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Persistent Activation (persistent + activation)
Selected AbstractsPersistent rhythmic oscillations induced by nicotine on neonatal rat hypoglossal motoneurons in vitroEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 9 2006Nerijus Lamanauskas Abstract Patch-clamp recording from hypoglossal motoneurons in neonatal Wistar rat brainstem slices was used to investigate the electrophysiological effects of bath-applied nicotine (10 µm). While nicotine consistently evoked membrane depolarization (or inward current under voltage clamp), it also induced electrical oscillations (3,13 Hz; lasting for , 8.5 min) on 40% of motoneurons. Oscillations required activation of nicotinic receptors sensitive to dihydro-,-erythroidine (0.5 µm) or methyllycaconitine (5 nm), and were accompanied by enhanced frequency of spontaneous glutamatergic events. The slight voltage dependence of oscillations and their block by the gap junction blocker, carbenoxolone, suggest they originate from electrically coupled neurons. Network nicotinic receptors desensitized more slowly than motoneuron ones, demonstrating that network receptors remained active longer to support heightened release of the endogenous glutamate necessary for enhancing the network excitability. The ionotropic glutamate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), and the group I metabotropic receptor antagonist, (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA), suppressed oscillations, while the NMDA receptor antagonist, d -amino-phosphonovaleriate (APV), produced minimal depression. Nicotine-evoked oscillations constrained spike firing at low rates, although motoneurons could still generate high-frequency trains of action potentials with unchanged gain for input depolarization. This is the first demonstration that persistent activation of nicotinic receptors could cause release of endogenous glutamate to evoke sustained oscillations in the theta frequency range. As this phenomenon likely represented a powerful process to coordinate motor output to tongue muscles, our results outline neuronal nicotinic acetylcholine receptors (nAChRs) as a novel target for pharmacological enhancement of motoneuron output in motor dysfunction. [source] Mechanisms by which inflammation may increase intestinal cancer risk in inflammatory bowel diseaseINFLAMMATORY BOWEL DISEASES, Issue 8 2010Pamela M. O'Connor PhD Abstract Patients with ulcerative colitis and Crohn's disease are at increased risk of developing intestinal cancers via mechanisms that remain incompletely understood. However, chronic inflammation and repeated events of inflammatory relapse in inflammatory bowel disease (IBD) expose these patients to a number of signals known to have tumorigenic effects including persistent activation of the nuclear factor-,B and cyclooxygenase-2/prostaglandin pathways, release of proinflammatory mediators such as tumor necrosis factor-, and interleukin-6, and enhanced local levels of reactive oxygen and nitrogen species. These inflammatory signals can contribute to carcinogenesis via 3 major processes: 1) by increasing oxidative stress, which promotes DNA mutagenesis thus contributing to tumor initiation; 2) by activating prosurvival and antiapoptotic pathways in epithelial cells, thereby contributing to tumor promotion; and 3) by creating an environment that supports sustained growth, angiogenesis, migration, and invasion of tumor cells, thus supporting tumor progression and metastasis. The present review integrates clinical and basic research observations in an attempt to provide a comprehensive understanding of how inflammatory processes may contribute to intestinal cancer development in IBD patients. (Inflamm Bowel Dis 2010) [source] Activation of Src-family tyrosine kinases in hyperproliferative epidermal disordersJOURNAL OF CUTANEOUS PATHOLOGY, Issue 3 2008Elias E. Ayli Background:, Src-family tyrosine kinases (SFKs) are important regulators of keratinocyte growth and differentiation. In a broad range of cell types, persistent activation of SFKs correlates with increased cell proliferation. In this study, we determined if SFK activity is increased in cutaneous neoplasia and psoriasis, common hyperproliferative epidermal disorders. Methods:, Formalin-fixed tissue sections of unremarkable epidermis, psoriasis, actinic keratoses (AKs), squamous cell carcinoma in situ (SCIS) and squamous cell carcinoma (SCC) were subjected to immunohistochemical staining for activated SFKs. Results:, All psoriasis specimens displayed significantly greater staining for activated SFKs than sections of unremarkable skin. In the psoriasis biopsies, the degree of epidermal hyperplasia was proportional to the level of activated SFK staining. All AKs, SCISs and SCCs exhibited more prominent staining than sections of unremarkable epidermis. No discernable difference in activated SFK staining was seen between AKs, SCIS and SCC specimens. Conclusions:, This study shows increased staining of activated SFKs in human biopsy specimens of psoriasis and cutaneous neoplasia. These data provide direct evidence for increased activation of SFKs in the pathogenesis of hyperproliferative epidermal disorders. [source] Ongoing activation of p53 pathway responses is a long-term consequence of radiation exposure in vivo and associates with altered macrophage activities,THE JOURNAL OF PATHOLOGY, Issue 5 2008PJ Coates Abstract The major adverse consequences of radiation exposure, including the initiation of leukaemia and other malignancies, are generally attributed to effects in the cell nucleus at the time of irradiation. However, genomic damage as a longer term consequence of radiation exposure has more recently been demonstrated due to untargeted radiation effects including delayed chromosomal instability and bystander effects. These processes, mainly studied in vitro, are characterized by un-irradiated cells demonstrating effects as though they themselves had been irradiated and have been associated with altered oxidative processes. To investigate the potential for these untargeted effects of radiation to produce delayed damaging events in vivo, we studied a well-characterized model of radiation-induced acute myeloid leukaemia in CBA/Ca mice. Haemopoietic tissues of irradiated CBA/Ca mice exhibit enhanced levels of p53 stabilization, increased levels of p21waf1, and increased amounts of apoptosis, as expected, in the first few hours post-irradiation, but also at much later times: weeks and months after the initial exposure. Because these responses are seen in cells that were not themselves directly irradiated but are the descendants of irradiated cells, the data are consistent with an initial radiation exposure leading to persistently increased levels of ongoing DNA damage, analogous to radiation-induced chromosomal instability. To investigate the potential source of ongoing oxidative processes, we show increased levels of 3-nitrotyrosine, a marker of damaging nitrogen/oxygen species in macrophages. Not all animals show increased oxidative activity or p53 responses as long-term consequences of irradiation, but increased levels of p53, p21, and apoptosis are directly correlated with increased 3-nitrotyrosine in individual mice post-irradiation. The data implicate persistent activation of inflammatory-type responses in irradiated tissues as a contributory bystander mechanism for causing delayed DNA damage. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Expression of ,-catenin in external auditory canal cholesteatoma (EACC)BIOFACTORS, Issue 3-4 2003Ramin Naim Abstract External auditory canal cholesteatoma (EACC) is a chronic inflammation of the external auditory canal and is composed of hyperproliferative epithelium. The upward migration of the epithelial cells requires permanent breakdown and reformation of intercellular connection. This is established by the modulation of the adherent junctions consisting of an E-Cadherin-,-catenin complex. Dissociated ,-catenin intranuclearly enables persistent activation of downstream transcription and growth factors and decreases the integrity of tissue. In our study we examined EACC and normal meatal auditory skin taken from 16 patients between 23 and 74 years of age. Immunostaining for ,-catenin was used for semiquantitative description of the specimens after assessing hematoxylin-eosin-stained slides. ,-catenin was expressed in all layers of AMS-epithelium, whereas in EACC only basal layer of the matrix epithelium showed positive immunostaining for ,-catenin. In the suprabasal layer of the epithelium only faint reactivity was detectable. The immunostaining was restricted to the membrane of the cells. We assumed that either the content of membranous ,-catenin was decreased or ,-catenin was changed due to molecular modification. It is known that stimulation of endothelial cells by certain growth factors, ,-catenin is maximally phosphorylated. In regard to the increased loss of immunoreactivity for ,-catenin in the suprabasal layers of the hyperplastic EACC-matrix, we assumed bio-molecular modification or loss of ,-catenin decreasing the cell-cell-integrity. Furthermore, this might result in desquamation of keratinocytes and accumulation of dead keratin debrids. In sum, this study should be understood as a descriptive analysis of ,-catenin expression in EACC. [source] Expression and role of Notch signalling in the regeneration of rat tracheal epitheliumCELL PROLIFERATION, Issue 1 2009X.-B. Ma Objectives:, This study is to explore the role of Notch signalling during the regeneration of rat tracheal epithelium after injury induced by 5-fluorouracil (5-FU). Materials and methods:, We developed an ex vivo model of rat tracheal epithelial regeneration using 5-FU to induce injury. Expression levels of members of the Notch signalling pathway, ABCG2, CK19, and proliferating cell nuclear antigen (PCNA) were examined by reverse transcription,polymerase chain reaction, Western blot, and immunofluorescence. One group of tracheas were cultured in the medium with a ,-secretase inhibitor or Jag-1 peptide after 5-FU treatment and another group were pre-treated with the ,-secretase inhibitor or Jag-1 peptide before 5-FU treatment. The expression changes of ABCG2, CK19, and PCNA were examined by Western blot or immunofluorescence and the morphologic changes were observed by haematoxylin and eosin stain during the recovery process. Results:, Expression levels of Notch3, Jagged1, and Hey1 were increased in rat tracheal epithelial cells after treatment with 5-FU. During injury recovery, disruption of Notch signalling by treatment with the ,-secretase inhibitor reduced expression of ABCG2 and PCNA, but promoted expression of CK19, while persistent activation of Notch signalling promoted expression of ABCG2 and PCNA, but reduced expression of CK19. Under both conditions, recovery from injury was reduced. However, blocking Notch signalling prior to 5-FU treatment led to the complete blockage of recovery, while activating Notch signalling before 5-FU treatment promoted recovery. Conclusions:, During tracheal epithelial regeneration, Notch signalling maintains an undifferentiated state and promotes proliferation among a population of tracheal epithelial cells. [source] | |||||||||||||