Aberrant methylation of UBE2Q1 promoter is associated with poor prognosis of acute-on-chronic hepatitis B pre-liver failure

Acute-on-chronic hepatitis B liver failure (ACHBLF) is one severe liver disease with rapid progression and high mortality. Identification of specific markers for the prediction of ACHBLF has important clinical significance. We explored the feasibility of UBE2Q1 gene promoter methylation as an early prediction and prognosis biomarker of ACHBLF.UBE2Q1 promoter methylation frequency was detected in 60 patients with acute-on-chronic hepatitis B pre-liver failure (Pre-ACHBLF), 40 patients with chronic hepatitis B and 20 cases of healthy control (HC). The UBE2Q1 mRNA was detected by quantitative real-time polymerase chain reaction.The methylation frequency of the UBE2Q1 promoter in pre-ACHBLF patients was 38.33%, which was significantly lower than that in chronic hepatitis B patients (60.00%) and HCs (65.00%). The UBE2Q1 mRNA expression in pre-ACHBLF patients with UBE1Q1 non-methylation was significantly higher than that in patients with UBE1Q1 promoter methylation. Further analysis showed that hypomethylation of the UBE2Q1 promoter was positively correlated with total bilirubin and international normalized ratio levels in patients with pre-ACHBLF, but negatively correlated with PTA level. COX multivariate analysis showed that the model for end-stage liver disease score and UBE2Q1 promoter hypomethylation status were potential early warning factors that can predict the progression of pre-ACHBLF to ACHBLF. The sensitivity and specificity of UBE2Q1 promoter methylation status combined with the model for end-stage liver disease score for early diagnosis of ACHBLF were 92.9% and 75.0%, respectively. The area under the receiver-operating characteristic curve was 0.895.The hypomethylation of UBE2Q1 promoter is associated with severity of Pre-ACHBLF, which could serve as a potential prognostic biomarker for pre-ACHBLF.     

Monitoring oxidative stress in acute-on-chronic liver failure by advanced oxidation protein products

Aim: Increased oxidative stress is important in the pathogenesis of acute‐on‐chronic liver failure (ACLF). This study aimed to investigate whether advanced oxidation protein products (AOPP) levels can monitor oxidative stress of ACLF patients. Furthermore, we aimed to study plasma exchange (PE) treatment and determine whether it can eliminate AOPP. Methods: We measured AOPP levels in 50 ACLF patients, 30 patients with compensated liver cirrhosis (CR), 30 patients with chronic hepatitis B (CHB) and 50 healthy controls by spectrophotometric assay. AOPP concentrations were also measured before and after PE treatment in ACLF patients. As an apoptosis marker, serum cytokeratin 18 (CK18 M 30) levels were detected to investigate the relationship between AOPP and apoptosis in ACLF patients. Results: Significantly higher AOPP levels at admission were found in patients with ACLF compared with CR, CHB and healthy controls (69.45 ± 29.04 µmol/L vs. 19.67 ± 7.02 µmol/L, 26.75 ± 5.21 µmol/L and 21.35 ± 6.15 µmol/L, respectively; P < 0.001). There was a positive relationship with total bilirubin, Child–Pugh, model for end‐stage liver disease scores and CK18 M 30. In ACLF patients, AOPP levels were higher in non‐survivors than survivors. An AOPP cut‐off of 74.21 µmol/L was used for predicting poor prognosis. Multivariate Cox regression analysis demonstrated that AOPP were independent risk factors for prognosis. Dynamic change of AOPP levels associated with prognosis appeared earlier than total bilirubin. Following PE treatment, AOPP levels reduced to 34.65 ± 18.14 µmol/L (P < 0.001). Conclusions: Advanced oxidation protein products were suitable for monitoring the levels of oxidative stress in ACLF patients. Increased AOPP may serve as an important biological marker of worse outcome. In addition, PE therapy was effective in reducing AOPP.     

Hypermethylation of the galectin-3 promoter is associated with poor prognosis of acute-on-chronic hepatitis B liver failure

Background and aimsThe possible role of galectin-3 in acute-on-chronic hepatitis B liver failure (ACHBLF) remains unknown. This study aimed to determine the methylation status of the galectin-3 promoter in patients with ACHBLF and analyze its prognostic value.MethodsThe methylation status of the galectin-3 promoter in patients with ACHBLF, chronic hepatitis B (CHB) and healthy controls (HCs) was determined by methylation-specific polymerase chain reaction (MSP). The galectin-3 mRNA level in peripheral blood mononuclear cells (PBMCs) was detected using real-time polymerase chain reaction (RT-PCR).ResultsThe methylation frequency of the galectin-3 promoter was significantly higher while galectin-3 mRNA was lower in ACHBLF than in CHB and HCs. Galectin-3 promoter methylation was negatively correlated with the mRNA level in ACHBLF. In addition, ACHBLF patients carrying the methylated promoter showed shorter survival time, higher 3-month mortality, and higher model for end-stage liver disease (MELD) score when compared to ACHBLF patients carrying the unmethylated promoter. Moreover, promoter methylation was a better predictor of 3-week mortality than the MELD score in ACHBLF patients.ConclusionOur results suggest that hypermethylation of the galectin-3 promoter might be an early biomarker for predicting disease severity and prognosis in patients with ACHBLF.     

No association between GSTP1 gene aberrant promoter methylation and prognosis in surgically resected hepatocellular carcinoma patients from the Basque Country (Northern Spain)

Aims: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, being linked etiologically to several factors. Glutathione‐S‐transferases (GSTs) are a family of enzymes that play an important role in detoxification. Hypermethylation of regulatory sequences at glutathione‐S‐transferase pi class gene (GSTP1) has been found in different human tumor types. In this study, we have studied the methylation status of the GSTP1 promoter region in patients from the Basque Country (Northern Spain) by methylation‐specific PCR (MSP). Methods and results: GSTP1 aberrant promoter methylation was present in 24 of 117 (20.5%) tumor samples being associated with late stages of tumor progression. Patients with multiple HCCs showed different patterns of methylation, which could suggest a different clonal origin of multicentric HCC or different degrees of differentiation. No effect on disease‐free survival or overall survival was observed in patients with GSTP1 methylated who underwent curative resection. Conclusions: We can conclude that GSTP1 promoter CpG island methylation appears to be a less common event during hepatocarcinogenesis in European populations than in Asian populations, being associated with late stages of tumor progression. These findings could also be useful to provide new therapeutic strategies through the use of demethylating agents.     

氧化应激、线粒体通透性转换与肝衰竭的相关性

目前治疗肝衰竭的主要手段有内科综合治疗、人工肝治疗、肝移植和干细胞移植治疗,虽然取得了较好的疗效,但是仍然有一部分患者由于病情凶险及治疗时机延误而最终死亡。氧化应激损伤是近年来研究的热点,抗氧化治疗也越来越受到关注。综合近年来的研究成果,对氧化应激损伤、线粒体膜通透性转换孔（MPTP）线粒体膜通透性转换孔及其与肝衰竭疾病的相关性做综述,阐明氧化应激损伤在肝衰竭发病中的重要性,为今后的进一步抗氧化治疗提供理论依据及思路。     

乙型肝炎病毒前C区/BCP区变异与慢加急性肝衰竭的关系

目的 探讨乙型肝炎病毒前C区/BCP区变异与乙型肝炎相关性慢加急性肝衰竭(ACLF)的关系. 方法 收集44例ACLF患者和28例慢性乙型肝炎患者(CHB)的血清及临床资料,并对其中10例ACLF患者进行随访,每周收集血清1次.依据MELD评分对患者的病情进行判断.采用巢氏PCR方法扩增HBV DNA,扩增产物直接测序.序列比对采用BioEdit (7.0.9.0)生物分析软件.采用荧光定量PCR法检测HBV DNA含量.数据采用SPSS13.0软件分析,两组间比较采用t检验及t'检验. 结果 44例ACLF患者基因型均为C型,28例CHB患者中仅两例基因型为B型,其余均为C型.ACLF组患者A1762T、G1764A、T1753V、G1896A、G1899A变异频率分别为88.6％(39/44)、93.2％(41/44)、61.4％(27/44)、63.6％(28/44)和29.5％(13/44),CHB组分别为64.3％(18/28)、67.9％(19/28)、14.3％(4/28)、21.4％(6/28)和3.6％(1/28),两组比较,x2值分别为6.152、7.901、15.468、12.331和7.370,P值均＜0.05,差异均有统计学意义.ACLF组内MELD评分＜ 20、20 ～ 25、＞25组间差异均无统计学意义.CHB组前C区、BCP区均未发生变异的频率为17.9％ (5/28),ACLF组为2.3％ (1/44),CHB组前C区、BCP区均未发生变异的频率高于ACLF组,x2=5.440,P=0.020,差异有统计学意义.ACLF组前C区、BCP区同时发生变异的频率为79.6％(35/44),CHB组为39.3％(11/28),两组比较,x2=12.021,P＜0.01,差异有统计学意义.CHB组仅BCP区有变异的发生频率为42.9％(12/28),ACLF组为20.5％(9/44),x2=4.157,P=0.041,差异有统计学意义.两组均未出现单独的前C区变异.10例ACLF患者均出现3个或3个以上的联合变异位点.G1896A、T1753C、A1846T变异随着病情好转而恢复.结论 乙型肝炎病毒前C区/BCP区变异可能与ACLF的发生相关.     

慢加急性乙型肝炎肝衰竭患者乙型肝炎病毒前C/CP区变异研究进展*

慢加急性肝衰竭（ACLF）是我国肝衰竭的主要类型,其病情发展迅速、预后不良、病死率较高。在我国,乙型肝炎病毒（HBV）感染是导致ACLF的主要病因,其中HBV前C（PC）/核心启动子（CP）区基因变异与ACLF的发生密切相关。本文重点介绍HBV PC/CP区基本结构和功能、PC/CP区变异后生物学特性的改变、ACLF的免疫病理损伤机制、PC/CP区变异与ACLF疾病进展的临床意义等方面的研究进展。     

临床氧化应激指标与糖尿病周围神经病变的相关研究

目的调查2型糖尿病患者的临床氧化应激指标情况,分析其与2型糖尿病患者伴发周围神经病变的相关性。方法收集2016年10月至2017年5月解放军第306医院内分泌科同期住院的212例2型糖尿病患者一般资料及临床资料。根据2型糖尿病患者伴发周围神经病变诊断标准,将入选患者分为伴发周围神经病变(n=97)和未伴发周围神经病变(n=115)2组。应用SPSS 23.0对2组患者的一般情况及临床资料进行比较,采用logistic回归分析2型糖尿病患者伴发周围神经病变的危险因素。探讨2型糖尿病患者伴发周围神经病变的特点及其与临床氧化应激指标的相关性。结果 2型糖尿病患者伴发周围神经病变组患者年龄、病程、糖化血红蛋白、总胆固醇显著高于未伴发周围神经病变组患者,空腹C肽、血红蛋白和总胆红素显著低于2型糖尿病非周围神经病变组患者(P0.05)。单因素logistic回归分析显示年龄、病程、糖化血红蛋白、总胆红素、血红蛋白可能与2型糖尿病患者伴发周围神经病变相关,进一步多因素logistic回归分析显示病程(OR=1.006,95%CI 1.003~1.010)、糖化血红蛋白(OR=1.403,95%CI 1.118~1.657)、血红蛋白(OR=0.976,95%CI0.958~0.994)是2型糖尿病患者伴发周围神经病变的独立危险因素。结论 2型糖尿病患者伴发周围神经病变患者临床氧化应激指标(总胆红素、血红蛋白)低于2型糖尿病非周围神经病变患者,且具有高龄、糖尿病病程长、血糖控制不佳及胰岛功能差的特点。     

慢性阻塞性肺疾病患者SIRT1表达与氧化应激的相关性研究

目的检测慢性阻塞性肺疾病(简称慢阻肺)患者外周血单个核细胞(PBMC)中沉默信息调节因子2相关酶1(SIRT-1)蛋白表达和血清丙二醛(MDA)和超氧化物歧化酶(SOD)水平,探讨SIRT-1和氧化应激的相关性。方法选择慢阻肺患者30例,分为慢阻肺低风险组和慢阻肺高风险组,每组各15例,并与20名健康非吸烟者(对照组)做比较。采用Western blot法检测3组研究对象PBMC中SIRT-1蛋白表达,同时测定血清MDA、SOD水平,分析SIRT-1蛋白表达和氧化应激相关性。结果与对照组相比,慢阻肺组患者PBMC中SIRT1蛋白表达显著降低;与慢阻肺低风险组相比,慢阻肺高风险组SIRT1蛋白表达进一步降低(P均0.05);慢阻肺血清MDA升高,SOD降低,在慢阻肺高风险组尤为明显(P均0.05);Pearson直线相关法分析SIRT-1蛋白表达水平与血清MDA呈显著负相关(r=-0.687,P0.05),与SOD呈正相关(r=0.471,P0.05)。结论慢阻肺患者PBMC中SIRT1蛋白表达显著降低,与氧化应激密切相关,提示SIRT1在慢阻肺发病过程中具有重要作用。     

Survival and prognostic factors in hepatitis B virus-related acute-on-chronic liver failure

AIM:To investigate the survival rates and prognostic factors in patients with hepatitis B virus-related acuteon-chronic liver failure(HBV-ACLF).METHODS:Clinical data in hospitalized patients with HBV-ACLF admitted from 2006 to 2009 were retrospectively analyzed.Their general conditions and survival were analyzed by survival analysis and Cox regression analysis.RESULTS:A total of 190 patients were included in this study.The overall 1-year survival rate was 57.6%.Patients not treated with antiviral drugs had ...     

血清高迁移率族蛋白1在乙型肝炎病毒相关慢加急性肝衰竭患者中的特点及其临床意义

目的 探讨血清高迁移率族蛋白1 (HMGB1)在HBV相关的慢加急性肝衰竭(HBV-ACLF)患者中的特点及其临床意义.方法 对60例HBV-ACLF患者血清HMGB1水平进行检测分析,并与30例慢性乙型肝炎患者和24例健康查体者进行对照研究,分析其与患者肝功能生物化学指标的相关性,并分析其与患者预后的关系.两组间比较采用独立样本的t检验或非参数检验,多组间比较采用方差分析,相关性分析采用多元线性回归法.结果 HBV-ACLF患者血清HMGB1水平高于慢性乙型肝炎患者[(10.03±3.08) μg/L比对(7.47+2.06) μg/L,t=2.667,P＜0.01],晚期HBV-ACLF患者血清HMGB1水平高于早期患者[(11.68±1.93) μg/L比对(9.11±3.15)μ g/L,t=2.214,P＜0.01],HBV-ACLF患者血清HMGB1水平与AST水平呈正相关(r=0.655,P＜0.01).随访2个月,感染组患者的HMGB1水平高于非感染组[(11.85±2.21)μ g/L比对(9.83±2.75) μg/L,Z=4.027,P＜0.05],死亡组患者的HMGB1水平高于生存组[(11.03±2.31)μg/L比对(9.52±3.01)μg/L,t=2.428,P＜0.05].结论 HBV-ACLF患者血清HMGB1水平随病情进展呈进行性升高,并可部分预测HBV-ACLF患者的预后.     

Predictors of the outcomes of acute-on-chronic hepatitis B liver failure

AIM:To identify the risk factors in predicting the outcome of acute-on-chronic hepatitis B liver failure patients.METHODS:We retrospectively divided 113 patients with acute-on-chronic liver failure-hepatitis B virus(ACLF-HBV) and without concurrent hepatitis C or D virus infection and hepatocellular carcinoma into two groups according to their outcomes after anti-HBV therapy.Their demographic,clinical,and biochemical data on the day of diagnosis and after the first week of treatment were analyzed using the Mann-Whitney U test,Fisher's exact test,and a multiple logistic regression analysis.RESULTS:The study included 113 patients(87 men and 26 women) with a mean age of 49.84 years.Fiftytwo patients survived,and 61 patients died.Liver failure(85.2%),sepsis(34.4%),and multiple organ failure(39.3%) were the main causes of death.Multivariate analyses showed that Acute Physiology and Chronic Health Evaluation(APACHE) Ⅱ scores ≥ 12 [odds ratio(OR) = 7.160,95% CI:2.834-18.092,P 0.001] and positive blood culture(OR = 13.520,95% CI:2.740-66.721,P = 0.001) on the day of diagnosis and model for end-stage liver disease(MELD) scores ≥ 28(OR = 8.182,95% CI:1.884-35.527,P = 0.005) after the first week of treatment were independent predictors of mortality.CONCLUSION:APACHE Ⅱ scores on the day of diagnosis and MELD scores after the first week of anti-HBV therapy are feasible predictors of outcome in ACLFHBV patients.     

老年男性慢性心力衰竭患者血浆睾酮与心室重构和氧化应激的关系

目的通过对老年男性慢性心力衰竭(CHF)患者血浆总睾酮、超氧化物歧化酶(SOD)、丙二醛水平及左心室质量指数(LVMI)、左心室舒张未内径(LVIDD)的观察,探讨男性CHF患者血浆睾酮水平与心脏重构及氧化应激的相互关系。方法选择男性CHF患者(CHF组)50例,另选年龄相匹配的男性患者(对照组)40例.检测血浆睾酮、丙二醛和SOD水平,应用超声心动图测量LVMI、LVIDD,进行对比和直线相关分析。结果与对照组比较,CHF组睾酮、SOD水平明显降低(P<0.01).丙二醛、LVIDD、LVMI明显增加(P<0.01);CHF组睾酮水平与LVMI、LVIDD、丙二醛呈负相关(r=-0.732、r=-0.629、r=-0.623,P<0.01);与SOD水平呈正相关(r=0.743,P<0.01);SOD水平与LVMI、LVIDD呈负相关(r=-0.621、r=-0.594,P<0.01)。结论男性CHF患者睾酮下降可致心室重构加剧及机体氧化应激水平提高。同时机体抗氧化物质的减少对心室重构有重要促进作用。     

酒精性肝病与氧化应激

酒精性肝病(ALD)是威胁人类健康的重大疾病之一,其发病机制错综复杂。氧化应激性肝损害在其中占有至关重要的地位,如何系统的认识机体的氧化与抗氧化系统在ALD发生发展过程中所扮演的角色,对ALD的防治工作具有一定的指导意义。     

慢性阻塞性肺疾病患者氧化应激与肺功能的相关性

目的探讨COPD患者氧化应激状态以及对肺功能的影响。方法选择COPD患者88例,行肺功能测定,根据FEV1%及FEV1/FVC分为轻、中、重三组,并对所有入选者抽取静脉血,化学比色法检测血清还原型谷胱甘肽(GSH)、丙二醛(MDA)、超氧化物歧化酶(SOD)的水平。结果与轻度组比较,中、重度COPD患者SOD、GSH水平明显下降,MDA明显升高(P<0.05、P<0.01)。相关分析显示:MDA与肺功能(FEV1%、FEV1/FVC)呈负相关(P<0.01、P<0.05),SOD、GSH与肺功能呈正相关(P<0.01、P<0.05)。结论 COPD患者体内存在氧化应激失衡,随着氧化/抗氧化功能失衡加重,肺功能下降加剧。     

氧化应激/还原应激在心力衰竭中的研究进展

氧化应激自1985年由德国科学家Sies第一次提出之后,关于氧化应激的研究已有30多年历史,且从未中断。国内外大量研究已经证实氧化应激参与心力衰竭的发生和发展。针对临床前环境中的抗氧化应激治疗也进行了广泛研究,并显示出非常有希望的结果,但是目前临床上采用的大多数抗氧化策略都未能改善心力衰竭患者的预后。原因可能是大部分研究忽略了还原应激的损伤作用。本文将概述心力衰竭时氧化应激/还原应激的变化特点,以期为未来抗氧化/还原应激方向提供新的见解。     

miR-708与慢性乙型肝炎相关慢加急性肝衰竭患者预后的关系

目的 探究miR-708与慢性乙型肝炎（CHB）相关慢加急性肝衰竭（ACLF）患者预后的关系。方法 前瞻性选取2018年3月至2020年6月在海南医学院第二附属医院就诊的128例CHB-ACLF患者（设为CHB-ACLF组）和100例CHB患者（设为CHB组）作为研究对象。根据CHB-ACLF患者的预后生存情况将其分为生存组（n=66）和死亡组（n=62）。采用实时荧光定量PCR法检测各组血清miR-708的表达水平,并分析其与CHB-ACLF患者预后90 d生存情况的关系。结果CHB-ACLF组的血清miR-708相对表达量低于CHB组（0.43±0.16比0.75±0.14）,两组差异有统计学意义（P<0.05）。生存组的血清miR-708相对表达量高于死亡组（0.52±0.14比0.33±0.11）,两组差异有统计学意义（P<0.05）。多因素logistic回归分析结果显示,国际标准化比值（INR）、肌酐和终末期肝病模型（MELD）评分是CHB-ACLF患者预后生存的独立危险因素（P<0.05）,miR-708是CHB-ACLF患者预后生存的独立保护因素（P&...     

老年糖尿病合并高血压患者血清网膜素水平与氧化应激的关系

目的探讨老年糖尿病(DM)合并高血压患者血清网膜素水平与氧化应激的关系。方法入选2015年6月至2016年12月期间在佳木斯市骨科医院内科治疗的老年2型DM患者127例,依据是否合并高血压分为2组:高血压组(n=69)和非高血压组(n=58)。另选取我院同期体检的健康老年人30名作为对照组。检测3组血清网膜素、丙二醛(MDA)、超氧化物岐化酶(SOD)、谷胱甘肽过氧化物酶(GSH-px)水平。采用SPSS 20.0统计软件进行统计学分析,两组计量资料间比较采用t检验。Pearson直线相关分析合并高血压组老年DM患者血清网膜素与MDA、SOD、GSH-px的关系。结果治疗前组间比较结果显示,与非高血压组相比,高血压组患者的网膜素、SOD和GSH-Px均进一步显著降低,而MDA水平进一步显著增加,差异均具有统计学意义(P0.01)。组内比较结果显示,与治疗前相比,高血压组患者的血清网膜素、SOD、GSH-px均显著升高,而血清MDA和MAP均显著降低,差异均具有统计学意义(P0.01)。合并高血压老年DM患者的血清网膜素水平与血清MDA(r=-0.587)和MAP(r=-0.542)水平呈显著负相关(P0.01)、与SOD(r=0.683)和GSH-px(r=0.596)水平呈显著正相关(P0.01)。结论由血清网膜素水平降低引起的氧化应激反应增强可能是老年DM患者合并高血压发病的重要原因之一。     

乙型肝炎相关慢加急性肝衰竭患者预后的危险因素分析

目的探讨乙型肝炎相关慢加急性肝衰竭(HBV-ACLF)患者的临床特征及远期预后的危险因素。方法回顾性分析第三军医大学西南医院2010年1月~(-2)015年1月住院的1116例HBV-ACLF患者的临床资料,观察影响患者1年生存时间及预后的危险因素,通过Cox回归模型筛选出影响预后的独立危险因素。计量资料组间比较采用t检验或t'检验,计数资料组间比较采用χ~2检验。结果在随访的1年时间内,562例患者死亡,病死率为50.4%。生存组和死亡组比较:年龄、ALT、TBil、尿素氮、血肌酐、国际标准化比值、血清Na+、白细胞(WBC)、中性粒细胞百分比、血小板(PLT)、HBV DNA载量、MELD评分、腹水、自发性细菌性腹膜炎、消化道出血、肺部感染、脓毒症、电解质紊乱、肝性脑病及急性肾损伤(AKI)在2组间的差异均有统计学意义(P值均0.05)。Cox回归分析结果显示:年龄、WBC、MELD评分、肝性脑病、电解质紊乱、AKI及PLT是HBV-ACLF患者1年病死率的独立危险因素(P值均0.05)。结论 HBV-ACLF是一个高病死率疾病,常常合并多种严重并发症。而影响HBV-ACLF患者1年病死率的主要危险因素包括年龄、WBC、MELD评分、肝性脑病、电解质紊乱、AKI及低PLT水平。