Our preliminary study shows that cinnamaldehyde (CA) could protect against intestinal ischemia/reperfusion (I/R) injuries,in which p53 and NF-KB 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 mesentedc ischemia followed by 2h 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-KB p65,IKKβ,IK-α,and NF-KB 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 pmol· L-1) significantly reversed H/R-induced reduction of IEC-6 cell viability.CA pretreatment significantly suppressed oxidative stress,NF-KB activation and apoptosis in H/R-treated IEC-6 cells.Moreover,CA pretreatment significantly reversed mitochonddal dysfunction in H/R-treated IEC-6 cells.CA pretreatment inhibited the nuclear transloCation of p53 and NF-KB p65 in H/R-treated IEC-6 cells.Double knockdown or overexpression of p53 and NF-KB p65 caused a synergistic reduction or elevation of p53 compared with knockdown or overexpression of p53 or NF-KB p65 alone.In H/R-treated IEC-6 cells with double knockdown or overexpression of NF-KB p65 and p53,CA pretreatment caused neither further decrease nor increase of NF-KB p65 or p53 expression,suggesting that CA-induced synergistic inhibition on both NF-KB 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-KB p65,showing the basis for CA-induced synergistic inhibition.Our results provide valuable information for further studies.