2007年，日本学者首先提出氢气具有选择性抗氧化作用，能治疗氧化应激损伤类疾病，随后众多国际同行开展相关研究，证明氢气对许多疾病具有非常理想的治疗作用，不仅发现具有抗氧化作用，而且证明具有抗炎症抗细胞凋亡的作用，不过抗炎症和抗凋亡的源头仍然是抗氧化。因此选择性抗氧化是氢气生物学效应最流行的说法。不过这一说法目前面临严重挑战。

最近来自瑞士理工学院有机化学研究所自由基生物学研究学者Willem H. Koppenol在《自由基生物医学》杂志发表论文，对氢气选择性抗氧化的观点提出挑战。这也是自2007年日本太田成男课题组在《自然医学》杂志发表氢气通过选择性抗氧化治疗脑缺血再灌注损伤以来遇到的最大挑战。这种反对声早在2007年就有人提出，主要依据是根据氢气和羟基自由基反应的速度远低于其他机体内还原性物质，推测氢气不可能通过选择性抗氧化发挥作用。但是这种说法并没有用实验证据来说明。后来曾经有日本学者也提出氢气并没有发现和羟基自由基发生反应的研究，但并没有引起大家关注，因此这种观点也一直成为氢气生物学领域的标准说法。

Koppenol是国际上自由基生物学领域的著名学者，他们这次采用比较严格的实验证明氢气和亚硝酸阴离子几乎不发生反应，与羟基自由基发生反应的可能性也不大，因此从实验上否定了氢气选择性抗氧化的说法。

不过这一研究并不能否定氢气的生物学效应，因为没有进行整体动物实验，过去的许多研究结果也提示，氢气的作用确实难以用选择性抗氧化来明确解释，有许多研究发现氢气能影响多种基因表达，促进内源性抗氧化系统的功能，这些现象都不能用选择性抗氧化直接解释。氢气生物学效应机制的研究7年来并没有明显突破，现在有学者对选择性抗氧化提出挑战应该值得鼓励的。本人在3月全国学会中也提出氢气选择性抗氧化存在许多疑问，不过目前仍没有正式发表。现在的研究说明，我们的疑问仍然不够彻底。也许选择性抗氧化根本就是个传说。因此，关于氢气效应机制的研究将成为这个领域的更为紧迫的问题。

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太田教授关于本文的解释

I essentially welcome various and critical discussions on the mechanismhow H2 exhibits so many great effects.  Istill feel them curious and have spent a lot of efforts to reveal the mechanismfor 7 years, but most of them were negative. I have examined whether H2 can reduce NAD+, FADH, Fe(III), Cu(II) oroxidized heame under suitable conditions in cell free systems, but all theresults were negative.  

  Everyone would have a right tohave a speculation, but the researchers should try to obtain experimentalevidence.  Without experimental evidence,I am afraid that the discussion would be poor. For constructing a workinghypothesis, we should be aware of the difference between circumstances of asimple solution and complicated cells. Sometimes, results obtained in a solution would be meaningless toexplain the effects by H2 in our body.

   Many mysteries on H2 therapyremain unsolved.  For initiating cellularsignals by H2, H2 should be too inert to react with most molecules excepthighly reactive molecules such as ·OH or ONOO–. To activate H2 to react with the other molecules, a putative catalyst(s)must be sufficiently present; however, it is highly unlikely that such theputative catalyst(s) would be abundant in cells.  Moreover, H2 should be too small to be boundto a putative H2 binding receptor(s) because their intra-molecular fluctuationshould disturb their bindings.  Thus, Ibelieve that H2 should not be a primary signaling molecule according to a definitionof signal transduction.

Under these circumstances,recent our results on the mechanism could answer most unresolved questions: howlow levels of exogenous H2 (inhalation of 1% of H2 gas, drinking H2 water toreach 10 microM of H2 in blood), regardless of H2 gas inhalation or drinking H2-water,exhibit unambiguously great efficacy; how low levels of H2 contribute tosignal-transduction to exhibit various effects by regulating various geneexpressions; and how H2 exhibits a variety of functions responding onlypathogenic statuses. It is essential to identify the primary target of H2.

  I constructed the workinghypothesis one and half year ago. We could verify the model and this paper willbe submitted in this September.

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