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Cinnamaldehyde protects against rat intestinal ischemia/reperfusion injuries by synergistic inhibition of NF-κB and p53.
Acta Pharmacologica Sinica ( IF 6.9 ) Pub Date : 2020-04-01 , DOI: 10.1038/s41401-020-0359-9
Marwan Almoiliqy 1 , Jin Wen 1 , Bin Xu 1 , Yu-Chao Sun 1 , Meng-Qiao Lian 1 , Yan-Li Li 1 , Eskandar Qaed 1 , Mahmoud Al-Azab 1 , Da-Peng Chen 2 , Abdullah Shopit 1 , Li Wang 1 , Peng-Yuan Sun 1 , Yuan Lin 1
Affiliation  

Our preliminary study shows that cinnamaldehyde (CA) could protect against intestinal ischemia/reperfusion (I/R) injuries, in which p53 and NF-κB p65 play a synergistic role. In this study, we conducted in vivo and in vitro experiments to verify this proposal. SD rats were pretreated with CA (10 or 40 mg · kg-1 · d-1, ig) for 3 days, then subjected to 1 h mesenteric ischemia followed by 2 h reperfusion. CA pretreatment dose-dependently ameliorated morphological damage and reduced inflammation evidenced by decreased TNF-α, IL-1β, and IL-6 levels and MPO activity in I/R-treated intestinal tissues. CA pretreatment also attenuated oxidative stress through restoring SOD, GSH, LDH, and MDA levels in I/R-treated intestinal tissues. Furthermore, CA pretreatment significantly reduced the expression of inflammation/apoptosis-related NF-κB p65, IKKβ, IK-α, and NF-κB p50, and downregulated apoptotic protein expression including p53, Bax, caspase-9 and caspase-3, and restoring Bcl-2, in I/R-treated intestinal tissues. We pretreated IEC-6 cells in vitro with CA for 24 h, followed by 4 h hypoxia and 3 h reoxygenation (H/R) incubation. Pretreatment with CA (3.125, 6.25, and 12.5 μmol · L-1) significantly reversed H/R-induced reduction of IEC-6 cell viability. CA pretreatment significantly suppressed oxidative stress, NF-κB activation and apoptosis in H/R-treated IEC-6 cells. Moreover, CA pretreatment significantly reversed mitochondrial dysfunction in H/R-treated IEC-6 cells. CA pretreatment inhibited the nuclear translocation of p53 and NF-κB p65 in H/R-treated IEC-6 cells. Double knockdown or overexpression of p53 and NF-κB p65 caused a synergistic reduction or elevation of p53 compared with knockdown or overexpression of p53 or NF-κB p65 alone. In H/R-treated IEC-6 cells with double knockdown or overexpression of NF-κB p65 and p53, CA pretreatment caused neither further decrease nor increase of NF-κB p65 or p53 expression, suggesting that CA-induced synergistic inhibition on both NF-κB and p53 played a key role in ameliorating intestinal I/R injuries. Finally, we used immunoprecipitation assay to demonstrate an interaction between p53 and NF-κB p65, showing the basis for CA-induced synergistic inhibition. Our results provide valuable information for further studies.

中文翻译:

肉桂醛通过协同抑制NF-κB和p53来防止大鼠肠缺血/再灌注损伤。

我们的初步研究表明,肉桂醛(CA)可以预防肠缺血/再灌注(I / R)损伤,其中p53和NF-κBp65发挥协同作用。在这项研究中,我们进行了体内和体外实验以验证该建议。SD大鼠用CA(10或40 mg·kg-1·d-1,ig)预处理3天,然后进行1 h肠系膜缺血,再灌注2 h。CA预处理剂量依赖性地减轻了形态学损伤,减轻了炎症,这是由经I / R处理的肠组织中TNF-α,IL-1β和IL-6水平降低以及MPO活性所证实的。CA预处理还可以通过恢复经I / R处理的肠组织中的SOD,GSH,LDH和MDA含量来减轻氧化应激。此外,CA预处理可显着降低炎症/细胞凋亡相关的NF-κBp65,IKKβ,IK-α,和NF-κBp50,并下调经I / R处理的肠道组织中的凋亡蛋白表达,包括p53,Bax,caspase-9和caspase-3,并恢复Bcl-2。我们在体外用CA预处理IEC-6细胞24小时,然后进行4小时缺氧和3小时复氧(H / R)孵育。用CA(3.125、6.25和12.5μmol·L-1)进行的预处理显着逆转了H / R诱导的IEC-6细胞活力的降低。CA预处理显着抑制了经H / R处理的IEC-6细胞的氧化应激,NF-κB活化和细胞凋亡。此外,CA预处理可显着逆转经H / R处理的IEC-6细胞中的线粒体功能障碍。CA预处理抑制了经H / R处理的IEC-6细胞中p53和NF-κBp65的核易位。与单独的p53或NF-κBp65的敲低或过表达相比,p53和NF-κBp65的双重敲低或过表达导致p53协同降低或升高。在经过H / R处理的具有双重敲除或NF-κBp65和p53双重表达的IEC-6细胞中,CA预处理既不会导致NF-κBp65或p53表达的进一步降低也不会增加,这表明CA诱导了对两种NF的协同抑制作用-κB和p53在改善肠I / R损伤中起关键作用。最后,我们使用免疫沉淀实验证明了p53和NF-κBp65之间的相互作用,为CA诱导的协同抑制奠定了基础。我们的结果为进一步研究提供了有价值的信息。CA预处理未引起NF-κBp65或p53表达的进一步降低或增加,这表明CA诱导的对NF-κB和p53的协同抑制在缓解肠I / R损伤中起关键作用。最后,我们使用免疫沉淀实验证明了p53和NF-κBp65之间的相互作用,为CA诱导的协同抑制奠定了基础。我们的结果为进一步研究提供了有价值的信息。CA预处理未引起NF-κBp65或p53表达的进一步降低或增加,这表明CA诱导的对NF-κB和p53的协同抑制在缓解肠I / R损伤中起关键作用。最后,我们使用免疫沉淀实验证明了p53和NF-κBp65之间的相互作用,为CA诱导的协同抑制奠定了基础。我们的结果为进一步研究提供了有价值的信息。
更新日期:2020-04-24
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