血红素氧合酶-1在氧化应激状态下的作用

1概述血红素氧合酶(hemeoxygenase,HO)催化血红素降解的限速步骤,生成铁、CO和胆绿素,胆绿素随即被还原成胆红素。最近研究的重点是在此酶促反应产生的生物学效应上。迄今发现三种HO的同工酶:诱导型HO-1,两种组织表达型HO-2和HO-3,它们是不同基因编码的产物犤1,2犦。HO-1主要分布在网状内皮细胞含量丰富的组织中,脾、肝内的含量最高犤3犦。HO-2主要分布在脑组织、睾丸等不含网状内皮细胞的组织中犤4犦。HO-2和HO-3具有90%的氨基酸同源性并有相似的组织分布特征。HO的底物血红素、重金属、过氧化物、紫外线、高盐、缺氧、高氧、氧化…     

血红素氧合酶1基因-413A/T位点多态性与阻塞性睡眠呼吸暂停低通气综合征相关性研究

<正>阻塞性睡眠呼吸暂停低通气综合征(OSAHS)是一种常见疾病,具有一定的家族遗传性。OSAHS常与高血压、肥胖、高血脂等并存[1]。基因多态性与OSAHS的研究近年来得到学者们的重视[2]。有研究指出,血红素氧合酶1(heme oxygenase-1,HO-1)基因参与抗氧化和应激[3],HO-1基因的表达产物与动脉粥样硬化关系密切。还有研究报道,HO-1在体内表达的水平和冠心病的发病状况紧密关联[4]。而众所周知,OSAHS的发病又与冠心病密切相关联[5]。HO-1基因的启动子区包含着2种基因多态性,分别是(GT)n短串联重复序列多态性和     

血红素加氧酶-1的研究进展

血红素加氧酶(heme oxygenase,HO)是一种最广泛存在的抗氧化防御酶,是热休克蛋白家族中的一个成员,可代谢血红素生成CO、胆红素和游离铁.在大多数组织内呈低水平表达,可被多种伤害性刺激包括血红素、高氧、缺氧、热休克、内毒素、过氧化氢、细胞因子、紫外线、重金属和NO等诱导产生高水平的表达.HO-1基因表达的调控主要发生在转录水平.HO-1具有抗炎抗氧化、抗凋亡、抗增生效应,但其保护作用的机制仍不是很清楚.HO-1的产生作为一种对伤害性刺激的适应性和保护性反应,与临床上一些相关疾病密切相关.有关此方面的研究现越来越多并且取得了重大的进展.本文就HO-1的产生、基因调控、功能及其与肺部和其他系统疾病的关联方面的研究现状作一综述.     

血红素氧合酶-1与心肌肥厚

血红素氧合酶-1（heineoxygenase-1，HO-1）是哺乳动物中血红素代谢的限速酶。越来越多的研究发现HO-1及其催化代谢产物通过各种途径在心血管疾病中发挥着抗炎、抗氧化、抗增殖、抑制凋亡、抑制血小板凝集、细胞保护及调节血管张力等许多重要生物学作用。近年来发现HO—1具有抗心肌肥厚的作用，现就HO-1与心肌肥厚的研究进展作一综述。     

诱导血红素氧化酶-1表达的化合物研究进展

血红素氧化酶-1(HO-1)是一种细胞应激性蛋白，它的表达在许多病理和生理过程中起着重要的调节作用。虽然它在机体多数组织中表达水平低或不表达，但大量的临床和药理实验证明很多化合物可通过调节不同的转录因子和信号传导途径而诱导HO-1表达，从而发挥一定的疗效。本文总结了近十年来该领域国内外研究的几类化合物，并对其诱导机制进行简要分析。     

乙酰唑胺对低氧大鼠肺组织的保护作用

目的研究低氧环境下乙酰唑胺对大鼠肺组织低氧诱导因子-1α(HIF-1α)、血红素氧化酶1(HO-1)、Caspase-3 mRNA表达的影响。方法采用常压低氧实验建立大鼠低氧模型,单次腹腔注射乙酰唑胺,分别在低氧0,3,6 h后取肺组织,观察肺组织病理学变化,并检测低氧相关基因HIF-1α、Caspase-3、HO-1 mRNA的表达。结果随着低氧时间的延长,模型组大鼠肺组织HIF-1α、Caspase-3和HO-1 mRNA表达均呈升高趋势;与模型组比较,乙酰唑胺组大鼠肺组织HIF-1α、Caspase-3 mRNA的表达明显降低,而HO-1mRNA的表达却更加升高。结论乙酰唑胺可通过降低HIF-1α、Caspase-3 mRNA的表达、增加HO-1 mRNA的表达,对低氧大鼠的肺组织起到保护作用。     

姜黄素对SH-SY5Y细胞血红素加氧酶同工酶表达的影响

目的研究姜黄素在神经母细胞瘤细胞(SH-SY5Y)中对血红素加氧酶(HO)同工酶表达的影响,探讨姜黄素通过维持HO-1和HO-2的平衡对神经细胞的保护作用。方法体外培养人神经母细胞瘤细胞(SH-SY5Y细胞),以不同浓度的姜黄素(0、1.25、5.0、20μmol·L-1)处理SH-SY5Y细胞24h,及用浓度为5.0μmol·L-1的姜黄素分别处理SH-SY5Y细胞0、12、24、48h。利用荧光探针DCFH-DA和荧光分光光度计检测细胞内活性氧的水平。通过RT-PCR检测HO-1、HO-2mRNA的水平,Western blot检测HO-1、HO-2蛋白的表达。结果姜黄素作用于SH-SY5Y细胞后活性氧水平降低(P<0.05)。HO-1mRNA和蛋白的表达增加(P<0.05),而HO-2mRNA和蛋白的表达水平明显减弱(P<0.05),并呈浓度-时间依赖性。结论姜黄素通过抗氧化应激保护SH-SY5Y细胞,并促进SH-SY5Y细胞中HO-1的表达,下调HO-2的表达(P<0.05),姜黄素对HO-1和HO-2的这种反向调节,可能是姜黄素抗氧化应激、发挥神经细胞保护作用的一个机制。     

血红素加氧酶-1在病毒感染过程中的保护作用研究进展

血红素加氧酶-1 (heme oxygenase-1, HO-1)是一种细胞保护酶,可催化血红素转化为一氧化碳、胆绿素和铁,共同保护细胞免受氧化和炎症损伤,在维持细胞稳态中有重要作用。近年来, HO-1被广泛发现具有抑制多种病毒的生物学作用, HO-1诱导表达可抑制丙型肝炎病毒、乙型肝炎病毒、人类免疫缺陷病毒、登革热病毒、埃博拉病毒、A型流感病毒、寨卡病毒、新型冠状病毒、人类呼吸道合胞病毒、甲型肝炎病毒、肠道病毒71等多种病毒的复制。研究显示, HO-1对病毒的抑制和机体的保护作用主要包括3种机制:HO-1及下游产物对病毒复制的直接抑制作用、通过HO-1激活宿主细胞Ⅰ型干扰素相关的先天免疫对抗病毒复制、HO-1及其下游产物抑制病毒感染引起的炎症损伤等。本文主要就HO-1抗病毒作用及其机制的最新进展进行综述,以期为HO-1作为潜在的抗病毒治疗靶点提供研究参考。     

血红素加氧酶-1重组乳酸乳球菌灌胃对内毒素血症大鼠肠道的保护作用

目的利用基因工程原理合成携带血红素加氧酶-1(HO-1)基因的乳酸乳球菌,通过对正常大鼠灌胃后,观察其是否有对内毒素血症大鼠肠道肠粘膜保护效应,及减轻肠道炎症反应。方法将24只健康清洁级♂SD大鼠随机分为携带HO-1基因的乳酸乳球菌灌胃组(HO-1组,n=8)、乳酸乳球菌灌胃组(LL组,n=8)、谷氨酰胺灌胃组(Glu组,n=8)。分别给予携带HO-1基因的乳酸乳球菌、乳酸乳球菌或谷氨酰胺,每日1次,共4次。d4腹腔内注射内毒素,12h后取末端回肠。比较各组动物的死亡率,检查肠组织病理学变化,并检测肠组织髓过氧化物酶(MPO)活性、肿瘤坏死因子α(TNF-α)、白细胞介素10(IL-10)含量和血红素加氧酶-1(HO-1)的表达量。结果与LL组比较,HO-1组的生存率均明显升高(P<0.05);HO-1组和Glu组chiu′s评分和肠组织MPO活性明显降低(均P<0.01);肠组织TNF-α的含量明显减低(P<0.01),IL-10的含量却明显升高(P<0.01);HO-1的含量明显增加(P<0.01);与Glu组比较,HO-1组的IL-10的含量和HO-1的含量明显增加(P<0.01,P<0.05)。结论携带HO-1基因的乳酸乳球菌对内毒素血症大鼠肠粘膜有较好的保护作用,且能明显减轻肠道炎症反应。     

丹参酮胶囊对咪喹莫特诱导的银屑病模型小鼠的抗炎和抗氧化应激作用

目的　探讨丹参酮胶囊对咪喹莫特诱导的银屑病模型小鼠的抗炎和抗氧化应激作用,寻找银屑病的治疗方法。方法　使用咪喹莫特乳膏构建银屑病样小鼠模型,通过PASI评分和组织病理评估丹参酮胶囊对银屑病样小鼠模型皮损炎性反应的影响;通过酶联免疫吸附实验检测小鼠血清中白细胞介素（IL）-17A和肿瘤坏死因子（TNF）-α的水平;通过免疫组化和实时荧光定量PCR检测小鼠皮损组织中核因子E2相关因子-2（Nrf2）、抗氧化基因［血红素加氧酶1（HO-1）和超氧化物歧化酶2（SOD2）］和二相解毒酶基因［NAD（P）H醌氧还原酶-1（NQO1）］的表达水平。统计学方法采用单因素方差分析。结果　丹参酮胶囊能明显改善银屑病样小鼠炎性反应程度,包括减轻皮肤红斑、鳞屑和皮损厚度。丹参酮胶囊能降低银屑病样小鼠血清中IL-17A和TNF-α水平（均P<0.05）。丹参酮胶囊还能诱导银屑病样小鼠皮肤组织中Nrf2、HO-1和SOD2水平升高（均P<0.05）。结论　丹参酮胶囊通过降低银屑病样小鼠血清中IL-17A和TNF-α水平以及激活Nrf2信号通路,从而发挥抗炎和抗氧化应激作用。     

Gene regulation of heme oxygenase-1 as a therapeutic target

Heme oxygenase (HO)-1 is the inducible isoform of the rate-limiting enzyme of heme degradation. HO regulates the cellular content of the pro-oxidant heme and produces catabolites with physiological functions. HO-1 is induced by a host of oxidative stress stimuli, and the activation of HO-1 gene expression is considered to be an adaptive cellular response to survive exposure to environmental stresses. Since overexpression of the HO-1 gene is also protective against the deleterious effects of experimental injuries, the specific induction of HO-1 by 'non-stressful' stimuli, eg. stimuli that are not associated with oxidative stress, such as adenosine 3', 5'-cyclic monophosphate or cyclic guanosine 3',5'-monophosphate, may have important clinical implications. This review summarizes recent advances in the understanding of regulatory mechanisms of HO-1 gene expression, in particular the role of various redox-dependent and redox-independent signaling pathways. Models of experimental injuries are highlighted in which specific overexpression of the HO-1 gene either by targeted gene transfer or by pharmacological modulation has been demonstrated to provide therapeutic effects.     

The heme oxygenase system: its role in liver inflammation

Heme Oxygenase is the rate-limiting enzyme in the degradation of heme into carbon monoxide (CO), iron and bilirubin. To date, three heme oxygenase isozymes have been identified: HO-1, HO-2 and HO-3. While HO-1 is structurally different from its counterparts, HO-2 and HO-3 are very similar (90% homology), with HO-3 being a poor heme catalyst. Of the three isozymes, HO-1 is believed to be the only inducible form. Constitutively expressed HO-2 has been identified in several organs including kidney and vascular smooth muscle, with the most abundant sources (and activity) being in the liver, brain, spleen and testes. Within the normal liver, HO-2 is constitutively expressed within hepatocytes, Kupffer cells, endothelial cells and Ito cells. Until recently, products of the HO reaction were regarded as potentially toxic waste destined only for excretion. However, this view is changing as evidence suggests that HO activity plays an important protective role against cellular stress during inflammatory diseases. Biliverdin is reduced to bilirubin, which has been shown to possess potent antioxidative properties. CO, which is produced in equimolar concentrations to biliverdin and ferrous iron during heme oxidation by HO, may function as a second messenger stimulating soluble guanylate cyclase (sGC) and regulating vascular tone in combination with the free radical gas NO. CO may also possess anti-inflammatory properties such as the capacity to inhibit platelet aggregation, or the expression of pro-inflammatory cytokines. Recently, it has been shown that CO regulates bile formation and bile flow. We review the functional role of HO in liver and the potential application of HO-1 in therapeutic approaches to the treatment of inflammation.     

Heat shock response in a rat model of septic multiple organ dysfunction syndrome

Severe sepsis is known to result in multiple organ dysfunction syndrome (MODS), which is thought to be mediated by oxidative stress, as a result of excessive systemic inflammation. Heme Oxygenase-1 (HO-1), the rate limiting enzyme in heme catabolism, is also known as HSP32. HO-1 is induced not only by its substrate heme but also by oxidative stress. We investigated gene expression of HO-1 and physiological significance of HO-1 induction in a rat model of septic MODS induced by intraperitoneal injection of bacterial lipopolysaccharide (LPS). Following administration of LPS, HO-1 mRNA was significantly induced in the liver, lung and kidney in an organ-specific manner. Hepatic HO-1 induction appears to be mediated by an increase in hepatic free heme concentration. Inhibition of HO activity by tin mesoporphyrin significantly exacerbated lung injury. These results suggest that HO-1 induction may play an important role in conferring protection on cells from oxidative damage not only by catalyzing heme, a pro-oxidant, but also by producing bilirubin, an anti-oxidant. Furthermore, HO-1 mRNA is induced markedly in the buffy coat of the blood at 3 h after LPS administration, coinciding with the increase in serum IL-6 level, suggesting that HO-1 may be one of the key markers of septic MODS.     

Cudratricusxanthone A protects mouse hippocampal cells against glutamate-induced neurotoxicity via the induction of heme oxygenase-1

Cudratricusxantone A (CTXA), isolated from the roots of Cudrania tricuspidata Bureau (Moraceae), has potent hepatoprotective, antiproliferative, and monoamine oxidase inhibitory effects. In this study, we examined whether CTXA could protect HT22-immortalized hippocampal cells against glutamate-induced oxidative stress through the induction of heme oxygenase (HO)-1 expression. CTXA induced the expression of HO-1 and increased HO activity dose- and time-dependently. CTXA also suppressed glutamate-induced ROS generation in HT22 cells. Interestingly, treatment of neuronal cells with CTXA enhanced cellular resistance to glutamate oxidative stress. The protective effect of CTXA was abrogated by tin protoporphyrin IX, an HO inhibitor. In addition, treatment with the HO-1 inducer, cobalt protoporphyrin IX, and bilirubin, one of the enzymatic products of HO-1, produced comparable protection. These results demonstrate that CTXA protects neuronal cells from glutamate-induced oxidative stress via the induction of HO-1.     

Induction of heme oxygenase-1 with hemin attenuates hippocampal injury in rats after acute carbon monoxide poisoning

Carbon monoxide (CO) poisoning is a major cause of brain injury and mortality; delayed neurological syndrome (DNS) is encountered in survivors of acute CO exposure. The toxic effects of CO have been attributed to oxidative stress induced by hypoxia. Heme oxygenase-1 (HO-1) is the inducible heme oxygenase isoform, and its induction acts as an important cellular defense mechanism against oxidative stress, cellular injury and disease. In this study, we examined the functional roles of HO-1 induction in a rat model of CO-exposured hippocampal injury. We report that acute CO exposure produces severe hippocampal injury in rats. However, hemin pretreatment reduced both the CO-induced rise in hippocampal water content and levels of neuronal damage in the hippocampus; survival rates at 24 h were significantly improved. Upregulation of HO-1 by hemin pretreatment resulted in a significant decrease in hippocampal levels of malondialdehyde (MDA), a marker of oxidative stress; levels of pro-apoptotic caspase-3 were also reduced. In contrast, inhibition of HO activity by administration of tin protoporphyrin IX (SnPP, a specific inhibitor of HO) abolished the neuroprotective effects of HO-1 induction. These data suggested that the upregulation of endogenous HO-1 expression therefore plays a pivotal protective role in CO neurotoxicity. Though the precise mechanisms underlying hemin-mediated HO-1 induction and neuroprotection are not known, these may involve the anti-oxidant and anti-apoptotic effects of HO-1 enzyme activity.