oa Editorial (Thematic Issue: The State of Art in the Treatment of Metal Toxicity)

In recent years, it has become more clear that metal intoxication represents a worldwide major health problem, both in developed and in emerging countries. Metal toxicity in humans may originate in different clinical settings, and may be related to multiple etiological factors including environmental, occupational, iatrogenic, and genetic ones. In this intriguing scientific and clinical contest, the need to bridge the gap between chemical research and patient care is felt today more than ever. In fact, the large research efforts invested in the study of metal intoxication from occupational exposure, intoxication by radio-nuclides and iron overload in beta-thalassemia have unfortunately resulted inadequate to halt the diffusion of the produced diseases. As a consequence, metal-related pathologies should be included in the group of orphan human diseases. A joint effort of chemical, biochemical, pathological and clinical researchers might be adequate to solve metal related clinical problems in healthcare, supported by large investments by central governments and health international organizations. Medicine will be in a position to respond in a proper way to the problems related to metal intoxication only by being aware of chemical complexity and biological variability acting in the clinical manifestations of metal-induced human pathology. In this special issue of CMC, a number of top researchers assured their contribution to give an updated and clear picture of the state of art on these topics, underlying the actual prospective for future research projects in this fascinating field of human medicine. In the following the principal subjects developed in the eight reviews will be outlined, pointing out the main features. Kozlowski and co-workers [1] (the corresponding author will be always mentioned, not necessarily the first author as in usual citations) focus on the general mechanisms of metal toxicity in humans, and discuss the possible and mainly confirmed mechanisms of action. The metals are divided into four groups due to their toxic effects. The first group comprises metal ions acting as Fenton reaction catalysts, mainly iron and copper, which participate in the generation of reactive oxygen species. Metals such as nickel, cadmium and chromium are considered as carcinogenic agents. Aluminium, lead and tin are involved in neurotoxicity. The representative of the last group is mercury, which may be considered as a generally toxic metal. Gumienna- Kontecka and co-workers [2] discuss on iron chelating strategies in systemic iron overload, neurodegeneration and cancer. Because the relationship between the development of overload/neurodegenerative disorders, or cancer, and iron is very complex, understanding the mechanisms involved in the regulation of iron homeostasis is a crucial step in the development of new pharmacological interventions based on iron chelation. In view of the various factors closely involved in the pathogenesis of such diseases, designing multifunctional metal-chelators seems to be the most promising approach, but it requires a lot of effort. In this perspective, the review summarizes systemic iron homeostasis, in brain and cancer cells, iron dysregulation in neurodegenerative disease and possible chelation strategies in the treatment of metal systemic overload, neurodegeneration and cancer. The review by Fanni and co-workers [3] reports on the main pathological changes observed with transmission electron microscopy in the liver of subjects affected by beta-thalassemia and by Wilson’s disease. The hepatic iron overload in beta-thalassemia patients is associated with haemosiderin storage both in Kupffer cells and in the cytoplasm of hepatocytes. Ultrastructural changes in liver biopsies from Wilson’s disease patients are characterized by severe mitochondrial changes. In patients affected by Wilson’s disease, nuclei are frequently involved, with disorganization of the nucleoplasm and with glycogen inclusions. On the contrary, no significant changes are detected in Kupffer cells. The presented data show that iron and copper are responsible for different pathological changes at ultrastructural level. These differences underlie the need for further studies in which biochemical analyses should be associated with ultrastructural data, in order to better understand the molecular ways associated with iron and copper related pathologies at subcellular level. Iron is a trace element required for normal performance of cellular processes. Because both the deficiency and excess of this metal are dangerous, its absorption, distribution and accumulation must be tightly regulated. The paper presented by Lachowicz and co-workers [4] deals with oral iron supplementation in nutritional iron deficiency. Nutritional iron deficiency represents a relevant health problem mainly in developing countries. A better understanding of the molecular pathways involved in iron absorption and metabolism should be considered as the basis for new strategies for developing a molecular therapy for iron deficiency. Different therapeutic strategies are here summarized, and iron fortification appears as the best tool. In the review by Remelli et al. [5], after a brief description of the homeostasis and of some cases of dyshomeostasis of copper, the main chelators are described; their properties in solution, even in relation to the presence of metal or ligand competitors, under physiological conditions, are discussed. The legislation of the most important Western countries, regarding both the use of chelating agents and the limits of copper in foods, drugs and cosmetics, is also outlined. Sammartano and co-workers [6] discuss the chelating agents for the sequestration of both mercury(II) and monomethyl mercury(II). The efficacy of the therapy and the reduction of side effects can be sensibly enhanced by an accurate knowledge of all the physiological mechanisms involved in metal uptake, transport and clearance. All these aspects, however, are strictly dependent on the chemical speciation of both the metal and the chelating agent in the system where they are present. The binding ability of various chelators toward mercury has been analyzed by modeling the behavior of the main classes of ligands present in biological fluids or used in chelation therapy. The sequestering ability of these chelators has been evaluated by a semiempirical parameter proposed by the authors and the main characteristics of an efficient mercury chelating agent have been evaluated on this basis.The toxicity of nanoparticles is the argument of the review by Zoroddu et al. [7], who provide a summary of what is known on the toxicology related to the specificity of nanoparticles, both as technological tools or ambient pollutants. The aim is to highlight their potential hazard and to provide a balanced update on all the important questions and directions that should be focused in the near future. The guidelines to evaluate their potential toxicity and to control their exposure are fully provided. The small size allows nanoparticles to enter the body by crossing several barriers, to pass into the blood stream and lymphatic system from where they can reach organs and tissues and strictly interact with biological structures, so damaging their normal functions in different ways. The way of entry of nanoparticles together with their specificities such as chemistry, chemical composition, size, shape or morphology, surface charge and area are taken into consideration with the aim of evaluating how these properties can influence their biological activities and effects. The last paper of this issue by Faa and co-workers [8] detaches from the previous ones and proposes an intriguing theory on the development of neurodegenerative diseases. The nine months of intrauterine development and the first three years of postnatal life are appearing to be extremely critical for making connections among neurons and among neuronal and glial cells that will shape a lifetime of experience. The multiple epigenetic factors acting during gestation, and their ability to modulate brain development, resulting in inter individual variability in the total neuronal and glial burden at birth are discussed. In conclusion, how early life events contribute to late-life development of adult neurodegenerative diseases, including Parkinson’s and Alzheimer’s diseases, is emerging as a new fascinating research focus. This assumption implies that research on the prevention of neurodegenerative diseases should center on events taking place early in life, during gestation and in the perinatal periods, thus presenting a new challenge to perinatologists: the prevention of neurodegenerative human diseases.