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981.
The effects of combined exposure to the checkpoint abrogator UCN-01 and pharmacologic MEK1/2 inhibitors were examined in human multiple myeloma (MM) cell lines. Treatment of RPMI8226, NCI-H929, and U266 MM cells with a minimally toxic concentration of UCN-01 (150 nM) for 24 hours resulted in mitogen-activated protein (MAP) kinase activation, an effect that was blocked by coadministration of the MEK1/2 inhibitor PD184352. These events were accompanied by enhanced activation of p34(cdc2) and a marked increase in mitochondrial damage (loss of DeltaPsim; cytochrome c and Smac/DIABLO (direct IAP binding protein with low pI) release), poly(ADP-ribose) polymerase (PARP) cleavage, and apoptosis. PD184352/UCN-01 also dramatically reduced clonogenic survival in each of the MM cell lines. In contrast to As(2)0(3), apoptosis induced by PD184352/UCN-01 was not blocked by the free-radical scavenger N-acetyl-L-cysteine. Whereas exogenous interleukin 6 substantially prevented dexamethasone-induced lethality in MM cells, it was unable to protect them from PD184352/UCN-01-induced apoptosis despite enhancing Akt activation. Insulinlike growth factor 1 (IGF-1) also failed to diminish apoptosis induced by this drug regimen. MM cell lines selected for a high degree of resistance to doxorubicin, melphalan, or dexamethasone, or displaying resistance secondary to fibronectin-mediated adherence, remained fully sensitive to PD184352/UCN-01-induced cell death. Finally, primary CD138(+) MM cells were also susceptible to UCN-01/MEK inhibitor-mediated apoptosis. Together, these findings suggest that simultaneous disruption of cell cycle and MEK/MAP kinase signaling pathways provides a potent stimulus for mitochondrial damage and apoptosis in MM cells, and also indicate that this strategy bypasses the block to cell death conferred by several other well-described resistance mechanisms. 相似文献
982.
Dai H Chen Y Chen S Mao Q Kennedy D Landback P Eyre-Walker A Du W Long M 《Proceedings of the National Academy of Sciences of the United States of America》2008,105(21):7478-7483
New genes can originate by the combination of sequences from unrelated genes or their duplicates to form a chimeric structure. These chimeric genes often evolve rapidly, suggesting that they undergo adaptive evolution and may therefore be involved in novel phenotypes. Their functions, however, are rarely known. Here, we describe the phenotypic effects of a chimeric gene, sphinx, that has recently evolved in Drosophila melanogaster. We show that a knockout of this gene leads to increased male-male courtship in D. melanogaster, although it leaves other aspects of mating behavior unchanged. Comparative studies of courtship behavior in other closely related Drosophila species suggest that this mutant phenotype of male-male courtship is the ancestral condition because these related species show much higher levels of male-male courtship than D. melanogaster. D. melanogaster therefore seems to have evolved in its courtship behaviors by the recruitment of a new chimeric gene. 相似文献
983.
目的:研究复方中药对非酒精性脂肪肝肝细胞色素P450ⅡE1表达的影响。方法:用高脂饲料诱导大鼠脂肪肝模型,同时给于复方中药干预,观察肝组织病理形态的变化和肝细胞色素P450ⅡE1的表达,测定肝MDA和SOD、GSH、Vit E以及TG含量的变化,并与对照组比较。结果:中药组的肝组织脂肪变性基本恢复正常.免疫组化证明复方中药能显著抑制脂肪肝肝细胞色素P450ⅡE1的表达,同时肝内MDA和SOD、GSH、Vit E及TG的含量回复到接近正常,结论:该复方中药能显著抑制脂肪肝肝细胞色素P450ⅡE1表达.因而具有防止脂肪肝的作用 相似文献
984.
Zeyi Li Shuang Zhao Keping Chen Yangang Su Wei Hua Silin Chen Zhaoguang Liang Wei Xu Yan Dai Xiaohan Fan Ruohan Chen Shu Zhang 《Journal of electrocardiology》2018,51(5):898-905
Background
Premature ventricular complex (PVC) was mainly studied by 24-hour Holter in previous studies. However, the value of long-term Home Monitoring of PVC burden early after ICD implantation is unknown.Methods
The data of 416 patients with ICD were analyzed. The percentage of days with frequent PVC (≥10/h) within 30th–90th days was calculated as the continuous frequent PVC (CfPVC) percentage. ROC curve of CfPVC percentages was plotted. Kaplan-Meier survival and Cox regression were used to assess the cumulative risks.Results
Based on ROC curves, the cut-off value for the CfPVC percentage was 40%. According to Kaplan-Meier analysis and multivariate Cox regression analysis, CfPVC percentage ≥40% was an independent predictor of higher incidences of VAEs, appropriate ATP, appropriate shocks, and cardiac death.Conclusion
A long-term continuous burden of frequent PVC with CfPVC percentage ≥40% can be a predictor of future VAEs, appropriate ATP, appropriate shocks and cardiac death in ICD recipients. 相似文献985.
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990.
Yun-Jian Dai ;Zheng-Hao Xu ;Bo Feng ;Ceng-Lin Xu ;Hua-Wei Zhao ;Deng-Chang Wu ;Wei-Wei Hu ;Zhong Chen 《神经科学通报》2014,(6):913-922
Gender differences are involved in many neurological disorders including epilepsy. However, little is known about the effect of gender difference on the risk of epilepsy in adults with a specific early pathological state such as complex febrile seizures(FSs) in infancy. Here we used a well-established complex FS model in rats and showed that:(1) the susceptibility to seizures induced by hyperthermia, pentylenetetrazol(PTZ), and maximal electroshock(MES) was similar in male and female rat pups, while males were more susceptible to PTZ- and MES-induced seizures than age-matched females in normal adult rats;(2) adult rats with complex FSs in infancy acquired higher seizure susceptibility than normal rats; importantly, female FS rats were more susceptible to PTZ and MES than male FS rats; and(3) the protein expression of interleukin-1β, an infl ammatory factor associated with seizure susceptibility, was higher in adult FS females than in males, which may reflect a gender-difference phenomenon of seizure susceptibility. Our results provide direct evidence that the acquired seizure susceptibility after complex FSs is gender-dependent. 相似文献