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Vivo Relevance (vivo + relevance)
Selected AbstractsNonstructural 3/4A protease of hepatitis C virus activates epithelial growth factor,induced signal transduction by cleavage of the T-cell protein tyrosine phosphatase,HEPATOLOGY, Issue 6 2009Erwin Daniel Brenndörfer The hepatitis C virus (HCV) is a worldwide major cause of chronic liver disease with a high tendency to establish a persistent infection. To permit persistent replication of viral genomes through the cellular translation machinery without affecting host cell viability, viruses must have developed mechanisms to control cellular cascades required for sufficient viral replication, on the one hand, and to adapt viral replication to the cellular requirements on the other hand. The present study aimed to further elucidate mechanisms by which HCV targets growth factor signaling of the host cell and their implications for viral replication. The study describes a novel mechanism by which HCV influences the activation of the epithelial growth factor receptor/Akt pathway through a nonstructural (NS)3/4A-dependent down-regulation of the ubiquitously expressed tyrosine phosphatase T cell protein tyrosine phosphatase (TC-PTP). NS3/4A is demonstrated to cleave TC-PTP protease-dependently in vitro at two cleavage sites. The in vivo relevance of this finding is supported by the fact that down-regulation of TC-PTP protein expression could also be demonstrated in HCV-infected individuals and in transgenic mice with intrahepatic expression of NS3/4A. Conclusion: This down-regulation of TC-PTP results in an enhancement of epithelial growth factor (EGF)-induced signal transduction and increases basal activity of Akt, which is demonstrated to be essential for the maintenance of sufficient viral replication. Hence, therapeutic targeting of NS3/4A may not only disturb viral replication by blocking the processing of the viral polyprotein but also exerts unforeseen indirect antiviral effects, further diminishing viral replication. (HEPATOLOGY 2009;49:1810,1820.) [source] Catalposide, a compound isolated from Catalpa Ovata, attenuates induction of intestinal epithelial proinflammatory gene expression and reduces the severity of trinitrobenzene sulfonic acid-induced colitis in miceINFLAMMATORY BOWEL DISEASES, Issue 5 2004Sang-Wook Kim MD Abstract Certain irinoid-producing plants have been used as herbal anti-inflammatory remedies. Here we evaluated whether catalposide (CATP), a single compound isolated from irinoid-producing plant Catalpa ovata, has a potential for preventing or ameliorating diseases characterized by mucosal inflammation. Preliminary microarray-based gene expression test revealed that CATP, which alone did not significantly affect expression of any of the >8,000 genes analyzed, attenuated the expression of tumor necrosis factor-, (TNF-,)-induced proinflammatory genes including interleukin-8 (IL-8) in human intestinal epithelial HT-29 cells. Down-regulation of IL-8 mRNA accumulation was also reflected by the decreased IL-8 secretion in CATP-treated HT-29 cells. The signal transduction study revealed that CATP significantly attenuates TNF-,-mediated p38 and extracellular signal-regulated kinase (ERK) phosphorylation. Further, CATP reduced NF-,B-mediated transcriptional activation as well as I,-B, degradation. To establish the in vivo relevance of these findings, we examined whether CATP could affect intestinal inflammation in vivo using the mouse model of trinitrobenzene sulfonic acid (TNBS)-induced inflammatory colitis. Intrarectal administration of CATP dramatically reduced the weight loss, colonic damage, and mucosal ulceration that characterize TNBS colitis. Moreover, CATP suppressed the expression of TNF-,, interleukin-1,, and intercellular adhesion molecule-1 along with the inhibition of NF-, B p65 translocation into nucleus in TNBS colitis. Collectively, current results demonstrate that CATP may be an effective agent for the treatment of diseases characterized by mucosal inflammation. [source] 2,,3,-Cyclic nucleotide 3,-phosphodiesterase: A novel RNA-binding protein that inhibits protein synthesisJOURNAL OF NEUROSCIENCE RESEARCH, Issue 5 2009Michel Gravel Abstract 2,,3,-Cyclic nucleotide 3,-phosphodiesterase (CNP) is one of the earliest myelin-related proteins to be specifically expressed in differentiating oligodendrocytes (ODCs) in the central nervous system (CNS) and is implicated in myelin biogenesis. CNP possesses an in vitro enzymatic activity, whose in vivo relevance remains to be defined, because substrates with 2,,3,-cyclic termini have not yet been identified. To characterize CNP function better, we previously determined the structure of the CNP catalytic domain by NMR. Interestingly, the structure is remarkably similar to the plant cyclic nucleotide phosphodiesterase (CPDase) from A. thaliana and the bacterial 2,-5, RNA ligase from T. thermophilus, which are known to play roles in RNA metabolism. Here we show that CNP is an RNA-binding protein. Furthermore, by using precipitation analyses, we demonstrate that CNP associates with poly(A)+ mRNAs in vivo and suppresses translation in vitro in a dose-dependent manner. With SELEX, we isolated RNA aptamers that can suppress the inhibitory effect of CNP on translation. We also demonstrate that CNP1 can bridge an association between tubulin and RNA. These results suggest that CNP1 may regulate expression of mRNAs in ODCs of the CNS. © 2008 Wiley-Liss, Inc. [source] Aluminium per se and in the anti-acid drug sucralfate promotes sensitization via the oral routeALLERGY, Issue 6 2009R. Brunner Background:, Aluminium (ALUM) is used as experimental and clinical adjuvant for parenteral vaccine formulation. It is also contained in anti-acid drugs like sucralfate (SUC). These anti-acids have been shown to cause sensitization to food proteins via elevation of the gastric pH. The aim of this study was to assess the oral adjuvant properties of ALUM, alone or contained in SUC, in a BALB/c mouse model. Methods:, Mice were fed SUC plus ovalbumin (OVA) and compared with groups where ALUM or proton pump inhibitors (PPI) were applied as adjuvants. The humoral and cellular immune responses were assessed on antigen-specific antibody and cytokine levels. The in vivo relevance was investigated in skin tests. Results:, The highest OVA-specific immunoglobulin G1 (IgG1) and IgE antibody levels were found in mice fed with OVA/SUC, followed by OVA/ALUM-treated animals, indicating a T helper 2 (Th2) shift in both groups. Antibody levels in other groups revealed lower (OVA/PPI-group) or baseline levels (control groups). Positive skin tests confirmed an allergic response in anti-acid or adjuvant-treated animals. Conclusions:, Our data show for the first time that ALUM acts as a Th2-adjuvant via the oral route. This suggests that orally applied SUC leads to an enhanced risk for food allergy, not only by inhibiting peptic digestion but also by acting as a Th2-adjuvant by its ALUM content. [source] Dendritic Cell Deficiency in the Blood of Kidney Transplant Patients on Long-Term Immunosuppression: Results of a Prospective Matched-Cohort StudyAMERICAN JOURNAL OF TRANSPLANTATION, Issue 12 2005Holger Hackstein Evidence from in vitro studies suggests that immunosuppressive drugs interfere with key functions of dendritic cells (DCs), but the in vivo relevance of these findings is elusive. We prospectively analyzed the major DC precursor subsets in the blood of kidney transplant recipients on long-term immunosuppression (,1 year). A total of 87 patients were compared to 87 age- and sex-matched controls. Total DC numbers and the precursor subsets, myeloid type 1 DCs, myeloid type 2 DCs (mDC1, mDC2) and plasmacytoid DCs (pDCs) were identified by four color flow cytometry. Long-term immunosuppression was associated with significant reduction of all major DC subsets in comparison to healthy controls (mDC1 p < 0.001; mDC2 p < 0.0001; two-tailed Mann-Whitney U -test) with the strongest negative impact on pDCs (p < 0.00001). In contrast, total leukocyte numbers were not significantly affected. Analysis of the relative impact of different agents revealed a significant impact of prednisolone on pDCs (p = 0.009) and mDCs2 (p = 0.006). The functional relevance of pDC deficiency was confirmed independently by Interferon-alpha analysis after Toll-like receptor 7 (p , 0.001) and 9 (p < 0.05) stimulation. These results indicate for the first time a profound negative impact of long-term immunosuppression on major DC subsets in kidney transplant recipients. DC deficiency may have important implications with respect to viral infections and tumor development. [source] The common inhalation anesthetic isoflurane induces caspase activation and increases amyloid ,-protein level in vivoANNALS OF NEUROLOGY, Issue 6 2008Zhongcong Xie MD Objective An estimated 200 million patients worldwide have surgery each year. Anesthesia and surgery have been reported to facilitate emergence of Alzheimer's disease. The commonly used inhalation anesthetic isoflurane has previously been reported to induce apoptosis, and to increase levels and aggregation of Alzheimer's disease,associated amyloid ,-protein (A,) in cultured cells. However, the in vivo relevance has not been addressed. Methods We therefore set out to determine effects of isoflurane on caspase activation and levels of ,-site amyloid precursor protein,cleaving enzyme (BACE) and A, in naive mice, using Western blot, immunohistochemistry, and reverse transcriptase polymerase chain reaction. Results Here we show for the first time that a clinically relevant isoflurane anesthesia (1.4% isoflurane for 2 hours) leads to caspase activation and modest increases in levels of BACE 6 hours after anesthesia in mouse brain. Isoflurane anesthesia induces caspase activation, and increases levels of BACE and A, up to 24 hours after anesthesia. Isoflurane may increase BACE levels by reducing BACE degradation. Moreover, the A, aggregation inhibitor, clioquinol, was able to attenuate isoflurane-induced caspase-3 activation in vivo. Interpretation Given that transient insults to brain may lead to long-term brain damage, these findings suggest that isoflurane may promote Alzheimer's disease neuropathogenesis and, as such, have implications for use of isoflurane in humans, pending human study confirmation. Ann Neurol 2008 [source] | ||||||||||