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NF-κB-iNOS-COX2-TNF α inflammatory signaling pathway plays an important role in methotrexate induced small intestinal injury in rats
Food and Chemical Toxicology ( IF 3.9 ) Pub Date : 2018-06-20 , DOI: 10.1016/j.fct.2018.06.040
Kasthuri Natarajan , Premila Abraham , Rekha Kota , Bina Isaac

Although methotrexate is widely used in clinics as an anticancer agent, it's utility is limited by its gastrointestinal toxicity, the mechanism of which is unclear. The role of NFκB inflammatory pathway in MTX induced mucositis was investigated in the present study. GI injury was induced in adult Wistar rats by the administration of 3 consecutive i.p . injections of MTX. On the fourth day, the rats were sacrificed and the small intestine was removed; A piece was used for light microscopy, immunohistochemistry, immunofluorescence studies . The mucosa was collected and used for the analysis of protein and mRNA expressions of NFκB and its target genes by the western blot, RT-PCR respectively. MTX treatment resulted in NFκB activation and nuclear translocation as evidenced by immunofluorescence, immunohistochemistry , and western blot. NFκB mRNA was also increased. There was increased protein and mRNA expressions of NFκB target genes, TNF-α, iNOS, COX-2, PLA2, HO-1, HSP70, MMPs 2 and 9 . Aminoguanidine pretreatment (30mg/ 50mg /kg body wt.) attenuated MTX induced activation of NFκB and its proinflammatory target genes and improved MTX induced morphological changes. Aminoguanidine has protective effects against MTX induced gastrointestinal mucositis in rats.



中文翻译:

NF-κB-iNOS-COX2-TNFα炎症信号通路在甲氨蝶呤致大鼠小肠损伤中起重要作用

尽管甲氨蝶呤在临床上广泛用作抗癌药,但其用途受到胃肠道毒性的限制,其机理尚不清楚。在本研究中研究了NFκB炎性途径在MTX诱导的粘膜炎中的作用。连续3次腹膜内注射对成年Wistar大鼠造成胃肠道损伤。注射MTX。第四天,处死大鼠并切除小肠。一块用于光学显微镜,免疫组织化学,免疫荧光研究。收集粘膜,分别通过蛋白质印迹,RT-PCR分析NFκB及其靶基因的蛋白和mRNA表达。免疫荧光,免疫组织化学和免疫印迹证明,MTX处理可导致NFκB活化和核易位。NFκBmRNA也增加。NFκB靶基因,TNF-α,iNOS,COX-2,PLA2,HO-1,HSP70,MMP 2和9的蛋白质和mRNA表达增加。氨基胍预处理(30mg / 50mg / kg体重)减弱了MTX诱导的NFκB及其促炎性靶基因的活化,并改善了MTX诱导的形态变化。氨基胍对大鼠MTX诱导的胃肠道粘膜炎具有保护作用。

更新日期:2018-06-20
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