Roles of iron in neoplasia

Research and clinical observations during the past six decades have shown that: 1. Iron promotes cancer cell growth; 2. Hosts attempt to withhold or withdraw iron from cancer cells; and 3. Iron is a factor in prevention and in therapy of neoplastic disease. Although normal and neoplastic cells have similar qualitative requirements for iron, the neoplastic cells have more flexibility in acquisition of the metal. Excessive iron levels in animals and humans are associated with enhanced neoplastic cell growth. In invaded hosts, cytokine-activated macrophages increase intracellular ferritin retention of the metal, scavenge iron in areas of tumor growth, and secrete reactive nitrogen intermediates to effect efflux of nonheme iron from tumor cells. Procedures associated with lowering host intake of excess iron can assist in prevention and in management of neoplastic disease. Chemical methods for prevention of iron assimilation by neoplastic cells are being developed in experimental and clinical protocols. The antineoplastic activity of a considerable variety of chemicals, as well as of radiation, is modulated by iron. The present article focuses on recent findings and suggests directions for further cancer-iron research.     

Iron, infection, and neoplasia

In nearly all forms of life, the number and diversity of enzymes that contain iron or that depend on the presence of this metal for activity are impressive. Not surprisingly, chemical mechanisms have been evolved by many organisms that permit them to solubilize and acquire iron while at the same time depriving their competitors or their pathogens of this element. Proteins such as transferrin and lactoferrin that are employed by vertebrate hosts for iron transport and acquisition can, to some extent, withhold the metal from the siderophores of invading bacteria and fungi. Attempts also are made by animal hosts to withhold iron from protozoa and neoplastic cells. Unfortunately, pathogenic microorganisms have developed a variety of counter measures that are especially dangerous in hosts stressed by iron overload in specific fluids, tissues, or cells. In recent years, however, a number of possible methods and agents for strengthening iron-withholding defense have become apparent. Nearly 3,000 papers on various aspects of iron withholding are contained in the 18-year Medline Database and numerous reviews have been published since 1966. The present paper will focus on developments that have been reported within the past 2 1/2 years.     

Candida albicans iron acquisition within the host

As a commensal and opportunistic pathogen, Candida albicans possesses a range of determinants that contribute to survival, persistence and virulence. Among this repertoire of fitness and virulence attributes are iron acquisition factors and pathways, which allow fungal cells to gain this essential mineral in the iron-poor environment of the host. The aim of this review is to present the strategies used by C. albicans to exploit host iron reservoirs and their impact on C. albicans pathogenicity. Because iron in the human host is mostly linked to host proteins, pathogens such as C. albicans must possess mechanisms to gain iron from these proteins. Here, we introduce the most important groups of human proteins, including haemoglobin, transferrin, lactoferrin and ferritin, which contain iron and that are potential iron sources for invading microorganisms. We then summarize and discuss the known and proposed strategies by which C. albicans exploits or may exploit iron from host proteins and compare these with strategies from other pathogenic microorganisms.     

A precious metal: Iron, an essential nutrient for all cells

Iron is an important cofactor required for a number of essential cell functions and hence is a vital nutrient. However, iron can also be dangerous as a catalyst of free radical reactions. Accordingly, intracellular iron homeostasis and body iron balance are tightly regulated. In this review, we presented an overview of the remarkable new insights that over the last years have been gained into the multifaceted and sophisticated molecular mechanisms controlling iron acquisition, storage and release. We also reviewed the data about nutrition-related abnormalities of iron metabolism, such as iron overload and deficiency. Finally, we discussed how pathogenic microorganisms and host cells compete for iron, a battle whose outcome has a relevant role in infectious disease.     

病原微生物对抗菌肽抗性机制的研究进展

抗菌肽(antimicrobial peptides, AMPs)是生物先天免疫系统的重要组成部分,可帮助宿主有效应对病原细菌、真菌和病毒等微生物的胁迫,被认为是医疗、食品加工和农业领域最具前途和潜力的抗生素替代物。病原微生物在与抗菌肽的互作中进化出了多种有针对性的抗性机制,本文从病原微生物对AMPs的感应与基因调控、细胞壁/膜成份的修饰、分泌蛋白酶降解及利用外排泵排出等四个方面综述了国内外的研究进展,并对AMPs类制品的研究前景进行了讨论与展望。     

Iron metabolism: microbes,mouse, and man

Recent advances in research on iron metabolism have revealed the identity of a number of genes, signal transduction pathways, and proteins involved in iron regulation in mammals. The emerging paradigm is a coordination of homeostasis within a network of classical iron metabolic pathways and other cellular processes such as cell differentiation, growth, inflammation, immunity, and a host of physiologic and pathologic conditions. Iron, immunity, and infection are intricately linked and their regulation is fundamental to the survival of mammals. The mutual dependence on iron by the host and invading pathogenic organisms elicits competition for the element during infection. While the host maintains mechanisms to utilize iron for its own metabolism exclusively, pathogenic organisms are armed with a myriad of strategies to circumvent these measures. This review explores iron metabolism in mammalian host, defense mechanisms against pathogenic microbes and the competitive devices of microbes for access to iron.     

Iron as a candidate in virulence and pathogenesis in mycobacteria and other microorganisms

Iron acquisition is one of the important virulence characteristics of a pathogen. Microorganisms elaborate different ways of acquiring iron. Siderophore-mediated iron acquisition is common in many microorganisms, while some like Neisseriae directly acquire iron from the host proteins. Microorganisms also elaborate systems for iron acquisition from ferric citrate and xenosiderophores. Such modes of uptake are also seen in mycobacteria. The siderophores produced by mycobacteria are well characterised. Iron-regulated envelope proteins (IREPs) are expressed in both saprophytic and pathogenic mycobacteria. In many bacterial systems, like that of Corynebacterium diphtheriae, low iron conditions favour the expression of virulence factors. The siderophore mycobactin has been recently implicated as a virulence factor in Mycobacterium tuberculosis. The role of the IdeR repressor in controlling the expression of the iron acquisition machinery was studied with the generation of the IdeR mutant. Development of other such mutants will facilitate the study of these mechanisms in greater detail and help to develop new drugs for combating tuberculosis and leprosy. This revised version was published online in November 2006 with corrections to the Cover Date.     

Dietary and prophylactic iron supplements

Mild hypoferremia represents an aspect of the ability of the body to withhold iron from pathogenic bacteria, fungi, and protozoa, and from neoplastic cells. However, our iron-withholding defense system can be thwarted by practices that enhance iron overload such as indiscriminate iron fortification of foods, medically prescribed iron supplements, alcohol ingestion, and cigarette smoking. Elevated standards for normal levels of iron can be misleading and even dangerous for individuals faced with medical insults such as chronic infection, neoplasia, cardiomyopathy, and arthritis. We are becoming increasingly aware that the wide-spread hypoferremia in human populations is a physiological response to insult rather than a pathological cause of insult, and that attempts to correct the condition by simply raising iron levels may not only be misguided but may actually impair host defense.     

Metal Acquisition and Homeostasis in Fungi

Transition metals, particularly iron, zinc and copper, have multiple biological roles and are essential elements in biological processes. Among other micronutrients, these metals are frequently available to cells in only limited amounts, thus organisms have evolved highly regulated mechanisms to cope and to compete with their scarcity. The homeostasis of such metals within the animal hosts requires the integration of multiple signals producing depleted environments that restrict the growth of microorganisms, acting as a barrier to infection. As the hosts sequester the necessary transition metals from invading pathogens, some, as is the case of fungi, have evolved elaborate mechanisms to allow their survival and development to establish infection. Metalloregulatory factors allow fungal cells to sense and to adapt to the scarce metal availability in the environment, such as in host tissues. Here we review recent advances in the identification and function of molecules that drive the acquisition and homeostasis of iron, copper and zinc in pathogenic fungi.     

禽坦布苏病毒诱导的宿主免疫应答

禽坦布苏病毒(Avian Tembusu virus,ATMUV)是近年来在我国新发现的一种病毒,可感染多种蛋禽,感染动物临床特征为采食量下降,产蛋量骤减,甚至停产,感染后期呈神经症状,如腿和翅膀麻痹、共济失调等。ATMUV在我国多个省市地区流行,给我国甚至世界养禽业带来严重影响。固有免疫是机体抵抗病原感染的第一道重要防线,是机体与生俱来的抵御病原微生物的能力。适应性免疫是机体免疫系统在抗原刺激下产生特异性抗体及免疫效应细胞的过程,以建立针对某种病原微生物的抵抗力,是机体免疫系统的重要部分。本文将从禽坦布苏病毒诱导宿主固有免疫应答和适应性免疫应答两方面进行综述。     

Hepcidin非铁调控因子研究进展

铁调素（Hepcidin）是由肝细胞分泌的维持人体系统性铁平衡的核心因子,其通过改变细胞膜铁转运蛋白（ferroportin,Fpn）的表达量以调控肠黏膜细胞和巨噬细胞内铁的转出水平,从而决定机体循环铁水平并影响肝脏等主要储铁脏器的铁负荷程度。根据近年来的研究发现,影响Hepcidin表达的主要因素可以归纳为两个方面：一是机体本身对铁的需求,而由于铁本身又是Hb（hemoglobin,血红蛋白）的合成原料以及携氧成份,因此还应包括机体对Hb合成和缺氧的反应,介导因子主要包括携铁转铁蛋白（holo—transferrin,holo—Tf）、促红细胞生成素（erythropoietin,EPO）和缺氧诱导因子-1（hypoxia．inducible factor1,HIF．1）;另一则是源于疾病病理过程中相关致病因素、细胞因子、激素等非铁调控因子的改变对其表达调控机制产生的影响,并通过扰乱机体铁稳态加速疾病的发展或加重病情。随着研究资料的积累,糖尿病、部分心血管疾病、酒精性或非酒精性脂肪肝等慢性疾病存在铁过负荷已是不争的事实,多种hepcidin非铁调控因子在代谢紊乱型铁过负荷综合征（sysmetabolic iron overload syndrome）发生过程中的作用受到了广泛重视。对一些常见疾病中引起hepcidin表达变化异常和铁代谢紊乱的非铁因子及其作用机制的研究进展进行综述。     

Molecular mechanisms of pathogenicity: how do pathogenic microorganisms develop cross-kingdom host jumps?

It is common knowledge that pathogenic viruses can change hosts, with avian influenza, the HIV, and the causal agent of variant Creutzfeldt-Jacob encephalitis as well-known examples. Less well known, however, is that host jumps also occur with more complex pathogenic microorganisms such as bacteria and fungi. In extreme cases, these host jumps even cross kingdom of life barriers. A number of requirements need to be met to enable a microorganism to cross such kingdom barriers. Potential cross-kingdom pathogenic microorganisms must be able to come into close and frequent contact with potential hosts, and must be able to overcome or evade host defences. Reproduction on, in, or near the new host will ensure the transmission or release of successful genotypes. An unexpectedly high number of cross-kingdom host shifts of bacterial and fungal pathogens are described in the literature. Interestingly, the molecular mechanisms underlying these shifts show commonalities. The evolution of pathogenicity towards novel hosts may be based on traits that were originally developed to ensure survival in the microorganism's original habitat, including former hosts.     

The Role of Iron In Protozoan and Fungal Infectious Diseases

To survive and replicate in vertebrate hosts, protozoan and fungal invaders must be capable of securing host iron. Successful pathogens obtain the metal from either extraction of heme, binding of siderophilins, binding of siderophores, and/or iron pools within host cells. The actual strategy can vary with the availability of iron in the particular host milieu. As a corollary, hosts have developed an elaborate iron withholding defense system. Conditions that can compromise the system as well as procedures that can strengthen it are reviewed.     

铁紊乱相关疾病的研究进展

铁作为一种必需的营养元素,在哺乳动物体内的重要作用越来越为人们所重视。动物体内存在着严格的铁代谢调节机制,以确保体内铁始终处于正常生理水平。如果铁代谢失调、体内铁缺乏或过负荷均会导致各种临床疾病。研究发现,肝脏抗菌多肽(hepcidin)很可能是一种控制小肠铁吸收及调节体内铁稳态的关键物质,是一种极为重要的铁调节激素。本文综述了铁的生理作用、铁缺乏引起的疾病(如:缺铁性贫血和儿童神经系统疾病)和铁过负荷引起的疾病(如:肝损伤、心血管疾病、帕金森病和癌症等),并对如何利用现代化技术手段在基因水平开展铁紊乱相关疾病的治疗做了展望。     

Extracellular iron reductase activity produced by Listeria monocytogenes

Little is known about how pathogenic microorganisms that do not produce low-molecular-weight iron-chelating agents, termed siderophores, acquire iron from their environment. We have identified an extracellular enzyme produced by Listeria monocytogenes that can mobilize iron from a variety of iron-chelate complexes via reduction of the metal. The iron reductase requires Mg²⁺, flavin mononucleotide (FMN), and reduced nicotinamide adenine dinucleotide (NADH) for activity. Saturation kinetics were found when initial velocity studies of iron reduction were carried out as a function of variable FMN concentrations in the presence of 100 μM NADH and 10 mM Mg²⁺. Hyperbolic kinetics were also found when these studies were repeated as a function of variable NADH concentrations along with 20 μM FMN and 10 mM Mg²⁺. This process of extracellular reduction, in all likelihood, could be involved in the mobilization of iron from soils and aqueous environments and from host tissues in pathogenic processes. This is the first report of the extracellular enzymic reduction of iron by microorganisms. Received: 12 March 1996 / Accepted: 16 April 1996     

Liver iron depletion and toxicity of the iron chelator Deferiprone (L, CP20) in the guinea pig

The use of the iron chelator deferiprone (L, CP20, 1,2-dimethyl-3-hydroxypyrid-4-one) for the treatment of diseases of iron overload and other disorders is problematic and requires further evaluation. In this study the efficacy, toxicity and mechanism of action of orally administered L were investigated in the guinea pig using the carbonyl iron model of iron overload. In an acute trial, depletion of liver non-heme iron in drug-treated guinea pigs (normal iron status) was maximal (approximately 50% of control) after a single oral dose of L1 of 200 mg kg, suggesting a limited chelatable pool in normal tissue. There was no apparent toxicity up to 600 mg kg. In each of two sub-acute trials, normal and iron-loaded animals were fed L (300 mg kg day) or placebo for six days. Final mortalities were 12/20 (L) and 0/20 (placebo). Symptoms included weakness, weight loss and eye discharge. Iron-loaded as well as normal guinea pigs were affected, indicating that at this drug level iron loading was not protective. In a chronic trial guinea pigs received L (50 mg kg day) or placebo for six days per week over eight months. Liver non-heme iron was reduced in animals iron-loaded prior to the trial. The increase in a wave latency (electroretinogram), the foci of hepatic, myocardial and musculo-skeletal necrosis, and the decrease in white blood cells in the drug-treated/normal diet group even at the low dose of 50 mg kg day suggests that L may be unsuitable for the treatment of diseases which do not involve Fe overload. However, the low level of pathology in animals treated with iron prior to the trial suggests that even a small degree of iron overload (two-fold after eight months) is protective at this drug level. We conclude that the relationship between drug dose and iron status is critical in avoiding toxicity and must be monitored rigorously as cellular iron is depleted.     

Iron and microbial infection

The use of iron as a cofactor in basic metabolic pathways is essential to both pathogenic microorganisms and their hosts. It is also a pivotal component of the innate immune response through its role in the generation of toxic oxygen and nitrogen intermediates. During evolution, the shared requirement of micro- and macroorganisms for this important nutrient has shaped the pathogen-host relationship. Here, we discuss how pathogens compete with the host for iron, and also how the host uses iron to counteract this threat.