Pharmacology and Toxicology Department, Faculty of Pharmacy, October 6 University, Giza, 12585, Egypt.
Pharmacology and Toxicology Department, Faculty of Pharmacy, Ahram Canadian University, Giza, 12566, Egypt.
Biomed Pharmacother. 2021 Feb;134:111130. doi: 10.1016/j.biopha.2020.111130. Epub 2020 Dec 24.
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.
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).
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.
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.
富马酸二甲酯（DMFU）是一种已知的 Nrf2 激活剂，已证明其在不同器官对缺血/再灌注（Is/Re）损伤具有积极作用。然而，其对调节肠道 Is/Re 诱导损伤的可能影响此前尚未得到证实。因此，本研究旨在研究 DMFU 对肠道 Is/Re 的作用机制。
为了实现这一目标，将 Wistar 大鼠分为四组；假手术（SOP）、肠道 Is/Re（1 小时/6 小时）和 14 天预 DMFU 处理（15 和 25mg/kg/天，口服）。
作用机制表明，DMFU 通过增强 Nrf2 的表达/含量及其下游 HO-1 的表达/含量来部分保护肠道。此外，DMFU 降低了 GSK-3β 的表达/含量，同时增加了 β-连环蛋白的表达/含量。抗氧化作用通过增强总抗氧化能力得到证实，同时降低 MDA、iNOS 及其副产物 NOx。DMFU 的作用涉及抗炎特性，表现为下调 NF-κB 的表达/含量，随后降低 TNF-α、IL-1β 和 P-选择素以及 MPO 活性的含量。此外，DMFU 通过增加 Bcl-2 水平和减少 caspase-3 水平表现出抗凋亡特性。
DMFU 提供了可行的新的保护机制，并减轻了肠道 Is/Re 损伤相关的事件，无论是低剂量还是高剂量，部分通过调节 Nrf2/HO-1、GSK-3β 和 Wnt/β-连环蛋白途径来纠正氧化应激和炎症。
