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首页> 外文期刊>World Journal of Gastroenterology >Hepatic preconditioning of doxorubicin in stop-flow chemotherapy: NF-kappaB/IkappaB-alpha pathway and expression of HSP72.
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Hepatic preconditioning of doxorubicin in stop-flow chemotherapy: NF-kappaB/IkappaB-alpha pathway and expression of HSP72.

机译：停止流化疗中阿霉素的肝预处理：NF-kappaB /IkappaB-α途径和HSP72的表达。

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AIM: To provide hepatic protection through administration of doxorubicin before stop-flow chemotherapy (SFC) and to investigate the expression of heat shock protein 72 (HSP72) and role of nuclear factor kappa B (NF-kappaB) in this effect. METHODS: The hepatic preconditioning of doxorubicin was established in a porcine model by injection of doxorubicin (1 mg/kg) before SFC. The experimental animals were randomized into two groups: groups receiving doxorubicin (DOX) and normal saline (NS). Serial serum and tissue samples were taken from both groups to evaluate the protection of doxorubicin. Western blot and immuno-precipitation were applied to detect the expression of HSP72, NF-kappaB p65 protein, inhibitor kappaB-alpha (IkappaB-alpha) and phosphorylated IkappaB-alpha as well. The expression of tumor necrosis factor alpha (TNF-alpha) was estimated by semiquantitative RT-PCR. And the extent of the hepatic injury was estimated with the level of serum aminotransferases. RESULTS: An abundance production of HSP72 in porcine liver was observed after 24 h of intravenous administration of doxorubicin, but without any change in the expression of NF-kappaB p65 subunit in cytoplasm. NF-kappaB p65 subunit accumulated in nuclei at the end of SFC and reached its highest level at 30 min after the restoration of the abdominal circulation and decreased gradually during the 6 h after SFC in NS group, while there was little change in DOX group. There was also a slight decrease of IkappaB-alpha at 30 min after the restoration of the abdominal circulation in NS group accompanying with the appearance of phosphorylated IkappaB-alpha. The expression of TNF-alpha was significantly higher in NS group than that in DOX group (average 1.40+/-0.17 vs 0.62+/-0.22, P<0.01) at serial time points after SFC. Serum ALT and AST levels of NS group were higher after 24 h than those of DOX group (93.2+/-7.8 IU/L vs 53.3+/-13.9 IU/L, 217.0+/-29.4 IU/L vs 155.0+/-15.6 IU/L for ALT and AST respectively, P<0.05) and after 48 h than those of DOX group(66.6+/-18.1 IU/L vs 43.3+/-16.7 IU/L, 174.4+/-21.3 IU/L vs 125.7+/-10.5 IU/L for ALT and AST respectively, P<0.05). CONCLUSION: Doxorubicin renders the liver to be tolerant to the hepatic influence in SFC in a porcine model through the NF-kappaB/IkappaB-alpha pathway with the expression of HSP72.
机译：目的：通过在停流化疗（SFC）之前施用阿霉素来提供肝保护作用，并研究热休克蛋白72（HSP72）的表达以及核因子κB（NF-κB）在这种作用中的作用。方法：通过在SFC前注射阿霉素（1 mg / kg）在猪模型中建立阿霉素的肝预处理。将实验动物随机分为两组：接受阿霉素（DOX）和生理盐水（NS）的组。从两组中采集连续的血清和组织样品以评估阿霉素的保护作用。免疫印迹和免疫沉淀法用于检测HSP72，NF-κBp65蛋白，抑制剂kappaB-alpha（IkappaB-alpha）和磷酸化的IkappaB-alpha的表达。通过半定量RT-PCR估计肿瘤坏死因子α（TNF-α）的表达。并根据血清转氨酶水平评估肝损伤程度。结果：静脉注射阿霉素24 h后，猪肝脏中产生大量HSP72，但细胞质中NF-κBp65亚基的表达没有变化。 NF-κBp65亚基在SFC结束时在细胞核中积累，并在腹腔恢复后30分钟达到最高水平，在NS组中在SFC后6h逐渐下降，而DOX组变化不大。 NS组腹部循环恢复后30分钟，IkappaB-α也略有减少，并伴有磷酸化的IkappaB-α的出现。在SFC后的连续时间点，NS组中TNF-α的表达明显高于DOX组（平均1.40 +/- 0.17对0.62 +/- 0.22，P <0.01）。 NS组24小时后的ALT和AST水平高于DOX组（93.2 +/- 7.8 IU / L vs 53.3 +/- 13.9 IU / L，217.0 +/- 29.4 IU / L vs 155.0 +/- ALT和AST分别为15.6 IU / L，P <0.05和48小时后比DOX组（66.6 +/- 18.1 IU / L vs 43.3 +/- 16.7 IU / L，174.4 +/- 21.3 IU / L vs ALT和AST分别为125.7 +/- 10.5 IU / L（P <0.05）。结论：阿霉素通过表达HSP72的NF-κB/ IkappaB-alpha途径使猪对SFC中的肝具有耐受性。

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