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61.
Gresz V Kwon TH Gong H Agre P Steward MC King LS Nielsen S 《American journal of physiology. Gastrointestinal and liver physiology》2004,287(1):G151-G161
In vitro studies of cultured salivary gland cells and gland slices have indicated that there may be regulated translocation of aquaporin (AQP)-5 between the apical plasma membrane and intracellular compartments of the secretory cells. However, it remains unknown whether AQP-5 in salivary glands is subject to regulated trafficking in vivo. To examine this possibility, we have investigated the subcellular localization of AQP-5 in rat parotid and submandibular glands fixed in vivo under conditions of stimulated or inhibited salivary secretion. Immunofluorescence and immunoelectron microscopy was used to determine the subcellular distribution of AQP-5 in control conditions following the stimulation of secretion with pilocarpine (a muscarinic agonist) or epinephrine (an alpha-adrenoceptor agonist) or during inhibition of basal secretion with atropine (a muscarinic antagonist) or phentolamine (an alpha-adrenoceptor antagonist). Under control conditions, >90% of AQP-5 was associated with the apical plasma membrane of acinar and intercalated duct cells, with only rare gold particles associated with intracellular membrane domains. Pilocarpine treatment dramatically increased saliva production but had no discernible effect on AQP-5 distribution. However, the increased salivary secretion was associated with luminal dilation and the appearance of a markedly punctate AQP-5 labeling pattern due to clustering of AQP-5 at the microvilli (especially evident in the parotid gland) after 10 min of drug injection. No changes in the subcellular localization of AQP-5 were seen in response to epinephrine, atropine, or phentolamine treatment compared with control tissues. Thus AQP-5 is localized predominantly in the apical plasma membrane under control conditions, and neither the onset nor the cessation of secretion is associated in vivo with any significant short-term translocation of AQP-5 between intracellular structures and the apical plasma membrane. 相似文献
62.
Barabás O Rumlová M Erdei A Pongrácz V Pichová I Vértessy BG 《The Journal of biological chemistry》2003,278(40):38803-38812
Betaretroviruses encode dUTPase, an essential factor in DNA metabolism and repair, in the pro open reading frame located between gag and pol. Ribosomal frame-shifts during expression of retroviral proteins provide a unique possibility for covalent joining of nucleocapsid (NC) and dUTPase within Gag-Pro polyproteins. By developing an antibody against the prototype betaretrovirus Mason-Pfizer monkey virus dUTPase, we demonstrate that i) the NC-dUTPase fusion protein exists both within the virions and infected cells providing the only form of dUTPase, and ii) the retroviral protease does not cleave NC-dUTPase either in the virion or in vitro. We show that recombinant betaretroviral NC-dUTPase and dUTPase are both inefficient catalysts compared with all other dUTPases. Dynamic light scattering and gel filtration confirm that the homotrimeric organization, common among dUTPases, is retained in the NC-dUTPase fusion protein. The betaretroviral dUTPase has been crystallized and single crystals contain homotrimers. Oligonucleotide and Zn2+ binding is well retained in the fusion protein, which is the first example of acquisition of a functional nucleic acid binding module by the DNA repair factor dUTPase. Binding of the hexanucleotide ACTGCC or the octanucleotide (TG)4 to NC-dUTPase modulates enzymatic function, indicating that the low catalytic activity may be compensated by adequate localization. 相似文献
63.
In our Department we have studied the first line treatment of 90 stage IIIA-IV non-small cell lung cancer patients using gemcitabine/cisplatin combination. Thirteen cases have been unevaluable for various reasons. At the time of evaluation the planned 4 cycles have been delivered to 38% of patients (34/90). The PR was 39% (30/77), the CR was 2.6% (2/77) while the ORR was found to be 41% (32/77). 226 treatment cycles have been evaluated for side effects. There was no treatment-induced death in this series. CTC grade 3-4 neutropenia occurred in 5.7% of the cycles and only in 2 cases combined with fever. CTC grade 3-4 thrombocytopenia occurred in 4.4% of the cycles but only one patient required platelet suspension administration. Grade 3-4 anaemia developed in 3.5% of the cycles where 5 cases have been treated with RBC concentrate while 3 cases with erythropoietin. Complete alopecia occurred in 6 patients but 3 of them received brain irradiation as well. CTC grade 3-4 nausea and vomiting occurred in 4.4 and 3% of the cycles, respectively, but rehydration was only necessary in 3% of the cycles. Delay of the therapy due to hematological toxicity or vomiting occurred in 8% of the cycles but did not last longer than 2 weeks. Severe CTC grade 3-4 nephrotoxicity did not occur in this study while grade 1-2 elevation of serum creatinine level was found in 1.7% of the cycles. We have concluded that the gemcitabine/cisplatin combination is a safe outpatient modality for the first line treatment of advanced non-small cell lung cancer patients. 相似文献
64.
Miskolci V Castro-Alcaraz S Nguyen P Vancura A Davidson D Vancurova I 《Archives of biochemistry and biophysics》2003,417(1):44-52
Human neutrophils differ from other cells by containing high amount of IkappaBalpha in the nucleus, and this increased nuclear IkappaBalpha accumulation is associated with the inhibition of NFkappaB activity and increased apoptosis. However, the mechanisms regulating NFkappaB activation and IkappaBalpha degradation in human neutrophils are little understood. The objective of this study was to provide a further insight into the mechanisms regulating NFkappaB activity and IkappaBalpha degradation in human neutrophils. We show that okadaic acid (OA), an inhibitor of protein phosphatases PP1 and PP2A, induces sustained activation of NFkappaB and degradation of the nuclear IkappaBalpha, and increases interleukin-8 expression in the neutrophils. Furthermore, inhibitors of protein kinase C-delta (PKCdelta) and IkappaB kinase (IKK) inhibit the OA-induced activation of NFkappaB. Collectively, our results indicate that in human neutrophils, the sustained activation of NFkappaB is regulated by a continuous phosphorylation and degradation of the nuclear IkappaBalpha. 相似文献
65.
Peroxisome proliferator-activated receptor gamma ligands attenuate immunological symptoms of experimental allergic asthma 总被引:4,自引:0,他引:4
Mueller C Weaver V Vanden Heuvel JP August A Cantorna MT 《Archives of biochemistry and biophysics》2003,418(2):186-196
Asthma is characterized by a predominant T(H)2 type immune response to airborne allergens. Controlling T(H)2 cell function has been proposed as therapy for this disease. We show here that ligands for the nuclear receptor peroxisome proliferator activated receptor (PPAR)gamma significantly reduced the immunological symptoms of allergic asthma in a murine model of this disease. A PPARgamma ligand, 15-deoxy-delta(12,14)-prostaglandin J(2), significantly inhibited production of the T(H)2 type cytokine IL-5 from T cells activated in vitro. More importantly, in a murine model of allergic asthma, mice treated orally with ciglitazone, a potent synthetic PPARgamma ligand, had significantly reduced lung inflammation and mucous production following induction of allergic asthma. T cells from these ciglitazone treated mice also produced less IFNgamma, IL-4, and IL-2 upon rechallenge in vitro with the model allergen. Our results suggest that ligands for PPARgamma may be effective treatments for asthmatic patients. 相似文献
66.
Gyémánt G Kandra L Nagy V Somsák L 《Biochemical and biophysical research communications》2003,312(2):334-339
This study is the first report on the effectiveness and specificity of glucopyranosylidene-spiro-thiohydantoin (G-TH) inhibitor on the 2-chloro-4-nitrophenyl-4-O-beta-D-galactopyranosyl-maltoside (GalG(2)CNP) hydrolysis catalysed by human salivary alpha-amylase (HSA). The inhibition of hydrolysis is a mixed-noncompetitive type. In any case, only one molecule of inhibitor binds to HSA. Since our substrate and inhibitor are small molecules the long enough active site facilitates accommodating both of them simultaneously. However, the product formation can be excluded from enzyme-substrate-inhibitor complex (ESI) since Dixon plots are linear. Kinetic constants calculated from secondary plots and nonlinear regression are almost entirely equal, confirming the fidelity of the suggested model. Kinetic constants (K(1i)=7.3mM, L(1i)=2.84 mM) show that G-TH is not such a potent inhibitor of HSA as acarbose and indicate higher stability for ESI than for enzyme-inhibitor complex. 相似文献
67.
68.
Interleukin-2 is one of the targets of 1,25-dihydroxyvitamin D3 in the immune system 总被引:6,自引:0,他引:6
Bemiss CJ Mahon BD Henry A Weaver V Cantorna MT 《Archives of biochemistry and biophysics》2002,402(2):249-254
Interleukin (IL)-2 knockout (KO) mice, which spontaneously develop symptoms of inflammatory bowel disease similar to ulcerative colitis in humans, were made vitamin D deficient (D-) or vitamin D sufficient (D+) or were supplemented with 1,25-dihydroxyvitamin D(3) (1,25D3). 1,25-Dihydroxyvitamin D3 supplementation, but not vitamin D supplementation, reduced the early mortality of IL-2 KO mice. However, colitis severity was not different in D-, D+, or 1,25D3 IL-2 KO mice. Cells from D- IL-2 KO mice produced more interferon (IFN)-gamma than cells from all other mice. Con A-induced proliferation was upregulated in IL-2 KO mice and downregulated in wildtype (WT) mice fed 1,25D3. All other measured immune responses in cells from IL-2 KO mice were unchanged by vitamin D status. In vitro addition of 1,25-dihydroxyvitamin D3 significantly reduced the production of IL-10 and IFN-gamma in cells from D- and D+ WT mice. Conversely, IFN-gamma and IL-10 production in cells from IL-2 KO mice were refractory to in vitro 1,25-dihydroxyvitamin D3 treatments. In the absence of IL-2, vitamin D was ineffective for suppressing colitis and ineffective for the in vitro downregulation of IL-10 or IFN-gamma production. One target of 1,25-dihydroxyvitamin D3 in the immune system is the IL-2 gene. 相似文献
69.
The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy 总被引:36,自引:0,他引:36
Knöll R Hoshijima M Hoffman HM Person V Lorenzen-Schmidt I Bang ML Hayashi T Shiga N Yasukawa H Schaper W McKenna W Yokoyama M Schork NJ Omens JH McCulloch AD Kimura A Gregorio CC Poller W Schaper J Schultheiss HP Chien KR 《Cell》2002,111(7):943-955
Muscle cells respond to mechanical stretch stimuli by triggering downstream signals for myocyte growth and survival. The molecular components of the muscle stretch sensor are unknown, and their role in muscle disease is unclear. Here, we present biophysical/biochemical studies in muscle LIM protein (MLP) deficient cardiac muscle that support a selective role for this Z disc protein in mechanical stretch sensing. MLP interacts with and colocalizes with telethonin (T-cap), a titin interacting protein. Further, a human MLP mutation (W4R) associated with dilated cardiomyopathy (DCM) results in a marked defect in T-cap interaction/localization. We propose that a Z disc MLP/T-cap complex is a key component of the in vivo cardiomyocyte stretch sensor machinery, and that defects in the complex can lead to human DCM and associated heart failure. 相似文献
70.
Piekorz RP Hoffmeyer A Duntsch CD McKay C Nakajima H Sexl V Snyder L Rehg J Ihle JN 《The EMBO journal》2002,21(4):653-664
TACC3 is a centrosomal/mitotic spindle-associated protein that is highly expressed in a cell cycle-dependent manner in hematopoietic lineage cells. During embryonic development, TACC3 is expressed in a variety of tissues in addition to the hematopoietic lineages. TACC3 deficiency causes an embryonic lethality at mid- to late gestation involving several lineages of cells. Hematopoietic stem cells, while capable of terminal differentiation, are unable to be expanded in vitro or in vivo in reconstitution approaches. Although gross alterations in centrosome numbers and chromosomal segregation are not observed, TACC3 deficiency is associated with a high rate of apoptosis and expression of the p53 target gene, p21(Waf1/Cip1). Hematopoietic stem cell functions, as well as deficiencies in other cell lineages, can be rescued by combining the TACC3 deficiency with p53 deficiency. The results support the concept that TACC3 is a critical component of the centrosome/mitotic spindle apparatus and its absence triggers p53-mediated apoptosis. 相似文献