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您的检索式：作者名="Xinmin You"
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| 1 | Mitochondrial malic enzyme 2 promotes breast cancer metastasis via stabilizing HIF-1α under hypoxia显示文摘Objective: α-ketoglutarate(α-KG) is the substrate to hydroxylate collagen and hypoxia-inducible factor-1α(HIF-1α), which are important for cancer metastasis. Previous studies have shown that the upregulation of collagen prolyl 4-hydroxylase in breast cancer cells stabilizes the expression of HIF-1α by depleting α-KG levels. We hypothesized that mitochondrial malic enzyme 2(ME2) might also affect HIF-1α expression via modulating α-KG levels in breast cancer cells.Methods: We evaluated ME2 protein expression in 100 breast cancer patients using immunohistochemistry and correlated with clinicopathological indicators. The effect of ME2 knockout on cancer metastasis was evaluated using an orthotopic breast cancer model. The effect of ME2 knockout or knockdown on the levels of α-KG and HIF-1α proteins in breast cancer cell lines was determined both in vitro and in vivo.Results: ME2 was found to be upregulated in the human breast cancerous tissues compared with the matched precancerous tissues(P<0.001). The elevated expression of ME2 was associated with a poor prognosis(P=0.019).ME2 upregulation was also related to lymph node metastasis(P=0.016), pathological staging(P=0.033), and vascular cancer embolus(P=0.014). Also, ME2 knockout significantly inhibited lung metastasis in vivo. In the tumors formed by ME2 knockout cells, the levels of α-KG were significantly increased and collagen hydroxylation level did not change significantly but HIF-1α protein expression was significantly decreased, compared to the control samples. In cell culture, cells with ME2 knockout or knockdown demonstrated significantly higher α-KG levels but significantly lower HIF-1α protein expression than control cells under hypoxia. Exogenous malate and α-KG exerted similar effect on HIF-1α in breast cancer cells to ME2 knockout or knockdown. Additionally,treatment with malate significantly decreased 4 T1 breast cancer lung metastasis. ME2 expression was associated with HIF-1α levels in human breast cancer samples(P=0.008).Conclusions: Our results provide evidence that upregulation of ME2 is associated with a poor prognosis of breast cancer patients and propose a mechanistic understanding of a link between ME2 and breast cancer metastasis. | Duo You Danfeng Du Xueke Zhao Xinmin Li Minfeng Ying Xun Hu | 2021 | Chinese Journal of Cancer Research2021，33，3： | 3 |
| 2 | Voltage-dependent blockade by bupivacaine of cardiac sodium channels expressed in Xenopus oocytes显示文摘Bupivacaine ranks as the most potent and efficient drug among class I local anesthetics, but its high potential for toxic reactions severely limits its clinical use.Although bupivacaine-induced toxicity is mainly caused by substantial blockade of voltage-gated sodium channels(VGSCs), how these hydrophobic molecules interact with the receptor sites to which they bind remains unclear.Nav1.5 is the dominant isoform of VGSCs expressed in cardiac myocytes, and its dysfunction may be the cause of bupivacainetriggered arrhythmia.Here, we investigated the effect of bupivacaine on Nav1.5 within the clinical concentration range.The electrophysiological measurements on Nav1.5 expressed in Xenopus oocytes showed that bupivacaine induced a voltageand concentration-dependent blockade on the peak of INa and the half-maximal inhibitory dose was 4.51 μmol/L.Consistent with other local anesthetics, bupivacaine also induced a use-dependent blockade on Nav1.5 currents.The underlying mechanisms of this blockade may contribute to the fact that bupivacaine not only dose-dependently affected the gating kinetics of Nav1.5 but also accelerated the development of its open-state slow inactivation.These results extend our knowledge of the action of bupivacaine on cardiac sodium channels, and therefore contribute to the safer and more efficient clinical use of bupivacaine. | Heng Zhang Hui Ji Zhirui Liu Yonghua Ji Xinmin You Gang Ding Zhijun Cheng | 2014 | Neuroscience Bulletin2014，30，4： | 0 |
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