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71.
Scheller C Sopper S Ehrhardt C Flory E Chen P Koutsilieri E Ludwig S ter Meulen V Jassoy C 《European journal of immunology》2002,32(9):2471-2480
CD95 is a major apoptosis receptor that induces caspase activation and programmed cell death in susceptible cells. CD95-induced apoptosis can be blocked by peptidic caspase inhibitors such as benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone or Ile-Glu-Thr-Asp-fluoromethyl ketone. Here we show that stimulation of CD95 in the presence of these inhibitors induces necrosis and expression of various proinflammatory cytokines in primary T lymphocytes, such as TNF-alpha, IFN-gamma and granulocyte/macrophage colony-stimulating factor. In the absence of caspase inhibition CD95 stimulation did not result in cytokine expression, indicating that this proinflammatory signaling pathway is suppressed by active caspases. Further analysis with A3.01 T cells revealed that the proinflammatory signaling activity of CD95 was mediated by MEK/ERK, p38 and NF-kappaB signaling pathways. These findings point to a pivotal role of caspases not only as mediators of apoptosis but also as enzymes that prevent proinflammatory signaling during CD95-induced apoptosis. Moreover, our findings may be useful for the development of novel pharmacological strategies. 相似文献
72.
73.
Transgenic rat model of Huntington's disease 总被引:12,自引:0,他引:12
von Hörsten S Schmitt I Nguyen HP Holzmann C Schmidt T Walther T Bader M Pabst R Kobbe P Krotova J Stiller D Kask A Vaarmann A Rathke-Hartlieb S Schulz JB Grasshoff U Bauer I Vieira-Saecker AM Paul M Jones L Lindenberg KS Landwehrmeyer B Bauer A Li XJ Riess O 《Human molecular genetics》2003,12(6):617-624
Huntington's disease (HD) is a late manifesting neurodegenerative disorder in humans caused by an expansion of a CAG trinucleotide repeat of more than 39 units in a gene of unknown function. Several mouse models have been reported which show rapid progression of a phenotype leading to death within 3-5 months (transgenic models) resembling the rare juvenile course of HD (Westphal variant) or which do not present with any symptoms (knock-in mice). Owing to the small size of the brain, mice are not suitable for repetitive in vivo imaging studies. Also, rapid progression of the disease in the transgenic models limits their usefulness for neurotransplantation. We therefore generated a rat model transgenic of HD, which carries a truncated huntingtin cDNA fragment with 51 CAG repeats under control of the native rat huntingtin promoter. This is the first transgenic rat model of a neurodegenerative disorder of the brain. These rats exhibit adult-onset neurological phenotypes with reduced anxiety, cognitive impairments, and slowly progressive motor dysfunction as well as typical histopathological alterations in the form of neuronal nuclear inclusions in the brain. As in HD patients, in vivo imaging demonstrates striatal shrinkage in magnetic resonance images and a reduced brain glucose metabolism in high-resolution fluor-deoxy-glucose positron emission tomography studies. This model allows longitudinal in vivo imaging studies and is therefore ideally suited for the evaluation of novel therapeutic approaches such as neurotransplantation. 相似文献
74.
Da Costa CU Wantia N Kirschning CJ Busch DH Rodriguez N Wagner H Miethke T 《European journal of immunology》2004,34(10):2874-2884
Heat shock protein 60 (HSP60) from Chlamydia pneumoniae was described to trigger in vitro inflammatory and cytokine responses including TNF and IL-12p40. Although it can be found in atherosclerotic plaques of patients, the stimulatory potential of chlamydial and other HSP60 in vivo is unclear. We now report that chlamydial HSP60 fails to induce TNF expression in vivo, and significant serum levels of IL-12p40 are only found upon intraperitoneal injection of high doses of HSP60 or after intravenous application. Upon purification of chlamydial HSP60 with polymyxin B-agarose columns, its ability to induce TNF secretion in vitro is much reduced. However, purified chlamydial HSP60 causes increased serum levels of the CXC chemokines KC and MIP2 in vivo, as well as a strong accumulation of polymorphonuclear neutrophils (PMN) in the peritoneal cavity upon intraperitoneal challenge. With respect to PMN accumulation, chlamydial HSP60 is more potent than endotoxin or the CpG oligonucleotide 1668. The responses observed are completely abolished in Toll-like receptor (TLR)2/4-double-deficient mice, while single-deficient mice respond almost normally. Furthermore, KC induction and PMN accumulation are largely dependent on MyD88. In conclusion, HSP60 from C. pneumoniae triggers inflammatory responses in vivo that differ from responses induced by endotoxin or CpG oligonucleotides and are dependent on TLR2 and 4. 相似文献
75.
Integrin-linked kinase (ILK) is required for polarizing the epiblast,cell adhesion,and controlling actin accumulation 总被引:15,自引:0,他引:15
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Sakai T Li S Docheva D Grashoff C Sakai K Kostka G Braun A Pfeifer A Yurchenco PD Fässler R 《Genes & development》2003,17(7):926-940
Integrin-mediated cell-matrix interactions are essential for development, tissue homeostasis, and repair. Upon ligand binding, integrins are recruited into focal adhesions (FAs). Integrin-linked kinase (ILK) is an FA component that interacts with the cytoplasmic domains of integrins, recruits adaptor proteins that link integrins to the actin cytoskeleton, and phosphorylates the serine/threonine kinases PKB/Akt and GSK-3beta. Here we show that mice lacking ILK expression die at the peri-implantation stage because they fail to polarize their epiblast and to cavitate. The impaired epiblast polarization is associated with abnormal F-actin accumulation at sites of integrin attachments to the basement membrane (BM) zone. Likewise, ILK-deficient fibroblasts showed abnormal F-actin aggregates associated with impaired cell spreading and delayed formation of stress fibers and FAs. Finally, ILK-deficient fibroblasts have diminished proliferation rates. However, insulin or PDGF treatment did not impair phosphorylation of PKB/Akt and GSK-3beta, indicating that the proliferation defect is not due to absent or reduced ILK-mediated phosphorylation of these substrates in vivo. Furthermore, expression of a mutant ILK lacking kinase activity and/or paxillin binding in ILK-deficient fibroblasts can rescue cell spreading, F-actin organization, FA formation, and proliferation. Altogether these data show that mammalian ILK modulates actin rearrangements at integrin-adhesion sites. 相似文献
76.
During hypoxic exercise some vasoconstriction is needed to match O2 delivery with O2 demand at the microcirculatory level. 总被引:1,自引:0,他引:1
Carsten Lundby Robert Boushel Paul Robach Kirsten M?ller Bengt Saltin José A L Calbet 《The Journal of physiology》2008,586(1):123-130
To test the hypothesis that the increased sympathetic tonus elicited by chronic hypoxia is needed to match O(2) delivery with O(2) demand at the microvascular level eight male subjects were investigated at 4559 m altitude during maximal exercise with and without infusion of ATP (80 mug (kg body mass)(-1) min(-1)) into the right femoral artery. Compared to sea level peak leg vascular conductance was reduced by 39% at altitude. However, the infusion of ATP at altitude did not alter femoral vein blood flow (7.6 +/- 1.0 versus 7.9 +/- 1.0 l min(-1)) and femoral arterial oxygen delivery (1.2 +/- 0.2 versus 1.3 +/- 0.2 l min(-1); control and ATP, respectively). Despite the fact that with ATP mean arterial blood pressure decreased (106.9 +/- 14.2 versus 83.3 +/- 16.0 mmHg, P < 0.05), peak cardiac output remained unchanged. Arterial oxygen extraction fraction was reduced from 85.9 +/- 5.3 to 72.0 +/- 10.2% (P < 0.05), and the corresponding venous O(2) content was increased from 25.5 +/- 10.0 to 46.3 +/- 18.5 ml l(-1) (control and ATP, respectively, P < 0.05). With ATP, leg arterial-venous O(2) difference was decreased (P < 0.05) from 139.3 +/- 9.0 to 116.9 +/- 8.4(-1) and leg .VO(2max) was 20% lower compared to the control trial (1.1 +/- 0.2 versus 0.9 +/- 0.1 l min(-1)) (P = 0.069). In summary, at altitude, some degree of vasoconstriction is needed to match O(2) delivery with O(2) demand. Peak cardiac output at altitude is not limited by excessive mean arterial pressure. Exercising leg .VO(2peak) is not limited by restricted vasodilatation in the altitude-acclimatized human. 相似文献
77.
Paternal behavior is associated with an increase in prolactin levels in fish, birds and mammals, including rodents. The striped mouse (Rhabdomys pumilio) from southern Africa shows highly developed paternal care. We investigated whether striped mouse fathers have higher prolactin levels than nonfathers, and whether there is a relationship between tactile stimulation with pups and prolactin secretion in fathers. We measured serum prolactin in 42 male striped mice assigned to one of four different experimental groups (single males, paired males, fathers housed with mother and pups, and fathers separated from their family by a wire-mesh partition). Our results revealed no increases in prolactin levels in fathers, and fathers with tactile contact with pups did not have higher prolactin levels than the fathers that were prevented from making tactile contact with pups. In contrast, experienced males had higher prolactin levels than inexperienced males. Male striped mice are polygynous in nature, living in groups, with three breeding females, and are permanently associated with pups during the breeding season. In a field study, males had higher prolactin levels during the breeding season than during the nonbreeding season. Thus, prolactin secretion in the polygynous striped mouse might be regulated by environmental stimuli, whereas social stimuli might be important for monogamous species. This is the first study to demonstrate seasonal changes in prolactin levels in a free-living male mammal. 相似文献
78.
Leukocyte migration in synovial tissue. Leukocyte distribution, orientation, and migratory pattern after immune complex deposition in rabbit knee joints. 总被引:1,自引:0,他引:1
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Complement-activating bovine serum albumin (BSA)-anti-BSA immune complexes (ICs) were injected into rabbit knee joint cavities; the contralateral control joint was injected with BSA together with normal rabbit serum. The migration of leukocytes from the synovial venules into the joint cavity was analyzed with light microscopy (LM), scanning (SEM) and transmission (TEM) electron microscopy. EM autoradiography was used to study the endocytosis of ICs by leukocytes. The shape, orientation, and distribution of migrating polymorphonuclear granulocytes (PMNGs) were analyzed by LM morphometry. PMNGs accumulated in the joints injected with ICs. The peak of the number of PMNGs in the synovial tissue was reached after 4 hours, in the joint cavity after 6 hours. PMNGs in the synovial tissue were concentrated in the intimal layer. Migrating PMNGs were polarized, as judged by the ratio between the long (D max) and short (D min) axes of the cells. There was a close association between the migrating PMNGs and the collagen fibers. The morphometric data showed that the nonflattened, cylindrically-shaped PMNGs were oriented along the collagen bundles, running parallel to the synovial surface, and did not migrate in the straight direction of a theoretic leukotactic gradient originating in the joint cavity after IC deposition. SEM and TEM showed that the PMNGs were aligned along the collagen fibers and interacted activity with the collagen by pseudopods and cytoplasmic projections. EM autoradiography showed that the PMNGs in the joint cavity had ingested 125I-labeled ICs and were degranulated. In contrast, the PMNGs within the synovial membrane did not show any signs of IC endocytosis or any apparent degranulation. Synovial type A cells were found to contain ICs. This study indicates that the response of PMNGs in IC-induced synovitis consists of two distinct phases: an initial, mainly migratory phase in the synovial membrane where the PMNGs appear to use the collagen fibres as a climbing framework, and a second phase, in the joint cavity, characterized by PMNG metabolic activation, endocytosis of ICs, and degranulation. The apparent inability of PMNGs in the synovial membrane to ingest ICs and become degranulated might be due to not only concentration differences of ICs and leukotactic factors between the joint cavity and the synovial tissue but also might be related to the apparently active interaction with collagen. 相似文献
79.
Immunohistochemical and molecular analysis of p53, RB,and PTEN in malignant peripheral nerve sheath tumors 总被引:3,自引:0,他引:3
Mawrin C Kirches E Boltze C Dietzmann K Roessner A Schneider-Stock R 《Virchows Archiv : an international journal of pathology》2002,440(6):610-615
The molecular basis of both sporadic and neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNSTs) is yet largely undetermined. Therefore, we analyzed a series of 12 MPNSTs - including two cases which arose in the setting of NF1 - for molecular alterations in the p53, retinoblastoma ( Rb), and PTEN tumor suppressor genes. Furthermore, the immunohistochemical expression of p53, RB, and PTEN protein was examined in these tumors. One mutation (8%), an A to T transversion leading to an amino acid exchange, was found in exon 5 of the p53 gene in a sporadic MPNST. In two other sporadic tumors (20%), loss of heterozygosity (LOH) of the p53 gene occurred. Nuclear overexpression of p53 protein was observed in ten tumors (83%). Loss of RB protein expression was seen in two MPNSTs (17%), and LOH of the Rb gene was detected in four tumors (44%), including the two NF1-associated MPNSTs, one of them showing concomitant loss of RB protein expression. No mutation in the PTEN gene was detected, and cytoplasmic immunoreactivity for the PTEN protein was maintained in eight MPNSTs (67%). We suggest that alterations in the p53 and RB pathway, both are essential in controlling the cell-cycle progression, are critical points in the tumorigenesis of sporadic and NF1-associated MPNSTs, whereas the PTEN gene seems to play no significant role in this process. 相似文献
80.
Christensen P Kragh-Sørensen P Sørensen C Thomsen HY Iversen AD Christensen KS Hüttel M Tønnesen E 《Convulsive therapy》1986,2(3):145-150
Electroencephalogram-monitored electroconvulsive therapy (ECT) was carried out in 20 depressed inpatients. Before treatment, patients were randomly allocated to treatment using etomidate (Hypnomidat) (n = 10) or thiopentone (n = 10) for anesthesia. The groups were matched for sex, age, weight, and type and severity of depression. The seizure duration (seconds) was measured by electroencephalography (EEG), and the electrical energy (Joules, J) was determined for each treatment. A ratio of seizure duration:electrical energy (s/J) was computed. Both seizure duration and seizure duration:electrical energy were greater in the etomidate group than in the thiopentone group, whereas electrical energy did not differ significantly. The number of treatments in the etomidate group did not differ from that in the thiopentone group, as may be expected, perhaps because of the small size. 相似文献