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In recent years, the role of inhibitor kappa B kinaseβ (IKKβ) in the process of tumorigenesis has gradually been elucidated. IKK is involved in tumor cell proliferation and survival by acting on multiple molecular pathways. Inhibition of IKKβ has been identified as a promising treatment for cancer. Researchers have developed a series of IKKβ inhibitors and found that they can effectively inhibit tumor growth, but no IKKβ inhibitors have been used clinically to treat cancer. We discuss progress in understanding the role of IKKβ in tumorigenesis and review the recent development of main inhibitors of IKKβ.
ABSTRACT
Background Researches demonstrated that the long-term application of glucocorticoids can induce cataract. However, its molecular mechanism is unclear. Objective Present study was to investigate the effects of dexamethasone on the regulation of nuclear factor kappa B( NF-κB)/ inhibitor kappa B alpha( IκBα) line on human lens epithelial cells (LECs) and the LECs apoptosis. Methods Human LECs line(HLE2B3) were cultured and passaged in DMEM containing 20% fetal bovine serum and treated by different concentrations of dexamethasone(0. 01,0. 1,1,10,100 μmol/L) for 24,36 and 48 hours respectively. The LECs cultured in free-serum DMEM without dexamethasone were as blank control group. The expressions of IκBo: in the LECs were examined by reverse transcription polymerase chain reaction ( RT-PCR) and Western blot, and the expressions of NF-κB neucleoprotein in LECs were detected by Western blot after exposure to dexamethasone. The apoptosis rate of LECs was determined by flow cytometer. Results Agarose gel electrophoresis showed that the amplified gene fragment was coincident to designed one. The expressing level of NF-κB neucleoprotein in LECs was significantly lowed with the increase of dexamethasone concentration ( F = 36. 077 , P = 0. 004 ) , and that of IkBo: was evidently ascended ( F = 35. 741 ,P = 0. 002). In the same concentration of dexamethasone group,the expression of NF-κB in LECs showed the considerable alteration in different duration after treated of dexamethasone with the lowest expressing level in 36 hours, and significant differences were found in the expressing level between 24 hours and 36 hours ( P = 0. 002) and between 24 hours and 48 hours (P = 0. 01). The differences of expression of IκBá in LECs appeared the same pattern to NF-κB neucleoprotein. Flow cytometry showed that the apoptosis rate of LECs was obviously enhanced after action of dexamethasone in a dose-dependent manner, showing a significant difference among different groups ( F = 73. 261, P = 0.001). Conclusion It is implied that dexamethasone results in the pathogenesis and development of glucocorticoid cataract by up-regulating the expression of IκBα in LECs and suppressing the activity of NF-κB and herein induce the apoptosis of LECs at concentration-and time-dependent manner. This might be one of cellular and biological mechanisms of glucocorticoid cataract formation.
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Objective:To investigate the effects of methylprednisolone(MP)on pneumocyte apoptosis during lung ischemia/reperfusion injury in rats and to study the possible role of MP in pneumocyte apoptosis.Methods:Forty-two male Sprague-Dawley rats used for unilateral lung ischemia/reperfusion model were randomly divided into three groups:sham operation group(Sh group),ischemia/reperfusion group(I/R group),and methylprednisolone group(MP group).Each group has two subgroups of three hours and six hours.Apoptosis rate in lung tissue was detected by the way of Annexin-V-PI in flow cytometer.Expression of I?B-? in lung was observed by immunohistochemical stain.The index of quantitative assessment of histological lung injury(IQA),the wet to dry weight ratio(W/D),the pathological and ultrastructure changes of lung tissue were measured.Results:Apoptosis rate,W/D,IQA of lung tissue were significantly higher in I/R group than which in Sh group(P
ABSTRACT
Objective To investigate the inhibitory effects of intensive insulin on myocardium expression of tumor necrosis factor alpha(TNF-?)in severely burnt rats and its correlative mechanism.Methods In eighteen SD rats the right jugular vein and the left ventricle were cathetetized,and were divided into three groups randomly:(1)the sham burn group,the rats were treated by sham burn;(2)the burn group,the rats were inflicted with 30%TBSA Ⅲ degree burn,and then given fluid resuscitation routinely;(3)the intensive insulin group,the rats received intensive insulin treatment after burn,and the liquid volume given was equal to the burn group.The level of plasma glucose contents,the left ventricular systolic pressure(LVSP)and left ventricular end-diastolic pressure(LVEDP)were recorded at 1,2,3,4,5,6h after burn,and animals were sacrificed at 6 hours after burn.The level of TNF-? in myocardium tissue was assayed by ELISA,and mRNA expression was determined by real-time PCR.Western blot was used to detect I?B? phosphorylation and degradation in left ventricle tissue.Meanwhile,burn serum-challenged cardiomyocytes were also used to detect the levels of insulin and LY294002,a specific insulin activation inhibitor,on the phosphorylation of I?B?.Results The animals showed stress hyperglycemia after burns,the function of heart was damaged(LVSP degraded and LVEDP increased),the level of TNF and the expression of mRNA in the myocardium increased apparently,I?B? phosphorylation and degradation increased in left ventricle tissue and burn serum-challenged cardiomyocytes.Given the intensive insulin treatment to keep the blood glucose level between 4.5 to 5.2 mmol/L,the function of heart was significantly improved,the level of TNF-? was apparently lowered,and the I?B? phosphorylation and degradation were significantly decreased.LY294002 could abolish the inhibitory effect of insulin,and it acted on the I?B? phosphorylation on burn serum-challenged cardiomyocytes model.Conclusion Intensive insulin may decrease the activation of NF-?B through diminishing the I?B? phosphorylation and degradation,which inhibit the transcription and expression of TNF-? in myocardial cell,and improve the heart function accordingly.