姜黄素对大鼠脑缺血后Janus蛋白酪氨酸激酶2信号转导和转录激活子3信号通路的影响
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摘要
目的探讨姜黄素对大鼠脑缺血损伤后Janus蛋白酪氨酸激酶2(JAK2)/信号转导和转录激活子3(STAT3)信号通路的影响。方法将68只SD大鼠随机分为假手术组、脑缺血组、姜黄素组(尾静脉注射姜黄素40mg/kg)和对照组(注射等量生理盐水),每组17只,后3组建立大鼠局灶性脑缺血模型,观察各组大鼠神经行为学变化,ELISA检测大鼠脑组织TNF-α、白细胞介素(IL)-1β、IL-6表达,Western blot检测大鼠脑组织JAK2、磷酸化JAK2(p-JAK2)、STAT3、磷酸化STAT3(p-STAT3)、高迁移率族蛋白1(HMGB1)表达。结果与脑缺血组比较,姜黄素组大鼠神经行为学评分减低[(1.53±0.62)分vs(2.94±0.87)分,P<0.05];与脑缺血组比较,对照组TNF-α、IL-1β和IL-6无明显变化(P>0.05),姜黄素组大鼠TNF-α[(57.63±10.27)ng/L vs(99.35±8.97)ng/L]、IL-1β[(33.67±9.10)ng/L vs(58.43±7.22)ng/L]和IL-6[(31.97±6.91)ng/L vs(49.23±6.28)ng/L]表达降低(P<0.01),p-JAK2/JAK2、p-STAT3/STAT3相对含量及HMGB1表达降低(P<0.05,P<0.01)。结论姜黄素可保护大鼠缺血后脑损伤,其机制可能是通过抑制JAK2/STAT3信号通路,减少HMGB1表达,减轻炎性反应。
Objective To study the effect of curcumin on JAK2/STAT3 signaling pathway following ischemic cerebral injury in rats.Methods Sixty-eight SD rats were divided into sham operation group,cerebral ischemia group,curcumin treatment group and control group(17 in each group).After a rat focal cerebral hemmorrahge model was established,the changes of neurological behaviors in rats were recorded,expressions of TNF-α,IL-1βand IL-6 were detected by ELISA and those of JAK2,p-JAK2,STAT3,p-STAT3 and HMGB1 were detected by Western blot.Results The neurological behavior score was lower in curcumin treatment group than in cerebral ischemia group(1.53±0.62 vs 2.94±0.87,P<0.05).No significant difference was found in expression levels of TNF-α,IL-1βand IL-6 between cerebral ischemia group and control group(P>0.05).The expression levels of TNF-α,IL-1βand IL-6 were lower in curcumin treatment group than in cerebral ischemia group(57.63±10.27 ng/L vs 99.35±8.97 ng/L,33.67±9.10 ng/L vs58.43±7.22 ng/L,31.97±6.91 ng/L vs 49.23±6.28 ng/L,P<0.01).The relative volume of p-JAK2/JAK2 and p-STAT3/STAT3 and the expression level of HMGB1 were lower in curcumin treatment group than in cerebral ischemia group(P<0.05).Conclusion Curcumin can protect rats against cerebral injury following ischemia by inhibiting the JAK2/STAT3 signaling pathway and downregulating the HMGB1 expression,and can thus alleviate inflammatory reactions.
Objective To study the effect of curcumin on JAK2/STAT3 signaling pathway following ischemic cerebral injury in rats.Methods Sixty-eight SD rats were divided into sham operation group,cerebral ischemia group,curcumin treatment group and control group(17 in each group).After a rat focal cerebral hemmorrahge model was established,the changes of neurological behaviors in rats were recorded,expressions of TNF-α,IL-1βand IL-6 were detected by ELISA and those of JAK2,p-JAK2,STAT3,p-STAT3 and HMGB1 were detected by Western blot.Results The neurological behavior score was lower in curcumin treatment group than in cerebral ischemia group(1.53±0.62 vs 2.94±0.87,P<0.05).No significant difference was found in expression levels of TNF-α,IL-1βand IL-6 between cerebral ischemia group and control group(P>0.05).The expression levels of TNF-α,IL-1βand IL-6 were lower in curcumin treatment group than in cerebral ischemia group(57.63±10.27 ng/L vs 99.35±8.97 ng/L,33.67±9.10 ng/L vs58.43±7.22 ng/L,31.97±6.91 ng/L vs 49.23±6.28 ng/L,P<0.01).The relative volume of p-JAK2/JAK2 and p-STAT3/STAT3 and the expression level of HMGB1 were lower in curcumin treatment group than in cerebral ischemia group(P<0.05).Conclusion Curcumin can protect rats against cerebral injury following ischemia by inhibiting the JAK2/STAT3 signaling pathway and downregulating the HMGB1 expression,and can thus alleviate inflammatory reactions.
引文
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[16]Li Y,Zhang X,Cui L,et al.Salvianolic acids enhance cerebral angiogenesis and neurological recovery by activating JAK2/STAT3signaling pathway after ischemic stroke in mice[J].J Neurochem,2017,143(1):87-99.DOI:10.1111/jnc.14140.
[2]Wilken R,Veena MS,Wang MB,et al.Curcumin:a review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma[J].Mol Cancer,2011,10:12.DOI:10.1186/1476-4598-10-12.
[3]Shehzad A,Rehman G,Lee YS.Curcumin in inflammatory diseases[J].Biofactors,2013,39(1):69-77.DOI:10.1002/biof.1066.
[4]Esatbeyoglu T,Huebbe P,Ernst IM,et al.Curcumin--from molecule to biological function[J].Angew Chem Int Ed Engl,2012,51(22):5308-5332.DOI:10.1002/anie.201107724.
[5]Chen S,Dong Z,Cheng M,et al.Homocysteine exaggerates microglia activation and neuroinflammation through microglia localized STAT3overactivation following ischemic stroke[J].J Neuroinflammation,2017,14(1):187.DOI:10.1186/s12974-017-0963-x.
[6]Weissenberger J,Priester M,Bernreuther C,et al.Dietary curcumin attenuates glioma growth in a syngeneic mouse model by inhibition of the JAK1,2/STAT3signaling pathway[J].Clin Cancer Res,2010,16(23):5781-5795.DOI:10.1158/1078-0432.CCR-10-0446.
[7]Saydmohammed M,Joseph D,Syed V.Curcumin suppresses constitutive activation of STAT-3by up-regulating protein inhibitor of activated STAT-3(PIAS-3)in ovarian and endometrial cancer cells[J].J Cell Biochem,2010,110(2):447-456.DOI:10.1002/jcb.22558.
[8]祖佳宁,庄金鹏,闫景龙,等.姜黄素经JAK2/STAT3通路抑制小胶质细胞活化的实验研究[J].哈尔滨医科大学学报,2017,51(2):109-112.DOI:10.3969/j.issn.1000-1905.2017.02.004.
[9]Khoshnam SE,Winlow W,Farzaneh M,et al.Pathogenic mechanisms following ischemic stroke[J].Neurol Sci,2017,38(7):1167-1186.DOI:10.1007/s10072-017-2938-1.
[10]Vidale S,Consoli A,Arnaboldi M,et al.Postischemic inflammation in acute stroke[J].J Clin Neurol,2017,13(1):1-9.DOI:10.3988/jcn.2017.13.1.1
[11]吴晓光,李玲,李蒙蒙,等.山楂叶总黄酮对慢性脑缺血大鼠p38MAPK信号通路及炎症因子表达的影响[J].中华行为医学与脑科学杂志,2016,25(2):103-107.DOI:10.3760/cma.j.issn.1674-6554.2016.02.002.
[12]Gao Q,Liang X,Shaikh AS,et al.JAK/STAT signal transduction:promising attractive targets for immune,inflammatory and hematopoietic diseases[J].Curr Drug Targets,2016,17(14):1578.DOI:10.2174/13894501176661612071630 54.
[13]Singh V,Roth S,Veltkamp R,et al.HMGB1as a key mediator of immune mechanisms in ischemic stroke[J].Antioxid Redox Signal,2016,24(12):635-651.DOI:10.1089/ars.2015.6397.
[14]Liu H,Yao YM,Yu Y,et al.Role of Janus kinase/signal transducer and activator of traascdption pathway in regulation of expression and inflammation-promotactivity of high mobility group box protein in rat peritoneal macrophages[J].Shock,2007,27(1):55-60.DOI:10.1097/01.shk.0000233197.40989.31.
[15]Tang Y,Tong X,Li Y,et al.JAK2/STAT3pathway is involved in the protective effects of epidermal growth factor receptor activation against cerebral ischemia/reperfusion injury in rats[J].Neurosci Lett,2018,66:219-226.DOI:10.1016/j.neulet.2017.10.037.
[16]Li Y,Zhang X,Cui L,et al.Salvianolic acids enhance cerebral angiogenesis and neurological recovery by activating JAK2/STAT3signaling pathway after ischemic stroke in mice[J].J Neurochem,2017,143(1):87-99.DOI:10.1111/jnc.14140.