Dehydroepiandrosterone ameliorates hepatocellular damage in obstructive jaundice

We aimed to investigate the ameliorating effect of dehydroepiandrosterone (DHEA) on the potential hepatocellular damage in experimental obstructive jaundice. Twenty‐four male rabbits in the study were randomly allocated into three groups. In the sham group, the choledochal canal was identified and explored. In the obstructive jaundice and treatment groups, the choledochal canal was ligated. Placebo and DHEA were administered to the obstructive jaundice and treatment groups, respectively. Blood samples were obtained at baseline, and both blood samples and liver tissue samples were obtained by re‐laparotomy performed on day 8. Biochemical parameters were measured in blood samples, and liver samples were histopathologically evaluated. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), alkaline phosphatase (ALP) and bilirubin levels were lower in the treatment group than in obstructive jaundice. Mononuclear inflammation in the portal region and hepatocyte degeneration were milder in the treatment group compared to obstructive jaundice group. Fibrosis and necrosis were also recovered by the DHEA treatment. In conclusion, these findings suggested that DHEA may reduce the obstructive jaundice‐induced hepatocellular damage. Copyright © 2010 John Wiley & Sons, Ltd.     

P4 ATPases - Lipid flippases and their role in disease

P4 ATPases (type 4 P-type ATPases) are multispan transmembrane proteins that have been implicated in phospholipid translocation from the exoplasmic to the cytoplasmic leaflet of biological membranes. Studies in Saccharomyces cerevisiae have indicated that P4 ATPases are important in vesicle biogenesis and are required for vesicular trafficking along several intracellular vesicular transport routes. Although little is known about mammalian P4 ATPases, some members of this subfamily appear to be associated with human disease or mouse pathophysiology. ATP8B1, a phosphatidylserine translocase, is the most extensively studied mammalian P4 ATPase. This protein is important for maintaining the detergent resistant properties of the apical membrane of the hepatocyte. Mutations in ATP8B1 give rise to severe liver disease. Furthermore, a role for Atp8b3 in mouse sperm cell capacitation has been suggested, whereas deficiency of Atp10a and Atp10d leads to insulin resistance and obesity in mice. Here we review the present status on the pathophysiological consequences of P4 ATPase deficiency.     

白藜芦醇通过促进SIRT1表达，抑制NF-κB和TNF-α表达抵抗牛磺胆酸诱导的胎盘合体滋养细胞HTR-8的炎症损伤

摘要 已有研究证明,沉默信息调节子1(silent information regulator , SIRT1）和核因子κB(nuclear factor-κB, NF-κB）参与多种炎性反应调节;SIRT1激活剂——白藜芦醇（resveratrol）可通过依赖或不依赖于SIRT1的途径抑制炎症反应。然而,SIRT1及白藜芦醇在妊娠期肝内胆汁瘀积症（intrahepatic cholestasis of pregnancy, ICP）炎性反应中的作用在国内外尚未见报道。本研究证明,白藜芦醇可通过上调SIRT1表达,下调NF-κB及肿瘤坏死因子α（tumor necrosis factor-alpha, TNF-α）表达保护牛磺胆酸 （taurocholic acid, TCA）引起的胎盘合体滋养细胞HTR-8炎性损伤。免疫组化及Western印迹显示,SIRT1蛋白在正常胎盘组织的表达水平明显高于妊娠期ICP胎盘组织,而NF-κB蛋白表达在正常胎盘组织的表达低于ICP胎盘组织。Western印迹揭示,SIRT1蛋白在HTR-8细胞中的表达水平随暴露的TCA浓度增高而降低;相反,NF-κB和TNF-α蛋白质水平随TCA浓度增高而升高。采用白藜芦醇处理HTR-8细胞,该差异可被逆转;且白藜芦醇这一作用可被Ex-527（一种SIRT1 抑制剂）阻断。上述结果证明,在ICP胎盘合体滋养细胞炎性反应中SIRT1表达下调,而NF-κB表达上调;其可能的机制是ICP高浓度胆汁酸干扰胎盘合体滋养细胞SIRT1-NF-κB通路,诱导炎症反应。上述结果还提示,SIRT1激动剂——白藜芦醇可通过诱导SIRT1表达,抑制NF-κB及TNF-α表达,保护牛磺胆酸诱导的胎盘合体滋养细胞的炎性损伤。本研究为白藜芦醇临床治疗（妊娠期）肝内胆汁瘀积症提供了新的证据。至于白藜芦醇是否可直接抑制NF-κB的表达还有待进一步探讨。     

Effect of surgically induced cholestasis on the levels of hepatic zinc and metallothionein in rat liver

Early effects of experimental cholestasis on the homeostasis of zinc (Zn) and metallothionein (MT) were studied in rats which had undergone bile duct ligation for 0, 3, 6, 9, 12, 16, 20, and 24 h. Transient increases in hepatic Zn levels were observed at 9 h but returned to control values at 12 h. Serum Zn levels increased at 24 h. Cholestasis was confirmed by increased serum alkaline phosphatase (AP) activity. MT increased at 3 h and reached a maximum level at 12 h and remained elevated even at 24 h after the onset of experimental cholestasis. No hepatocellular damage was detected according to the results of alanine aminotransferase (ALT) activities in serum. These results shown that the increases in Zn observed in liver are related to bile stagnation rather than to a hepatocellular damage and that increased MT occurs concurrently with increased hepatic Zn. These observations suggest that the cellular levels of Zn in cholestasis is regulated by homeostatic mechanisms, of which one could be mediated by MT.     

A case of active incomplete biliary cirrhosis in an aged female Japanese macaque (Macaca fuscata)

We describe the first case of biliary cirrhosis in Japanese macaque. Clinical signs had not been detected. The liver was nodular. Histopathologically, portal‐to‐portal pattern of fibrosis might have indicated chronic cholestasis. Fibrotic septa were infiltrated with inflammatory cells. Therefore, this case could be diagnosed as active incomplete biliary cirrhosis.     

丁二磺酸腺苷蛋氨酸联合熊去氧胆酸对妊娠期肝内胆汁淤积症患者肝功能及妊娠结局的影响

目的:探讨丁二磺酸腺苷蛋氨酸联合熊去氧胆酸对妊娠期肝内胆汁淤积症(ICP)患者肝功能及妊娠结局的影响。方法:选取2016年1月至2017年10月我院接诊的96例ICP患者,按照随机数字表法分为观察组和对照组,每组各48例,两组患者均给予常规基础治疗,对照组在此基础上给予熊去氧胆酸治疗,观察组在对照组基础上给予丁二磺酸腺苷蛋氨酸治疗,比较两组患者瘙痒、黄疸改善时间及治疗前后胆酸和肝功能指标检测结果,观察并对比两组母婴预后情况。结果:观察组瘙痒改善时间及黄疸改善时间均低于对照组(P0.05)。两组患者治疗前总胆汁酸(TBA)、甘胆酸(CG)、谷丙转氨酶(ALT)、谷草转氨酶(AST)、总胆红素(TBiL)、直接胆红素(DBiL)水平对比差异无统计学意义(P0.05);两组患者治疗后TBA、CG、ALT、AST、TBiL、DBiL水平均低于治疗前,且观察组低于对照组(P0.05)。观察组羊水污染、胎儿窘迫、早产、剖宫产及新生儿Apgar评分7分发生率均低于对照组(P0.05),两组患者产后出血、死胎发生率对比差异无统计学意义(P0.05)。结论:丁二磺酸腺苷蛋氨酸联合熊去氧胆酸能够有效改善ICP症状和肝功能,降低不良母婴预后发生风险,可作为优选治疗方案。     

Loss of cilia causes embryonic lung hypoplasia,liver fibrosis,and cholestasis in the talpid3 ciliopathy mutant

Sonic hedgehog plays an essential role in maintaining hepatoblasts in a proliferative non-differentiating state during embryogenesis. Transduction of the Hedgehog signaling pathway is dependent on the presence of functional primary cilia and hepatoblasts, therefore, must require primary cilia for normal function. In congenital syndromes in which cilia are absent or non-functional (ciliopathies) hepatorenal fibrocystic disease is common and primarily characterized by ductal plate malformations which underlie the formation of liver cysts, as well as less commonly, by hepatic fibrosis, although a role for abnormal Hedgehog signal transduction has not been implicated in these phenotypes. We have examined liver, lung and rib development in the talpid³ chicken mutant, a ciliopathy model in which abnormal Hedgehog signaling is well characterized. We find that the talpid³ phenotype closely models that of human short-rib polydactyly syndromes which are caused by the loss of cilia, and exhibit hypoplastic lungs and liver failure. Through an analysis of liver and lung development in the talpid³ chicken, we propose that cilia in the liver are essential for the transduction of Hedgehog signaling during hepatic development. The talpid³ chicken represents a useful resource in furthering our understanding of the pathology of ciliopathies beyond the treatment of thoracic insufficiency as well as generating insights into the role Hedgehog signaling in hepatic development.     

妊娠期肝内胆汁淤积导致新生儿肺损伤的高危因素及干预对策

目的:探讨妊娠期肝内胆汁淤积症综合症所致新生儿肺损伤的危险因素,并采取相应的措施以提高临床治疗水平。方法:选取2010年1月-2013年1月我院收治的70例妊娠肝内胆汁淤积症综合症患者作为观察组,另选取同期接受体检的65例正常晚期妊娠妇女为对照组。分析新生儿肺损伤的相关因素。结果:妊娠肝内胆汁淤积症综合症所致新生儿肺损伤高危险因素有高雌激素水平、机体免疫失衡、高微量元素硒、高总胆汁酸、高甘胆酸(p均0.05)。结论:妊娠肝内胆汁淤积症综合症所致新生儿肺损伤的高危因素较多,临床上要积极采取措施,避免产后母婴并发症的发生。     

Identification of intrahepatic cholangiocarcinoma related genes by comparison with normal liver tissues using expressed sequence tags

Intrahepatic cholangiocarcinoma (ICC), a malignant tumor derived from the bile duct epithelium, is one of the leading causes of death from cancer, worldwide. However, the mechanisms related to it remain largely unknown. In this study, an analysis of the gene expression profiles for ICC was done using the frequency of the ESTs obtained from nine cDNA libraries that constructed from 4 ICC cell lines and 4 normal liver tissues. One hundred and thirty-seven genes were identified as being either up- or down-regulated in human ICC cells. Thirty genes were randomly selected to confirm their differential expression in 4 human ICC cell lines and 5 ICC tissues compared to normal liver tissues by semi-quantitative RT-PCR. Among these genes, ANXA1, ANXA2, AMBP, and SERPINC1 were further verified by immunohistochemical analyses. In conclusion, these identified genes represent potential biomarkers for ICC and represent potential targets for elucidating the molecular mechanisms that are associated with ICC.