Current Medicinal Chemistry - Volume 21, Issue 33, 2014

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.

This review is focused on the general mechanisms of metal toxicity in humans. The possible and mainly confirmed mechanisms of their action are discussed. The metals are divided into four groups due to their toxic effects. First group comprises of metal ions acting as Fenton reaction catalyst mainly iron and copper. These types of metal ions participate in generation of the reactive oxygen species. Metals such as nickel, cadmium and chromium are considered as carcinogenic agents. Aluminum, lead and tin are involved in neurotoxicity. The representative of the last group is mercury, which may be considered as a generally toxic metal. Fenton reaction is a naturally occurring process producing most active oxygen species, hydroxyl radical: Fe2+ + He2O2 ↔ Fe3+ + OH- + OH• It is able to oxidize most of the biomolecules including DNA, proteins, lipids etc. The effect of toxicity depends on the damage of molecules i.e. production site of the hydroxyl radical. Chromium toxicity depends critically on its oxidation state. The most hazardous seems to be Cr6+ (chromates) which are one of the strongest inorganic carcinogenic agents. Cr6+ species act also as oxidative agents damaging among other nucleic acids. Redox inactive Al3+, Cd2+ or Hg2+ may interfere with biology of other metal ions e.g. by occupying metal binding sites in biomolecules. All these aspects will be discussed in the review.

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. Disturbances of iron homeostasis and an increase in its level may lead to overload and neurodegenerative diseases. Phlebotomy was for a long time the only way of removing excess iron. But since there are many possible disadvantages of this method, chelation therapy seems to be a logical approach to remove toxic levels of iron. In clinical use, there are three drugs: desferrioxamine, deferiprone and deferasirox. FBS0701, a novel oral iron chelator, is under clinical trials with very promising results. Developing novel iron-binding chelators is an urgent matter, not only for systemic iron overload, but also for neurodegenerative disorders, such as Parkinson’s disease. Deferiprone is also used in clinical trials in Parkinson’s disease. In neurodegenerative disorders the main goal is not only to remove iron from brain tissues, but also its redistribution in system. Few chelators are tested for their potential use in neurodegeneration, such as nonhalogeneted derivatives of clioquinol. Such compounds gave promising results in animal models of neurodegenerative diseases. Drugs of possible use in neurodegeneration must meet certain criteria. Their development includes the improvement in blood brain barrier permeability, low toxicity and the ability to prevent lipid peroxidation. One of the compounds satisfying these requirements is VK28. In rat models it was able to protect neurons in very low doses without significantly changing the iron level in liver or serum. Also iron chelators able to regulate activity of monoamine oxidase were tested. Polyphenols and flavonoids are able to prevent lipid peroxidation and demonstrate neuroprotective activity. While cancer does not involve true iron overload, neoplastic cells have a higher iron requirement and are especially prone to its depletion. It was shown, that desferrioxamine and deferasirox are antiproliferative agents active in several types of cancer. Very potent compounds with possible use as anticancer drugs are thiosemicarbazones. They are able to inhibit ribonucleotide reductase, an enzyme involved in DNA synthesis. Because the relationship between the development of overload / neurodegenerative disorders, or cancer, and iron are very complex, comprehension of the mechanisms involved in the regulation of iron homeostasis is a crucial factor in the development of new pharmacological strategies based on iron chelation. In view of various factors closely involved in 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, and in brain and cancer cells, iron dysregulation in neurodegenerative disease and possible chelation strategies in the treatment of metal systemic overload, neurodegeneration and cancer.

Iron and copper ions play important roles in many physiological functions of our body, even though the exact mechanisms regulating their absorption, distribution and excretion are not fully understood. Metal-related human pathology may be observed in two different clinical settings: deficiency or overload. The overload in liver cells of both trace elements leads to multiple cellular lesions. Here we report the main pathological changes observed at 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. Haemosiderin granules are grouped inside voluminous lysosomes, also called siderosomes. Other ultrastructural changes are fat droplets, proliferation of the smooth endoplasmic reticulum and fibrosis. Apoptosis of hepatocytes and infiltration of sinusoids by polymorphonucleates is also detected in beta-thalassemia. Ultrastructural changes in liver biopsies from Wilson’s disease patients are characterized by severe mitochondrial changes, associated with an increased number of perossisomes, cytoplasmic lipid droplets and the presence of lipolysosomes, characteristic cytoplasmic bodies formed by lipid vacuoles surrounded by electron-dense lysosomes. 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. Our data show that iron and copper, even though are both transition metals, are responsible of different pathological changes at ultrastructural level. In particular, copper overload is associated with mitochondrial damage, whereas iron overload only rarely may cause severe mitochondrial changes. These differences underlay 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 pathology at subcellular level.

Nutritional iron deficiency represents a relevant health problem mainly in developing countries. Children and pregnant women represent the main target of this disease, and the low amount of bio-available iron mostly depends on plant-based diets. Iron deficiency may have serious consequences, with severe impairment of the immune function leading to infectious diseases. The brain development in embryos and fetuses during gestation can be greatly affected by iron deficiency of the mother with heavy outcomes on the cognition status of children. A better understanding of molecular pathways involved in iron absorption and metabolism are the basis for new strategies for developing a therapy for iron deficiency. Different therapeutic strategies are summarized, and iron fortification appears the best tool.

Copper is present in different concentrations and chemical forms throughout the earth crust, surface and deep water and even, in trace amounts, in the atmosphere itself. Copper is one of the first metals used by humans, the first artifacts dating back 10,000 years ago. Currently, the world production of refined copper exceeds 16,000 tons / year. Copper is a micro-element essential to life, principally for its red-ox properties that make it a necessary cofactor for many enzymes, like cytochrome-c oxidase and superoxide dismutase. In some animal species (e.g. octopus, snails, spiders, oysters) copper-hemocyanins also act as carriers of oxygen instead of hemoglobin. However, these red-ox properties also make the pair Cu+/Cu2+ a formidable catalyst for the formation of reactive oxygen species, when copper is present in excess in the body or in tissues. The treatment of choice in cases of copper overloading or intoxication is the chelation therapy. Different molecules are already in clinical use as chelators or under study or clinical trial. It is worth noting that chelation therapy has also been suggested to treat some neurodegenerative diseases or cardiovascular disorders. In this review, after a brief description of the homeostasis and some cases of dyshomeostasis of copper, the main (used or potential) 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.

Both mercury(II) and monomethyl mercury(II) poisonings are of great concern for several reasons. As it happens for other metals, chelation therapy is the most indicated treatment for poisoned patients. 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 within and between various tissues, and (possibly) clearance. All these aspects, however, are strictly dependent on the chemical speciation (i.e., the distribution of the chemical species of a component in a given system) of both the metal and the chelating agent in the systems where they are present. In this light, this review analyzes the state of the art of research performed in this field for mercury(II) and methylmercury(II). After a brief summary of their main sources, the physiological patterns for the treatment of mercury poisoning have also been considered. The binding ability of various chelating agents toward mercury has been then analyzed by modeling the behavior of the main classes of ligands present in biological fluids and/or frequently used in chelation therapy. Their sequestering ability has been successively evaluated by means of a semiempirical parameter already proposed for its objective quantification, and the main characteristics of an efficient chelating agent have been evaluated on this basis.

Nowadays more than thousands of different nanoparticles are known, though no well-defined guidelines to evaluate their potential toxicity and to control their exposure are fully provided. The way of entry of nanoparticles together with their specificities such as chemistry, chemical composition, size, shape or morphology, surface charge and area can influence their biological activities and effects. A specific property may give rise to either a safe particle or to a dangerous one. 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, thus damaging their normal functions in different ways. This review provides 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.

In recent years, evidence is growing on the role played by gestational factors in shaping brain development and on the influence of intrauterine experiences on later development of neurodegenerative diseases including Parkinson’s (PD) and Alzheimer’s disease (AD). 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. Here, the multiple epigenetic factors acting during gestation - including maternal diet, malnutrition, stress, hypertension, maternal diabetes, fetal hypoxia, prematurity, low birth weight, prenatal infection, intrauterine growth restriction, drugs administered to the mother or to the baby – are reported, and their ability to modulate brain development, resulting in interindividual variability in the total neuronal and glial burden at birth is discussed. Data from recent literature suggest that prevention of neurodegeneration should be identified as the one method to halt the diffusion of neurodegenerative diseases. The “two hits” hypothesis, first introduced for PD and successfully applied to AD and other neurodegenerative human pathologies, should focus our attention on a peculiar period of our life: the intrauterine and perinatal periods. The first hit to our nervous system occurs early in life, determining a PD or AD imprinting to our brain that will condition our resistance or, alternatively, our susceptibility to develop a neurodegenerative disease later in life. In conclusion, how early life events contribute to late-life development of adult neurodegenerative diseases, including PD and AD, is emerging as a new fascinating research focus. This assumption implies that research on 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.