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1.
Ge F Yao J Fu X Guo Z Yan J Zhang B Zhang H Tomozawa H Miyazaki J Sawashita J Mori M Higuchi K 《Laboratory investigation; a journal of technical methods and pathology》2007,87(7):633-643
In mice, apolipoprotein A-II (apoA-II) self-associates to form amyloid fibrils (AApoAII) in an age-associated manner. We postulated that the two most important factors in apoA-II amyloidosis are the Apoa2(c) allele, which codes for the amyloidogenic protein APOA2C (Gln5, Ala38) and transmission of amyloid fibrils. To characterize further the contribution of the Apoa2(c) allele to amyloidogenesis and improve detection of amyloidogenic materials, we established transgenic mice that overexpress APOA2C protein under the cytomegalovirus (CMV) immediate early gene (CMV-IE) enhancer/chicken beta promoter. Compared to transgene negative (Tg(-/-)) mice that express apoA-II protein mainly in the liver, mice homozygous (Tg(+/+)) and heterozygous (Tg(+/-)) for the transgene express a high level of apoA-II protein in many tissues. They also have higher plasma concentrations of apoA-II, higher ratios of ApoA-II/apolipoprotein A-I (ApoA-I) and higher concentrations of high-density lipoprotein (HDL) cholesterol. Following injection of AApoAII fibrils into Tg(+/+) mice, amyloid deposition was observed in the testis, liver, kidney, heart, lungs, spleen, tongue, stomach and intestine but not in the brain. In Tg(+/+) mice, but not in Tg(-/-) mice, amyloid deposition was induced by injection of less than 10(-8) mug AApoAII fibrils. Furthermore, deposition in Tg(+/+) mice occurred more rapidly and to a greater extent than in Tg(-/-) mice. These studies indicate that increased levels of APOA2C protein lead to earlier and greater amyloid deposition and enhanced sensitivity to the transmission of amyloid fibrils in transgenic mice. This transgenic mouse model should prove valuable for studies of amyloidosis. 相似文献
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Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes 总被引:11,自引:0,他引:11
Graham J Hagopian WA Kockum I Li LS Sanjeevi CB Lowe RM Schaefer JB Zarghami M Day HL Landin-Olsson M Palmer JP Janer-Villanueva M Hood L Sundkvist G Lernmark A Breslow N Dahlquist G Blohmé G;Diabetes Incidence in Sweden Study Group;Swedish Childhood Diabetes Study Group 《Diabetes》2002,51(5):1346-1355
Age-dependent associations between type 1 diabetes risk genes HLA, INS VNTR, and CTLA-4 and autoantibodies to GAD65 (GADAs), ICA512/IA-2, insulin, and islet cells were determined by logistic regression analysis in 971 incident patients with type 1 diabetes and 702 control subjects aged 0-34 years. GADAs were associated with HLA-DQ2 in young but not in older patients (P = 0.009). Autoantibodies to insulin were negatively associated with age (P < 0.0001) but positively associated with DQ8 (P = 0.03) and with INS VNTR (P = 0.04), supporting possible immune tolerance induction. ICA512/IA-2 were negatively associated with age (P < 0.0001) and with DQ2 (P < 0.0001) but positively associated with DQ8 (P = 0.04). Males were more likely than females to be negative for GADA (P < 0.0001), autoantibodies to islet cells (P = 0.04), and all four autoantibody markers (P = 0.004). The CTLA-4 3' end microsatellite marker was not associated with any of the autoantibodies. We conclude that age and genetic factors such as HLA-DQ and INS VNTR need to be combined with islet autoantibody markers when evaluating the risk for type 1 diabetes development. 相似文献
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Horikawa Y Otaka M Komatsu K Jin M Odashima M Wada I Matsuhashi T Ohba R Oyake J Hatakeyama N Dubois RN Watanabe S 《Digestive diseases and sciences》2007,52(10):2757-2765
Resistance to chemotherapeutic agents is one of the distinct features of cancer cells. We evaluate the role of activated MEK-ERK
signaling in Camptotecin/irinotecan (CPT-11)-induced cell death using constitutively activated MEK1-transfected normal rat
intestinal epithelial cells (IEC-caMEK cells). A CPT-11-induced inhibitory concentration of 50% was determined by WST assay.
Apoptosis was evaluated by DNA staining and fragmented DNA analysis. Protein expressions were analyzed by western blotting.
We also examined the role of cyclooxygenase-2 in the cell systems. IEC-caMEK cells possessed survival advantages compared
to control cells. Apoptosis was remarkably suppressed in IEC-caMEK cells. Western blot analysis revealed increased expression
of Bcl-2, Bcl-xL, Mcl-1, and COX-2 and decreased expression of Bak in IEC-caMEK cells. The COX-2 selective inhibitor ameliorated
the antiapoptotic nature of IEC-caMEK cells. MEK activation suppressed CPT-11-induced apoptosis in IEC-caMEK cells via a COX-2-
dependent mechanism. Therefore, MEK-ERK signaling may contribute to the drug-resistant nature of cancer cells. 相似文献
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BACKGROUND: Subinhibitory concentrations of mupirocin can suppress flagellar formation in Pseudomonas aeruginosa. In this study, we evaluated the effect of mupirocin on biofilm formation in P. aeruginosa. METHODS: P. aeruginosa PAO-1 (MIC, >1,024 microg/ml for mupirocin) was used. Viable bacteria adhering or forming biofilm on a Cell Desk were counted and observed by scanning electron microscopy. RESULTS: With or without continuous exposure to 256 microg/ml of mupirocin, counts of adherent and/or biofilm-forming bacteria showed no difference until day 10. Whereas biofilm formation with glycocalyx was observed on day 6-10 without mupirocin, mupirocin reduced biofilm formation and glycocalyx production for 10 days. CONCLUSIONS: Subinhibitory concentrations of mupirocin can reduce biofilm formation in vitro in P. aeruginosa. 相似文献
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Odashima M Otaka M Jin M Komatsu K Wada I Matsuhashi T Horikawa Y Hatakeyama N Oyake J Ohba R Linden J Watanabe S 《Journal of gastroenterology and hepatology》2005,20(2):275-280
BACKGROUND: Activation of adenosine A(2A) receptors reduces the production of various pro-inflammatory cytokines and suppresses neutrophil activation. Water-immersion restraint is well known to cause gastric mucosal lesions due to stress. The pathogenesis of stress-induced gastric mucosal lesions is characterized by activation of inflammatory cells and production of inflammatory cytokines. Agonists of adenosine A(2A) receptors are known to be anti-inflammatory, but the effects of these compounds on the development of gastric mucosal lesions has not been reported. In the present study, the effect of a potent and selective adenosine A(2A) receptor agonist, ATL-146e, on water-immersion stress-induced gastric mucosal lesions was studied. METHODS: Rats were subjected to water-immersion stress with or without pretreatment with a single intraperitoneal injection of a potent and selective agonist of the adenosine A(2A) receptor. The gastric concentrations of myeloperoxidase (MPO), as an index of neutrophil accumulation, and the pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), were measured. RESULTS: The total length of gastric erosions (ulcer index) in control rats was 21.6 +/- 3.23 mm and was reduced by 86% to 3.1 +/- 0.83 mm by pretreatment with 5.0 microg/kg ATL146e (P < 0.001). The gastric content of MPO, TNF-alpha and IL-1beta were all increased after water-immersion stress and reduced to near normal levels by ATL-146e. CONCLUSION: A specific adenosine A(2A) agonist inhibits stress-induced gastric inflammation and damage. A(2A) agonist compounds may be useful for preventing ulcers and appear to act by blocking gastric inflammation. 相似文献
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Lanosterol synthase mutations cause cholesterol deficiency-associated cataracts in the Shumiya cataract rat
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Mori M Li G Abe I Nakayama J Guo Z Sawashita J Ugawa T Nishizono S Serikawa T Higuchi K Shumiya S 《The Journal of clinical investigation》2006,116(2):395-404
The Shumiya cataract rat (SCR) is a hereditary cataractous strain. It is thought that the continuous occurrence of poorly differentiated epithelial cells at the bow area of the lens forms the pathophysiological basis for cataract formation in SCRs. In this study, we attempted to identify the genes associated with cataract formation in SCRs by positional cloning. Genetic linkage analysis revealed the presence of a major cataract locus on chromosome 20 as well as a locus on chromosome 15 that partially suppressed cataract onset. Hypomorphic mutations were identified in genes for lanosterol synthase (Lss) on chromosome 20 and farnesyl diphosphate farnesyl transferase 1 (Fdft1) on chromosome 15, both of which function in the cholesterol biosynthesis pathway. A null mutation for Lss was also identified. Cataract onset was associated with the specific combination of Lss and Fdft1 mutant alleles that decreased cholesterol levels in cataractous lenses to about 57% of normal. Thus, cholesterol insufficiency may underlie the deficient proliferation of lens epithelial cells in SCRs, which results in the loss of homeostatic epithelial cell control of the underlying fiber cells and eventually leads to cataractogenesis. These findings may have some relevance to other types of cataracts, inborn defects of cholesterol synthesis, and the effects of cholesterol-lowering medication. 相似文献
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The brains of rats injected intravenously with65ZnCl2 or54MnCl2 were subjected to high resolution autoradiography.65Zn and54Mn were largely concentrated in choroid plexus 1 h after injection and then gradually decreased, with increases in other brain regions, suggesting that both metals were taken up gradually into brain mainly via cerebrospinal fluid in the choroid plexus. By 3 days after injection, relatively high level of65Zn was seen in the dentate gyrus and CA3 region of the hippocampus and in the cerebral cortex. The level of54Mn was also high in the former, while relatively low in the latter. 相似文献