活性氧在动脉粥样硬化中作用的研究进展

动脉粥样硬化(Atherosclerosis, AS)是心血管疾病的病理基础。活性氧(Reactive oxygen species, ROS)与机体的各种生理过程相关,过高的ROS可以对血管相关的细胞造成损伤,影响其正常功能,并参与AS中血管的损伤和斑块生成。ROS介导的氧化应激参与AS的发生发展,通过调节机体内的抗氧化反应是预防和治疗AS的方向之一,而调节抗氧化相关的转录因子是主要的手段。文章主要从ROS及抗氧化相关转录因子对AS的影响进行综述。     

NADPH氧化酶2在脑缺血再灌注损伤中作用机制研究进展

在脑缺血再灌注损伤的病理过程中,现有的文献数据表明氧自由基在其中发挥重要作用,而其来源有多种途径。在许多细胞中,NADPH氧化酶是过氧化物产生的一个主要因素,与氧自由基的病理作用关系密切。NADPH氧化酶2(NOX2)是NADPH氧化酶的一个亚型,近年研究表明,其过度表达与脑缺血再灌注损伤的发生发展关系密切。主要对NOX2在脑缺血再灌注损伤中的作用机制进行综述。     

活性氧在肿瘤发生和治疗中的作用研究进展

活性氧(ROS)增多可导致机体内氧化/抗氧化失衡,其累积一方面会对生物大分子产生损害,比如对DNA产生损伤,从而引起包括癌症在内的多种疾病;另一方面,通过调节细胞内ROS水平,可选择性杀死瘤细胞。本文主要综述ROS在多种肿瘤相关信号通路中的作用,包括ROS与肿瘤细胞增殖、迁移、细胞周期与凋亡、干细胞间的关系,以及ROS在肿瘤发展中的作用。此外,还综述了针对ROS的传统抗癌药物和ROS响应性载体在肿瘤治疗中的作用,为肿瘤防治提供新思路。     

活性氧在肿瘤顺铂耐药中的作用研究进展

顺铂是目前应用最广泛的抗癌药物之一。作为DNA络合物,顺铂不仅能够通过结合并损伤细胞核DNA,诱导DNA损伤应答,而且能够通过结合线粒体DNA,诱导线粒体功能紊乱,活性氧（ROS）过度产生,最终导致细胞凋亡坏死。ROS是一类化学性质活泼的氧分子衍生物的统称,主要由细胞内线粒体以及NADPH过氧化物酶产生。过量的ROS能够导致核酸、脂质以及蛋白质发生氧化损伤,是顺铂抗肿瘤效应的重要介质。然而,在肿瘤顺铂耐药的进程中,ROS亦发挥了重要作用。因此,本文综述了顺铂耐药肿瘤中ROS的代谢特点和ROS调控顺铂耐药的多种机制,包括上调顺铂转运体表达、增强细胞DNA损伤修复能力、提高核转录因子红系2相关因子2、低氧诱导因子-1α的蛋白水平和转录活性以及调控线粒体动态活动等方面。最后,本文还总结了ROS诱导剂和抗氧化系统抑制剂这两类ROS调节药物的相关研究,希望为提高顺铂疗效,克服肿瘤顺铂耐药提供治疗新思路。     

自噬在创伤性脑损伤中作用的研究进展

自噬是一种在进化过程中高度保守的细胞内机制,其主要作用为将细胞内异常的蛋白、细胞器降解,维持细胞稳定。已有多项研究表明自噬在创伤性脑损伤后激活。但是自噬在创伤性脑损伤中的作用提供新的方向。     

内质网应激在心室重构中作用的研究进展

内质网是真核细胞的重要细胞器,是蛋白折叠与成熟的加工厂。内质网应激是细胞针对错误折叠或未折叠蛋白质的一种适应性机制,但持续或过强的内质网应激则诱导细胞凋亡与自噬失衡,造成组织损伤。研究显示内质网应激是冠状动脉粥样硬化性心脏病、缺血性心脏病、心力衰竭及糖尿病心肌病等心血管疾病发生、发展的共同通路,可诱导心肌细胞肥大、纤维化、凋亡,致使心室重构的发生。故调控内质网应激可能成为预防心室重构进而治疗相关心血管疾病的新靶点。     

牙周炎与糖尿病关系的研究进展

近年来，牙周炎与全身性疾病的关系不仅引起国内外口腔医学界学者的关注，同时也受到其他医学界的重视。其中牙周炎与糖尿病关系的研究更是倍受瞩目。目前，牙周炎与糖尿病之间的关系虽已基本确立，但两者相互作用的内在机制尚未完全明确，本文主要就牙周炎与糖尿病的相关性及其相互作用机制进行综述。     

自噬在药物性肝损伤中的作用研究进展

药物性肝损伤(DILI)是临床上最为常见的一类药源性病变,可导致急性肝衰竭,严重时可造成肝硬化、肝癌甚至死亡.近年来,DILI的发生率呈逐年增加的趋势,成为药物研发失败和已上市药物被撤市的重要原因.自噬是细胞内蛋白质和受损细胞器进行清除的过程,对细胞稳态、质量与数量乃至存活与死亡等调控有着十分重要的意义.越来越多研究表...     

miRNA对自噬的调控及其在肿瘤中的作用研究进展

自噬是细胞内受严格调控的分解代谢过程,它与肿瘤的发生发展密切相关。miRNA是细胞内一类重要的调控分子,它也参与对肿瘤的调节过程。目前miRNA与自噬的关系受到广泛关注。该文旨在介绍miRNA对自噬各环节的调控作用,及其对肿瘤细胞生长和药物敏感性的作用。     

海藻糖治疗帕金森病的作用机制研究进展

帕金森病是一种常见的神经变性疾病,特征性病理改变主要是黑质多巴胺能神经元丢失和路易小体的形成。路易小体中主要成分是纤维化的α-突触核蛋白,研究表明多巴胺能神经元中异常的蛋白质沉积可能与溶酶体自噬途径的失调有关。自噬调节剂的治疗潜力已在帕金森病动物模型中得到证实。海藻糖是一种天然双糖,被认为是治疗神经退行性疾病的新候选药物。它具有类似伴侣活性,防止蛋白质错误折叠或聚集,并有助于通过促进自噬去除积聚的蛋白质。总结异常自噬在帕金森病疾病发展过程中的潜在机制,讨论使用海藻糖对抗帕金森病的促进自噬、蛋白质稳定和抗神经炎症作用。     

Potential role of autophagy in smokeless tobacco extract-induced cytotoxicity and in morin-induced protection in oral epithelial cells

Toxic components of STE induced serious, adverse human oral health outcomes. In the present study, we observed that STE was involved in oral toxicity by reducing the viability of human squamous epithelial cells, SCC-25, along with the simultaneous induction of both apoptosis and autophagic signaling. STE was also found to induce significant amount ROS generation in SCC-25 cells. The dietary flavonoid morin, found abundantly in a variety of herbs, fruits and wine, has been reported to attenuate ROS-induced pathogenesis including autophagy. In this study we designed three different treatment regimes of morin treatment, such as pre, co, and post – treatment of STE challenged SCC-25 cells. In all cases morin provided cytoprotection to STE challenged SCC-25 cells by augmenting STE induced ROS-dependent cytotoxic autophagy. Hence, morin is a potential option for antioxidant therapy in treatment of STE induced toxicity.     

Important role of oxygen metabolites in quinolone antibacterial agent-induced cutaneous phototoxicity in mice

We investigated whether or not the generation of reactive oxygens and toxic photoproducts participated in the cutaneous phototoxicity mechanisms induced by the quinolone derivatives, ofloxacin (OFLX), enoxacin, lomefloxacin, ciprofloxacin and DR-3355 (the s-isomer of OFLX) in a mouse model. Pretreatment of Balb/c mice with allopurinol, soybean trypsin inhibitor, catalase and beta-carotene gave significant protection against ear swelling reactions induced by oral administration of quinolones and following ultraviolet-A (UVA) irradiation. Pretreatment with diethyldithiocarbamate augmented the swelling. No swelling was observed with direct injection into the auricle of UVA-pretreated photoproducts of the quinolones. These results showed that cutaneous phototoxicity did not depend on the generation of toxic photoproducts and suggested that oxygen metabolites generated in the xanthine oxidase pathway participated in the toxicity.     

Maternally administered lipopolysaccharide (LPS) upregulates the expression of heme oxygenase-1 in fetal liver: the role of reactive oxygen species

Heme oxygenase-1 (HO-1) is an inducible enzyme that catalyzes the rate-limiting step in the degradation of heme to biliverdin, carbon monoxide and iron. Previous studies have demonstrated that lipopolysaccharide (LPS) upregulates the expression of HO-1 in adult mouse liver. The present study aimed to investigate the effects of maternal LPS exposure on the expression of HO-1 in fetal liver. The pregnant mice were intraperitoneally injected with different doses of LPS (1, 10, 75 microg/kg) on gestational day 17. Results showed that the expression of HO-1 in fetal liver was increased, beginning 2h after LPS, being at the highest level 24h after LPS, and remaining elevated up to 48h after LPS, whereas HO-2, the constitutive form, did not change at the various time points observed. LPS-induced upregulation of HO-1 was blocked by alpha-phenyl-N-t-butylnitrone (PBN), a free radical spin trapping agent. Correspondingly, PBN pretreatment significantly attenuated LPS-induced lipid peroxidation and glutathione (GSH) depletion in fetal liver. However, aminoguanidine (AG), a selective inhibitor of inducible nitric oxide synthase (iNOS), and pentoxifylline (PTX), an inhibitor of tumor necrosis factor alpha (TNF-alpha) synthesis, had no effect on LPS-induced upregulation of HO-1 in fetal liver. In conclusion, reactive oxygen species (ROS), rather than TNF-alpha or nitric oxide (NO), are involved in LPS-induced upregulation of HO-1 in fetal liver. These results provide new evidence that maternal LPS exposure results in oxidative stress in fetuses, which may contribute to LPS-induced developmental toxicity.     

The role of reactive oxygen species in the genotoxicity of surface-modified magnetite nanoparticles

The generation of reactive oxygen species (ROS) has been proposed as the underlying mechanism involved in the genotoxicity of iron oxide nanoparticles. The data published to date are, however, inconsistent, and the mechanism underlying ROS formation has not been completely elucidated. Here, we investigated the capacity of several surface-modified magnetite nanoparticles (MNPs) to generate ROS in A549 human lung adenocarcinoma epithelial cells and HEL 12469 human embryonic lung fibroblasts. All MNPs, regardless of the coating, induced significant levels of DNA breakage in A549 cells but not in HEL 12469 cells. Under the same treatment conditions, variable low levels of intracellular ROS were detected in both A549 and HEL 12469 cells, but compared with control treatment, none of the coated MNPs produced any significant increase in oxidative damage to DNA in either of these cell lines. Indeed, no significant changes in the total antioxidant capacity and intracellular glutathione levels were observed in MNPs-treated human lung cell lines regardless of surface coating. In line with these results, none of the surface-modified MNPs increased significantly the GPx activity in A549 cells and the SOD activity in HEL 12469 cells. The GPx activity was significantly increased only in SO-Fe₃O₄-treated HEL 12469 cells. The SOD activity was significantly increased in SO-PEG-PLGA-Fe₃O₄-treated A549 cells but significantly decreased in SO-Fe₃O₄-treated A549 cells. Our data indicate that oxidative stress plays, at most, only a marginal role in the genotoxicity of surface-modified MNPs considered in this study in human lung cells.     

维生素E对去甲肾上腺素刺激心肌细胞内活性氧产生的影响

目的 探讨维生素E对心肌细胞内活性氧(ROS)生成的影响。方法 用DCFH—DA荧光探针标记培养乳鼠心肌细胞，流式细胞仪检测细胞荧光强度(反映ROS水平)，观察不同浓度维生素E对去甲肾上腺素(NE，20μmol／L)N心肌细胞ROS生成的干预效果。结果 NE呈时间依赖性增加心肌细胞内荧光强度，中、高浓度维生素E可明显减弱心肌细胞荧光强度。结论 NE呈时间依赖性增加心肌细胞内ROS的产生，维生素E抑制ROS产生的作用呈剂量依赖性。     

Mechanisms of nanotoxicity: Generation of reactive oxygen species

Nanotechnology is a rapidly developing field in the 21^st century, and the commercial use of nanomaterials for novel applications is increasing exponentially. To date, the scientific basis for the cytotoxicity and genotoxicity of most manufactured nanomaterials are not understood. The mechanisms underlying the toxicity of nanomaterials have recently been studied intensively. An important mechanism of nanotoxicity is the generation of reactive oxygen species (ROS). Overproduction of ROS can induce oxidative stress, resulting in cells failing to maintain normal physiological redox-regulated functions. This in turn leads to DNA damage, unregulated cell signaling, change in cell motility, cytotoxicity, apoptosis, and cancer initiation. There are critical determinants that can affect the generation of ROS. These critical determinants, discussed briefly here, include: size, shape, particle surface, surface positive charges, surface-containing groups, particle dissolution, metal ion release from nanometals and nanometal oxides, UV light activation, aggregation, mode of interaction with cells, inflammation, and pH of the medium.     

Toxicological and pathophysiological roles of reactive oxygen and nitrogen species

‘Oxidative and Nitrative Stress in Toxicology and Disease’ was the subject of a symposium held at the EUROTOX meeting in Dresden 15th September 2009. Reactive oxygen (ROS) and reactive nitrogen species (RNS) produced during tissue pathogenesis and in response to viral or chemical toxicants, induce a complex series of downstream adaptive and reparative events driven by the associated oxidative and nitrative stress. As highlighted by all the speakers, ROS and RNS can promote diverse biological responses associated with a spectrum of disorders including neurodegenerative/neuropsychiatric and cardiovascular diseases. Similar pathways are implicated during the process of liver and skin carcinogenesis. Mechanistically, reactive oxygen and nitrogen species drive sustained cell proliferation, cell death including both apoptosis and necrosis, formation of nuclear and mitochondrial DNA mutations, and in some cases stimulation of a pro-angiogenic environment. Here we illustrate the pivotal role played by oxidative and nitrative stress in cell death, inflammation and pain and its consequences for toxicology and disease pathogenesis. Examples are presented from five different perspectives ranging from in vitro model systems through to in vivo animal model systems and clinical outcomes.     

Antioxidants and reactive oxygen species in human fertility

The cellular components of the human reproductive system are as vulnerable as other cells to the potential detrimental effects of reactive oxygen species (ROS). Antioxidant protection is thus required, though not yet fully characterized, at sites of gametogenesis, fertilization and implantation. Spermatozoa are highly susceptible to oxidative damage due to the high content of polyunsaturated fatty acids within their plasma membrane and such damage may underlie certain aspects of male infertility. However, oral antioxidant therapy with, for example, Vitamin E or glutathione has to date only achieved limited success in treatment programmes. Infertility treatments involve in vitro manipulation of gametes and embryos, ranging from simple spermatozoa preparation techniques to several days culture, exposing cells to increased oxygen levels and potential oxidative stress compared with in vivo. A considerable body of data has demonstrated the benefits for animal embryo culture and human sperm preparation of antioxidant supplementation as well as the removal of sources of ROS such as leucocytes, although data supporting supplementation for human embryo culture are limited. However, the use of exogenous superoxide dismutase may improve embryo development to the blastocyst stage. Evidence is accumulating for a role for ROS in signalling events mediating both sperm capacitation and luteal function. Potential also exists for ROS (including nitric oxide) to fulfill as yet unidentified roles in modulation signalling, gene expression and/or apoptotic events during fertilization, embryo development and implantation. Increasing knowledge of the mechanisms whereby ROS and endogenous antioxidant systems influence reproductive processes can assist to optimise the application of exogenous antioxidants to fertility treatment.     

JNK-dependent Atg4 upregulation mediates asperphenamate derivative BBP-induced autophagy in MCF-7 cells

N-Benzoyl-O-(N′-(1-benzyloxycarbonyl-4-piperidiylcarbonyl) -D-phenylalanyl)-D-phenylalaninol (BBP), a novel synthesized asperphenamate derivative with the increased solubility, showed growth inhibitory effect on human breast carcinoma MCF-7 cells in a time- and concentration-dependent manner. The growth inhibitory effect of BBP was associated with induction of autophagy, which was demonstrated by the development of acidic vesicular organelles, cleavage of LC3 and upregulation of Atg4 in BBP-treated MCF-7 cells. Since the application of Atg4 siRNA totally blocked the cleavage of LC3, we demonstrated a central role of Atg4 in BBP-induced autophagy. The further studies showed that BBP increased the levels of reactive oxygen species (ROS), and pretreatment with NAC effectively blocked the accumulation of ROS, autophagy and growth inhibition triggered by BBP. Moreover, BBP induced the activation of JNK, and JNK inhibitor SP600125 reversed autophagy, the increase of Atg4 levels, conversion of LC3 and growth inhibition induced by BBP. Knockdown of JNK by siRNA efficiently inhibited ROS production and autophagy, but antioxidant NAC failed to block JNK activation induced by BBP, indicating that JNK activation may be a upstream signaling of ROS and should be a core component in BBP-induced autophagic signaling pathway. These results suggest that BBP produces its growth inhibitory effect through induction of the autophagic cell death in MCF-7 cells, which is modulated by a JNK-dependent Atg4 upregulation involving ROS production.     

Reactive oxygen species modulators in pulmonary medicine

Adapted to effectively capture oxygen from inhaled air and deliver it to all other parts of the body, the lungs constitute the organ with the largest surface area. This makes the lungs more susceptible to airborne pathogens and pollutants that mediate pathologies through generation of reactive oxygen species (ROS). One pathological consequence of excessive levels of ROS production is pulmonary diseases that account for a large number of mortality and morbidity in the world. Of the various mechanisms involved in pulmonary disease pathogenesis, mitochondrial dysfunction takes prominent importance. Herein, we briefly describe the significance of oxidative stress caused by ROS in pulmonary diseases and some possible therapeutic strategies.