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161.
162.
ASK1 associates with troponin T and induces troponin T phosphorylation and contractile dysfunction in cardiomyocytes 总被引:5,自引:0,他引:5
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He X Liu Y Sharma V Dirksen RT Waugh R Sheu SS Min W 《The American journal of pathology》2003,163(1):243-251
There is increasing support for the idea that excessive production of proinflammatory mediators such as tumor necrosis factor (TNF) and reactive oxygen species (ROS) contribute to the pathogenesis of cardiac dysfunction. However, the mechanisms by which cytokine/ROS production mediates cardiac dysfunction have not been established. Given that apoptosis signal-regulating kinase 1 (ASK1) is highly expressed in cardiac muscle and that ASK1 is an important mediator in the signaling pathways induced by tumor necrosis factor, interleukin-1, and ROS, we used the yeast two-hybrid system with ASK1 as bait to identify ASK1 substrates from a human heart cDNA library. The cDNA encoding the cardiac troponin T (cTnT) was isolated. ASK1 specifically interacted with cTnT, but not cTnI, in vitro and in vivo via the C-terminal ASK1 domain. ASK1 specifically phosphorylated cTnT in vitro and in vivo. Mutations in cTnT (T194/S198) at an ASK1-phosphorylation consensus sequence significantly reduced phosphorylation by ASK1. ROS-induced ASK1 activation, cTnT phosphorylation, and contractile dysfunction in cardiomyocytes showed similar kinetics. Moreover, overexpression of constitutively active ASK1 induces cTnT phosphorylation and inhibits shortening and calcium transient in adult cardiomyocytes. We conclude that ASK1 plays an important role in regulation of cardiac contractile function by phosphorylating cTnT and may participate in cytokine/ROS-induced pathogenesis of cardiomyopathy and heart failure. 相似文献
163.
Cloning, Expression, and Sequencing of a Cell Surface Antigen Containing a Leucine-Rich Repeat Motif from Bacteroides forsythus ATCC 43037 总被引:2,自引:0,他引:2
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Ashu Sharma Hakimuddin T. Sojar Ingrid Glurich Kiyonobu Honma Howard K. Kuramitsu Robert J. Genco 《Infection and immunity》1998,66(12):5703-5710
Bacteroides forsythus is a recently recognized human periodontopathogen associated with advanced, as well as recurrent, periodontitis. However, very little is known about the mechanism of pathogenesis of this organism. The present study was undertaken to identify the surface molecules of this bacterium that may play roles in its adherence to oral tissues or triggering of a host immune response(s). The gene (bspA) encoding a cell surface-associated protein of B. forsythus with an apparent molecular mass of 98 kDa was isolated by immunoscreening of a B. forsythus gene library constructed in a lambda ZAP II vector. The encoded 98-kDa protein (BspA) contains 14 complete repeats of 23 amino acid residues that show partial homology to leucine-rich repeat motifs. A recombinant protein containing the repeat region was expressed in Escherichia coli, purified, and utilized for antibody production, as well as in vitro binding studies. The purified recombinant protein bound strongly to fibronectin and fibrinogen in a dose-dependent manner and further inhibited the binding of B. forsythus cells to these extracellular matrix (ECM) components. In addition, adult patients with B. forsythus-associated periodontitis expressed specific antibodies against the BspA protein. We report here the cloning and expression of an immunogenic cell surface-associated protein (BspA) of B. forsythus and speculate that it mediates the binding of bacteria to ECM components and clotting factors (fibronectin and fibrinogen, respectively), which may be important in the colonization of the oral cavity by this bacterium and is also a target for the host immune response. 相似文献
164.
A conserved peptide sequence of the Plasmodium falciparum circumsporozoite protein and antipeptide antibodies inhibit Plasmodium berghei sporozoite invasion of Hep-G2 cells and protect immunized mice against P. berghei sporozoite challenge.
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Minutes after injection into the circulation, malaria sporozoites enter hepatocytes. The speed and specificity of the invasion process suggest that it is receptor mediated. The region II sequence of Plasmodium falciparum circumsporozoite (CS) protein includes a nonapeptide (WSPCSVTCG) which is highly conserved in all of the CS proteins sequenced to data, including the one from Plasmodium berghei. We have found that two peptides based on the P. falciparum region II sequence, P18 (EWSPCSVTCGNGIQVRIK) and P32 (IEQYLKKIKNS ISTEWSPCSVTCGNGIQVRIK), significantly inhibited P. berghei sporozoite invasion into Hep-G2 cells in vitro. This inhibition was enhanced if either peptide was preincubated with Hep-G2 cells prior to sporozoite invasion. We confirm that region II is a sporozoite ligand for the hepatocyte receptor; moreover, despite the few differences between P. falciparum and P. berghei region II sequences around the nonapeptide sequence (66% homology), the functional characteristics of the motif sequences are not affected. Since the conserved motifs represent a crucial sequence involved in Plasmodium sporozoite invasion of hepatocytes, antibodies to region II should inhibit sporozite invasion into hepatocytes. Indeed, we found that polyclonal antibodies generated to the P. falciparum-based peptide P32 inhibited P. berghei sporozoite invasion of Hep-G2 cells. Furthermore, inbred mice (C57BL/6) immunized with P32 were protected against a lethal challenge of P. berghei sporozoites. Our results suggest that the conserved region II of the CS protein contains crucial B- and T-cell epitopes, that such peptide sequences from the human malaria parasite P. falciparum can be screened in the P. berghei rodent model, and, finally, that region II can be considered useful as one of the components of a malaria vaccine. 相似文献
165.
Inhibition of interleukin-2 production by adherent cell factors from lepromatous leprosy patients. 总被引:1,自引:2,他引:1
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I Nath J Jayaraman M Sathish L K Bhutani A K Sharma 《Clinical and experimental immunology》1984,58(3):531-538
Twenty-four hour supernatants (MoF) were obtained from monocyte rich 2 h adherent cells of 19 leprosy patients and four healthy contacts. MoF from borderline and lepromatous patients produced 52-61% inhibition of human interleukin-2 (IL-2) production by a PHA conditioned T cell line (Jurkat). Non-adherent cell supernatants and MoF from tuberculoid and healthy individuals had little effect on IL-2 production. The suppression effected by MoF was in the first 12 h of initiation of PHA stimulated Jurkat cell cultures. Suppressive MoF did not interfere with (1) IL-2 release, (2) IL-2 utilization by Con A-induced T cell blasts or (3) constitutive proliferation of Jurkat cells. Such MoF were released spontaneously from adherent cells of bacilliferous leprosy patients but required in vitro antigen triggering in long term treated lepromatous patients. It is possible that the unresponsiveness associated with lepromatous leprosy is related to the inhibition of IL-2 production by suppressive factors, thereby, preventing the further expansion of antigen reactive T cells. 相似文献
166.
Loss of the O4 antigen moiety from the lipopolysaccharide of an extraintestinal isolate of Escherichia coli has only minor effects on serum sensitivity and virulence in vivo.
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The O-specific antigen in extraintestinal isolates of Escherichia coli is believed to be an important virulence factor. To assess its role in the pathogenic process, proven isogenic derivatives with either a complete (CP921) or nearly complete (CP920) deficiency of the O4 antigen were obtained by TnphoA'1-mediated transposon mutagenesis of an O4/K54/H5 blood isolate (CP9). By utilizing a previously reported isogenic K54 capsule-deficient derivative (CP9.137), additional isogenic derivatives deficient in both the K54 capsular antigen and either all (CP923) or nearly all (CP922) of the O4 antigen were also constructed. These strains and their wild-type parent were evaluated in vitro for serum sensitivity and in vivo by intraperitoneal challenge of outbred mice. The complete or nearly complete loss of the O4 antigen (CP920 and CP921) resulted in only a minor increase in serum sensitivity. In contrast, CP9.137 had a significant increase in serum sensitivity, and CP922 and CP923 were extremely serum sensitive. When tested in vivo, the complete or nearly complete loss of the O4 antigen resulted in a small but significant increase (P < or = 0.05), not the expected decrease, in virulence compared with its wild-type parent. In contrast, CP9.137 and CP922 were significantly less virulent (P < or = 0.05). These studies do not exclude a role for the O4 antigen moiety of lipopolysaccharide in the pathogenesis of extraintestinal E. coli infection; however, they demonstrate that the O4 antigen plays only a minor role in serum resistance in vitro and that its loss does not diminish and perhaps enhances the virulence of CP9 in vivo after intraperitoneal challenge. 相似文献
167.
168.
Kranenburg AR Willems-Widyastuti A Mooi WJ Saxena PR Sterk PJ de Boer WI Sharma HS 《The Journal of pathology》2005,206(1):28-38
An important feature of chronic obstructive pulmonary disease (COPD) is airway remodelling, the molecular mechanisms of which are poorly understood. In this study, the role of fibroblast growth factors (FGF-1 and FGF-2) and their receptor, FGFR-1, was assessed in bronchial airway wall remodelling in patients with COPD (FEV1 < 75%; n = 15) and without COPD (FEV1 > 85%; n = 16). FGF-1 and FGFR-1 were immunolocalized in bronchial epithelium, airway smooth muscle (ASM), submucosal glandular epithelium, and vascular smooth muscle. Quantitative digital image analysis revealed increased cytoplasmic expression of FGF-2 in bronchial epithelium (0.35 +/- 0.03 vs 0.20 +/- 0.04, p < 0.008) and nuclear localization in ASM (p < 0.0001) in COPD patients compared with controls. Elevated levels of FGFR-1 in ASM (p < 0.005) and of FGF-1 (p < 0.04) and FGFR-1 (p < 0.001) in bronchial epithelium were observed. In cultured human ASM cells, FGF-1 and/or FGF-2 (10 ng/ml) induced cellular proliferation, as shown by [3H]thymidine incorporation and by cell number counts. Steady-state mRNA levels of FGFR-1 were elevated in human ASM cells treated with either FGF-1 or FGF-2. The increased bronchial expression of fibroblast growth factors and their receptor in patients with COPD, and the mitogenic response of human ASM cells to FGFs in vitro suggest a potential role for the FGF/FGFR-1 system in the remodelling of bronchial airways in COPD. 相似文献
169.
170.
Quantitative Analysis of Mycobacterial and Propionibacterial DNA in Lymph Nodes of Japanese and European Patients with Sarcoidosis 总被引:10,自引:0,他引:10
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Yoshinobu Eishi Moritaka Suga Ikuo Ishige Daisuke Kobayashi Tetsuo Yamada Tamiko Takemura Touichiro Takizawa Morio Koike Shoji Kudoh Ulrich Costabel Josune Guzman Gianfranco Rizzato Marcello Gambacorta Ronald du Bois Andrew G. Nicholson Om P. Sharma Masayuki Ando 《Journal of clinical microbiology》2002,40(1):198-204
The cause(s) of sarcoidosis is unknown. Mycobacterium spp. are suspected in Europe and Propionibacterium spp. are suspected in Japan. The present international collaboration evaluated the possible etiological links between sarcoidosis and the suspected bacterial species. Formalin-fixed and paraffin-embedded sections of biopsy samples of lymph nodes, one from each of 108 patients with sarcoidosis and 65 patients with tuberculosis, together with 86 control samples, were collected from two institutes in Japan and three institutes in Italy, Germany, and England. Genomes of Propionibacterium acnes, Propionibacterium granulosum, Mycobacterium tuberculosis, Mycobacterium avium subsp. paratuberculosis, and Escherichia coli (as the control) were counted by quantitative real-time PCR. Either P. acnes or P. granulosum was found in all but two of the sarcoid samples. M. avium subsp. paratuberculosis was found in no sarcoid sample. M. tuberculosis was found in 0 to 9% of the sarcoid samples but in 65 to 100% of the tuberculosis samples. In sarcoid lymph nodes, the total numbers of genomes of P. acnes or P. granulosum were far more than those of M. tuberculosis. P. acnes or P. granulosum was found in 0 to 60% of the tuberculosis and control samples, but the total numbers of genomes of P. acnes or P. granulosum in such samples were less than those in sarcoid samples. Propionibacterium spp. are more likely than Mycobacteria spp. to be involved in the etiology of sarcoidosis, not only in Japanese but also in European patients with sarcoidosis. 相似文献