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Manganese (Mn), although important for multiple cellular processes, has posed environmental health concerns due to its neurotoxic effects. In recent years, there have been extensive studies on the mechanism of Mn-induced neuropathology, as well as the sex-dependent vulnerability to its neurotoxic effects. Nonetheless, cellular mechanisms influenced by sex differences in susceptibility to Mn have yet to be adequately characterized. Since oxidative stress is a key mechanism of Mn neurotoxicity, here, we have probed Hsp70 and Nrf2 proteins to investigate the sex-dependent changes following exposure to Mn. Male and female rats were administered intraperitoneal injections of MnCl2 (10 mg/kg and 25 mg/kg) 48 hourly for a total of eight injections (15 days). We evaluated changes in body weight, as well as Mn accumulation, Nrf2 and Hsp70 expression across four brain regions; striatum, cortex, hippocampus and cerebellum in both sexes. Our results showed sex-specific changes in body-weight, specifically in males but not in females. Additionally, we noted sex-dependent accumulation of Mn in the brain, as well as in expression levels of Nrf2 and Hsp70 proteins. These findings revealed sex-dependent susceptibility to Mn-induced neurotoxicity corresponding to differential Mn accumulation, and expression of Hsp70 and Nrf2 across several brain regions.
Selenoneine and ergothioneine in human blood cells determined simultaneously by HPLC/ICP-QQQ-MS
(2019)
The possible relevance to human health of selenoneine and its sulfur-analogue ergothioneine has generated interest in their quantitative determination in biological samples. To gain more insight into the similarities and differences of these two species, a method for their simultaneous quantitative determination in human blood cells using reversed-phase high performance liquid chromatography (RP-HPLC) coupled to inductively coupled plasma triple quadrupole mass spectrometry (ICP-QQQ-MS) is presented. Spectral interferences hampering the determination of sulfur and selenium by ICPMS are overcome by introducing oxygen to the reaction cell. To access selenoneine and ergothioneine in the complex blood matrix, lysis of the cells with cold water followed by cut-off filtration (3000 Da) is performed. Recoveries based on blood cells spiked with selenoneine and ergothioneine were between 80% and 85%. The standard deviation of the method was around 0.10 mg S per L for ergothioneine (corresponding to relative standard deviations (RSD) between 10-1% for ergothioneine concentrations of 1-10 mg S per L) and 0.25 g Se per L for selenoneine (RSDs of 25-2% for concentrations of 1-10 g Se per L). The method was applied to blood cell samples from three volunteers which showed selenoneine and ergothioneine concentrations in the range of 3.25 to 7.35 g Se per L and 0.86 to 6.44 mg S per L, respectively. The method is expected to be of wide use in future studies investigating the dietary uptake of selenoneine and ergothioneine and their relevance in human health.
Scope: Selenoneine (2-selenyl-N-alpha, N-alpha, N-alpha-trimethyl-L-histidine), the selenium (Se) analogue of the ubiquitous thiol compound and putative antioxidant ergothioneine, is the major organic selenium species in several marine fish species. Although its antioxidant efficacy has been proposed, selenoneine has been poorly characterized, preventing conclusions on its possible beneficial health effects. Methods and results: Treatment of Caenorhabditis elegans (C. elegans) with selenoneine for 18 h attenuated the induction of reactive oxygen and nitrogen species (RONS). However, the effect was not immediate, occurring 48 h post-treatment. Total Se and Se speciation analysis revealed that selenoneine was efficiently taken up and present in its original form directly after treatment, with no metabolic transformations observed. 48 h posttreatment, total Se in worms was slightly higher compared to controls and no selenoneine could be detected. Conclusion: The protective effect of selenoneine may not be attributed to the presence of the compound itself, but rather to the activation of molecular mechanisms with consequences at more protracted time points.
The essential micronutrient selenium (Se) is required for various systemic functions, but its beneficial range is narrow and overexposure may result in adverse health effects. Additionally, the chemical form of the ingested selenium contributes crucially to its health effects. While small Se species play a major role in Se metabolism, their toxicological effects, bioavailability and metabolic transformations following elevated uptake are poorly understood. Utilizing the tractable invertebrate Caenorhabditis elegans allowed for an alternative approach to study species-specific characteristics of organic and inorganic Se forms in vivo, revealing remarkable species-dependent differences in the toxicity and bioavailability of selenite, selenomethionine (SeMet) and Se-methylselenocysteine (MeSeCys). An inverse relationship was found between toxicity and bioavailability of the Se species, with the organic species displaying a higher bioavailability than the inorganic form, yet being less toxic. Quantitative Se speciation analysis with HPLC/mass spectrometry revealed a partial metabolism of SeMet and MeSeCys. In SeMet exposed worms, identified metabolites were Se-adenosylselenomethionine (AdoSeMet) and Se-adenosylselenohomocysteine (AdoSeHcy), while worms exposed to MeSeCys produced Se-methylselenoglutathione (MeSeGSH) and -glutamyl-MeSeCys (-Glu-MeSeCys). Moreover, the possible role of the sole selenoprotein in the nematode, thioredoxin reductase-1 (TrxR-1), was studied comparing wildtype and trxr-1 deletion mutants. Although a lower basal Se level was detected in trxr-1 mutants, Se toxicity and bioavailability following acute exposure was indistinguishable from wildtype worms. Altogether, the current study demonstrates the suitability of C. elegans as a model for Se species dependent toxicity and metabolism, while further research is needed to elucidate TrxR-1 function in the nematode.
Excessive levels of the essential metal manganese (Mn) may cause a syndrome similar to Parkinson’s disease. The model organism Caenorhabditis elegans mimics some of Mn effects in mammals, including dopaminergic neurodegeneration, oxidative stress, and increased levels of AKT. The evolutionarily conserved insulin/insulin-like growth factor-1 signaling pathway (IIS) modulates worm longevity, metabolism, and antioxidant responses by antagonizing the transcription factors DAF-16/FOXO and SKN-1/Nrf-2. AKT-1, AKT-2, and SGK-1 act upstream of these transcription factors. To study the role of these proteins in C. elegans response to Mn intoxication, wild-type N2 and loss-of-function mutants were exposed to Mn (2.5 to 100 mM) for 1 h at the L1 larval stage. Strains with loss-of-function in akt-1, akt-2, and sgk-1 had higher resistance to Mn compared to N2 in the survival test. All strains tested accumulated Mn similarly, as shown by ICP-MS. DAF-16 nuclear translocation was observed by fluorescence microscopy in WT and loss-of-function strains exposed to Mn. qRT-PCR data indicate increased expression of γ-glutamyl cysteine synthetase (GCS-1) antioxidant enzyme in akt-1 mutants. The expression of sod-3 (superoxide dismutase homologue) was increased in the akt-1 mutant worms, independent of Mn treatment. However, dopaminergic neurons degenerated even in the more resistant strains. Dopaminergic function was evaluated with the basal slowing response behavioral test and dopaminergic neuron integrity was evaluated using worms expressing green fluorescent protein (GFP) under the dopamine transporter (DAT-1) promoter. These results suggest that AKT-1/2 and SGK-1 play a role in C. elegans response to Mn intoxication. However, tissue-specific responses may occur in dopaminergic neurons, contributing to degeneration.
The existence of cancer stem cells (CSCs) poses a major obstacle for the success of current cancer therapies, especially the fact that non-CSCs can spontaneously turn into CSCs, which lead to the failure of the treatment and tumor relapse. Therefore, it is very important to develop effective strategies for the eradication of the CSCs. In this work, we have developed a CSCs-specific targeted, retinoic acid (RA)-loaded gold nanostars-dendritic polyglycerol (GNSs-dPG) nanoplatform for the efficient eradication of CSCs. The nanocomposites possess good biocompatibility and exhibit effective CSCs-specific multivalent targeted capability due to hyaluronic acid (HA) decorated on the multiple attachment sites of the bioinert dendritic polyglycerol (dPG). With the help of CSCs differentiation induced by RA, the self-renewal of breast CSCs and tumor growth were suppressed by the high therapeutic efficacy of photothermal therapy (PTT) in a synergistic inhibitory manner. Moreover, the stemness gene expression and CSC-driven tumorsphere formation were significantly diminished. In addition, the in vivo tumor growth and CSCs were also effectively eliminated, which indicated superior anticancer activity, effective CSCs suppression, and prevention of relapse. Taken together, we developed a CSCs-specific targeted, RA-loaded GNSs-dPG nanoplatform for the targeted eradication of CSCs and for preventing the relapse.
Pesticides guarantee us high productivity in agriculture, but the long-term costs have proved too high. Acute and chronic intoxication of humans and animals, contamination of soil, water and food are the consequences of the current demand and sales of these products. In addition, pesticides such as glyphosate are sold in commercial formulations which have inert ingredients, substances with unknown composition and proportion. Facing this scenario, toxicological studies that investigate the interaction between the active principle and the inert ingredients are necessary. The following work proposed comparative toxicology studies between glyphosate and its commercial formulation using the alternative model Caenorhabditis elegans. Worms were exposed to different concentrations of the active ingredient (glyphosate in monoisopropylamine salt) and its commercial formulation. Reproductive capacity was evaluated through brood size, morphological analysis of oocytes and through the MD701 strain (bcIs39), which allows the visualization of germ cells in apoptosis. In addition, the metal composition in the commercial formulation was analyzed by ICP-MS. Only the commercial formulation of glyphosate showed significant negative effects on brood size, body length, oocyte size, and the number of apoptotic cells. Metal analysis showed the presence of Hg, Fe, Mn, Cu, Zn, As, Cd and Pb in the commercial formulation, which did not cause reprotoxicity at the concentrations found. However, metals can bio-accumulate in soil and water and cause environmental impacts. Finally, we demonstrated that the addition of inert ingredients increased the toxic profile of the active ingredient glyphosate in C. elegans, which reinforces the need of components description in the product labels. (C) 2019 Elsevier Ltd. All rights reserved.
We recently found that macrophages from RhoA/RhoB double knockout mice had increased motility of the cell body, but severely impaired retraction of the tail and membrane extensions, whereas RhoA-or RhoB-deficient cells exhibited mild phenotypes. Here we extended this work and investigated the roles of Rho signaling in primary human blood monocytes migrating in chemotactic gradients and in various settings. Monocyte velocity, but not chemotactic navigation, was modestly dependent on Rho-ROCK-myosin II signaling on a 2D substrate or in a loose collagen type I matrix. Viewed by time-lapse epi-fluorescence microscopy, monocytes appeared to flutter rather than crawl, such that the 3D surface topology of individual cells was difficult to predict. Spinning disk confocal microscopy and 3D reconstruction revealed that cells move on planar surfaces and in a loose collagen matrix using prominent, curved planar protrusions, which are rapidly remodeled and reoriented, as well as resorbed. In a dense collagen type I matrix, there is insufficient space for this mode and cells adopt a highly Rho-dependent, lobular mode of motility. Thus, in addition to its role in tail retraction on 2D surfaces, Rho is critical for movement in confined spaces, but is largely redundant for motility and chemotaxis in loose matrices.
Quantitative determination of the sulfur-containing antioxidant ergothioneine by HPLC/ICP- QQQ-MS
(2017)
Interest in the sulfur-containing antioxidant ergothioneine calls for reliable analytical methods for its quantification. In this work, a method based on reversed-phase high performance liquid chromatography (RP-HPLC) coupled with elemental mass spectrometry detection in mass shift mode (inductively coupled plasma triple quadrupole mass spectrometry, ICP-QQQ-MS) using oxygen as the reaction gas was developed for the element-selective determination of ergothioneine in complex biological matrices. Application of an instrumental setup using a 6-port-valve and the introduction of a methanol gradient allowed the time-efficient analysis of samples containing strongly retained sulfur species besides ergothioneine without compromising ICPMS detection. In aqueous solution, limits of detection and quantification (LOD and LOQ) of the optimized method for m/z 32 -> 48 (SO+) were 0.23 mu g S per L and 0.80 mu g S per L, respectively; measurements in a complex matrix (human hepatocyte carcinoma cells, HepG2) resulted in an LOD of 0.6 mu g S per L and an LOQ of 2.3 mu g S per L. Recoveries of ergothioneine from cell pellets spiked with the analyte before cell lysis (97 +/- 3%) matched those obtained for cell culture medium spiked before syringe filtration (96 +/- 9%) demonstrating that sample preparation did not impair the quantitative determination of ergothioneine. When HepG2 cells were exposed to ergothioneine via the culture medium, they showed low absorption; approximately 3% of the added ergothioneine was found in cell lysates, while most of it (>= 85%) remained in the cell culture medium. The method is capable of separating ergothioneine from other biologically relevant sulfur-containing species and is expected to be of broad future use. Furthermore, the potential use for the simultaneous separation of selenium species, thereby extending the scope of possible applications, was demonstrated by applying it to water extracts of oyster mushrooms.
Quantitative Bioimaging to Investigate the Uptake of Mercury Species in Drosophila melanogaster
(2015)
The uptake of mercury species in the model organism Drosophila melanogaster was investigated by elemental bioimaging using laser ablation-inductively coupled plasma mass spectrometry (LA-ICPMS). The mercury distribution in Drosophila melanogaster was analyzed for the three species mercury(II) chloride, methylmercury chloride, and thimerosal after intoxication. A respective analytical method was developed and applied to the analysis of the entire Drosophila melanogaster first, before a particular focus was directed to the cerebral areas of larvae and adult flies. For quantification of mercury, matrix-matched standards based on gelatin were prepared. Challenges of spatially dissolved mercury determination, namely, strong evaporation issues of the analytes and an inhomogeneous distribution of mercury in the standards due to interactions with cysteine containing proteins of the gelatin were successfully addressed by complexation with meso-2,3-dimercaptosuccinic acid (DMSA). No mercury was detected in the cerebral region for mercury(II) chloride, whereas both organic species showed the ability to cross the blood brain barrier. Quantitatively, the mercury level in the brain exceeded the fed concentration indicating mercury enrichment, which was approximately 3 times higher for methylmercury chloride than for thimerosal.
The knowledge of transformation pathways and identification of transformation products (TPs) of veterinary drugs is important for animal health, food, and environmental matters. The active agent Monensin (MON) belongs to the ionophore antibiotics and is widely used as a veterinary drug against coccidiosis in broiler farming. However, no electrochemically (EC) generated TPs of MON have been described so far. In this study, the online coupling of EC and mass spectrometry (MS) was used for the generation of oxidative TPs. EC-conditions were optimized with respect to working electrode material, solvent, modifier, and potential polarity. Subsequent LC/HRMS (liquid chromatography/high resolution mass spectrometry) and MS/MS experiments were performed to identify the structures of derived TPs by a suspected target analysis. The obtained EC-results were compared to TPs observed in metabolism tests with microsomes and hydrolysis experiments of MON. Five previously undescribed TPs of MON were identified in our EC/MS based study and one TP, which was already known from literature and found by a microsomal assay, could be confirmed. Two and three further TPs were found as products in microsomal tests and following hydrolysis, respectively. We found decarboxylation, O-demethylation and acid-catalyzed ring-opening reactions to be the major mechanisms of MON transformation.
Plant proteins have become increasingly important for ecological reasons. Rapeseed is a novel source of plant proteins with high biological value, but its metabolic impact in humans is largely unknown. A randomized, controlled intervention study including 20 healthy subjects was conducted in a crossover design. All participants received a test meal without additional protein or with 28 g of rapeseed protein isolate or soy protein isolate (control). Venous blood samples were collected over a 360-min period to analyze metabolites; satiety was assessed using a visual analog scale. Postprandial levels of lipids, urea, and amino acids increased following the intake of both protein isolates. The postprandial insulin response was lower after consumption of the rapeseed protein than after intake of the soy protein (p< 0.05), whereas the postmeal responses of glucose, lipids, interleukin-6, minerals, and urea were comparable between the two protein isolates. Interestingly, the rapeseed protein exerted stronger effects on postprandial satiety than the soy protein (p< 0.05). The postmeal metabolism following rapeseed protein intake is comparable with that of soy protein. The favorable effect of rapeseed protein on postprandial insulin and satiety makes it a valuable plant protein for human nutrition.
Methylglyoxal (MG), a highly reactive dicarbonyl, interacts with proteins to form advanced glycation end products (AGEs). AGEs include a variety of compounds which were shown to have damaging potential and to accumulate in the course of different conditions such as diabetes mellitus and aging. After confirming collagen as a main target for MG modifications in vivo within the extracellular matrix, we show here that MG-collagen disrupts fibroblast redox homeostasis and induces endoplasmic reticulum (ER) stress and apoptosis. In particular, MG-collagen-induced apoptosis is associated with the activation of the PERK-eIF2 alpha pathway and caspase-12. MG-collagen contributes to altered redox homeostasis by directly generating hydrogen peroxide and oxygen-derived free radicals. The induction of ER stress in human fibroblasts was confirmed using collagen extracts isolated from old mice in which MG-derived AGEs were enriched. In conclusion, MG-derived AGEs represent one factor contributing to diminished fibroblast function during aging.
In order to reveal the time-depending mercury species uptake by human astrocytes, a novel approach for total mercury analysis is presented, which uses an accelerated sample introduction system combined on-line with an inductively coupled plasma mass spectrometer equipped with a collision/reaction cell. Human astrocyte samples were incubated with inorganic mercury (HgCl2), methylmercury chloride (MeHgCl), and thimerosal. After 1-h incubation with Hg2+, cellular concentrations of 3 mu M were obtained, whereas for organic species, concentrations of 14-18 mu M could be found. After 24 h, a cellular accumulation factor of 0.3 was observed for the cells incubated with Hg2+, whereas the organic species both showed values of about 5. Due to the obtained steady-state signals, reliable results with relative standard deviations of well below 5 % and limits of detection in the concentration range of 1 ng L-1 were obtained using external calibration and species-unspecific isotope dilution analysis approaches. The results were further validated using atomic fluorescence spectrometry.
Manganese (Mn) and zinc (Zn) are not only essential trace elements, but also potential exogenous risk factors for various diseases. Since the disturbed homeostasis of single metals can result in detrimental health effects, concerns have emerged regarding the consequences of excessive exposures to multiple metals, either via nutritional supplementation or parenteral nutrition. This study focuses on Mn-Zn-interactions in the nematode Caenorhabditis elegans (C. elegans) model, taking into account aspects related to aging and age-dependent neurodegeneration.
Hazelnuts are rarely cultivated in Germany, although they are a valuable source for macro- and micronutrients and can thus contribute to a healthy diet. Near the present, 15 varieties were cultivated in Thuringia, Germany, as a pilot study for further research. The aim of our study was to evaluate the micro- and macronutrient composition of representative, randomly mixed samples of the 15 different hazelnut cultivars. Protein, fat, and fiber contents were determined using established methods. Fatty acids, tocopherols, minerals, trace elements, and ultra-trace elements were analyzed using gas chromatography, high-performance liquid chromatography, and inductively coupled plasma triple quadrupole mass-spectrometry, respectively. We found that the different hazelnut varieties contained valuable amounts of fat, protein, dietary fiber, minerals, trace elements, and alpha-tocopherol, however, in different quantities. The variations in nutrient composition were independent of growth conditions, which were identical for all hazelnut varieties. Therefore, each hazelnut cultivar has its specific nutrient profile.
Over the last few decades, there has been a tremendous increase in research on antibacterial surface coatings as an alternative strategy against bacterial infections. Although there are several examples of effective strategies to prevent bacterial adhesion, the effect of the wetting properties on the coating was rarely considered as a crucial factor. Here we report an in-depth study on the effect of extreme wettability on the antibacterial efficiency of a silver nanoparticles ( AgNPs)-based coating. By controlling surface polymerization of mussel-inspired dendritic polyglycerol ( MI-dPG) and post-functionalization, surfaces with wetting properties ranging from superhydrophilic to superhydrophobic were fabricated. Subsequently, AgNPs were embedded into the coatings by applying in situ reduction using the free catechols-moieties present in the MI-dPG coating. The resulting polymer coatings exhibited excellent antibacterial ability against planktonic Escherichia coli ( E. coli) DH5a and Staphylococcus aureus ( S. aureus) SH1000. The antibacterial efficiency of the coatings was analyzed by using inductively coupled plasma mass spectrometry ( ICP-MS) and bacterial viability tests. Furthermore, the antifouling properties of the coatings in relation to the antibacterial properties were evaluated.
Metabolic footprint and intestinal microbial changes in response to dietary proteins in a pig model
(2019)
Epidemiological studies revealed that dietary proteins can contribute to the modulation of the cardiovascular disease risk. Still, direct effects of dietary proteins on serum metabolites and other health-modulating factors have not been fully explored. Here, we compared the effects of dietary lupin protein with the effects of beef protein and casein on the serum metabolite profile, cardiovascular risk markers and the fecal microbiome. Pigs were fed diets containing 15% of the respective proteins for 4 weeks. A classification analysis of the serum metabolites revealed six biomarker sets of two metabolites each that discriminated between the intake of lupin protein, lean beef or casein. These biomarker sets included 1- and 3-methylhistidine, betaine, carnitine, homoarginine and methionine. The study revealed differences in the serum levels of the metabolites 1- and 3- methylhistidine, homoarginine, methionine and homocysteine, which are involved in the one-carbon cycle. However, these changes were not associated with differences in the methylation capacity or the histone methylation pattern. With the exception of serum homocysteine and homoarginine levels, other cardiovascular risk markers, such as the homeostatic model assessment index, trimethylamine-N-oxide and lipids, were not influenced by the dietary protein source. However, the composition of the fecal microorganisms was markedly changed by the dietary protein source. Lupin-protein-fed pigs exhibited more species from the phyla Bacteroidetes and Firmicutes than the other two groups. In conclusion, different dietary protein sources induce distinct serum metabolic fingerprints, have an impact on the cardiovascular risk and modulate the composition of the fecal microbiome. (C) 2019 Elsevier Inc. All rights reserved.
Mechanistic studies on the adverse effects of manganese overexposure in differentiated LUHMES cells
(2022)
Manganese (Mn) is an essential trace element, but overexposure is associated with toxicity and neurological dysfunction. Accumulation of Mn can be observed in dopamine-rich regions of the brain in vivo and Mn-induced oxidative stress has been discussed extensively. Nevertheless, Mn-induced DNA damage, adverse effects of DNA repair, and possible resulting consequences for the neurite network are not yet characterized. For this, LUHMES cells were used, as they differentiate into dopaminergic-like neurons and form extensive neurite networks. Experiments were conducted to analyze Mn bioavailability and cytotoxicity of MnCl2, indicating a dose-dependent uptake and substantial cytotoxic effects. DNA damage, analyzed by means of 8-oxo-7,8-dihydro-2'-guanine (8oxodG) and single DNA strand break formation, showed significant dose- and time-dependent increase of DNA damage upon 48 h Mn exposure. Furthermore, the DNA damage response was increased which was assessed by analytical quantification of poly(ADP-ribosyl)ation (PARylation). Gene expression of the respective DNA repair genes was not significantly affected. Degradation of the neuronal network is significantly altered by 48 h Mn exposure. Altogether, this study contributes to the characterization of Mn-induced neurotoxicity, by analyzing the adverse effects of Mn on genome integrity in dopaminergic-like neurons and respective outcomes.
The toxicologically most relevant mercury (Hg) species for human exposure is methylmercury (MeHg). Thiomersal is a common preservative used in some vaccine formulations. The aim of this study is to get further mechanistic insight into the yet not fully understood neurotoxic modes of action of organic Hg species. Mercury species investigated include MeHgCl and thiomersal. Additionally HgCl2 was studied, since in the brain mercuric Hg can be formed by dealkylation of the organic species. As a cellular system astrocytes were used. In vivo astrocytes provide the environment necessary for neuronal function. In the present study, cytotoxic effects of the respective mercuricals increased with rising alkylation level and correlated with their cellular bioavailability. Further experiments revealed for all species at subcytotoxic concentrations no induction of DNA strand breaks, whereas all species massively increased H2O2-induced DNA strand breaks. This co- genotoxic effect is likely due to a disturbance of the cellular DNA damage response. Thus, at nanomolar, sub-cytotoxic concentrations, all three mercury species strongly disturbed poly(ADP-ribosyl)ation, a signalling reaction induced by DNA strand breaks. Interestingly, the molecular mechanism behind this inhibition seems to be different for the species. Since chronic PARP-1 inhibition is also discussed to sacrifice neurogenesis and learning abilities, further experiments on neurons and in vivo studies could be helpful to clarify whether the inhibition of poly(ADP-ribosyl) ation contributes to organic Hg induced neurotoxicity.