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31.
32.
R L Mellgren 《The Journal of biological chemistry》1991,266(21):13920-13924
Purified calpains are capable of proteolyzing several high Mr nuclear proteins and solubilizing a histone H1 kinase activity from rat liver nuclei upon exposure to 10(-6) - 10(-5) M Ca2+. Major nuclear substrates displayed apparent molecular masses of 200, 130, 120, and 60 kDa on Coomassie Blue-stained SDS-PAGE gels. The nuclear proteins and the H1 kinase were released from Triton-treated nuclei following incubation with buffer containing 0.5 M NaCl. They therefore appeared to be internal nuclear matrix proteins. The nuclear H1 kinase activity solubilized by incubation with m-calpain was eluted in the void volume of a Bio-Gel A-1.5m column, indicating an apparent mass greater than 1,500 kDa. Treatment of the calpain-solubilized kinase with 0.5 M NaCl dissociated it to a form having an apparent mass of 300 kDa (Stokes radius = 5.6 nm), suggesting that the 300-kDa (Stokes radius = 5.6 nm), nuclei by calpain treatment as a large complex containing other internal matrix proteins. Purified human erythrocyte mu-calpain was capable of proteolyzing the nuclear matrix proteins at 10(-6) M Ca2+. In contrast, human erythrocyte multicatalytic protease complex produced little cleavage of the nuclear proteins. Proteolysis of nuclear proteins by either mu-calpain or m-calpain was inhibited by calpastatin. These experiments suggest a physiologic role for the calpains in the turnover of nuclear proteins. 相似文献
33.
On the mechanism of binding of calpastatin, the protein inhibitor of calpains, to biologic membranes 总被引:2,自引:0,他引:2
R L Mellgren 《Biochemical and biophysical research communications》1988,150(1):170-176
Bovine myocardial calpastatin, the endogenous inhibitor of the calcium-dependent proteinases, calpains, could bind to sarcoplasmic reticulum preparations at neutral pH and low ionic strength. Even in the presence of 100 to 200 mM KCl, 4 to 5 micrograms of calpastatin was bound per mg of membrane. Although calpastatin is found associated with bovine myocardial sarcolemma, neither canine nor human erythrocyte calpastatins were present in isolated erythrocyte membrane preparations. The bovine myocardial calpastatin, but not human erythrocyte calpastatin, could associate with purified phospholipid vesicles at low ionic strength. Thus, phospholipids appear to be involved in the binding of calpastatin to membranes. 相似文献
34.
35.
36.
Teng YK Verburg RJ Verpoort KN Diepenhorst GM Bajema IM van Tol MJ Jol-van der Zijde EC Toes RE Huizinga TW van Laar JM 《Arthritis research & therapy》2007,9(5):R106
In order to identify pathogenic correlates of refractory rheumatoid arthritis (RA), antibodies against anti-cyclic citrullinated
protein (ACPAs) were investigated in RA patients in whom the dysregulated immune system had been ablated by high-dose chemotherapy
(HDC) and autologous haematopoietic stem cell transplantation (HSCT). Six patients with refractory RA were extensively characterized
in terms of levels of total immunoglobulins, RA-specific autoantibodies (ACPAs and rheumatoid factor) and antibodies against
rubella, tetanus toxoid (TT) and phosphorylcholine before and after HDC plus HSCT. Additionally, the avidity of ACPAs was
measured before and after treatment and compared with the avidity of TT antibodies following repeated immunizations. Synovial
biopsies were obtained by arthroscopy before HDC plus HSCT, and analyzed by immunohistochemistry. In the three patients with
clinically long-lasting responses to HDC plus HSCT (median 423 days), significant reductions in ACPA-IgG levels after therapy
were observed (median level dropped from 215 to 34 arbitrary units/ml; P = 0.05). In contrast, stable ACPA-IgG levels were observed in three patients who relapsed shortly after HDC plus HSCT (median
of 67 days). Clinical responders had ACPA-IgG of lower avidity (r = 0.75; P = 0.08) and higher degree of inflammation histologically (r = 0.73; P = 0.09). Relapse (after 38 to 530 days) in all patients was preceded by rising levels of low avidity ACPA-IgG (after 30 to
388 days), in contrast to the stable titres of high avidity TT antibodies. In conclusion, humoral autoimmune responses were
differentially modulated by immunoablative therapy in patients with synovial inflammation and low avidity ACPA-IgG autoantibodies
as compared with patients with high levels of high avidity ACPA-IgG. The distinct clinical disease course after immunoablative
therapy based on levels and avidity of ACPA-IgG indicates that refractory RA is not a single disease entity. 相似文献
37.
Plant pathogenic bacteria, such as Pseudomonas syringae pv. tomato strain DC3000, the causative agent of tomato bacterial speck disease, grow to high levels in the apoplastic space between plant cells. Colonization of plant tissue requires expression of virulence factors that modify the apoplast to make it more suitable for pathogen growth or facilitate adaptation of the bacteria to the apoplastic environment. To identify new virulence factors involved in these processes, DC3000 Tn5 transposon insertion mutants with reduced virulence on Arabidopsis thaliana were identified. In one of these mutants, the Tn5 insertion disrupted the malate:quinone oxidoreductase gene (mqo), which encodes an enzyme of the tricarboxylic acid cycle. mqo mutants do not grow to wild-type levels in plant tissue at early time points during infection. Further, plants infected with mqo mutants develop significantly reduced disease symptoms, even when the growth of the mqo mutant reaches wild-type levels at late stages of infection. Mutants lacking mqo function grow more slowly in culture than wild-type bacteria when dicarboxylates are the only available carbon source. To explore whether dicarboxylates are important for growth of DC3000 in the apoplast, we disrupted the dctA1 dicarboxylate transporter gene. DC3000 mutants lacking dctA1 do not grow to wild-type levels in planta, indicating that transport and utilization of dicarboxylates are important for virulence of DC3000. Thus, mqo may be required by DC3000 to meet nutritional requirements in the apoplast and may provide insight into the mechanisms underlying the important, but poorly understood process of adaptation to the host environment.One important aspect of interactions between plant pathogens and their hosts is the ability of the pathogen to obtain nutrients within the plant tissue. Nutrient acquisition is essential for growth within the host, since both cell division and DNA replication can be influenced by nutrient availability. Bacterial plant pathogens differ in the strategies they use to get necessary nutrients during infection. Some pathogens, such as Agrobacterium tumefaciens, elicit production of specific carbon and nitrogen sources by the plant (1). Other pathogens may rely on metabolites that are readily available in the plant apoplast or may stimulate the release of water or nutrients from surrounding plant cells (27).Little is known about how pathogenic Pseudomonas syringae strains acquire nutrients when growing in their hosts. P. syringae strains are gram-negative gammaproteobacteria, which as a group cause disease on many agriculturally important plants. For example, P. syringae pv. tomato strain DC3000 causes disease on tomato, A. thaliana, and several agriculturally important Brassicas, such as turnip, mustard, collard, and cauliflower (8, 51). Initially, DC3000 colonizes plant surfaces and then enters the plant tissue through natural openings (such as stomata) or wounds (34, 38). DC3000 then establishes itself in the plant apoplast, the intercellular space between plant cells (38). Once in the apoplast of susceptible hosts, DC3000 multiplies to high levels, and the infected plants develop disease symptoms, including chlorosis (yellowing) of the leaf tissue and necrotic spots or patches called lesions (38, 49). Pseudomonads, such as P. aeruginosa and P. fluorescens, preferentially utilize tricarboxylic acid (TCA) cycle intermediates (20, 29, 33, 44), and DC3000 utilizes these carbon sources in culture (19). Some studies to investigate nutrient acquisition of DC3000 have been carried out (3, 7, 40); however, it is not clear what carbon sources DC3000 utilizes when growing in plant tissue.Several virulence factors are necessary for DC3000 to enter, grow inside the plant, and cause disease. Like many other bacterial pathogens, DC3000 uses a type III secretion system (TTSS) (15), which is encoded by the hrp/hrc genes, to inject effector proteins into plant cells (16, 27). Many of these effectors suppress host defenses, and it is likely that some may be involved in modulating the apoplastic environment or nutrient acquisition (16). DC3000 also produces the phytotoxin coronatine, which promotes entry of the bacteria into the plant apoplast by stimulating the opening of stomata (34) and is required for bacterial growth in the apoplast by suppressing salicylic acid (SA)-dependent host defenses (4, 45). Coronatine also promotes disease symptom development via an SA-independent mechanism (4). While much emphasis has been placed on exploring how type III-secreted effectors and coronatine promote DC3000 virulence, other factors are also likely to be important during pathogenesis.To identify additional factors involved in pathogenesis, we undertook a genetic screen to identify novel virulence factors (5, 24). DC3000 mutants with reduced virulence were identified by assaying for their ability to elicit disease symptoms on A. thaliana and tomato plants (24, 37). One of these mutants, AK4C9, had reduced virulence on both hosts. The gene disrupted in this mutant is the malate:quinone oxidoreductase gene (mqo), which encodes an enzyme of the TCA cycle. mqo mutants grow more slowly than wild-type DC3000 in planta and in culture when dicarboxylates are the only carbon source, suggesting that dicarboxylates are important for the growth of DC3000 in the apoplast. In the present study, we explore the role of Mqo and a dicarboxylate transporter, DctA1, in DC3000 pathogenesis. 相似文献
38.
Therese H. Røst Line L. Haugan Moi Kjetil Berge Bart Staels Gunnar Mellgren Rolf K. Berge 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2009,1791(11):1076-1083
Tetradecylthioacetic acid (TTA) is a hypolipidemic modified fatty acid and a peroxisome proliferator-activated receptor (PPAR) ligand. The mechanisms of TTA-mediated effects seem to involve the PPARs, but the effects have not been assigned to any specific PPAR subtype. PPARα−/− mice were employed to study the role of PPARα after TTA treatment. We also performed in vitro transfection assays to obtain mechanistic knowledge of how TTA affected PPAR activation in the presence of PPARγ coactivator (PGC)-1 and steroid receptor coactivators (SRC)-1 and SRC-2, which are associated with energy balance and mitochondrial biogenesis. We show that TTA increases hepatic fatty acid β-oxidation in PPARα−/− mice. TTA acts as a pan-PPAR ligand in vitro, and PGC-1, SRC-1 and SRC-2 have cell type and PPAR-specific effects together with TTA. In the absence of exogenous ligands, SRC-1 did not induce PPAR activity, while PGC-1 was the most potent PPAR coactivator. When the coactivators were overexpressed, pronounced effects of TTA were observed especially for PPARδ and PPARγ. We conclude that PPARα is involved in, but not required for, the hypolipidemic mechanisms of TTA. It appears that the activity of PPARδ, with substantial contribution of nuclear receptor coactivators, PGC-1 in special, is conducive to TTA's mechanism of action. 相似文献
39.
EM Tazi I Lalya MF Tazi Y Ahellal H M'rabti H Errihani 《World journal of surgical oncology》2010,8(1):1-3
Goblet cell carcinoid of the large intestine is a rare neoplasm, usually located in ascending colon and rectum. A 60-year-old male patient underwent surgery after the diagnosis of acute abdomen. Exploratory laparotomy revealed perforation with a diameter of 1 cm at the site of the previously performed gastroenterostomy and dilatation of the right colic flexure, secondary to a solid obstructive mass located in the mid-portion of transverse colon. Histopathological investigation of the biopsies, taken from the gastroenterostomy site and the tumor, revealed mixed carcinoid-adenocarcinoma with carcinoid component, predominantly composed of goblet cells. Three cycles of FOLFOX-4 protocol was administered. Following respiratory distress secondary to pulmonary metastasis, the patient's condition deteriorated and subsequently died in the fourth postoperative month. Our aim with this paper is to point out that more cases should be reported for more effective diagnosis, histopathological study, clinical investigation, treatment and prognosis of this specific neoplasm. 相似文献
40.
Irene EM Bultink 《Arthritis research & therapy》2010,12(1):107
Cardiovascular disease (CVD) has been identified as a major contributor to morbidity and mortality in patients with systemic
lupus erythematosus (SLE). The etiology of premature CVD in SLE is supposed to have many factors, including traditional coronary
artery disease (CAD) risk factors, antiphospholipid antibodies, and metabolic and inflammatory factors. Despite the overwhelming
interest in CVD in SLE research, prospective studies evaluating risk factors for hard endpoints (that is, cardiovascular events)
are relatively scarce. The article by Gustafsson and colleagues suggests that prothrombotic factors play an important role
in SLE-related CVD and that the influence of traditional CAD risk factors might be limited. 相似文献