低氧诱导因子在心血管疾病中的研究进展

低氧诱导因子(HIF)为缺氧敏感性转录因子,是细胞对缺氧反应的主要调节因子,可诱导炎症、脂质代谢、内皮功能障碍、血管平滑肌细胞(VSMC)增殖,调控心血管疾病(CVD)的发生发展。该文综述了近年来HIF在CVD中的作用及作用机制的研究进展,讨论HIF对血管构成细胞类型的作用及机制以及与CVD发生发展之间的关系,可为解析CVD的发病机制和发现新的治疗靶点提供参考,旨在为进一步了解HIF在CVD发病机制中的作用及机制提供理论参考,并为设计靶向HIF的新型有效治疗药物提供依据。     

缺氧诱导因子-1在脑缺血后细胞凋亡中的作用

缺氧诱导因子-1(hypoxia-induciible factor-1,HIF-1)是细胞在缺氧环境中适应低氧的一种重要调节因子,其在细胞内的数量改变可调控低氧反应性基因的转录.脑缺血时,HIF-1可能抑制神经元凋亡而发挥神经保护作用,也可能通过诱导神经元凋亡而呈现神经毒性作用.     

缺氧诱导因子1-α在酒精性肝病形成中的表达

目的 研究缺氧诱导因子1-α(HIF1-α)在洒精性肝病动物模型的表达情况,探讨其与酒精性肝病的关系。方法 采用酒精灌胃法建立酒精性肝病动物模型,应用逆转录聚合酶链反应(RT-PCR)法和免疫组织化学染色法检测大鼠肝组织HIF1-α mRNA和蛋白水平。结果 RT-PCR结果显示模型组大鼠HIF1-α mRNA表达阳性率为62.5％(5/8),对照组为16.7％(2/12),x~2=3.94,P<0.05。两组大鼠肝脏HIF1-α多克隆抗体免疫组织化学染色评分分别为3.13±0.83和0.83±1.27,差异有非常显著必,t=4.88,P<0.01。结论 HIF1-α在酒精性肝病动物模型的表达明显增高,缺氧是酒精性肝病的发病机制之一。     

缺氧对非酒精性脂肪性肝病发病的影响*

非酒精性脂肪性肝病（NAFLD）患者存在系统性和肝脏局部缺氧。对于呼吸睡眠暂停综合征与脂肪性肝病的研究显示机体缺氧程度与胰岛素抵抗、肝脏脂肪变、炎症和纤维化程度相关。动物实验和分子生物学研究显示缺氧及其缺氧诱导因子能促进肝细胞脂肪堆积,加速肝脏炎症、纤维化,甚至肿瘤的发生和发展。     

Hypoxia,angiogenesis and liver fibrogenesis in the progression of chronic liver diseases

Angiogenesis is a dynamic,hypoxia-stimulated and growth factor-dependent process,and is currently referred to as the formation of new vessels from preexisting blood vessels.Experimental and clinical studies have unequivocally reported that hepatic angiogenesis,irrespective of aetiology,occurs in conditions of chronic liver diseases(CLDs) characterized by perpetuation of cell injury and death,inflammatory response and progressive fibrogenesis.Angiogenesis and related changes in liver vascular architecture,th...     

低氧诱导因子在慢性肾脏病中的作用研究进展

慢性肾脏病(chronic kidney diseases,CKD)是严重危害人类健康甚至致命的常见病。加强对CKD的防治,已成为不可忽视的公共卫生问题。CKD发病机制复杂多样,其中低氧诱导因子(hypoxia inducible factor,HIF)在CKD及其相关并发症的发生发展中起重要作用。HIF是机体内调节氧稳态的关键核转录因子,其通过调控下游靶基因的转录及与多种信号通路交互作用等方式,在肾脏纤维化病理进程中起关键作用。此外,HIF在急性肾损伤(acute kidney injury,AKI)转变为CKD的过程中亦起重要作用。因此,靶向研究HIF及其相关信号通路具有重要的临床意义。该文就HIF的病理生理特点及其在CKD发生发展中的调节作用进行综述。     

Chronic venous diseases: roles of various pathophysiological factors

Disturbances in haemodynamic, biochemical and enzymatic factors have been observed in chronic venous diseases (CVD). These changes lead to the development of varices, telangiectasies and skin disorders. They affect vessels, blood, skin tissues and cells. It is now possible to describe their time course and interdependance of these changes. Orthostatism pressure on vein wall may lead to fluid leakage and oedema, these resulting in vein enlargement. These processes may be further influenced by genetic or acquired risk factors. Skin microvessels suffer more from hypoxia than from hypertension. Indeed, hypoxia affects not only endothelial cells, but also red and white blood cells and modifies particularly, but not exclusively, TGF-beta1 production. This substance is, an important modulator of zinc dependent-metallo-proteinases and their tissue inhibitor of metallo-proteinases (TIMP) in the skin. Imbalance in this enzymatic system seems to lead either to sclerosis or ulcer. Of course, other biochemical events (also in this review) play a role in vessel wall and skin deterioration in CVD. The aim of the present review is to assess the role of pathophysiological factors in CVD and the influence of different therapies, including the venotropic agent calcium dobesilate, on some of these haemodynamic or biochemical aspects.     

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

Circadian rhythms and clock gene expressions are regulated by the suprachiasmatic nucleus in the hypothalamus, and melatonin is produced in the pineal gland. Although the brain detects the light through retinas and regulates rhythms and melatonin secretion throughout the body, the liver has independent circadian rhythms and expressions as well as melatonin production. Previous studies indicate the association between circadian rhythms with various liver diseases, and disruption of rhythms or clock gene expression may promote liver steatosis, inflammation, or cancer development. It is well known that melatonin has strong antioxidant effects. Alcohol drinking or excess fatty acid accumulation produces reactive oxygen species and oxidative stress in the liver leading to liver injuries. Melatonin administration protects these oxidative stress-induced liver damage and improves liver conditions. Recent studies have demonstrated that melatonin administration is not limited to antioxidant effects and it has various other effects contributing to the management of liver conditions. Accumulating evidence suggests that restoring circadian rhythms or expressions as well as melatonin supplementation may be promising therapeutic strategies for liver diseases. This review summarizes recent findings for the functional roles and therapeutic potentials of circadian rhythms and melatonin in liver diseases.     

Respective roles of hypoxia and halothane metabolism in halothane-induced liver injury in rats

To evaluate the respective roles of halothane metabolism and hypoxia in rats with halothane hepatotoxicity, experiments were designed with special reference to blood gas. After pretreatment with phenobarbital (80 mg per kg., i.p.) for four consecutive days, rats were exposed to 1.0% halothane under a mildly hypoxic condition (FiO2 = 14%) for 2 hr. Since halothane anesthesia caused significant decrease in PaO2 levels, rats exposed to a highly hypoxic atmosphere (FiO2 = 10%) in which PaO2 levels were comparable to those in the halothane group, served as the control. In the halothane group, marked centrilobular necrosis and elevation of SGPT activity were observed; neither significant histological lesions nor elevation of transaminase activity occurred in the highly hypoxic group. Although phenobarbital treatment did not decrease PaO2 levels during halothane anesthesia, the serum fluoride level, which appears to reflect quantitatively the reductive pathway of halothane metabolism, increased. These results strongly indicate that halothane metabolism rather than hypoxia, per se, plays a major role in development of halothane-induced liver injury in rats.     

肝纤维化的负性调控因素及其作用

肝纤维化是各种形式肝损伤之后组织修复反应,是促进肝纤维化正性调控因素与抑制肝纤维化负性调控因素相互作用的结果,本文就肝纤维化的各种负性调控因素及其作用阐述如下。     

Possible roles of Golgi protein-73 in liver diseases

Golgi protein 73 (also known as GP73 or GOLPH2) is a transmembrane glycoprotein present in the Golgi apparatus. In diseased states, GP73 is expressed by hepatocytes rather than by bile duct epithelial cells. Many studies have reported that serum GP73 (sGP73) is a marker for hepatocellular carcinoma (HCC). For HCC diagnosis, the sensitivities of sGP73 were higher than that of other markers but the specificities were lower. Considering that the concentration of GP73 is consistent with the stage of liver fibrosis and cirrhosis, some studies have implied that GP73 may be a marker for liver fibrosis and cirrhosis. Increased sGP73 levels may result from hepatic inflammatory activity. During liver inflammation, GP73 facilitates liver tissue regeneration. By summarizing the studies on GP73 in liver diseases, we wish to focus on the mechanism of GP73 in diseases.     

NLRP3炎症小体在肝脏疾病发病中的作用研究进展

炎症小体是一种存在于细胞浆中的多蛋白复合物,是机体固有免疫的重要组分之一。在核苷酸结合寡聚化结构域（NOD）样受体家族（NOD-like receptors,NLRs）中,NLRP3炎症小体主要是由NLRP3、凋亡相关的斑点样蛋白（ASC）和半胱氨酸的天冬氨酸蛋白水解酶（Caspase-1）等相互结合而形成的,具有调节免疫和抗微生物等作用。近年来发现其在多种肝脏疾病的发生、发展过程中发挥着巨大作用。本文主要介绍NLRP3炎症小体的激活通路、作用机制、表达调控及其与肝脏疾病发病的关系。     

Toll样受体在肝脏疾病中的功能

Toll样受体（Toll—like receptors，TLRs）是近年来发现的在天然免疫和获得性免疫系统中都发挥重要作用的模式识别受体（pattern recognition receptors，PRR）家族，能够识别病原微生物表达的保守结构基序（Motifs），即病原相关的分子模式（pathogen-associated molecular pattern，PAMP），包括细菌的细胞壁成分，含有胞嘧啶-腺嘌呤（CpG）的细菌DNA，病毒的单链及双链RNA等。作为一种PRR，TLRs构成了免疫系统识别“非己”的第一道防线，通过其信号转导途径，可以启动细胞因子的释放，激发机体对病原体的免疫响应。     

组学在肝脏疾病研究中的应用

在本世纪初,科学家们成功的完成了“人类基因组计划”（HGP）和“人类单倍型图”。人类基因组计划研究结果显示,两个不相关个体间基因组的差异大约为0．1％,然而正是因为这0．1％的不同导致了数百万个核苷酸序列的差异,最终引起人类不同人群和个体在生理特点及疾病易感性上的于差万别。近年来随着现代遗传研究技术的进步,为我们阐明人类疾病的发病机制及发展个性化的诊断和治疗开辟了广阔的前景。本文对现代遗传学在肝脏疾病研究中的进展作一简述。     

缺氧诱导因子-1α在大鼠肝纤维化组织中的表达及其意义

目的 观察缺氧诱导因子-1α(HIF-1α)、基质金属蛋白酶-9(MMP-9)和转化生长因子(TGF)-β1在大鼠肝纤维化组织中的表达以及TGF-β1疫苗对这些因子表达的影响.方法 二甲基亚硝胺建立大鼠肝纤维化模型,并予以TGF-β1疫苗干预.在实验6周末用免疫组织化学方法 检测HIF-1α、MMP-9和TGF-β1在大鼠肝纤维化组织中的表达情况.组间比较采用单因素方差分析.方差齐性者两两比较采用LSD法,方差不齐者进行Dunnet's T3检验.结果与对照组比较,肝纤维化模型组及TGF-β1疫苗干预组HIF-1α、MMP-9、TGF-β1表达显著增加(P＜0.01),且与肝纤维化程度呈正相关关系(r值分别为0.911、0.814、0.836,P＜0.01);与肝纤维化模型组比较,TGF-β1疫苗干预组HIF-1α、MMP-9和TGF-β1表达显著降低(t值分别为2.62、4.03、3.43,P＜0.01).结论肝纤维化发生发展过程中,HIF-1α促进了TGF-β1、MMP-9等基因的转录表达.