Metals associated neurodegeneration in Parkinson's disease: Insight to physiological, pathological mechanisms and management.

Parkinson's disease (PD) is a deliberately progressive neurological disorder, arises due to degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The loss of dopaminergic nerves and dopamine deficiency leads to motor symptoms characterized by rigidity, tremor, and bradykinesia. Heavy metals and trace elements play various physiological and pathological roles in the nervous system. Excessive exposure to toxic metals like mercury (Hg), lead (Pb), copper (Cu), zinc (Zn), iron (Fe), manganese (Mn), aluminium (Al), arsenic (As), cadmium(cd), and selenium (Se) cross the blood-brain barrier to enter into the brain and leads to dopaminergic neuronal degeneration. Excessive concentrations of heavy metals in the brain promote oxidative stress, mitochondrial dysfunction, and the formation of α-synuclein leads to dopaminergic neuronal damage. There is increasing evidence that heavy metals normally present in the human body in minute concentration also cause accumulation to initiate the free radical formation and affecting the basal ganglia signaling. In this review, we explored how these metals affect brain physiology and their roles in the accumulation of toxic proteins (α-synuclein and Lewy bodies). We have also discussed the metals associated with neurotoxic effects and their prevention as management of PD. Our goal is to increase the awareness of metals as players in the onset and progression of PD.

Protective effect of lycopene against chemical and natural toxins: A review.

People are exposed to a number of environmental, occupational, and therapeutic toxic agents which may be natural or man made. These hazardous substances may manifest as direct side effects on the function of organs or indirectly induced alteration of gene expression, cancer-associated metabolic pathways, and/or alter homeostasis. Lycopene, as a one of the most potent antioxidant, is found in fruits and vegetables. High-intake of lycopene has been shown to be effective in decreasing the risk of both natural toxins including mycotoxins, bacterial toxins, and chemical toxins including heavy metals, pesticides as well as herbicides. Recently, there is growing attention in understanding the mechanisms of the phytochemicals and carotenoids as antioxidative, antiapoptotic, radical scavenging, and chelating agents and their roles in the modulation of inflammatory pathways. This review summarizes available data from several recent studies about lycopene and its role against chemical and natural toxicants. © 2018 BioFactors, 45(1):5-23, 2019.

Sulphur-containing Amino Acids: Protective Role Against Free Radicals and Heavy Metals.

BACKGROUND: Sulphur is an abundant element in biological systems, which plays an important role in processes essential for life as a constituent of proteins, vitamins and other crucial biomolecules. The major source of sulphur for humans is plants being able to use inorganic sulphur in the purpose of sulphur-containing amino acids synthesis. Sulphur-containing amino acids include methionine, cysteine, homocysteine, and taurine. Methionine and cysteine are classified as proteinogenic, canonic amino acids incorporated in protein structure. Sulphur amino acids are involved in the synthesis of intracellular antioxidants such as glutathione and N-acetyl cysteine. Moreover, naturally occurring sulphur-containing ligands are effective and safe detoxifying agents, often used in order to prevent toxic metal ions effects and their accumulation in human body. METHODS: Literature search for peer-reviewed articles was performed using PubMed and Scopus databases, and utilizing appropriate keywords. RESULTS: This review is focused on sulphur-containing amino acids - methionine, cysteine, taurine, and their derivatives - glutathione and N-acetylcysteine, and their defense effects as antioxidant agents against free radicals. Additionally, the protective effects of sulphur-containing ligands against the toxic effects of heavy and transition metal ions, and their reactivation role towards the enzyme inhibition are described. CONCLUSION: Sulphur-containing amino acids represent a powerful part of cell antioxidant system. Thus, they are essential in the maintenance of normal cellular functions and health. In addition to their worthy antioxidant action, sulphur-containing amino acids may offer a chelating site for heavy metals. Accordingly, they may be supplemented during chelating therapy, providing beneficial effects in eliminating toxic metals.

STRUCTURAL CHANGES IN SUBMANDIBULAR SALIVARY GLAND, CAUSED BY HEAVY METAL SALTS, AND THEIR CORRECTION WITH DIALIPON (EXPERIMENTAL STUDY).

Setting of possibilities of structural changes correction in submandibular salivary gland with a Dialipone drug, caused by adverse effect of heavy metals salts on an organisms of different age group rats. Structural changes and their correction were studied on the histological preparations basis painted by hematoxylin-eozin, Van-Gizon, PAS reaction, investigated and photographed by means of the digital image display system "SEO Scan". In comparison to the results of submandibular salivary gland tissue histological research of animals without any correction of microelementosis, animals that took Dialipone are marked with a better glandular epithelium saving, less widespreading of dystrophic and dyscirculatory changes, sclerotization processes in stroma. When comparing of Dialipone restoration possibilities, it was set, that different age group animals show different application efficiency of the corrector. The rats of young and mature age have more complete renewal of structural changes. The rats of advanced age show worse reparative capabilities, less complete and effective renewal of structural changes.

Kinetics of heavy metal inhibition of 1,2-dichloroethane biodegradation in co-contaminated water.

Sites co-contaminated with heavy metals and 1,2-DCA may pose a greater challenge for bioremediation, as the heavy metals could inhibit the activities of microbes involved in biodegradation. Therefore, this study was undertaken to quantitatively assess the effects of heavy metals (arsenic, cadmium, mercury, and lead) on 1,2-DCA biodegradation in co-contaminated water. The minimum inhibitory concentrations (MICs) and concentrations of the heavy metals that caused half-life doubling (HLDs) of 1,2-DCA as well as the degradation rate coefficient (k(1)) and half-life (t(½)) of 1,2-DCA were measured and used to predict the toxicity of the heavy metals in the water microcosms. An increase in heavy metal concentration resulted in a progressive increase in the t(½) and relative t(½) and a decrease in k(1). The MICs and HLDs of the heavy metals were found to vary, depending on the heavy metals type. In addition, the presence of heavy metals was shown to inhibit 1,2-DCA biodegradation in a dose-dependent manner, with the following order of decreasing inhibitory effect: Hg(2+) > As(3+) > Cd(2+) > Pb(2+). Findings from this study have significant implications for the development of bioremediation strategies for effective degradation of 1,2-DCA and other related compounds in wastewater co-contaminated with heavy metals.

Engineering catalyst microenvironments for metal-catalyzed hydrogenation of biologically derived platform chemicals.

It is shown that microenvironments formed around catalytically active sites mitigate catalyst deactivation by biogenic impurities that are present during the production of biorenewable chemicals from biologically derived species. Palladium and ruthenium catalysts are inhibited by the presence of sulfur-containing amino acids; however, these supported metal catalysts are stabilized by overcoating with poly(vinyl alcohol) (PVA), which creates a microenvironment unfavorable for biogenic impurities. Moreover, deactivation of Pd catalysts by carbon deposition from the decomposition of highly reactive species is suppressed by the formation of bimetallic PdAu nanoparticles. Thus, a PVA-overcoated PdAu catalyst was an order of magnitude more stable than a simple Pd catalyst in the hydrogenation of triacetic acid lactone, which is the first step in the production of biobased sorbic acid. A PVA-overcoated Ru catalyst showed a similar improvement in stability during lactic acid hydrogenation to propylene glycol in the presence of methionine.

Electroanalytical and isothermal calorimetric study of As(III) complexation by the metal poisoning remediators, 2,3-dimercapto-1-propanesulfonate and meso-2,3-dimercaptosuccinic acid.

A recently developed methodology, which combines voltammetry, ITC, ESI-MS and several chemometric tools, has been applied for the first time to the study of As(III) complexes. The ligands considered, DMSA and DMPS, are commonly used to treat heavy metal poisoning. The study yields a reliable and consistent picture of the binding of As(III) by the chelating therapy agents DMSA and DMPS providing an unambiguous description of the stoichiometries of the complexes (ML(2), with the occasional appearance of ML in the case of DMSA), both ligands have stability constants of the same order, with a logß(2) of 9.2 and 9.8, respectively. These values confirm the potential efficiency of both ligands in the treatment of As(III) poisoning.

[Relationship of the quality of drinking water to its use regimens and the types of water supply pipes].

Drinking water running along the pipes made from different materials was investigated. Two experiments could determine the material that assured at least of all the quality of drinking water in accordance with SanPin 2.1.4.1074-01. The mechanism for worsening the quality of water supplied to a user was revealed in relation to the water use regimen. Short-term flow stoppage of water was found to result in its lower oxygen levels, a larger number of different groups of iron- and manganese-reducing bacteria and an enhanced bacterial reduction of oxides. The latter was accompanied by the dissolution of heavy metals, which induced secondary water contamination.

The role of thiol-reducing agents on modulation of glutamate binding induced by heavy metals in platelets.

In the present study, we investigated if thiol-reducing agents are capable of altering mercury (Hg2+), lead (Pb2+) and cadmium (Cd2+) effects on platelet glutamatergic system. Dimercaprol (BAL), a dithiol chelating agent therapeutically used for the treatment of heavy metals poisoning, was capable of protecting the [3H]-glutamate binding against the effects caused by Pb2+ and Hg2+. 2,3-Dimercaptopropane-1-sulfonic acid (DMPS), another dithiol-reducing chelating agent, was capable of protecting the effect caused by Cd2+, Pb2+ and Hg2+. The similar effect was observed with addition of dithiothreitol (DTT) on [3H]-glutamate binding in human platelets. Dithiol-reducing agents (BAL, DMPS and DTT) alone did not alter [3H]-glutamate binding. In contrast, reduced glutathione (GSH), a monothiol-reducing agent, caused a significant inhibition on [3H]-glutamate binding at all concentrations tested. GSH did not modify heavy metal effects on [3H]-glutamate binding in platelets. The findings of the present investigation indicate that dithiol-reducing agents are capable of altering Hg2+, Pb2+ and Cd2+ effects on platelet glutamatergic system. In vitro data on chelating-metal interactions provide only an estimated guide to the treatment of heavy metal poisoning. Consequently, more studies in intoxicated patients are necessary to determine the precise use of the peripheral models and chelating agents.

[The transmembranous passes of K+ in brain cortex under radiation and chemical influences and their modification with natural adaptogen].

An investigation of the influence of chronic low-intensity irradiation with 0.25 Gr dose and of a mixture of heavy metal salts both apart and together, as well as when correcting with a natural adaptogen such as Spirulina platensis, on passive and active transport of potassium and the work efficiency of Na,K-pump in slices of brain cortex was the problem of this study. As a biological model for in vivo researches on molecular-cellular level the thin layers of a rat brain cortex were used. It was shown that both radiation and chemical factors cause reliable changes of passive membrane permeability and operation of Na,K-pump, whose function is the maintenance of the certain gradient of potassium ions on the plasmatic membrane, the normalization of ion homeostasis, the stabilization of membranous potential. The analysis of calculated indexes of passive and of active ion transport show that at modification of X-rays influence with a mixture of heavy metal salts exactly the last makes the main contribution to efficiency decrease of energy-dependent transport of potassium. The natural adaptogen spirulina renders a better effect in the case of toxic action of the mixture of heavy metal salts, enlarging not only active transport of potassium ions, but its efficiency as well.

Porphyrinuria in childhood autistic disorder: implications for environmental toxicity.

To address a possible environmental contribution to autism, we carried out a retrospective study on urinary porphyrin levels, a biomarker of environmental toxicity, in 269 children with neurodevelopmental and related disorders referred to a Paris clinic (2002-2004), including 106 with autistic disorder. Urinary porphyrin levels determined by high-performance liquid chromatography were compared between diagnostic groups including internal and external control groups. Coproporphyrin levels were elevated in children with autistic disorder relative to control groups. Elevation was maintained on normalization for age or to a control heme pathway metabolite (uroporphyrin) in the same samples. The elevation was significant (P < 0.001). Porphyrin levels were unchanged in Asperger's disorder, distinguishing it from autistic disorder. The atypical molecule precoproporphyrin, a specific indicator of heavy metal toxicity, was also elevated in autistic disorder (P < 0.001) but not significantly in Asperger's. A subgroup with autistic disorder was treated with oral dimercaptosuccinic acid (DMSA) with a view to heavy metal removal. Following DMSA there was a significant (P = 0.002) drop in urinary porphyrin excretion. These data implicate environmental toxicity in childhood autistic disorder.

Inhibition of Na+/K(+)-ATPase and Mg(2+)-ATPase by metal ions and prevention and recovery of inhibited activities by chelators.

Kinetics and inhibition of Na(+)/K(+)-ATPase and Mg(2+)-ATPase activity from rat synaptic plasma membrane (SPM), by separate and simultaneous exposure to transition (Cu(2+), Zn(2+), Fe(2+) and Co(2+)) and heavy metals (Hg(2+) and Pb(2+)) ions were studied. All investigated metals produced a larger maximum inhibition of Na(+)/K(+)-ATPase than Mg(2+)-ATPase activity. The free concentrations of the key species (inhibitor, MgATP(2-), MeATP(2-)) in the medium assay were calculated and discussed. Simultaneous exposure to the combinations Cu(2+)/Fe(2+) or Hg(2+)/Pb(2+) caused additive inhibition, while Cu(2+)/Zn(2+) or Fe(2+)/Zn(2+) inhibited Na(+)/K(+)-ATPase activity synergistically (i.e., greater than the sum metal-induced inhibition assayed separately). Simultaneous exposure to Cu(2+)/Fe(2+) or Cu(2+)/Zn(2+) inhibited Mg(2+)-ATPase activity synergistically, while Hg(2+)/Pb(2+) or Fe(2+)/Zn(2+) induced antagonistic inhibition of this enzyme. Kinetic analysis showed that all investigated metals inhibited Na(+)/K(+)-ATPase activity by reducing the maximum velocities (V(max)) rather than the apparent affinity (Km) for substrate MgATP(2-), implying the noncompetitive nature of the inhibition. The incomplete inhibition of Mg(2+)-ATPase activity by Zn(2+), Fe(2+) and Co(2+) as well as kinetic analysis indicated two distinct Mg(2+)-ATPase subtypes activated in the presence of low and high MgATP(2-) concentration. EDTA, L-cysteine and gluthathione (GSH) prevented metal ion-induced inhibition of Na(+)/K(+)-ATPase with various potencies. Furthermore, these ligands also reversed Na(+)/K(+)-ATPase activity inhibited by transition metals in a concentration-dependent manner, but a recovery effect by any ligand on Hg(2+)-induced inhibition was not obtained.

Heavy metals modulate the activity of the purinergic P2X4 receptor.

To further characterize the nature of the regulatory metal-binding sites of the rat P2X(4) receptor, several transition heavy metals were tested to examine their ability to mimic the facilitator action of zinc or the inhibitory action of copper. cDNA coding for the rat P2X(4) receptor was injected into Xenopus laevis oocytes; the two-electrode voltage-clamp technique was used to measure and quantify the ATP-evoked currents in the absence or presence of the metals. Cadmium facilitated the ATP-gated currents in a reversible and voltage-independent manner; maximal potentiation occurred within less than 1 min. Cadmium displaced leftward, in a concentration-dependent manner, the ATP concentration-response curve. In contrast, mercury reduced the ATP-gated currents in a reversible, time, and concentration manner. Maximal inhibition occurred after about 5 min of metal application. Cobalt also augmented the ATP-evoked currents, but its action was long lasting and did not reverse even after 45 min of metal washout. Other metals such as lead, nickel, manganese, silver, or gallium did not significantly alter the ATP-gated currents. The co-application of cadmium plus zinc or mercury plus copper caused additive effects. Mutation of H140 by alanine (H140A) augmented both the cadmium-induced facilitation and the mercury-induced inhibition. In contrast, the H241A mutant showed characteristics indistinguishable from the wild type. The H286A mutant showed a normal cadmium-induced potentiation, but an increased mercury inhibition. Out of the metals examined, only cadmium mimicked closely the action of zinc, evidencing commonalities. While mercury mimicked the action of copper, both metals apparently interact at distinct metal-binding sites. The present findings allow us to infer that heavy metals modulate the P2X(4) receptor by acting in at least three separate metal-binding sites.

Effect of metal-based anticancer drugs on wild type and metallothionein null cell lines.

Metallothioneins (MT) are ubiquitous low-molecular-weight metal-binding intracellular proteins. We used wild type mouse embryo fibroblasts, GKA1, and its MT-null variant, named GKA2, in order to correlate the presence of MT to the response to a number of different antitumor drugs with different mechanisms of action. We studied sensitivity of GKA1 and GKA2 cells to metal-based compounds having alkylating property, or able to generate reactive oxygen species (ROS); as well as to drugs acting with different mechanisms. The absence of MT in GKA2 cells was correlated to higher sensitivity to the metal-based drugs compared to that of GKA1. No marked differences in sensitivity of two cell lines against gemcitabine, taxol, and vinblastine were observed. No significant change in sensitivity of either GKA1 or GKA2 cells to these non-alkylating drugs was seen after heavy metal pretreatments. In GKA1 cells, MT biosynthesis was induced by copper and cadmium but not by zinc treatment under the conditions of these experiments. Induction of MT was directly proportional to decrease in sensitivity of GKA1 cells to the compounds used in this experiment. In contrast to GKA1 cells, the MT-null cells (GKA2) expressed no detectable metallothionein either constitutively or after treatment with zinc, copper, or cadmium. Nonetheless, heavy metal pretreatment of GKA2 cells did not cause any change in their sensitivity.

Recent studies on metallothionein: protection against toxicity of heavy metals and oxygen free radicals.

Metallothionein (MT) is a ubiquitous, cysteine-rich, metal-binding protein. MT synthesis is induced by various stimuli such as cadmium, mercury, zinc, oxidative stress, glucocorticoid, and anticancer agents. Recently, transgenic mice with loss-of-function mutations in the MT-I/-II genes were established. It has been assumed that MT plays a role in the detoxification of heavy metals. In recent studies using MT-null mice, the ability of MT to protect against cadmium-induced renal, liver and bone injuries has been confirmed. Moreover, MT is also capable of scavenging oxygen free radicals. MT is involved in the protection of tissues against various forms of oxidative injury, including radiation, lipid peroxidation, oxidative stress caused by anticancer drugs, and conditions of hyperoxia. However, MT still lacks an established biological function. Unexpectedly, the MT-null mice were apparently in good health, and the critical biological roles of MT have been questioned. MT seems to be a protective protein produced in response to a variety of stresses. Here, current studies on the protective roles of MT against toxicity of heavy metals and reactive oxygen species are reviewed, and the putative biological functions of MT are discussed.

[The resistance of soil microorganisms to soil pollution by heavy metals]. / Rezystentnist' hruntovykh mikroorhanizmiv do zabrudnennia hruntiv vazhkymy metalamy.

Microbial communities of grey podzolized soil of Left-Bank Ukraine are characterized by high potential resistance to pollution with heavy metals: above 40% of organotrophic microorganisms are capable to resist to pollution with a mixture of heavy metals (Cu2+, Cd2+, Pb2+, Zn2+) in a dose of 20 MPC of each metal. Relative amount of resistant microorganisms in polluted soil increases up to 93%. White zeolites and biohumus are promising for reclamation of soils polluted with heavy metals. They decrease toxic effect of heavy metals on soil microflora and promote development of microflora resistant to pollution.

Toxicología ambiental: metalotioneínas y metabolismo celular / Environmental toxicology: metallothioneins and cellular metabolism

Las metalotioneínas (MT) constituyen una familia de proteínas de bajo peso molecular (6-8 kDa), presentes en procariotes y eucariotes, con elevado contenido en cisteína (30-35 por ciento) y marcada capacidad para combinarse con iones metálicos. dentro del metabolismo celular, se le han asignado múltiples funciones, desde un papel central en la homeostasis celular de ciertos metales pesados esenciales ("pool" citosólico de Zn y/o Cu), la detoxificación de metales pesados no esenciales, hasta su participación en ciertos procesos inflamatorios y la inactivación de radicales libres. La variación en el nivel de MT es indicador de exposición a xenobióticos, de situaciones ambientales adversas así como de situaciones de estrés fisiológico. Como tal, esta respuesta puede utilizarse tanto a nivel de la toxicología laboral, clínica y en estudios ecotoxicológicos. A este respecto, se encuentra en fase experimental su utilización con fines de diagnóstico ambiental. Esta revisión tiene como objeto constituir una breve reseña sobre los principales conocimientos reunidos hasta la fecha. Se ha avanzado significativamente en los aspectos básicos y metodológicos de la inducción de metalotioneínas en situaciones de estrés. Sin embargo, y a pesar de contarse con un número importante de estudios específicos, y a diferencia de otras proteínas menos estudiadas, queda aún sin precisar su función básica dentro del metabolismo celular

Toxicología ambiental: metalotioneínas y metabolismo celular / Environmental toxicology: metallothioneins and cellular metabolism

Las metalotioneínas (MT) constituyen una familia de proteínas de bajo peso molecular (6-8 kDa), presentes en procariotes y eucariotes, con elevado contenido en cisteína (30-35 por ciento) y marcada capacidad para combinarse con iones metálicos. dentro del metabolismo celular, se le han asignado múltiples funciones, desde un papel central en la homeostasis celular de ciertos metales pesados esenciales ("pool" citosólico de Zn y/o Cu), la detoxificación de metales pesados no esenciales, hasta su participación en ciertos procesos inflamatorios y la inactivación de radicales libres. La variación en el nivel de MT es indicador de exposición a xenobióticos, de situaciones ambientales adversas así como de situaciones de estrés fisiológico. Como tal, esta respuesta puede utilizarse tanto a nivel de la toxicología laboral, clínica y en estudios ecotoxicológicos. A este respecto, se encuentra en fase experimental su utilización con fines de diagnóstico ambiental. Esta revisión tiene como objeto constituir una breve reseña sobre los principales conocimientos reunidos hasta la fecha. Se ha avanzado significativamente en los aspectos básicos y metodológicos de la inducción de metalotioneínas en situaciones de estrés. Sin embargo, y a pesar de contarse con un número importante de estudios específicos, y a diferencia de otras proteínas menos estudiadas, queda aún sin precisar su función básica dentro del metabolismo celular (AU)