Iron deficiency

Iron deficiency and anemia affect a substantial portion of the world’s population, provoking severe health problems to the people suffering these conditions, as well as important economic losses to the regions in which this nutritional deficiency is significant. In this work, the principal causes and consequences produced by this deficiency are discussed, as well as the different strategies that can be applied in order to prevent and solve this nutritional problem.     

Tetrahydrobiopterin deficiency increases neuronal vulnerability to hypoxia

Tetrahydrobiopterin (BH4) is an essential co-factor for nitric oxide synthases (NOS). The aim of the present work was to study whether BH4 deficiency affects the vulnerability of neurones in primary culture to hypoxia. Intracellular BH4 levels were depleted by pre-incubating neurones with 5 mm 2,4-diamino-6-hydroxypyrimidine (DAHP) for 18 h, after which cells were exposed for 1 h to normoxic or hypoxic conditions. Our results showed that whereas neurones were resistant to hypoxia-induced cellular damage, BH4 deficiency in neurones led to oxidative stress, mitochondrial depolarization, ATP depletion and necrosis after 1 h of hypoxia. Indeed, hypoxia specifically inhibited mitochondrial complex IV activity in BH4-deficient neurones. All these effects were counteracted when neuronal BH4 levels were restored by incubating cells with exogenous BH4 during the hypoxic period. Moreover, hypoxia-induced damage in BH4-deficient neurones was prevented when Nomega-nitro-l-arginine monomethyl ester (NAME), haemoglobin or superoxide dismutase plus catalase were present during the hypoxic period, suggesting that peroxynitrite might be involved in the process. In fact, BH4 deficiency elicited neuronal NO dysfunction, resulting in an increase in peroxynitrite generation by cells, as shown by the enhancement in tyrosine nitration; this was prevented by supplements of BH4, NAME, haemoglobin or superoxide dismutase plus catalase during hypoxia. Our results suggest that BH4 deficiency converts neuronal NOS into an efficient peroxynitrite synthase, which is responsible for the increase in neuronal vulnerability to hypoxia-induced mitochondrial damage and necrosis.     

PEX11 beta deficiency is lethal and impairs neuronal migration but does not abrogate peroxisome function

Zellweger syndrome is a lethal neurological disorder characterized by severe defects in peroxisomal protein import. The resulting defects in peroxisome metabolism and the accumulation of peroxisomal substrates are thought to cause the other Zellweger syndrome phenotypes, including neuronal migration defects, hypotonia, a developmental delay, and neonatal lethality. These phenotypes are also manifested in mouse models of Zellweger syndrome generated by disruption of the PEX5 or PEX2 gene. Here we show that mice lacking peroxisomal membrane protein PEX11 beta display several pathologic features shared by these mouse models of Zellweger syndrome, including neuronal migration defects, enhanced neuronal apoptosis, a developmental delay, hypotonia, and neonatal lethality. However, PEX11 beta deficiency differs significantly from Zellweger syndrome and Zellweger syndrome mice in that it is not characterized by a detectable defect in peroxisomal protein import and displays only mild defects in peroxisomal fatty acid beta-oxidation and peroxisomal ether lipid biosynthesis. These results demonstrate that the neurological pathologic features of Zellweger syndrome can occur without peroxisomal enzyme mislocalization and challenge current models of Zellweger syndrome pathogenesis.     

Iron deficiency: lessons from anemic mice.

Iron is an essential nutrient, and disorders of iron metabolism are common. Nonetheless, intestinal iron absorption and cellular iron transport are poorly understood. Biochemical approaches to elucidating these processes have yielded little in the past decade. As an alternative approach, we have begun to study spontaneous mouse mutants, that have inherited defects in key steps in iron transport. We have undertaken positional cloning of the gene responsible for microcytic anemia (gene symbol mk). This report describes the important characteristics of these mice, and our progress in studying them.     

Iron deficiency differently affects peroxidase isoforms in sunflower

The response of both specific (ascorbate peroxidase, APX) and unspecific (POD) peroxidases and H(2)O(2) content of sunflower plants (Helianthus annuus L. cv. Hor) grown hydroponically with (C) or without (-Fe) iron in the nutrient solution were analysed to verify whether iron deficiency led to cell oxidative status. In -Fe leaves a significant increase of H(2)O(2) content was detected, a result confirmed by electron microscopy analysis. As regards extracellular peroxidases, while APX activity significantly decreased, no change was observed in either soluble guaiacol or syringaldazine-dependent POD activity following iron starvation. Moreover, guaiacol-dependent POD activity was found to decrease in both ionically and covalently-cell-wall bound fractions, while syringaldazine-POD activity decreased only in the covalently-bound fraction. At the intracellular level both guaiacol-POD and APX activities underwent a significant decrease. The overall reduction of peroxidase activity was confirmed by the electrophoretic separation of POD isoforms and, at the extracellular level, by cytochemical localization of peroxidases by diaminobenzidine staining. The electrophoretic separation, besides quantitative differences, also revealed quantitative changes, particularly evident for ionically and covalently-bound fractions. Therefore, in sunflower plants, iron deficiency seems to affect the different peroxidase isoenzymes to different extents and to induce a secondary oxidative stress, as indicated by the increased levels of H(2)O(2). However, owing to the almost completely lack of catalytic iron capable of triggering the Fenton reaction, iron-deficient sunflower plants are probably still sufficiently protected against oxidative stress.     

Current aspects of thiamine deficiency on heart function

Beriberi is a disease caused by thiamine deficiency (TD), which may lead to heart problems, including heart failure. Despite the fact that thiamine prevalence is reduced in the industrialized world, it remains a health hazard especially due to chronic alcohol consumption. Diagnosing the presence of TD based on both electrocardiogram and echocardiogram exams is particularly challenging because of its non-specific symptoms. TD diagnosis is unique, which then leads to determination of its severity. If thiamine infusion abrogates its symptomology, only then can the case be definitely diagnosed as TD. Another condition eliciting increased likelihood of developing TD in humans is furosemide administration to heart failure patients. Furosemide administration worsens heart failure due to heightened TD. However, literature data provided are contradictory and require clarification. Up until now, the rat has been the preferred TD animal model. However, the results are even more contradictory than those in humans. It seems that if the rat TD models are separated into two distinct groups, according to animal age, the results appear to be more consistent: younger rats are more prone to develop TD signs similar to those found in humans. Their symptoms stem from changes in cardiac myocyte function that are reversed after thiamine supplementation. However, it remains an open question as to why only younger rats are able to develop human-like symptoms and deserve further investigation.     

Glial cells in neuronal network function

Numerous evidence demonstrates that astrocytes, a type of glial cell, are integral functional elements of the synapses, responding to neuronal activity and regulating synaptic transmission and plasticity. Consequently, they are actively involved in the processing, transfer and storage of information by the nervous system, which challenges the accepted paradigm that brain function results exclusively from neuronal network activity, and suggests that nervous system function actually arises from the activity of neuron–glia networks. Most of our knowledge of the properties and physiological consequences of the bidirectional communication between astrocytes and neurons resides at cellular and molecular levels. In contrast, much less is known at higher level of complexity, i.e. networks of cells, and the actual impact of astrocytes in the neuronal network function remains largely unexplored. In the present article, we summarize the current evidence that supports the notion that astrocytes are integral components of nervous system networks and we discuss some functional properties of intercellular signalling in neuron–glia networks.     

Nuclear transport factors in neuronal function

Active nucleocytoplasmic transport of macromolecules requires soluble transport carriers of the importin/karyopherin superfamily. Although the nuclear transport machinery is essential in all eukaryotic cells, neurons must also mobilise importins and associated proteins to overcome unique spatiotemporal challenges. These include switches in importin α subtype expression during neuronal differentiation, localized axonal synthesis of importin β1 to coordinate a retrograde injury signaling complex on axonal dynein, and trafficking of regulatory and signaling molecules from synaptic terminals to cell bodies. Targeting of RNAs encoding critical components of the importins complex and the Ran system to axons allows sophisticated local regulation of the system for mobilization upon need. Finally, a number of importin family members have been associated with mental or neurodegenerative diseases. The extended roles recently discovered for importins in the nervous system might also be relevant in non-neuronal cells, and the localized modes of importin regulation in neurons offer new avenues to interrogate their cytoplasmic functions.