Cinnamaldehyde protects against rat intestinal ischemia/reperfusion injuries by synergistic inhibition of NF-κB and p53.

Abstract

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.

• Authors: Marwan Almoiliqy, Jin Wen, Bin Xu, Yu-Chao Sun, Meng-Qiao Lian, Yan-Li Li, Eskandar Qaed, Mahmoud Al-Azab, Da-Peng Chen, Abdullah Shopit, Li Wang, Peng-Yuan Sun, Yuan Lin
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 41 Issue 9 Pg. 1208-1222 (Sep 2020) ISSN: 1745-7254 [Electronic] United States
• PMID: 32238887 (Publication Type: Journal Article)

Chemical References

• Protective Agents
• Rela protein, rat
• Tp53 protein, rat
• Transcription Factor RelA
• Tumor Suppressor Protein p53
• Acrolein
• cinnamaldehyde

Topics

• Acrolein (analogs & derivatives, therapeutic use)
• Animals
• Cell Line
• Inflammation (prevention & control)
• Intestines (drug effects, pathology)
• Male
• Membrane Potential, Mitochondrial (drug effects)
• Mesenteric Ischemia (complications)
• Mitochondria (drug effects)
• Oxidative Stress (drug effects)
• Protective Agents (therapeutic use)
• Rats, Sprague-Dawley
• Reperfusion Injury (epidemiology, prevention & control)
• Transcription Factor RelA (antagonists & inhibitors)
• Tumor Suppressor Protein p53 (antagonists & inhibitors)