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POLY(ADP-RIBOSE) SIGNALISE IN OXIDATIVE STRESS 聚腺苷核糖(adp -核糖)在氧化应激中发出信号
Pub Date : 2016-07-08 DOI: 10.18143/JISANH_V3I2_1447
L. Virág
Poly-ADP-ribosylation is an NAD-dependent protein modification reaction. In various oxidative stress-related paradigms DNA breaks activate poly(ADP-ribose) polymerase (PARP) enzymes which in turn modify target proteins with NAD-derived (ADP-ribose)n polymers. This reversible protein modification (PARylation) regulates transcription, kinase cascades, metabolism, differentiation, autophagy, cell death only to name a few cell functions and fates. Moreover, it leads to diverse biological outcomes with wide ranging implications for diseases as diverse as diabetes, inflammation, ischemia-reperfusion injury and cancer.Pathways leading to the formation of advanced glycation endproducts (AGEs) as well as cellular effects of AGEs are accompanied by overproduction of reactive oxygen and nitrogen species and as such may be intertwined with PARylation-related pathologies. The lecture aims to highlight proven and possible interactions between the oxidative stress-induced PARylation events and AGE-related pathologies.
聚adp核糖基化是一种依赖于nadd的蛋白质修饰反应。在各种与氧化应激相关的范式中,DNA断裂激活聚(adp -核糖)聚合酶(PARP)酶,PARP酶反过来用nadd衍生的(adp -核糖)n聚合物修饰靶蛋白。这种可逆的蛋白质修饰(PARylation)调节转录,激酶级联,代谢,分化,自噬,细胞死亡,仅举几例细胞功能和命运。此外,它还导致多种生物学结果,对糖尿病、炎症、缺血再灌注损伤和癌症等多种疾病具有广泛的影响。导致晚期糖基化终产物(AGEs)形成的途径以及AGEs的细胞效应伴随着活性氧和活性氮的过量产生,因此可能与paryl相关的病理交织在一起。讲座旨在强调氧化应激诱导的PARylation事件与age相关病理之间已证实的和可能的相互作用。
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引用次数: 0
MITOCHONDRIA AND OXIDATIVE STRESS IN AGE-RELATED MUSCLE LOSS (SARCOPENIA) 线粒体和氧化应激在年龄相关性肌肉损失(肌肉减少症)中的作用
Pub Date : 2016-07-08 DOI: 10.18143/JISANH_V3I3_1475
F. L. Verso, S. Carnio, M. Baraibar, M. Longa, M. Maffei, M. Canepari, B. Friguet, R. Bottinelli, M. Sandri
Muscle wasting is due to an excessive activation of degradative pathways. It occurs in different pathologies such as cancer, AIDS, diabetes but inevitably it occurs in everybody’s life during aging. Sarcopenia is the degenerative loss of skeletal muscle mass and strength associated with aging. The ability to activate compensatory mechanisms in response to environmental stress and physiological changing is an important factor for survival and maintenance of cellular functions. A system that is often activated both in short and prolonged stress conditions is autophagy. Autophagy is required to clear the cell from dysfunctional organelles and altered proteins and is reported to decline during ageing. This reduction might contribute to age-related organ dysfunction and, in general, to ageing. Here we report that specific autophagy inhibition in muscle has a major impact on this tissue that ultimately affect life span of animals. Inhibition of autophagy exacerbates the aging-related features of muscle such as atrophy, mitochondrial dysfunction, oxidative stress and profound weakness. Mitochondrial dysfunction and oxidative stress directly affect acto-myosin interaction and force generation. These results demonstrate that aging-related muscle dysfunction is mainly caused by a failure of the autophagy system. It has been reported that lifestyle adaptations, such as caloric restriction and physical exercise are able to ameliorate several features during ageing process, moreover physical activity has been recently documented to play a fundamental physiological role in the regulation of autophagy in several tissues. Here we address also the role of autophagy during exercise. We reveal that autophagy is critical for the preservation of mitochondrial function during damaging muscle contraction. We establish that basal oxidative stress plays a crucial role in mitochondrial maintenance during normal physical activity. Therefore, autophagy is an adaptive response to exercise that ensures effective mitochondria-quality control during damaging physical activity.
肌肉萎缩是由于过度激活的降解途径。它发生在不同的病理,如癌症,艾滋病,糖尿病,但不可避免地发生在每个人的生活中,随着年龄的增长。骨骼肌减少症是骨骼肌质量和力量与衰老相关的退行性损失。激活补偿机制以应对环境应激和生理变化的能力是细胞功能生存和维持的重要因素。在短期和长期的应激条件下,一个经常被激活的系统是自噬。自噬是清除细胞功能失调的细胞器和改变的蛋白质所必需的,据报道,自噬在衰老过程中会下降。这种减少可能会导致与年龄相关的器官功能障碍,总的来说,会导致衰老。在这里,我们报告了特异性自噬抑制对肌肉组织产生重大影响,最终影响动物的寿命。抑制自噬会加剧与衰老相关的肌肉特征,如萎缩、线粒体功能障碍、氧化应激和严重无力。线粒体功能障碍和氧化应激直接影响肌动蛋白相互作用和力的产生。这些结果表明,衰老相关的肌肉功能障碍主要是由自噬系统的失败引起的。据报道,生活方式的适应,如热量限制和体育锻炼能够改善衰老过程中的一些特征,而且最近有文献表明,体育活动在几种组织的自噬调节中起着基本的生理作用。在这里,我们还讨论了自噬在运动中的作用。我们发现自噬对于在损伤性肌肉收缩期间保存线粒体功能至关重要。我们确定基础氧化应激在正常身体活动期间的线粒体维持中起着至关重要的作用。因此,自噬是一种对运动的适应性反应,可确保在有害的身体活动期间有效地控制线粒体质量。
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引用次数: 0
THE CHICKEN OR THE EGG QUESTION OF OXIDATIVE AND ENDOPLASMIC RETICULUM STRESSES IN CANCER THERAPY 氧化应激和内质网应激在癌症治疗中的鸡还是蛋的问题
Pub Date : 2016-07-08 DOI: 10.18143/JISANH_V3I3_1463
M. Nikiforov
Cellular responses to oxidative and endoplasmic reticulum (ER) stress are among the most evolutionarily conserved pathways within the cell. Tumor cells commonly encounter both ER and oxidative stress due to high levels of metabolism, including increased rates of protein translation. Yet drugs aimed primarily at interference with these stress response pathways comprise only a small portion of currently available anti-neoplastic agents. Moreover, little is known about the interrelating connection between ER stress and oxidative stress caused by these few anticancer drugs. For instance, it is generally accepted that intracellular oxidative stress induced by proteasome inhibitors is a byproduct of ER stress.Here, we report a mechanism underlying the ability of proteasome inhibitor bortezomib (BTZ) to directly induce both oxidative and ER stress in multiple myeloma (MM) cells via transcriptional repression of the gene encoding mitochondrial thioredoxin reductase (TXNRD2). TXNRD2 is critical for maintenance of intracellular redox status and detoxification of reactive oxygen species.Depletion of TXNRD2 to the levels detected in BTZ-treated cells causes oxidative stress, ER stress and death similar to those induced by proteasome inhibitors. Reciprocally, restoration of near-wildtype TXNRD2 levels in MM cells treated with proteasome inhibitors reduces oxidative stress, ER stress and cell death by ~46%, ~35% and ~50%, respectively, compared to cells with depleted TXNRD2 levels. Moreover, cells from three MM cell lines selected for resistance to BTZ demonstrate elevated levels of TXNRD2, indirectly confirming its functional role in BTZ resistance.Accordingly, ectopic expression of TXNRD2 in MM cell xenografts in immunocompromised mice blunts the therapeutic effects of BTZ.Our data identifies TXNRD2 as a potential clinically relevant target, inhibition of which is critical for proteasome inhibitor-dependent cytotoxicity, oxidative stress, and ER stress.
细胞对氧化和内质网(ER)应激的反应是细胞内最保守的进化途径之一。由于高水平的代谢,包括蛋白质翻译率的增加,肿瘤细胞通常会遇到内质网和氧化应激。然而,主要针对干扰这些应激反应途径的药物仅占目前可用的抗肿瘤药物的一小部分。此外,我们对内质网应激与这几种抗癌药物引起的氧化应激之间的相互关系知之甚少。例如,人们普遍认为蛋白酶体抑制剂诱导的细胞内氧化应激是内质网应激的副产物。在这里,我们报告了蛋白酶体抑制剂硼替佐米(BTZ)通过转录抑制编码线粒体硫氧还蛋白还原酶(TXNRD2)的基因,直接诱导多发性骨髓瘤(MM)细胞氧化应激和内质网应激的机制。TXNRD2对维持细胞内氧化还原状态和活性氧解毒至关重要。在btz处理的细胞中,TXNRD2消耗到检测到的水平会引起氧化应激、内质网应激和死亡,类似于蛋白酶体抑制剂引起的氧化应激、内质网应激和死亡。反过来,在蛋白酶体抑制剂处理的MM细胞中,恢复接近野生型的TXNRD2水平,与TXNRD2水平耗尽的细胞相比,分别减少了46%、35%和50%的氧化应激、内质网应激和细胞死亡。此外,三种MM细胞系的BTZ抗性细胞显示TXNRD2水平升高,间接证实了其在BTZ抗性中的功能作用。因此,TXNRD2在免疫功能低下小鼠MM细胞异种移植物中的异位表达减弱了BTZ的治疗作用。我们的数据确定TXNRD2是一个潜在的临床相关靶点,抑制它对蛋白酶体抑制剂依赖性细胞毒性、氧化应激和内质网应激至关重要。
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引用次数: 0
FERMENTATION OF BIOACTIVE SOLID LIPID NANOPARTICLES BY HUMAN GUT MICROBIOTA 人体肠道菌群发酵生物活性固体脂质纳米颗粒
Pub Date : 2016-07-08 DOI: 10.18143/JISANH_V3I4_1423
R. Madureira
Solid lipid nanoparticles (SLN) can be used for the oral delivery of phenolic compounds in order to protect them from the harsh conditions of digestion and improve their bioavailability in the intestinal epithelium. Recently, the production and characterization of SLN loaded with rosmarinic acid and herbal extracts was performed for future use as functional food ingredients. On the other hand, a hot topic of the moment is the knowledge that diet components have a huge impact on gut microbiota viability and metabolic activity. Hence, this communication concerns the study of the effect of SLN and released phenolic compounds on gut microbiota.I will make an overview on the results of the fermentations in anaerobic batch cultures using volunteer human faeces during 48h. The impact of these phenolic compounds free and encapsulated in SLN on the main gut bacterial groups population and metabolic activities will be discussed.
固体脂质纳米颗粒(SLN)可用于酚类化合物的口服递送,以保护它们免受恶劣的消化条件并提高它们在肠上皮中的生物利用度。近年来,对迷迭香酸和草药提取物负载的SLN的制备和表征进行了研究,以期将来作为功能性食品原料。另一方面,目前的一个热门话题是饮食成分对肠道微生物群活力和代谢活动有巨大影响的知识。因此,本通讯涉及SLN和释放的酚类化合物对肠道微生物群的影响的研究。我将概述在厌氧间歇培养中使用志愿者的粪便发酵48小时的结果。我们将讨论这些游离和包封在SLN中的酚类化合物对主要肠道细菌群数量和代谢活性的影响。
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引用次数: 0
RESVERATROL MODULATES CELL MEMBRANES: WHAT’S THE STORY? 白藜芦醇调节细胞膜:这是怎么回事?
Pub Date : 2016-07-08 DOI: 10.18143/JISANH_V3I4_1417
A. Neves, F. Almeida, S. Reis
Resveratrol is one of the most promising naturally occurring polyphenols with great therapeutic potential. Despite the well know anti-oxidant activity, anti-inflammatory action, cardiovascular protection, neuroprotection and cancer chemoprevention, the mechanism of action of resveratrol is still uncertain. This work brings a new membrane approach to understand resveratrol action through the modulation of lipid domains present in biological membranes, and consequently the activity of anchored proteins that are involved in intracellular cascades. The potential molecular interactions between resveratrol and lipid rafts found in cell membranes were assessed by means of Forster resonance energy transfer, X-ray diffraction analysis, derivative spectrophotometry, fluorescence quenching and anisotropy studies. This polyphenol compound seems to induce phase separation in lipid bilayers, stabilizing and promoting the formation of ordered domains (lipid rafts) which can act as organizing centers for the assembly of proteins involved in cell signaling pathways.
白藜芦醇是最有前途的天然多酚之一,具有很大的治疗潜力。尽管白藜芦醇具有众所周知的抗氧化、抗炎、心血管保护、神经保护和癌症化学预防作用,但其作用机制仍不确定。这项工作带来了一种新的膜方法来理解白藜芦醇的作用,通过调节存在于生物膜中的脂质结构域,从而参与细胞内级联的锚定蛋白的活性。通过福斯特共振能量转移、x射线衍射分析、导数分光光度法、荧光猝灭和各向异性研究,评估了白藜芦醇与细胞膜脂膜之间潜在的分子相互作用。这种多酚化合物似乎可以诱导脂质双层的相分离,稳定和促进有序结构域(脂筏)的形成,这些结构域可以作为参与细胞信号通路的蛋白质组装的组织中心。
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引用次数: 0
REACTIVE OXYGEN-RELATED DISEASES: THERAPEUTIC TARGETS AND EMERGING CLINICAL INDICATIONS 活性氧相关疾病:治疗靶点和新出现的临床指征
Pub Date : 2016-07-08 DOI: 10.18143/JISANH_V3I3_1451
Harald Schmidt
Numerous diseases and disease models have been suggested to be associated with oxidative stress; however very few if any have resulted in clinical application; some trials have been giant failures. Two innovations may provide a more successful and evidence-based way forward: the therapeutic move from focussing on ROS to their enzymatic sources and targets and the differentiation of physiological and pathological functions of these. Moreover a cluster of disease phenotypes within the so-called ‘diseasesome’ seems specifically linked to ROS- mediate pathologies.Here we present examples for such target validation within this cluster in diabetic end-organ damage and stroke, both linked by shared common redox mechanisms.These therapeutic advances will be backed-up by precision diagnostics that enable early detection, patient stratification, detecting target engagement and therapeutic monitoring.
许多疾病和疾病模型都被认为与氧化应激有关;然而,很少有临床应用;一些试验是巨大的失败。两项创新可能会提供一种更成功和基于证据的前进道路:治疗从关注ROS转向其酶源和靶点,以及它们的生理和病理功能的分化。此外,在所谓的“疾病体”内的一组疾病表型似乎与ROS介导的病理特异性相关。在这里,我们提出了在糖尿病终末器官损伤和中风中这类靶标验证的例子,两者都与共同的氧化还原机制有关。这些治疗方面的进步将得到精确诊断的支持,从而实现早期发现、患者分层、检测目标接触和治疗监测。
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引用次数: 0
THE CURRENT STATE ON THE DEVELOPMENT OF NANOPARTICLES FOR USE AGAINST BACTERIAL GASTROINTESTINAL PATHOGENS 纳米颗粒抗胃肠道细菌病原体的研究现状
Pub Date : 2016-07-08 DOI: 10.18143/JISANH_V3I4_1424
M. Pintado
Gastrointestinal diseases have a huge impact especially in third world countries, making it urgent to seek new effective antimicrobial therapies. Thus, the study of new antimicrobial solutions has been the target of research over the past years. The development of nanoparticles (NPs) with natural bioactive compounds exhibiting antimicrobial activity may be promising to overcome the problems associated with antibiotic resistance caused by many pathogenic bacteria. In addition, the phenolic compounds are a class of bioactive compounds for which their antimicrobial activity was already tested on the production of NPs. Polymeric or lipidic NPs systems have been investigated to deliver these compounds. As example, chitosan is a polymer widely known for their properties, especially its unique antimicrobial activity and its ability to adhere to intestinal epithelium. In this presentation the discussion of the recent developments of new delivery systems for phenolic compounds with antimicrobial activity against gastrointestinal pathogens, their production processes, activities, focusing on NPs produced using chitosan as the main structural and functional material including case studies will be made.
胃肠道疾病的影响巨大,特别是在第三世界国家,因此迫切需要寻求新的有效的抗菌疗法。因此,研究新的抗菌溶液一直是过去几年研究的目标。具有天然生物活性化合物的纳米颗粒(NPs)具有抗菌活性,有望克服许多致病菌引起的抗生素耐药性问题。此外,酚类化合物是一类生物活性化合物,其抗菌活性已经在NPs的生产中进行了测试。聚合物或脂质NPs系统已被研究用于递送这些化合物。例如,壳聚糖是一种聚合物,以其特性而闻名,特别是其独特的抗菌活性和粘附在肠上皮上的能力。在本报告中,将讨论具有胃肠道病原体抗菌活性的酚类化合物的新递送系统的最新进展,其生产工艺,活性,重点介绍以壳聚糖为主要结构和功能材料生产的NPs,包括案例研究。
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引用次数: 5
RECENT INVESTIGATIONS ON PHYTOCHEMICALS AND QUORUM SENSING/BIOFILMS 植物化学物质与群体感应/生物膜的研究进展
Pub Date : 2016-07-08 DOI: 10.18143/JISANH_V3I4_1426
M. Simões
Biofilms are supposed to be the first form of communitarian life recorded on the planet, being estimated that most microorganisms on Earth are organized in sessile state and they even occur in extreme environments. This ubiquity of biofilms is potentially beneficial, but can also cause significant problems of public health, medicine and industry concern. In the health context, some diseases and adverse medical conditions are now recognized to be the result of a biofilm infection. In fact, the degree of severity and the persistence of infections is worsened when microorganisms form biofilm. Therefore, efforts are being applied to develop new drugs not so vulnerable as the current therapeutics to bacterial resistance mechanisms, and also able to target bacteria in biofilms. Natural products, especially those obtained from plants, have proven to be outstanding compounds with unique properties, making them perfect candidates for this much-needed therapeutics. This study presents current knowledge on the potentialities of plant products as biofilm control agents. Data will be provided on their mode of action focusing their activity to interfere with bacterial quorum sensing signaling pathways and underlying phenotypes.
生物膜被认为是地球上记录的第一种社群生命形式,据估计,地球上的大多数微生物都是在无根状态下组织的,甚至在极端环境中也会出现。这种无所不在的生物膜可能是有益的,但也可能引起公共卫生、医学和工业关注的重大问题。在健康方面,一些疾病和不良医疗状况现在被认为是生物膜感染的结果。事实上,当微生物形成生物膜时,感染的严重程度和持久性会恶化。因此,人们正在努力开发新的药物,不像目前的治疗方法那样容易受到细菌耐药机制的影响,同时也能够靶向生物膜中的细菌。天然产物,特别是从植物中提取的天然产物,已被证明是具有独特特性的杰出化合物,使它们成为这种急需的治疗方法的完美候选者。本研究介绍了植物产品作为生物膜控制剂的潜力的最新知识。将提供有关其作用模式的数据,聚焦其干扰细菌群体感应信号通路和潜在表型的活动。
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引用次数: 0
EXTRACELLULAR MATRIX GLYCATION, REDOX STATUS AND CROSS-LINKING 细胞外基质糖基化,氧化还原状态和交联
Pub Date : 2016-07-08 DOI: 10.18143/JISANH_v3i2_1431
S. Ricard-Blum
Extracellular matrix (ECM) is mostly comprised of proteins and proteoglycans, which form supramolecular assemblies. It provides shape and mechanical properties - mediated by covalent cross-links - to tissues and organs, and regulates cell behavior. Covalent cross-linking of the ECM is mediated by transglutaminase-2, glycation and more specifically by enzymes of the lysyl oxidase family. Lysyl oxidase, or protein-lysine 6-oxidase, contains the redox cofactor lysyl-tyrosine quinone and is a source of hydrogen peroxide, a reactive oxygen species. We have investigated ECM cross-links formed via glycation and lysyl oxidase in liver and skin fibrosis and we are currently building the interaction network of lysyl oxidase to determine if it plays further biological roles in ECM and in pericellular matrix at the cell surface.
细胞外基质(ECM)主要由蛋白质和蛋白聚糖组成,它们形成超分子组装体。它通过共价交联为组织和器官提供形状和机械特性,并调节细胞行为。ECM的共价交联是由转谷氨酰胺酶-2、糖基化介导的,更具体地说是由赖氨酸氧化酶家族的酶介导的。赖氨酸氧化酶,或蛋白质赖氨酸6-氧化酶,含有氧化还原辅助因子赖氨酸酪氨酸醌,是过氧化氢的来源,一种活性氧。我们已经研究了通过糖基化和赖氨酸氧化酶在肝脏和皮肤纤维化中形成的ECM交联,我们目前正在构建赖氨酸氧化酶的相互作用网络,以确定它是否在ECM和细胞表面的细胞周基质中发挥进一步的生物学作用。
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引用次数: 0
ANTIDIABETIC THERAPY, ANTIOXIDANTS AND TUMOR INITIATION 抗糖尿病治疗,抗氧化剂和肿瘤起始
Pub Date : 2016-07-08 DOI: 10.18143/JISANH_v3i3_1465
Hui Wang
Accumulating evidence found that antidiabetic therapy is closely associated with tumor. Oxidative stress contributes to the onset of diabetes and diabetic complications, and antioxidant agents are the important component in the treatment of diabetes and its complications. Furthermore, oxidative stress plays a pivotal role in tumor. So antioxidant antidiabetic agents may have the potential effect on the biology of tumors. In our study recently published on Science Translational Medicine, we found that some of the antioxidant antidiabetic agents could increase NRF2 expression which correlated with potentially accelerating tumor metastasis in mice models. Our findings suggest that antioxidants that activate NRF2 signaling may need to be administered with caution in cancer patients, such as diabetic patients with cancer.
越来越多的证据表明,抗糖尿病治疗与肿瘤密切相关。氧化应激有助于糖尿病及其并发症的发生,抗氧化剂是治疗糖尿病及其并发症的重要组成部分。此外,氧化应激在肿瘤中起着关键作用。因此抗氧化抗糖尿病药物可能对肿瘤生物学有潜在的影响。在我们最近发表在《科学转化医学》上的研究中,我们发现一些抗氧化抗糖尿病药物可以增加NRF2的表达,这与小鼠模型中潜在的加速肿瘤转移有关。我们的研究结果表明,激活NRF2信号的抗氧化剂可能需要谨慎地用于癌症患者,如患有癌症的糖尿病患者。
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引用次数: 0
期刊
Journal of the International Society of Antioxidants in Nutrition & Health
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