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991.
Wu D Ahrens R Osterfeld H Noah TK Groschwitz K Foster PS Steinbrecher KA Rothenberg ME Shroyer NF Matthaei KI Finkelman FD Hogan SP 《The Journal of biological chemistry》2011,286(15):13357-13369
Interleukin-13 (IL-13) has been linked to the pathogenesis of inflammatory diseases of the gastrointestinal tract. It is postulated that IL-13 drives inflammatory lesions through the modulation of both hematopoietic and nonhematopoietic cell function in the intestine. To delineate the relevant contribution of elevated levels of intestinal IL-13 to intestinal structure and function, we generated an intestinal IL-13 transgenic mouse (iIL-13Tg). We show that constitutive overexpression of IL-13 in the small bowel induces modification of intestinal epithelial architecture (villus blunting, goblet cell hyperplasia, and increased epithelial proliferation) and epithelial function (altered basolateral → apical Cl(-) ion conductance). Pharmacological analyses in vitro and in vivo determined that elevated Cl(-) conductance is mediated by altered cystic fibrosis transmembrane conductance regulator expression and activity. Generation of iIL-13Tg/Il13rα1(-/-), iIL-13Tg/Il13rα2(-/-), and iIL-13Tg/Stat6(-/-) mice revealed that IL-13-mediated dysregulation of epithelial architecture and Cl(-) conductance is dependent on IL-13Rα1 and STAT-6. These observations demonstrate a central role for the IL-13/IL-13Rα1 pathway in the regulation of intestinal epithelial cell Cl(-) secretion via up-regulation of cystic fibrosis transmembrane conductance regulator, suggesting an important role for this pathway in secretory diarrhea. 相似文献
992.
Verwaest KA Vu TN Laukens K Clemens LE Nguyen HP Van Gasse B Martins JC Van Der Linden A Dommisse R 《Biochimica et biophysica acta》2011,1812(11):1371-1379
Huntington disease (HD) is a hereditary brain disease. Although the causative gene has been found, the exact mechanisms of the pathogenesis are still unknown. Recent investigations point to metabolic and energetic dysfunctions in HD neurons. Both univariate and multivariate analyses were used to compare proton nuclear magnetic resonance spectra of serum and cerebrospinal fluid (CSF) taken from presymptomatic HD transgenic rats and their wild-type littermates. N-acetylaspartate (NAA), was found to be significantly decreased in the serum of HD rats compared to wild-type littermates. Moreover, in the serum their levels of glutamine, succinic acid, glucose and lactate are significantly increased as well. An increased concentration of lactate and glucose is also found in CSF. There is a 1:1 stoichiometry coupling glucose utilization and glutamate cycling. The observed increase in the glutamine concentration, which indicates a shutdown in the neuronal-glial glutamate-glutamine cycling, results therefore in an increased glucose concentration. The elevated succinic acid concentration might be due to an inhibition of succinate dehydrogenase, an enzyme linked to the mitochondrial respiratory chain and TCA cycle. Moreover, reduced levels of NAA may reflect an impairment of mitochondrial energy production. In addition, the observed difference in lactate supports a deficiency of oxidative energy metabolism in rats transgenic for HD as well. The observed metabolic alterations seem to be more profound in serum than in CSF in presymptomatic rats. All findings suggest that even in presymptomatic rats, a defect in energy metabolism is already apparent. These results support the hypothesis of mitochondrial energy dysfunction in HD. 相似文献
993.
994.
T-cell receptor-induced JNK activation requires proteolytic inactivation of CYLD by MALT1 总被引:2,自引:0,他引:2
Staal J Driege Y Bekaert T Demeyer A Muyllaert D Van Damme P Gevaert K Beyaert R 《The EMBO journal》2011,30(9):1742-1752
The paracaspase mucosa-associated lymphoid tissue 1 (MALT1) is central to lymphocyte activation and lymphomagenesis. MALT1 mediates antigen receptor signalling to NF-κB by acting as a scaffold protein. Furthermore, MALT1 has proteolytic activity that contributes to optimal NF-κB activation by cleaving the NF-κB inhibitor A20. Whether MALT1 protease activity is involved in other signalling pathways, and the identity of the relevant substrates, is unknown. Here, we show that T-cell receptors (TCR) activation, as well as overexpression of the oncogenic API2-MALT1 fusion protein, results in proteolytic inactivation of CYLD by MALT1, which is specifically required for c-jun N-terminal kinase (JNK) activation and the inducible expression of a subset of genes. These results indicate a novel role for MALT1 proteolytic activity in TCR-induced JNK activation and reveal CYLD cleavage as the underlying mechanism. 相似文献
995.
996.
Background
Guanylyl Cyclase C (GCC) signaling via uroguanylin (UGN) and guanylin activation is a critical mediator of intestinal fluid homeostasis, intestinal cell proliferation/apoptosis, and tumorigenesis. As a mechanism for some of these effects, we hypothesized that GCC signaling mediates regulation of intestinal barrier function.Methodology/Principal Findings
Paracellular permeability of intestinal segments was assessed in wild type (WT) and GCC deficient (GCC−/−) mice with and without lipopolysaccharide (LPS) challenge, as well as in UGN deficient (UGN−/−) mice. IFNγ and myosin light chain kinase (MLCK) levels were determined by real time PCR. Expression of tight junction proteins (TJPs), phosphorylation of myosin II regulatory light chain (MLC), and STAT1 activation were examined in intestinal epithelial cells (IECs) and intestinal mucosa. The permeability of Caco-2 and HT-29 IEC monolayers, grown on Transwell filters was determined in the absence and presence of GCC RNA interference (RNAi). We found that intestinal permeability was increased in GCC−/− and UGN−/− mice compared to WT, accompanied by increased IFNγ levels, MLCK and STAT1 activation in IECs. LPS challenge promotes greater IFNγ and STAT1 activation in IECs of GCC−/− mice compared to WT mice. Claudin-2 and JAM-A expression were reduced in GCC deficient intestine; the level of phosphorylated MLC in IECs was significantly increased in GCC−/− and UGN−/− mice compared to WT. GCC knockdown induced MLC phosphorylation, increased permeability in IEC monolayers under basal conditions, and enhanced TNFα and IFNγ-induced monolayer hyperpermeability.Conclusions/Significance
GCC signaling plays a protective role in the integrity of the intestinal mucosal barrier by regulating MLCK activation and TJ disassembly. GCC signaling activation may therefore represent a novel mechanism in maintaining the small bowel barrier in response to injury. 相似文献997.
Diversity in protein glycosylation among insect species 总被引:1,自引:0,他引:1
Vandenborre G Smagghe G Ghesquière B Menschaert G Nagender Rao R Gevaert K Van Damme EJ 《PloS one》2011,6(2):e16682
Background
A very common protein modification in multicellular organisms is protein glycosylation or the addition of carbohydrate structures to the peptide backbone. Although the Class of the Insecta is the largest animal taxon on Earth, almost all information concerning glycosylation in insects is derived from studies with only one species, namely the fruit fly Drosophila melanogaster.Methodology/Principal Findings
In this report, the differences in glycoproteomes between insects belonging to several economically important insect orders were studied. Using GNA (Galanthus nivalis agglutinin) affinity chromatography, different sets of glycoproteins with mannosyl-containing glycan structures were purified from the flour beetle (Tribolium castaneum), the silkworm (Bombyx mori), the honeybee (Apis mellifera), the fruit fly (D. melanogaster) and the pea aphid (Acyrthosiphon pisum). To identify and characterize the purified glycoproteins, LC-MS/MS analysis was performed. For all insect species, it was demonstrated that glycoproteins were related to a broad range of biological processes and molecular functions. Moreover, the majority of glycoproteins retained on the GNA column were unique to one particular insect species and only a few glycoproteins were present in the five different glycoprotein sets. Furthermore, these data support the hypothesis that insect glycoproteins can be decorated with mannosylated O-glycans.Conclusions/Significance
The results presented here demonstrate that oligomannose N-glycosylation events are highly specific depending on the insect species. In addition, we also demonstrated that protein O-mannosylation in insect species may occur more frequently than currently believed. 相似文献998.
Johan Vellekoop Kris H. Van Tilborgh Paul Van Knippenberg John W. M. Jagt Peter Stassen Stijn Goolaerts Robert P. Speijer 《Palaeontology》2020,63(2):349-367
The study of the global mass extinction event at the Cretaceous–Palaeogene (K/Pg) boundary can aid in understanding patterns of selective extinction, and survival and dynamics of ecosystem recovery. Outcrops in the Maastrichtian type area (south-east Netherlands, north-east Belgium) comprise a stratigraphically expanded K/Pg boundary succession that offers a unique opportunity to study marine ecosystem recovery within the first few thousand years following the mass extinction event. A quantitative analysis was performed on systematically sampled macrofossils of the topmost Maastrichtian and lowermost Danian strata at the former Ankerpoort-Curfs quarry (Geulhem), which represent ‘snapshots’ of the latest Cretaceous and earliest Palaeogene marine ecosystems, respectively. Molluscs in particular are diverse and abundant in the studied succession. Regional ecosystem changes across the K/Pg boundary are relatively minor, showing a decline in suspension feeders, accompanied by an ecological shift to endobenthic molluscs. The earliest Paleocene gastropod assemblage retains many ‘Maastrichtian’ features and documents a fauna that temporarily survived into the Danian. The shallow, oligotrophic carbonate platform in this area was inhabited by taxa that were adapted to low nutrient levels and resistant to starvation. As a result, the local taxa were less affected by the short-lived detrimental conditions related to K/Pg boundary perturbations, such as darkness, cooling, starvation and ocean acidification. This resulted in relatively high survival rates, which enabled rapid recolonization and recovery of marine faunas in the Maastrichtian type area. 相似文献
999.
Sanne Govaert Camille Meeussen Thomas Vanneste Kurt Bollmann Jrg Brunet Sara A. O. Cousins Martin Diekmann Bente J. Graae Per‐Ola Hedwall Thilo Heinken Giovanni Iacopetti Jonathan Lenoir Sigrid Lindmo Anna Orczewska Michael P. Perring Quentin Ponette Jan Plue Federico Selvi Fabien Spicher Matteo Tolosano Pieter Vermeir Florian Zellweger Kris Verheyen Pieter Vangansbeke Pieter De Frenne 《植被学杂志》2020,31(2):281-292