Bioavailable Trace Metals in Neurological Diseases

Medical treatment in Wilson’s disease includes chelators (d-penicillamine and trientine) or zinc salts that have to be maintain all the lifelong. This pharmacological treatment is categorised into two phases; the first being a de-coppering phase and the second a maintenance one. The best therapeutic approach remains controversial, as only a few non-controlled trials have compared these treatments. During the initial phase, progressive increase of chelators’ doses adjusted to exchangeable copper and urinary copper might help to avoid neurological deterioration. Liver transplantation is indicated in acute fulminant liver failure and decompensated cirrhosis; in cases of neurologic deterioration, it must be individually discussed. During the maintenance phase, the most important challenge is to obtain a good adherence to lifelong medical therapy. Neurodegenerative diseases that lead to a mislocalisation of iron can be caused by a culmination of localised overload (pro-oxidant siderosis) and localised deficiency (metabolic distress). A new therapeutic concept with conservative iron chelation rescues iron-overloaded neurons by scavenging labile iron and, by delivering this chelated metal to endogenous apo-transferrin, allows iron redistribution to avoid systemic loss of iron

Alterations in Energy/Redox Metabolism Induced by Mitochondrial and Environmental Toxins: A Specific Role for Glucose-6-Phosphate-Dehydrogenase and the Pentose Phosphate Pathway in Paraquat Toxicity

Parkinson’s disease (PD) is a multifactorial disorder with a complex etiology including genetic risk factors, environmental exposures, and aging. While energy failure and oxidative stress have largely been associated with the loss of dopaminergic cells in PD and the toxicity induced by mitochondrial/environmental toxins, very little is known regarding the alterations in energy metabolism associated with mitochondrial dysfunction and their causative role in cell death progression. In this study, we investigated the alterations in the energy/redox-metabolome in dopaminergic cells exposed to environmental/mitochondrial toxins (paraquat, rotenone, 1-methyl-4-phenylpyridinium [MPP+], and 6-hydroxydopamine [6-OHDA]) in order to identify common and/or different mechanisms of toxicity. A combined metabolomics approach using nuclear magnetic resonance (NMR) and direct-infusion electrospray ionization mass spectrometry (DI-ESI-MS) was used to identify unique metabolic profile changes in response to these neurotoxins. Paraquat exposure induced the most profound alterations in the pentose phosphate pathway (PPP) metabolome. 13C-glucose flux analysis corroborated that PPP metabolites such as glucose-6-phosphate, fructose-6-phosphate, glucono-1,5-lactone, and erythrose-4-phosphate were increased by paraquat treatment, which was paralleled by inhibition of glycolysis and the TCA cycle. Proteomic analysis also found an increase in the expression of glucose-6-phosphate dehydrogenase (G6PD), which supplies reducing equivalents by regenerating nicotinamide adenine dinucleotide phosphate (NADPH) levels. Overexpression of G6PD selectively increased paraquat toxicity, while its inhibition with 6-aminonicotinamide inhibited paraquat-induced oxidative stress and cell death. These results suggest that paraquat “hijacks” the PPP to increase NADPH reducing equivalents and stimulate paraquat redox cycling, oxidative stress, and cell death. Our study clearly demonstrates that alterations in energy metabolism, which are specific for distinct mitochondiral/environmental toxins, are not bystanders to energy failure but also contribute significant to cell death progression

Pre-treatment of striatal slices by DCF decreases HDA uptake (a) and dopamine content (b)

The concentration of DCF is indicated at the bottom of respective columns. The results are expressed in kBq/g [H]DA uptake and pmol/mg protein (dopamine content), respectively. Means ± SE of observations are presented. The number of experiments is indicated below the columns.* < 0.05, ** < 0.01, significance versus the control non-pre-treated slice.<p><b>Copyright information:</b></p><p>Taken from "Modulation of dopaminergic neurotransmission in rat striatum upon and diclofenac treatment"</p><p></p><p>Journal of Neurochemistry 2008;105(2):360-368.</p><p>Published online 01 Apr 2008</p><p>PMCID:PMC2324205.</p><p>© 2007 The Authors Journal compilation © 2007 International Society for Neurochemistry</p

Immunostaining for TH in the striatal brain sections of Sprague–Dawley rats

Staining was performed on 40-μm Vibratome sections of the brain tissue blocks containing the upper part of the striatum with adjacent cortex. Fixation was performed by 4%-formaldehyde, 0.5% glutaraldehyde, and 15% saturated picric acid in 0.1 mol/L phosphate buffer, pH 7.4. Dilution of applied TH antibody (Sigma) was 1 : 1000. Detection of antigen–antibody complexes was performed by DAB as chromogen. Original magnification: 10× S, striatum; C, cortex. (a) Control staining. TH-antibody was omitted from the incubation medium. Brain section from untreated animal. (b) Immunostaining for TH in the brain section of untreated animal. Strong immunoreactivity in the striatum. (c) Striatal brain section of a sham-operated Sprague–Dawley rat. Intensity of immunostaining for TH antibody is comparable with the control staining. (d, e, and f) Different intensity of the TH-staining in the striatal sections after long-term (4 weeks) of DCF treatment (selected samples from the results of TH-immunostaining of eight treated animals). (d) Significantly weaker immunoreactivity in the striatum (two cases). (e) Intensity of the TH-staining is comparable with the staining found in the striatal sections of sham-operated or control animals (two cases). (f) TH-immunoreactivity is stronger after DCF treatment than control (four cases).<p><b>Copyright information:</b></p><p>Taken from "Modulation of dopaminergic neurotransmission in rat striatum upon and diclofenac treatment"</p><p></p><p>Journal of Neurochemistry 2008;105(2):360-368.</p><p>Published online 01 Apr 2008</p><p>PMCID:PMC2324205.</p><p>© 2007 The Authors Journal compilation © 2007 International Society for Neurochemistry</p

Chronic DCF treatment decreases ATP content (a) and the energy charge (b) of striatal slices

Sham controls, open bars; DCF i.v. treated animals, filled bars. The number of experiments is given in parentheses. Means ± SE of observations are presented.* < 0.05, ** < 0.01, significance versus the sham-operated control.<p><b>Copyright information:</b></p><p>Taken from "Modulation of dopaminergic neurotransmission in rat striatum upon and diclofenac treatment"</p><p></p><p>Journal of Neurochemistry 2008;105(2):360-368.</p><p>Published online 01 Apr 2008</p><p>PMCID:PMC2324205.</p><p>© 2007 The Authors Journal compilation © 2007 International Society for Neurochemistry</p

Statistical model for Plum pox virus prediction in Prunus nursery blocks using vector and virus incidence data in four different European ecological areas

This is the peer reviewed version of the following article: [FULL CITE], which has been published in final form at [Link to final article using the DOI]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.[EN] Plum pox virus(PPV) is the causal agent of sharka, the most devastating virus disease ofPrunusspecies. PPV is transmitted by vegetative propagation, particularly by grafting, as well as by aphid species in a nonpersistent manner. The objective of this paper was to evaluate the prevalence and diversity of PPV-vector aphid species in representative European areas of prunus cultivation. Four experimental nursery plots were established in Skierniewice (Poland), Liria (Spain), Plovdiv (Bulgaria) and Bistrita (Romania). Aphid population was weekly monitored using the sticky shoot method in spring and/or autumn in each nursery plot. Furthermore, we estimated the relative efficiency factor for the main PPV-vector aphid species using bibliographic and reference data. Aphid diversity in each nursery plot was assessed using the Shannon index and the number of estimated aphid species was calculated by the rarefaction method. The highest diversity of aphid species population was reported in Plovdiv in spring while the lowest diversity was found in Liria in spring. A cluster analysis based on Morisita-Horn similarity index was performed to study the differences in species composition between the four nursery plots and seasons. Aphid population was clearly grouped by location and season. Results showedAphis spiraecolaandHyalopterus prunicomplex were typically spring aphid species, whileAnoecia corniandRhopalosiphum padidominated autumn catch. Regarding PPV-vector aphid species present in nursery plots,A. spiraecolawas the most prevalent PPV-vector aphid species in Liria and in Bistrita, showing a high relative efficiency factor of PPV transmission (0.91). Consequently,A. spiraecolashould be considered a key actor in the spread of PPV in these regions.Hyalopterus prunicomplex was the most prevalent PPV-vector aphid species in Skierniewice and Plovdiv, showing a very low relative efficiency factor of PPV transmission (0.09). Therefore, the role ofH. prunicomplex in spread of PPV in these regions can be considered negligible. Furthermore, we statistically demonstrated that the presence of specific PPV-vector aphid species is associated with the spread of the disease, whereas the biodiversity of aphid species population does not affect the spread of PPV. Finally, the advantages of the use of vector pressure index in the management of sharka disease are discussed.The research leading to these results were funded by the EU Seventh Framework Programme (FP7/2007-2013), SharCo project grant no. 204429 and by grants from the Spanish Ministry of Science and Education (MEC, AGL2009-07531 and INIA RTA2005-00190). Authors thank I. Baias, S. Sabin (SCDP, Bistrita), B. Tamargo and J. Micó (Cooperativa Vinícola, Líria) for technical assistance in the experimental plots, Viveros Orero and Agromillora Iberia for providing the certified rootstock plants. E. Vidal was recipient of a grant from the Spanish Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA).Vidal, E.; Zagrai, LA.; Malinowski, T.; Soika, G.; Warabieda, W.; Tasheva-Terzieva, E.; Milusheva, S.... (2020). Statistical model for Plum pox virus prediction in Prunus nursery blocks using vector and virus incidence data in four different European ecological areas. 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