Dimethyl fumarate protects against intestinal ischemia/reperfusion lesion: Participation of Nrf2/HO-1, GSK-3β and Wnt/β-catenin pathway.
OBJECTIVE
Dimethyl fumarate (DMFU), a known Nrf2 activator, has proven its positive effect in different organs against ischemia/reperfusion (Is/Re) injury. Nevertheless, its possible impact to modulate intestinal Is/Re-induced injury has not been previously demonstrated before. Hence, this study aimed to investigate DMFU mechanistic maneuver against intestinal Is/Re.


METHODS
To accomplish this goal, Wistar rats were allocated into four groups; Sham-operated (SOP), intestinal Is/Re (1 h/6 h), and 14 days pre-treated DMFU (15 and 25 mg/kg/day, p.o).


RESULTS
The mechanistic maneuver divulged that DMFU safeguarded the intestine partly via amplifying the expression/content of Nrf2 along with enhancing its downstream, HO-1 expression/content. In addition, DMFU lessened GSK-3β expression/content accompanied by enriching β-catenin expression/content. The antioxidant action was affirmed by enhancing total antioxidant capacity, besides reducing MDA, iNOS, and its by-product, NOx. The DMFU action entailed anti-inflammatory character manifested by down-regulation of expression/content NF-κB with subsequent rebating the contents of TNF-α, IL-1β, and P-selectin, as well as MPO activity. Moreover, DMFU had anti-apoptotic nature demonstrated through enriching Bcl-2 level and diminishing that of caspase-3.


CONCLUSION
DMFU purveyed tenable novel protective mechanisms and mitigated events associated with intestinal Is/Re mischief either in the lower or the high dose partly by amending of oxidative stress and inﬂammation through the modulation of Nrf2/HO-1, GSK-3β, and Wnt/β-catenin pathways.
['Gendy|Abdallah|A|', 'Soubh|Ayman|A|', 'Al-Mokaddem|Asmaa|A|', 'Kotb El-Sayed|Mohamed|M|']
D000818:Animals D000893:Anti-Inflammatory Agents D000975:Antioxidants D017209:Apoptosis D000069462:Dimethyl Fumarate D004195:Disease Models, Animal D000071679:Glycogen Synthase Kinase 3 beta D006419:Heme Oxygenase (Decyclizing) D007410:Intestinal Diseases D007422:Intestines D008297:Male D051267:NF-E2-Related Factor 2 D000073039:Nitrosative Stress D017208:Rats, Wistar D015427:Reperfusion Injury D060449:Wnt Signaling Pathway
Dimethyl fumarate Intestinal ischemia/reperfusion Nrf2/HO-1 GSK-3β Wnt/β-catenin