Differential changes in MAP kinases, histone modifications, and liver injury in rats acutely treated with ethanol.
Differential changes in MAP kinases, histone modifications, and liver injury in rats acutely treated with ethanol.
复制标题
DOI：
10.1111/j.1530-0277.2010.01239.x
复制
发表时间：
2010-09-01
期刊：
影响因子：
--
通讯作者：
Shukla SD
中科院分区：
文献类型：
--
作者：
Aroor AR;James TT;Jackson DE;Shukla SD
已知急性乙醇会影响细胞和器官，但其潜在的分子机制尚不清楚。最近的发展突出了有丝分裂原活化蛋白激酶、MAPK（即ERK 1/2、p38和JNK 1/2）信号传导和组蛋白修饰（即乙酰化、甲基化和磷酸化）在乙醇在肝细胞中的作用中的潜在重要性。因此，我们研究了这些分子步骤在体内使用模型，其中大鼠急性给药乙醇腹腔内（IP）的意义。向12周龄雄性Sprague-Dawley大鼠IP给予乙醇（3.5 gm/kg体重）。随后在1小时和4小时取出肝脏。血清用于酒精和ALT测定。在取出肝脏时，将每个肝脏的一小部分福尔马林固定并用苏木精和伊红（H&E）染色，并用于光学显微镜检查。用特异性一抗对各种参数进行Western印迹分析。在1小时和4小时，血液乙醇、ALT、脂肪变性和裂解的半胱天冬酶3存在明显差异。急性酒精引起ERK 1/2磷酸化的显著增加和p38 MAPK和JNK磷酸化的中度增加。组蛋白H3在Ser-10和Ser-28处发生时间上不同的磷酸化，并且组蛋白H3在Lys 9处的乙酰化进行性增加。肝脏急性短时间暴露于乙醇后，三种MAP激酶的激活和组蛋白修饰的行为存在明显差异。虽然所有三种MAPK在1小时迅速激活，但在4小时发生的坏死与ERK 1/2的持续激活相关。p38的瞬时激活与组蛋白H3的快速磷酸化相关，而ERK 1/2的长期激活与组蛋白H3的持续乙酰化相关。
Acute ethanol is known to affect cells and organs but the underlying molecular mechanisms are poorly explored. Recent developments highlight the potential importance of mitogen activated protein kinases, MAPKs (i.e. ERK1/2, p38 and JNK1/2) signaling, and histone modifications (i.e. acetylation, methylation and phosphorylation) in the actions of ethanol in hepatocytes. We have therefore investigated significance of these molecular steps in vivo using a model in which rats were acutely administered ethanol intraperitoneally (IP). Ethanol was administered IP (3.5 gm/kg body weight) to 12 weeks old male Sprague–Dawley rats. Liver was subsequently removed at 1 and 4 hr. Serum was used for alcohol and ALT assays. At the time of the removal of liver, small portions of each liver were formalin-fixed and stained with hematoxylin and eosin (H&E) and used for light microscopy. Western blot analysis was done with specific primary antibodies for various parameters. There were clear differences at 1 and 4 hr in blood ethanol, ALT, steatosis, and cleaved caspase 3. Apoptosis at 1 h was followed by necrosis at 4 hr. Acute alcohol elicited a marked increase in the phosphorylation of ERK1/2 and moderate increases in the phosphorylation of p38 MAPK and JNK. Temporally different phosphorylation of histone H3 at ser-10 and ser -28 occurred and acetylation of histone H3 at lys 9 increased progressively. There were distinct differences in the behavior of the activation of the three MAP kinases and histone modifications after acute short exposure of liver to ethanol in vivo. Although all three MAPKs were rapidly activated at 1 h, the necrosis, occuring at 4 h, correlated to sustained activation of ERK1/2. Transient activation of p38 is associated with rapid phosphorylation of histone H3 whereas prolonged activation of ERK1/2 is correlated to persistent histone H3 acetylation.
登录
查看更多内容
DOI：
10.1111/j.1530-0277.2008.00827.x
发表时间：
2009-02
期刊：
ALCOHOL-CLINICAL AND EXPERIMENTAL RESEARCH
影响因子：
--
作者：
Purohit, Vishnudutt;Gao, Bin;Song, Byoung-Joon
通讯作者：
Song, Byoung-Joon
DOI：
10.1124/jpet.108.136721
发表时间：
2008-06-01
影响因子：
3.5
作者：
Beier, Juliane I.;Guo, Luping;Arteel, Gavin E.
通讯作者：
Arteel, Gavin E.
DOI：
10.1152/ajpgi.00091.2005
发表时间：
2005-12-01
影响因子：
4.5
作者：
Park, PH;Lim, RW;Shukla, SD
通讯作者：
Shukla, SD
DOI：
10.1097/bcr.0b013e3181a28df3
发表时间：
2009-05
期刊：
Journal of burn care & research : official publication of the American Burn Association
影响因子：
--
作者：
Emanuele NV;Emanuele MA;Morgan MO;Sulo D;Yong S;Kovacs EJ;Himes RD;Callaci JJ
通讯作者：
Callaci JJ
影响因子：
64.8
作者：
Kawasaki, H;Schiltz, L;Yokoyama, KK
通讯作者：
Yokoyama, KK