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医学气体和内源性抗氧化
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来自日本九州大学Mami Noda课题组，最近针对氢气和内源性抗氧化系统的关系进行了综述，文章发表在Oxidative Medicine and Cellular Longevity doi:10.1155/2012/324256。
九州大学Noda课题组曾在Plos One上报道过氢气对巴金森病治疗效果的研究。关于氢气治疗疾病机制的观点，主要有两类，一是氢气的直接抗氧化效应，二是氢气可以诱导体内抗氧化系统，使自身抗损伤能力提高。直接抗氧化效应的观点主要是根据氢气的还原性，并证明可以和毒性自由基发生中和反应。由于氢气的有效剂量非常低，持续作用时间非常短，用直接抗氧化解释显得无法让人信服，后来许多研究发现氢气对一些抗氧化酶具有诱导效应，例如氢气治疗后HO-1和SOD等会显著增加，而这些抗氧化酶本身就对许多疾病具有保护效应，因此有观点认为氢气真正发挥治疗疾病的作用是由于可激活身体自身的保护机制。当然这些机制仍需要比较详细的分子细节才能让人最终接受。
氧化应激导致神经细胞死亡，是许多中枢神经系统退行性疾病的关键病理生理学过程，例如老年性痴呆、巴金森病、亨廷顿病和肌萎缩性侧索硬化等。针对氧化损伤，许多保护性信号传导系统能上调细胞内抗氧化酶表达，例如血红素加氧酶（HO-1）和超氧化物岐化酶（SOD-1/2）。这些抗氧化酶的表达可被许多转录因子或协同因子如核因子2（网织红细胞衍生细胞）相关因子2（Nrf2）和氧化酶体增殖激活受体γ共激活1α(PGC-1α/PPARγ)。这些抗氧化酶在许多神经退行性疾病动物模型中发挥重要作用，有时具有保护作用。这些酶可以被许多内源性介质或天然化合物，也可以被许多气体，如一氧化碳、硫化氢和氢气诱导激活。这种启动内源性抗氧化的途径可以作为对许多神经退行性疾病的治疗策略。
尽管脑组织只有体重的2%，但可以消耗身体20-50%的氧气，说明脑功能主要依赖氧气的供应。在正常生理情况下，细胞消耗的氧气中2-5%会转化成活性氧副产物，在病理情况下，活性氧产生更多。因此，清除和调节脑组织中活性氧对维持大脑的功能是非常重要的。尽管许多神经退行性疾病如老年性痴呆、巴金森病、亨廷顿病和肌萎缩性侧索硬化等，脑组织活性氧过度增加是非常关键的病理生理机制，抗氧化系统可有效保护许多神经损伤。氧化应激可激活应激反应，对抗活性氧诱导的细胞损伤，维持氧化还原平衡，保护细胞免于致命损伤的威胁。这些适应性反应都需要内源性抗氧化酶的上调，这些抗氧化酶的上调可被许多转录因子调控。Nrf2和PGC-1α就是两个非常关键的转录因子。抗氧化酶HO-1和SOD在神经退行性疾病中具有重要作用。本综述重要针对几种重要的医学气体，一氧化碳、硫化氢和氢气在上述转录因子和重要抗氧化酶功能调节中的最新研究进展。
The transcriptional upregulation of antioxidant enzymes in neurodegenerative diseases. Both neurons and astrocytes can increase several antioxidant enzymes including heme oxygenase-1 (HO-1), copper and zinc-containing SOD (Cu/ZnSOD), manganese-containing SOD (MnSOD), and glutathione peroxidase (GPx). By drug application or genetic overexpression of transcription factor, the transcriptional responses via NF-κB (p50/p65), AP-1 (c-Jun/c-Fos), Nrf2/sMaf, and NRF1/PGC-1α in response to oxidative stress and related neurodegenerative disease are activated.
Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan.
Oxidative stress in the central nervous system is strongly associated with neuronal cell death in the pathogenesis of several neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. In order to overcome the oxidative damage, there are some protective signaling pathways related to transcriptional upregulation of antioxidant enzymes, such as heme oxygenase-1 (HO-1) and superoxide dismutase (SOD)-1/-2. Their expression is regulated by several transcription factors and/or cofactors like nuclear factor-erythroid 2 (NF-E2) related factor 2 (Nrf2) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α). These antioxidant enzymes are associated with, and in some cases, prevent neuronal death in animal models of neurodegenerative diseases. They are activated by endogenous mediators and phytochemicals, and also by several gases such as carbon monoxide (CO), hydrogen sulphide (H(2)S), and hydrogen (H(2)). These might thereby protect the brain from severe oxidative damage and resultant neurodegenerative diseases. In this paper, we discuss how the expression levels of these antioxidant enzymes are regulated. We also introduce recent advances in the therapeutic uses of medical gases against neurodegenerative diseases.
https://blog.sciencenet.cn/blog-41174-595632.html
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