Another tool in the toolkit to manage iron overload.
Another tool in the toolkit to manage iron overload.
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另一个管理铁过载的工具。
DOI：
10.1073/pnas.2208868119
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发表时间：
2022-08-02
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
铁很难。它是几乎所有生物体的必需营养素;然而，在我们富氧的大气中，它主要以三价铁（Fe+ 3）状态存在，几乎不溶于支持生命的水环境。大多数生物系统利用亚铁，Fe+ 2形式，其易于溶解但也具有高度化学反应性。虽然这种化学反应性在以铁辅因子的形式存在于酶或携氧分子中时非常有用，但未陪伴的铁也可能对细胞具有高度毒性，因为它催化活性氧物质的形成，这些活性氧物质可以破坏脂质，蛋白质和核酸（1）。对于许多生物体来说，低铁生物利用度限制了生长。人类长期以来一直在与膳食铁不足作斗争，因为维持世界上大多数人的植物性饮食往往铁含量低（2）。因此，毫不奇怪，人类已经进化到非常有效地利用饮食和身体中的铁储备。我们在铁的再利用方面是如此有效，以至于人类没有有效的方法来消除体内多余的铁。如果没有排泄铁的方法，我们的铁吸收系统必须精确调节，以满足不断变化的代谢需求，避免铁过载。虽然一个健康的人可以活100年而不会出现缺铁或铁超载，但许多疾病状态都与这种平衡的破坏有关。与铁过载相关的疾病是遗传和获得性的，由内在失调的铁运输或红细胞输注形式的医源性铁负荷引起（3）。过量的铁通常积聚在网状内皮系统的细胞中，但是，在严重的铁过载中，实质细胞，特别是肝、心脏和肾的实质细胞可能受到影响。这些铁储存可以通过简单的干预措施，如放血来去除，但如果由于贫血而不能耐受放血，则需要药理学手段。目前有三种药物被批准用作螯合剂来治疗铁超载：去铁胺，去铁酮和地拉罗司（4）。每种方法都有其优点和局限性。Ekaputri等人(5)在PNAS上讨论了扁柏酚的生物活性和潜在的治疗用途，扁柏酚是一种用于传统亚洲医学的植物衍生小分子，也有可能在铁过载的情况下动员铁。在哺乳动物中，身体铁平衡由唯一的细胞铁外排泵ferroportin的活性控制（6）。肠上皮细胞通过铁输入者二价金属转运蛋白1（DMT 1）摄取膳食铁（7），血液中循环转铁蛋白结合铁的摄取通过转铁蛋白受体（Tfr 1和Tfr 2）、内体铁还原酶（Steap 3）和输入者（DMT 1和Zip 14）的联合活性发生（8）。尽管细胞铁摄取受细胞自主系统（肠道中的Hif-2和其他细胞中的Irp 1和Irp 2）调节（9，10），但身体和组织铁平衡通过膜铁转运蛋白和主要调节激素铁调素的活性控制（6）。铁调素是主要由肝细胞合成和分泌的小肽。循环铁调素直接结合定位于铁输出细胞表面上的膜铁转运蛋白。铁调素结合通过物理阻塞铁输出通道并通过触发输出者的内化和降解来灭活膜铁转运蛋白。循环铁调素的水平通过感知身体铁需求以及来自肾脏、骨髓、免疫细胞和肝窦内皮的信号分子的合成和释放来控制。这些系统在很大程度上影响通过骨形态发生蛋白的信号传导。
Iron is difficult. It is an essential nutrient for almost every organism; yet, in our oxygen-rich atmosphere, it largely exists in the ferric, Fe+ 3 state, which is practically insoluble in the aqueous milieu that supports life. Most biological systems utilize the ferrous, Fe+ 2 form, which is readily soluble but also highly chemically reactive. Although this chemical reactivity is very useful when present in the form of an iron cofactor in an enzyme or oxygen-carrying molecule, unchaperoned iron can also be highly toxic to cells because it catalyzes the formation of reactive oxygen species that can damage lipids, proteins, and nucleic acids (1). For many organisms, low iron bioavailability limits growth. Humans have long struggled with dietary iron insufficiency because the plant-based diets that sustain most of the peoples of the world tend to be low in iron (2). Thus, it is unsurprising that humans have evolved to be very efficient in their utilization of dietary and bodily reservoirs of iron. We are so efficient in iron reutilization that humans express no effective means of ridding the body of excess iron. Without a means to excrete iron, our systems of iron uptake must be precisely regulated to meet changing metabolic needs and avoid iron overload. Although a healthy human can live for 100 y without developing iron deficiency or iron overload, many disease states are associated with disruption of this balance. Disorders associated with iron overload are both inherited and acquired and caused by intrinsically dysregulated iron trafficking or by iatrogenic iron loading in the form of red blood cell transfusions (3). Excess iron typically accumulates in cells of the reticuloendothelial system, but, in severe iron overload, parenchymal cells, especially of the liver, heart, and kidney, can be affected. These iron stores can be removed by simple interventions, such as phlebotomy, but pharmacologic means are necessary where phlebotomy is not tolerated due to anemia. There are three drugs currently approved for use as chelators to treat iron overload: deferoxamine, deferiprone, and deferasirox (4). Each has its advantages and limitations. Ekaputri et al.(5) discuss, in PNAS, the biological activity and potential therapeutic use of hinokitiol, a small, plant-derived molecule used in traditional Asian medicine that also has the potential to mobilize iron in the setting of iron overload. In mammals, body iron balance is controlled by the activity of the sole cellular iron efflux pump, ferroportin (6). Uptake of dietary iron in the intestinal epithelium occurs through the iron importer divalent metal transporter 1 (DMT1)(7), and uptake of circulating transferrin-bound iron in the blood occurs through the combined activities of the transferrin receptors (Tfr1 and Tfr2), endosomal iron reductases (Steap3), and importers (DMT1 and Zip14)(8). Although cellular iron uptake is regulated by cell-autonomous systems (Hif-2 in the gut and Irp1 and Irp2 in other cells)(9, 10), body and tissue iron balance is controlled through the activities of ferroportin and the major regulatory hormone, hepcidin (6). Hepcidin is a small peptide synthesized and secreted primarily by hepatocytes. Circulating hepcidin binds directly to ferroportin localized on the surface of iron-exporting cells. Hepcidin binding inactivates ferroportin by physically occluding the iron export channel and by triggering internalization and degradation of the exporter. The levels of circulating hepcidin are controlled through the sensing of body iron requirements and the synthesis and release of signaling molecules from the kidney, bone marrow, immune cells, and liver sinusoidal endothelium. These systems largely impact signaling through the bone morphogenetic protein …
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影响因子：
3.2
作者：
Wang CY;Babitt JL
通讯作者：
Babitt JL
影响因子：
3.6
作者：
Maio N;Zhang DL;Ghosh MC;Jain A;SantaMaria AM;Rouault TA
通讯作者：
Rouault TA
影响因子：
7.4
作者：
Berdoukas, Vasilios;Coates, Thomas D.;Cabantchik, Zvi Ioav
通讯作者：
Cabantchik, Zvi Ioav
影响因子：
5.6
作者：
Nemeth E;Ganz T
通讯作者：
Ganz T
DOI：
10.1007/s10534-016-9952-2
发表时间：
2016-08
期刊：
Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine
影响因子：
--
作者：
Duck KA;Connor JR
通讯作者：
Connor JR