核因子-κB与酒精性肝病

本文总结了NF-κB在酒精性肝病发生发展中所起的作用:可促进炎症反应和氧化应激,同时还有促进肝细胞再生和抗凋亡作用,针对NF-κB活性的激活与抑制,可以从不同环节寻找药物用于治疗和预防酒精性肝病。     

核因子—kB在实验性酒精性肝病大鼠模型中的表达

近年来 ,随着人民生活水平的日益提高 ,酒精性肝病已成为危害我国人民身体健康的一个重要原因。因此 ,深入探讨酒精性肝病的发病机制并寻求有效的防治方法尤为重要。核因子 κＢ(ＮＦ κＢ)作为一种多功能的细胞转录因子 ,在肝脏炎症、纤维化及肝细胞再生、凋亡等病理生理中起着重要作用[1] 。一、材料和方法1.动物模型的建立 :Ｗｉｓｔａｒ大鼠 5 5只随机分为两组 :对照组 2 0只 ,模型组 35只[2 ] 。大鼠经 1周的喂养适应期后 ,模型组给予 4 0 %乙醇 (国产分析纯 ) ,8ｇ·ｋｇ-1·ｄ-1,分 3次灌胃至 4周末。自第 5周开始 ,将乙醇浓度增至 5…     

核因子-κB与肺脏疾病

核因子是调控基因表达的DNA结合蛋白。核因子一KB(NF-κB)是1986年首次由Sen和Baltimore发现并报道的，当时被认为是一种存在于B细胞内的调控kappa轻链基因表达的增强子结合蛋白，并因而得名。现已知，NF-κB是一种广泛存在的转录因子，在应激、炎症和免疫反应等过程中发挥重要作用，本对NF-κB在肺部疾病中的重要作用作一综述。     

核因子-κB与非酒精性脂肪性肝病

非酒精性脂肪性肝病(NAFLD)是临床上最为常见的肝病之一,其发病机制至今尚未完全阐明.目前认为胰岛素抵抗(IR)、氧化应激和脂质过氧化在NAFID发生中起关键性作用.核因子(NF)-κB是一类重要的转录调控因子,通过调节免疫和炎症相关因子的表达在炎症和免疫反应中起枢纽作用.NF-κB与NAFLD的关系密切,对NF-κB的研究可能为探讨NAFLD的发病机制和治疗方案提供新的线索.本文就NF-κB的生物学特性、功能及其在NAFLD发生、发展中的作用作一综述.     

清肝解毒活血颗粒对酒精性肝病大鼠核转录因子-κB及肝脏脂质过氧化水平的影响

目的观察清肝解毒活血颗粒对酒精性肝病大鼠核转录因子-κB(NF-κB)的表达及肝脏脂质过氧化水平的影响。方法采用酒精灌胃法诱发大鼠酒精性肝病模型,同时以清肝解毒活血颗粒进行干预,造模12w后,采用逆转录酶PCR(RT-PCR)法检测大鼠肝组织NF-κB mRNA表达水平,采用化学比色法检测大鼠肝组织中SOD、MDA和GSH-PX的变化。结果清肝解毒活血颗粒能明显减弱肝组织中NF-κB mRNA的表达。经治疗后,用药组SOD和GSH-PX与模型组相比活性明显上升(P0.01);MDA与模型组相比含量明显降低(P0.01)。结论清肝解毒活血颗粒能有效地防治酒精性肝病,其作用机制可能与抑制NF-κB mRNA的表达及抗脂质过氧化反应有关。     

衰老进程中核转录因子-κB表达的变化

1986年Sen和Baltimore首次报道了核转录因子-κB（NF-κB）,由于它可以被多种刺激所激活,更由于它可以调节大多数细胞因子和多向调整细胞的生长发育、增殖和凋亡,而受到空前持续的关注。在衰老调控网络中，NF-κB在衰老进程的免疫障碍中扮演了核心角色，     

核因子-κB与肾脏疾病

核因子 (ｎｕｃｌｅａｒｆａｃｔｏｒ ,ＮＦ) ＫａｐｐａＢ(κＢ)是一种重要的核转录因子 ,它参予细胞内的信号传递 ,调控多种基因的表达。它的异常激活或完全抑制与多种疾病的发生有关[1～ 4 ] 。多种肾脏疾病 ,如肾小球肾炎、肾细胞癌、糖尿病肾病、间质性肾炎及肾纤维化等 ,均伴有ＮＦ κΒ转录活性的异常。1　ＮＦ κＢ的结构及特点现已明确 ,ＮＦ κΒ是一序列特异性的ＤＮＡ结合蛋白 ,与其细胞内抑制物ＩκΒ结合 ,以非活性形式存在于胞浆中。多种物质 ,如肿瘤坏死因子α(ＴＮＦ α)、脂多糖 (ＬＰＳ)或佛波乙酯 (ＰＭＡ)等 ,可刺激…     

核因子-κB及抑制因子I-κB在类阿尔茨海默病模型大鼠脑组织中的表达

为探讨核因子 κB(NF κB)及抑制因子I κB在阿尔茨海默病 (AD)发病机制中的作用 ,我们于 2 0 0 0年 12月至2 0 0 1年 12月用免疫组化法检测了两者在类AD模型大鼠脑组织中的表达。　　一、材料与方法　　 1.动物及分组 :健康雄性Wister大鼠 ,3～ 5个月龄 ,体重 2 5 0～ 30 0g(由中国医科大学实验动物中心提供 ) ,共 6 0只 ,随机分成实验组 30只 ,对照组 30只。　　 2 .类AD模型大鼠制备及确定 :参照何蕴绍等〔1〕 报道的方法 ,即采用单侧 (左侧 )穹隆 海马伞切断制成类AD模型。大鼠术后 2周 ,经Morris水迷宫测试平均逃避潜伏期大于…     

核因子-κB抑制剂及其在肺部疾病中的应用

核因子-κB(NF-κB)是一个多功能核转录因子，能在基因转录水平调控多种炎症因子的表达，与肺部炎症疾病关系密切。人们研究发现体内外多种物质可抑制NF-κB的活性，这些NF-κB抑制剂通过不同的机制抑制其活化，从而阻断炎症因子的生成。探索新的NF-κB抑制剂，进一步研究其临床应用价值，必将对炎症疾病的治疗带来新的契机。     

核因子-κB与急性胰腺炎

核因子 κB是一类能与多种细胞因子、粘附分子基因启动子部位的κB位点结合并增强这些基因转录的蛋白质。近年研究证实细胞因子、粘附分子在急性胰腺炎的发病中起着非常重要的作用 ,因此有关核因子 κB在急性胰腺炎发病中的作用最近已引起人们的极大关注。本文着重就核因子 κB的组成结构、活化调节及其与急性胰腺炎的关系等作一综述。     

Activation of nuclear factor kappa B and cytokine imbalance in experimental alcoholic liver disease in the rat.

Inflammatory stimuli and lipid peroxidation activate nuclear factor kappa B (NF-kappaB) and upregulate proinflammatory cytokines and chemokines. The present study evaluated the relationship between pathological liver injury, endotoxemia, lipid peroxidation, and NF-kappaB activation and imbalance between pro- and anti-inflammatory cytokines. Rats (5 per group) were fed ethanol and a diet containing saturated fat, palm oil, corn oil, or fish oil by intragastric infusion. Dextrose isocalorically replaced ethanol in control rats. Pathological analysis was performed and measurements of endotoxin were taken, lipid peroxidation, NF-kappaB, and messenger RNA (mRNA) levels of proinflammatory cytokines (tumor necrosis factor-alpha [TNFalpha], interleukin-1 beta [IL-1beta], interferon-gamma, [IFN-gamma], and IL-12), C-C chemokines (regulated upon activation, normal T cell expressed and secreted [RANTES], monocyte chemotactic protein [MCP]-1, macrophage inflammatory protein [MIP]-1alpha), C-X-C chemokines (cytokine induced neutrophil chemoattractant (CINC), MIP-2, IP-10, and epithelial neutrophil activating protein [ENA]-78), and anti-inflammatory cytokines (IL-10, IL-4, and IL-13). Activation of NF-kappaB and increased expression of proinflammatory cytokines C-C and C-X-C chemokines was seen in the rats exhibiting necroinflammatory injury (fish oil-ethanol [FE] and corn oil-ethanol[CE]). These groups also had the highest levels of endotoxin and lipid peroxidation. Levels of IL-10 and IL-4 mRNA were lower in the group exhibiting inflammatory liver injury. Thus, activation of NF-kappaB occurs in the presence of proinflammatory stimuli and results in increased expression of proinflammatory cytokines and chemokines. The Kupffer cell is probably the major cell type showing activation of NF-kappaB although the contribution of endothelial cells and hepatocytes cannot be excluded. Downregulation of anti-inflammatory cytokines may additionally exacerbate liver injury.     

Melatonin inhibits nuclear factor kappa B activation and oxidative stress and protects against thioacetamide induced liver damage in rats

BACKGROUND/AIMS: Free radical-mediated oxidative stress has been implicated in the pathogenesis of acute liver injury. The aim of our study was to investigate whether melatonin, a potent free radical scavenger could prevent fulminant hepatic failure in rats. METHODS: Liver damage was induced by two consecutive injections of thioacetamide (TAA, 300 mg/kg/i.p.) at 24 h intervals. Treatment with melatonin (3 mg/kg/daily, i.p) was initiated 24 h prior to TAA. RESULTS: Twenty-four h after the second TAA injection, serum liver enzymes and blood ammonia were lower in rats treated with TAA+melatonin compared to TAA (P<0.001). Liver histology was significantly improved and the mortality in the melatonin-treated rats was decreased (P<0.001). The increased nuclear binding of nuclear factor kappa B in the livers of the TAA-treated rats, was inhibited by melatonin. The hepatic levels of thiobarbituric acid reactive substances, protein carbonyls and inducible nitric oxide synthase were lower in the TAA+melatonin-treated group (P<0.01), indicating decreased oxidative stress and inflammation. CONCLUSIONS: In a rat model of TAA-induced fulminant hepatic failure, melatonin improves survival and reduces liver damage and oxidative stress. The results suggest a causative role of oxidative stress in TAA-induced hepatic damage and suggest that melatonin may be utilized to reduce liver injury associated with oxidative stress.     

环氧合酶-2在大鼠酒精性肝炎中的表达及作用机制

目的　观察环氧合酶 2 (cyclooxygenase_2 ,COX_2 )在大鼠酒精性肝炎中的表达 ,探讨COX_2与酒精性肝炎的关系。方法　随机将 2 8只雄性SD大鼠分为正常组 7只 ,乙醇组 7只 ,以 10～ 12g·kg-1·d-1乙醇灌胃复制大鼠酒精性肝炎动物模型 ,实验组 2组 (每组 7只 ) ,以相同的方式复制动物模型后分别给予 0 4%和 0 8%的特异性COX 2抑制剂塞莱西布 (celecoxib)灌胃。测定肝组织中丙二醛 (malonaldehyde ,MDA)及血清ALT和AST水平 ,在光镜下观察肝脏的形态学改变 ,并应用RT_PCR技术检测COX 2mRNA在酒精性肝炎中的表达 ,其结果用凝胶分析系统测定相对表达量。结果　乙醇组大鼠肝组织中MDA含量较实验组大鼠和正常组大鼠明显增高 (P <0 .0 5 ) ;正常组和实验组大鼠血清ALT、AST浓度均明显低于乙醇组 (P <0 .0 5 )。HE染色光镜下见乙醇组大鼠肝细胞脂肪变性 ,炎性细胞浸润及细胞坏死。在正常组大鼠肝组织中COX 2mRNA无表达 ,乙醇组表达阳性 ,且显著高于两实验组COX_2mRNA的表达 (P <0 .0 5 )。结论　高表达的COX 2参与到酒精性肝炎的发生发展过程 ,应用特异性 (COX 2 )抑制剂塞莱西布有可能减轻乙醇诱导的肝损害     

Protease-activated receptor-2 regulates cyclooxygenase-2 expression in human bile duct cancer via the pathways of mitogen-activated protein kinases and nuclear factor kappa B

Background/purpose

Recent studies have suggested that protease-activated receptor-2 (PAR-2) activity correlates with cell proliferation and tumor growth, and its activation induces expression of cyclooxygenase-2 (COX-2). However, no previous reports have investigated PAR-2 signaling pathways in bile duct cancer. The aim of this study was to determine whether PAR-2 activation can regulate COX-2 expression via mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-??B) in human bile duct cancer cells.

Methods

We immunohistochemically examined PAR-2 and COX-2 expression in 104 resected human specimens of extrahepatic bile duct cancer. We then determined how inhibitors of MAPKs and NF-??B signaling pathways influence COX-2 expression under PAR-2 activation in HuCCT1 and TKKK, human bile duct cancer cell lines.

Results

PAR-2 and COX-2 proteins were immunohistochemically recognized in 63 and 57% of specimens and were significantly correlated. PAR-2 agonist peptide activated mRNA and protein expression of COX-2 in HuCCT1 and TKKK. Pharmacologic blockade of p44/42 or p38 MAPK significantly inhibited PAR-2-activated mRNA and protein expression of COX-2 in both cells. COX-2 protein expression was also inhibited by the blocker of NF-??B pathway in both cells.

Conclusions

PAR-2 may regulate COX-2 expression in human bile duct cancer via the MAPKs and NF-??B pathways.     

Role of osteoprotegerin/receptor activator of nuclear factor kappa B/receptor activator of nuclear factor kappa B ligand axis in nonalcoholic fatty liver disease

Concomitantly with the increase in the prevalences of overweight/obesity, nonalcoholic fatty liver disease(NAFLD) has worldwide become the main cause of chronic liver disease in both adults and children. Patients with fatty liver display features of metabolic syndrome(Met S), like insulin resistance(IR), glucose intolerance, hypertension and dyslipidemia. Recently, epidemiological studies have linked obesity, Met S, and NAFLD to decreased bone mineral density and osteoporosis, highlighting an intricate interplay among bone, adipose tissue, and liver. Osteoprotegerin(OPG), an important symbol of the receptor activator of nuclear factor-B ligand/receptor activator of nuclear factor kappa B/OPG system activation, typically considered for its role in bone metabolism, may also play critical roles in the initiation and perpetuation of obesityrelated comorbidities. Clinical data have indicated that OPG concentrations are associated with hypertension, left ventricular hypertrophy, vascular calcification, endothelial dysfunction, and severity of liver damage in chronic hepatitis C. Nonetheless, the relationship between circulating OPG and IR as a key feature of Met S as well as between OPG and NAFLD remains uncertain. Thus, the aims of the present review are to provide the existent knowledge on these associations and to discuss briefly the underlying mechanisms linking OPG and NAFLD.     

NF-kB在大鼠肝缺血再灌注损伤中的活化及意义

目的探讨NFkB在肝缺血再灌注损伤过程中的作用。方法选择健康雌性Wistar大鼠24只,随机分为手术对照组,肝缺血90min组,肝缺血90min/再灌注120min组,每组8只。常规方法观察肝脏组织学改变,检测血清酶学水平和肝组织中髓过氧化物酶(MPO)含量,采用sABC免疫组织化学方法测定肝组织中NFkB的活化程度。结果手术对照组肝组织形态正常,无NFkB活化,肝功能酶学和MPO正常水平;缺血组动物肝细胞索排列紊乱,肝小叶变形,肝细胞和内皮细胞普遍水肿变性,NFkB呈中重度活化,血清酶学和MPO水平升高(P<0.01);肝缺血/再灌注组肝组织在缺血组改变基础上合并中央区局灶性肝细胞坏死,血窦内微血栓形成,汇管区中性粒细胞浸润,NFkB活化最为明显,血清酶学和MPO升高最为显著(P<0.01)。结论肝缺血再灌注时,NFkB被活化,使中性粒细胞组织浸润,对肝脏缺血再灌注损伤病理过程起到重要的作用。     

环氧合酶-2在低分子肝素干预大鼠酒精性肝病中的作用机制研究

目的研究低分子肝素干预大鼠酒精性肝病模型的作用机制。方法 56%(V/V)的白酒平均以8 g/kg的剂量2次/d灌胃10周,初步制备大鼠酒精性肝病模型,成模后部分大鼠低分子肝素(100 IU/kg)皮下注射进行干预,4周后观察低分子肝素对大鼠的血清生物化学指标、肝组织中丙二醛及环氧化酶-2的影响。结果与模型组比较,低分子肝素治疗组大鼠血清转氨酶、血脂及丙二醛含量明显下降(P<0.05);光学显微镜观察HE染色见脂肪变性、炎症反应程度明显减轻(P<0.01),免疫组织化学染色及逆转录聚合酶链反应显示环氧化酶-2的表达均明显降低(P<0.05)。结论低分子肝素通过改善脂肪代谢、抑制氧化应激及降低环氧化酶-2的表达而对酒精性肝病大鼠起到一定的保护治疗作用。     

檞皮素对大鼠酒精性脂肪肝核转录因子表达的影响

目的:探讨檞皮素对大鼠酒精性脂肪肝的防治作用及其可能机制。方法:wistaur(?)鼠48只,随机分为:正常对照、酒精性脂肪肝模型、檞皮素处理、纳洛酮处理4组,实验4 wk末,处死所有大鼠,检测血AST,ALT和TNF-α,并行肝脏病理组织学及核转录因子(NF-ΚB)表达的检测。结果:檞皮素和纳洛酮组血AST,ALT和TNF-α明显低于模型组(檞皮素组:150.7±23.6 U/L,57.4±8.4 U/L,0.83±0.27μg/L;纳洛酮组:148.3±21.4 U/L,55.2±7.3 U/L,0.85±0.34μg/L vs 205.0±31.5 U/L,70.5±9.2 U/L,4.08±1.23μg/L;P<0.05),而高于正常对照组(127.6±17.8 U/L,47.9±7.1 U/L,0.22±0.10μg/L;P<0.05).檞皮素和纳洛酮组肝脏脂肪变程度较模型组轻,且懈皮素组肝内NF-ΚB表达水平显著低于模型组(60.27个/HP vs 28.49个/HP,P<0.05)。结论:檞皮素可能通过抑制NF-ΚB及TNF-α的表达,发挥防治酒精性脂肪肝的作用.     

模拟失重大鼠肝组织中NF-κB的表达及意义

目的:研究模拟失重环境下大鼠肝脏组织中NF-κB的表达及意义.方法:成年♂ Wistar 大鼠84只,随机分为模拟失重组和对照组,每组又分别设1、2、3、4、5、6和7 d共7个时相点,每时相点模拟失重和同步对照各6只大鼠.采用尾悬吊法建立模拟失重动物模型.各组大鼠肝组织中NF-κB表达分别应用Western blot 和免疫组化PV-6001法进行检测.结果:在尾悬吊1-2 d期间,大鼠焦躁不安,饮食量减少,精神较差,活动减弱,2-3 d后有所适应,逐渐恢复稳定状态.模拟失重环境下大鼠肝脏NF-κB表达水平明显升高,1、2 d悬尾组大鼠肝组织中NF-κB表达率明显高于对照组(F=271.36,P＜0.01),其后,NF-κB表达水平呈明显下降趋势势(F=60.68,P＜0.05),5-7 d悬尾组NF-κB表达水平接近对照组,差异无统计学意义.NF-κB阳性产物主要见于实验大鼠肝细胞内,亦见于炎细胞及Kupffer 细胞内,可分为胞质型、核型、核浆型等三个类型,单独或混合存在.结论:模模拟失重使大鼠肝脏组织中NF-κB表达发生明显变化,提示在失重环境中肝脏NF-κB的早期高表达和逐渐恢复过程与失重应激反应及失重耐受有密切关系.     

核因子-κB在免疫复合物型急性肺损伤中的作用

目的 探讨核因子-κB(NF-κB)在免疫复合物型急性肺损伤中的作用.方法 将30只家兔按随机数字表法随机分成5组(N组、M2h组、M4h组、M6h组、M8h组),每组6只.N组为正常对照组,余4组为模型组.N组家兔耳缘静脉按2 ml/kg注入无菌生理盐水,气管内按每只1 ml注入无菌生理盐水,模型组家兔耳缘静脉按2 ml/kg注入牛血清白蛋白(BSA)溶液,气管内按每只1 ml注入抗BSA血清.N组在8 h时处死动物,M2h组、M4h组、M6h组、M8h组分别在2、4、6和8 h时处死动物.检测各组BALF中的丙二醛(MDA)含量、超氧化物歧化酶(SOD)活性、蛋白质含量、肺组织湿重/干重比值(W/D)及肺组织中NF-κB的亚基P65在细胞的表达情况.采用SPSS 11.5统计软件包,多组计量资料间比较采用单因素方差分析,两组间比较采用LSD-t检验,两变量相关分析采用Pearson相关法.结果 (1)模型各组BALF中蛋白质含量、MDA含量、肺湿干重比值均高于正常对照组(均P<0.05).与之相反,模型各组BALF中SOD活性均低于正常对照组(均P<0.05).(2)M2h组、M4h组、M6h组、M8h组肺组织中NF-KB P65阳性细胞数[(26.5±5.9),(39.9±6.9),(51.0±6.3),(58.0±5.3)]均高于N组(7.4±1.9)(t值分别为8.73、12.80、18.73及25.33,均P<0.01).结论 静脉和气管分别注入抗原和抗体可建立免疫复合物型急性肺损伤动物模型,NF-κB在炎症细胞中的激活提示NF-κB与急性肺损伤炎症反应机制有关.