Takasu Chie, Vaziri Nosratola D, Li Shiri, Robles Lourdes, Vo Kelly, Takasu Mizuki, Pham Christine, Farzaneh Seyed H, Shimada Mitsuo, Stamos Michael J, Ichii Hirohito
Chie Takasu, Nosratola D Vaziri, Shiri Li, Lourdes Robles, Kelly Vo, Mizuki Takasu, Christine Pham, Seyed H Farzaneh, Michael J Stamos, Hirohito Ichii, Department of Surgery, Medicine, University of California, Irvine, CA 92868, United States.
World J Gastroenterol. 2017 Jul 7;23(25):4508-4516. doi: 10.3748/wjg.v23.i25.4508.
To investigate the hypothesis that treatment with dimethyl fumarate (DMF) may ameliorate liver ischemia/reperfusion injury (I/RI).
Rats were divided into 3 groups: sham, control (CTL), and DMF. DMF (25 mg/kg, twice/d) was orally administered for 2 d before the procedure. The CTL and DMF rats were subjected to ischemia for 1 h and reperfusion for 2 h. The serum alanine aminotransferase (ALT) and malondialdehyde (MDA) levels, adenosine triphosphate (ATP), NO × metabolites, anti-oxidant enzyme expression level, anti-inflammatory effect, and anti-apoptotic effect were determined.
Histological tissue damage was significantly reduced in the DMF group (Suzuki scores: sham: 0 ± 0; CTL: 9.3 ± 0.5; DMF: 2.5 ± 1.2; sham CTL, < 0.0001; CTL DMF, < 0.0001). This effect was associated with significantly lower serum ALT (DMF 5026 ± 2305 U/L CTL 10592 ± 1152 U/L, = 0.04) and MDA (DMF 18.2 ± 1.4 μmol/L CTL 26.0 ± 1.0 μmol/L, = 0.0009). DMF effectively improved the ATP content (DMF 20.3 ± 0.4 nmol/mg CTL 18.3 ± 0.6 nmol/mg, = 0.02), myeloperoxidase activity (DMF 7.8 ± 0.4 mU/mL CTL 6.0 ± 0.5 mU/mL, = 0.01) and level of endothelial nitric oxide synthase expression (DMF 0.38 ± 0.05-fold 0.17 ± 0.06-fold, = 0.02). The higher expression levels of anti-oxidant enzymes (catalase and glutamate-cysteine ligase modifier subunit and lower levels of key inflammatory mediators (nuclear factor-kappa B and cyclooxygenase-2 were confirmed in the DMF group.
DMF improved the liver function and the anti-oxidant and inflammation status following I/RI. Treatment with DMF could be a promising strategy in patients with liver I/RI.
探讨富马酸二甲酯（DMF）治疗能否改善肝脏缺血/再灌注损伤（I/RI）这一假说。
将大鼠分为3组：假手术组、对照组（CTL）和DMF组。在手术前2天口服给予DMF（25mg/kg，每日2次）。CTL组和DMF组大鼠经历1小时缺血和2小时再灌注。测定血清丙氨酸氨基转移酶（ALT）和丙二醛（MDA）水平、三磷酸腺苷（ATP）、NO×代谢产物、抗氧化酶表达水平、抗炎作用和抗凋亡作用。
DMF组组织学损伤明显减轻（铃木评分：假手术组：0±0；CTL组：9.3±0.5；DMF组：2.5±1.2；假手术组vs CTL组，<0.0001；CTL组vs DMF组，<0.0001）。这种作用与血清ALT（DMF组5026±2305U/L vs CTL组10592±1152U/L，P = 0.04）和MDA（DMF组18.2±1.4μmol/L vs CTL组26.0±1.0μmol/L，P = 0.0009）显著降低有关。DMF有效提高了ATP含量（DMF组20.3±0.4nmol/mg vs CTL组18.3±0.6nmol/mg，P = 0.02）、髓过氧化物酶活性（DMF组7.8±0.4mU/mL vs CTL组6.0±0.5mU/mL，P = 0.01）以及内皮型一氧化氮合酶表达水平（DMF组0.38±0.05倍vs 0.17±0.06倍，P = 0.02）。DMF组抗氧化酶（过氧化氢酶和谷氨酸-半胱氨酸连接酶修饰亚基）表达水平较高，关键炎症介质（核因子-κB和环氧化酶-2）水平较低。
DMF改善了I/RI后的肝功能以及抗氧化和炎症状态。DMF治疗可能是肝脏I/RI患者的一种有前景的策略。
