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Reactivity of mitochondrial peroxiredoxins with biological hydroperoxides 线粒体过氧化物还毒素与生物氢过氧化物的反应性
Pub Date : 2023-09-26 DOI: 10.1016/j.rbc.2023.100017
Madia Trujillo , Lucía Piacenza , Rafael Radi

Mitochondria are main sources of biological hydroperoxides, including hydrogen peroxide, peroxynitrite and various organic hydroperoxides. Most of these species are involved in the regulation of cellular functions when formed at low, physiological levels. Additionally, they can cause oxidative damage when formed at higher rates, eventually leading to mitochondrial disfunction and cytotoxicity. Different peroxidases sense the levels and catalyze the reduction of mitochondrial hydroperoxides. Among them, peroxiredoxin 3 and peroxiredoxin 5 decompose most hydrogen peroxide, peroxynitrite and free fatty acid hydroperoxides formed in the mitochondrial matrix. Kinetic considerations indicate that the role of selenol-dependent glutathione peroxidases in the reduction of these soluble hydroperoxides in mitochondria would be secondary. Glutathione peroxidase 4, which has a unique phospholipid hydroperoxide peroxidase activity, is only expressed in the mitochondria of selected tissues. Peroxiredoxin 3 catalyzes the reduction of hydroperoxides, but is also hyperoxidized and inactivated by them, in particular by free fatty acid hydroperoxides which react at high rate constants. Indeed, computer-assisted simulations support that free fatty acid hydroperoxides significantly contribute to Prdx3 hyperoxidation under biologically-relevant conditions. In addition, kinetic data indicate that hydroperoxides may partially diffuse to the cytosol. Several open questions regarding the oxidizing substrate specificities of mitochondrial peroxiredoxins and their modulation by CO2 are presented. Thus, peroxiredoxins 3 and 5 are the main sensors of mitochondrial hydroperoxides, provide protection from their excess and also determine the ability of these reactive species to diffuse through mitochondria; these combined actions of the mitochondrial peroxiredoxins impact redox regulation and outcomes of physiological or pathological processes.

线粒体是生物氢过氧化物的主要来源,包括过氧化氢、过氧亚硝酸盐和各种有机氢过氧化物。这些物种中的大多数在低生理水平形成时参与细胞功能的调节。此外,当它们以较高的速率形成时,会引起氧化损伤,最终导致线粒体功能障碍和细胞毒性。不同的过氧化物酶感知水平并催化线粒体氢过氧化物的还原。其中,过氧还蛋白3和过氧还蛋白5分解线粒体基质中形成的大部分过氧化氢、过氧亚硝酸盐和游离脂肪酸氢过氧化物。动力学方面的考虑表明,硒醇依赖性谷胱甘肽过氧化物酶在线粒体中这些可溶性氢过氧化物的还原中的作用是次要的。谷胱甘肽过氧化物酶4具有独特的磷脂氢过氧化物酶活性,仅在选定组织的线粒体中表达。过氧还蛋白3催化氢过氧化物的还原,但也被它们过度氧化和失活,特别是被以高速率常数反应的游离脂肪酸氢过氧化物。事实上,计算机辅助模拟支持游离脂肪酸氢过氧化物在生物相关条件下显著促进Prdx3的高氧化。此外,动力学数据表明氢过氧化物可能部分扩散到细胞质中。提出了几个关于线粒体过氧化物还毒素的氧化底物特异性及其CO2调节的开放问题。因此,过氧化物还毒素3和5是线粒体氢过氧化物的主要传感器,对它们的过量提供保护,并决定这些活性物质通过线粒体扩散的能力;这些线粒体过氧化物还毒素的联合作用影响氧化还原调节和生理或病理过程的结果。
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引用次数: 0
Cellular reductive stress: Is plasma membrane electron transport an evolutionarily-conserved safety valve? 细胞还原性应激:质膜电子传递是进化保守的安全阀吗?
Pub Date : 2023-09-20 DOI: 10.1016/j.rbc.2023.100016
M.V. Berridge , P.M. Herst , C. Prata

Cellular respiration is highly regulated, changes dynamically in response to the microenvironment of individual cells and during differentiation and differs between cell and tissue types. Too little cell respiration can cause an accumulation of reductants, leading to reductive stress, while inefficient respiration, that causes a build-up of reactive oxygen species (ROS), can result in oxidative stress. Most of the discussion of this central redox dichotomy has centred around oxidative stress because the damaging effects of cellular oxidants on DNA, lipids and proteins are well-established, and have been shown to contribute to health issues including, mitochondrial and cardiovascular diseases, tumorigenesis, and to the effects of ageing. Much less attention has been paid to cellular reductive stress. Nevertheless, excessive levels of key cellular reductants including NADH, NADPH and glutathione, as well as an imbalance in protein thiols, and insufficient levels of ROS to maintain cell signalling pathways, can be harmful to cells and result in poor health outcomes. Recently, cellular mechanisms that sense and regulate cellular reductive stress associated with low ROS levels have been identified. In addition, plasma membrane electron transport has been shown to be a key player in cellular redox homeostasis involving NAD(P)H/NAD(P)+ ratios. It is now well-established that the plasma membrane contains coenzyme Q-mediated electron transport pathways capable of oxidizing intracellular NAD(P)H and reducing extracellular electron acceptors such as molecular oxygen. A better understanding of the origins, cellular and subcellular compartmentalization and regulation of cellular reductants could lead to the development of new anticancer strategies.

细胞呼吸受到高度调节,在分化过程中随着单个细胞的微环境而动态变化,并且在细胞和组织类型之间有所不同。细胞呼吸过少会导致还原剂的积累,导致还原应激,而低效的呼吸会导致活性氧(ROS)的积累,从而导致氧化应激。大多数关于这种中心氧化还原二分法的讨论都集中在氧化应激上,因为细胞氧化剂对DNA、脂质和蛋白质的破坏作用是公认的,并已被证明会导致健康问题,包括线粒体和心血管疾病、肿瘤发生和衰老的影响。对细胞还原应激的关注要少得多。然而,包括NADH、NADPH和谷胱甘肽在内的关键细胞还原剂水平过高,蛋白质硫醇失衡,ROS水平不足以维持细胞信号通路,可能对细胞有害,并导致健康状况不佳。最近,已经确定了感知和调节与低ROS水平相关的细胞还原应激的细胞机制。此外,质膜电子传输已被证明是涉及NAD(P)H/NAD(P)+比率的细胞氧化还原稳态的关键参与者。现在已经证实,质膜含有辅酶Q介导的电子传递途径,其能够氧化细胞内NAD(P)H并还原细胞外电子受体如分子氧。更好地了解细胞还原剂的起源、细胞和亚细胞的区室化和调节,可以开发新的抗癌策略。
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引用次数: 1
Unveiling the enigmatic traits of Corynebacterium glutamicum mycoredoxin-3: A tiny redox protein displaying swapped homodimer formation and DsbA-like oxidase activity 揭示谷氨酰胺棒状杆菌的神秘特性:一种微小的氧化还原蛋白,显示交换的二聚体形成和dbas样氧化酶活性
Pub Date : 2023-09-19 DOI: 10.1016/j.rbc.2023.100014
Khadija Wahni , Ekaterina Baranova , Daria Ezeriņa , Inge Van Molle , Koen Van Laer , Joris Messens

Mycoredoxins (Mrxs) are a group of small dithiol oxidoreductases that share a conserved CXXC active site sequence motif resembling glutaredoxins. They are commonly found in saprophytic microorganisms, including Actinobacteria such as Mycobacterium tuberculosis. Among the known mycoredoxins, Corynebacterium glutamicum (Cg) Mrx1, featuring a conserved CVQC active site, functions as a mycothiol-dependent monothiol oxidoreductase. On the other hand, Mrx2, also known as NrdH-redoxin and containing the same CVQC motif, exhibits dithiol oxidoreductase properties and receives electrons from thioredoxin reductase (TrxR). Recently, it has been reported that CgMrx3, featuring a CGSC motif, acts as a thioredoxin, although its structural and biophysical characteristics remain unexplored.

In this study, we successfully determined the X-ray structure of CgMrx3 at a resolution of 1.7 Å, revealing a swapped dimer arrangement. We compared the structure of CgMrx3 with those of CgMrx1 and CgMrx2 and with the AlphaFold2 predicted structure of Mrx3 from Mycobaterium tuberculosis (MtMrx3). We correlated the number of hydrogen bonds accepted by the nucleophilic cysteines with the relatively low pKa's determined for MtMrx3 and CgMrx3. Finally, we showed that CgMrx3 has DsbA-like oxidase activity. Taken together, our results provide valuable insights into the structural and functional characteristics of Mrx3, thereby enhancing our understanding of mycoredoxin-dependent redox biology.

霉氧还蛋白(Mrxs)是一组小的二硫醇氧化还原酶,它们共享一个类似于戊二氧还蛋白的保守CXXC活性位点序列基序。它们通常存在于腐生微生物中,包括放线菌,如结核分枝杆菌。在已知的分枝杆菌氧还蛋白中,谷氨酸棒杆菌(Cg)Mrx1具有保守的CVQC活性位点,起到分枝杆菌硫醇依赖性单硫醇氧化还原酶的作用。另一方面,Mrx2,也称为NrdH氧还蛋白,含有相同的CVQC基序,表现出二硫醇氧化还原酶性质,并从硫氧还蛋白还原酶(TrxR)接收电子。最近,有报道称,具有CGSC基序的CgMrx3作为硫氧还蛋白发挥作用,尽管其结构和生物物理特征尚未探索。在这项研究中,我们成功地以1.7Å的分辨率确定了CgMrx3的X射线结构,揭示了交换的二聚体排列。我们将CgMrx3的结构与CgMrx1和CgMrx2的结构以及来自结核分枝杆菌(MtMrx3)的AlphaFold2预测的Mrx3结构进行了比较。我们将亲核半胱氨酸所接受的氢键数量与MtMrx3和CgMrx3所确定的相对较低的pKa相关联。最后,我们发现CgMrx3具有DsbA样氧化酶活性。总之,我们的研究结果为Mrx3的结构和功能特征提供了有价值的见解,从而增强了我们对真菌氧还蛋白依赖性氧化还原生物学的理解。
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引用次数: 0
The oxidation of fenamic acid NSAIDs by neutrophil myeloperoxidase produces toxic reactive metabolites that induce leukemic cell death 中性粒细胞髓过氧化物酶氧化非甾体抗炎药产生毒性反应性代谢物,诱导白血病细胞死亡
Pub Date : 2023-08-12 DOI: 10.1016/j.rbc.2023.100013
Newton H. Tran , Dinesh Babu , Steven Lockhart , Andrew G. Morgan , Nadine Commandeur , Md Harunur Rashid , Béla Reiz , Lusine Tonoyan , Arno G. Siraki

Fenamic acids are a group of non-steroidal anti-inflammatory drugs (NSAIDs) that are among the most common drugs prescribed globally. However, they have been associated with many adverse effects, such as agranulocytosis, neutropenia, hepatotoxicity, and nephrotoxicity. The interactions between peroxidase enzymes and fenamic acid-like NSAIDs cause the formation of reactive species, potentially involved in side effects. The aim of this study was to investigate the neutrophil myeloperoxidase (MPO)-mediated bioactivation of fenamic acids based on N-phenylanthranilic acid (NPA) and its four drug analogues: flufenamic acid (FFA), mefenamic acid (MFA), meclofenamic acid (MCFA), and tolfenamic acid (TFA). We hypothesized that the enzymatic oxidation of fenamic acids by MPO/hydrogen peroxide (H2O2) would produce reactive metabolites, cause oxidative damage and induce cytotoxicity. We utilized UV–Vis spectrophotometry, liquid chromatography-mass spectrometry (LC-MS), and electron paramagnetic spin resonance (EPR) spectroscopy using purified MPO from human neutrophils. In addition, in vitro studies were performed with MPO-containing human promyelocytic leukemia (HL-60) cells for cytotoxicity and immuno-spin trapping to detect protein-free radicals. UV–Vis spectrophotometry revealed that MPO oxidized the fenamic acids. LC-MS analyses revealed the formation of dimers, hydroxylated, and quinoneimine species, and glutathione (GSH) conjugates. EPR spin trapping with DMPO using GSH revealed that fenamic acids produced glutathionyl radicals in a concentration-dependent manner. We also detected the formation of protein-free radicals in HL-60 cells, which correlated with cytotoxicity. Despite the minor structural differences between the fenamic acids, there were variations in their oxidation potential. These findings revealed a correlation between pro-oxidant metabolite reactivity and cytotoxicity caused by fenamic acid NSAIDs.

芬太尼酸是一组非甾体抗炎药,是全球最常见的处方药之一。然而,它们与许多不良反应有关,如粒细胞缺乏症、中性粒细胞减少症、肝毒性和肾毒性。过氧化物酶和非那米酸类非甾体抗炎药之间的相互作用导致活性物质的形成,可能涉及副作用。本研究的目的是研究中性粒细胞髓过氧化物酶(MPO)介导的基于N-苯基邻苯二甲酸(NPA)及其四种药物类似物:氟非那胺酸(FFA)、甲非那酰胺酸(MFA)、甲氯芬酸(MCFA)和托非那胺酸(TFA)的非那胺酸类生物活性。我们假设MPO/过氧化氢(H2O2)对酚胺酸的酶促氧化会产生反应性代谢产物,引起氧化损伤并诱导细胞毒性。我们使用来自人类中性粒细胞的纯化MPO,利用紫外-可见分光光度法、液相色谱-质谱法(LC-MS)和电子顺磁自旋共振(EPR)光谱法。此外,对含有MPO的人早幼粒细胞白血病(HL-60)细胞进行了细胞毒性和免疫自旋捕获以检测蛋白质自由基的体外研究。紫外-可见分光光度法显示MPO氧化了酚胺酸。LC-MS分析揭示了二聚体、羟基化物和喹啉类物质以及谷胱甘肽(GSH)缀合物的形成。使用GSH用DMPO进行EPR自旋捕获表明,酚胺酸以浓度依赖的方式产生谷胱甘肽自由基。我们还检测到HL-60细胞中蛋白质自由基的形成,这与细胞毒性有关。尽管芬那米酸之间存在微小的结构差异,但它们的氧化电位存在差异。这些发现揭示了促氧化代谢产物的反应性与非那米酸非甾体抗炎药引起的细胞毒性之间的相关性。
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引用次数: 0
Inter(pseudo)halogens with relevance to peroxidase-mediated reactions 与过氧化物酶介导的反应相关的间(伪)卤素
Pub Date : 2023-08-07 DOI: 10.1016/j.rbc.2023.100012
Jürgen Arnhold , Ernst Malle

In mammals, heme peroxidases are well known to generate oxidized (pseudo)halide products such as hypochlorous acid, hypobromous acid, oxidized iodine species, and hypothiocyanite. In addition, inter(pseudo)halogens are also oxidized (pseudo)halide compounds where two or more different (pseudo)halides are combined within a molecule without participation of other atoms. However, the information of this group of chemicals as potential products of peroxidases is limited and very fragmentary. In this review, we summarize current knowledge about chemical properties of inter(pseudo)halogens, their role as products of peroxidase-mediated conversions, and possible applications of these compounds in antimicrobial defense. The major focus is directed on bromyl chloride, cyanogen halides, and some products derived from interaction of oxidized iodine with thiocyanate.

在哺乳动物中,众所周知,血红素过氧化物酶会产生氧化(伪)卤化物产物,如次氯酸、次溴酸、氧化碘物种和低硫氰酸盐。此外,间(伪)卤素也被氧化(伪)卤化物化合物,其中两种或多种不同(伪)的卤化物在一个分子内结合,而没有其他原子的参与。然而,这类化学品作为过氧化物酶的潜在产物的信息是有限的,而且非常零碎。在这篇综述中,我们总结了关于间(伪)卤素的化学性质、它们作为过氧化物酶介导的转化产物的作用以及这些化合物在抗菌防御中的可能应用的最新知识。主要关注溴酰氯、卤化氰以及氧化碘与硫氰酸盐相互作用产生的一些产物。
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引用次数: 0
Lipid biology of plasmalogen-derived halolipids: Signature molecules of myeloperoxidase and eosinophil peroxidase activity 磷脂源衍生的脂质生物学:髓过氧化物酶和嗜酸性粒细胞过氧化物酶活性的特征分子
Pub Date : 2023-08-02 DOI: 10.1016/j.rbc.2023.100011
Reagan M. McGuffee , Christy M. Hadfield , David A. Ford

Myeloperoxidase and eosinophil peroxidase exert their antimicrobial functions through the oxidative actions of their hypohalous acid products. Plasmalogen phospholipids are particularly susceptible to oxidation of their vinyl ether functional group by hypohalous acids. This produces a family of halogenated lipid products with pro-inflammatory roles and potential biomarker utility. The initial product of plasmalogen oxidation by HOCl is 2-chlorofatty aldehyde, which has been shown to play a key role at the blood-endothelium interface. In vitro and in vivo studies indicate increased endothelial barrier permeability, neutrophil chemotaxis, neutrophil and platelet adherence to endothelium, and promotion of erythrocyte lysis as some of its effects. These effects may be due to protein modification by 2-chlorofatty aldehyde. 2-Chlorofatty aldehyde is metabolized by host dehydrogenases to 2-chlorofatty acid. While it is less chemically reactive, 2-chlorofatty acid has partial overlap of pro-inflammatory effects with 2-chlorofatty aldehyde and unique actions such as induction of neutrophil extracellular trap formation. The stability of 2-chlorofatty acid in plasma also makes it well-suited as a biomarker of HOCl generation, and its plasma levels may be predictive of disease outcomes. 2-Bromofatty aldehydes and acids are produced analogously from HOBr reaction with plasmalogens. Their functions have yet to be well-elucidated, though similarities with chlorolipids have been observed, and increased reactivity with proteins is expected through enhanced electrophilicity of the alpha carbon. Altogether, these halogenated lipids represent underexplored mediators of diseases involving excess hypohalous acid production.

髓过氧化物酶和嗜酸性粒细胞过氧化物酶通过其低卤酸产物的氧化作用发挥其抗菌功能。疟原虫磷脂特别容易被次卤酸氧化其乙烯基醚官能团。这产生了一个卤代脂质产品家族,具有促炎作用和潜在的生物标志物用途。血浆logen被HOCl氧化的初始产物是2-氯脂肪醛,它已被证明在血液内皮界面发挥关键作用。体外和体内研究表明,增加内皮屏障通透性、中性粒细胞趋化性、中性粒和血小板对内皮的粘附以及促进红细胞裂解是其一些作用。这些作用可能是由于2-氯脂肪醛对蛋白质的修饰。2-氯脂肪醛被宿主脱氢酶代谢为2-氯脂肪酸。虽然2-氯脂肪酸的化学反应性较低,但其促炎作用与2-氯脂肪醛部分重叠,并具有独特的作用,如诱导中性粒细胞外陷阱的形成。2-氯脂肪酸在血浆中的稳定性也使其非常适合作为HOCl生成的生物标志物,其血浆水平可能预测疾病结果。2-溴代tty醛和酸类似地由HOBr与浆蛋白反应产生。尽管已经观察到它们与氯脂质的相似性,但它们的功能尚未得到很好的阐明,并且预计通过增强α-碳的亲电性来增加与蛋白质的反应性。总之,这些卤代脂质代表了涉及过量次卤酸产生的疾病的未被充分探索的介质。
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引用次数: 0
Electron paramagnetic resonance (EPR) for investigating relevant players of redox reactions: Radicals, metalloproteins and transition metal ions 电子顺磁共振(EPR)用于研究氧化还原反应的相关参与者:自由基、金属蛋白和过渡金属离子
Pub Date : 2023-07-29 DOI: 10.1016/j.rbc.2023.100009
Ohara Augusto, Daniela Ramos Truzzi, Edlaine Linares

Electron paramagnetic resonance (EPR) spectroscopy is unique in providing robust information about free radicals, transition metal ions and metalloenzymes, which are crucial players in redox processes. EPR had a major role in advancing the redox biology field during the 20th century, but the interest in this methodology considerably decreased in recent years. Here, we discuss potential reasons for this decline as well as potential reasons for maintaining the mind open to the many possibilities brought by EPR and associated methodologies to the redox field. We present the fundamentals of EPR using pictorial images and minimal physicochemical language. We also present EPR derived methodologies developed to detect radical metabolites, that is, direct EPR of solutions (static and continuous-flow), direct EPR of frozen solutions, spin-trapping and spin-scavenging, showing examples and discussing the advantages and drawbacks of each one. Finally, we discuss the EPR spectra of metalloproteins and metal ion complexes of biological interest, which are more complex than those of radical metabolites in solution. In addition to introduce EPR methodologies to those new to the redox field, our goal is to show that these methodologies can contribute to advance the field.

电子顺磁共振(EPR)光谱在提供关于自由基、过渡金属离子和金属酶的可靠信息方面是独特的,这些是氧化还原过程中的关键参与者。EPR在20世纪的氧化还原生物学领域中发挥了重要作用,但近年来对这种方法的兴趣大大下降。在这里,我们讨论了这种下降的潜在原因,以及保持对EPR和相关方法给氧化还原领域带来的许多可能性持开放态度的潜在原因。我们使用图像和最小物理化学语言介绍EPR的基本原理。我们还介绍了为检测自由基代谢产物而开发的EPR衍生方法,即溶液的直接EPR(静态和连续流动)、冷冻溶液的直接EPR、自旋捕获和自旋清除,展示了实例并讨论了每种方法的优缺点。最后,我们讨论了具有生物学意义的金属蛋白和金属离子复合物的EPR光谱,它们比溶液中的自由基代谢产物更复杂。除了将EPR方法引入氧化还原领域的新方法之外,我们的目标是证明这些方法可以促进该领域的发展。
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引用次数: 0
Modification of histones by the myeloperoxidase-derived oxidant hypochlorous acid (HOCl) alters their reactivity with vascular smooth muscle cells 髓过氧化物酶衍生的氧化剂次氯酸(HOCl)对组蛋白的修饰改变了它们与血管平滑肌细胞的反应性
Pub Date : 2023-07-29 DOI: 10.1016/j.rbc.2023.100010
Els A. Hartsema, Line A.E. Hallberg, Kristine Barlous, Clare L. Hawkins

In the nucleus, histones are essential in the packaging of DNA and the regulation of gene expression. These histones can also be released to the extracellular space by mechanisms such as necrosis and neutrophil extracellular trap (NET) formation. Histones are cytotoxic and cause sterile inflammation, and as a result, have been implicated in tissue damage in several pathologies, including atherosclerosis. Myeloperoxidase (MPO) is also present on NETs, which is catalytically active and able to produce hypochlorous acid (HOCl). This could modify histones and alter their extracellular reactivity. In this study, we compared the reactivity of histones with and without modification by HOCl with primary human coronary artery smooth muscle cells (HCASMCs). Histones induced a loss in viability and cell death primarily by apoptosis, which was attenuated on modification of the histones by HOCl. Exposure of HCASMCs to histones also resulted in the increased expression of the pro-inflammatory genes monocyte chemoattractant protein-1 (MCP-1), interleukin 6 (IL-6), and vascular cell adhesion molecule-1 (VCAM-1) and a decrease in intracellular thiols. In addition, there were changes in the expression of the stress related gene heme oxygenase-1 (HO-1). Modification of the histones with HOCl had no significant influence on changes in gene expression or thiol loss, in contrast to the cytotoxicity studies. Together, these studies provide new insight into the pathways by which histones could promote vascular dysfunction, which could be relevant to inflammatory diseases, such as atherosclerosis and sepsis, which are associated with elevated NET release and high circulating histones, respectively.

在细胞核中,组蛋白在DNA的包装和基因表达的调控中是必不可少的。这些组蛋白也可以通过坏死和中性粒细胞外陷阱(NET)形成等机制释放到细胞外空间。组蛋白具有细胞毒性,可引起无菌炎症,因此与包括动脉粥样硬化在内的多种病理中的组织损伤有关。髓过氧化物酶(MPO)也存在于NETs上,它具有催化活性,能够产生次氯酸(HOCl)。这可以改变组蛋白并改变其细胞外反应性。在本研究中,我们比较了HOCl修饰组蛋白和未经HOCl修饰的组蛋白与原代人冠状动脉平滑肌细胞(HCASMCs)的反应性。组蛋白主要通过细胞凋亡诱导生存能力丧失和细胞死亡,HOCl修饰组蛋白后细胞凋亡减弱。HCASMCs暴露于组蛋白还导致促炎基因单核细胞趋化蛋白-1(MCP-1)、白细胞介素-6(IL-6)和血管细胞粘附分子-1(VCAM-1)的表达增加,并导致细胞内硫醇的减少。此外,应激相关基因血红素加氧酶-1(HO-1)的表达也发生了变化。与细胞毒性研究相比,用HOCl修饰组蛋白对基因表达或硫醇损失的变化没有显著影响。总之,这些研究为组蛋白促进血管功能障碍的途径提供了新的见解,这可能与炎症性疾病有关,如动脉粥样硬化和败血症,它们分别与NET释放和高循环组蛋白有关。
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引用次数: 0
In vivo measurement of mitochondrial ROS production in mouse models of photoreceptor degeneration 小鼠光感受器变性模型中线粒体ROS生成的体内测量
Pub Date : 2023-07-27 DOI: 10.1016/j.rbc.2023.100007
Katja E. Menger , Angela Logan , Ulrich F.O. Luhmann , Alexander J. Smith , Alan F. Wright , Robin R. Ali , Michael P. Murphy

Retinitis pigmentosa (RP) is a disease characterised by photoreceptor cell death. It can be initiated by mutations in a number of different genes, primarily affecting rods, which will die first, resulting in loss of night vision. The secondary death of cones then leads to loss of visual acuity and blindness. We set out to investigate whether increased mitochondrial reactive oxygen species (ROS) formation, plays a role in this sequential photoreceptor degeneration. To do this we measured mitochondrial H2O2 production within mouse eyes in vivo using the mass spectrometric probe MitoB. We found higher levels of mitochondrial ROS that preceded photoreceptor loss in four mouse models of RP: Pde6brd1/rd1; Prhp2rds/rds; RPGR−/−; Cln6nclf. In contrast, there was no increase in mitochondrial ROS in loss of function models of vision loss (GNAT−/−, OGC), or where vision loss was not due to photoreceptor death (Cln3). Upregulation of Nrf2 transcriptional activity with dimethylfumarate (DMF) lowered mitochondrial ROS in RPGR−/− mice. These findings have important implications for the mechanism and treatment of RP.

色素性视网膜炎(RP)是一种以感光细胞死亡为特征的疾病。它可以由许多不同基因的突变引发,主要影响视杆,视杆会首先死亡,导致夜视能力丧失。视锥的继发性死亡会导致视力下降和失明。我们开始研究线粒体活性氧(ROS)形成的增加是否在这种连续的光感受器退化中起作用。为此,我们使用质谱探针MitoB在体内测量了小鼠眼睛内线粒体H2O2的产生。我们发现,在四种RP小鼠模型中,光感受器丧失前线粒体ROS水平较高:Pde6brd1/rd1;Prhp2rds/rds;RPGR−/−;Cln6包括。相反,在视力丧失的功能丧失模型(GNAT−/−,OGC)中,或在视力丧失不是由光感受器死亡引起的情况下(Cln3),线粒体ROS没有增加。富马酸二甲酯上调Nrf2转录活性可降低RPGR−/−小鼠的线粒体ROS。这些发现对RP的机制和治疗具有重要意义。
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引用次数: 0
Hypochlorous acid inactivates myeloperoxidase inside phagocytosing neutrophils 次氯酸使吞噬中性粒细胞内的髓过氧化物酶失活
Pub Date : 2023-07-26 DOI: 10.1016/j.rbc.2023.100008
Martina Paumann-Page , Louisa V. Ashby , Irada Khalilova , Nicholas J. Magon , Stefan Hofbauer , Louise N. Paton , Paul G. Furtmüller , Christian Obinger , Anthony J. Kettle

When neutrophils phagocytose bacteria, they release myeloperoxidase (MPO) into phagosomes to catalyse the conversion of superoxide to the potent antimicrobial oxidant hypochlorous acid (HOCl). Here we show that within neutrophils, MPO is inactivated by HOCl. In this study, we aimed to identify the effects of HOCl on the structure and function of MPO, and determine the enzyme's susceptibility to oxidative inactivation during phagocytosis. When hydrogen peroxide was added to a neutrophil granule extract containing chloride, MPO activity was rapidly lost in a HOCl-dependent reaction. With high concentrations of hydrogen peroxide, western blotting demonstrated that MPO was both fragmented and converted to high molecular weight aggregates. Using the purified enzyme, we showed that HOCl generated by MPO inactivated the enzyme by destroying its prosthetic heme groups and releasing iron. MPO protein was additionally modified by forming high molecular weight aggregates. Before inactivation occurred, MPO chlorinated itself to convert most of its amine groups to dichloramines. When human neutrophils phagocytosed Staphylococcus aureus, they released MPO that was largely inactivated in a process that required production of superoxide. Enzyme inactivation occurred inside neutrophils because it was not blocked when extracellular HOCl was scavenged with methionine. The inactivated enzyme contained a chlorinated tyrosine residue, establishing that it had reacted with HOCl. Our results demonstrate that MPO will substantially inactivate itself during phagocytosis, which may limit oxidant production inside phagosomes. Other neutrophil proteins are also likely to be inactivated. The chloramines formed on neutrophil proteins may contribute to the bactericidal milieu of the phagosome.

当中性粒细胞吞噬细菌时,它们将髓过氧化物酶(MPO)释放到吞噬体中,催化超氧化物转化为强效抗菌氧化剂次氯酸(HOCl)。在这里,我们发现在中性粒细胞中,MPO被HOCl灭活。在本研究中,我们旨在确定HOCl对MPO结构和功能的影响,并确定该酶在吞噬过程中对氧化失活的敏感性。当将过氧化氢添加到含有氯化物的中性粒细胞颗粒提取物中时,MPO活性在HOCl依赖性反应中迅速丧失。在高浓度过氧化氢的情况下,蛋白质印迹显示MPO既被碎片化又转化为高分子量聚集体。使用纯化的酶,我们发现MPO产生的HOCl通过破坏其辅血红素基团和释放铁来灭活酶。MPO蛋白通过形成高分子量聚集体而被另外修饰。在失活发生之前,MPO通过氯化自身将其大部分胺基转化为二氯胺。当人类中性粒细胞吞噬金黄色葡萄球菌时,它们释放出MPO,而MPO在一个需要产生超氧化物的过程中基本上被灭活。酶失活发生在中性粒细胞内,因为当用甲硫氨酸清除细胞外HOCl时,酶不被阻断。灭活的酶含有一个氯化酪氨酸残基,证明它与HOCl发生了反应。我们的研究结果表明,MPO在吞噬过程中会显著失活,这可能会限制吞噬体内氧化剂的产生。其他中性粒细胞蛋白也可能失活。中性粒细胞蛋白上形成的氯胺可能有助于吞噬体的杀菌环境。
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引用次数: 2
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Redox Biochemistry and Chemistry
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