Cytoprotective gene heme oxygenase 1 (HO-1) could be induced by nuclear factor E2-related factor 2 (Nrf2) nuclear translocation. The purpose of this study was to determine the role of Brahma-related gene 1 (Brg1), a catalytic subunit of SWI2/SNF2-like chromatin remodeling complexes, in Nrf2/HO-1 pathway activation during hepatic ischemia–reperfusion (HIR). Our results showed that hepatic Brg1 was inhibited during early HIR while Brg1 overexpression reduced oxidative injury in CMV-Brg1 mice subjected to HIR. Moreover, promoter-driven luciferase assay showed that overexpression of Brg1 by adenovirus transfection in AML12 cells selectively enhanced HO-1 gene expression after hypoxia/reoxygenation (H/R) treatment but did not affect the other Nrf2 target gene NQO1. Furthermore, inhibition of HO-1 by the selective HO-1 inhibitor zinc protoporphyria could partly reverse the hepatic protective effects of Brg1 overexpression while HO-1-Adv attenuated AML12 cells H/R damage. Further, chromatin immunoprecipitation analysis revealed that Brg1 overexpression, which could significantly increase the recruitment of Brg1 protein to HO-1 but not NQO1 promoter, was recruited by Nrf2 to the HO-1 regulatory regions in AML12 hepatocytes subjected to H/R. In conclusion, our results demonstrated that restoration of Brg1 during reperfusion could enhance Nrf2-mediated inducible expression of HO-1 during HIR to effectively increase antioxidant ability to combat against hepatocytes damage.

Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling plays a dominant role in the pathogenesis of liver ischemia-reperfusion (IR) injury. Dexmedetomidine (Dex) protects the liver against IR injury via α2-adrenoceptor activation, but the contribution of TLR4 signaling remains unknown. The authors aimed to examine whether pretreatment with Dex produces hepatic protection and investigate the influence of Dex on TLR4/NF-κB signaling. Dex was given via intraperitoneal injection 30 min prior to orthotopic autologous liver transplantation (OALT) in rats, and three α2-adrenoceptor antagonists including atipamezole (a nonselective α2 receptor blocker), ARC-239 (a specific α2B/C blocker) and BRL-44408 (a specific α2A blocker) were injected intraperitoneally 10 min before Dex administration. Histopathologic evaluation of the liver and the measurement of serum alanine aminotransferase activity, TLR4/NF-κB expression in the liver, and pro-inflammatory factors (serum tumor necrosis factor-α, interleukin-1β and hepatic myeloperoxidase) concentrations were performed 8 h after OALT. Dex ameliorated liver injury after OALT probably by suppressing the TLR4/NF-κB pathway and decreasing inflammatory mediator levels. The protective effects of Dex were reversed by atipamezole and BRL-44408, but not by ARC-239, suggesting that these effects were mediated in part by the α2A subtype. In conclusion, Dex attenuates liver injury partly via the α2A-adrenoceptor subtype, and the mechanism is due to the suppression of the TLR4/NF-κB pathway.

Background:To investigate the effects of intraoperative application of dexmedetomidine (Dex) on early gastrointestinal motility after laparoscopic resection of colorectal cancer.Methods:In this prospective, randomized double-blind investigation, 60 patients who underwent laparoscopic resection of colorectal cancer were randomly allocated to receive Dex (DEX group, n = 30) or saline (CON group, n = 30). In the DEX group, Dex was loaded (1 μg/kg) before anesthesia induction and was infused (0.3 μg/kg/h) during surgery. Time to postoperative first flatus (FFL) and first feces (FFE), and time to regular diet were recorded. Serum diamine oxidase (DAO) activity and intestinal fatty acid-binding protein (I-FABP) were detected.Results:Both the time to the FFL (44.41 ± 4.51 hours vs 61.03 ± 5.16 hours, P = 0.02) and the time to the FFE (60.67 ± 4.94 hours vs 82.50 ± 6.88 hours, P = 0.014) were significantly shorter in the DEX group than the CON group. Furthermore, the time to regular diet of the DEX group was shorter than that of the CON group (76.15 ± 4.11 hours vs 91.50 ± 5.70 hours, P = 0.037). Both DAO and I-FABP increased significantly from beginning of surgery to postoperative day 1 in the CON group (2.49 ± 0.41 ng/mL vs 4.48 ± 0.94 ng/mL for DAO, P = 0.028, 1.32 ± 0.09 ng/mL vs 2.17 ± 0.12 ng/mL for I-FABP, P = 0.045, respectively), whereas no significant change was observed in the DEX group. Furthermore, patients in the DEX group had stable hemodynamics and shorter hospital stay than those in the CON group.Conclusion:Dex administration intraoperatively benefits recovery of gastrointestinal motility function after laparoscopic resection of colorectal cancer with stable hemodynamics during surgery though further studies are needed to explore the mechanisms of Dex on gastrointestinal motility.