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Activation Leads (activation + lead)
Selected AbstractsHeterozygous SOX9 Mutations Allowing for Residual DNA-binding and Transcriptional Activation Lead to the Acampomelic Variant of Campomelic Dysplasia,HUMAN MUTATION, Issue 6 2010Alex Staffler Abstract Campomelic dysplasia is a malformation syndrome with multiple symptoms including characteristic shortness and bowing of the long bones (campomelia). CD, often lethal due to airway malformations, is caused by heterozygous mutations in SOX9, an SRY-related gene regulating testis and chondrocyte development including expression of many cartilage genes such as type II collagen. Male to female sex reversal occurs in the majority of affected individuals with an XY karyotype. A mild form without campomelia exists, in which sex-reversal may be also absent. We report here two novel SOX9 missense mutations in a male (c.495C>G; p.His165Gln) and a female (c.337A>G; p.Met113Val) within the DNA-binding domain leading to non-lethal acampomelic CD. Functional analyses of mutant proteins demonstrate residual DNA-binding and transactivation of SOX9-regulated genes. Combining our data and reports from the literature we postulate a genotype-phenotype correlation: SOX9 mutations allowing for residual function lead to a mild form of CD in which campomelia and sex reversal may be absent. © 2010 Wiley-Liss, Inc. [source] AMPK activators , potential therapeutics for metabolic and other diseasesACTA PHYSIOLOGICA, Issue 1 2009G. Zhou Abstract AMP-activated protein kinase (AMPK)-mediated cellular metabolic responses to tissue-specific and whole-body stimuli play a vital role in the control of energy homeostasis. As a cellular energy-sensing mechanism, AMPK activation stimulates glucose uptake and fat oxidation, while it suppresses lipogenesis and gluconeogenesis. The cumulative effects of AMPK activation lead to beneficial metabolic states in liver, muscle and other peripheral tissues that are critical in the pathogenesis of obesity, type 2 diabetes and related metabolic disorders. Activators of AMPK that target selected tissues hold potential as novel therapeutics for diseases in which altered energy metabolism contributes to aetiology. [source] Advanced glycation end-products and the kidneyEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 8 2010Martin Busch Eur J Clin Invest 2010; 40 (8): 742,755 Abstract Background, Advanced glycation end-products (AGEs) are increased in situations with hyperglycemia and oxidative stress such as diabetes mellitus. They are products of nonenzymatic glycation and oxidation of proteins and lipids. The kidney plays an important role in clearance and metabolism of AGEs. Methods, Medline© and other relevant databases were searched. In addition, key review articles were scanned for relevant original publication. Finally, original data from our research group were also included. Results, Kidney podocytes and endothelial cells express specific receptors for AGEs. Their activation leads to multiple pathophysiological effects including hypertrophy with cell cycle arrest and apoptosis, altered migration, and generation of proinflammatory cytokines. AGEs have been primarily implicated in the pathophysiology of diabetic nephropathy and diabetic microvascular complications. AGEs are also involved in other primary renal diseases as well as in the development and progression of atherosclerosis. However, serum or plasma concentrations of AGEs do not correlate well with cardiovascular events in patients with chronic kidney disease (CKD). This is likely due to the fact that serum concentrations failed to correlate with AGEs deposited in target tissues. Several inhibitors of the AGE-RAGE axis are currently tested for various indications. Conclusion, AGEs and their receptors are involved in the pathogenesis of vascular and kidney disease. The role of circulating AGEs as biomarkers for cardiovascular risk estimation is questionable. Whether putative inhibitors of AGEs will get the maturity for its therapeutic use in the future remains open. [source] The induction of HIF-1 reduces astrocyte activation by amyloid beta peptideEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2009David Schubert Abstract Reduced glucose metabolism and astrocyte activation in selective areas of the brain are pathological features of Alzheimer's disease (AD). The underlying mechanisms of low energy metabolism and a molecular basis for preventing astrocyte activation are not, however, known. Here we show that amyloid beta peptide (A,)-dependent astrocyte activation leads to a long-term decrease in hypoxia-inducible factor (HIF)-1, expression and a reduction in the rate of glycolysis. Glial activation and the glycolytic changes are reversed by the maintenance of HIF-1, levels with conditions that prevent the proteolysis of HIF-1,. A, increases the long-term production of reactive oxygen species (ROS) through the activation of nicotinamide adenine dinucleotide phosphate oxidase and reduces the amount of HIF-1, via the activation of the proteasome. ROS are not required for glial activation, but are required for the reduction in glycolysis. These data suggest a significant role for HIF-1,-mediated transcription in maintaining the metabolic integrity of the AD brain and identify the probable cause of the observed lower energy metabolism in afflicted areas. They may also explain the therapeutic success of metal chelators in animal models of AD. [source] WIF1, an inhibitor of the Wnt pathway, is rearranged in salivary gland tumors,GENES, CHROMOSOMES AND CANCER, Issue 3 2007Lurdes Queimado Chromosome rearrangements involving 12q13-15 are frequent among several tumors, including pleomorphic adenomas. The common molecular target for these aberrations is the HMGA2 gene, but various fusion partners of HMGA2 have been reported in tumors. Here we report the identification of the WNT inhibitory factor 1 (WIF1) gene as a novel HMGA2 fusion partner in a salivary gland pleomorphic adenoma. In normal salivary gland tissue WIF1 is expressed at a high level and HMGA2 is not expressed. However, in the pleomorphic adenoma expressing the HMGA2/WIF1 fusion transcript, we observed re-expression of HMGA2 wild-type transcripts and very low levels of WIF1 expression. These data suggest a possible synergistic effect between upregulation of HMGA2 and downregulation of WIF1. We screened 13 additional benign and malignant salivary gland tumors and detected WIF1 rearrangement in one out of two carcinomas ex-pleomorphic adenoma analyzed. In this malignant tumor, the rearrangement of one WIF1 allele coexists with loss of the other allele, a classic signature of a tumor suppressor gene. WIF1 is an antagonist of the Wnt signaling pathway, which plays a critical role in human cancer. In transgenic mouse models, Wnt activation leads to a high frequency of benign and malignant salivary gland tumors. To our knowledge, this is the first report suggesting that WIF1 is a recurrent target in human salivary gland oncogenesis and that downregulation of WIF1 plays a role in the development and/or progression of pleomorphic adenomas. © 2006 Wiley-Liss, Inc. [source] Structure and biology of complement protein C3, a connecting link between innate and acquired immunityIMMUNOLOGICAL REVIEWS, Issue 1 2001Arvind Sahu Summary: Complement protein C3 is a central molecule in the complement system whose activation is essential for all the important functions performed by this system. After four decades of research it is now well established that C3 functions like a double-edged sword: on the one hand it promotes phagocytosis, supports local inflammatory responses against pathogens, and instructs the adaptive immune response to select the appropriate antigens for a humoral response; on the other hand its unregulated activation leads to host cell damage. In addition, its interactions with the proteins of foreign pathogens may provide a mechanism by which these microorganisms evade complement attack. Therefore, a clear knowledge of the molecule and its interactions at the molecular level not only may allow the rational design of molecular adjuvants but may also lead to the development of complement inhibitors and new therapeutic agents against infectious diseases. A.S. is a Wellcome Trust Overseas Senior Research Fellow in Biomedical Science in India. This research was supported by National Institutes of Health grants AI 30040, GM 56698, HL28220, and AI 48487. [source] Endogenous cGMP regulates adult longevity via the insulin signaling pathway in Caenorhabditis elegansAGING CELL, Issue 4 2009Jeong-Hoon Hahm Summary G-proteins, including GPA-3, play an important role in regulating physiological responses in Caenorhabditis elegans. When confronted with an environmental stimulus such as dauer pheromone, or poor nutrients, C. elegans receives and integrates external signals through its nervous system (i.e. amphid neurons), which interprets and translates them into biological action. Here it is shown that a suppressed neuronal cGMP level caused by GPA-3 activation leads to a significant increase (47.3%) in the mean lifespan of adult C. elegans through forkhead transcription factor family O (FOXO)-mediated signal. A reduced neuronal cGMP level was found to be caused by an increased cGMP-specific phosphodiesterase activity at the transcriptional level. Our results using C. elegans mutants with specific deficits in TGF-, and FOXO RNAi system suggest a mechanism in that cGMP, TGF-,, and FOXO signaling interact to differentially produce the insulin-like molecules, ins-7 and daf-28, causing suppression of the insulin/IGF-1 pathway and promoting lifespan extension. Our findings provide not only a new mechanism of cGMP-mediated induction of longevity in adult C. elegans but also a possible therapeutic strategy for neuronal disease, which has been likened to brain diabetes. [source] Trade-offs between longevity and pathogen resistance in Drosophila melanogaster are mediated by NF,B signalingAGING CELL, Issue 6 2006Sergiy Libert Summary The innate immune response protects numerous organisms, including humans, from the universe of pathogenic molecules, viruses and micro-organisms. Despite its role in promoting pathogen resistance, inappropriate activation and expression of NF,B and other immunity-related effector molecules can lead to cancer, inflammation, and other diseases of aging. Understanding the mechanisms leading to immune system activation as well as the short- and long-term consequences of such activation on health and lifespan is therefore critical for the development of beneficial immuno-modulating and longevity-promoting interventions. Mechanisms of innate immunity are highly conserved across species, and we take advantage of genetic tools in the model organism, Drosophila melanogaster, to study the effects of acute and chronic activation of immunity pathways on pathogen resistance and general fitness of adult flies. Our findings indicate that fat body specific overexpression of a putative pathogen recognition molecule, peptidoglycan recognition protein (PGRP-LE), is sufficient for constitutive up-regulation of the immune response and for enhanced pathogen resistance. Primary components of fitness are unaffected by acute activation, but chronic activation leads to an inflammatory state and reduced lifespan. These phenotypes are dependent on the NF,B-related transcriptional factor, Relish, and they establish a mechanistic basis for a link between immunity, inflammation, and longevity. [source] Muscle mitochondrial activity increases rapidly after an endotoxin challenge in human volunteersACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 3 2009K. FREDRIKSSON Background: Mitochondrial derangements in muscle of patients suffering from sepsis have been established in several studies and have been related to muscle dysfunction and organ failure. It is not possible to study the early phase of sepsis in patients; therefore, we used a human endotoxaemia model to study the effect of early sepsis on muscle mitochondria. Methods: Seven healthy male volunteers received a standardised endotoxin challenge. Muscle biopsies were obtained immediately before the challenge, and at 2 and 4 h following the endotoxin challenge. The muscle biopsies were analysed for maximal activities of citrate synthase and complexes I and IV of the respiratory chain. In addition, total and mitochondrial superoxide dismutase (SOD) activities were analysed. The concentrations of ATP, creatine phosphate and lactate were analysed to assess the cellular energy status. Total and phosphorylated AMP-activated protein kinase (AMPK-P), a key regulator in intracellular energy metabolism, was measured. Results: Activities of citrate synthase and complex I were significantly increased 2 h after the endotoxin challenge. SOD activities were unaffected by the endotoxin challenge. No changes in ATP, creatine phosphate or lactate were observed. Neither total nor AMPK-P changed. Conclusions: An endotoxin challenge given to healthy volunteers rapidly increases mitochondrial enzyme activity in skeletal muscle. The results of this human model indicate that possibly early during sepsis, mitochondrial activity might be increased in contrast to what has been shown in the later phases of sepsis. It is possible that this early activation leads to exhaustion of the mitochondria and a decreased function later during sepsis. [source] Regulation of glutamate carboxypeptidase II hydrolysis of N -acetylaspartylglutamate (NAAG) in crayfish nervous tissue is mediated by glial glutamate and acetylcholine receptorsJOURNAL OF NEUROCHEMISTRY, Issue 3 2005Albert K. Urazaev Abstract Glutamate carboxypeptidase II (GCPII), a glial ectoenzyme, is responsible for N -acetylaspartylglutamate (NAAG) hydrolysis. Its regulation in crayfish nervous tissue was investigated by examining uptake of [3H]glutamate derived from N -acetylaspartyl-[3H]glutamate ([3H]NAAG) to measure GCPII activity. Electrical stimulation (100 Hz, 10 min) during 30 min incubation with [3H]NAAG increased tissue [3H]glutamate tenfold. This was prevented by 2-(phosphonomethyl)-pentanedioic acid (2-PMPA), a GCPII inhibitor, suggesting that stimulation increased the hydrolysis of [3H]NAAG and metabolic recycling of [3H]glutamate. Antagonists of glial group II metabotropic glutamate receptors (mGLURII), NMDA receptors and acetylcholine (ACh) receptors that mediate axon,glia signaling in crayfish nerve fibers decreased the effect of stimulation by 58,83%, suggesting that glial receptor activation leads to stimulation of GCPII activity. In combination, they reduced [3H]NAAG hydrolysis during stimulation to unstimulated control levels. Agonist stimulation of mGLURII mimicked the effect of electrical stimulation, and was prevented by antagonists of GCPII or mGLURII. Raising extracellular K+ to three times the normal level stimulated [3H]NAAG release and GCPII activity. These effects were also blocked by antagonists of GCPII and mGLURII. No receptor antagonist or agonist tested or 2-PMPA affected uptake of [3H]glutamate. We conclude that NAAG released from stimulated nerve fibers activates its own hydrolysis via stimulation of GCPII activity mediated through glial mGLURII, NMDA and ACh receptors. [source] From bench to bedside , translational research in psoriasisJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 2010JC Prinz Abstract For many years, psoriasis was firmly believed to be a disease of epidermal keratinocytes, but now is attributed to a combination of genetic and environmental factors that promote a T-cell mediated immune response in the skin. Psoriasis is now understood to be a systemic T-cell mediated autoimmune disease with the innate immune system playing an important role. Progress in understanding the pathogenesis of psoriasis has shown that following a stimulus, dendritic and T cell activation leads to the release of cytokines, chemokines and growth factors that initiate the proliferation and altered differentiation of keratinocytes. These factors subsequently lead to continuous activation of T cells and antigen-presenting cells, particularly dendritic cells, within the psoriatic plaque. This vicious cycle of psoriasis, in which the cytokines interleukin 12 (IL-12) and IL-23 play a pivotal role, is a logical target for biological therapy. [source] Formation of platelet strings and microthrombi in the presence of ADAMTS-13 inhibitor does not require P-selectin or ,3 integrinJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 3 2007A. K. CHAUHAN Summary. Background:,Ultra-large von Willebrand factor (ULVWF) and the receptor P-selectin are released from endothelial Weibel,Palade bodies during injury or inflammation. VWF mediates platelet adhesion and P-selectin promotes leukocyte rolling. ADAMTS-13 limits the duration of platelet adhesion by cleaving the ULVWF. In the absence of ADAMTS-13, long VWF filaments decorated with platelets form. Recent in vitro studies suggested that P-selectin might anchor these platelet strings to endothelium, but whether the same mechanism exists in vivo remains to be elucidated. Methods:,We address the role of P-selectin and ,3 integrin in platelet string formation in vivo using intravital microscopy by infusing inhibitory ADAMTS-13 antibody in P-selectin-/- and ,3 -deficient mice and activating the endothelium by injecting histamine. Results:,We show that inhibition of ADAMTS-13 combined with endothelial activation leads to similar extents of platelet string formation in wild-type, P-selectin- and integrin ,3 -deficient mice. Further, in venules the platelet strings can coalesce into VWF-platelet aggregates. This process utilizes neither the platelet ,3 integrin nor P-selectin. We also show in vitro that platelets can act as a bridge between the VWF fibers and that VWF can self-associate even in areas devoid of platelets. Conclusions:,The formation or retention of the platelet strings does not require P-selectin or the endothelial VWF receptor ,v,3. Furthermore, in the presence of low ADAMTS-13 activity, VWF-dependent and ,IIb,3 -independent platelet clustering occurs in veins, as has been shown at high arterial shear rates. Our study further supports the importance of regulation of VWF multimer size upon secretion from Weibel,Palade bodies. [source] Functional protease-activated receptors in the dorsal motor nucleus of the vagusNEUROGASTROENTEROLOGY & MOTILITY, Issue 4 2010H. Wang Abstract Background, Protease-activated receptors (PARs), a family member of G-protein coupled receptors, are present and functionally active in a wide variety of cells. The object of this study was to demonstrate the presence and function of PAR-1 and PAR-2 in the dorsal motor nucleus of the vagus (DMV). Methods, DMNV neurons were isolated from neonatal rat brainstems using micro-dissection and enzymatic digestion. Neurons were cultured in Neurobasal medium A containing 2% B27 supplement. Intracellular calcium concentration ([Ca2 + ]i) was measured using fura-2 based microspectrometry. Expression of PARs was detected by RT-PCR and immunofluorescent staining. Key Result, Thrombin and PAR-1 agonist peptide activate PAR-1 with a maximum change in [Ca2 + ]i expressed as ,F/F0 of 229 ± 14% and 137 ± 7%, respectively. Trypsin and PAR-2 agonist peptide activate PAR-2 with a maximum ,F/F0 change of 258 ± 12% and 242 ± 10%, respectively. Inhibition of phospholipase C (PLC) by U73312 (1 ,m) decreased the maximal change in ,F/F0 induced by PAR-1 activation from 140 ± 17% to 21 ± 3%, while the PAR-2-mediated maximal change in ,F/F0 decreased from 185 ± 21% to 19 ± 6%. Blockade of IP3 receptor with 2APB inhibited the maximal change in ,F/F0 due to PAR-1 and PAR-2 activation by 72 ± 13% and 71 ± 20% respectively. PAR-1 immnuoreactivity was present in DMV neurons. Increase in transcripts for PAR-1 and PAR-2 were detected in DMV tissues derived from IBD rats relative to control animals. Conclusions & Inferences, Our results indicate that PAR-1 and PAR-2 are present in the DMV neurons, and their activation leads to increases in intracellular calcium via signal transduction mechanism that involves activation of PLC and the production of IP3. [source] Increased KIT signalling with up-regulation of cyclin D correlates to accelerated proliferation and shorter disease-free survival in gastrointestinal stromal tumours (GISTs) with KIT exon 11 deletions,THE JOURNAL OF PATHOLOGY, Issue 2 2008F Haller Abstract Gastrointestinal stromal tumours (GISTs) with deletions in KIT exon 11 are characterized by higher proliferation rates and shorter disease-free survival times, compared to GISTs with KIT exon 11 point mutations. Up-regulation of cyclin D is a crucial event for entry into the G1 phase of the cell cycle, and links mitogenic signalling to cell proliferation. Signalling from activated KIT to cyclin D is directed through the RAS/RAF/ERK, PI3K/AKT/mTOR/EIF4E, and JAK/STATs cascades. ERK and STATs initiate mRNA transcription of cyclin D, whereas EIF4E activation leads to increased translation efficiency and reduced degradation of cyclin D protein. The aim of the current study was to analyse the mRNA and protein expression as well as protein phosphorylation of central hubs of these signalling cascades in primary GISTs, to evaluate whether tumours with KIT exon 11 deletions and point mutations differently utilize these pathways. GISTs with KIT exon 11 deletions had significantly higher mitotic counts, higher proliferation rates, and shorter disease-free survival times. In line with this, they had significantly higher expression of cyclin D on the mRNA and protein level. Furthermore, there was a significantly higher amount of phosphorylated ERK1/2, and a higher protein amount of STAT3, mTOR, and EIF4E. PI3K and phosphorylated AKT were also up-regulated, but this was not significant. Ultimately, GISTs with KIT exon 11 deletions had significantly higher phosphorylation of the central negative cell-cycle regulator RB. Phosphorylation of RB is accomplished by activated cyclin D/CDK4/6 complex, and marks a central event in the release of the cell cycle. Altogether, these observations suggest increased KIT signalling with up-regulation of cyclin D as the basis for the unfavourable clinical course in GISTs with KIT exon 11 deletions. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Members of the Plag gene family are expressed in complementary and overlapping regions in the developing murine nervous systemDEVELOPMENTAL DYNAMICS, Issue 3 2005Sharmila Alam Abstract In the developing nervous system, cell fate specification and proliferation are tightly coupled events, ensuring the coordinated generation of the appropriate numbers and correct types of neuronal and glial cells. While it has become clear that tumor suppressor genes and oncogenes are key regulators of cell division in tumor cells, their role in normal cellular and developmental processes is less well understood. Here we present a comparative analysis of the expression profiles of the three members of the pleiomorphic adenoma gene (Plag) family, which encode zinc finger transcription factors previously characterized as tumor suppressors (Zac1) or oncogenes (Plag1, Plag-l2). We focused our analysis on the developing nervous system of mouse where we found that the Plag genes were expressed in both unique and overlapping patterns in the central and peripheral nervous systems, and in olfactory and neuroendocrine lineages. Based on their patterns of expression, we suggest that members of the Plag gene family might control cell fate and proliferation decisions in the developing nervous system and propose that deciphering these functions will help to explain why their inappropriate inactivation/activation leads to tumor formation. Developmental Dynamics 234:772,782, 2005. © 2005 Wiley-Liss, Inc. [source] | |||||||||||||