Antioxidant status and mineral contents in tissues of rutin and baicalin fed rats

The versatile benefit effects of flavonoids lead some nutritionists to believe that they are micronutrients. However, excess intake of flavonoids may cause side effects. In this paper, the effects produced by a higher intake of rutin and baicalin on antioxidant status as well as trace minerals such as iron, copper and zinc in rat tissues were studied. When rats were fed a rutin or baicalin containing diet (1%) for 20 days, the body weight gain was lower than that of the control group. Both rutin and baicalin caused significant a decrease of catalase activity and a moderate increase of total superoxide dismutase activity in the liver. The total antioxidant status of flavonoid fed rats was increased in the liver but decreased in the serum. In comparison to the control group, the lipid peroxidation level in the liver of the rutin fed group was significantly decreased; however, there was no statistical significance in the liver of the baicalin fed group and the brain of both flavonoids groups. The liver homogenates of both flavonoid fed rats significantly inhibited alkyl radical-induced lipid peroxidation. The iron contents in the liver of flavonoid fed rats were significantly decreased; rutin also caused zinc and copper decrease in the liver. These results indicated that high flavonoid intake can improve rat antioxidant systems in the liver; while it can also cause a trace mineral decrease and, in turn, reduce the activities of some metal-containing enzymes and may cause harmful effects on health.     

A site-specific mechanism for free radical induced biological damage: the essential role of redox-active transition metals

The metal-mediated site-specific mechanism for free radical-induced biological damage is reviewed. According to this mechanism, cooper- or iron-binding sites on macromolecules serve as centers for repeated production of hydroxyl radicals that are generated via the Fenton reaction. The aberrations induced by superoxide, ascorbate, isouramil, and paraquat are summarized. An illustrative example is the enhancement of double-strand breaks by ascorbate/copper. Prevention of the site-specific free radical damage can be accomplished by using selective chelators for iron and copper, by displacing these redox-active metals with other redox-inactive metals such as zinc, by introducing high concentrations of hydroxyl radicals scavengers and spin trapping agents, and by applying protective enzymes that remove superoxide or hydrogen peroxide. Histidine is a special agent that can intervene in free radical reactions in variety of modes. In biological systems, there are traces of copper and iron that are at high enough levels to catalyze free-radical reactions, and account for such deleterious processes. In the human body Fe/Cu = 80/1 (w/w). Nevertheless, both (free) copper and iron are soluble enough, and the rate constants of their reduced forms with hydrogen peroxide are sufficiently high to suggest that they might be important mediators of free radical toxicity.     

The role of the placenta in iron transfer from mother to fetus and the relationship between iron status and fetal outcome

During pregnancy, iron is transferred from the mother to the fetus across the placenta. The mechanism has been extensively studied. Altered iron metabolism changes transfer, but also has other consequences. In this review, we examine how the placenta adapts to altered iron supply, both in terms of changing cytokine expression and in relation to the proteins of iron transfer. Changing iron levels alters the levels of other metals, especially copper, and we review how this is related to changing function. There are also consequences to the placenta itself, to vascularisation and other aspects of the physiology. In turn, this has effects on the fetus and we review how growth and development are modified. Finally, we examine in more detail the efflux process, how it is regulated and, especially, the putative role of the placental Cu oxidase in the efflux process. As appropriate, we draw on data from humans, from animal models and from cell culture systems to illustrate the information.     

Sulphate and micronutrients can modulate the expression levels of myrosinases in Sinapis alba plants

The myrosinase‐glucosinolate system is considered to be a major component of the preformed defence system of Brassicaceae species. This hypothesis has influenced the belief that the components of the myrosinase‐glucosinolate system are present at fixed levels which are independent of environmental factors. In the present study we show that external availability of nutrients can modulate the expression levels of myrosinase enzymes (EC 3.2.3.1). Nutrients such as sulphate, iron, copper, zinc and manganese were tested for their modulation effect on myrosinase expression levels and activity in roots, stems, cotyledons and buds of Sinapis alba seedlings at four different developmental stages. The most sensitive organ was the bud where iron deficiency approximately doubled the myrosinase activity. Removal of sulphate and all four micronutrients reduced the myrosinase activity to approximately half of the activity in plants supplemented with all these nutrients. The myrosinase polypeptides can be divided into classes based on molecular mass after reduction. The nutritional status influenced mainly the 68‐kDa class of myrosinases as revealed by western blot and laser scan densitometry of the immunolabelled blots.     

Copper microenvironments in the human body define patterns of copper adaptation in pathogenic bacteria

Copper is an essential micronutrient for most organisms that is required as a cofactor for crucial copper-dependent enzymes encoded by both prokaryotes and eukaryotes. Evidence accumulated over several decades has shown that copper plays important roles in the function of the mammalian immune system. Copper accumulates at sites of infection, including the gastrointestinal and respiratory tracts and in blood and urine, and its antibacterial toxicity is directly leveraged by phagocytic cells to kill pathogens. Copper-deficient animals are more susceptible to infection, whereas those fed copper-rich diets are more resistant. As a result, copper resistance genes are important virulence factors for bacterial pathogens, enabling them to detoxify the copper insult while maintaining copper supply to their essential cuproenzymes. Here, we describe the accumulated evidence for the varied roles of copper in the mammalian response to infections, demonstrating that this metal has numerous direct and indirect effects on immune function. We further illustrate the multifaceted response of pathogenic bacteria to the elevated copper concentrations that they experience when invading the host, describing both conserved and species-specific adaptations to copper toxicity. Together, these observations demonstrate the roles of copper at the host–pathogen interface and illustrate why bacterial copper detoxification systems can be viable targets for the future development of novel antibiotic drug development programs.     

Localized micronutrient patches induce lateral root foraging and chemotropism in Nicotiana attenuata

Nutrients are distributed unevenly in the soil.Phenotypic plasticity in root growth and proliferation may enable plants to cope with this variation and effectively forage for essential nutrients. However, how micronutrients shape root architecture of plants in their natural environments is poorly understood. We used a combination of field and laboratory-based assays to determine the capacity of Nicotiana attenuata to direct root growth towards localized nutrient patches in its native environment. Plants growing in nature displayed a particular root phenotype consisting of a single primary root and a few long, shallow lateral roots. Analysis of bulk soil surrounding the lateral roots revealed a strong positive correlation between lateral root placement and micronutrient gradients, including copper, iron and zinc. In laboratory assays, the application of localized micronutrient salts close to lateral root tips led to roots bending in the direction of copper and iron. This form of chemotropism was absent in ethylene and jasmonic acid deficient lines,suggesting that it is controlled in part by these two hormones. This work demonstrates that directed root growth underlies foraging behavior, and suggests that chemotropism and micronutrient-guided root placement are important factors that shape root architecture in nature.     

铜稳态对铁代谢平衡的影响

铜是人体必需的微量元素,参与体内多种蛋白和酶的组成,机体内存在严格的铜稳态调控机制。作为血浆中最主要的多铜亚铁氧化酶——铜蓝蛋白,与另外两种同源亚铁氧化酶——膜铁转运辅助蛋白和zyklopen,共同参与体内铁的转运,维持铁代谢的平衡。将对调节铜和铁平衡的重要意义以及铜和铁在机体代谢过程中的相互作用、发展动态进行讨论。     

Effects of rutin supplementation on antioxidant status and iron,copper, and zinc contents in mouse liver and brain

The effect of rutin on total antioxidant status as well as on trace elements such as iron, copper, and zinc in mouse liver and brain were studied. Mice were administrated with 0.75 g/kg or 2.25 g/kg P. O. of rutin for 30 d consecutively. Following the treatment, the activity of total antioxidant status, catalase, Cu,Zn-superoxide dismutase, Mn-superoxide dismutase, zinc, copper, and iron were measured in mouse liver and brain. The results showed that rutin significantly increased the antioxidant status and Mn-superoxide dismutase activities in mouse liver, but it had no effect on these variables in the brain. Treatment with a higher concentration of rutin significantly decreased catalase activity and iron, zinc, and copper contents in mouse liver; it also resulted in a slower weight gain for the first 20 d. These results indicate that rutin taken in proper amount can effectively improve antioxidant status, whereas at an increased dosage, it may cause trace element (such as iron, zinc, and copper) deficiencies and a decrease in the activities of related metal-containing enzymes.     

Effects of carbon source, phosphorus concentration, and several micronutrients on biomass and geosmin production by Streptomyces halstedii

The effects of various carbon sources, phosphorus concentration, and different concentrations of the micronutrients calcium, cobalt, copper, iron, manganese, potassium, and zinc were determined on biomass dry weight production, geosmin production, and geosmin/biomass (G/B) values for Streptomyces halstedii, a geosmin-producing actinomycete isolated from the sediment of an aquaculture pond. Of the substrates tested, maltose as a sole carbon source promoted maximal growth by S. halstedii while mannitol promoted maximal geosmin production, and galactose yielded the highest G/B values. Fish-food pellets and galactose were poor substrates for growth. Increasing phosphorus concentrations enhanced geosmin production and G/B values. Of the seven micronutrients tested, zinc, iron, and copper had the most profound effects on biomass and geosmin production. Increasing zinc concentrations promoted biomass production while inhibiting geosmin production and G/B values; increasing concentrations of copper and iron inhibited biomass and geosmin production. Increased copper concentrations had the greatest effect in preventing growth and geosmin production by S. halstedii. Journal of Industrial Microbiology & Biotechnology (2001) 26, 241–247. Received 20 September 2000/ Accepted in revised form 17 January 2001     

Acute inhibition of iron bioavailability by zinc: studies in humans

Iron (Fe) and zinc (Zn) deficiencies constitute two of the most important nutritional and public health problems affecting developing countries. Combined supplementation or fortification with Zn and Fe are strategies that can be used to improve the Zn and Fe status of a population. However, there is concern about potential negative interactions between these two micronutrients due to a competitive binding to DMT1 and Zip14 transporter. Studies performed in humans have shown an inhibitory effect of Zn on Fe absorption when both minerals are given together as a solution in fasting conditions. We found that at low doses of iron (0.5 mg) the threshold for the inhibition of iron bioavailability was at a Zn:Fe wt/wt ratio ≥5.9:1, whereas at higher doses of Fe (10 mg) this inhibition occurred at 1:1 Zn:Fe wt/wt ratio. This differential response could be explained by the variation in the abundance of both cations as they compete for a limited number of shared transporters at the enterocyte. Conflicting results have been obtained when this interaction was studied in different food matrices. A negative interaction was not observed when Fe and Zn were provided in a composite hamburger meal, premature formula, human milk, or cow milk. A decrease on Fe absorption was observed in only 1 of 3 studies when Fe and Zn were supplied in wheat flour. The possibility of a negative interaction should be considered for supplementation or fortification programs with both microminerals.     

How growth affects the fate of cellular metabolites

Cellular metabolites frequently have more than a single function in the cell. For example they may be sources of energy as well as building blocks for several macromolecules. The relative cellular needs for these different functions depend on environmental and intracellular factors. The intermediary products of phosphorylation of pyruvate by mitochondria, for example, are used for growth, while the released ATP is used for both growth and maintenance. Since maintenance has priority over growth, and maintenance is proportional to a cell’s mass, a cell’s need for ATP vs. building blocks depends on the growth rate, and hence on substrate availability. We show how the concept of Synthesising Units (SUs) in linear and cyclic pathways takes care of the correct variation of the ATP/building block ratio in the context of the Dynamic Energy Budget (DEB) theory. This can only be achieved by an interaction between subsequent SUs in transferring metabolites. Apart from this interaction we also needed an essential feature of the performance of the pathway in the DEB context: the relative amount of enzymes varies with the growth rate in a special way.We solved an important consistency problem between the DEB model at the whole-cell level and a model for pathway dynamics. We observe that alternative whole-cell models, such as the Marr-Pirt model, that keep the relative amount of enzymes constant, and hence independent of the growth rate, will have problems in explaining how pathways can meet cells’ growth-dependent needs for building blocks vs. ATP.     

Yeast, a model organism for iron and copper metabolism studies

Virtually all organisms on earth depend on transition metals for survival. Iron and copper are particularly important because they participate in vital electron transfer reactions, and are thus cofactors of many metabolic enzymes. Their ability to transfer electrons also render them toxic when present in excess. Disturbances of iron and copper steady-state levels can have profound effects on cellular metabolism, growth and development. It is critical to maintain these metals in a narrow range between utility and toxicity. Organisms ranging from bacteria and plants to mammals have developed sophisticated mechanisms to control metal homeostasis. In this review, we will present an overview of the current understanding of iron and copper metabolism in yeast, and the utility of yeast as a model organism to investigate iron and copper metabolism in mammals and plants.     

Old Iron, Young Copper: from Mars to Venus

Iron and copper are metals which play an important role in the living world. From a brief consideration of their chemistry and biochemistry we conclude that the early chemistry of life used water soluble ferrous iron while copper was in the water-insoluble Cu(I) state as highly insoluble sulphides. The advent of oxygen was a catastrophic event for most living organisms, and can be considered to be the first general irreversible pollution of the earth. In contrast to the oxidation of iron and its loss of bioavailability as insoluble Fe(III), the oxidation of insoluble Cu(I) led to soluble Cu(II). A new iron biochemistry became possible after the advent of oxygen, with the development of chelators of Fe(III), which rendered iron once again accessible, and with the control of the potential toxicity of iron by its storage in a water soluble, non-toxic, bio-available storage protein (ferritin). Biology also discovered that whereas enzymes involved in anaerobic metabolism were designed to operate in the lower portion of the redox spectrum, the arrival of dioxygen created the need for a new redox active metal which could attain higher redox potentials. Copper, now bioavailable, was ideally suited to exploit the oxidizing power of dioxygen. The arrival of copper also coincided with the development of multicellular organisms which had extracellular cross-linked matrices capable of resisting attack by oxygen free radicals. After the initial `iron age' subsequent evolution moved, not towards a `copper age', but rather to an `iron-copper' age. In the second part of the review, this symbiosis of iron and copper is examined in yeast. We then briefly consider iron and copper metabolism in mammals, before looking at iron-copper interactions in mammals, particularly man, and conclude with the reflection that, as in Greek and Roman mythology, a better understanding of the potentially positive interactions between Mars (iron) and Venus (copper) can only be to the advantage of our species.     

Wi-Fi (2.45 GHz)- and Mobile Phone (900 and 1800 MHz)-Induced Risks on Oxidative Stress and Elements in Kidney and Testis of Rats During Pregnancy and the Development of Offspring

The present study was designed to determine the effects of both Wi-Fi (2.45 GHz)- and mobile phone (900 and 1800 MHz)-induced electromagnetic radiation (EMR) on oxidative stress and trace element levels in the kidney and testis of growing rats from pregnancy to 6 weeks of age. Thirty-two rats and their 96 newborn offspring were equally divided into four different groups, namely, control, 2.45 GHz, 900 MHz, and 1800 MHz groups. The 2.45 GHz, 900 MHz, and 1,800 MHz groups were exposed to EMR for 60 min/day during pregnancy and growth. During the fourth, fifth, and sixth weeks of the experiment, kidney and testis samples were taken from decapitated rats. Results from the fourth week showed that the level of lipid peroxidation in the kidney and testis and the copper, zinc, reduced glutathione (GSH), glutathione peroxidase (GSH-Px), and total antioxidant status (TAS) values in the kidney decreased in the EMR groups, while iron concentrations in the kidney as well as vitamin A and vitamin E concentrations in the testis increased in the EMR groups. Results for fifth-week samples showed that iron, vitamin A, and β-carotene concentrations in the kidney increased in the EMR groups, while the GSH and TAS levels decreased. The sixth week results showed that iron concentrations in the kidney and the extent of lipid peroxidation in the kidney and testis increased in the EMR groups, while copper, TAS, and GSH concentrations decreased. There were no statistically significant differences in kidney chromium, magnesium, and manganese concentrations among the four groups. In conclusion, Wi-Fi- and mobile phone-induced EMR caused oxidative damage by increasing the extent of lipid peroxidation and the iron level, while decreasing total antioxidant status, copper, and GSH values. Wi-Fi- and mobile phone-induced EMR may cause precocious puberty and oxidative kidney and testis injury in growing rats.     

Parallels and contrasts between iron and copper metabolism

This paper reviews the Second International Workshop on Iron and Copper Homeostasis, held in Pucón, Chile 10–13 November, 2001. We cover the presentations and papers published (this issue) with the intent to point out parallels, contrasts and cutting edge areas rather than to say something about every paper. Iron and copper metabolism have been intertwined for nearly 150 years and the interrelationship is growing with advances in understanding the role of ceruloplasmin as one example and the probable role of hephaestin as another. The transporter DMT1 (divalent metal transporter 1) clearly plays a major part in iron uptake and trafficking. Emerging evidence suggests that it plays a lesser role in manganese, cadmium and copper transport; but it is still being evaluated there. Yet another interaction may come from the IRE/IRP (Iron Responsive Element/Iron Regulatory Protein) story where a paradigmatic role in iron homeostasis is well established, but interaction with copper is only now emerging. Parallels include the nutrient status of both metals based on their utility for redox reactions as well as their toxicity primarily via reactive oxygen species. The workshop also revealed that alternate splicing of pre-mRNAs for iron and copper related proteins and tissue specific responses are additional similarities. Regulation of gene expression and excretion offered contrasts between the two metals. The workshop also considered a series of continuing and emerging issues.     

Adequacy of Maternal Iron Status Protects against Behavioral,Neuroanatomical, and Growth Deficits in Fetal Alcohol Spectrum Disorders

Fetal alcohol spectrum disorders (FASD) are the leading non-genetic cause of neurodevelopmental disability in children. Although alcohol is clearly teratogenic, environmental factors such as gravidity and socioeconomic status significantly modify individual FASD risk despite equivalent alcohol intake. An explanation for this variability could inform FASD prevention. Here we show that the most common nutritional deficiency of pregnancy, iron deficiency without anemia (ID), is a potent and synergistic modifier of FASD risk. Using an established rat model of third trimester-equivalent binge drinking, we show that ID significantly interacts with alcohol to impair postnatal somatic growth, associative learning, and white matter formation, as compared with either insult separately. For the associative learning and myelination deficits, the ID-alcohol interaction was synergistic and the deficits persisted even after the offsprings’ iron status had normalized. Importantly, the observed deficits in the ID-alcohol animals comprise key diagnostic criteria of FASD. Other neurobehaviors were normal, showing the ID-alcohol interaction was selective and did not reflect a generalized malnutrition. Importantly ID worsened FASD outcome even though the mothers lacked overt anemia; thus diagnostics that emphasize hematological markers will not identify pregnancies at-risk. This is the first direct demonstration that, as suggested by clinical studies, maternal iron status has a unique influence upon FASD outcome. While alcohol is unquestionably teratogenic, this ID-alcohol interaction likely represents a significant portion of FASD diagnoses because ID is more common in alcohol-abusing pregnancies than generally appreciated. Iron status may also underlie the associations between FASD and parity or socioeconomic status. We propose that increased attention to normalizing maternal iron status will substantially improve FASD outcome, even if maternal alcohol abuse continues. These findings offer novel insights into how alcohol damages the developing brain.     

Haemolysis and Perturbations in the Systemic Iron Metabolism of Suckling,Copper-Deficient Mosaic Mutant Mice – An Animal Model of Menkes Disease

The biological interaction between copper and iron is best exemplified by the decreased activity of multicopper ferroxidases under conditions of copper deficiency that limits the availability of iron for erythropoiesis. However, little is known about how copper deficiency affects iron homeostasis through alteration of the activity of other copper-containing proteins, not directly connected with iron metabolism, such as superoxide dismutase 1 (SOD1). This antioxidant enzyme scavenges the superoxide anion, a reactive oxygen species contributing to the toxicity of iron via the Fenton reaction. Here, we analyzed changes in the systemic iron metabolism using an animal model of Menkes disease: copper-deficient mosaic mutant mice with dysfunction of the ATP7A copper transporter. We found that the erythrocytes of these mutants are copper-deficient, display decreased SOD1 activity/expression and have cell membrane abnormalities. In consequence, the mosaic mice show evidence of haemolysis accompanied by haptoglobin-dependent elimination of haemoglobin (Hb) from the circulation, as well as the induction of haem oxygenase 1 (HO1) in the liver and kidney. Moreover, the hepcidin-ferroportin regulatory axis is strongly affected in mosaic mice. These findings indicate that haemolysis is an additional pathogenic factor in a mouse model of Menkes diseases and provides evidence of a new indirect connection between copper deficiency and iron metabolism.