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随着我国经济的发展以及居民生活水平的提高,越来越多的人来到高原生活、工作和旅游,但由于高原地区氧分压较低,高原病的发病率呈现逐年上升的趋势[1]。高原脑水肿(HACE)是高原病发生发展过程中最为严重的阶段,其临床表现为头痛、协调丧失、虚弱、意识水平降低[2],并对机体造成不可逆的损伤。7-羟乙基白杨素(7-hydroxyethyl chrysin,7-HEC)是课题组前期筛选发现并合成的具有自主知识产权的抗高原缺氧化合物[3],研究发现[4-5],其对脑缺血再灌注大鼠和模拟高原低压性缺氧致脑组织损伤大鼠均具有明显的保护作用,并能够减轻低压低氧诱导的认知功能损伤[6],在抗高原缺氧方面表现出优异的活性与前景。因此,本文主要从7-HEC对高原脑水肿的可能作用机制出发,探究其与自噬、周期、凋亡等通路之间的关系,为防治高原脑水肿的可能作用机制奠定基础。
A preliminary study on the mechanism of 7-HEC on high altitude cerebral edema
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摘要:
目的 研究7-羟乙基白杨素(7-HEC)对高原脑水肿(HACE)的可能作用机制。 方法 建立大鼠高原脑水肿模型,测定大鼠脑组织中超氧化物歧化酶(SOD)的活性及丙二醛(MDA)的含量,采用蛋白质印迹法检测细胞凋亡、周期及自噬相关蛋白的表达水平,探究7-HEC对高原脑水肿的保护作用及其机制。 结果 与对照组相比,缺氧模型组大鼠脑组织中MDA含量显著上调,SOD活力显著下调,周期蛋白CyclinD1、CyclinE1、CDK6、CDK2,凋亡蛋白Bcl-2、PARP,自噬蛋白LC3-B相对表达下调,凋亡蛋白Bax,自噬蛋白P62的相对表达上调,差异均具有统计学意义(P<0.05);与缺氧模型组相比,7-HEC给药组MDA含量下调,SOD活力显著上调,周期蛋白CyclinD1、CyclinE1、CDK6、CDK2,凋亡蛋白Bcl-2、PARP,自噬蛋白LC3-B的相对表达上调,凋亡蛋白Bax,自噬蛋白P62的相对表达下调,差异均具有统计学意义(P<0.05)。 结论 7-HEC对高原脑水肿具有一定的保护作用,其机制可能与调控细胞周期、自噬、凋亡以及氧化应激等通路有关。 Abstract:Objective To study the possible mechanism of 7-hydroxyethyl chrysin (7-HEC) on high altitude cerebral edema (HACE). Methods A rat model of high altitude cerebral edema was established. The activity of superoxide dismutase (SOD) and the content of malondialdehyde (MDA) in rat brain tissues were measured. The expression levels of apoptosis, cell cycle and autophagy related proteins were detected by Western blotting to explore the protective effect of 7-HEC on high altitude cerebral edema and its mechanism. Results Compared with the control group, the content of MDA in the brain tissue of the hypoxia model group was significantly up-regulated; the activity of SOD was significantly down-regulated, the relative expression of CyclinD1, CyclinE1, CDK6 and CDK2, apoptotic proteins Bcl-2, PARP, and autophagy protein LC3-B were down-regulated; and the relative expression of apoptotic protein Bax and autophagy protein P62 were up-regulated; the difference was statistically significant (P<0.05); Compared with the hypoxia model group, the content of MDA was down-regulated and the activity of SOD was significantly up-regulated in the 7-HEC administration group. The relative expression of CyclinD1, CyclinE1, CDK6, CDK2, apoptotic proteins Bcl-2, PARP, autophagy protein LC3-B was up-regulated and the relative expression of apoptotic proteins Bax and the relative expression of autophagy protein P62 was down-regulated in the 7-HEC administration group. The difference was statistically significant (P<0.05). Conclusion 7-HEC has a certain protective effect on high altitude cerebral edema, and its mechanism may be related to the regulation of cell cycle, autophagy, apoptosis and oxidative stress pathways. -
Key words:
- high altitude cerebral edema /
- oxidative stress /
- apoptosis /
- cycle /
- autophagy
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[1] 邱友竹, 王旭萍. 急进高原环境对血管内皮功能的影响及其与急性高原病的关系[J]. 高原医学杂志, 2016, 26(4):11. [2] MACINNIS M J, KOEHLE M S. Evidence for and against genetic predispositions to acute and chronic altitude illnesses[J]. High Alt Med Biol,2016,17(4):281-293. doi: 10.1089/ham.2016.0024 [3] 马慧萍, 景临林, 樊鹏程, 等. 7-羟乙基白杨素的合成方法及其在制备抗缺氧药物中的应用: CN104926769B[P]. 2018-12-04. [4] 吴金华. 白杨素及羟乙基白杨素对急慢性脑缺血大鼠的保护作用[D]. 兰州: 兰州大学, 2015. [5] 景临林, 杨颖, 邵瑾, 等. 7-羟乙基白杨素对低压低氧致脑组织损伤的保护作用[J]. 中国现代应用药学, 2020, 37(9):1025-1029. doi: 10.13748/j.cnki.issn1007-7693.2020.09.001 [6] 景临林, 杨颖, 邵瑾, 等. 7-羟乙基白杨素对低压低氧大鼠认知功能的保护作用及机制研究[J]. 中国医院药学杂志, 2020, 40(15):1622-1626. doi: 10.13286/j.1001-5213.2020.15.05 [7] JING L L, WU N Z, HE L, et al. Establishment of an experimental rat model of high altitude cerebral edema by hypobaric hypoxia combined with temperature fluctuation[J]. Brain Res Bull,2020,165:253-262. doi: 10.1016/j.brainresbull.2020.10.017 [8] CHENG Y J, CHEN B, XIE W Q, et al. Ghrelin attenuates secondary brain injury following intracerebral hemorrhage by inhibiting NLRP3 inflammasome activation and promoting Nrf2/ARE signaling pathway in mice[J]. Int Immunopharmacol,2020,79:106180. doi: 10.1016/j.intimp.2019.106180 [9] DONG Y S, WANG J L, FENG D Y, et al. Protective effect of quercetin against oxidative stress and brain edema in an experimental rat model of subarachnoid hemorrhage[J]. Int J Med Sci,2014,11(3):282-290. doi: 10.7150/ijms.7634 [10] LIU T H, WU Y F, DONG X L, et al. Identification and characterization of the BmCyclin L1-BmCDK11A/B complex in relation to cell cycle regulation[J]. Cell Cycle,2017,16(9):861-868. doi: 10.1080/15384101.2017.1304339 [11] FARSHADI E, YAN J, LECLERE P, et al. The positive circadian regulators CLOCK and BMAL1 control G2/M cell cycle transition through Cyclin B1[J]. Cell Cycle,2019,18(1):16-33. doi: 10.1080/15384101.2018.1558638 [12] TEMEL Y, KUCUKLER S, YıLDıRıM S, et al. Protective effect of chrysin on cyclophosphamide-induced hepatotoxicity and nephrotoxicity via the inhibition of oxidative stress, inflammation, and apoptosis[J]. Naunyn Schmiedebergs Arch Pharmacol,2020,393(3):325-337. doi: 10.1007/s00210-019-01741-z [13] ZHANG L, FEI M X, WANG H D, et al. Sodium aescinate provides neuroprotection in experimental traumatic brain injury via the Nrf2-ARE pathway[J]. Brain Res Bull,2020,157:26-36. doi: 10.1016/j.brainresbull.2020.01.019 [14] DHUPPAR S, MAZUMDER A. Measuring cell cycle-dependent DNA damage responses and p53 regulation on a cell-by-cell basis from image analysis[J]. Cell Cycle,2018,17(11):1358-1371. doi: 10.1080/15384101.2018.1482136 [15] ZI D, ZHOU Z W, YANG Y J, et al. Danusertib induces apoptosis, cell cycle arrest, and autophagy but inhibits epithelial to mesenchymal transition involving PI3K/Akt/mTOR signaling pathway in human ovarian cancer cells[J]. Int J Mol Sci,2015,16(11):27228-27251. doi: 10.3390/ijms161126018 [16] WANG J L, WANG J J, CAI Z N, et al. The effect of curcumin on the differentiation, apoptosis and cell cycle of neural stem cells is mediated through inhibiting autophagy by the modulation of Atg7 and p62[J]. Int J Mol Med,2018,42(5):2481-2488. [17] URANO Y, MORI C, FUJI A, et al. 6-Hydroxydopamine induces secretion of PARK7/DJ-1 via autophagy-based unconventional secretory pathway[J]. Autophagy,2018,14(11):1943-1958. doi: 10.1080/15548627.2018.1493043