核因子E2相关因子2在肾缺血-再灌注损伤中的作用

肾缺血-再灌注损伤（RIRI）是导致急性肾损伤（AKI）最主要的原因,常见于外科手术、严重创伤、休克和药物性肾损伤中。目前仍然缺乏有效的治疗手段应对RIRI。氧化应激是RIRI主要的病理损伤机制,核因子E2相关因子2(Nrf2)是抗氧化应激反应的关键转录因子,可激活与氧化还原和解毒相关的各种细胞保护基因。近年来研究表明,Nrf2可通过调节氧化应激、炎症反应、细胞凋亡以及细胞自噬等途径,在RIRI的防治中发挥保护作用。因此,本文围绕Nrf2的结构及其生物学功能、Nrf2相关信号通路及Nrf2在RIRI发生发展中的作用及可能机制进行综述,以期为RIRI的预防和治疗提供新的思路。     

自噬标记性分子LC3-Ⅱ在肝脏缺血再灌注损伤中的研究

肝癌、外伤性肝破裂等肝脏疾病行手术治疗时,常常面临剩余肝缺血再灌注损伤的问题,明显增加了手术治疗的风险和影响患者术后的恢复.细胞自噬是肝脏缺血再灌注损伤后细胞程序性死亡方式之一,在动物实验模拟肝脏缺血再灌注研究时,常以检测自噬标记性分子LC3-Ⅱ的水平变化代表细胞自噬活动的强弱.现就LC3-Ⅱ在肝脏缺血再灌注损伤中的研究作一综述.     

线粒体自噬在肝相关疾病中的作用

细胞自噬是细胞依赖溶酶体的分解代谢过程,能降解受损蛋白、衰老或损伤的细胞器等细胞结构,来维持细胞内稳态。众所周知,线粒体调节异常是许多疾病的发病机制。本文主要探讨线粒体自噬在肝相关疾病如非酒精性脂肪肝病、肝癌和肝缺血再灌注损伤中的作用。     

活性氧的内源性心肌保护作用及其机制

既往认为在心肌缺血/再灌注过程中活性氧是一种有害的细胞损伤因子,但最近研究发现也是可产生细胞保护作用的信号分子.活性氧(reactive oxygen species,ROS)在缺血,再灌注及其内源性心肌保护作用中具有双重作用,内源性心肌保护过程中活性氧主要来自线粒体呼吸链,主要通过mKATP-ROS通路产生;活性氧通过改变细胞氧化还原状态和调节线粒体膜通透性转换孔道开放状态,传递线粒体和细胞之间的信息联系.因此.活性氧不单是缺血/再灌注氧化应激的损伤因子,也是产生内源性心肌保护作用的重要信号分子.     

活性氧的内源性心肌保护作用及其机制

既往认为在心肌缺血/再灌注过程中活性氧是一种有害的细胞损伤因子,但最近研究发现也是可产生细胞保护作用的信号分子.活性氧(reactive oxygen species,ROS)在缺血,再灌注及其内源性心肌保护作用中具有双重作用,内源性心肌保护过程中活性氧主要来自线粒体呼吸链,主要通过mKATP-ROS通路产生;活性氧通过改变细胞氧化还原状态和调节线粒体膜通透性转换孔道开放状态,传递线粒体和细胞之间的信息联系.因此.活性氧不单是缺血/再灌注氧化应激的损伤因子,也是产生内源性心肌保护作用的重要信号分子.     

活性氧的内源性心肌保护作用及其机制

既往认为在心肌缺血/再灌注过程中活性氧是一种有害的细胞损伤因子,但最近研究发现也是可产生细胞保护作用的信号分子.活性氧(reactive oxygen species,ROS)在缺血,再灌注及其内源性心肌保护作用中具有双重作用,内源性心肌保护过程中活性氧主要来自线粒体呼吸链,主要通过mKATP-ROS通路产生;活性氧通过改变细胞氧化还原状态和调节线粒体膜通透性转换孔道开放状态,传递线粒体和细胞之间的信息联系.因此.活性氧不单是缺血/再灌注氧化应激的损伤因子,也是产生内源性心肌保护作用的重要信号分子.     

Nrf2/HO-1 信号通路与缺血再灌注损伤的研究进展

各组织器官在一定时间的缺血基础上恢复血流后,组织功能代谢障碍及结构破坏较缺血时反而加重的现象被称为缺血再灌注损伤(IRI)。IRI 是一种不同于缺血时期损伤情况的复杂病理反应,也一直都是临床工作者研究的热点。核因子E2 相关因子2(Nrf2)/ 血红素加氧酶1(HO-1)途径是参与机体抗氧化应激反应的重要信号通路,很多研究已显示激活Nrf2/HO-1 通路后能够减轻缺血再灌注引起的损伤。本文对Nrf2/HO-1 信号通路在IRI 中所起的作用进行综述。     

肝脏缺血再灌注损伤的研究进展

肝脏缺血再灌注损伤是肝脏外科常见的病理生理过程,是集肝窦血管内皮损伤、氧化应激、炎症反应、细胞凋亡与自噬等多种机制共同作用的结果,对于肝切除、肝移植等肝脏外科手术后肝功能恢复和围手术期安全具有显著影响.然而,迄今为止,其具体的损伤机制尚未完全阐明,在临床上也始终缺乏有效的干预手段.因此,对于肝脏缺血再灌注损伤发病机制以及防御举措的深入研究具有重要的临床意义.笔者结合近年来最新文献报道,对该领域的实验研究进展予以简要综述.     

caspase-1及下游炎性因子与急性肾缺血-再灌注损伤

在缺血-再灌注过程中细胞因子的表达异常活跃,正常情况下抑炎因子和促炎因子之间的动态平衡状态被打破.目前这种过度的细胞因子表达被认为是引起包括炎症、细胞凋亡等一系列再灌注损伤的基础.近年的研究表明caspase-1及其下游因子IL-18、IL-1β、IFN-γ这组功能密切相关的前炎性因子,在急性肾缺血-再灌注损伤中发挥重要作用.现将它们在急性肾缺血-再灌注损伤的作用及其作用机制作一综述.     

热休克蛋白70保护肝缺血再灌注损伤的研究进展

肝缺血再灌注（IR）损伤是引起肝脏损害的重要因素，已成为研究的热点和难点。近年来研究发现HSP70在组织、器官的IR损伤中起了重要的保护作用，笔者就其在肝IR损伤中的作用作一综述，并重点阐述其作用机制，如调控炎症因子、抗细胞凋亡以及抗氧化作用等。     

The contemporary role of antioxidant therapy in attenuating liver ischemia-reperfusion injury: a review.

Oxidative stress is an important factor in many pathological conditions such as inflammation, cancer, ageing and organ response to ischemia-reperfusion. Humans have developed a complex antioxidant system to eliminate or attenuate oxidative stress. Liver ischemia-reperfusion injury occurs in a number of clinical settings, including liver surgery, transplantation, and hemorrhagic shock with subsequent fluid resuscitation, leading to significant morbidity and mortality. It is characterized by significant oxidative stress but accompanied with depletion of endogenous antioxidants. This review has 2 aims: firstly, to highlight the clinical significance of liver ischemia-reperfusion injury, the underlying mechanisms and the main pathways by which the antioxidants function, and secondly, to describe the new developments that are ongoing in antioxidant therapy and to present the experimental and clinical evidence about the role of antioxidants in modulating hepatic ischemia-reperfusion injury.     

线粒体途径在肝脏缺血再灌注损伤中的作用的研究进展

肝胆外科手术常发生肝脏缺血再灌注损伤,并且术后肝功能恢复及预后与之密切相关。虽然肝脏缺血再灌注损伤的机制复杂多样,但线粒体结构功能障碍是重要的参与者。本综述旨在总结肝脏缺血再灌注过程中线粒体变化、线粒体自噬和凋亡在缺血再灌注损伤中的作用。为减轻肝脏缺血再灌注损伤提供新靶点和新思路。     

Hippo-Yap信号通路在肝脏疾病中的作用及其研究进展

河马（Hippo）信号通路最初作为一种抑制果蝇组织生长的通路被发现,主要由MST1/2、LATS1/2和Yap/TAZ三种激酶级联组成。随着研究的进展,在哺乳动物中Hippo信号通路的同源基因也得到了证实,并且在控制器官大小和其他生理功能当中也发挥着关键的作用。Hippo信号通路主要通过调控Yap的核移位发生相应的作用。当Hippo信号通路的上游激酶失活时,Yap/TAZ被去磷酸化并且能够作为转录共激活因子进入细胞核,与相应的转录因子结合发挥作用。既往Hippo-Yap信号通路研究主要集中于细胞命运、新陈代谢、肿瘤发生和免疫系统等方面。随着研究的逐步深入以及肝脏疾病的发生率逐步升高,Hippo信号通路在肝脏疾病的发生与发展过程中的相关研究取得一定的进展。笔者从多种临床常见相关肝脏疾病（胆汁淤积性肝损伤、肝缺血再灌注损伤、非酒精性脂肪性肝病、酒精性肝病、对乙酰氨基酚诱导肝损伤、肝纤维化以及肝癌）阐述Hippo-Yap信号通路在其中所发挥作用。     

Adipose delivered stem cells protect liver after ischemia-reperfusion injury by controlling autophagy

Objective: Ischemia-reperfusion(I/R) injury is an unavoidable side effect of liver surgery and transplantation. A potentially useful tool for cellular therapy and tissue engineering is adipose-derived stem cells (ADSCs).The process of autophagy is used by the cell to break down inappropriate molecules.The study's goal was to examine the impact of ADSCs on the autophagic pathway after rat hepatic ischemia-reperfusion injury.Material and Methods: Thirty male rats used in our study were divided into control, ADSC, ischemia, I/R, and I/R+ ADSC groups (n = 6). Liver tissues were stained with hematoxylin-eosin and histological changes were evaluated with Suzuki scoring. Immunoexpressions of transforming growth factor (TGF-β) and autophagy markers LC3B, p62 were analyzed using the immunohistochemical method.Results: As a result of histological evaluation the ischemia and I/R groups displayed sinusoid congestion, vacuolization, and necrosis in liver tissues. We showed that the immunostaining of LC3B and TGF- β were elevated, and p62 decreased in the rat liver from ischemia and I/R groups when compared to the control group.Conclusion: ADSCs reduced the excessive level of autophagy and structural damage to hepatocytes and the pathological alterations in the liver after ıschemia-reperfusion injury.     

Exogenous biliverdin ameliorates ischemia-reperfusion injury in small-for-size rat liver grafts

OBJECTIVE: This study sought to investigate the protective potential of exogenous biliverdin (BV) for small-for-size rat liver transplants. METHODS AND RESULTS: We employed a rat orthotopic liver transplantation model using small-for-size grafts. BV (50 mumol/kg, intravenously) given to the recipient immediately before reperfusion increased 7-day survival rates (90% vs 40% in controls) and significantly diminished hepatocyte injury, as compared with a control group. These effects correlated with improved liver function and preserved hepatic architecture. BV adjuvant increased antioxidant ability, suppressed proinflammatory tumor necrosis factor-alpha expression, down-regulated proapoptotic molecules (cytochrome C and caspase-3), and inhibited most apoptotic cells. After reperfusion, there was a significant increase of c-Jun NH(2)-terminal kinase (JNK) activation and AP-1 binding ability. BV treatment effectively repressed JNK/AP-1 activation, indicating that a beneficial effect of BV treatment may be related to suppression of the JNK/AP-1 pathway. CONCLUSIONS: BV treatment alleviated ischemia-reperfusion injury at least in part via inhibition of the proinflammatory and proapoptotic JNK/AP-1 pathway. Our findings provide a rationale for a novel therapeutic approach using BV to maximize the availability of small-for-size liver grafts.     

Augmenter of liver regeneration-mediated mitophagy protects against hepatic ischemia/reperfusion injury

Augmenter of liver regeneration (ALR) is an anti-apoptotic protein found mainly in mitochondria. It protects hepatocytes from ischemia-reperfusion (I/R) injury, but the underlying mechanism is not clear. We found that in rats, delivery of the ALR gene alleviated hepatic I/R injury during orthotopic liver transplantation as evidenced by reduced serum aminotransferase, oxidative stress and apoptosis, and increased expression of autophagy markers. In an in vitro hypoxia/reoxygenation (H/R) model, overexpression of the ALR gene activated autophagy and relieved defective mitophagy via the PINK1/Parkin pathway. Mechanistically, ALR transfection induced the expression of mitofusin 2 (Mfn2) in the H/R model, which led to PINK1 accumulation and mitochondrial translocation of Parkin. Deletion of Mfn2 abolished mitophagy activation induced by ALR transfection, promoted mitochondrial dysfunction, and eventually increased cell apoptosis. Mfn2 administration prevented the inhibition of mitophagy in ALR-knockout (KO) cells, thus attenuated mitochondrial dysfunction and cell apoptosis. In heterozygous ALR-knockout mice treated with a warm I/R injury, marked aggravation of liver injury was associated with mitophagy inhibition and reduction in Mfn2 expression. Taken together, our results confirm that ALR accelerated Parkin translocation and mitophagy via Mfn2, and protected hepatocytes from I/R-induced injury. Our findings provide a novel rationale for the treatment of hepatic I/R injury.     

海藻糖对肝脏缺血再灌注损伤的保护作用及机制研究

目的探讨海藻糖是否对肝脏缺血再灌注损伤具有保护作用及其相关机制。方法C57BL/6J小鼠数字随机分为无缺血组、缺血再灌注组、海藻糖处理组和生理盐水对照组,缺血90 min后于再灌注的0h和6h,收集血液和肝组织,通过分离血清测丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)肝功能指标及肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)和白细胞介素-2(IL-2)炎症因子水平和肝组织病理改变研究海藻糖在肝脏缺血再灌注损伤中的作用;AML12小鼠肝细胞系构建缺糖缺氧-复糖复氧细胞模型,分为实验组和对照组,实验组根据给予的海藻糖浓度不同分为低剂量组和高剂量组,对照组无海藻糖,收集细胞,流式细胞仪检测凋亡水平以研究海藻糖对肝脏缺血再灌注损伤诱导的细胞凋亡的影响,蛋白印迹法检测Caspase-3、Cleaved Caspase-3和Bcl-2蛋白水平以研究海藻糖在肝脏缺血再灌注损伤诱导的细胞凋亡中的分子机制。结果体内动物实验显示肝脏缺血再灌注后,缺血再灌注组ALT、AST及TNF-α、IL-1β和IL-2等肝功能指标及炎症因子水平升高(P<0.05),且肝组织发生坏死;而在给予海藻糖处理后,ALT、AST、TNF-α、IL-1β和IL-2等水平较生理盐水对照组降低且肝组织坏死面积也减少(P<0.05)。体外细胞实验显示与对照组相比,实验组肝细胞凋亡水平下降;且实验组活化的促凋亡蛋白Cleaved Caspase-3水平下降、抗凋亡蛋白Bcl-2水平升高。结论在体内和体外条件下海藻糖对肝脏缺血再灌注损伤有保护作用,其机制可能是通过抑制肝脏缺血再灌注损伤诱导的炎症发生和抑制Caspase-3的活化并促进Bcl-2的表达,减轻细胞凋亡,从而保护肝脏缺血再灌注损伤。     

Current strategies to minimize hepatic ischemia-reperfusion injury by targeting reactive oxygen species

Ischemia-reperfusion is a major component of injury in vascular occlusion both during liver surgery and during liver transplantation. The pathophysiology of hepatic ischemia-reperfusion includes a number of mechanisms including oxidant stress that contribute to various degrees to the overall organ damage. A large volume of recent research has focused on the use of antioxidants to ameliorate this injury, although results in experimental models have not translated well to the clinic. This review focuses on critical sources and mediators of oxidative stress during hepatic ischemia-reperfusion, the status of current antioxidant interventions, and emerging mechanisms of protection by preconditioning. While recent advances in regulation of antioxidant systems by Nrf2 provide interesting new potential therapeutic targets, an increased focus must be placed on more in-depth mechanistic investigations in hepatic ischemia-reperfusion injury and translational research in order to refine current strategies in disease management.