to evaluate the benefit of interventions targeted toward anti-IL-1,, our findings suggest opportunities of therapeutic interest in human RA. [source] Calcium-activated potassium channels and endothelial dysfunction: therapeutic options?BRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2009Michel Félétou The three subtypes of calcium-activated potassium channels (KCa) of large, intermediate and small conductance (BKCa, IKCa and SKCa) are present in the vascular wall. In healthy arteries, BKCa channels are preferentially expressed in vascular smooth muscle cells, while IKCa and SKCa are preferentially located in endothelial cells. The activation of endothelial IKCa and SKCa contributes to nitric oxide (NO) generation and is required to elicit endothelium-dependent hyperpolarizations. In the latter responses, the hyperpolarization of the smooth muscle cells is evoked either via electrical coupling through myo-endothelial gap junctions or by potassium ions, which by accumulating in the intercellular space activate the inwardly rectifying potassium channel Kir2.1 and/or the Na+/K+ -ATPase. Additionally, endothelium-derived factors such as cytochrome P450-derived epoxyeicosatrienoic acids and under some circumstances NO, prostacyclin, lipoxygenase products and hydrogen peroxide (H2O2) hyperpolarize and relax the underlying smooth muscle cells by activating BKCa. In contrast, cytochrome P450-derived 20-hydroxyeicosatetraenoic acid and various endothelium-derived contracting factors inhibit BKCa. Aging and cardiovascular diseases are associated with endothelial dysfunctions that can involve a decrease in NO bioavailability, alterations of EDHF-mediated responses and/or enhanced production of endothelium-derived contracting factors. Because potassium channels are involved in these endothelium-dependent responses, activation of endothelial and/or smooth muscle KCa could prevent the occurrence of endothelial dysfunction. Therefore, direct activators of these potassium channels or compounds that regulate their activity or their expression may be of some therapeutic interest. Conversely, blockers of IKCa may prevent restenosis and that of BKCa channels sepsis-dependent hypotension. Mandarin translation of abstract [source] Curcumin: potential for hepatic fibrosis therapy?BRITISH JOURNAL OF PHARMACOLOGY, Issue 3 2008M A O'Connell The beneficial antioxidative, anti-inflammatory and antitumorigenic effects of curcumin have been well documented in relation to cancer and other chronic diseases. Recent evidence suggests that it may be of therapeutic interest in chronic liver disease. Hepatic fibrosis (scarring) occurs in advanced liver disease, where normal hepatic tissue is replaced with collagen-rich extracellular matrix and, if left untreated, results in cirrhosis. Curcumin inhibits liver cirrhosis in a rodent model and exerts multiple biological effects in hepatic stellate cells (HSCs), which play a central role in the pathogenesis of hepatic fibrosis. In response to liver injury, these cells proliferate producing pro-inflammatory mediators and extracellular matrix. Curcumin induces apoptosis and suppresses proliferation in HSCs. In addition, it inhibits extracellular matrix formation by enhancing HSC matrix metalloproteinase expression via PPAR, and suppressing connective tissue growth factor (CTGF) expression. In this issue, Chen and co-workers propose that curcumin suppresses CTGF expression in HSC by inhibiting ERK and NF-,B activation. These studies suggest that curcumin modulates several intracellular signalling pathways in HSC and may be of future interest in hepatic fibrosis therapy. British Journal of Pharmacology (2008) 153, 403,405; doi:10.1038/sj.bjp.0707580; published online 26 November 2007 [source] Kinin B1 receptors: key G-protein-coupled receptors and their role in inflammatory and painful processesBRITISH JOURNAL OF PHARMACOLOGY, Issue 7 2004João B Calixto Kinins are a family of peptides implicated in several pathophysiological events. Most of their effects are likely mediated by the activation of two G-protein-coupled receptors: B1 and B2. Whereas B2 receptors are constitutive entities, B1 receptors behave as key inducible molecules that may be upregulated under some special circumstances. In this context, several recent reports have investigated the importance of B1 receptor activation in certain disease models. Furthermore, research on B1 receptors in the last years has been mainly focused in determining the mechanisms and pathways involved in the process of induction. This was essentially favoured by the advances obtained in molecular biology studies, as well as in the design of selective and stable peptide and nonpeptide kinin B1 receptor antagonists. Likewise, development of kinin B1 receptor knockout mice greatly helped to extend the evidence about the relevance of B1 receptors during pathological states. In the present review, we attempted to remark the main advances achieved in the last 5 years about the participation of kinin B1 receptors in painful and inflammatory disorders. We have also aimed to point out some groups of chronic diseases, such as diabetes, arthritis, cancer or neuropathic pain, in which the strategic development of nonpeptidic oral-available and selective B1 receptor antagonists could have a potential relevant therapeutic interest. British Journal of Pharmacology (2004) 143, 803,818. doi:10.1038/sj.bjp.0706012 [source] | |||||||||||||