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        NEDD8-activating enzyme inhibitor, MLN4924 (Pevonedistat) induces NOXA-dependent apoptosis through up-regulation of ATF-4

        Liu, Xiaojun,Jiang, Yanan,Wu, Jianfu,Zhang, Wenjuan,Liang, Yupei,Jia, Lijun,Yu, Jinha,Jeong, L.S.,Li, Lihui Elsevier 2017 Biochemical and biophysical research communication Vol. No.

        <P><B>Abstract</B></P> <P>It has been reported that MLN4924 can inhibit cell growth and metastasis in various kinds of cancer. We have reported that MLN4924 is able to inhibit angiogenesis through the induction of cell apoptosis both in vitro and in vivo models. Moreover, Neddylation inhibition using MLN4924 triggered the accumulation of pro-apoptotic protein NOXA in Human umbilical vein endothelial cells (HUVECs). However, the mechanism of MLN4924-induced NOXA up-regulation has not been addressed in HUVECs yet. In this study, we investigated how MLN4924 induced NOXA expression and cellular apoptosis in HUVECs treated with MLN4924 at indicated concentrations. MLN4924-induced apoptosis was evaluated by Annexin V-FITC/PI analysis and expression of genes associated with apoptosis was assessed by Quantitative RT-PCR and western blotting. As a result, MLN4924 triggered NOXA-dependent apoptosis in a dose-dependent manner in HUVECs. Mechanistically, inactivation of Neddylation pathway caused up-regulation of activating transcription factor 4 (ATF-4), a substrate of Cullin-Ring E3 ubiquitin ligases (CRL). NOXA was subsequently transactivated by ATF-4 and further induced apoptosis. More importantly, knockdown of ATF-4 by siRNA significantly decreased NOXA expression and apoptotic induction in HUVECs. In summary, our study reveals a new mechanism underlying MLN4924-induced NOXA accumulation in HUVECs, which may help extend further study of MLN4924 for angiogenesis inhibition treatment.</P> <P><B>Highlights</B></P> <P> <UL> <LI> MLN4924 triggered NOXA-dependent apoptosis in a dose-dependent manner in HUVECs. </LI> <LI> Inactivation of neddylation caused up-regulation of ATF4, a substrate of CRL. </LI> <LI> NOXA was transactivated by ATF4 and further induced apoptosis. </LI> <LI> Knockdown of ATF-4 significantly decreased NOXA expression and apoptotic induction. </LI> <LI> We revealed a new mechanism underlying MLN4924-induced NOXA accumulation in HUVECs. </LI> </UL> </P>

      • KCI등재

        Frequency-Dependent Effects on Bladder Reflex by Saphenous Nerve Stimulation and a Possible Action Mechanism of Tibial Nerve Stimulation in Cats

        Xing Li,Xiaoping Wan,Zhaoxia Wang,Yanan Liang,Zhuo Jia,Xu Zhang,Limin Liao 대한배뇨장애요실금학회 2021 International Neurourology Journal Vol.25 No.2

        Purpose: The present study determined the effects of saphenous nerve stimulation (SNS) at different stimulation frequencies on bladder reflex and explored a possible action mechanism of tibial nerve stimulation (TNS) on bladder activity in cats. Methods: Two bipolar nerve cuff electrodes were implanted on the saphenous nerve and the contralateral tibial nerve in 13 cats, respectively. Multiple cystometrograms were obtained to determine the effects of single SNS at different frequencies and that of combined SNS and TNS on the micturition reflex by infusing normal saline. Results: SNS at 1 Hz significantly reduced the bladder capacity (BC) to 59.8%±7.7% and 59.3%±5.8% of the control level at the intensity threshold (T) and 2T, respectively (P<0.05), while that at 20 Hz significantly increased the BC to 130.6%±4.2% of the control level at 6T (P<0.05). The TNS and SNS at 20 Hz did not significantly change the BCs at 1T (P>0.05), while combined stimulation at 1T significantly increased the BC to 122.7%±1.9% of the control level and induced an inhibitory effect which was similar to that TNS at 2T. Conclusions: The current study revealed that SNS reduced and increased BC depending on different stimulation frequencies. The combined SNS and TNS maximized the clinical efficacy at a low intensity. Also, SNS may be a potential therapeutic mechanism of TNS.

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        Measurement of elasticity of normal placenta using the Virtual Touch quantification technique

        Size Wu,Ruixia Nan,Yueping Li,Xiaojing Cui,Xian Liang,Yanan Zhao 대한초음파의학회 2016 ULTRASONOGRAPHY Vol.35 No.3

        Purpose: The aim of this study was to measure the elasticity of normal placentas using the VirtualTouch quantification (VTQ) technique. Methods: This study was approved by the Institutional Ethics Committee. Fifty randomly selected,healthy pregnant women in their second trimester and 50 randomly selected, healthy pregnantwomen in their third trimester with a single fetus were included, and their placentas underwentVTQ through shear wave velocity (SWV) measurements. The measurements were performed atdifferent locations to sample different areas of the placenta. Measurements were performed 3-4times in each location, the mean shear wave velocities were calculated without the highest andlowest values of measurements in each region, and the results were compared. Results: The SWV of the placenta was 0.983±0.260 m/sec, and the minimal and maximal speedwas 0.63 m/sec and 1.84 m/sec, respectively. There was no significant difference between thesecond and third trimester of VTQ of the placenta in terms of SWV (0.978±0.255 m/sec vs. 0.987±0.266 m/sec, P=0.711). The maternal age between second and third trimester was27.9±4.3 years and 29.2±4.4 years, respectively; there was no significant difference betweenthem (P=0.159). Conclusion: The results of this study show that the SWV of normal placenta tissue is 0.983±0.260m/sec, it has little variation between the second and third trimesters, and the VTQ technique maypotentially play an additional role in placenta evaluation.

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