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A Kaushansky P G Metzger A N Douglass S A Mikolajczak V Lakshmanan H S Kain S HI Kappe 《Cell death & disease》2013,4(8):e762
Intracellular eukaryotic parasites and their host cells constitute complex, coevolved cellular interaction systems that frequently cause disease. Among them, Plasmodium parasites cause a significant health burden in humans, killing up to one million people annually. To succeed in the mammalian host after transmission by mosquitoes, Plasmodium parasites must complete intracellular replication within hepatocytes and then release new infectious forms into the blood. Using Plasmodium yoelii rodent malaria parasites, we show that some liver stage (LS)-infected hepatocytes undergo apoptosis without external triggers, but the majority of infected cells do not, and can also resist Fas-mediated apoptosis. In contrast, apoptosis is dramatically increased in hepatocytes infected with attenuated parasites. Furthermore, we find that blocking total or mitochondria-initiated host cell apoptosis increases LS parasite burden in mice, suggesting that an anti-apoptotic host environment fosters parasite survival. Strikingly, although LS infection confers strong resistance to extrinsic host hepatocyte apoptosis, infected hepatocytes lose their ability to resist apoptosis when anti-apoptotic mitochondrial proteins are inhibited. This is demonstrated by our finding that B-cell lymphoma 2 family inhibitors preferentially induce apoptosis in LS-infected hepatocytes and significantly reduce LS parasite burden in mice. Thus, targeting critical points of susceptibility in the LS-infected host cell might provide new avenues for malaria prophylaxis. 相似文献
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Yu‐Chiang Lai Chandana Kondapalli Ronny Lehneck James B Procter Brian D Dill Helen I Woodroof Robert Gourlay Mark Peggie Thomas J Macartney Olga Corti Jean‐Christophe Corvol David G Campbell Aymelt Itzen Matthias Trost Miratul MK Muqit 《The EMBO journal》2015,34(22):2840-2861
Mutations in the PTEN‐induced kinase 1 (PINK1) are causative of autosomal recessive Parkinson''s disease (PD). We have previously reported that PINK1 is activated by mitochondrial depolarisation and phosphorylates serine 65 (Ser65) of the ubiquitin ligase Parkin and ubiquitin to stimulate Parkin E3 ligase activity. Here, we have employed quantitative phosphoproteomics to search for novel PINK1‐dependent phosphorylation targets in HEK (human embryonic kidney) 293 cells stimulated by mitochondrial depolarisation. This led to the identification of 14,213 phosphosites from 4,499 gene products. Whilst most phosphosites were unaffected, we strikingly observed three members of a sub‐family of Rab GTPases namely Rab8A, 8B and 13 that are all phosphorylated at the highly conserved residue of serine 111 (Ser111) in response to PINK1 activation. Using phospho‐specific antibodies raised against Ser111 of each of the Rabs, we demonstrate that Rab Ser111 phosphorylation occurs specifically in response to PINK1 activation and is abolished in HeLa PINK1 knockout cells and mutant PINK1 PD patient‐derived fibroblasts stimulated by mitochondrial depolarisation. We provide evidence that Rab8A GTPase Ser111 phosphorylation is not directly regulated by PINK1 in vitro and demonstrate in cells the time course of Ser111 phosphorylation of Rab8A, 8B and 13 is markedly delayed compared to phosphorylation of Parkin at Ser65. We further show mechanistically that phosphorylation at Ser111 significantly impairs Rab8A activation by its cognate guanine nucleotide exchange factor (GEF), Rabin8 (by using the Ser111Glu phosphorylation mimic). These findings provide the first evidence that PINK1 is able to regulate the phosphorylation of Rab GTPases and indicate that monitoring phosphorylation of Rab8A/8B/13 at Ser111 may represent novel biomarkers of PINK1 activity in vivo. Our findings also suggest that disruption of Rab GTPase‐mediated signalling may represent a major mechanism in the neurodegenerative cascade of Parkinson''s disease. 相似文献
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【目的】为研究土壤细菌对蔬菜灰霉病的生防价值, 从辽宁、山东等地区的蔬菜种植基地采集土壤样本56份, 分离、筛选出对灰霉病具有稳定拮抗作用的细菌9株。【方法】采用平板对峙培养法进行初筛、复筛, 用抑菌圈法测定其抑菌效果, 并进行离体果实试验验证其对蔬菜灰霉病的防治效果, 通过形态学特征、生理生化特征及16S rRNA基因序列分析研究其分类地位。【结果】细菌CNY-04对蔬菜灰霉病的拮抗能力最强且遗传稳定, 抑菌圈直径达到34 mm; 初步鉴定该菌株为格氏沙雷菌(Serratia grimesii), 尚未见该菌在生防上的报道; CNY-04液体菌剂对离体番茄果实灰霉病的防效为69.23%, 50%多菌灵防效为75.39%, 24 h时接种CNY-04处理的番茄发病率为40.0%, 而48 h时接种处理的发病率为51.1%。【结论】CNY-04是一株较为理想的拮抗菌, 丰富了生防资源。 相似文献
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Davis C.; Campbell E. J.; Openshaw P.; Pride N. B.; Woodroof G. 《Journal of applied physiology》1980,48(4):695-701
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目的:观察非对称性二甲基精氨酸(ADMA)对内皮细胞中microRNA-21(miR-21)表达的影响,探讨microRNA-21在ADMA诱导的内皮细胞衰老中的作用。方法:人脐静脉内皮细胞(HUVEC)与10uM的ADMA孵育48小时后收集细胞提取总RNA及蛋白,荧光定量实时RT—PCR检测miR-21表达,Westernblot检测超氧化物歧化酶2(SOD2)表达,衰老相关半乳糖苷酶(SA-β-gal)染色鉴定衰老的内皮细胞;然后HUVEC与miR-21抑制剂转染6小时后继续与10uM的ADMA孵育48小时留取细胞按上述方法检测相关指标。结果:HUVEC与ADMA孵育后miR-21表达量明显增加(P〈0.01),同时衰老的内皮细胞数量增多(P〈0.05),而SOD2表达减少(P〈0.01);MiR-21抑制剂转染HUVEC后ADMA诱导的miR-21表达明显减少,同时衰老的内皮细胞减少,而SOD2表达明显增加(所有P〈0.01)。结论:ADMA诱导了HUVEC中miR-21表达及细胞衰老,miR-21介导了ADMA诱导的内皮细胞衰老作用,其机制可能与其抑制SOD2表达有关。 相似文献
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J E Fincham R Hewlett A S de Graaf J J Taljaard J G Steytler C J Rabie J V Seier F S Venter C W Woodroof S Wynchank 《Journal of medical primatology》1991,20(5):240-250
During recent historical times many Africans changed their diet to one based on maize. The grain is regularly contaminated by fungi which are toxigenic to domestic animals and birds. After one of the fungi, Diplodia maydis, in pure culture on maize, was added to the food of omnivorous primates there was demyelination of nerves, atrophy, degeneration and necrosis of muscle, and hepatitis. These preliminary results are applicable to veterinary and laboratory animal sciences. They may also be medically significant since neuromuscular syndromes of unknown cause are prevalent among Africans. Nerve conduction velocities and organ weights are defined for vervet monkeys. 相似文献
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Gabriela V Meirelles Júlio C Silva Yuri de A Mendonça Carlos HI Ramos Iris L Torriani Jörg Kobarg 《BMC structural biology》2011,11(1):12