妊娠期肝内胆汁淤积症患者胎盘差异表达蛋白的筛选及功能研究
|
摘要
妊娠期肝内胆汁淤积症(Intrahepatic cholestasis of pregnancy, ICP)是妊娠期特有的一种疾病，以皮肤瘙痒伴随血清胆汁酸水平升高为主要临床特征。该病主要好发于妊娠中晚期，随着分娩结束，患者临床症状体征及血清生化指标迅速恢复正常。ICP虽然对母体不会造成严重危害，但是它常可导致早产、胎儿宫内窘迫、死胎等严重胎儿不良并发症的发生。虽然已有研究表明该病发生有明显的种族及地域特征，并且与激素水平，免疫因素及环境因素等密切相关，但该病具体发病机制及导致不良妊娠结局机制尚不明确。为了进一步研究ICP的发病机制及导致不良妊娠结局的机制，本研究首次采用同位素标记相对和绝对定量技术(isobaric tags for relative and absolute quantification, iTRAQ)为基础的蛋白质组学研究方法，在“整体”蛋白组范围内，对ICP患者及正常对照胎盘组织进行高通量的“全组”蛋白直接鉴定和相对定量分析，在ICP患者及正常对照的胎盘组织中共鉴定到7399个肽段，对应2120个蛋白，经统计学分析，ICP组与正常对照组比较，两组间差异倍数大于1.5倍的差异表达蛋白总共有38个，其中上调蛋白有29个，下调蛋白有9个。聚类分析显示这38个差异蛋白在病例组与对照组中表达模式特异，生物信息学分析提示这些差异蛋白主要参与细胞凋亡，氧化应激，脂质代谢，免疫调节等生物学事件。我们挑选了三个差异表达蛋白(ERp29、PRDX6及MPO)，应用免疫组化及Western blot的方法进行差异验证，结果表明ICP患者胎盘组织ERp29及PRDX6明显高于正常对照，而MPO表达明显低于正常对照，差异均具有统计学意义(P <0.05)，实验结果与质谱鉴定结果一致。根据已有的文献报道及我们的蛋白质组学研究结果均提示ICP患者存在胎盘凋亡现象，因此我们应用TUNEL方法对ICP患者胎盘组织凋亡进行了检测，结果显示ICP患者胎盘凋亡明显高于正常对照(P=0.003)。研究报道ERp29是一种内质网蛋白，多种肿瘤组织如乳腺癌中高表达ERp29可以诱导肿瘤细胞凋亡，抑制细胞周期，从而抑制肿瘤发生发展。本研究通过蛋白质组学研究发现ERp29在ICP患者胎盘组织存在高表达现象，并经过免疫组化及Western blot验证。因此，我们推测ERp29在ICP患者胎盘凋亡及胎儿不良并发症发生中可能起了关键作用，为了进一步明确ICP时胎盘凋亡的发生机制，我们挑选了ERp29这个差异蛋白进一步进行体外实验研究。体外培养人胎盘滋养细胞系HTR-8/SVneo并进行胆酸(taurocholic acid, TCA)干预实验，我们发现ERp29表达水平及胎盘细胞凋亡率在100μM TCA组明显高于10μM TCA组及空白对照组，细胞周期检测结果显示各胆酸浓度组无明显差异；同时我们进行了磷酸化p38检测及caspase-3活性检测，结果表明100μM TCA组磷酸化p38及caspase-3活性明显高于10μM TCA组及空白对照组，差异均具有统计学意义(P <0.05)。ICP患者胎盘差异表达蛋白的筛选及功能研究为进一步深入研究该病发病机制提供了理论基础。我们的研究结果表明ICP患者存在ERp29过表达现象，ERp29的过表达可能通过激活p38磷酸化从而诱导胎盘滋养细胞凋亡，提示ERp29可以作为ICP靶向治疗的一个分子靶标。
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific disease,which is characterized by pruritus and elevated liver enzymes and/or serum bile acids.ICP usually occurs during the third trimester and the symptoms of the disease and theliver dysfunction resolve quickly after delivery. However, it can have severeconsequences for the fetus and is associated with an increased risk of spontaneouspre-term labour, fetal distress and sudden intrauterine death. Up to date, the exactcause of this disease is unknown, although genetic and hormonal, and probablyenvironmental factors are involved in the development of ICP. To explore thepathogenesis of ICP and fetal complications, we performed an isobaric tags forrelative and absolute quantification (iTRAQ) based proteomics approach andidentified2120proteins (7399peptides) in the placental tissues of all samplesincluding ICP patients and normal controls, and a total of38differentially expressedproteins were separated, of which29were upregulated and9were downregulated inICP. Cluster analysis was performed to characterize the specific and uniqueexpression patterns of the38differentially expressed proteins, it displayed thesignificantly altered expression levels of the proteins in ICP patients and normalcontrols. Bioinformatic analysis was performed to analyze the role of these proteinsin cellular processes and the results showed that most of the identified proteins werefunctionally related to specific cell processes, including apoptosis, oxidative stress,lipid metabolism, cell cycle, immune response, cell proliferation and cell growth.Three differentially expressed proteins, namely endoplasmic reticulum protein29(ERp29), myeloperoxidase (MPO) and peroxiredoxin6(PRDX6) were chosen forverification in4cases of ICP patients and4controls using Western blotting andimmunohistochemical analysis. The results showed that PRDX6and ERp29wereupregulated, whereas MPO was downregulated in ICP patients versus controls (P < 0.05). The expression patterns of the three proteins were consistent with theproteomic and Western blotting analysis. Based on previous studies and ourproteomic results, which suggested the appearance of apoptosis in the placental tissueof ICP patients, we also quantified the apoptotic index in the placenta. We found thatthere were few TUNEL-positive cells in the placental tissue of the normal controls,whereas, the apoptotic index was significantly higher in the placental tissue of ICPpatients. Recent studies have shown that ERp29is an endoplasmic reticulum protein,and high expression of ERp29inversely correlates with tumor progression due toinduction of apoptosis and inhibition of the cell cycle in a variety of cancer cells,including breast cancer cells. In this study, we found that ERp29was upregulated inthe placental tissue of ICP patients. So, we speculated that ERp29may play a key rolein the molecular pathogenesis of apoptosis in the placenta and ICP-related fetalcomplications. In order to verify this hypothesis, we quantified the expression ofERp29and apoptotic index in HTR-8/SVneo cells after treatment with differentconcentrations of taurocholic acid (TCA) for6h. We demonstrated that theexpression of ERp29and apoptotic index were significantly higher in the100μMTCA group than the10μM TCA groups and negative control group (P <0.05),respectively. Cell cycle analysis showed that the proportions of cells in the G1phase,S phase and G2/M phase at different time points (24h,48h and72h) were notsignificantly different among different concentrations of TCA groups, respectively. Tofurther explore the mechanism of ERp29overexpression on apoptosis in the placentaof ICP patients, we investigated the expression of p38and phosphorylated (p)-p38inHTR-8/SVneo cells after treatment with TCA. Western blotting result indicated thatthe levels of p-p38significantly increased in the100μM TCA group, compared withthe10μM TCA group and negative control group (P <0.01). Caspase-3activity alsosignificantly increased in the100μM TCA group, compared with the10μM TCAgroup and negative control group (P <0.01). This quantitative proteomics mayprovide us new insights into the pathophysiology and novel treatment targets for ICP.Among the38differentially expressed proteins, we discovered that ERp29may playa key role in placental apoptosis by inducing p38phosphorylation and activating caspase-3, which suggests that ERp29may represent a novel target for the treatment
of ICP.
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific disease,which is characterized by pruritus and elevated liver enzymes and/or serum bile acids.ICP usually occurs during the third trimester and the symptoms of the disease and theliver dysfunction resolve quickly after delivery. However, it can have severeconsequences for the fetus and is associated with an increased risk of spontaneouspre-term labour, fetal distress and sudden intrauterine death. Up to date, the exactcause of this disease is unknown, although genetic and hormonal, and probablyenvironmental factors are involved in the development of ICP. To explore thepathogenesis of ICP and fetal complications, we performed an isobaric tags forrelative and absolute quantification (iTRAQ) based proteomics approach andidentified2120proteins (7399peptides) in the placental tissues of all samplesincluding ICP patients and normal controls, and a total of38differentially expressedproteins were separated, of which29were upregulated and9were downregulated inICP. Cluster analysis was performed to characterize the specific and uniqueexpression patterns of the38differentially expressed proteins, it displayed thesignificantly altered expression levels of the proteins in ICP patients and normalcontrols. Bioinformatic analysis was performed to analyze the role of these proteinsin cellular processes and the results showed that most of the identified proteins werefunctionally related to specific cell processes, including apoptosis, oxidative stress,lipid metabolism, cell cycle, immune response, cell proliferation and cell growth.Three differentially expressed proteins, namely endoplasmic reticulum protein29(ERp29), myeloperoxidase (MPO) and peroxiredoxin6(PRDX6) were chosen forverification in4cases of ICP patients and4controls using Western blotting andimmunohistochemical analysis. The results showed that PRDX6and ERp29wereupregulated, whereas MPO was downregulated in ICP patients versus controls (P < 0.05). The expression patterns of the three proteins were consistent with theproteomic and Western blotting analysis. Based on previous studies and ourproteomic results, which suggested the appearance of apoptosis in the placental tissueof ICP patients, we also quantified the apoptotic index in the placenta. We found thatthere were few TUNEL-positive cells in the placental tissue of the normal controls,whereas, the apoptotic index was significantly higher in the placental tissue of ICPpatients. Recent studies have shown that ERp29is an endoplasmic reticulum protein,and high expression of ERp29inversely correlates with tumor progression due toinduction of apoptosis and inhibition of the cell cycle in a variety of cancer cells,including breast cancer cells. In this study, we found that ERp29was upregulated inthe placental tissue of ICP patients. So, we speculated that ERp29may play a key rolein the molecular pathogenesis of apoptosis in the placenta and ICP-related fetalcomplications. In order to verify this hypothesis, we quantified the expression ofERp29and apoptotic index in HTR-8/SVneo cells after treatment with differentconcentrations of taurocholic acid (TCA) for6h. We demonstrated that theexpression of ERp29and apoptotic index were significantly higher in the100μMTCA group than the10μM TCA groups and negative control group (P <0.05),respectively. Cell cycle analysis showed that the proportions of cells in the G1phase,S phase and G2/M phase at different time points (24h,48h and72h) were notsignificantly different among different concentrations of TCA groups, respectively. Tofurther explore the mechanism of ERp29overexpression on apoptosis in the placentaof ICP patients, we investigated the expression of p38and phosphorylated (p)-p38inHTR-8/SVneo cells after treatment with TCA. Western blotting result indicated thatthe levels of p-p38significantly increased in the100μM TCA group, compared withthe10μM TCA group and negative control group (P <0.01). Caspase-3activity alsosignificantly increased in the100μM TCA group, compared with the10μM TCAgroup and negative control group (P <0.01). This quantitative proteomics mayprovide us new insights into the pathophysiology and novel treatment targets for ICP.Among the38differentially expressed proteins, we discovered that ERp29may playa key role in placental apoptosis by inducing p38phosphorylation and activating caspase-3, which suggests that ERp29may represent a novel target for the treatment
of ICP.
引文
[1]. Perez MJ, Macias RI, Marin JJ. Maternal cholestasis induces placentaloxidative stress and apoptosis. Protective effect of ursodeoxycholic acid.Placenta,2006,27(1):34-41.
[2]. Rook M, Vargas J, Caughey A, Bacchetti P, Rosenthal P, Bull L. Fetal outcomesin pregnancies complicated by intrahepatic cholestasis of pregnancy in aNorthern California cohort. PloS one,2012,7(3): e28343.
[3]. Glantz A, Reilly SJ, Benthin L, Lammert F, Mattsson LA, Marschall HU.Intrahepatic cholestasis of pregnancy: Amelioration of pruritus by UDCA isassociated with decreased progesterone disulphates in urine. Hepatology,2008,47(2):544-551.
[4]. Lee RH, Incerpi MH, Miller DA, Pathak B, Goodwin TM. Sudden fetal death inintrahepatic cholestasis of pregnancy. Obstet Gynecol,2009,113(2):528-531.
[5]. Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy:Relationships between bile acid levels and fetal complication rates. Hepatology,2004,40(2):467-474.
[6]. Dixon PH, van Mil SW, Chambers J, Strautnieks S, Thompson RJ, Lammert F,Kubitz R, Keitel V, Glantz A, Mattsson LA, Marschall HU, Molokhia M, Moore,GE, Linton KJ, Williamson C. Contribution of variant alleles of ABCB11tosusceptibility to intrahepatic cholestasis of pregnancy. Gut,2009,58(4):537-544.
[7]. Chappell LC, Gurung V, Seed PT, Chambers J, Williamson C, Thornton JG.Ursodeoxycholic acid versus placebo, and early term delivery versus expectantmanagement, in women with intrahepatic cholestasis of pregnancy:semifactorial randomised clinical trial. BMJ,2012,344: e3799.
[8]. Reyes H. Sex hormones and bile acids in intrahepatic cholestasis of pregnancy.Hepatology,2008,47(2):376-379.
[9]. Geenes V, Williamson C. Intrahepatic cholestasis of pregnancy. World JGastroenterol,2009,15(17):2049-2066.
[10]. Stieger B, Geier A. Genetic variations of bile salt transporters as predisposingfactors for drug-induced cholestasis, intrahepatic cholestasis of pregnancy andtherapeutic response of viral hepatitis. Expert Opin Drug Metab Toxicol,2011,7(4):411-425.
[11]. van der Woerd WL, van Mil SW, Stapelbroek JM, Klomp LW, van de Graaf SF,Houwen RH. Familial cholestasis: progressive familial intrahepatic cholestasis,benign recurrent intrahepatic cholestasis and intrahepatic cholestasis ofpregnancy. Best Pract Res Clin Gastroenterol,2010,24(5):541-553.
[12]. Pata O, Vardareli E, Ozcan A, Serteser M, Unsal I, Saruc M, Unlu C, Tozun N.Intrahepatic cholestasis of pregnancy: correlation of preterm delivery with bileacids. Turk J Gastroenterol,2011,22(6):602-605.
[13]. Wikstrom Shemer EA, Thorsell M, Marschall HU, Kaijser M. Risks ofemergency cesarean section and fetal asphyxia after induction of labor inintrahepatic cholestasis of pregnancy: A hospital-based retrospective cohortstudy. Sex Reprod Healthc,2013,4(1):17-22.
[14]. Laatikainen T, Tulenheimo A. Maternal serum bile acid levels and fetal distressin cholestasis of pregnancy. Int J Gynaecol Obstet,1984,22(2):91-94.
[15]. Lee RH, Kwok KM, Ingles S, Wilson ML, Mullin P, Incerpi M, Pathak B,Goodwin TM. Pregnancy outcomes during an era of aggressive management forintrahepatic cholestasis of pregnancy. Am J Perinatol,2008,25(6):341-345.
[16]. Marin JJ, Macias RI, Serrano MA. The hepatobiliary-like excretory function ofthe placenta. A review. Placenta,2003,24(5):431-438.
[17]. Serrano MA, Macias RI, Briz O, Monte MJ, Blazquez AG, Williamson C,Kubitz R, Marin JJ. Expression in human trophoblast and choriocarcinoma celllines, BeWo, Jeg-3and JAr of genes involved in the hepatobiliary-likeexcretory function of the placenta. Placenta,2007,28(2-3):107-117.
[18]. Marin JJ, Briz O, Serrano MA. A review on the molecular mechanismsinvolved in the placental barrier for drugs. Curr Drug Deliv,2004,1(3):275-289.
[19]. Geenes VL, Lim YH, Bowman N, Tailor H, Dixon PH, Chambers J, Brown L,Wyatt-Ashmead J, Bhakoo K, Williamson C. A placental phenotype forintrahepatic cholestasis of pregnancy. Placenta,2011,32(12):1026-1032.
[20]. Wasinger VC, Cordwell SJ, Cerpa-Poljak A, Yan JX, Gooley AA, Wilkins MR,Duncan MW, Harris R, Williams KL, Humphery-Smith I. Progress withgene-product mapping of the Mollicutes: Mycoplasma genitalium.Electrophoresis,1995,16(7):1090-1094.
[21]. Sawicki G, Dakour J, Morrish DW. Functional proteomics of neurokinin B inthe placenta indicates a novel role in regulating cytotrophoblast antioxidantdefences. Proteomics,2003,3(10):2044-2051.
[22]. Choi DH, Lee WS, Won M, Park M, Park HO, Kim E, Lee KA, Bae J. Theapolipoprotein A-I level is downregulated in the granulosa cells of patients withpolycystic ovary syndrome and affects steroidogenesis. J Proteome Res,2010,9(9):4329-4336.
[23]. Wu WW, Wang G, Baek SJ, Shen RF. Comparative study of three proteomicquantitative methods, DIGE, cICAT, and iTRAQ, using2D gel-or LC-MALDITOF/TOF. J Proteome Res,2006,5(3):651-658.
[24]. Ross PL, Huang YN, Marchese JN, Williamson B, Parker K, Hattan S,Khainovski N, Pillai S, Dey S, Daniels S, Purkayastha S, Juhasz P, Martin S,Bartlet-Jones M, He F, Jacobson A, Pappin DJ. Multiplexed protein quantitationin Saccharomyces cerevisiae using amine-reactive isobaric tagging reagents.Mol Cell Proteomics,2004,3(12):1154-1169.
[25]. Manavalan A, Feng L, Sze SK, Hu JM, Heese K. New insights into the brainprotein metabolism of Gastrodia elata-treated rats by quantitative proteomics. JProteomics,2012,75(8):2468-2479.
[26].张岩,印永祥,许倩,赵华,项静英,许建娟.胎盘组织中胆酸调节蛋白的表达及其与妊娠期肝内胆汁郁积症发病的关系.中华妇产科杂志,2010,45(8):615-617.
[27]. Bacq Y, Sentilhes L, Reyes HB, Glantz A, Kondrackiene J, Binder T, NicastriPL, Locatelli A, Floreani A, Hernandez I, Di Martino V. Efficacy ofursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: ameta-analysis. Gastroenterology,2012,143(6):1492-1501.
[28].妊娠期肝内胆汁淤积症诊疗指南(第1版).中华妇产科杂志,2011,46(5)391:395.
[29]. Kersey PJ, Duarte J, Williams A, Karavidopoulou Y, Birney E, Apweiler R. TheInternational Protein Index: an integrated database for proteomics experiments.Proteomics,2004,4(7):1985-1988.
[30]. Cox J, Mann M. MaxQuant enables high peptide identification rates,individualized p.p.b.-range mass accuracies and proteome-wide proteinquantification. Nat Biotechnol,2008,26(12):1367-1372.
[31]. Deutsch EW, Mendoza L, Shteynberg D, Farrah T, Lam H, Tasman N, Sun Z,Nilsson E, Pratt B, Prazen B, Eng JK, Martin DB, Nesvizhskii AI, Aebersold R.A guided tour of the Trans-Proteomic Pipeline. Proteomics,2010,10(6):1150-1159.
[32]. Saeed AI, Bhagabati NK, Braisted JC, Liang W, Sharov V, Howe EA, Li J,Thiagarajan M, White JA, Quackenbush J. TM4microarray software suite.Methods Enzymol,2006,411:134-193.
[33]. Nikitin A, Egorov S, Daraselia N, Mazo I. Pathway studio--the analysis andnavigation of molecular networks. Bioinformatics,2003,19(16):2155-2157.
[34]. Pusl T, Beuers U. Intrahepatic cholestasis of pregnancy. Orphanet J Rare Dis,2007,2:26.
[35]. Pathak B, Sheibani L, Lee RH. Cholestasis of pregnancy. Obstet Gynecol ClinNorth Am.2010,37(2):269-282.
[36]. Zapata R, Sandoval L, Palma J, Hernandez I, Ribalta J, Reyes H, Sedano M,Toha D, Silva JJ. Ursodeoxycholic acid in the treatment of intrahepaticcholestasis of pregnancy. A12-year experience. Liver Int,2005,25(3):548-554.
[37]. Beuers U. Drug insight: Mechanisms and sites of action of ursodeoxycholicacid in cholestasis. Nature clinical practice. Nat Clin Pract GastroenterolHepatol,2006,3(6):318-328.
[38]. Mehan MR, Ostroff R, Wilcox SK, Steele F, Schneider D, Jarvis TC, Baird GS,Gold L, Janjic N. Highly multiplexed proteomic platform for biomarkerdiscovery, diagnostics, and therapeutics. Adv Exp Med Biol,2013,734:283-300.
[39]. Honda K, Ono M, Shitashige M, Masuda M, Kamita M, Miura N, Yamada T.Proteomic approaches to the discovery of cancer biomarkers for early detectionand personalized medicine. Jpn J Clin Oncol,2013,43(2):103-109.
[40]. Pollard HB, Eidelman O, Jozwik C, Huang W, Srivastava M, Ji XD, McGowanB, Norris CF, Todo T, Darling T, Mogayzel PJ, Zeitlin PL, Wright J, GugginoWB, Metcalf E, Driscoll WJ, Mueller G, Paweletz C, Jacobowitz DM. De novobiosynthetic profiling of high abundance proteins in cystic fibrosis lungepithelial cells. Mol Cell Proteomics,2006,5(9):1628-1637.
[41]. Cao Z, Yende S, Kellum JA, Robinson RA. Additions to the Human PlasmaProteome via a Tandem MARS Depletion iTRAQ-Based Workflow. Int JProteomics,2013,2013:654356.
[42]. Marzinke MA, Choi CH, Chen L, Shih Ie M, Chan DW, Zhang H. Proteomicanalysis of temporally stimulated ovarian cancer cells for biomarker discovery.Mol Cell Proteomics,2013,12(2):356-368.
[43]. DeSouza LV, Grigull J, Ghanny S, Dube V, Romaschin AD, Colgan TJ, Siu KW.Endometrial carcinoma biomarker discovery and verification usingdifferentially tagged clinical samples with multidimensional liquidchromatography and tandem mass spectrometry. Mol Cell Proteomics,2007,6(7):1170-1182.
[44]. Garbis SD, Tyritzis SI, Roumeliotis T, Zerefos P, Giannopoulou EG, Vlahou A,Kossida S, Diaz J, Vourekas S, Tamvakopoulos C, Pavlakis K, Sanoudou D,Constantinides CA. Search for potential markers for prostate cancer diagnosis,prognosis and treatment in clinical tissue specimens using amine-specificisobaric tagging (iTRAQ) with two-dimensional liquid chromatography andtandem mass spectrometry. J Proteome Res,2008,7(8):3146-3158.
[45]. Wei J, Wang H, Yang X, Dong M, Wang Z. Altered gene profile of placentafrom women with intrahepatic cholestasis of pregnancy. Arch Gynecol Obstet,2010,281(5):801-810.
[46]. Zhang D, Richardson DR. Endoplasmic reticulum protein29(ERp29): Anemerging role in cancer. Int J Biochem Cell Biol,2011,43(1):33-36.
[47]. Ying X, Liu Y, Guo Q, Qu F, Guo W, Zhu Y, Ding Z. Endoplasmic reticulumprotein29(ERp29), a protein related to sperm maturation is involved insperm-oocyte fusion in mouse. Reprod Biol Endocrinol,2010,8:10.
[48]. Wagner BA, Buettner GR, Oberley LW, Darby CJ, Burns CP. Myeloperoxidaseis involved in H2O2-induced apoptosis of HL-60human leukemia cells. J BiolChem,2000,275(29):22461-22469.
[49]. El Kebir D, Jozsef L, Pan W, Filep JG. Myeloperoxidase delays neutrophilapoptosis through CD11b/CD18integrins and prolongs inflammation. Circ Res,2008,103(4):352-359.
[50]. Saed GM, Ali-Fehmi R, Jiang ZL, Fletcher NM, Diamond MP, Abu-Soud HM,Munkarah AR. Myeloperoxidase serves as a redox switch that regulatesapoptosis in epithelial ovarian cancer. Gynecol oncol,2010,116(2):276-281.
[51]. Nakazato T, Sagawa M, Yamato K, Xian M, Yamamoto T, Suematsu M, Ikeda Y,Kizaki M. Myeloperoxidase is a key regulator of oxidative stress mediatedapoptosis in myeloid leukemic cells. Clin Cancer Res,2007,13(18):5436-5445.
[52]. Chowdhury I, Mo Y, Gao L, Kazi A, Fisher AB, Feinstein SI. Oxidant stressstimulates expression of the human peroxiredoxin6gene by a transcriptionalmechanism involving an antioxidant response element. Free Radic Biol Med,2009,46(2):146-153.
[53]. Manevich Y, Sweitzer T, Pak JH, Feinstein SI, Muzykantov V, Fisher AB.1-Cysperoxiredoxin overexpression protects cells against phospholipidperoxidation-mediated membrane damage. Proc Natl Acad Sci U S A,2002,99(18):11599-11604.
[54]. Pak JH, Manevich Y, Kim HS, Feinstein SI, Fisher AB. An antisenseoligonucleotide to1-cys peroxiredoxin causes lipid peroxidation and apoptosisin lung epithelial cells. J Biol Chem,2002,277(51):49927-49934.
[55]. Rao RV, Ellerby HM, Bredesen DE. Coupling endoplasmic reticulum stress tothe cell death program. Cell Death Differ,2004,11(4):372-380.
[56]. Bambang IF, Xu S, Zhou J, Salto-Tellez M, Sethi SK, Zhang D. Overexpressionof endoplasmic reticulum protein29regulates mesenchymal-epithelialtransition and suppresses xenograft tumor growth of invasive breast cancer cells.Lab Invest,2009,89(11):1229-1242.
[57]. Fang HY, Chen SB, Guo DJ, Pan SY, Yu ZL. Proteomic identification ofdifferentially expressed proteins in curcumin-treated MCF-7cells.Phytomedicine,2011,18(8-9):697-703.
[58]. Haslinger P, Haider S, Sonderegger S, Otten JV, Pollheimer J, Whitley G,Knofler M. AKT Isoforms1and3Regulate Basal and Epidermal GrowthFactor-Stimulated SGHPL-5Trophoblast Cell Migration in Humans. Biol Reprod.2013,88(3):54.
[59]. Dai Y, Qiu Z, Diao Z, Shen L, Xue P, Sun H, Hu Y. MicroRNA-155inhibitsproliferation and migration of human extravillous trophoblast derivedHTR-8/SVneo cells via down-regulating cyclin D1. Placenta,2012,33(10):824-829.
[60]. Filomeni G, Piccirillo S, Rotilio G, Ciriolo MR. p38(MAPK) and ERK1/2dictate cell death/survival response to different pro-oxidant stimuli via p53andNrf2in neuroblastoma cells SH-SY5Y. Biochem Pharmacol,2012,83(10):1349-1357.
[61]. Tian XY, Yung LH, Wong WT, Liu J, Leung FP, Liu L, Chen Y, Kong SK,Kwan KM, Ng SM, Lai PB, Yung LM, Yao X, Huang Y. Bone morphogenicprotein-4induces endothelial cell apoptosis through oxidative stress-dependentp38MAPK and JNK pathway. J Mol Cell Cardiol,2012,52(1):237-244.
[62]. Liu B, Jian Z, Li Q, Li K, Wang Z, Liu L, Tang L, Yi X, Wang H, Li C, Gao T.Baicalein protects human melanocytes from H(2)O(2)-induced apoptosis viainhibiting mitochondria-dependent caspase activation and the p38MAPKpathway. Free Radic Biol Med,2012,53(2):183-193.
[63]. Gao D, Bambang IF, Putti TC, Lee YK, Richardson DR, Zhang D. ERp29induces breast cancer cell growth arrest and survival through modulation ofactivation of p38and upregulation of ER stress protein p58IPK. Lab Invest,2012,92(2):200-213.
[64]. Demmer J, Zhou C, Hubbard MJ. Molecular cloning of ERp29, a novel andwidely expressed resident of the endoplasmic reticulum. FEBS lett,1997,402(2-3):145-150.
[65]. Mkrtchian S, Fang C, Hellman U, Ingelman-Sundberg M. A stress-inducible ratliver endoplasmic reticulum protein, ERp29. Eur J Biochem,1998,251(1-2):304-313.
[66]. Qi L, Wu P, Zhang X, Qiu Y, Jiang W, Huang D, Liu Y, Tan P, Tian Y. InhibitingERp29expression enhances radiosensitivity in human nasopharyngealcarcinoma cell lines. Med Oncol,2012,29(2):721-728.
[67]. Bambang IF, Lu D, Li H, Chiu LL, Lau QC, Koay E, Zhang D. Cytokeratin19regulates endoplasmic reticulum stress and inhibits ERp29expression via p38MAPK/XBP-1signaling in breast cancer cells. Exp Cell Res,2009,315(11):1964-1974.
[68]. Bambang IF, Lee YK, Richardson DR, Zhang D. Endoplasmic reticulumprotein29regulates epithelial cell integrity during the mesenchymal-epithelialtransition in breast cancer cells. Oncogene,2013,32(10):1240-1251.
[69]. Brewster JL, de Valoir T, Dwyer ND, Winter E, Gustin MC. An osmosensingsignal transduction pathway in yeast. Science,1993,259(5102):1760-1763.
[70]. Zhou L, Opalinska J, Verma A. p38MAP kinase regulates stem cell apoptosis inhuman hematopoietic failure. Cell Cycle,2007,6(5):534-537.
[71]. Liang C, Liao J, Deng Z, Song C, Zhang J, Zabeau L, Tavernier J Zhang K, XueH, Yan G. Leptin attenuates lipopolysaccharide-induced apoptosis ofthymocytes partially via down-regulation of cPLA2and p38MAPK activation.Int Immunopharmacol.2013,15(3):620-627.
[72]. Antoon JW, Nitzchke AM, Martin EC, Rhodes LV, Nam S, Wadsworth S, SalvoVA, Elliott S, Collins-Burow B, Nephew KP, Burow ME. Inhibition of p38mitogen-activated protein kinase alters microRNA expression and reversesepithelial-to-mesenchymal transition. Int J Oncol,2013,42(4):1139-1150.
[73]. Bodur C, Kutuk O, Karsli-Uzunbas G, Isimjan TT, Harrison P, Basaga H. PLoSOne,2013,8(2):e56369.
[74]. Zhang B, Wang X, Cai F, Chen W, Loesch U, Zhong XY. Antitumor propertiesof salinomycin on cisplatin-resistant human ovarian cancer cells in vitro and invivo: involvement of p38MAPK activation. Oncol Rep,2013,29(4):1371-1378.
[75]. Woo JS, Kim SM, Jeong CH, Ryu CH, Jeun SS. Lipoxygenase inhibitorMK886potentiates TRAIL-induced apoptosis through CHOP-and p38MAPK-mediated up-regulation of death receptor5in malignant glioma.Biochem Biophys Res Commun,2013,431(2):354-359.
[1]. Hardikar W, Kansal S, Oude Elferink RP, Angus P. Intrahepatic cholestasis ofpregnancy: when should you look further? World J Gastroenterol,2009,15(9):1126-1129.
[2]. Rook M, Vargas J, Caughey A, Bacchetti P, Rosenthal P, Bull L. Fetal outcomesin pregnancies complicated by intrahepatic cholestasis of pregnancy in aNorthern California cohort. PLoS one,2012,7(3): e28343.
[3]. Azzaroli F, Turco L, Lisotti A, Calvanese C, Mazzella G. The pharmacologicalmanagement of intrahepatic cholestasis of pregnancy. Curr Clin Pharmacol,2011,6(1):12-17.
[4]. Glantz A, Reilly SJ, Benthin L, Lammert F, Mattsson LA, Marschall HU.Intrahepatic cholestasis of pregnancy: Amelioration of pruritus by UDCA isassociated with decreased progesterone disulphates in urine. Hepatology,2008,47(2):544-551.
[5]. Lu J, Qi H. Sudden fetal death in a patient with intrahepatic cholestasis ofpregnancy complicated with gestational diabetes mellitus. Arch Gynecol Obstet,2013,287(1):179-182.
[6]. Lee RH, Incerpi MH, Miller DA, Pathak B, Goodwin TM. Sudden fetal death inintrahepatic cholestasis of pregnancy. Obstet Gynecol,2013,113(2)528-531.
[7]. Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy:Relationships between bile acid levels and fetal complication rates. Hepatology,2004,40(2):467-474.
[8]. Medina Lomeli JM, Jauregui Melendrez RA, Medina Castro N, Medina CastroD.[Intrahepatic cholestasis of pregnancy: review]. Ginecol Obstet Mex,2012,80(4):285-294.
[9]. Dixon PH, van Mil SW, Chambers J, Strautnieks S, Thompson RJ, Lammert F,Kubitz R, Keitel V, Glantz A, Mattsson LA, Marschall HU, Molokhia M, MooreGE, Linton KJ, Williamson C. Contribution of variant alleles of ABCB11tosusceptibility to intrahepatic cholestasis of pregnancy. Gut,2009,58(4):537-544.
[10]. Reyes H. Sex hormones and bile acids in intrahepatic cholestasis of pregnancy.Hepatology,2008,47(2):376-379.
[11]. Chappell LC, Gurung V, Seed PT, Chambers J, Williamson C, Thornton JG.Ursodeoxycholic acid versus placebo, and early term delivery versus expectantmanagement, in women with intrahepatic cholestasis of pregnancy:semifactorial randomised clinical trial. BMJ,2012,344: e3799.
[12]. Geenes V, Williamson C. Intrahepatic cholestasis of pregnancy. World JGastroenterol,2009,15(17):2049-2066.
[13]. Paternoster DM, Fabris F, Palu G, Santarossa C, Bracciante R, Snijders D,Floreani A. Intra-hepatic cholestasis of pregnancy in hepatitis C virus infection.Acta Obstet Gynecol Scand,2002,81(2):99-103.
[14]. Williamson C, Miragoli M, Sheikh Abdul Kadir S, Abu-Hayyeh S,Papacleovoulou G, Geenes V, Gorelik J. Bile acid signaling in fetal tissues:implications for intrahepatic cholestasis of pregnancy. Dig Dis,2011,29(1):58-61.
[15]. Bunchorntavakul C, Reddy KR. Pruritus in chronic cholestatic liver disease.Clin Liver Dis,2012,16(2):331-346.
[16]. Laifer SA, Stiller RJ, Siddiqui DS, Dunston-Boone G, Whetham JC.Ursodeoxycholic acid for the treatment of intrahepatic cholestasis of pregnancy.J Matern Fetal Med,2001,10(2):131-135.
[17]. Ambros-Rudolph CM, Glatz M, Trauner M, Kerl H, Mullegger RR. Theimportance of serum bile acid level analysis and treatment withursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a case seriesfrom central Europe. Arch Dermatol,2007,143(6):757-762.
[18]. Pata O, Vardareli E, Ozcan A, Serteser M, Unsal I, Saruc M, Unlu C, Tozun N.Intrahepatic cholestasis of pregnancy: correlation of preterm delivery with bileacids. Turk J Gastroenterol,2011,22(6):602-605.
[19]. Barth A, Rost M, Kindt A, Peiker G. Serum bile acid profile in women duringpregnancy and childbed. Exp Clin Endocrinol Diabetes,2005,113(7):372-375.
[20]. Cui T, Liu Y, Men X, Xu Z, Wu L, Liu S, Xing A. Bile acid transport correlativeprotein mRNA expression profile in human placenta with intrahepaticcholestasis of pregnancy. Saudi Med J,2009,30(11):1406-1410.
[21]. Abu-Hayyeh S, Papacleovoulou G, Williamson C. Nuclear receptors, bile acidsand cholesterol homeostasis series-Bile acids and pregnancy. Mol CellEndocrinol,2013,368(1):120-128.
[22]. Reyes H. The spectrum of liver and gastrointestinal disease seen in cholestasisof pregnancy. Gastroenterol Clin North Am,1992,21(4)905-921.
[23]. Favre N, Bourdel N, Sapin V, Abergel A, Gallot D.[Importance of bile acids forintra-hepatic cholestasis of pregnancy]. Gynecol Obstet Fertil,2010,38(4):293-295.
[24]. Lee RH,. Kwok KM, Ingles S, Wilson ML, Mullin P, Incerpi M, Pathak B,Goodwin TM. Pregnancy outcomes during an era of aggressive management forintrahepatic cholestasis of pregnancy. Am J Perinatol,2008,25(6):341-345.
[25].妊娠期肝内胆汁淤积症诊疗指南(第1版).中华妇产科杂志,2011,46(5):391:395.
[26]. Williamson C, Hems LM, Goulis DG, Walker I, Chambers J, Donaldson O,Swiet M, Johnston DG. Clinical outcome in a series of cases of obstetriccholestasis identified via a patient support group. BJOG,2011,111(7)676-681.
[27]. Vallejo M, Briz O, Serrano MA, Monte MJ, Marin JJ. Potential role oftrans-inhibition of the bile salt export pump by progesterone metabolites in theetiopathogenesis of intrahepatic cholestasis of pregnancy. J Hepatol,2006,44(6):1150-1157.
[28]. Yamamoto Y, Moore R, Hess HA, Guo GL, Gonzalez FJ, Korach KS, MaronpotRR, Negishi M. Estrogen receptor alpha mediates17alpha-ethynylestradiolcausing hepatotoxicity. J Biol Chem,2006,281(24):16625-16631.
[29]. Milona A, Owen BM, Cobbold JF, Willemsen EC, Cox IJ, Boudjelal M, CairnsW, Schoonjans K, Taylor-Robinson SD, Klomp LW, Parker MG, White R, vanMil SW, Williamson C. Raised hepatic bile acid concentrations duringpregnancy in mice are associated with reduced farnesoid X receptor function.Hepatology,2010,52(4):1341-1349.
[30]. Dixon PH, Weerasekera N, Linton KJ, Donaldson O, Chambers J, Egginton E,Weaver J, Nelson-Piercy C, de Swiet M, Warnes G, Elias E, Higgins CF,Johnston DJ, McCarthy MI, Williamson C. Heterozygous MDR3missensemutation associated with intrahepatic cholestasis of pregnancy: evidence for adefect in protein trafficking. Hum Mol Genet,2000,9(8):1209-1217.
[31]. Mangalam AK, Taneja V, David CS. HLA class II molecules influencesusceptibility versus protection in inflammatory diseases by determining thecytokine profile. J Immunol,2013,190(2):513-518.
[32]. Meng XQ, Chen HG, Ma YL, Liu KZ. Influence of HLA class II molecules onthe outcome of hepatitis B virus infection in population of Zhejiang Province inChina. Hepatobiliary Pancreat Dis Int,2003,2(2):230-233.
[33]. Mella JG, Roschmann E, Glasinovic JC, Alvarado A, Scrivanti M, Volk BA.Exploring the genetic role of the HLA-DPB1locus in Chileans withintrahepatic cholestasis of pregnancy. J Hepatol,1996,24(3):320-323.
[34]. Ding Y, Shen H, Wang X, Fan X, Wu X, Yang X. The polymorphism ofHLA-DR and-DQ allelic genes associated with intrahepatic cholestasis ofpregnancy. Genet Test,2008,12(2):215-220.
[35]. Jacquemin E. Role of multidrug resistance3deficiency in pediatric and adultliver disease: one gene for three diseases. Semin Liver Dis,2001,21(4):551-562.
[36]. Eloranta ML, Hakli T, Hiltunen M, Helisalmi S, Punnonen K, Heinonen S.Association of single nucleotide polymorphisms of the bile salt export pumpgene with intrahepatic cholestasis of pregnancy. Scand J Gastroenterol,2003,38(6):648-652.
[37]. Mullenbach R, Bennett A, Tetlow N, Patel N, Hamilton G, Cheng F, Chambers J,Howard R, Taylor-Robinson SD, Williamson C. ATP8B1mutations in Britishcases with intrahepatic cholestasis of pregnancy. Gut,2005,54(6)829-834.
[38]. Stieger B, Geier A. Genetic variations of bile salt transporters as predisposingfactors for drug-induced cholestasis, intrahepatic cholestasis of pregnancy andtherapeutic response of viral hepatitis. Expert Opin Drug Metab Toxicol,2011,7(4):411-425.
[39]. Bacq Y, Gendrot C, Perrotin F, Lefrou L, Chretien S, Vie-Buret V, Brechot MC,Andres CR. ABCB4gene mutations and single-nucleotide polymorphisms inwomen with intrahepatic cholestasis of pregnancy. J Med Genet,2009,46(10)711-715.
[40]. Keitel V, Vogt C, Haussinger D, Kubitz R. Combined mutations of canaliculartransporter proteins cause severe intrahepatic cholestasis of pregnancy.Gastroenterology,2006,131(2):624-629.
[41]. Kitsiou-Tzeli S, Traeger-Synodinos J, Giannatou E, Kaminopetros P, Roma E,Makrythanasis P, Tsezou A. The c.504T>C (p.Asn168Asn) polymorphism in theABCB4gene as a predisposing factor for intrahepatic cholestasis of pregnancyin Greece. Liver Int,2010,30(3):489-491.
[42]. Mullenbach R, Linton KJ, Wiltshire S, Weerasekera N, Chambers J, Elias E,Higgins CF, Johnston DJ, McCarthy MI, Williamson C. ABCB4gene sequencevariation in women with intrahepatic cholestasis of pregnancy. J Med Genet,2003,40(5): e70.
[43]. Pauli-Magnus C, Lang T, Meier Y, Zodan-Marin T, Jung D, Breymann C,Zimmermann R, Kenngott S, Beuers U, Reichel C, Kerb R, Penger A, Meier PJ,Kullak-Ublick GA. Sequence analysis of bile salt export pump (ABCB11) andmultidrug resistance p-glycoprotein3(ABCB4, MDR3) in patients withintrahepatic cholestasis of pregnancy. Pharmacogenetics,2004,14(2):91-102.
[44]. Wasmuth HE, Glantz A, Keppeler H, Simon E, Bartz C, Rath W, Mattsson LA,Marschall HU, Lammert F. Intrahepatic cholestasis of pregnancy: the severeform is associated with common variants of the hepatobiliary phospholipidtransporter ABCB4gene. Gut,2007,56(2):265-270.
[45]. Mealey KL, Minch JD, White SN, Snekvik KR, Mattoon JS. An insertionmutation in ABCB4is associated with gallbladder mucocele formation in dogs.Comp Hepatol,2010,9:6.
[46]. Delaunay JL, Durand-Schneider AM, Delautier D, Rada A, Gautherot J,Jacquemin E, Ait-Slimane T, Maurice M. A missense mutation in ABCB4geneinvolved in progressive familial intrahepatic cholestasis type3leads to afolding defect that can be rescued by low temperature. Hepatology,2009,49(4):1218-1227.
[47]. van der Woerd WL, van Mil SW, Stapelbroek JM, Klomp LW, van de Graaf SF,Houwen RH. Familial cholestasis: progressive familial intrahepatic cholestasis,benign recurrent intrahepatic cholestasis and intrahepatic cholestasis ofpregnancy. Best Pract Res Clin Gastroenterol.2010,24(5):541-553.
[48]. Jacquemin E, Hadchouel M. Genetic basis of progressive familial intrahepaticcholestasis. J Hepatol,1999,31(2):377-381.
[49]. Lam P, Soroka CJ, Boyer JL. The bile salt export pump: clinical andexperimental aspects of genetic and acquired cholestatic liver disease. SeminLiver Dis,2010,30(2):125-133.
[50]. an Mil SW, Milona A, Dixon PH, Mullenbach R, Geenes VL, Chambers J,Shevchuk V, Moore GE, Lammert F, Glantz AG, Mattsson LA, Whittaker J,Parker MG, White R, Williamson C. Functional variants of the central bile acidsensor FXR identified in intrahepatic cholestasis of pregnancy.Gastroenterology,2007,133(2):507-516.
[51]. Yayi H, Danqing W, Shuyun L, Jicheng L. Immunologic abnormality ofintrahepatic cholestasis of pregnancy. Am J Reprod Immunol,2010,63(4):267-273.
[52]. Ling B, Yao F, Zhou Y, Chen Z, Shen G, Zhu Y. Cell-mediated immunityimbalance in patients with intrahepatic cholestasis of pregnancy. Cell MolImmunol,2007,4(1):71-75.
[53].彭冰,刘淑芸.辅助性T淋巴细胞哑型与妊娠期肝内胆汁淤积症发病的关系.中华妇产科杂志,2002,37(9):516-518.
[54].曲广第,王冬梅. TNF-α，IL-6在妊娠肝内胆汁淤积症胎盘上的表达.新疆医科大学学报,2004,27(3):264-266.
[55].时青云,刘淑芸,熊庆.妊娠肝内胆汁淤积症患者雌孕激素水平及免疫功能的变化.中华妇产科杂志,1998,33(12):724-727.
[56].袁佩,虞斌,王秋伟,董一善,吕文燕,狄志英.妊娠期肝内胆汁淤积症患者淋巴细胞亚群分析.江苏大学学报(医学版),2004,14(1):49-50.
[57]. Kauppila A, Korpela H, Makila UM, Yrjanheikki E. Low serum seleniumconcentration and glutathione peroxidase activity in intrahepatic cholestasis ofpregnancy. Br Med J (Clin Res Ed),1987,294(6565):150-152.
[58]. Reyes H, Baez ME, Gonzalez MC, Hernandez I, Palma J, Ribalta J, Sandoval L,Zapata R. Selenium, zinc and copper plasma levels in intrahepatic cholestasis ofpregnancy, in normal pregnancies and in healthy individuals, in Chile. J Hepatol,2000,32(4)542-549.
[59].王竹晨,刘淑芸.孕妇静脉血及其新生儿脐血硒水平及谷胱甘肽过氧化物酶活性与妊娠肝内胆汁淤积症的关系.中华妇产科杂志,2000,35(9)520-522.
[60].古航,胡电.妊娠期肝内胆汁淤积症.中华妇产科杂志,2003,38(2):121-129.
[61]. Marin JJ, Macias RI, Serrano MA. The hepatobiliary-like excretory function ofthe placenta. A review. Placenta,2003,24(5)431-438.
[62]. Marin JJ, Briz O, Serrano MA. A review on the molecular mechanismsinvolved in the placental barrier for drugs. Curr Drug Deliv,2004,1(3):275-289.
[63].张岩,印永祥,许倩,赵华,项静英,许建娟.胎盘组织中胆酸调节蛋白的表达及其与妊娠期肝内胆汁郁积症发病的关系.中华妇产科杂志,2010,45(8):615-617.
[64]. Perez MJ, Macias RI, Marin JJ. Maternal cholestasis induces placentaloxidative stress and apoptosis. Protective effect of ursodeoxycholic acid.Placenta,2006,27(1):34-41.
[65]. Geenes VL, Lim YH, Bowman N, Tailor H, Dixon PH, Chambers J, Brown L,Wyatt-Ashmead J, Bhakoo K, Williamson C. A placental phenotype forintrahepatic cholestasis of pregnancy. Placenta,2011,32(12):1026-1032.
[66]. Paumgartner G, Beuers U. Mechanisms of action and therapeutic efficacy ofursodeoxycholic acid in cholestatic liver disease. Clin Liver Dis,2004,8(1):67-81.
[67]. Bacq Y, Sentilhes L, Reyes HB, Glantz A, Kondrackiene J, Binder T, NicastriPL, Locatelli A, Floreani A, Hernandez I, Di Martino V. Efficacy ofursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: ameta-analysis. Gastroenterology,2012,143(6):1492-1501.
[68]. Pusl T, Beuers U. Intrahepatic cholestasis of pregnancy. Orphanet J Rare Dis,2007,2:26.
[69]. Pathak B, Sheibani L, Lee RH. Cholestasis of pregnancy. Obstet Gynecol ClinNorth Am,2010,37(2):269-282.
[70]. Zapata R, Sandoval L, Palma J, Hernandez I, Ribalta J, Reyes H, Sedano M,Toha D, Silva JJ. Ursodeoxycholic acid in the treatment of intrahepaticcholestasis of pregnancy. A12-year experience. Liver Int,2005,25(3)548-554.
[71]. Beuers U. Drug insight: Mechanisms and sites of action of ursodeoxycholicacid in cholestasis. Nat Clin Pract Gastroenterol Hepatol,2006,3(6):318-328.
[72]. Binder T, Salaj P, Zima T, Vitek L. Randomized prospective comparative studyof ursodeoxycholic acid and S-adenosyl-L-methionine in the treatment ofintrahepatic cholestasis of pregnancy. J Perinat Med,2006,34(5)383-391.
[73]. Perin E, Cacciaguerra G, Driul L, Marchesoni D,[Intrahepatic cholestasis ofpregnancy: diagnosis and obstetric management]. Minerva Ginecol,2010,62(2):97-103.
[2]. Rook M, Vargas J, Caughey A, Bacchetti P, Rosenthal P, Bull L. Fetal outcomesin pregnancies complicated by intrahepatic cholestasis of pregnancy in aNorthern California cohort. PloS one,2012,7(3): e28343.
[3]. Glantz A, Reilly SJ, Benthin L, Lammert F, Mattsson LA, Marschall HU.Intrahepatic cholestasis of pregnancy: Amelioration of pruritus by UDCA isassociated with decreased progesterone disulphates in urine. Hepatology,2008,47(2):544-551.
[4]. Lee RH, Incerpi MH, Miller DA, Pathak B, Goodwin TM. Sudden fetal death inintrahepatic cholestasis of pregnancy. Obstet Gynecol,2009,113(2):528-531.
[5]. Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy:Relationships between bile acid levels and fetal complication rates. Hepatology,2004,40(2):467-474.
[6]. Dixon PH, van Mil SW, Chambers J, Strautnieks S, Thompson RJ, Lammert F,Kubitz R, Keitel V, Glantz A, Mattsson LA, Marschall HU, Molokhia M, Moore,GE, Linton KJ, Williamson C. Contribution of variant alleles of ABCB11tosusceptibility to intrahepatic cholestasis of pregnancy. Gut,2009,58(4):537-544.
[7]. Chappell LC, Gurung V, Seed PT, Chambers J, Williamson C, Thornton JG.Ursodeoxycholic acid versus placebo, and early term delivery versus expectantmanagement, in women with intrahepatic cholestasis of pregnancy:semifactorial randomised clinical trial. BMJ,2012,344: e3799.
[8]. Reyes H. Sex hormones and bile acids in intrahepatic cholestasis of pregnancy.Hepatology,2008,47(2):376-379.
[9]. Geenes V, Williamson C. Intrahepatic cholestasis of pregnancy. World JGastroenterol,2009,15(17):2049-2066.
[10]. Stieger B, Geier A. Genetic variations of bile salt transporters as predisposingfactors for drug-induced cholestasis, intrahepatic cholestasis of pregnancy andtherapeutic response of viral hepatitis. Expert Opin Drug Metab Toxicol,2011,7(4):411-425.
[11]. van der Woerd WL, van Mil SW, Stapelbroek JM, Klomp LW, van de Graaf SF,Houwen RH. Familial cholestasis: progressive familial intrahepatic cholestasis,benign recurrent intrahepatic cholestasis and intrahepatic cholestasis ofpregnancy. Best Pract Res Clin Gastroenterol,2010,24(5):541-553.
[12]. Pata O, Vardareli E, Ozcan A, Serteser M, Unsal I, Saruc M, Unlu C, Tozun N.Intrahepatic cholestasis of pregnancy: correlation of preterm delivery with bileacids. Turk J Gastroenterol,2011,22(6):602-605.
[13]. Wikstrom Shemer EA, Thorsell M, Marschall HU, Kaijser M. Risks ofemergency cesarean section and fetal asphyxia after induction of labor inintrahepatic cholestasis of pregnancy: A hospital-based retrospective cohortstudy. Sex Reprod Healthc,2013,4(1):17-22.
[14]. Laatikainen T, Tulenheimo A. Maternal serum bile acid levels and fetal distressin cholestasis of pregnancy. Int J Gynaecol Obstet,1984,22(2):91-94.
[15]. Lee RH, Kwok KM, Ingles S, Wilson ML, Mullin P, Incerpi M, Pathak B,Goodwin TM. Pregnancy outcomes during an era of aggressive management forintrahepatic cholestasis of pregnancy. Am J Perinatol,2008,25(6):341-345.
[16]. Marin JJ, Macias RI, Serrano MA. The hepatobiliary-like excretory function ofthe placenta. A review. Placenta,2003,24(5):431-438.
[17]. Serrano MA, Macias RI, Briz O, Monte MJ, Blazquez AG, Williamson C,Kubitz R, Marin JJ. Expression in human trophoblast and choriocarcinoma celllines, BeWo, Jeg-3and JAr of genes involved in the hepatobiliary-likeexcretory function of the placenta. Placenta,2007,28(2-3):107-117.
[18]. Marin JJ, Briz O, Serrano MA. A review on the molecular mechanismsinvolved in the placental barrier for drugs. Curr Drug Deliv,2004,1(3):275-289.
[19]. Geenes VL, Lim YH, Bowman N, Tailor H, Dixon PH, Chambers J, Brown L,Wyatt-Ashmead J, Bhakoo K, Williamson C. A placental phenotype forintrahepatic cholestasis of pregnancy. Placenta,2011,32(12):1026-1032.
[20]. Wasinger VC, Cordwell SJ, Cerpa-Poljak A, Yan JX, Gooley AA, Wilkins MR,Duncan MW, Harris R, Williams KL, Humphery-Smith I. Progress withgene-product mapping of the Mollicutes: Mycoplasma genitalium.Electrophoresis,1995,16(7):1090-1094.
[21]. Sawicki G, Dakour J, Morrish DW. Functional proteomics of neurokinin B inthe placenta indicates a novel role in regulating cytotrophoblast antioxidantdefences. Proteomics,2003,3(10):2044-2051.
[22]. Choi DH, Lee WS, Won M, Park M, Park HO, Kim E, Lee KA, Bae J. Theapolipoprotein A-I level is downregulated in the granulosa cells of patients withpolycystic ovary syndrome and affects steroidogenesis. J Proteome Res,2010,9(9):4329-4336.
[23]. Wu WW, Wang G, Baek SJ, Shen RF. Comparative study of three proteomicquantitative methods, DIGE, cICAT, and iTRAQ, using2D gel-or LC-MALDITOF/TOF. J Proteome Res,2006,5(3):651-658.
[24]. Ross PL, Huang YN, Marchese JN, Williamson B, Parker K, Hattan S,Khainovski N, Pillai S, Dey S, Daniels S, Purkayastha S, Juhasz P, Martin S,Bartlet-Jones M, He F, Jacobson A, Pappin DJ. Multiplexed protein quantitationin Saccharomyces cerevisiae using amine-reactive isobaric tagging reagents.Mol Cell Proteomics,2004,3(12):1154-1169.
[25]. Manavalan A, Feng L, Sze SK, Hu JM, Heese K. New insights into the brainprotein metabolism of Gastrodia elata-treated rats by quantitative proteomics. JProteomics,2012,75(8):2468-2479.
[26].张岩,印永祥,许倩,赵华,项静英,许建娟.胎盘组织中胆酸调节蛋白的表达及其与妊娠期肝内胆汁郁积症发病的关系.中华妇产科杂志,2010,45(8):615-617.
[27]. Bacq Y, Sentilhes L, Reyes HB, Glantz A, Kondrackiene J, Binder T, NicastriPL, Locatelli A, Floreani A, Hernandez I, Di Martino V. Efficacy ofursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: ameta-analysis. Gastroenterology,2012,143(6):1492-1501.
[28].妊娠期肝内胆汁淤积症诊疗指南(第1版).中华妇产科杂志,2011,46(5)391:395.
[29]. Kersey PJ, Duarte J, Williams A, Karavidopoulou Y, Birney E, Apweiler R. TheInternational Protein Index: an integrated database for proteomics experiments.Proteomics,2004,4(7):1985-1988.
[30]. Cox J, Mann M. MaxQuant enables high peptide identification rates,individualized p.p.b.-range mass accuracies and proteome-wide proteinquantification. Nat Biotechnol,2008,26(12):1367-1372.
[31]. Deutsch EW, Mendoza L, Shteynberg D, Farrah T, Lam H, Tasman N, Sun Z,Nilsson E, Pratt B, Prazen B, Eng JK, Martin DB, Nesvizhskii AI, Aebersold R.A guided tour of the Trans-Proteomic Pipeline. Proteomics,2010,10(6):1150-1159.
[32]. Saeed AI, Bhagabati NK, Braisted JC, Liang W, Sharov V, Howe EA, Li J,Thiagarajan M, White JA, Quackenbush J. TM4microarray software suite.Methods Enzymol,2006,411:134-193.
[33]. Nikitin A, Egorov S, Daraselia N, Mazo I. Pathway studio--the analysis andnavigation of molecular networks. Bioinformatics,2003,19(16):2155-2157.
[34]. Pusl T, Beuers U. Intrahepatic cholestasis of pregnancy. Orphanet J Rare Dis,2007,2:26.
[35]. Pathak B, Sheibani L, Lee RH. Cholestasis of pregnancy. Obstet Gynecol ClinNorth Am.2010,37(2):269-282.
[36]. Zapata R, Sandoval L, Palma J, Hernandez I, Ribalta J, Reyes H, Sedano M,Toha D, Silva JJ. Ursodeoxycholic acid in the treatment of intrahepaticcholestasis of pregnancy. A12-year experience. Liver Int,2005,25(3):548-554.
[37]. Beuers U. Drug insight: Mechanisms and sites of action of ursodeoxycholicacid in cholestasis. Nature clinical practice. Nat Clin Pract GastroenterolHepatol,2006,3(6):318-328.
[38]. Mehan MR, Ostroff R, Wilcox SK, Steele F, Schneider D, Jarvis TC, Baird GS,Gold L, Janjic N. Highly multiplexed proteomic platform for biomarkerdiscovery, diagnostics, and therapeutics. Adv Exp Med Biol,2013,734:283-300.
[39]. Honda K, Ono M, Shitashige M, Masuda M, Kamita M, Miura N, Yamada T.Proteomic approaches to the discovery of cancer biomarkers for early detectionand personalized medicine. Jpn J Clin Oncol,2013,43(2):103-109.
[40]. Pollard HB, Eidelman O, Jozwik C, Huang W, Srivastava M, Ji XD, McGowanB, Norris CF, Todo T, Darling T, Mogayzel PJ, Zeitlin PL, Wright J, GugginoWB, Metcalf E, Driscoll WJ, Mueller G, Paweletz C, Jacobowitz DM. De novobiosynthetic profiling of high abundance proteins in cystic fibrosis lungepithelial cells. Mol Cell Proteomics,2006,5(9):1628-1637.
[41]. Cao Z, Yende S, Kellum JA, Robinson RA. Additions to the Human PlasmaProteome via a Tandem MARS Depletion iTRAQ-Based Workflow. Int JProteomics,2013,2013:654356.
[42]. Marzinke MA, Choi CH, Chen L, Shih Ie M, Chan DW, Zhang H. Proteomicanalysis of temporally stimulated ovarian cancer cells for biomarker discovery.Mol Cell Proteomics,2013,12(2):356-368.
[43]. DeSouza LV, Grigull J, Ghanny S, Dube V, Romaschin AD, Colgan TJ, Siu KW.Endometrial carcinoma biomarker discovery and verification usingdifferentially tagged clinical samples with multidimensional liquidchromatography and tandem mass spectrometry. Mol Cell Proteomics,2007,6(7):1170-1182.
[44]. Garbis SD, Tyritzis SI, Roumeliotis T, Zerefos P, Giannopoulou EG, Vlahou A,Kossida S, Diaz J, Vourekas S, Tamvakopoulos C, Pavlakis K, Sanoudou D,Constantinides CA. Search for potential markers for prostate cancer diagnosis,prognosis and treatment in clinical tissue specimens using amine-specificisobaric tagging (iTRAQ) with two-dimensional liquid chromatography andtandem mass spectrometry. J Proteome Res,2008,7(8):3146-3158.
[45]. Wei J, Wang H, Yang X, Dong M, Wang Z. Altered gene profile of placentafrom women with intrahepatic cholestasis of pregnancy. Arch Gynecol Obstet,2010,281(5):801-810.
[46]. Zhang D, Richardson DR. Endoplasmic reticulum protein29(ERp29): Anemerging role in cancer. Int J Biochem Cell Biol,2011,43(1):33-36.
[47]. Ying X, Liu Y, Guo Q, Qu F, Guo W, Zhu Y, Ding Z. Endoplasmic reticulumprotein29(ERp29), a protein related to sperm maturation is involved insperm-oocyte fusion in mouse. Reprod Biol Endocrinol,2010,8:10.
[48]. Wagner BA, Buettner GR, Oberley LW, Darby CJ, Burns CP. Myeloperoxidaseis involved in H2O2-induced apoptosis of HL-60human leukemia cells. J BiolChem,2000,275(29):22461-22469.
[49]. El Kebir D, Jozsef L, Pan W, Filep JG. Myeloperoxidase delays neutrophilapoptosis through CD11b/CD18integrins and prolongs inflammation. Circ Res,2008,103(4):352-359.
[50]. Saed GM, Ali-Fehmi R, Jiang ZL, Fletcher NM, Diamond MP, Abu-Soud HM,Munkarah AR. Myeloperoxidase serves as a redox switch that regulatesapoptosis in epithelial ovarian cancer. Gynecol oncol,2010,116(2):276-281.
[51]. Nakazato T, Sagawa M, Yamato K, Xian M, Yamamoto T, Suematsu M, Ikeda Y,Kizaki M. Myeloperoxidase is a key regulator of oxidative stress mediatedapoptosis in myeloid leukemic cells. Clin Cancer Res,2007,13(18):5436-5445.
[52]. Chowdhury I, Mo Y, Gao L, Kazi A, Fisher AB, Feinstein SI. Oxidant stressstimulates expression of the human peroxiredoxin6gene by a transcriptionalmechanism involving an antioxidant response element. Free Radic Biol Med,2009,46(2):146-153.
[53]. Manevich Y, Sweitzer T, Pak JH, Feinstein SI, Muzykantov V, Fisher AB.1-Cysperoxiredoxin overexpression protects cells against phospholipidperoxidation-mediated membrane damage. Proc Natl Acad Sci U S A,2002,99(18):11599-11604.
[54]. Pak JH, Manevich Y, Kim HS, Feinstein SI, Fisher AB. An antisenseoligonucleotide to1-cys peroxiredoxin causes lipid peroxidation and apoptosisin lung epithelial cells. J Biol Chem,2002,277(51):49927-49934.
[55]. Rao RV, Ellerby HM, Bredesen DE. Coupling endoplasmic reticulum stress tothe cell death program. Cell Death Differ,2004,11(4):372-380.
[56]. Bambang IF, Xu S, Zhou J, Salto-Tellez M, Sethi SK, Zhang D. Overexpressionof endoplasmic reticulum protein29regulates mesenchymal-epithelialtransition and suppresses xenograft tumor growth of invasive breast cancer cells.Lab Invest,2009,89(11):1229-1242.
[57]. Fang HY, Chen SB, Guo DJ, Pan SY, Yu ZL. Proteomic identification ofdifferentially expressed proteins in curcumin-treated MCF-7cells.Phytomedicine,2011,18(8-9):697-703.
[58]. Haslinger P, Haider S, Sonderegger S, Otten JV, Pollheimer J, Whitley G,Knofler M. AKT Isoforms1and3Regulate Basal and Epidermal GrowthFactor-Stimulated SGHPL-5Trophoblast Cell Migration in Humans. Biol Reprod.2013,88(3):54.
[59]. Dai Y, Qiu Z, Diao Z, Shen L, Xue P, Sun H, Hu Y. MicroRNA-155inhibitsproliferation and migration of human extravillous trophoblast derivedHTR-8/SVneo cells via down-regulating cyclin D1. Placenta,2012,33(10):824-829.
[60]. Filomeni G, Piccirillo S, Rotilio G, Ciriolo MR. p38(MAPK) and ERK1/2dictate cell death/survival response to different pro-oxidant stimuli via p53andNrf2in neuroblastoma cells SH-SY5Y. Biochem Pharmacol,2012,83(10):1349-1357.
[61]. Tian XY, Yung LH, Wong WT, Liu J, Leung FP, Liu L, Chen Y, Kong SK,Kwan KM, Ng SM, Lai PB, Yung LM, Yao X, Huang Y. Bone morphogenicprotein-4induces endothelial cell apoptosis through oxidative stress-dependentp38MAPK and JNK pathway. J Mol Cell Cardiol,2012,52(1):237-244.
[62]. Liu B, Jian Z, Li Q, Li K, Wang Z, Liu L, Tang L, Yi X, Wang H, Li C, Gao T.Baicalein protects human melanocytes from H(2)O(2)-induced apoptosis viainhibiting mitochondria-dependent caspase activation and the p38MAPKpathway. Free Radic Biol Med,2012,53(2):183-193.
[63]. Gao D, Bambang IF, Putti TC, Lee YK, Richardson DR, Zhang D. ERp29induces breast cancer cell growth arrest and survival through modulation ofactivation of p38and upregulation of ER stress protein p58IPK. Lab Invest,2012,92(2):200-213.
[64]. Demmer J, Zhou C, Hubbard MJ. Molecular cloning of ERp29, a novel andwidely expressed resident of the endoplasmic reticulum. FEBS lett,1997,402(2-3):145-150.
[65]. Mkrtchian S, Fang C, Hellman U, Ingelman-Sundberg M. A stress-inducible ratliver endoplasmic reticulum protein, ERp29. Eur J Biochem,1998,251(1-2):304-313.
[66]. Qi L, Wu P, Zhang X, Qiu Y, Jiang W, Huang D, Liu Y, Tan P, Tian Y. InhibitingERp29expression enhances radiosensitivity in human nasopharyngealcarcinoma cell lines. Med Oncol,2012,29(2):721-728.
[67]. Bambang IF, Lu D, Li H, Chiu LL, Lau QC, Koay E, Zhang D. Cytokeratin19regulates endoplasmic reticulum stress and inhibits ERp29expression via p38MAPK/XBP-1signaling in breast cancer cells. Exp Cell Res,2009,315(11):1964-1974.
[68]. Bambang IF, Lee YK, Richardson DR, Zhang D. Endoplasmic reticulumprotein29regulates epithelial cell integrity during the mesenchymal-epithelialtransition in breast cancer cells. Oncogene,2013,32(10):1240-1251.
[69]. Brewster JL, de Valoir T, Dwyer ND, Winter E, Gustin MC. An osmosensingsignal transduction pathway in yeast. Science,1993,259(5102):1760-1763.
[70]. Zhou L, Opalinska J, Verma A. p38MAP kinase regulates stem cell apoptosis inhuman hematopoietic failure. Cell Cycle,2007,6(5):534-537.
[71]. Liang C, Liao J, Deng Z, Song C, Zhang J, Zabeau L, Tavernier J Zhang K, XueH, Yan G. Leptin attenuates lipopolysaccharide-induced apoptosis ofthymocytes partially via down-regulation of cPLA2and p38MAPK activation.Int Immunopharmacol.2013,15(3):620-627.
[72]. Antoon JW, Nitzchke AM, Martin EC, Rhodes LV, Nam S, Wadsworth S, SalvoVA, Elliott S, Collins-Burow B, Nephew KP, Burow ME. Inhibition of p38mitogen-activated protein kinase alters microRNA expression and reversesepithelial-to-mesenchymal transition. Int J Oncol,2013,42(4):1139-1150.
[73]. Bodur C, Kutuk O, Karsli-Uzunbas G, Isimjan TT, Harrison P, Basaga H. PLoSOne,2013,8(2):e56369.
[74]. Zhang B, Wang X, Cai F, Chen W, Loesch U, Zhong XY. Antitumor propertiesof salinomycin on cisplatin-resistant human ovarian cancer cells in vitro and invivo: involvement of p38MAPK activation. Oncol Rep,2013,29(4):1371-1378.
[75]. Woo JS, Kim SM, Jeong CH, Ryu CH, Jeun SS. Lipoxygenase inhibitorMK886potentiates TRAIL-induced apoptosis through CHOP-and p38MAPK-mediated up-regulation of death receptor5in malignant glioma.Biochem Biophys Res Commun,2013,431(2):354-359.
[1]. Hardikar W, Kansal S, Oude Elferink RP, Angus P. Intrahepatic cholestasis ofpregnancy: when should you look further? World J Gastroenterol,2009,15(9):1126-1129.
[2]. Rook M, Vargas J, Caughey A, Bacchetti P, Rosenthal P, Bull L. Fetal outcomesin pregnancies complicated by intrahepatic cholestasis of pregnancy in aNorthern California cohort. PLoS one,2012,7(3): e28343.
[3]. Azzaroli F, Turco L, Lisotti A, Calvanese C, Mazzella G. The pharmacologicalmanagement of intrahepatic cholestasis of pregnancy. Curr Clin Pharmacol,2011,6(1):12-17.
[4]. Glantz A, Reilly SJ, Benthin L, Lammert F, Mattsson LA, Marschall HU.Intrahepatic cholestasis of pregnancy: Amelioration of pruritus by UDCA isassociated with decreased progesterone disulphates in urine. Hepatology,2008,47(2):544-551.
[5]. Lu J, Qi H. Sudden fetal death in a patient with intrahepatic cholestasis ofpregnancy complicated with gestational diabetes mellitus. Arch Gynecol Obstet,2013,287(1):179-182.
[6]. Lee RH, Incerpi MH, Miller DA, Pathak B, Goodwin TM. Sudden fetal death inintrahepatic cholestasis of pregnancy. Obstet Gynecol,2013,113(2)528-531.
[7]. Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy:Relationships between bile acid levels and fetal complication rates. Hepatology,2004,40(2):467-474.
[8]. Medina Lomeli JM, Jauregui Melendrez RA, Medina Castro N, Medina CastroD.[Intrahepatic cholestasis of pregnancy: review]. Ginecol Obstet Mex,2012,80(4):285-294.
[9]. Dixon PH, van Mil SW, Chambers J, Strautnieks S, Thompson RJ, Lammert F,Kubitz R, Keitel V, Glantz A, Mattsson LA, Marschall HU, Molokhia M, MooreGE, Linton KJ, Williamson C. Contribution of variant alleles of ABCB11tosusceptibility to intrahepatic cholestasis of pregnancy. Gut,2009,58(4):537-544.
[10]. Reyes H. Sex hormones and bile acids in intrahepatic cholestasis of pregnancy.Hepatology,2008,47(2):376-379.
[11]. Chappell LC, Gurung V, Seed PT, Chambers J, Williamson C, Thornton JG.Ursodeoxycholic acid versus placebo, and early term delivery versus expectantmanagement, in women with intrahepatic cholestasis of pregnancy:semifactorial randomised clinical trial. BMJ,2012,344: e3799.
[12]. Geenes V, Williamson C. Intrahepatic cholestasis of pregnancy. World JGastroenterol,2009,15(17):2049-2066.
[13]. Paternoster DM, Fabris F, Palu G, Santarossa C, Bracciante R, Snijders D,Floreani A. Intra-hepatic cholestasis of pregnancy in hepatitis C virus infection.Acta Obstet Gynecol Scand,2002,81(2):99-103.
[14]. Williamson C, Miragoli M, Sheikh Abdul Kadir S, Abu-Hayyeh S,Papacleovoulou G, Geenes V, Gorelik J. Bile acid signaling in fetal tissues:implications for intrahepatic cholestasis of pregnancy. Dig Dis,2011,29(1):58-61.
[15]. Bunchorntavakul C, Reddy KR. Pruritus in chronic cholestatic liver disease.Clin Liver Dis,2012,16(2):331-346.
[16]. Laifer SA, Stiller RJ, Siddiqui DS, Dunston-Boone G, Whetham JC.Ursodeoxycholic acid for the treatment of intrahepatic cholestasis of pregnancy.J Matern Fetal Med,2001,10(2):131-135.
[17]. Ambros-Rudolph CM, Glatz M, Trauner M, Kerl H, Mullegger RR. Theimportance of serum bile acid level analysis and treatment withursodeoxycholic acid in intrahepatic cholestasis of pregnancy: a case seriesfrom central Europe. Arch Dermatol,2007,143(6):757-762.
[18]. Pata O, Vardareli E, Ozcan A, Serteser M, Unsal I, Saruc M, Unlu C, Tozun N.Intrahepatic cholestasis of pregnancy: correlation of preterm delivery with bileacids. Turk J Gastroenterol,2011,22(6):602-605.
[19]. Barth A, Rost M, Kindt A, Peiker G. Serum bile acid profile in women duringpregnancy and childbed. Exp Clin Endocrinol Diabetes,2005,113(7):372-375.
[20]. Cui T, Liu Y, Men X, Xu Z, Wu L, Liu S, Xing A. Bile acid transport correlativeprotein mRNA expression profile in human placenta with intrahepaticcholestasis of pregnancy. Saudi Med J,2009,30(11):1406-1410.
[21]. Abu-Hayyeh S, Papacleovoulou G, Williamson C. Nuclear receptors, bile acidsand cholesterol homeostasis series-Bile acids and pregnancy. Mol CellEndocrinol,2013,368(1):120-128.
[22]. Reyes H. The spectrum of liver and gastrointestinal disease seen in cholestasisof pregnancy. Gastroenterol Clin North Am,1992,21(4)905-921.
[23]. Favre N, Bourdel N, Sapin V, Abergel A, Gallot D.[Importance of bile acids forintra-hepatic cholestasis of pregnancy]. Gynecol Obstet Fertil,2010,38(4):293-295.
[24]. Lee RH,. Kwok KM, Ingles S, Wilson ML, Mullin P, Incerpi M, Pathak B,Goodwin TM. Pregnancy outcomes during an era of aggressive management forintrahepatic cholestasis of pregnancy. Am J Perinatol,2008,25(6):341-345.
[25].妊娠期肝内胆汁淤积症诊疗指南(第1版).中华妇产科杂志,2011,46(5):391:395.
[26]. Williamson C, Hems LM, Goulis DG, Walker I, Chambers J, Donaldson O,Swiet M, Johnston DG. Clinical outcome in a series of cases of obstetriccholestasis identified via a patient support group. BJOG,2011,111(7)676-681.
[27]. Vallejo M, Briz O, Serrano MA, Monte MJ, Marin JJ. Potential role oftrans-inhibition of the bile salt export pump by progesterone metabolites in theetiopathogenesis of intrahepatic cholestasis of pregnancy. J Hepatol,2006,44(6):1150-1157.
[28]. Yamamoto Y, Moore R, Hess HA, Guo GL, Gonzalez FJ, Korach KS, MaronpotRR, Negishi M. Estrogen receptor alpha mediates17alpha-ethynylestradiolcausing hepatotoxicity. J Biol Chem,2006,281(24):16625-16631.
[29]. Milona A, Owen BM, Cobbold JF, Willemsen EC, Cox IJ, Boudjelal M, CairnsW, Schoonjans K, Taylor-Robinson SD, Klomp LW, Parker MG, White R, vanMil SW, Williamson C. Raised hepatic bile acid concentrations duringpregnancy in mice are associated with reduced farnesoid X receptor function.Hepatology,2010,52(4):1341-1349.
[30]. Dixon PH, Weerasekera N, Linton KJ, Donaldson O, Chambers J, Egginton E,Weaver J, Nelson-Piercy C, de Swiet M, Warnes G, Elias E, Higgins CF,Johnston DJ, McCarthy MI, Williamson C. Heterozygous MDR3missensemutation associated with intrahepatic cholestasis of pregnancy: evidence for adefect in protein trafficking. Hum Mol Genet,2000,9(8):1209-1217.
[31]. Mangalam AK, Taneja V, David CS. HLA class II molecules influencesusceptibility versus protection in inflammatory diseases by determining thecytokine profile. J Immunol,2013,190(2):513-518.
[32]. Meng XQ, Chen HG, Ma YL, Liu KZ. Influence of HLA class II molecules onthe outcome of hepatitis B virus infection in population of Zhejiang Province inChina. Hepatobiliary Pancreat Dis Int,2003,2(2):230-233.
[33]. Mella JG, Roschmann E, Glasinovic JC, Alvarado A, Scrivanti M, Volk BA.Exploring the genetic role of the HLA-DPB1locus in Chileans withintrahepatic cholestasis of pregnancy. J Hepatol,1996,24(3):320-323.
[34]. Ding Y, Shen H, Wang X, Fan X, Wu X, Yang X. The polymorphism ofHLA-DR and-DQ allelic genes associated with intrahepatic cholestasis ofpregnancy. Genet Test,2008,12(2):215-220.
[35]. Jacquemin E. Role of multidrug resistance3deficiency in pediatric and adultliver disease: one gene for three diseases. Semin Liver Dis,2001,21(4):551-562.
[36]. Eloranta ML, Hakli T, Hiltunen M, Helisalmi S, Punnonen K, Heinonen S.Association of single nucleotide polymorphisms of the bile salt export pumpgene with intrahepatic cholestasis of pregnancy. Scand J Gastroenterol,2003,38(6):648-652.
[37]. Mullenbach R, Bennett A, Tetlow N, Patel N, Hamilton G, Cheng F, Chambers J,Howard R, Taylor-Robinson SD, Williamson C. ATP8B1mutations in Britishcases with intrahepatic cholestasis of pregnancy. Gut,2005,54(6)829-834.
[38]. Stieger B, Geier A. Genetic variations of bile salt transporters as predisposingfactors for drug-induced cholestasis, intrahepatic cholestasis of pregnancy andtherapeutic response of viral hepatitis. Expert Opin Drug Metab Toxicol,2011,7(4):411-425.
[39]. Bacq Y, Gendrot C, Perrotin F, Lefrou L, Chretien S, Vie-Buret V, Brechot MC,Andres CR. ABCB4gene mutations and single-nucleotide polymorphisms inwomen with intrahepatic cholestasis of pregnancy. J Med Genet,2009,46(10)711-715.
[40]. Keitel V, Vogt C, Haussinger D, Kubitz R. Combined mutations of canaliculartransporter proteins cause severe intrahepatic cholestasis of pregnancy.Gastroenterology,2006,131(2):624-629.
[41]. Kitsiou-Tzeli S, Traeger-Synodinos J, Giannatou E, Kaminopetros P, Roma E,Makrythanasis P, Tsezou A. The c.504T>C (p.Asn168Asn) polymorphism in theABCB4gene as a predisposing factor for intrahepatic cholestasis of pregnancyin Greece. Liver Int,2010,30(3):489-491.
[42]. Mullenbach R, Linton KJ, Wiltshire S, Weerasekera N, Chambers J, Elias E,Higgins CF, Johnston DJ, McCarthy MI, Williamson C. ABCB4gene sequencevariation in women with intrahepatic cholestasis of pregnancy. J Med Genet,2003,40(5): e70.
[43]. Pauli-Magnus C, Lang T, Meier Y, Zodan-Marin T, Jung D, Breymann C,Zimmermann R, Kenngott S, Beuers U, Reichel C, Kerb R, Penger A, Meier PJ,Kullak-Ublick GA. Sequence analysis of bile salt export pump (ABCB11) andmultidrug resistance p-glycoprotein3(ABCB4, MDR3) in patients withintrahepatic cholestasis of pregnancy. Pharmacogenetics,2004,14(2):91-102.
[44]. Wasmuth HE, Glantz A, Keppeler H, Simon E, Bartz C, Rath W, Mattsson LA,Marschall HU, Lammert F. Intrahepatic cholestasis of pregnancy: the severeform is associated with common variants of the hepatobiliary phospholipidtransporter ABCB4gene. Gut,2007,56(2):265-270.
[45]. Mealey KL, Minch JD, White SN, Snekvik KR, Mattoon JS. An insertionmutation in ABCB4is associated with gallbladder mucocele formation in dogs.Comp Hepatol,2010,9:6.
[46]. Delaunay JL, Durand-Schneider AM, Delautier D, Rada A, Gautherot J,Jacquemin E, Ait-Slimane T, Maurice M. A missense mutation in ABCB4geneinvolved in progressive familial intrahepatic cholestasis type3leads to afolding defect that can be rescued by low temperature. Hepatology,2009,49(4):1218-1227.
[47]. van der Woerd WL, van Mil SW, Stapelbroek JM, Klomp LW, van de Graaf SF,Houwen RH. Familial cholestasis: progressive familial intrahepatic cholestasis,benign recurrent intrahepatic cholestasis and intrahepatic cholestasis ofpregnancy. Best Pract Res Clin Gastroenterol.2010,24(5):541-553.
[48]. Jacquemin E, Hadchouel M. Genetic basis of progressive familial intrahepaticcholestasis. J Hepatol,1999,31(2):377-381.
[49]. Lam P, Soroka CJ, Boyer JL. The bile salt export pump: clinical andexperimental aspects of genetic and acquired cholestatic liver disease. SeminLiver Dis,2010,30(2):125-133.
[50]. an Mil SW, Milona A, Dixon PH, Mullenbach R, Geenes VL, Chambers J,Shevchuk V, Moore GE, Lammert F, Glantz AG, Mattsson LA, Whittaker J,Parker MG, White R, Williamson C. Functional variants of the central bile acidsensor FXR identified in intrahepatic cholestasis of pregnancy.Gastroenterology,2007,133(2):507-516.
[51]. Yayi H, Danqing W, Shuyun L, Jicheng L. Immunologic abnormality ofintrahepatic cholestasis of pregnancy. Am J Reprod Immunol,2010,63(4):267-273.
[52]. Ling B, Yao F, Zhou Y, Chen Z, Shen G, Zhu Y. Cell-mediated immunityimbalance in patients with intrahepatic cholestasis of pregnancy. Cell MolImmunol,2007,4(1):71-75.
[53].彭冰,刘淑芸.辅助性T淋巴细胞哑型与妊娠期肝内胆汁淤积症发病的关系.中华妇产科杂志,2002,37(9):516-518.
[54].曲广第,王冬梅. TNF-α，IL-6在妊娠肝内胆汁淤积症胎盘上的表达.新疆医科大学学报,2004,27(3):264-266.
[55].时青云,刘淑芸,熊庆.妊娠肝内胆汁淤积症患者雌孕激素水平及免疫功能的变化.中华妇产科杂志,1998,33(12):724-727.
[56].袁佩,虞斌,王秋伟,董一善,吕文燕,狄志英.妊娠期肝内胆汁淤积症患者淋巴细胞亚群分析.江苏大学学报(医学版),2004,14(1):49-50.
[57]. Kauppila A, Korpela H, Makila UM, Yrjanheikki E. Low serum seleniumconcentration and glutathione peroxidase activity in intrahepatic cholestasis ofpregnancy. Br Med J (Clin Res Ed),1987,294(6565):150-152.
[58]. Reyes H, Baez ME, Gonzalez MC, Hernandez I, Palma J, Ribalta J, Sandoval L,Zapata R. Selenium, zinc and copper plasma levels in intrahepatic cholestasis ofpregnancy, in normal pregnancies and in healthy individuals, in Chile. J Hepatol,2000,32(4)542-549.
[59].王竹晨,刘淑芸.孕妇静脉血及其新生儿脐血硒水平及谷胱甘肽过氧化物酶活性与妊娠肝内胆汁淤积症的关系.中华妇产科杂志,2000,35(9)520-522.
[60].古航,胡电.妊娠期肝内胆汁淤积症.中华妇产科杂志,2003,38(2):121-129.
[61]. Marin JJ, Macias RI, Serrano MA. The hepatobiliary-like excretory function ofthe placenta. A review. Placenta,2003,24(5)431-438.
[62]. Marin JJ, Briz O, Serrano MA. A review on the molecular mechanismsinvolved in the placental barrier for drugs. Curr Drug Deliv,2004,1(3):275-289.
[63].张岩,印永祥,许倩,赵华,项静英,许建娟.胎盘组织中胆酸调节蛋白的表达及其与妊娠期肝内胆汁郁积症发病的关系.中华妇产科杂志,2010,45(8):615-617.
[64]. Perez MJ, Macias RI, Marin JJ. Maternal cholestasis induces placentaloxidative stress and apoptosis. Protective effect of ursodeoxycholic acid.Placenta,2006,27(1):34-41.
[65]. Geenes VL, Lim YH, Bowman N, Tailor H, Dixon PH, Chambers J, Brown L,Wyatt-Ashmead J, Bhakoo K, Williamson C. A placental phenotype forintrahepatic cholestasis of pregnancy. Placenta,2011,32(12):1026-1032.
[66]. Paumgartner G, Beuers U. Mechanisms of action and therapeutic efficacy ofursodeoxycholic acid in cholestatic liver disease. Clin Liver Dis,2004,8(1):67-81.
[67]. Bacq Y, Sentilhes L, Reyes HB, Glantz A, Kondrackiene J, Binder T, NicastriPL, Locatelli A, Floreani A, Hernandez I, Di Martino V. Efficacy ofursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: ameta-analysis. Gastroenterology,2012,143(6):1492-1501.
[68]. Pusl T, Beuers U. Intrahepatic cholestasis of pregnancy. Orphanet J Rare Dis,2007,2:26.
[69]. Pathak B, Sheibani L, Lee RH. Cholestasis of pregnancy. Obstet Gynecol ClinNorth Am,2010,37(2):269-282.
[70]. Zapata R, Sandoval L, Palma J, Hernandez I, Ribalta J, Reyes H, Sedano M,Toha D, Silva JJ. Ursodeoxycholic acid in the treatment of intrahepaticcholestasis of pregnancy. A12-year experience. Liver Int,2005,25(3)548-554.
[71]. Beuers U. Drug insight: Mechanisms and sites of action of ursodeoxycholicacid in cholestasis. Nat Clin Pract Gastroenterol Hepatol,2006,3(6):318-328.
[72]. Binder T, Salaj P, Zima T, Vitek L. Randomized prospective comparative studyof ursodeoxycholic acid and S-adenosyl-L-methionine in the treatment ofintrahepatic cholestasis of pregnancy. J Perinat Med,2006,34(5)383-391.
[73]. Perin E, Cacciaguerra G, Driul L, Marchesoni D,[Intrahepatic cholestasis ofpregnancy: diagnosis and obstetric management]. Minerva Ginecol,2010,62(2):97-103.