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The tea plants cultivated in acidic soils are vulnerable to excessive manganese (Mn), which increases the risk of Mn 2+ toxicity to physiology and development. Mn-cation diffusion facilitator (CDF) family genes have been implicated in regulating Mn homeostasis and tolerance. However, the mechanism of Mn tolerance of tea plants in acidic environments is still unknown. In this study, we initially examined the phenotypic characteristics and Mn contents variability in different tissues of tea plants under various Mn concentration at pH 5 and 4. We observed that tea plants exhibited remarkably high Mn tolerance at pH 4, with Mn accumulation notably elevated in the aboveground tissues under pH 4 condition after 28-day treatment. We found the expression levels of Mn-CDF genes, had different subcellular localization, were tissue-specific and significantly induced by high Mn concentrations at pH 4 condition. Furthermore, the yeast complementation assays indicated that the heterologous expression of Mn-CDF genes restored the growth of a Mn 2+ sensitive yeast strain, Δpmr1. Taken together, these results suggest that Mn-CDF family genes function as Mn transporters to participate in Mn tolerance in acidic environments. This study provides reference for further study on the mechanism of maintaining Mn homeostasis in tea plants under soil acidification., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Soybean is one of the most important crops for producing high quality oil and protein. Mineral nutrient deficiencies are frequently observed in soybeans. However, there are few studies to understand the absorption process of mineral nutrients in soybeans. Here, we investigated the functions of soybean (Glycine max L.) IRT1.1 (IRON-REGULATED TRANSPORTER 1.1) in the transportation of mineral elements. Heterologous expression of GmIRT1.1 in yeast mutants revealed that GmIRT1.1 compensated for the growth defects of Δfet3fet4 and Δsmf1 mutants under iron (Fe) and manganese (Mn) deficiency conditions, respectively, and enhanced the sensitivity of the Δycf1 mutant to cadmium (Cd) toxicity. Expression analysis revealed that GmIRT1.1 was only significantly induced by Fe deficiency and was primarily expressed in roots. Furthermore, the GmIRT1.1 overexpression lines enhanced Arabidopsis tolerance to Fe deficiency, leading to increased accumulation of Fe in the roots and shoots. Additionally, the transgenic lines increased the sensitivity to Mn and Cd toxicity. Subcellular localization analysis revealed that GmIRT1.1 was localized on the plasma membrane. Moreover, the results obtained from the soybean hairy roots system indicated that the localization of GmIRT1.1 was dependent on the regulation of Fe homeostasis in plant. Consequently, these results suggested that GmIRT1.1 was responsible for the transportation of Fe, Mn and Cd., Competing Interests: Declaration of competing interest All authors declare no conflict of interest., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Manganese (Mn) is considered as an essential element for plant growth. Mn starvation has been shown to affect photosystem II, the site of the Mn 4 CaO 5 cluster responsible for water oxidation. Less is known on the effect of Mn starvation on photosystem I. Here we studied the effects of Mn deficiency in vivo on redox changes of P700 and plastocyanin (Pc) in the liverwort Marchantia polymorpha using the KLAS-NIR spectrophotometer. Far-red illumination is used to excite preferentially photosystem I, thus facilitating cyclic electron transport. Under Mn starvation, we observed slower oxidation of P700 and a decrease in the Pc signal relative to P700. The lower Pc content under Mn deficiency was confirmed by western blots. Re-reduction kinetics of P700 + and Pc + were faster in Mn deficient thalli than in the control. The above findings show that the kinetics studied under Mn deficiency not only depend on the number of available reductants but also on how quickly electrons are transferred from stromal donors via the intersystem chain to Pc + and P700 + . We suggest that under Mn deficiency a structural reorganization of the thylakoid membrane takes place favoring the formation of supercomplexes between ferredoxin, cytochrome b 6 f complex, Pc and photosystem I, and thus an enhanced cyclic electron transport., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Anja Krieger-Liszkay reports financial support was provided by French National Research Agency. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

The effect mechanism of Mn on Cd uptake by Celosia argentea was investigated via a series of hydroponics experiments. The results showed that different manganese treatments had different effects on Cd uptake by C. argentea. Mn pretreatment increased Cd uptake by root protoplasts at Cd concentrations (4 and 6 μM). Protoplasts reached peak Cd uptake rate at 6 μM Cd and 25 °C, with 67.71 ± 0.13 μM h -1 mL -1 in the control, and 77.99 ± 0.49 μM h -1 mL -1 in the 50 μM Mn pretreatment group. However, simultaneous treatment with Cd and Mn reduced the Cd 2+ uptake by root protoplasts. This discrepancy may be attributed to the fact that cadmium and manganese share some transporters in root cells. The transcriptome analysis in roots revealed that ten genes (including ABCC, ABCA, ABCG, ABCB, ABC1, BZIP19, and ZIP5) were significantly upregulated in response to Mn stress (p < 0.05). These genes regulate the expression of transporters belonging to the ABC, and ZIP families, which may be involved in Cd uptake by root cells of C. argentea. Mn pretreatment upregulates the expression of Mn/Cd transporters, enhancing Cd uptake by root protoplasts. For the simultaneous treatment of Cd and Mn, inhibition of Cd uptake was due to the competition of the same transporters. These findings provide helpful insights for understanding the mechanism of Mn and Cd uptake in hyperaccumulators and give implications to improve the phytoremediation of Cd-contaminated soil by C. argentea., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Inhalation of welding fumes can cause metal accumulation in the brain, leading to Parkinsonian-like symptoms. Metal accumulation and altered neurochemical profiles have been observed using magnetic resonance imaging (MRI) in highly exposed welders, being associated with decreased motor function and cognition. While MRI is impractical to use as a health risk assessment tool in occupational settings, toenail metal levels are easier to assess and have been demonstrated to reflect an exposure window of 7-12 months in the past. Yet, it is unclear whether toenail metal levels are associated with brain metal levels or changes in metabolism, which are the root of potential health concerns. This study investigates whether toenail manganese (Mn) and iron (Fe) levels, assessed at several time points, correlate with brain Mn and Fe levels, measured by MRI, as well as brain GABA, glutamate (Glu), and glutathione (GSH) levels, measured by Magnetic Resonance Spectroscopy (MRS), in seventeen Mn-exposed welders. Quantitative T1 and R2* MRI maps of the whole brain, along with GABA, Glu, and GSH MRS measurements from the thalamus and cerebellum were acquired at baseline (T0). Toenail clippings were collected at T0 and every three months after the MRI for a year to account for different exposure periods being reflected by toenail clippings and MRI. Spearman correlations of toenail metal levels were run against brain metal and metabolite levels, but no significant associations were found for Mn at any timepoint. Cerebellar GSH positively correlated with toenail Fe clipped twelve months after the MRI (p = 0.05), suggesting an association with Fe exposure at the time of the MRI. Neither thalamic GABA nor Glu correlated with toenail Fe levels. In conclusion, this study cannot support toenail Mn as a proxy for brain Mn levels or metabolic changes, while toenail Fe appears linked to brain metabolic alterations, underscoring the importance of considering other metals, including Fe, in studying Mn neurotoxicity., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ulrike Dydak reports a relationship with American Regent Inc that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The development of the mining industry and the overuse of inorganic fertilizers have led to an excess of manganese (Mn) in the soil, thereby, contaminating the soil environment and people's health. On heavy metal-contaminated soils, the combined arbuscular mycorrhizal fungi (AMF)-phytoremediation technique becomes a hotspot because of its environmentally friendly, in situ remediation. AMF inoculation often leads to a decrease in host Mn acquisition, which provides a basis for its application in phytoremediation of contaminated soils. Moreover, the utilization value of native AMF is greater than that of exotic AMF, because native AMF can adapt better to Mn-contaminated soils. In addition to the fact that AMF enhance plant Mn tolerance responses such as regionalization, organic matter chelation, limiting uptake and efflux, and so on, AMF also develop plant-independent fungal pathways such as direct biosorption of Mn by mycorrhizal hyphae, fungal Mn transporter genes, and sequestration of Mn by mycorrhizal hyphae, glomalin, and arbuscule-containing root cortical cells, which together mitigate excessive Mn toxicity to plants. Clarifying AMF-plant interactions under Mn stress will provide support for utilizing AMF as a phytoremediation in Mn-contaminated soils. The review reveals in detail how AMF develop its own mechanisms for responding to excess Mn and how AMF enhance plant Mn tolerance, accompanied by perspectives for future research., Competing Interests: Declaration of competing interest Authors declare there is no conflict of interest., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Manganese (Mn) deficiency is a widespread occurrence across different landscapes, including agricultural systems and managed forests, and causes interruptions in the normal metabolic functioning of plants. The microelement is well-characterized for its role in the oxygen-evolving complex in photosystem II and maintenance of photosynthetic structures. Mn is also required for a variety of enzymatic reactions in secondary metabolism, which play a crucial role in defense strategies for trees. Despite the strong relationship between Mn availability and the biosynthesis of defense-related compounds, there are few studies addressing how Mn deficiency can impact tree defense mechanisms and the ensuing ecological patterns and processes. Understanding this relationship and highlighting the potentially deleterious effects of Mn deficiency in trees can also inform silvicultural and management decisions to build more robust forests. In this review, we address this relationship, focusing on forest trees. We describe Mn availability in forest soils, characterize the known impacts of Mn deficiency in plant susceptibility, and discuss the relationship between Mn and defense-related compounds by secondary metabolite class. In our review, we find several lines of evidence that low Mn availability is linked with lowered or altered secondary metabolite activity. Additionally, we compile documented instances where Mn limitation has altered the defense capabilities of the host plant and propose potential ecological repercussions when studies are not available. Ultimately, this review aims to highlight the importance of untangling the effects of Mn limitation on the ecophysiology of plants, with a focus on forest trees in both managed and natural stands., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Dark pericarp disease (DPD), a physiological disorder induced by excess Manganese (Mn) in litchi, severely impacts the appearance and its economic value. To elucidate the underlying mechanisms of DPD, this study investigated the variations of phenolic compound, antioxidant defense system, subcellular structure, and transcriptome profiles in both normal fruit and dark pericarp fruit (DPF) at three developmental stages (green, turning, and maturity) of 'Guiwei' litchi. The results reveal that excess Mn in DPF pericarp resulted in a significant increase in reactive oxygen species, especially H 2 O 2, and subsequent alterations in antioxidant enzyme activities. Notably, SOD (EC 1.15.1.1) activity at the green stage, along with POD (EC 1.11.1.7) and APX (EC 1.11.1.11) activities at the turning and the maturity stages, and GST (EC 2.5.1.18) activity during fruit development, were markedly higher in DPF. Cell injury was observed in pericarp, facilitating the formation of dark materials in DPF. Transcriptome profiling further reveals that genes involved in flavonoid and anthocyanin synthesis were up-regulated during the green stage but down-regulated during the turning and maturity stages. In contrast, PAL (EC 4.3.1.24), C4H (EC 1.14.14.91), 4CL (EC 6.2.1.12), CAD (EC 1.1.1.195), and particularly POD, were up-regulated, leading to reduced flavonoid and anthocyanin accumulation and increased lignin content in DPF pericarp. The above suggests that the antioxidant system and phenolic metabolism jointly resisted the oxidative stress induced by Mn stress. We speculate that phenols, terpenes, or their complexes might be the substrates of the dark substances in DPF pericarp, but more investigations are needed to identify them., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lixian Yao reports financial support was provided by China Agriculture Research System of MOF and MARA., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

We used manganese (Mn)-tolerant 'Xuegan' (Citrus sinensis) seedlings as materials and examined the characterization of Mn uptake and Mn-activated-release of root exudates under hydroponic conditions. We observed that root and shoot Mn bioaccumulation factor (BCF) reduced with the increase of Mn supply, and that Mn transfer factor (T f ) reduced greatly as Mn supply increased from 0 to 500 μM, beyond which T f slightly increased with increasing Mn supply, suggesting that Mn supply reduced the ability to absorb and accumulate Mn in roots and shoots, as well as root-to-shoot Mn translocation. Without Mn, roots alkalized the solution pH from 5.0 to above 6.2, while Mn supply reduced root-induced alkalization. As Mn supply increased from 0 to 2000 μM, the secretion of root total phenolics (TPs) increased, while the solution pH decreased. Mn supply did not alter the secretion of root total free amino acids, total soluble sugars, malate, and citrate. Mn-activated-release of TPs was inhibited by low temperature and anion channel inhibitors, but not by protein biosynthesis inhibitor. Using widely targeted metabolome, we detected 48 upregulated [35 upregulated phenolic compounds + 13 other secondary metabolites (SMs)] and three downregulated SMs, and 39 upregulated and eight downregulated primary metabolites (PMs). These findings suggested that reduced ability to absorb and accumulate Mn in roots and shoots and less root-to-shoot Mn translocation in Mn-toxic seedlings, rhizosphere alkalization, and Mn-activated-release of root exudates (especially phenolic compounds) contributed to the high Mn tolerance of C. sinensis seedlings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Plant natural resistance-associated macrophage protein (NRAMP) plays important roles in metal transport and tolerance. Tobacco is a typical cadmium (Cd) accumulator, while research on NRAMP in tobacco has been limited. In the current study, two novel NRAMP genes (NtNRAMP6a and NtNRAMP6b) were identified from the allotetraploid plant Nicotiana tabacum L. Real time‒PCR and GUS (β-glucuronidase) staining results showed that the two genes were expressed in roots, stems, leaves and flowers and induced by Cd stress. Subcellular localization revealed that they were located in the plasma membrane. Heterologously expressed NtNRAMP6a and NtNRAMP6b significantly increased the Cd sensitivity of the Δycf1 mutant, indicating that NtNRAMP6a and NtNRAMP6b had Cd transport functions in yeast. The difference in the manganese (Mn) transport activity of the two genes was demonstrated by point mutation, which was caused by the difference in the 18th amino acid. NRAMP6-N18K is a new key active site for manganese transport. After 50 μM Cd treatment for 7 days, the contents of Cd and Mn of the ntnramp6a/6b mutants was significantly lower than those of wild type in shoots, while the contents in roots were higher. Additionally, the mutant lines showed higher chorphyll contentration and lighter leaf damage. Knockout of NtNRAMP6a and NtNRAMP6b reduced Cd and Mn accumulation in tobacco shoots by influence root-to-shoot translocation. This provides new idea for cultivating tobacco varieties with low cadmium accumulation and high cadmium tolerance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Chenopodium ambrosioides is a manganese (Mn) hyperaccumulator that can be used for Mn-polluted soil phytoremediation. However, the mechanism of Mn tolerance of C. ambrosioides remains largely unknown. In this study, the key factors for Mn tolerance of C. ambrosioides was investigated from the aspects of DNA methylation pattern, gene expression regulation and physiological function. We found that the two genotypes of C. ambrosioides populations have differentiated tolerance to Mn stress (Mn-tolerant: CS and XC, Mn-sensitive: WH). Although there was no difference in Mn accumulation between two types under excess Mn, the biomass and photosynthetic systems were more severely inhibited in Mn-sensitive type, as well as suffering more serious oxidative damage. More differentially expressed genes (DEGs) were downregulated in the Mn-tolerant type, indicating that the Mn-tolerant type tends to inhibit gene expression to cope with Mn stress. DEGs related to metal transport, antioxidant system, phytohormone and transcription factors contribute to the tolerance of C. ambrosioides to Mn, and account for difference in Mn stress sensitivities between the Mn-sensitive and tolerant types. We also found that DNA methylation variation may help to cope with Mn stress. The global DNA methylation level in C. ambrosioides increased under Mn stress, especially in the Mn-sensitive type. Dozens of methylated loci were significantly associated with the Mn accumulation trait of C. ambrosioides, and some critical DEGs were regulated by DNA methylation. Our study comprehensively demonstrated the Mn tolerance mechanism of C. ambrosioides for the first time, and highlighted the roles of epigenetic modification in C. ambrosioides response to Mn stress. Our findings may contribute to elucidating the adaptation mechanism of hyperaccumulator to the heavy metal toxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Iron (Fe) deficiency is one of the most common problems of soybean. It causes upper leaves yellowing, interveinal chlorosis, stunted growth and yield loss. Manganese (Mn) deficiency affects the reactions in the oxygen evolving complex (OEC) of photosystem II and increase the accumulation of reactive oxygen species (ROS). The aim of this research is to study the effect of Fe and Mn deficiencies applied separately and simultaneously on physiological, biochemical, nutritional and growth (morphological) parameters of soybean cultivars (Glycine max L.). The experiment was conducted in nutrient hydroponic solution lacking Fe or Mn or both Fe and Mn. Chlorophyll content index (CCI) and chlorophyll a fluorescence were measured through time to detect nutritional disorders at an early growth stage before the apparition of visual symptoms. The results showed that Fe and Mn deficiencies had a significant negative effect on the photosynthetic efficiency, CCI, stomatal conductance, protein content and shoot/root nutrient uptakes. Iron and manganese stress conditions were found to enhance the accumulation of secondary metabolites and increase the antioxidant activity such as total polyphenol content (TPC), malondialdehyde (MDA) and superoxide dismutase (SOD). These impacts were more accentuated when Fe and Mn stress were applied simultaneously than when any of the deficiencies was applied alone. More than that, Mn stress alone did not significantly affect the biomass accumulation. The obtained results showed that, in hydroponic conditions, iron and manganese rational fertilization can improve the studied parameters., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Manganese (Mn) is an essential metal that serves as a cofactor for metalloenzymes important in moderating oxidative stress and the glutamate/glutamine cycle. Mn is typically obtained through the diet, but toxic overexposure can occur through other environmental or occupational exposure routes such as inhalation. Mn is known to accumulate in the brain following exposure and may contribute to the etiology of neurodegenerative disorders such as Alzheimer's disease (AD) even in the absence of acute neurotoxicity. In the present study, we used in vitro primary cell culture, ex vivo slice electrophysiology and in vivo behavioral approaches to determine if Mn-induced changes in glutamatergic signaling may be altered by genetic risk factors for AD neuropathology. Primary cortical astrocytes incubated with Mn exhibited early rapid clearance of glutamate compared to saline treated astrocytes but decreased clearance over longer time periods, with no effect of the AD genotype. Further, we found that in vivo exposure to a subcutaneous subacute, high dose of Mn as manganese chloride tetrahydrate (3 ×50 mg/kg MnCl 2 ·4(H 2 O) over 7 days) resulted in increased expression of cortical GLAST protein regardless of genotype, with no changes in GLT-1. Hippocampal long-term potentiation was not altered in APP/PSEN1 mice at this age and neither was it disrupted following Mn exposure. Mn exposure did increase sensitivity to seizure onset following treatment with the excitatory agonist kainic acid, with differing responses between APP/PSEN1 and control mice. These results highlight the sensitivity of the glutamatergic system to Mn exposure. Experiments were performed in young adult APP/PSEN1 mice, prior to cognitive decline or accumulation of hallmark amyloid plaque pathology and following subacute exposure to Mn. The data support a role of Mn in pathophysiology of AD in early stages of the disease and support the need to better understand neurological consequences of Mn exposure in vulnerable populations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Over the last decade, several clinical reports have outlined cases of early-onset manganese (Mn)-induced dystonia-parkinsonism, resulting from loss of function mutations of the Mn transporter gene SLC39A14. Previously, we have performed characterization of the behavioral, neurochemical, and neuropathological changes in 60-day old (PN60) Slc39a14-knockout (KO) murine model of the human disease. Here, we extend our studies to aging Slc39a14-KO mice to assess the progression of the disease. Our results indicate that 365-day old (PN365) Slc39a14-KO mice present with markedly elevated blood and brain Mn levels, similar to those found in the PN60 mice and representative of the human cases of the disease. Furthermore, aging Slc39a14-KO mice consistently manifest a hypoactive and dystonic behavioral deficits, similar to the PN60 animals, suggesting that the behavioral changes are established early in life without further age-associated deterioration. Neurochemical, neuropathological, and functional assessment of the dopaminergic system of the basal ganglia revealed absence of neurodegenerative changes of dopamine (DA) neurons in the substantia nigra pars compacta (SNc), with no changes in DA or metabolite concentrations in the striatum of Slc39a14-KO mice relative to wildtype (WT). Similar to the PN60 animals, aging Slc39a14-KO mice expressed a marked inhibition of potassium-stimulated DA release in the striatum. Together our findings indicate that the pathophysiological changes observed in the basal ganglia of aging Slc39a14-KO animals are similar to those at PN60 and aging does not have a significant effect on these parameters., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Manganese (Mn) is an essential micronutrient but excessive levels induce neurotoxic effects. Increasing evidence suggests a deficit of bioavailable Mn in Huntington disease (HD), an inherited neurodegenerative disease characterized by motor and cognitive disturbances. Previous studies have shown rescue of some molecular HD phenotypes by acute Mn exposure. This study simultaneously examined the potential for chronic Mn exposure to attenuate HD behavioral phenotypes, and for the HD genotype to offer protection against detrimental effects of chronic Mn exposure. In two independent studies a chronic Mn exposure paradigm was implemented in the YAC128 mouse model of HD and behavior was assessed at several timepoints. Study 1 exposed WT and YAC128 mice to twice weekly subcutaneous injections of 0, 5, 15, or 50 mg/kg MnCl[2] tetrahydrate from 12 to 32 weeks of age. A promising protective effect against motor coordination decline in 5 mg/kg MnCl[2] tetrahydrate-treated YAC128 mice was detected. Study 2 thus exposed WT and YAC128 mice to either 0 or 5 mg/kg MnCl[2] tetrahydrate from 12 to 52 weeks of age (with a partial randomized treatment crossover at 31 weeks). The same protective effect was not observed under these conditions at higher statistical power. We report subtle toxicological changes in exploratory behavior and total activity induced by chronic Mn exposure in WT mice only, despite similar total increases in brain Mn in WT and YAC128 mice. Further, chronic Mn treatment resulted in a 10-12 % decrease in striatal NeuN positive cell density in WT mice but not YAC128 mice, despite vehicle cell counts already being reduced compared to WT mice as expected for the HD genotype. The subtle changes observed in specific outcome measures, but not others, following long-term low-level Mn exposure in WT mice delineate the neurobehavioral and neuropathological effects at the threshold of chronic Mn toxicity. We conclude that these chronic low-dose Mn exposures do not significantly rescue behavioral HD phenotypes, but YAC2128 mice are protected against the subtle Mn-induced behavioral changes and decreased striatal neuron density observed in Mn-exposed WT mice., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Manganese (Mn) is an essential micronutrient for plants. This study elucidates the physiological consequences and characterization of TaNRAMP1 transporter in Mn-starved wheat. The cellular integrity, redox status, chlorophyll score, and Fv/Fm were severely affected, accompanied by decreased Mn concentration in root and shoot in Mn-deficient wheat. However, Fe concentration and root phytosiderophore release were not affected, contradicting the interactions of Fe status with Mn under Mn shortage. The genome-wide identification of TaNRAMP1 (natural resistance-associated macrophage protein 1), known as high-affinity Mn transporter, showed several polymorphisms within genome A, B, and D. The expression of TaNRAMP1 significantly decreased in roots of genome A and B but was constitutively expressed in genome D due to Mn-deficiency. The TaNRAMP1 was located in the plasma membrane and showed six motifs matched to Nramp (divalent metal transport). Further, TaNRAMP1 showed a close partnership with cation transporter associated with P-type ATPase/cation transport network. In the RNASeq platform, TaNRAMP1, located in all three genomes, showed the highest expression potential in microspore. Besides, only TaNRAMP1 in genome D was upregulated due to heat and drought stress but showed downregulation in response to excess sulfur and Puccinia triticina infection in all three genomes. The cis-regulatory analysis implies the transcriptional regulation of TaNRAMP1 linked to methyl jasmonate and abscisic acid synthesis. Furthermore, TaNRAMP1 proteins showed similar physicochemical properties, but the C-terminus position of genome D was different than genome A and B. This is the first study on the responses and genome-wide characterization of TaNRAMP1 in Mn-starved wheat., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

In many acidic soils, high concentrations of toxic Al 3+ hamper plant growth by restricting root growth which in turn restricts water and nutrient absorption. Previous research showed variation among chickpea (Cicer arietinum L.) and wild Cicer species in root elongation at 15 μM Al or more, but effects on nutrient absorption have not been examined. The variation in nutrient uptake of two chickpea varieties (PBA HatTrick and PBA Striker) and two wild Cicer species (C. echinospermum (C. echi) and C. reticulatum (C. reti)) was determined in low pH (4.2) nutrient solution with increasing Al concentrations (0, 7.5, 15, 30 μM Al). While C. echi, PBA HatTrick and PBA Striker had thicker roots and more lateral roots compared to C. reti, C. reti had greater aluminium tolerance index (AlTI) at 15 and 30 μM Al. The C. echi had higher uptake of root and shoot Al (7.5, 15 and 30 μM Al), P and S (15 and 30 μM Al) while its uptake was marginally lower for Mg, Ca (all Al treatments) and K (15 and 30 μM Al). By contrast, C. reti contained higher shoot Ca concentration at 15 and 30 μM Al and it had lower root Al uptake. Manganese uptake by C. reti roots and shoots were high enough to induce moderate Mn toxicity at 0 and 7.5 μM Al. Therefore, in response to Al toxicity, C. reti maintained greater AlTI and restricted Al uptake while increasing Ca uptake., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Hypoxia in tumor microenvironment is responsible for resistance to conventional modes of cancer therapeutics. A manganese-clay hybrid compound MHC was shown to generate molecular oxygen in aqueous solution. In this study we have shown that MHC, in hypoxia, causes cancer cell death, through release of molecular oxygen and via p53-dependent apoptosis. MHC treatment of cells results in depletion of mitochondrial membrane potential and inhibition of ROS production, in a cell-specific manner. In hypoxia, the oxygen from MHC releases cells from S-phase arrest thus causing p53-dependent apoptosis. The induction of apoptosis by MHC is higher in p53 Wt/Wt cells when it is compared with p53 Mt/Mt cells. The released oxygen from MHC triggers apoptosis via p53 activation through its enhanced homo-oligomerization, post-translational modifications and nuclear localization. Thus MHC as a cellular oxygen-releasing compound has high potential as a drug for hypoxic tumor regression., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Manganese (Mn) is an essential trace metal for all organisms. However, in excess it causes toxic effects but the impact on aquatic environments has so far been highly overlooked. Manganese is abundant both in costal and deep sea sediments and becomes bioavailable (Mn 2+ ) during redox conditions. This is an increasing phenomenon due to eutrophication-induced hypoxia and aggravated through the ongoing climate change. Intracellular accumulation of Mn 2+ causes oxidative stress and activates evolutionary conserved pathways inducing apoptosis and cell cycle arrest. Here, studies are compiled on how excess of dissolved Mn suppresses the immune system of various aquatic organisms by adversely affecting both renewal of immunocytes and their functionality, such as phagocytosis and activation of pro-phenoloxidase. These impairments decrease the animal's bacteriostatic capacity, indicating higher susceptibility to infections. Increased distribution of pathogens, which is believed to accompany climate change, requires preserved immune sentinel functions and Mn can be crucial for the outcome of host-pathogen interactions., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The adverse effects of ionizing radiation (IR) on biological tissues are mediated via increased production of reactive oxygen species (ROS) often resulting in life-threatening injuries. The effects of ionizing radiation on cells include the formation of ROS, DNA single-strand breaks, double-strand breaks, and extensive base modifications inducing the complex DNA damage. The capacity to endure the radiation insult lies in the biochemical mechanisms and structural properties in many bacterial species such as Deinococcus radiodurans and Thermococcus radiotolerans. In addition, a mechanistic link has established between the presence and accumulation of short peptides and Mn 2+ in the protection of bacteria (Deinococcus radiodurans) from the harmful ionizing radiation. This paradigm has opened up novel avenues of radioprotection in diverse settings and systems for human application. We hereby report a new bifunctional system that comprises of thiol groups in the form of Glutathione (GSH), and manganese to mimic the above system for radioprotection. The present study, therefore, adopts a novel approach to use GSH complexed Mn, and this conjugated system is complying with the prerequisite for radioprotection as seen in the above mechanism. This unique conjugate DT(GS) 2 Mn(II) was evaluated for its efficacy invitro and invivo. Radioprotective efficacy of DT(GS) 2 Mn(II) on NIH/3T3 cells revealed that compound could significantly protect cells against radiation-induced toxicity as compared to the standard compound N-acetyl cysteine. Pre-treatment of DT(GS) 2 Mn(II) increased the survival of mice by 50% compared to radiation alone treatment group. A significant decrease in cytochrome c levels in the group pre-treated with test compound (0.50 ± 0.14) compared to radiation alone group (1.60 ± 0.07) was observed. DT(GS) 2 Mn(II) attenuated radiation induced apoptosis by promoted expression of anti-apoptotic Bcl-2 along with suppression of cyt-c release and augmented cell survival following irradiation. A distinct improvement in villi length was observed in the group treated with DT(GS) 2 Mn(II) with an average of 1546 ± 61 μm versus 763 ± 154 μm for radiation alone group. The present findings suggested DT(GS) 2 Mn(II) is a promising radioprotective agent and exerts it protective effect both invitro and invivo systems by decreasing radiation induced cytotoxicity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

There is increasing evidence that environmental manganese (Mn) exposure early in life can have negative effects on children's neurodevelopment and increase the risk of behavioral problems, including attention deficit hyperactivity disorder (ADHD). Factors that may contribute to differences in sensitivity to Mn exposure are sex and genetic variation of proteins involved in the regulation of Mn concentrations. Here we investigate if sex and polymorphisms in Mn transporter genes SLC30A10 and SLC39A8 influence the association between Mn exposure and ADHD-related behavioral problems in children. The SNPs rs1776029 and rs12064812 in SLC30A10, and rs13107325 in SLC39A8 were genotyped by TaqMan PCR or pyrosequencing in a population of Italian children (aged 11-14 years; n = 645) with a wide range of environmental Mn exposure. Mn in surface soil was measured in situ using XRF technology or modeled by geospatial analysis. Linear regression models or generalized additive models (GAM) were used for analyzing associations between soil Mn and neurobehavioral problems assessed by the Conners' behavior rating scales (self-, and parent-reported). Gene-environment interactions (Mn transporter genotype x soil Mn) were evaluated using a genetic score in which genotypes for the three SNPs were combined based on their association with blood Mn, as an indication of their influence on Mn regulation. We observed differences in associations between soil Mn and neurobehavior between sexes. For several self-reported Conners' scales, girls showed U-shaped relationships with higher (worse) Conners' scoring at higher soil Mn levels, and several parent-reported scales showed positive linear relationships between increasing soil Mn and higher Conner's scores. For boys, we observed a positive linear relationship with soil Mn for one Conner's outcome only (hyperactivity, parent-reported). We also observed some interactions between soil Mn and the genetic score on Conner's scales in girls and girls with genotypes linked to high blood Mn showed particularly strong positive associations between soil Mn and parent-reported Conners' scales. Our results indicate that sex and polymorphisms in Mn transporter genes contribute to differences in sensitivity to Mn exposure from the environment and that girls that are genetically less efficient at regulating Mn, may be a particularly vulnerable group., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Throughout the history of life on Earth, abiotic components of the environment have shaped the evolution of life, and in turn life has shaped the environment. The element manganese embodies a special aspect of this collaboration; its history is closely entwined with those of photosynthesis and O 2 -two reigning features that characterize the biosphere today. Manganese chemistry was central to the environmental context and evolutionary innovations that enabled the origin of oxygenic photosynthesis and the ensuing rise of O 2 . It was also manganese chemistry that provided an early, fortuitous antioxidant system that was instrumental in how life came to cope with oxidative stress and ultimately thrive in an aerobic world. Subsequently, the presence of O 2 transformed the biogeochemical dynamics of the manganese cycle, enabling a rich suite of environmental and biological processes involving high-valent manganese and manganese redox cycling. Here, we describe insights from chemistry, biology, and geology, to examine manganese dynamics in the environment, and its unique role in the history of life., (Copyright © 2019 Elsevier Inc. All rights reserved.)

MAPK phosphatases (MKPs) are relevant negative regulators of MAPKs in eukaryotes as they mediate the feedback control of MAPK cascades in multiple cellular processes. Despite their relevance, our knowledge on the role of cereal MKPs in stress tolerance is scarce and TMKP1 remains today the only studied MKP in wheat. TMKP1 was previously reported to be involved in plant salt stress tolerance. Moreover, TMKP1 was shown to interact with calmodulin (CaM), 14-3-3 and TMPK3/TMPK6 proteins, which regulate its catalytic activity. To further understand the functional properties of TMKP1, we investigate here the contribution of its phosphorylation status, and of TMPK3 together with CaM and bivalent cations on the catalytic activity. In-gel kinase assays revealed that TMKP1 can be phosphorylated by similar wheat and Arabidopsis MAPKs, including most likely MPK3 and MPK6. In addition, we provide evidence for the capacity of wheat TMPK3 to bind to TMKP1 via a conserved Kinase Interacting Domain (KID) located on its C-terminal part. This interaction leads to a stimulation of TMKP1 activity in the presence of Mn 2+ or Mg 2+ ions, but to its inhibition in the presence of Ca 2+ ions. However, the phosphorylation status of TMKP1 seems to be dispensable for TMKP1 activation by TMPK3. Remarkably, in assays combining TMPK3 with CaM/Ca 2+ complex, we registered rather an inhibition of TMKP1 activity which however can be suppressed by Mn 2+ cations. Our data are in favor of complex differential regulation of TMKP1 by its MPK substrates, metallic cations that might help in fine-tuning the plant cellular responses to various stresses., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Rice stripe tenuivirus (RSV) initiates its mRNA transcription by using the cap-snatching mechanism during which an endonuclease activity is required for the cleavage of host mRNA. In this study, we aim to characterize the endonuclease in RSV. Sequence alignment revealed the presence of a cap-snatching endonuclease domain in RSV Pc1. Expression and in vitro enzymatic activity assay demonstrated that this domain indeed had a manganese-dependent endonuclease activity. The enzyme could efficiently degrade ssRNA with preference for unstructured ssRNA, but not DNA. Mutations in the endonuclease domain allowed the identification of four key residues (D547, D567, E585 and K604). The endonuclease of RSV was similar but not identical to other known viral endonucleases, suggesting that RSV endonuclease may have some distinct catalytic characteristics., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Fumarase (EC 4.2.1.2) is encoded in sunflower (Helianthus annuus L.) by two genes (FUM1 and FUM2) expressing correspondingly the mitochondrial and the cytosolic form. Both forms have been purified from sunflower cotyledons and characterized. Three quarters of fumarase activity is located in the mitochondrial and one quarter in the cytosolic fraction. The cytosolic form has lower pH optimum than the mitochondrial form, it possesses higher affinity to malate, activated by Mn 2+ and less efficiently by Mg 2+ while the mitochondrial form is activated only by Mg 2+ . It is proposed that the mitochondrial form is involved in the respiratory processes linked to the tricarboxylic acid cycle and the cytosolic form participates in the utilization of succinate produced in the glyoxylate cycle providing the flux to gluconeogenesis in germinating sunflower seeds., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

A protective effect by silicon in the amelioration of iron chlorosis has recently been proved for Strategy 1 species, at acidic pH. However in calcareous conditions, the Si effect on Fe acquisition and distribution is still unknown. In this work, the effect of Si on Fe, Mn, Cu and Zn distribution was studied in rice (Strategy 2 species) under Fe sufficiency and deficiency. Plants (+Si or-Si) were grown initially with Fe, and then Fe was removed from the nutrient solution. The plants were then analysed using a combined approach including LA-ICP-MS images for each element of interest, the analysis of the Fe and Si concentration at different cell layers of root and leaf cross sections by SEM-EDX, and determining the apoplastic Fe, total micronutrient concentration and oxidative stress indexes. A different Si effect was observed depending on plant Fe status. Under Fe sufficiency, Si supply increased Fe root plaque formation, decreasing Fe concentration inside the root and increasing the oxidative stress in the plants. Therefore, Fe acquisition strategies were activated, and Fe translocation rate to the aerial parts was increased, even under an optimal Fe supply. Under Fe deficiency, +Si plants absorbed Fe from the plaque more rapidly than -Si plants, due to the previous activation of Fe deficiency strategies during the growing period (+Fe + Si). Higher Fe plaque formation due to Si supply during the growing period reduced Fe uptake and could activate Fe deficiency strategies in rice, making it more efficient against Fe chlorosis alterations. Silicon influenced Mn and Cu distribution in root., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Lead (Pb) is a neurotoxic heavy metal, but the mechanism of its neurotoxicity is not clearly understood. Expression of metallothioneins (MTs) is induced in response to heavy metal exposure as a protective mechanism against heavy metal toxicity. There are several isoforms of MTs (MT-1 to 4), of which MT-3 is the neuron specific isoform, which also has neurite growth inhibitory effects. Whereas, the induction of MT-1 and 2 in response to Pb has been reported, the effect of Pb on the expression of MT-3 in the brain has not been documented. This study aimed at investigating the effect of Pb exposure on the expression of MT-3 in the cerebrum and hippocampus. Wistar rat pups were exposed to Pb via their dams' drinking water (0.2% lead acetate in deionized water) from postnatal day (PND) 0 to 21 and directly via drinking water until PND30. Expression of MT-3 was measured by Western blot and quantitative RT-PCR. MT-3 localization was done by immunohistochemistry. Divalent metal ions were analysed by atomic absorption spectrophotometry. Levels of Pb in blood and cerebrum were significantly increased, while that of copper (Cu), zinc (Zn) and manganese (Mn) were significantly decreased in the Pb-exposed rats at both PND21 and PND30. MT-3 protein was significantly increased in the cerebrum (by 2.5-fold) and in hippocampus (1.4 to 3.2-fold) in both PND21 and PND30 Pb-exposed rats over controls. MT-3 gene expression also increased in the cerebrum (by 42%), and in the hippocampus (by 65% and 43% in the PND21 and PND30 rats, respectively), in the Pb-exposed rats over controls, but the increase was statistically significant (p < 0.05) only in the PND30 rats. Pb exposure significantly increased (p < 0.05) percentage of MT-3 immunoreactive cells in Cornu Ammonis and dentate gyrus regions in the PND21 rats, and in the Cornu Ammonis 1, dentate gyrus and cortex regions in the PND30 rats. Our data thus provide convincing evidence that exposure to low levels of Pb during preweaning period increases the expression of MT-3 in the brain of rats., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Manganese (Mn) toxicity is frequently encountered in crops grown on soils with low pH or low redox potential, and harmful to plant development and growth. This study aimed at exploring adaptive mechanisms to Mn toxicity in rice, and investigated the effects of Mn toxicity on shoot lignification. Sixteen rice genotypes were grown in hydroponic solutions and exposed to normal (0.5 mg dm -3 ) or toxic (5 mg dm -3 ) Mn concentrations for three weeks. Morphological responses to Mn toxicity included a significant reduction in shoot length and the formation of visible symptoms scored as leaf damage index (LDI). Based on shoot Mn concentrations in the Mn toxic treatment, genotypes were classified as Mn includers and excluders. Across different genotypes, shoot Mn concentrations were significantly negatively correlated with relative shoot length and positively correlated with LDI. Consequently, the most tolerant genotypes in terms of morphology were all excluders, while the most sensitive genotypes were includers. The sensitive genotypes were also more responsive to manganese in terms of lipid peroxidation than tolerant genotypes. Shoots of rice plants grown in the high Mn treatment showed a higher level of lignification measured as thioglycolic acid lignin (TGAL), especially among Mn includers. TGAL was positively correlated with shoot Mn concentration and the levels of phenolics. In contrast, peroxidase activity was not responsive to the Mn treatment and was not significantly correlated with shoot lignification. In conclusion, exclusion is a dominant tolerance mechanism to Mn toxicity in rice. Further, Mn stimulated lignin biosynthesis in rice, especially in genotypes that were unable to exclude Mn., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: East Liverpool, Ohio, the site of a hazardous waste incinerator and a manganese (Mn) processor, has had air Mn concentrations exceeding United States Environmental Protection Agency reference levels for over a decade. Save Our County, Inc., a community organization, was formed to address community environmental health concerns related to local industry. Researchers from the University of Cincinnati partnered with Save Our County to determine if air Mn had an impact on the neurocognitive function of children in the community., Methods: Children 7-9 years of age from East Liverpool and its surrounding communities, were enrolled (N=106) in the Communities Actively Researching Exposure Study from between March 2013-June 2014. Blood and hair were analyzed for Mn and lead, and serum was analyzed for cotinine. We used linear regression to assess associations between biological measures and IQ subscale scores., Results: Geometric mean blood lead (n=67), blood Mn (n=66), hair Mn (n=98), and serum cotinine (n=69) concentrations were 1.13±1.96μg/dL, 10.06±1.30μg/L, and 360.22±2.17ng/g, 0.76±6.12μg/L respectively. After adjusting for potential confounders, hair Mn was negatively associated with Full Scale IQ., Conclusions: Hair Mn was negatively associated with child IQ scores. Community partners were instrumental in the conception and implementation of this study., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In a recent study, we found that blocking the protein kinase ataxia telangiectasia mutated (ATM) with the small molecule inhibitor (SMI) KU-55933 can completely abrogate Mn-induced phosphorylation of p53 at serine 15 (p-p53) in human induced pluripotent stem cell (hiPSC)-differentiated striatal neuroprogenitors. However, in the immortalized mouse striatal progenitor cell line STHdh Q7/Q7 , a concentration of KU55933 far exceeding its IC 50 for ATM was required to inhibit Mn-induced p-p53. This suggested an alternative signaling system redundant with ATM kinase for activating p53 in this cell line- one that was altered by KU55933 at these higher concentrations (i.e. mTORC1, DNApk, PI3K). To test the hypothesis that one or more of these signaling pathways contributed to Mn-induced p-p53, we utilized a set of SMIs (e.g. NU7441 and LY294002) known to block DNApk, PI3K, and mTORC1 at distinct concentrations. We found that the SMIs inhibit Mn-induced p-p53 expression near the expected IC 50s for PI3K, versus other known targets. We hypothesized that inhibiting PI3K reduces intracellular Mn and thereby decreases activation of p53 by Mn. Using the cellular fura-2 manganese extraction assay (CFMEA), we determined that KU55933/60019, NU7441, and LY294002 (at concentrations near their IC 50s for PI3K) all decrease intracellular Mn (∼50%) after a dual, 24-h Mn and SMI exposure. Many pathways are activated by Mn aside from p-p53, including AKT and mTOR pathways. Thus, we explored the activation of these pathways by Mn in STHdh cells as well as the effects of other pathway inhibitors. p-AKT and p-S6 activation by Mn is almost completely blocked upon addition of NU7441(5μM) or LY294002(7μM), supporting PI3K's upstream role in the AKT/mTOR pathway. We also investigated whether PI3K inhibition blocks Mn uptake in other cell lines. LY294002 exposure did not reduce Mn uptake in ST14A, Neuro2A, HEK293, MEF, or hiPSC-derived neuroprogenitors. Next, we sought to determine whether inhibition of PI3K blocked p53 phosphorylation by directly blocking an unknown PI3K/p53 interaction or indirectly reducing intracellular Mn, decreasing p-p53 expression. In-Cell Western and CFMEA experiments using multiple concentrations of Mn exposures demonstrated that intracellular Mn levels directly correlated with p-p53 expression with or without addition of LY294002. Finally, we examined whether PI3K inhibition was able to block Mn-induced p-p53 activity in hiPSC-derived striatal neuroprogenitors. As expected, LY294002 does not block Mn-induced p-p53 as PI3K inhibition is unable to reduce Mn net uptake in this cell line, suggesting the effect of LY294002 on Mn uptake is relatively specific to the STHdh mouse striatal cell line., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: In the state of Hidalgo, Mexico, is found the largest second deposit of Manganese (Mn) in Latin America. Various studies on the sources of emission, exposure, and the effects on the health of children and adults have been conducted utilizing an ecosystem approach. Given the findings of Mn levels in air and the neurocognitive effects, an Environmental Management Program (EMP) was designed and implemented with the purpose of reducing exposure to Mn of the population, including various actions for reducing Mn emissions into the atmosphere., Objective: To evaluate the impact of the EMP on the concentrations of Mn in air, as well as the modification of exposure to Mn in the blood and hair of adult residents of the communities intervened., Methods: A quasi-experimental study was conducted in five rural communities, in which Mn concentrations were evaluated in air and in blood in the years 2002 and 2007, pre-intervention, and in 2013, postintervention. In 2003, the concentration of hair Mn among the communities was evaluated. Measurements were carried out of Particulate Matter (PM) of >10 and 2.5μm (PM10 and PM2.5), and Mn in PM10 and PM2.5 were measured using proton-induced X-ray emissions (PIXE). The method of Difference in Differences (DID) was applied to estimate the impact of EMP on Mn concentrations in particulate matter via linear regression through multilevel models. To evaluate the effect of Mn concentrations in air over Mn concentrations in blood in both study periods in the mining communities per year (2002 and 2013), a linear regression model for each year was employed., Results: We estimated that the EMP contributed to reducing the average daily concentrations of Mn in PM10 and PM2.5 by 92 and 85%, respectively. The adjusted model did not show an effect of Mn concentrations in air over Mn concentrations in blood in both study periods., Conclusions: The results suggest that the measures implemented to reduce Mn emissions in air exerted a significant impact on the reduction of inhaled exposure in adult population., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Exposure to high levels of manganese (Mn) in occupational settings is known to lead to adverse neurological effects. Since Mn is an essential nutrient, there are mechanisms that maintain its homeostatic control in the body, and there is some level of Mn in air that does not perturb Mn homeostasis. However, the Mn exposure concentrations at which no adverse effects are expected in occupational settings vary considerably across regulatory agencies. We set out to derive a Mn Occupational Exposure Level (OEL) for welders based on a review of studies that evaluated Mn exposure concentrations from welding fumes and: (1) neurological effects in welders; (2) levels of Mn in the brains of welders (via pallidal index [PI] estimated from magnetic resonance imaging [MRI]); (3) other biomarkers of Mn exposure in welders (i.e., blood and urine); and (4) Mn brain concentrations, PI, and corresponding neurological effects in non-human primates. Our analysis suggests uncertainty in quantifying dose-response associations for Mn from many of the occupational welding studies. The few welding studies that adequately estimate exposure suggest a possible OEL of 100-140μg/m 3 for respirable Mn. This range is consistent with other epidemiology studies, studies of biomarkers of Mn exposure in welders, and with studies in non-human primates, though future studies could provide a stronger basis for deriving a Mn occupational guideline for welders., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Over the last few years, two rare, familial diseases that lead to the onset of manganese (Mn)-induced neurotoxicity have been discovered. Loss-of-function mutations in SLC30A10, a Mn efflux transporter, or SLC39A14, a Mn influx transporter, increase Mn levels in blood and brain, and induce severe neurotoxicity. The discoveries of these genetic diseases have transformed our understanding of Mn homeostasis, detoxification, and neurotoxicity. Current knowledge about the mechanisms by which mutations in these transporters alter Mn homeostasis to induce human disease is reviewed here., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Although an essential nutrient, manganese (Mn) can be toxic at high doses. There is, however, uncertainty regarding the effects of chronic low-level Mn-exposure. This review provides an overview of Mn-related brain and functional changes based on studies of a cohort of asymptomatic welders who had lower Mn-exposure than in most previous work. In welders with low-level Mn-exposure, we found: 1) Mn may accumulate in the brain in a non-linear fashion: MRI R1 (1/T1) signals significantly increased only after a critical level of exposure was reached (e.g., ≥300 welding hours in the past 90days prior to MRI). Moreover, R1 may be a more sensitive marker to capture short-term dynamic changes in Mn accumulation than the pallidal index [T1-weighted intensity ratio of the globus pallidus vs. frontal white matter], a traditional marker for Mn accumulation; 2) Chronic Mn-exposure may lead to microstructural changes as indicated by lower diffusion tensor fractional anisotropy values in the basal ganglia (BG), especially when welding years exceeded more than 30 years; 3) Mn-related subtle motor dysfunctions can be captured sensitively by synergy metrics (indices for movement stability), whereas traditional fine motor tasks failed to detect any significant differences; and 4) Iron (Fe) also may play a role in welding-related neurotoxicity, especially at low-level Mn-exposure, evidenced by higher R2* values (an estimate for brain Fe accumulation) in the BG. Moreover, higher R2* values were associated with lower phonemic fluency performance. These findings may guide future studies and the development of occupation- and public health-related polices involving Mn-exposure., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: Magnetic resonance spectroscopy (MRS) is a non-invasive method to quantify neurometabolite concentrations in the brain. Within the framework of the WELDOX II study, we investigated the association of exposure to manganese (Mn) and iron (Fe) with γ-aminobutyric acid (GABA) and other neurometabolites in the striatum and thalamus of 154 men., Material and Methods: GABA-edited and short echo-time MRS at 3T was used to assess brain levels of GABA, glutamate, total creatine (tCr) and other neurometabolites. Volumes of interest (VOIs) were placed into the striatum and thalamus of both hemispheres of 47 active welders, 20 former welders, 36 men with Parkinson's disease (PD), 12 men with hemochromatosis (HC), and 39 male controls. Linear mixed models were used to estimate the influence of Mn and Fe exposure on neurometabolites while simultaneously adjusting for cerebrospinal fluid (CSF) content, age and other factors. Exposure to Mn and Fe was assessed by study group, blood concentrations, relaxation rates R1 and R2* in the globus pallidus (GP), and airborne exposure (active welders only)., Results: The median shift exposure to respirable Mn and Fe in active welders was 23μg/m 3 and 110μg/m 3 , respectively. Airborne exposure was not associated with any other neurometabolite concentration. Mn in blood and serum ferritin were highest in active and former welders. GABA concentrations were not associated with any measure of exposure to Mn or Fe. In comparison to controls, tCr in these VOIs was lower in welders and patients with PD or HC. Serum concentrations of ferritin and Fe were associated with N-acetylaspartate, but in opposed directions. Higher R1 values in the GP correlated with lower neurometabolite concentrations, in particular tCr (exp(β)=0.87, p<0.01) and choline (exp(β)=0.84, p=0.04). R2* was positively associated with glutamate-glutamine and negatively with myo-inositol., Conclusions: Our results do not provide evidence that striatal and thalamic GABA differ between Mn-exposed workers, PD or HC patients, and controls. This may be due to the low exposure levels of the Mn-exposed workers and the challenges to detect small changes in GABA. Whereas Mn in blood was not associated with any neurometabolite content in these VOIs, a higher metal accumulation in the GP assessed with R1 correlated with generally lower neurometabolite concentrations., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Excessive manganese (Mn) accumulation in the brain may induce an extrapyramidal disorder known as manganism. Inflammatory processes play a critical role in neurodegenerative diseases. Therapeutically, non-steroidal anti-inflammatory drugs or analogous anti-inflammatory therapies have neuroprotective effects. As a non-steroidal anti-inflammatory drug, p-aminosalicylic acid (PAS) has anti-inflammatory effects, which are mediated by decreased prostaglandins E2 (PGE2) levels. The aim of the current study was to investigate whether PAS-Na treatment prevents Mn-induced behavioral changes and neuroinflammation in vivo. Male Sprague-Dawley rats were intraperitoneally (i.p.) injected with MnCl 2 ·4H 2 O (15mg/kg) for 12 weeks, followed by 6 weeks PAS-Na treatment. Sub-chronic Mn exposure increased Mn levels in the whole blood, cortex, hippocampus and thalamus, and induced learning and memory deficits, concomitant with astrocytes activation in the cortex, hippocampus and thalamus. Moreover inflammatory cytokine levels in serum and brain of Mn-treated group were increased, including IL-1β, IL-6, TNF-αand PGE2, especially in the hippocampus and thalamus. Furthermore, sub-chronic Mn exposure also increased inflammatory cytokines and COX-2 in transcription levels concomitant with increased MAPK signaling and COX-2 in the same selected brain regions. PAS-Na treatment at the highest doses also decreased Mn levels in the whole blood and selected brain tissues, and reversed the Mn-induced learning and memory deficits. PAS-Na inhibited astrocyte activation as well as the Mn-induced increase in inflammatory cytokine levels, reducing p38, ERK MAPK pathway and COX-2 activity. In contrast PAS-Na had no effects on the JNK MAPK pathway. These data establish the efficacy of PAS-Na not only as a chelating agent to mobilize whole blood Mn, but also as an anti-inflammatory agent., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Loss of function mutations in the P 5 -ATPase ATP13A2 are associated with Kufor-Rakeb Syndrome and Neuronal Ceroid Lipofuscinosis. While the function of ATP13A2 is unclear, in vitro studies suggest it is a lysosomal protein that interacts with the metals manganese (Mn) and zinc and the presynaptic protein alpha-synuclein. Loss of ATP13A2 function in mice causes sensorimotor deficits, enhanced autofluorescent storage material, and accumulation of alpha-synuclein. The present study sought to determine the effect of Mn administration on these same outcomes in ATP13A2-deficient mice. Wildtype and ATP13A2-deficient mice received saline or Mn at 5-9 or 12-19 months for 45days. Sensorimotor function was assessed starting at day 30. Autofluorescence was quantified in multiple brain regions and alpha-synuclein protein levels were determined in the ventral midbrain. Brain Mn, iron, zinc, and copper concentrations were measured in 5-9 month old mice. The results show Mn enhanced sensorimotor function, increased autofluorescence in the substantia nigra, and increased insoluble alpha-synuclein in the ventral midbrain in older ATP13A2-deficient mice. In addition, the Mn regimen used increased Mn concentration in the brain and levels were higher in Mn-treated mutants than controls. These results indicate loss of ATP13A2 function leads to increased sensitivity to Mn in vivo., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Manganese (Mn) is an essential metal that can become neurotoxic at elevated levels with negative consequences on neurodevelopment. We have evaluated the influence of single nucleotide polymorphisms (SNPs) in Mn transporter genes SLC30A10 and SLC39A8 on Mn concentrations in dentine, a validated biomarker that reflects Mn tissue concentrations early in life., Methods: The study included 195 children with variable environmental Mn exposure. Mn concentrations in dentine representing fetal, early postnatal and early childhood developmental periods were measured using laser ablation-inductively coupled plasma mass spectrometry. SLC30A10 rs12064812 (T/C) and SLC39A8 rs13107325 (C/T) were genotyped by TaqMan real time PCR and SLC30A10 rs1776029 (G/A) by pyrosequencing; and SNPs were analyzed in association with Mn in dentine., Results: SLC39A8 rs13107325 rare allele (T) carriers had significantly higher Mn concentrations in postnatal dentine (110%, p=0.008). For all SNPs we also observed non-significant associations with Mn concentrations in dentine in opposite directions for fetal and early postnatal periods. Furthermore, there were significant differences in the influence of SLC30A10 rs1776929 genotypes on Mn concentrations in dentine between sexes., Discussion: The findings from this study indicate that common SNPs in Mn transporters influence Mn homeostasis in early development and may therefore be important to consider in future studies of early life Mn exposure and health effects. Our results also suggest that the influence of these transporters on Mn regulation may differ by developmental stage, as well as between girls and boys., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Phosphoenolpyruvate carboxykinase (PEPCK) is well known as a key enzyme involved in the metabolic pathway of gluconeogenesis in organisms, but the information about its involvement in immune response is still very limited. In the present study, a novel PEPCK homolog named CgPEPCK was identified from oyster Crassostrea gigas. The deduced amino acid sequence of CgPEPCK shared 52%-74% similarities with those from other known PEPCKs. There were one conserved guanosine triphosphate (GTP) binding site, one substrate binding site, one metal binding site and one active site in CgPEPCK. The mRNA transcripts of CgPEPCK were constitutively expressed in all the tested tissues including hemolymph, mantle, gill, muscle, gonad and hepatopancreas. CgPEPCK proteins were mainly distributed in adductor muscle, gonad, gill and mantle, and rarely detected in hepatopancreas by using immunohistochemical analysis. After the stimulations with lipopolysaccharide (LPS), peptidoglycan (PGN), Vibrio splendidus and V. anguillarum, CgPEPCK transcripts in hemocytes were significantly up-regulated and peaked at 6 h (LPS, 9.62-fold, p < 0.01), 9 h (PGN, 4.25-fold, p < 0.01), 12 h (V. splendidus, 5.72-fold, p < 0.01), 3 h (V. anguillarum, 2.87-fold, p < 0.01), respectively. The recombinant CgPEPCK protein (rCgPEPCK) exhibited Mn 2+ /Mg 2+ dependent GTP binding activity, and the activities to bind LPS and PGN, but not β-1,3-glucan (GLU), lipoteichoic acid (LTA), mannan (MAN) nor polyinosinic-polycytidylic (Poly I: C). It could also bind Escherichia coli, Staphylococcus aureus, Micrococcus luteus and significantly inhibit their growth. All these results collectively suggested that CgPEPCK could not only exert GTP binding activity involved in gluconeogenesis, but also mediate the bacteria recognition and clearance in immune response of oysters., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Mentha aquatica is an aromatic herb which possesses valuable terpenoids constituents. Here, we intended to evaluate the effects of the different manganese (Mn) concentrations on the physiological, biochemical and molecular responses in M. aquatica. Basic Hoagland's solution (control), 40, 80, and 160 μM of Mn supplied as MnSO 4 ·H 2 O were applied to the nutrient solution. The results indicated that the different concentrations of Mn differently affected the physiological, biochemical and molecular responses in M. aquatica. The growth parameters (biomass and photosynthetic pigments) and expression levels of β-caryophyllene synthase (CPS), limonene synthase (Ls), geranyl diphosphate synthase (Gpps), and menthofuran synthase (Mfs) genes were increased at the moderate Mn concentrations (40 and 80 μM) and began to decrease at the higher levels. However, the contents of anthocyanins, flavonoids, malonaldehyde (MDA) and hydrogen peroxide (H 2 O 2 ), Mn accumulation, activities of antioxidant enzymes, yield of essential oils and the expression levels of 1-Deoxy d-xylulose-5-phosphate synthase (Dxs) and isopentenyl diphosphate isomerase (Ippi) genes were gradually increased with increasing concentration of Mn in the nutrient solution. Also, the content and chemical composition of terpenoid constituents were altered in the Mn-treated plants. Here, we suggest that the application of external Mn in nutrient solution elevates the growth and expression levels of the genes that are involved in the terpenoid biosynthesis pathway in M. aquatica. Nevertheless, the extent and stability of these growth and gene expression elevation are varied among the different Mn treatments., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

In order to study the response of tea plants to P stress, we conducted the ionomic and metabolomic analysis by ICP-OES, GC-MS and LC-MS. The results demonstrated that P was antagonistic with S, and was cooperative with Cu, Zn, Mn and Fe under P-deficiency. However, P was antagonistic with Mn, Fe and S, and was cooperative with Cu and Zn under P-excess. Moreover, P-deficiency or excess reduced the syntheses of flavonoids and phosphorylated metabolites. P-deficiency decreased the amount of glutamate and increased the content of glutamine, while P-excess decreased the content of glutamine. Besides, P-deficiency increased three organic acids and decreased three organic acids. P-excess increased the contents of malic acid, oxalic acid, ribonic acid and etc. involved in primary metabolism, but decreased the contents of p-coumaric acid, indoleacrylic acid, related to secondary metabolism. Furthermore, the contents of Mn and Zn were found to be positively related to the amounts of myricetin and quercetin, and the content of Mn to be positively related to the amount of arabinose. The results implied that the P stresses severely disturbed the metabolism of minerals and metabolites in tea plants, which influenced the yield and quality of tea., (Copyright © 2017. Published by Elsevier Masson SAS.)

We studied physiological traits and Mn transporter genes expression in ryegrass genotypes (One-50, Banquet-II, Halo-AR1 and Nui) under increasing Mn (2.4-750 μM) at short-term (8-24 h) in nutrient solution. An increment in Mn concentration occurred early in roots of all genotypes at increased Mn doses relative to control. Banquet-II and Nui roots showed the greatest Mn concentration at the highest Mn supply. Net photosynthesis (Pn) of Banquet-II and Halo-AR1 were not perturbed by Mn doses, whereas One-50 and Nui, decayed strongly at the highest Mn dose, concomitant with reduced total chlorophyll concentration. A high accumulation of Mn in roots together the maintained Pn under increased Mn doses in Banquet-II and Halo-AR1 suggest a higher Mn resistance of these genotypes. Stomatal conductance (gs) of all genotypes did not vary in presence of Mn. In roots of Banquet-II an augment of lipid peroxidation (LP) by Mn excess was observed earlier decreasing afterwards, being attenuated by the augment of the radical scavenging activity (RSA) and total phenols (TP) of this genotype. Mn concentration and LP in tissues of One-50 and Nui genotypes rose together, may be due to its Mn sensitivity. Differential expression of Mn transporter genes were found in the studied genotypes grown under increasing supplies of Mn, being MTP8.1 expressed in shoots and NRAMP2-like in roots. We concluded that Banquet-II showed greater Mn concentration associated to high roots NRAMP2-like gene expression, without changes in photosynthetic performance. Despite, this genotype showed an increase of LP at the first hours of Mn-excess, it was decreased by the RSA and TP. Halo-AR1 appears to be Mn-resistant in the short-term due to its photosynthetic performance was unchanged by Mn-toxicity, whilst One-50 and Nui were Mn-sensitive., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Over the last ten years, Chikungunya virus (CHIKV), an Old World alphavirus has caused numerous outbreaks in Asian and European countries and the Americas, making it an emerging pathogen of great global health importance. Venezuelan equine encephalitis virus (VEEV), a New World alphavirus, on the other hand, has been developed as a bioweapon in the past due to its ease of preparation, aerosol dispersion and high lethality in aerosolized form. Currently, there are no FDA approved vaccines against these viruses. In this study, we used a novel approach to develop inactivated vaccines for VEEV and CHIKV by applying gamma-radiation together with a synthetic Mn-decapeptide-phosphate complex (MnDpPi), based on manganous-peptide-orthophosphate antioxidants accumulated in the extremely radiation-resistant bacterium Deinococcus radiodurans. Classical gamma-irradiated vaccine development approaches are limited by immunogenicity-loss due to oxidative damage to the surface proteins at the high doses of radiation required for complete virus-inactivation. However, addition of MnDpPi during irradiation process selectively protects proteins, but not the nucleic acids, from the radiation-induced oxidative damage, as required for safe and efficacious vaccine development. Previously, this approach was used to develop a bacterial vaccine. In the present study, we show that this approach can successfully be applied to protecting mice against viral infections. Irradiation of VEEV and CHIKV in the presence of MnDpPi resulted in substantial epitope preservation even at supra-lethal doses of gamma-rays (50,000Gy). Irradiated viruses were found to be completely inactivated and safe in vivo (neonatal mice). Upon immunization, VEEV inactivated in the presence of MnDpPi resulted in drastically improved protective efficacy. Thus, the MnDpPi-based gamma-inactivation approach described here can readily be applied to developing vaccines against any pathogen of interest in a fast and cost-effective manner., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Brain manganese deposition is led by liver dysfunction and/or portal-systemic shunting in minimal hepatic encephalopathy (MHE). Manganese is toxic and can cause cognitive disorders and extrapyramidal symptoms. Thus, reduction of manganese intake might be considered as a potential treatment strategy for MHE. In this study we aimed to investigate whether low- or no-manganese feed can improve the neuropsychological manifestations in MHE rats. Rats with MHE were established by partially ligating the portal vein and fed a manganese diet (MHE-M, 10mg per kg feed; n=24), a no-manganese diet (MHE-N; n=24) and a half-manganese diet (MHE-H; n=24) for 2, 4, 6 and 8weeks, with six rats in each subgroup. Morris water maze (MWM), open-field test and narrow beam test (NBT) were used to evaluate the cognitive and locomotor situations. Fasted blood ammonia, manganese content and glutamine synthetase (GS) activity in basal ganglia and cortex were measured. A significantly longer MWM escape latency, less locomotor activity, longer NBT latency and total time, higher blood ammonia, higher brain manganese content and GS activity were found in MHE-M rats. However, a significantly shorter MWM escape latency, increased locomotor activity, shorter NBT latency and total time, lower blood ammonia, lower brain manganese content and lower GS activity were found in MHE-N rats after no-manganese feed treatment. Partial improvements were found in MHE rats with half-manganese feed treatment. Reduction of manganese intake can significantly improve the cognitive and locomotor situations in MHE rats by reducing brain manganese content and regulating GS activity., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

Manganese (Mn) is an essential element for plants; however, high concentrations in certain soil conditions can cause toxicity symptoms in the plant tissue. Here, we describe Mn toxicity symptoms and Mn toxicity responses in soybean plants. Soybean plants exposed to excess Mn showed reductions in the CO 2 assimilation rate and stomatal conductance, which in turn resulted in decreased shoot biomass. Furthermore, peroxidase (POD), superoxide dismutase (SOD), and catalase (CAT) activity were higher in plants grown with the highest Mn concentration. The Mn doses increased the activity of antioxidant enzymes such as CAT, POD, and SOD. The toxicity symptoms presented by the leaves included hypertrophying of the adaxial epidermis and the formation of necrotic areas with purple-colored veins. Dramatic movement of calcium from the healthy region to the purple-colored necrotic region was observed, as was the exit of potassium from the necrotic area to the healthy region of the tissue. The high activities of POD and SOD in the presence of high Mn compartmented in the roots was the main physiological responses at high Mn uptake by soybean plants., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Mn is an essential element that causes neurotoxicity in humans when inhaled at high concentrations. This metal has well-recognized route-dependent differences in absorption, with greater proportionate uptake for inhalation versus dietary exposure. Physiologically-based pharmacokinetic (PBPK) models for Mn have included these route specific differences in uptake and their effect on delivery of Mn to target tissues via systemic circulation. These PBPK models include components describing ingestion and inhalation, homeostatic control (concentration dependent biliary elimination and gastrointestinal absorption), and delivery to target sites within the brain. The objective of this study was to combine PBPK modeling of target tissue Mn concentration and categorical regression analysis to identify Mn intake levels (both by food and air) that are expected to cause minimal toxicity. We first used the human PBPK model to describe blood Mn data from three occupational exposure studies, demonstrating consistency between model predictions and measured data. The PBPK model was then used to predict concentrations of Mn in the globus pallidus (the presumed target tissue for motor function disruption in humans) for various epidemiological studies. With the predicted globus pallidus concentration of Mn, we conducted categorical regression modeling between globus pallidus Mn and severity-scored neurological outcome data from the human cohorts. This structured tissue dose - response analysis led to an estimated 10% extra risk concentration (ERC 10 ) of 0.55μg/g Mn in the globus pallidus, which is comparable to similar values estimated by the Agency of Toxic Substances and Disease Registry and Health Canada (after translation from external exposure to tissue dose). The steep dose-response curve below this ERC 10 value may be used to inform the choice of adjustment factor to translate the ERC 10 as a point of departure to a reference concentration for occupational or environmental exposure to Mn. Because these results are based on human epidemiological data and a human PBPK model, adjustment or translation of results from animals to humans is not required., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Boca de Camichin Estuary is one of the main producers of Crassostrea corteziensis oysters in Mexico, but the presence of pollutants can affect oyster production. Molluscs produce reactive oxygen species (ROS) in response to changes in the environment and pollution. These ROS induce oxidative damage in biomolecules. The main objective of this study was to evaluate pollution in the estuary and the subsequent oxidative stress in C. corteziensis oysters during the 2010 production cycle. For this aim, we performed monthly samplings in the oyster farms from January to May. We took water samples to quantify polycyclic aromatic hydrocarbon (PAH) and metal content; also, we evaluated oxidative damage (lipoperoxidation, lipidic hydroperoxides, protein oxidation) and enzyme activity (CAT, SOD, GPx, GST and AChE) in oyster gills. The results show the presence of Cu, Fe, Mn, naphthalene, benz[a]anthracene, pyrene, benz[a]pyrene and benzo[k]fluoranthene. On the other hand, AChE activity was not inhibited, which suggests that organophosphorus pollutants or carbamates were absent. Regarding oxidative stress, oysters from the estuary had oxidative damage in lipids, not proteins, and altered antioxidant enzyme activity, when compared to control organisms. Interestingly, we did not observe any correlation between the pollutants and the oxidative stress parameters evaluated in this study. Thus, we cannot rule out that a synergistic effect between the environmental variables and the pollutants is causing the oxidative stress in these oysters., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The degenerative actions of Mn caused by persistent exposure to high atmospheric levels not only provokes irreversible damage to the CNS with symptoms comparable to that of Parkinson's disease but also may have deleterious consequences to other organs including the auditory system. The putative deleterious consequences of prolonged Mn overexposure on hearing, however, is confounded by the fact that chronically-exposed individuals often work in high noise environments where noise by itself is known to cause hearing loss. Thus, the question as to whether Mn alone is actually ototoxic and whether exposure to Mn when combined with noise increases the risk of hearing loss and cochlear pathology has never been examined. To examine whether noise effects Mn ototoxicity, we exposed rats to a moderate dose of Mn (10mg MnCl2/liter water) alone, a high level of noise (octave band noise, 8-16kHz, presented at 90dB SPL for 8h/d) alone or the combination of Mn plus noise and measured the changes in auditory function and the cochlear histopathologies. Results of these studies, based on various measures of hearing including histological examination of cochlear tissue suggest that noise alone produced significant hearing deficits whereas semi-chronic exposure to moderate levels of Mn in drinking water for 90days either in the presence or absence of noise had, at best, only a minor effect on hearing., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Ellagic acid, a natural phenol compound found in numerous fruits and vegetables, causes various physiological effects in different cell models. However, the effect of this compound on Ca(2+) homeostasis in liver cells is unknown. This study examined the effect of ellagic acid on intracellular Ca(2+) concentration ([Ca(2+)]i) and established the relationship between Ca(2+) signaling and cytotoxicity in liver cells. The data show that ellagic acid induced concentration-dependent [Ca(2+)]i rises in HepG2 human hepatoma cells, but not in HA22T, HA59T human hepatoma cells or AML12 mouse hepatocytes. In HepG2 cells, this Ca(2+) signal response was reduced by removing extracellular Ca(2+) and was inhibited by store-operated Ca(2+) channel blockers (2-APB, econazole or SKF96365) and the protein kinase C (PKC) inhibitor GF109203X. In Ca(2+)-free medium, pretreatment with the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin abolished ellagic acid-induced [Ca(2+)]i rises. Conversely, incubation with ellagic acid abolished thapsigargin-induced [Ca(2+)]i rises. Inhibition of phospholipase C (PLC) with U73122 also abolished ellagic acid-induced [Ca(2+)]i rises. Ellagic acid (25-100μM) concentration-dependently caused cytotoxicity in HepG2, HA22T or HA59T cells, but not in AML12 cells. Furthermore, this cytotoxic effect was partially prevented by prechelating cytosolic Ca(2+) with BAPTA-AM only in HepG2 cells. Together, in HepG2 cells, ellagic acid induced [Ca(2+)]i rises by inducing PLC-dependent Ca(2+) release from the endoplasmic reticulum and Ca(2+) entry via PKC-sensitive store-operated Ca(2+) channels. Moreover, ellagic acid induced Ca(2+)-associated cytotoxicity., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Manganese catalases (Mn-catalases), a class of H2O2 detoxifying proteins, are structurally and mechanistically distinct from the commonly occurring catalases, which contain heme. Active site of Mn-catalases can serve as template for the synthesis of catalase mimetics for therapeutic intervention in oxidative stress related disorders. However, unlike the heme catalases, structural aspects of Mn-catalases remain inadequately explored. The genome of the ancient cyanobacterium Anabaena PCC7120, shows the presence of two Mn-catalases, KatA and KatB. Here, we report the biochemical and structural characterization of KatB. The KatB protein (with a C-terminal his-tag) was over-expressed in Escherichia coli and purified by affinity chromatography. On the addition of Mn(2+) to the E. coli growth medium, a substantial increase in production of the soluble KatB protein was observed. The purified KatB protein was an efficient catalase, which was relatively insensitive to inhibition by azide. Crystal structure of KatB showed a hexameric assembly with four-helix bundle fold, characteristic of the Ferritin-like superfamily. With canonical Glu4His2 coordination geometry and two terminal water ligands, the KatB active site was distinctly different from that of other Mn-catalases. Interestingly, the KatB active site closely resembled the active sites of ruberythrin/bacterioferritin, bi-iron members of the Ferritin-like superfamily. The KatB crystal structure provided fundamental insights into the evolutionary relationship within the Ferritin-like superfamily and further showed that Mn-catalases can be sub-divided into two groups, each with a distinct active site configuration., (Copyright © 2016 Elsevier Inc. All rights reserved.)