Metales de transición y enfermedad de Alzheimer / Transition metals and Alzheimer´s disease

El hipocampo y la corteza del cerebro de pacientes con enfermedad de Alzheimer (EA), presentan: a) una extensa lesión neuronal; b) un incremento de los productos de daño oxidativo, y c) una acumulación de agregados/oligómeros proteicos, que en conjunto podrían ser responsables de la pérdida progresiva de las capacidades cognitivas observadas en la EA. El principal componente de los agregados/oligómeros proteicos, llamados placas seniles (PS), es el péptido β-amiloide (βA), generado por el corte proteolítico de la proteína precursora del amiloide (PPA). Las evidencias genéticas, bioquímicas y de biología celular obtenidas hasta el momento sugieren que los oligómeros del péptido βA serían los responsables del daño neuronal observado en la EA. Además, se ha propuesto que moléculas accesorias modularían la toxicidad del péptido βA. En este contexto, se ha demostrado que algunos metales de transición como el cobre, el hierro y el cinc, que se acumulan en las placas seniles, se asocian al péptido βA, induciendo su agregación y la producción de especies reactivas de oxígeno. Por lo tanto, la interacción entre estos metales de transición y el péptido βA podría explicar en parte la lesión neuronal y la presencia de daño oxidativo detectado en el cerebro de pacientes que presentan EA

The hippocampus and cortex of the brains of patients with Alzheimer´s disease (AD) show 1) extensive neuronal death; 2) an increase in oxidative damage products; and 3) an accumulation of proteinaceous oligomers/aggregates, which all together may be responsible for the progressive loss of cognitive capacities observed in AD. The principal component of these proteinaceous oligomers/aggregates, called senile plaques (SP), is the amyloid-β peptide (Aβ), which is generated by proteolytic processing of the amyloid precursor protein. The genetic, cellular and biochemical evidence obtained so far suggests that the oligomeric species of the Aβ peptide may be responsible for the neuronal damage in AD. Moreover, it has been proposed that some accessory molecules could modulate Aβ peptide toxicity. In this context, it has been shown that transition metals such as copper, iron and zinc, which accumulate in SP, can interact with the Aβ peptide, promoting amyloid aggregation and the formation of reactive oxygen species. Therefore, the interaction between transition metals and the Aβ peptide may partially explain the neuronal and oxidative damage detected in the brains of patients with AD

Micronutrient requirements in older women.

The nutritional requirements of older women is an area of great interest because the extended life expectancy leads to an increase in women living into their 80s, 90s, and longer. The recommended dietary allowances (RDAs) and dietary reference intakes (DRIs) are not specific for women living to advanced ages, and little research has been conducted specifically on the micronutrient needs of elderly women. Older adults are at greater risk for nutritional deficiencies than are younger adults due to physiologic changes associated with aging, acute and chronic illnesses, prescription and over-the-counter medications, financial and social status, and functional decline. Among the significant age-associated changes in nutrient requirements, the need for energy decreases and the requirements for protein increase with age. Among the micronutrients, the significant ones that may be associated with deficiencies in elderly women include vitamin B-12, vitamin A, vitamin C, vitamin D, calcium, iron, zinc, and other trace minerals. In old and very old women, these are micronutrients of interest but there is a great need for research to determine appropriate recommendations. The importance of these selected nutrients and the reasons for the likelihood of deficiency are discussed briefly. However, there is little specific information regarding micronutrient requirements for elderly women. One reason for this is the difficulty in conducting reliable and valid studies due to the heterogeneity of older adults and their unique rate of aging associated with their health status, limited income, disability, and living situation.

Mutational analysis of the adcCBA genes in Streptococcus gordonii biofilm formation.

Streptococcus gordonii, a primary colonizer, is part of the pioneer biofilm consortium that initiates dental plaque development on tooth surfaces. An insertion of Tn917-lac transposon into the adcR gene produced a biofilm-defective phenotype. S. gordonii adcR is a regulatory gene and is part of an operon (adc) that includes three other genes, adcCBA. AdcC contains a putative consensus-binding site for adenosine triphosphate, AdcB is a putative hydrophobic membrane protein, and AdcA is a putative lipoprotein permease. Mutants were constructed by insertional inactivation in each of the three adcCBA genes and their effects on biofilm formation examined. The adcC::spec(R) and adcB::spec(R) mutations displayed a biofilm-defective phenotype, whereas the adcA::spec(R) mutant was biofilm-positive in a static polystyrene microtiter plate biofilm assay. All three mutants formed poor biofilms in a flow-cell system and were competence-defective, suggesting the adc operon plays an important role in S. gordonii biofilm formation and competence.

[Function and toxicity of trace metals in the central nervous system].

Trace metals such as zinc, manganese and iron usually serve the function of metalloproteins in neurons and glial cells, while a portion of trace metals exists in the presynaptic vesicles, and may be released with neurotransmitters. Zinc released into the synaptic cleft may serve as an inhibitory neuromodulator of glutamate release in the hippocampus, while neuromodulation by other trace metals such as manganese and copper might mean both functional and toxic aspects in the synapse. Dietary zinc deficiency affects zinc homeostasis in the brain, followed by an enhanced susceptibility to excitotoxicity of glutamate in the hippocampus. The homeostasis of trace metals in the brain is important for brain function and also prevention of brain diseases.

Wasted sheep and premature infants: the role of trace metals in hematopoiesis.

Trace element deficiencies and toxicities are not commonly encountered in clinical practice, particularly in regions where there is access to adequate nutrition and occupational exposures are regulated. However, specific clinical scenarios associated with trace metal deficiency and toxicity states do exist. Often, clues to the presence of these states may lie in the development of blood count abnormalities. The consultant haematologist is frequently involved in the care of these patients, and it is with this audience that this review is intended. This review will focus on the trace metals required for normal hematopoiesis including their function, metabolism, deficiency and toxicity states, and the clinical situations underlying these. As much of the information regarding trace metal disease states has arisen from veterinary medicine and from human case reports, these will be summarized and highlighted in this review.

[Essential trace metals and brain function].

Trace metals such as zinc, manganese, and iron are necessary for the growth and function of the brain. The transport of trace metals into the brain is strictly regulated by the brain barrier system, i.e., the blood-brain and blood-cerebrospinal fluid barriers. Trace metals usually serve the function of metalloproteins in neurons and glial cells, while a portion of trace metals exists in the presynaptic vesicles and may be released with neurotransmitters into the synaptic cleft. Zinc and manganese influence the concentration of neurotransmitters in the synaptic cleft, probably via the action against neurotransmitter receptors and transporters and ion channels. Zinc may be an inhibitory neuromodulator of glutamate release in the hippocampus, while neuromodulation by manganese might mean functional and toxic aspects in the synapse. Dietary zinc deficiency affects zinc homeostasis in the brain, followed by an enhanced susceptibility to the excitotoxicity of glutamate in the hippocampus. Transferrin may be involved in the physiological transport of iron and manganese into the brain and their utilization there. It is reported that the brain transferrin concentration is decreased in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease and that brain iron metabolism is also altered. The homeostasis of trace metals in the brain is important for brain function and also for the prevention of brain diseases.

Identification of trace element-containing proteins in genomic databases.

Development of bioinformatics tools provided researchers with the ability to identify full sets of trace element-containing proteins in organisms for which complete genomic sequences are available. Recently, independent bioinformatics methods were used to identify all, or almost all, genes encoding selenocysteine-containing proteins in human, mouse, and Drosophila genomes, characterizing entire selenoproteomes in these organisms. It also should be possible to search for entire sets of other trace element-associated proteins, such as metal-containing proteins, although methods for their identification are still in development.

Nutritional modulation of neonatal outcomes.

In humans, growth and development continues until early adulthood when bone, muscle, and nervous tissue reaches final stages of maturity. Adequate levels of nutritional intake and utilization are critical to optimize ongoing growth. The goal of nutritional therapy for premature or ill neonates has been to provide sufficient nutrients to allow growth to continue at rates seen in utero. Functional immaturity of the gut in the premature infant makes absorption and utilization of nutritional substrates difficult. Premature infants are at risk for developing necrotizing enterocolitis, a potentially lethal bowel disorder. The etiology of necrotizing enterocolitis is not well understood, and a number of theories of causation have been proposed. Breast milk, the optimal source of nutrition for the neonate, is believed to confer some protection against necrotizing enterocolitis. A number of breast milk components have been credited with antiinflammatory properties. Breast milk is recognized for its benefits, yet for preterm infants breast milk alone does not promote adequate growth. A number of breast milk supplements have been investigated to facilitate growth and development and to prevent necrotizing enterocolitis. This article addresses development of the fetal gastrointestinal system, focusing on the biological mediators for normal function and the role of human breast milk and its additives in optimizing neonatal growth. The possible etiologies of necrotizing enterocolitis are discussed in terms of the relationship between this disease and enteral feeding practices.

Trace elements in human physiology and pathology. Copper.

Copper is a trace element, important for the function of many cellular enzymes. Copper ions can adopt distinct redox states oxidized Cu(II) or reduced (I), allowing the metal to play a pivotal role in cell physiology as a catalytic cofactor in the redox chemistry of enzymes, mitochondrial respiration, iron absorption, free radical scavenging and elastin cross-linking. If present in excess, free copper ions can cause damage to cellular components and a delicate balance between the uptake and efflux of copper ions determines the amount of cellular copper. In biological systems, copper homeostasis has been characterized at the molecular level. It is coordinated by several proteins such as glutathione, metallothionein, Cu-transporting P-type ATPases, Menkes and Wilson proteins and by cytoplasmic transport proteins called copper chaperones to ensure that it is delivered to specific subcellular compartments and thereby to copper-requiring proteins.

Trace elements, innate immune response and parasites.

Micronutrient deficiencies and infectious disease often coexist and show complex interactions leading to mutually reinforced detrimental clinical effects. Such a combination is predominantly observed in underprivileged people of developing countries, particularly in rural regions. Several micronutrients such as trace elements (zinc, iron, selenium) modulate immune function and influence the susceptibility of the host to infection. Nevertheless, the effect of individual micronutrients on components of innate immunity is difficult to design and interpret. Micronutrient deficiency, in general, has a widespread effect on nearly all components of the innate immune response. Chagas' disease is a pertinent model to study interaction of nutrition, immunity and infection, as it implies many components of innate immunity. An important question is whether alterations on micronutrient intake modify the course of infection. Some interactions of trace elements with innate immunity and acute inflammatory response are reviewed in this article with a special focus on selenium deficiency and Trypanosoma cruzi infection.

Zinc-altered immune function.

Zinc is known to be essential for all highly proliferating cells in the human body, especially the immune system. A variety of in vivo and in vitro effects of zinc on immune cells mainly depend on the zinc concentration. All kinds of immune cells show decreased function after zinc depletion. In monocytes, all functions are impaired, whereas in natural killer cells, cytotoxicity is decreased, and in neutrophil granulocytes, phagocytosis is reduced. The normal functions of T cells are impaired, but autoreactivity and alloreactivity are increased. B cells undergo apoptosis. Impaired immune functions due to zinc deficiency are shown to be reversed by an adequate zinc supplementation, which must be adapted to the actual requirements of the patient. High dosages of zinc evoke negative effects on immune cells and show alterations that are similar to those observed with zinc deficiency. Furthermore, when peripheral blood mononuclear cells are incubated with zinc in vitro, the release of cytokines such as interleukins (IL)-1 and -6, tumor necrosis factor-alpha, soluble IL-2R and interferon-gamma is induced. In a concentration of 100 micro mol/L, zinc suppresses natural killer cell killing and T-cell functions whereas monocytes are activated directly, and in a concentration of 500 micro mol/L, zinc evokes a direct chemotactic activation of neutrophil granulocytes. All of these effects are discussed in this short overview.

Cellular zinc and redox states converge in the metallothionein/thionein pair.

The paramount importance of zinc for a wide range of biological functions is based on its occurrence in thousands of known zinc proteins. To regulate the availability of zinc dynamically, eukaryotes have compartmentalized zinc and the metallothionein/thionein pair, which controls the pico- to nanomolar concentrations of metabolically active cellular zinc. Interactions of zinc with sulfur ligands of cysteines turn out to be critical both for tight binding and creation of a redox-active coordination environment from which the redox-inert zinc can be distributed. Biological oxidants such as disulfides and S-nitrosothiols oxidize the zinc/thiolate clusters in metallothionein with concomitant zinc release. In addition, selenium compounds that have the capacity to form selenol(ate)s catalytically couple with the glutathione/glutathione disulfide and metallothionein/thionein redox pairs to either release or bind zinc. In this pathway, selenium expresses its antioxidant effects through redox catalysis in zinc metabolism. Selenium affects the redox state of thionein, an endogenous chelating agent. With its 20 cysteines, thionein contributes significantly to the zinc- and thiol-redox-buffering capacity of the cell. Thus, hitherto unknown interactions between the essential micronutrients zinc and selenium on the one hand and zinc and redox metabolism on the other are key features of the cellular homeostatic zinc system.

Trace element biology: the knowledge base and its application for the nutrition of individuals and populations.

Impressive strides are being made in the understanding of trace element metabolism and function. This is underscored by the many contributions in these proceedings. However, not so impressive are: i) the precise recognition of mild trace element deficiencies and how to establish their functional consequences, possibly confounded by concurrent trace element inadequacies, are difficult to assess, ii) approaches to the quantitative determination of requirements for trace elements remain unsatisfactory and archaic, in so many ways, iii) our understanding of the extent of the biological basis for the variation in requirements among apparently similar individuals is poor, and iv) much needs to be learned about the quantitative extent to which genetic, epigenetic and dietary factors interact to determine the nutritional phenotype. Some ideas are presented as to how we might embrace, in the context of a reconstructive approach, the exciting new knowledge and related techniques emerging during the postgenome era and develop new paradigms for assessing trace element needs and status, and for establishing effective nutrient intake under different conditions of complex genotype-environment interactions. Metabolites are functional cellular entities and I also urge a vigorous application of metabolomics and of metabolic profiling that is closely linked with genomics, proteomics, trace element kinetics and system analysis, as components of the new integrative paradigm. We need to understand the system and its strategy, not only the molecular details of its component parts and its individual controls. An interdisciplinary research and teaching enterprise will be necessary to best achieve this aim. All of this is related to our common goal to promote, through expanded biological knowledge and its effective application, the enhanced role of trace elements for human well-being.

[Transitional elements and free radicals]. / Prechodné prvky a volné radikály.

Iron and copper are essential trace elements, which in certain conditions, namely in the ionised form or in low-molecular complexes, can participate in single electron reactions and catalyse formation of free radicals, including the dangerous hydroxyl radical. Similar behavior have also some other transitive metals. Our overview is aimed on the role of transitive elements in the formation of free radicals and on the mechanisms that organisms have to prevent it. The highest attendance is given to the metabolism of iron and cooper. Consistent protection against free transitive metals (by binding with proteins, by oxidation or sequestration in a special compartment) enables organism to use their beneficial and required features without impairment of cell. Knowledge of these mechanisms provides the means to predict and effectively prevent the brake down of such defend systems in situations of the intravascular hemolysis, hemodialysis, administration of iron, impairments of the iron and copper metabolism, intoxication by oxidising substances etc.

The role of trace minerals in the pathogenesis of postmenopausal osteoporosis and a new effect of calcitonin.

The physiologic role of calcitonin in mineral and bone homeostasis is not very well understood. Very few longitudinal studies have reported the effects of calcitonin therapy on trace minerals in postmenopausal osteoporosis despite the documented involvement of trace minerals in normal skeletal metabolism. Several trace minerals, particularly magnesium (Mg) and zinc (Zn), essential for organic bone matrix synthesis have been known for at least three decades. The present study was designed to determine whether the mineral profile was different between 70 osteoporotic and 30 nonosteoporotic postmenopausal women and to evaluate the efficacy of calcitonin therapy for 6 months on these trace minerals in postmenopausal osteoporotic women. In our study, the serum values of Mg, copper (Cu), and Zn (P < 0.05) were significantly lower in the patient group than those in the control group. After 3 months of treatment, serum Cu, Zn, and Mg levels did not differ between the patients and controls, and this situation has continued after the end of 6 months of therapy. Serum Cu, Zn, and Mg levels increased consistently during the 6-month treatment period. The higher levels of serum Mg in the 3rd and 6th months of therapy were found to be statistically significant compared to those before treatment (P < 0.05). Serum Cu and Zn levels were found to be significantly higher at all measurements during the treatment period as well as at the end of therapy (P < 0.05). These results suggest that (1) calcitonin therapy regulates Mg, Cu, and Zn levels in postmenopausal osteoporosis; (2) when serum calcium and phosphorus were normal in postmenopausal osteoporosis, serum Mg, Cu, and Zn were more useful for evaluation; and (3) further studies are essential to evaluate the role of dietary composition on the manifestations of osteoporosis.

Trace metals and the elderly.

The elderly are at nutritional risk as a result of multiple physiological, social, psychological, and economic factors. Elderly persons have a higher incidence of chronic diseases and associated intake of medications that may affect nutrient utilization. Social and economic conditions can adversely affect dietary choices and eating patterns. Physiological functions naturally decline with age, which may influence absorption and metabolism. Loneliness and reluctance to eat may complicate an already marginal situation. This article reviews specific trace metals in relation to the elderly. Our objectives are to provide Dietary Reference Intakes for older adults, to provide information on presenting features and functional consequences of trace metal deficiency, and to discuss potential effects and/or benefits of trace metal supplementation in the elderly.