Synergistic toxicity of reactive oxygen species

过氧化氢是一种生物特有的毒素，与常见的有机或无机分子具有惰性， 但在足够的浓度下，使用细胞铁几乎可以杀死接触到的任何类型的细胞 产生高活性的氧化物种(芬顿反应)。染色体DNA是 HP中毒的主要细胞靶点，尽管致命的染色体损伤的本质是 仍然未知。更令人困惑的是，惠普被证明是一个令人惊讶的选择 武器，因为杀戮浓度是生理浓度的1000倍， 虽然幽门螺杆菌在特定细胞隔间的积累是有问题的，因为它的 小尺寸和不带电荷的性质有利于通过膜扩散。然而，我们的免疫力 细胞不知何故利用这些低得多的幽门螺杆菌浓度来有效地杀死入侵的微生物， 不清楚的机制。值得注意的是，幽门螺杆菌的毒性与其他简单分子协同作用，如 一氧化氮(NO)或氰化物(CN)。我们假设我们的免疫细胞使用不同的 HP浓度不足以通过积累增强剂分子来杀灭细菌(用于 例如，否)在不累积高[HP]的隔室中。然而， 增强幽门螺杆菌毒性背后的代谢机制，被认为是提高细胞内 游离铁，与最新的结果不一致，而机理是不可修复的 染色体受损的情况大多仍不清楚。我们最近对HP+CN共毒性的研究 发现了这一现象的新方面，比如从细胞内仓库中重新招募铁 直接导致DNA，或灾难性的染色体断裂，这是细胞的责任 杀戮。我们建议研究HP+NO的联合毒性，具体有三个目标：1)这种毒性的性质 协同毒性与NO作用靶点；2)DNA作用机制 灾难性的染色体碎裂；3)饥饿休克是幽门螺杆菌的代谢增强剂 毒性。我们的方法与以前工作的主要不同之处在于强调 DNA和染色体损伤，关于显著扩大的遗传范围和测试 增强芬顿的具体方法。我们在这个项目中的长期目标是了解 一方面，灾难性的染色体断裂背后的机制，以及那些 负责增强幽门螺杆菌的毒性。

Hydrogen peroxide is a bio-specific toxin, inert with common organic or inorganic molecules, but in sufficient concentrations killing any type of cells almost on contact, using cellular iron to produce highly-reactive oxidizing species (Fenton's reaction). Chromosomal DNA is the main cellular target of HP poisoning, although the nature of lethal chromosomal damage is still unknown. Even more confusingly, HP turns out to be a surprising choice for a bio- weapon, as the killing concentrations are 1,000-fold higher than the physiological ones, while accumulation of HP in a particular cellular compartment is problematic, because its small size and uncharged nature facilitates diffusion through membranes. Yet, our immune cells somehow use these much lower HP concentrations to efficiently kill invading microbes, by unclear mechanisms. Remarkably, HP toxicity is synergized by other simple molecules, like nitric oxide (NO) or cyanide (CN). We hypothesize that our immune cells use otherwise insufficient HP concentrations to kill bacteria by accumulating potentiator molecules (for example, NO) in the compartments where high [HP] does not accumulate. However, the metabolic mechanisms behind potentiated HP toxicity, thought to elevate the intracellular free iron, are inconsistent with the newest results, while the mechanisms of irreparable chromosomal damage remain mostly unclear. Our recent studies of HP+CN co-toxicity uncovered new aspects of the phenomenon, like iron recruitment from intracellular depots directly to DNA, or catastrophic chromosome fragmentation, which is responsible for the cell killing. We propose to study HP+NO co-toxicity with three specific aims: 1) the nature of this synergistic toxicity and the targets of NO action; 2) the DNA mechanisms behind the catastrophic chromosomal fragmentation; 3) hunger shock as a metabolic potentiator of HP toxicity. The major difference of our approach from the previous work is the emphasis on DNA and chromosome damage, on the significantly expanded genetic scope and on testing specific ways to enhance Fenton. Our long-term goals in this project are to understand the mechanisms behind the catastrophic chromosome fragmentation on the one hand, and those responsible for potentiation of HP toxicity on the other.