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首页> 外文期刊>Archives of Toxicology >Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson's, Huntington's, Alzheimer's, prions, bactericides, chemical toxicology and others as examples.
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Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson's, Huntington's, Alzheimer's, prions, bactericides, chemical toxicology and others as examples.

机译:朝着统一的系统生物学理解大规模细胞死亡和破坏造成的,帕金森,亨廷顿,阿尔茨海默,朊病毒,杀菌剂,化学毒理学等。

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摘要

Exposure to a variety of toxins and/or infectious agents leads to disease, degeneration and death, often characterised by circumstances in which cells or tissues do not merely die and cease to function but may be more or less entirely obliterated. It is then legitimate to ask the question as to whether, despite the many kinds of agent involved, there may be at least some unifying mechanisms of such cell death and destruction. I summarise the evidence that in a great many cases, one underlying mechanism, providing major stresses of this type, entails continuing and autocatalytic production (based on positive feedback mechanisms) of hydroxyl radicals via Fenton chemistry involving poorly liganded iron, leading to cell death via apoptosis (probably including via pathways induced by changes in the NF-kappaB system). While every pathway is in some sense connected to every other one, I highlight the literature evidence suggesting that the degenerative effects of many diseases and toxicological insults converge on iron dysregulation. This highlights specifically the role of iron metabolism, and the detailed speciation of iron, in chemical and other toxicology, and has significant implications for the use of iron chelating substances (probably in partnership with appropriate anti-oxidants) as nutritional or therapeutic agents in inhibiting both the progression of these mainly degenerative diseases and the sequelae of both chronic and acute toxin exposure. The complexity of biochemical networks, especially those involving autocatalytic behaviour and positive feedbacks, means that multiple interventions (e.g. of iron chelators plus antioxidants) are likely to prove most effective. A variety of systems biology approaches, that I summarise, can predict both the mechanisms involved in these cell death pathways and the optimal sites of action for nutritional or pharmacological interventions.
机译:暴露于各种毒素和/或传染性药物导致疾病,退化和死亡,通常是细胞或组织不仅仅是死亡并且不再运作的情况,而且可以或多或少完全被灭绝的情况。然后,尽管所涉及多种代理人,但是,尽管涉及多种代理人,但是这种细胞死亡和破坏可能至少有一些统一机制。我总结了在许多情况下,一种潜在的机制,提供这种类型的主要压力,通过芬顿化学涉及伴有较善的铁,导致细胞死亡的羟基自由基的羟基自由基的持续和自催化机制。细胞凋亡(可能包括通过NF-Kappab系统中的变化引起的途径)。虽然每个途径有些途径与其他人相连,但我突出了文献证据,表明许多疾病和毒理学侮辱的退行性效果会聚在铁呼吸困难中。这种亮点特别是铁代谢的作用,以及铁,化学和其他毒理学中的铁的详细形态,并对使用铁螯合物质(可能与适当的抗氧化剂合作)具有显着影响,作为抑制中的营养或治疗剂这些主要是退行性疾病的进展和慢性和急性毒素暴露的后遗症。生物化学网络的复杂性,尤其是涉及自催化行为和正反馈的复杂性,意味着多次干预(例如铁螯合剂加抗氧化剂)可能证明最有效的干预措施。我总结的各种系统生物学方法可以预测这些细胞死亡途径和营养或药理学干预的最佳动作的机制。

著录项

  • 来源
    《Archives of Toxicology》 |2010年第11期|共65页
  • 作者

    Kell DB;

  • 作者单位

    School of Chemistry and the Manchester Interdisciplinary Biocentre The University of Manchester Manchester M1 7DN UK.;

  • 收录信息
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 毒物学(毒理学);
  • 关键词

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