Search

Cerebral ischemia is the important cause of worldwide disability and mortality, that is one of the obstruction of blood vessels supplying to the brain. In early stage, glutamate excitotoxicity and high level of intracellular calcium (Ca2+) are the major processes which can promote many downstream signaling involving in neuronal death and brain tissue damaging. Moreover, autophagy, the reusing of damaged cell organelles, is affected in early ischemia. Under ischemic conditions, autophagy plays an important role to maintain energy of the brain and its function. In the other hand, over intracellular Ca2+ accumulation triggers excessive autophagic process and lysosomal degradation leading to autophagic process impairment which finally induce neuronal death. This article reviews the association between intracellular Ca2+ and autophagic process in acute stage of ischemic stroke. [ABSTRACT FROM AUTHOR]

Sphagnum mosses are poikilohydric bryophytes, i.e. dependent on nearly-constant wet conditions. Exposure to mineral-enriched water has long been recognised as a threat to Sphagnum mosses and a driver of niche formation. Atrophy of Sphagnum is currently attributed to high pH in combination with high calcium concentration. Because the natural occurrence of high pH regularly auto-correlates with alkalinity and calcium concentration it remains unclear which of these factors is detrimental to Sphagnum. In a ten-week controlled laboratory experiment we measured the effects of high pH and bicarbonate concentration in combination with various cations (Ca2+, Na+, K+, Mg2+, Fe3+) on K+ leakage and survival in Sphagnum palustre L. Increased pH (7.2) combined with low (≤ 200 µmol L-1) bicarbonate concentration had no effect. In contrast, high bicarbonate levels (supplied or formed in solution) combined with pH values of 8.0 and higher produced signs of physiological stress (chlorosis and electrolyte leakage) within two weeks and were toxic in all treatments. Cations failed to modulate the adverse effects of high alkalinity; nor could additional potassium alleviate detrimental effects. This study shows that S. palustre is adversely affected by increased bicarbonate concentration and alkalinity, which both show a tight correlation with pH and often with calcium levels in water and bedrock. The management of groundwater and surface water sources for restoration of Sphagnum-dominated habitats and irrigation of Sphagnum farms should focus on lowering alkalinity levels (including pH), whereas cation concentrations may remain elevated.

Abstract: To study mechanism underpinning the calcifuge habit of some Lupinus species, especially under low‐phosphorus (P) conditions, Lupinus species that were likely to respond differently to calcium (Ca) availability were assembled, and the sensitivity to Ca under a low‐P supply was assessed. Seven Lupinus species (9 genotypes, L. albus L. cv Kiev, L. albus L. P26766, L. angustifolius L. cv Mandelup, L. angustifolius L. P26723, L. luteus L. cv Pootalong, L. hispanicus ssp. bicolor Boiss. and Reut. P22999, L. pilosus Murr. P27440, L. cosentinii Guss. P27225, and L. atlanticus Gladst. P27219) were grown hydroponically at 10 or 6000 μM Ca. Leaf symptoms, gas exchange and biomass were recorded; leaf and root nutrient concentrations were analysed, and the leaf cell types in which Ca and P accumulated were determined using elemental X‐ray microanalyses. Calcium toxicity was demonstrated for L. angustifolius P26723, L. hispanicus ssp. bicolor. P22999, and L. cosentinii P27225, whereas the other species were tolerant of a high Ca supply under low‐P conditions. In addition, genotypic differences in Ca toxicity were found within L. angustifolius. Most Ca accumulated in the mesophyll cells in all species, whereas most P was located in epidermal cells. [ABSTRACT FROM AUTHOR]

Despite its key role in the molecular pathology of Alzheimer's disease (AD), the physiological function of amyloid precursor protein (APP) is unknown. Increasing evidence, however, points towards a neuroprotective role of this membrane protein in situations of metabolic stress. A key observation is the up-regulation of APP following acute (stroke, cardiac arrest) or chronic (cerebrovascular disease) hypoxic-ischemic conditions. While this mechanism may increase the risk or severity of AD, APP by itself or its soluble extracellular fragment APPsα can promote neuronal survival. Indeed, different animal models of acute hypoxia-ischemia, traumatic brain injury (TBI) and excitotoxicity have revealed protective effects of APP or APPsα. The underlying mechanisms involve APP-mediated regulation of calcium homeostasis via NMDA receptors (NMDAR), voltage-gated calcium channels (VGCC) or internal calcium stores. In addition, APP affects the expression of survival- or apoptosis-related genes as well as neurotrophic factors. In this review, we summarize the current understanding of the neuroprotective role of APP and APPsα and possible implications for future research and new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Phosphogypsum (PG) is a metal and radionuclide rich-waste produced by the phosphate ore industry, which has been used as soil fertilizer in many parts of the world for several decades. The positive effects of PG in ameliorating some soil properties and increasing crop yields are well documented. More recently concerns are emerging related with the increase of metal/radionuclide residues on soils and crops. However, few studies have focused on the impact of PG applications on soil biota, as well as the contribution to soils with elements in mobile fractions of PG which may affect freshwater species as well. In this context the main aim of this study was to assess the ecotoxicity of soils amended with different percentages of Tunisian phosphogypsum (0.0, 4.9, 7.4, 11.1, 16.6 and 25%) and of elutriates obtained from PG – amended soil (0.0, 6.25, 12.5 and 25% of PG) to a battery of terrestrial ( Eisenia andrei , Enchytraeus crypticus , Folsomia candida , Hypoaspis aculeifer , Zea mays , Lactuca sativa ) and aquatic species ( Vibrio fischeri , Daphnia magna , Raphidocelis subcapitata , Lemna minor ). Both for amended soils and elutriates, invertebrates (especially D. magna and E. andrei ) were the most sensitive species, displaying acute (immobilization) and chronic (reproduction inhibition) effects, respectively. Despite the presence of some concerning metals in PG and elutriates (e.g., zinc and cadmium), the extremely high levels of calcium found in both test mediums, suggest that this element was the mainly responsible for the ecotoxicological effects observed. Terrestrial and aquatic plants were the most tolerant species, which is in line with studies supporting the application of PG to increase crop yields. Nevertheless, no stimulatory effects on growth were observed for any of the species tested despite the high levels of phosphorus added to soils by PG. Given the importance of soil invertebrates for several soil functions and services, this study gives rise to new serious concerns about the consequences of PG applications on agricultural soils. [ABSTRACT FROM AUTHOR]

The effluents discharged from Mansoura Company for Resins and Chemicals Industry were evaluated for drinking and irrigation purposes. Calcium-alginate beads were used for effluents treatment in this study. Young male rats were also allowed to drink effluents at different concentrations (10%, 50%, 100%) and treated 100% effluents with calcium-alginate for 11 weeks. Results indicated high concentrations of some physicochemical parameters and Cd, Co, Fe, Mn, Ni, Pb, and Zn in effluents that exceeded the permissible limits for drinking and irrigation purposes. Treatment by calcium-alginate alleviate heavy metals concentration but did not affect the physicochemical parameters. Depending on effluents concentration, the liver of young male rats showed high accumulation of Fe, Mn, Zn, Pb, Cd, Co, Cu, Cr, and Ni compared to the control group. Serum levels of liver enzymes, total bilirubin significantly increased while total protein, and albumin contents decreased in effluent groups. Liver concentrations of malondialdehyde and protein carbonyl significantly elevated along with significant decrease in superoxide dismutase, catalase, glutathione-S-transferase activities, and glutathione content. Moreover, growth and thyroid hormones were significantly reduced along with significant elevation in thyroid stimulating hormone. This was accompanied by significant decrease in the body weight, especially with 100% effluents concentration compared to control group. Also, histological investigations of both liver and thyroid gland using hematoxylin and eosin showed distortion in the structure of both organs especially with 50% and 100% effluent groups. However, treatment of effluents by calcium-alginate improved these changes. The study revealed that calcium-alginate are effective biosorbents for heavy metals and consequently decrease animal and human health hazards, but further studies are needed to alleviate physicochemical characteristics., (© 2022. The Author(s).)

Copyright of Neuroscience Bulletin is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Whereas alcohol itself, even in high concentrations, has little effect on the functional performance of isolated pancreatic acinar cells, non-oxidative metabolites (fatty acid ethyl esters [FAEE] and fatty acids [FA]) can cause Ca2+-dependent necrosis. The mechanism of action of FAEE has been investigated using a combination of patch clamp whole-cell current recording and Ca2+ imaging. At low stimulation intensities, FAEE evoke repetitive short-lasting cytosolic Ca2+ spikes, which are inhibited by caffeine, used as an inositol trisphosphate receptor antagonist. With more intense stimulation, sustained elevations of the cytosolic Ca2+ concentration are observed, which can be prevented by pharmacological inhibition of the conversion of FAEE to FA. It is therefore the FA and not the FAEE that cause necrosis. The effect of FA cannot be blocked by inositol trisphosphate receptor antagonists. Fatty acids elicit a marked reduction in the cytosolic adenosine triphosphate (ATP) level. The patch clamp experiments show that the toxic sustained Ca2+ signal generation induced by FA can be prevented by adding ATP to the cell interior. The toxic alcohol effects are principally due to FAEE produced under non-oxidative conditions and their subsequent conversion to FA. The FA-induced necrosis is Ca2+-dependent. The destructive sustained Ca2+ signals are due to inhibition of mitochondrial function with failure of ATP generation. [ABSTRACT FROM AUTHOR]

In orthopedic surgery, metals are preferred to support or treat damaged bones due to their high mechanical strength. However, the necessity for a second surgery for implant removal after healing creates problems. Therefore, biodegradable metals, especially magnesium (Mg), gained importance, although their extreme susceptibility to galvanic corrosion limits their applications. The focus of this study was to control the corrosion of Mg and enhance its biocompatibility. For this purpose, surfaces of magnesium-calcium (MgCa1) alloys were modified with calcium phosphate (CaP) or CaP doped with zinc (Zn) or gallium (Ga) via microarc oxidation. The effects of surface modifications on physical, chemical, and mechanical properties and corrosion resistance of the alloys were studied using surface profilometry, goniometry, scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), nanoindentation, and electrochemical impedance spectroscopy (EIS). The coating thickness was about 5-8 μm, with grain sizes of 43.1 nm for CaP coating and 28.2 and 58.1 nm for Zn- and Ga-doped coatings, respectively. According to EIS measurements, the capacitive response ( Y c ) decreased from 11.29 to 8.72 and 0.15 Ω -1 cm -2 s n upon doping with Zn and Ga, respectively. The E corr value, which was -1933 mV for CaP-coated samples, was found significantly electropositive at -275 mV for Ga-doped ones. All samples were cytocompatible according to indirect tests. In vitro culture with Saos-2 cells led to changes in the surface compositions of the alloys. The numbers of cells attached to the Zn-doped (2.6 × 10 4 cells/cm 2 ) and Ga-doped (6.3 × 10 4 cells/cm 2 ) coatings were higher than that on the surface of the undoped coating (1.0 × 10 3 cells/cm 2 ). Decreased corrosivity and enhanced cell affinity of the modified MgCa alloys (CaP coated and Zn and Ga doped, with Ga-doped ones having the greatest positive effect) make them novel and promising candidates as biodegradable metallic implant materials for the treatment of bone damages and other orthopedic applications.

Enamel cells handle large amounts of calcium, particularly during the developmental phase (termed maturation) when dental enamel is hypermineralized. The extent of intracellular calcium burden, and the nature of calcium homeostasis machinery used to accommodate it. are largely unknown. Here, the calcium-binding capacity of enamel cell cytosol was found to increase during development, in parallel with the putative transcellular flux of calcium. At maturation, the abundance of calcium-binding proteins in enamel cells exceeded that in brain and other established calcium-oriented tissues, which implies a large calcium burden. A search for likely cytosolic calcium transporters revealed only one high-affinity calcium-binding protein (12 kDa. distinguished from a-parvalbumin) that was up-regulated during maturation, but its low abundance (0.02% of soluble protein) precluded a major calcium transport or cytoprotective role. Two low-affinity calcium-binding proteins up-regulated during maturation (by 1.8-fold and 2.1- fold, respectively) were identified as calreticulin and endoplasmin. both residents of the endoplasmic reticulum. Together. calreticulin and endoplasmin constituted an exceptionally high proportion (5%) of soluble protein during maturation, which gives an inferred calcium capacity 67-fold higher than that of the principal cytosolic calcium-binding protein. 28-kDa calbindin. Evidence that endoplasmin expression varied inversely with serum calcium concentration, and that the inositol trisphosphate receptor also was highly expressed during maturation, supported the novel hypothesis that non-mitochondrial calcium stores play a major role in transcellular calcium transport. In conclusion: (a) enamel cells contain a general high abundance of calcium homeostasis proteins, consistent with a heavy intracellular calcium burden; (b) the expression pattern (phenotype) of calcium-binding proteins varies with enamel cell function: (c) enamel cells appear to contain unusually large non-mitochondrial calcium stores: (d) contrary to the prevailing view that calcium passes mainly through the cytosol of calcium-transporting cells, the findings imply a route through the endoplasmic reticulum. This study gives novel information about how a highly calcium- oriented tissue avoids calcium toxicity. and provides a new focus for investigations into the mechanisms of transcellular calcium transport. [ABSTRACT FROM AUTHOR]

Although calcium plays an important role in the activation of leukocytes for such processes as eicosanoid biosynthesis, secretion of granular constituents and superoxide generation, sustained high levels of intracellular calcium ions may be toxic. We have previously found that high concentrations of calcium ionophores induce a rapid-onset 'calcium overload' toxicity in rat peritoneal leukocytes, in which functional responses such as β-glucuronidase secretion, superoxide generation and leukotriene B synthesis are greatly attenuated, and some leakage of cytoplasmic LDH occurs. We have now compared this phenomenon in peritoneal leukocytes elicited from animals pretreated in three ways: glycogen, interleukin-1β (IL-1β) alone or glycogen plus IL-1β. Peritoneal administration of IL-1β caused elicitation of cells which were enriched in eosinophils; however, the functional responses of the cells in all three groups were broadly similar in terms of the ability of the agonists FMLP, PMA and A23187 to initiate superoxide generation, β-glucuronidase secretion and leukotriene generation. Cells from all three treatment groups showed diminished responsiveness at 10 M A23187, indicative of calcium overload toxicity. This was most evident for the superoxide and β-glucuronidase responses. Some quantitative differences observed between treatment groups may reflect the different sensitivities of the various cells contained in the mixed leukocyte preparations. We conclude that IL-1β induces leukocyte emigration into the peritoneal cavity but that the cell population is different from that induced by glycogen. However, the cells retain susceptibility to calcium overload toxicity. [ABSTRACT FROM AUTHOR]

The quality and quantity of groundwater resources are affected by landuse/landcover (LULC) dynamics, particularly the increasing urbanization coupled with high household wastewater discharge and decreasing open lands. This study evaluates temporal changes of groundwater quality for 2012 and 2019, its relation to Landuse/landcover, and its impact on Peshawar's residents (study area), Pakistan. A total of 105 and 112 groundwater samples were collected from tube wells in 2012 and 2019. Samples were then analyzed for seven standard water quality parameters (i.e., pH, electric conductivity (EC), turbidity, chloride, calcium, magnesium, and nitrate). Patient data for waterborne diseases were also collected for the years 2012 and 2019 to relate the impact of groundwater quality on human health. Landsat satellite images were classified for the years 2012 and 2019 to observe landuse/landcover dynamics concerning groundwater quality. Results manifested a decrease in groundwater quality for the year 2019 compared to 2012 and were more highlighted in highly populated areas. The nitrate concentration level was found high in the vicinity of agricultural areas due to the excessive use of nitrogenous fertilizers and pesticides, and thus the methemoglobinemia patients ratio increased by 14% (48-62% for the year 2012 and 2019, respectively). Besides, Urinary Tract Infections, Peptic Ulcer, and Dental Caries diseases increased due to the high calcium and magnesium concentration. The overall results indicate that anthropogenic activities were the main driver of Spatio-temporal variability in groundwater quality of the study area. The study could help district health administration understand groundwater quality trends, make appropriate site-specific policies, and formulate future health regulations., (© 2021. The Author(s).)

Background: Rodent brain slices-particularly hippocampal slices-are widely used in experimental investigations of epileptiform activity. Oxygenated artificial cerebrospinal fluid (ACSF) is used to maintain slices in vitro. Physiological or standard ACSF containing 3-3.5 mM K + , 1-2 mM Mg 2+ , and 1-3 mM Ca 2+ generally does not induce population epileptiform activity, which can be induced by ACSF with high K + (8-10 mM), low Mg 2+ , or low Ca 2+ alone or in combination. While low-Mg 2+ ACSF without intentionally added Mg salt but with contaminating Mg 2+ (≤ 50-80 µM) from other salts can induce robust epileptiform activity in slices, it is unclear whether such epileptiform activity can be achieved using ACSF with moderately decreased Mg 2+ . To explore this issue, we examined the effects of moderately modified (m)ACSF with 0.8 mM Mg 2+ , 1.3 mM Ca 2+ , and 5.7 mM K + on induction of epileptiform discharges in mouse hippocampal slices., Results: Hippocampal slices were prepared from young (21-28 days old), middle-aged (13-14 months old), and aged (24-26 months old) C57/BL6 mice. Conventional thin (0.4 mm) and thick (0.6 mm) slices were obtained using a vibratome and pretreated with mACSF at 35-36 °C for 1 h prior to recordings. During perfusion with mACSF at 35-36 °C, spontaneous or self-sustained epileptiform field potentials following high-frequency stimulation were frequently recorded in slices pretreated with mACSF but not in those without the pretreatment. Seizure-like ictal discharges were more common in thick slices than in thin slices., Conclusions: Prolonged exposure to mACSF by pretreatment and subsequent perfusion can induce epileptiform field potentials in mouse hippocampal slices., (© 2021. The Author(s).)

Background: Metals play an important role in type 2 diabetes mellitus (T2DM). This study aimed to explore the association of T2DM risk with single metal exposure and multi-metal co-exposure., Methods: A case-control study with 223 T2DM patients and 302 controls was conducted. Serum concentrations of 19 metals were determined by inductively coupled plasma mass spectrometry (ICP-MS). Those metals with greater effects were screened out and co-exposure effects of metals were assessed by least absolute shrinkage and selection operator (LASSO) regression., Results: Serum calcium (Ca), selenium (Se) and vanadium (V) were found with greater effects. Higher levels of Ca and Se were associated with increased T2DM risk (OR = 2.23, 95%CI: 1.38-3.62, P trend  = 0.002; OR = 3.16, 95%CI: 1.82-5.50, P trend  < 0.001), but higher V level was associated with decreased T2DM risk (OR = 0.58, 95%CI: 0.34-0.97, P trend  < 0.001). Serum Ca and V concentrations were nonlinearly associated with T2DM risk (P overall  < 0.001, P nonliearity  < 0.001); however, Se concentration was linearly associated with T2DM risk (P overall  < 0.001, P nonliearity  = 0.389). High co-exposure score of serum Ca, Se and V was associated with increased T2DM risk (OR = 3.50, 95%CI: 2.08-5.89, P trend  < 0.001) as a non-linear relationship (P overall  < 0.001, P nonliearity  = 0.003)., Conclusions: This study suggest that higher levels of serum Ca and Se were associated with increased T2DM risk, but higher serum V level was associated with decreased T2DM risk. Moreover, co-exposure of serum Ca, Se and V was nonlinearly associated with T2DM risk, and high co-exposure score was positively associated with T2DM risk., 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 Ltd. All rights reserved.)

Accumulation of toxic metals in infants/children is of serious concern worldwide, from the viewpoint of their harmful effects on the normal growth and development. This metallomics study investigates the extent of toxic metal burdens in infants/children and the relationship to those in their mothers for 77 child/mother pair subjects. For mercury, its geometric mean concentration in infants/children was of similar level to that in their mothers, and a high-significant close correlation was observed between infants/children and their mothers (β = 0.758, r = 0.539, p < 0.0001). A significant but less intimate mother/child relationship was observed for arsenic (β = 0.301, r = 0.433), lead (β = 0.444, r = 0.471) and aluminum (β = 0.379, r = 0.451). Remarkably, the burden levels of lead, cadmium and aluminum in infants/children were approximately three times higher than those in their mothers ( p < 0.0001), and the burden levels in some individuals were several tens of times higher than in the mothers. In contrast, some essential metal levels such as zinc, magnesium and calcium in infants/children were significantly lower than those in their mothers, and 29 individuals (37.7%) in the child subjects were estimated to be zinc-deficient. In addition, significant inverse correlations were observed between zinc and lead (r = -0.267, p = 0.019), and magnesium and arsenic (r = -0.514, p < 0.0001). These findings suggest that these toxic metal burdens and essential metal deficiencies in infants/children are of serious concern for their neurodevelopment, indicating that the early assessment and intervention are crucial. It is expected that larger epidemiological and intervention studies will provide a reasonable and essential pathway for intervention of neurodevelopment disorders.

Therapy resistance is a major roadblock in oncology. Exacerbation of molecular dysfunctions typical of cancer cells have proven effective in twisting oncogenic mechanisms to lethal conditions, thus offering new therapeutic avenues for cancer treatment. Here, we demonstrate that selective agonists of Transient Receptor Potential cation channel subfamily M member 8 (TRPM8), a cation channel characteristic of the prostate epithelium frequently overexpressed in advanced stage III/IV prostate cancers (PCa), sensitize therapy refractory models of PCa to radio, chemo or hormonal treatment. Overall, our study demonstrates that pharmacological-induced Ca 2+ cytotoxicity is an actionable strategy to sensitize cancer cells to standard therapies.

This study investigates the impacts of exposure to an environment Ca 2+ challenge and the mechanism of action of dibutyl phthalate (DBP) on Ca 2+ influx in the gills of Danio rerio. In vitro profile of 45 Ca 2+ influx in gills was verified through the basal time-course. Fish were exposed to low, normal and high Ca 2+ concentrations (0.02, 0.7 and 2 mM) for 12 h. So, gills were morphologically analysed and ex vivo 45 Ca 2+ influx at 30 and 60 min was determined. For the in vitro studies, gills were treated for 60 min with DBP (1 pM, 1 nM and 1 μM) with/without blockers/activators of ionic channels, Ca 2+ chelator, inhibitors of ATPases, ionic exchangers and protein kinase C to study the mechanism of DBP-induced 45 Ca 2+ influx. Exposure to high environmental Ca 2+ augmented 45 Ca 2+ influx when compared to fish exposed to normal and low Ca 2+ concentrations. Additionally, histopathological changes were observed in the gills of fish maintained for 12 h in low and high Ca 2+ . In vitro exposure of gills to DBP (1 pM) disturbed Ca 2+ homeostasis. DBP stimulated 45 Ca 2+ influx in gills through the transitory receptor potential vanilloid 1 (TRPV1), and reverse-mode Na + /Ca 2+ exchanger (NCX) activation, protein kinase C and K + channels and sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA). These data suggest that in vivo short-term exposure of gills to low and high Ca 2+ leads to 45 Ca 2+ influx and histopathological changes. Additionally, the DBP-induced rapid 45 Ca 2+ influx is mediated by TRPV1, NCX activation with the involvement of PKC, K + -channels and SERCA, thereby altering Ca 2+ homeostasis., 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 Ltd. All rights reserved.)

Metal exposure has recently been related to the risk of hypertension. However, the association remains unclear and relevant epidemiologic studies are limited. The present study aimed to assess the associations between exposure to metals and the odds of hypertension, as well as blood pressure (BP) levels. A total of 816 participants were enrolled in southwestern China. Hypertension was defined as a systolic BP (SBP) of ≥140 mmHg or diastolic BP (DBP) of ≥90 mmHg, a self-reported physician diagnosis, or current use of antihypertensive medication. Blood samples were used to detect the levels of exposure to metals, ie, magnesium (Mg), calcium (Ca), iron (Fe), zinc (Zn), arsenic (As), cadmium (Cd), copper (Cu) and lead (Pb). Logistic and linear regression models were used to assess the potential associations. The results show that positive trends for elevated odds of hypertension with increasing quartiles of Fe in a polluted area; and of Mg, Ca and Cu in an unpolluted area. Compared with those in the lowest quartiles, participants in the highest quartiles of Fe, Mg and Ca had 2.7-, 9.0- and 5.1-fold increased odds of hypertension, respectively. High blood Fe and Pb levels in the Cd-polluted area, and Mg and Fe in the unpolluted area were found to be related to increasing SBP and DBP levels. Our findings suggest that exposure to Fe and/or Pb in the polluted area; and Mg, Ca and Fe in the unpolluted area might increase the risk of hypertension or elevate BP levels., (© 2020 John Wiley & Sons, Ltd.)

Type 2 diabetes (T2D) is caused by loss of pancreatic β-cell mass and failure of the remaining β-cells to deliver sufficient insulin to meet demand. β-Cell glucolipotoxicity (GLT), which refers to combined, deleterious effects of elevated glucose and fatty acid levels on β-cell function and survival, contributes to T2D-associated β-cell failure. Drugs and mechanisms that protect β-cells from GLT stress could potentially improve metabolic control in patients with T2D. In a phenotypic screen seeking low-molecular-weight compounds that protected β-cells from GLT, we identified compound A that selectively blocked GLT-induced apoptosis in rat insulinoma cells. Compound A and its optimized analogs also improved viability and function in primary rat and human islets under GLT. We discovered that compound A analogs decreased GLT-induced cytosolic calcium influx in islet cells, and all measured β-cell-protective effects correlated with this activity. Further studies revealed that the active compound from this series largely reversed GLT-induced global transcriptional changes. Our results suggest that taming cytosolic calcium overload in pancreatic islets can improve β-cell survival and function under GLT stress and thus could be an effective strategy for T2D treatment., (© 2020 by the American Diabetes Association.)

Mitochondrial dysfunction is critically involved in Parkinson's disease, characterized by loss of dopaminergic neurons (DaNs) in the substantia nigra (SNc), whereas DaNs in the neighboring ventral tegmental area (VTA) are much less affected. In contrast to VTA, SNc DaNs engage calcium channels to generate action potentials, which lead to oxidant stress by yet unknown pathways. To determine the molecular mechanisms linking calcium load with selective cell death in the presence of mitochondrial deficiency, we analyzed the mitochondrial redox state and the mitochondrial membrane potential in mice of both sexes with genetically induced, severe mitochondrial dysfunction in DaNs (MitoPark mice), at the same time expressing a redox-sensitive GFP targeted to the mitochondrial matrix. Despite mitochondrial insufficiency in all DaNs, exclusively SNc neurons showed an oxidized redox-system, i.e., a low reduced/oxidized glutathione (GSH-GSSG) ratio. This was mimicked by cyanide, but not by rotenone or antimycin A, making the involvement of reactive oxygen species rather unlikely. Surprisingly, a high mitochondrial inner membrane potential was maintained in MitoPark SNc DaNs. Antagonizing calcium influx into the cell and into mitochondria, respectively, rescued the disturbed redox ratio and induced further hyperpolarization of the inner mitochondrial membrane. Our data therefore show that the constant calcium load in SNc DaNs is counterbalanced by a high mitochondrial inner membrane potential, even under conditions of severe mitochondrial dysfunction, but triggers a detrimental imbalance in the mitochondrial redox system, which will lead to neuron death. Our findings thus reveal a new mechanism, redox imbalance, which underlies the differential vulnerability of DaNs to mitochondrial defects. SIGNIFICANCE STATEMENT Parkinson's disease is characterized by the preferential degeneration of dopaminergic neurons (DaNs) of the substantia nigra pars compacta (SNc), resulting in the characteristic hypokinesia in patients. Ubiquitous pathological triggers cannot be responsible for the selective neuron loss. Here we show that mitochondrial impairment together with elevated calcium burden destabilize the mitochondrial antioxidant defense only in SNc DaNs, and thus promote the increased vulnerability of this neuron population., (Copyright © 2020 the authors.)

In chronic kidney disease (CKD), the first cause of mortality is cardiovascular disease induced mainly by vascular calcification (VC). Recently, iron-based phosphate binders have been proposed in advanced CKD to treat hyperphosphatemia. We studied the effect of iron citrate (iron) on the progression of calcification in high-phosphate (Pi) calcified VSMC. Iron arrested further calcification when added on days 7-15 in the presence of high Pi (1.30 ± 0.03 vs 0.61 ± 0.02; OD/mg protein; day 15; Pi vs Pi + Fe, p < 0.01). We next investigated apoptosis and autophagy. Adding iron to high-Pi-treated VSMC, on days 7-11, decreased apoptotic cell number (17.3 ± 2.6 vs 11.6 ± 1.6; Annexin V; % positive cells; day 11; Pi vs Pi + Fe; p < 0.05). The result was confirmed thorough analysis of apoptotic nuclei both in VSMCs and aortic rings treated on days 7-15 (3.8 ± 0.2 vs 2.3 ± 0.3 and 4.0 ± 0.3 vs 2.2 ± 0.2; apoptotic nuclei; arbitrary score; day 15; Pi vs Pi + Fe; VSMCs and aortic rings; p < 0.05). Studying the prosurvival axis GAS6/AXL, we found that iron treatment on days 9-14 counteracted protein high-Pi-stimulated down-regulation and induced its de novo synthesis. Moreover, iron added on days 9-15 potentiated autophagy, as detected by an increased number of autophagosomes with damaged mitochondria and an increase in autophagic flux. Highlighting the effect of iron on apoptosis, we demonstrated its action in blocking the H 2 O 2 -induced increase in calcification added both before high Pi treatment and when the calcification was already exacerbated. In conclusion, we demonstrate that iron arrests further high Pi-induced calcium deposition through an anti-apoptotic action and the induction of autophagy on established calcified VSMC.

Poor vitamin D status is associated with a higher relapse rate and earlier disability in multiple sclerosis. Based on these associations, patients with multiple sclerosis are frequently supplemented with the vitamin D precursor cholecalciferol, although it is unclear whether this regimen is of therapeutic benefit. To model consequences of this common practice, mice were fed for more than 3 months with a low, medium or high dose of cholecalciferol, representative of vitamin D deficiency, modest and disproportionally high supplementation, respectively, in patients with multiple sclerosis. Compared to vitamin D-deprived mice, its moderate supplementation reduced the severity of subsequent experimental autoimmune encephalomyelitis, which was associated with an expansion of regulatory T cells. Direct exposure of murine or human T cells to vitamin D metabolites inhibited their activation. In contrast, mice with 25-(OH) vitamin D levels above 200 nmol/l developed fulminant experimental autoimmune encephalomyelitis with massive CNS infiltration of activated myeloid cells, Th1 and Th17 cells. When dissecting this unexpected outcome, we observed that high, but not medium dose vitamin D had caused mild hypercalcaemia, which rendered T cells more prone to pro-inflammatory activation. Exposing murine or human T cells to equivalent calcium concentrations in vitro enhanced its influx, triggering activation, upregulation of pro-inflammatory gene products and enhanced transmigration across a blood-brain barrier model. These findings suggest that vitamin D at moderate levels may exert a direct regulatory effect, while continuous high dose vitamin D treatment could trigger multiple sclerosis disease activity by raising mean levels of T-cell excitatory calcium., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Cadmium is a persistent contaminant of surface waters. The effects of cadmium on early life stages of fish are not well understood, although they are often disproportionately affected by contaminants. The objectives of this study were to examine effects of chronic exposure to environmentally relevant concentrations on growth, development, cellular stress, and glucose metabolism of channel catfish, Ictalurus punctatus. Eggs were wet-fertilized in treatment water at concentrations of 0.4 (control), 2.2 (low), or 8.5 (high) μg L -1 and monitored through swim-up, black fry stage. Eggs and fry accumulated cadmium dose-dependently. Fertilization rates were unaffected, yet hatch rate was significantly reduced in the high treatment. Survival to black fry and overall size and condition factor were not affected; however, differences in yolk sac size, and presumably energetics of yolk fry, was detected. Physiological pathways were also affected, demonstrated by altered gene expression, most notably in genes related to carbohydrate metabolism. Elevated expression of HK and G6PD, rather than G6P and GADPH, suggests glucose may be shunted towards the pentose-phosphate pathway. Overall, observations indicate cadmium negatively affects development in early life stages of channel catfish, which could lead to shifts in population structure and life history patterns in exposed populations of wild fish., (Copyright © 2018. Published by Elsevier Inc.)

Background: The hippocampus is vulnerable to severe damage after cerebral ischaemia-reperfusion (I/R) injury. This study aimed to explore the effect of electroacupuncture (EA) on cognitive impairment and its relationship with Ca 2+ neurotoxicity in a rat model of I/R injury induced by middle cerebral artery occlusion (MCAO)., Methods: 60 adult male Sprague-Dawley rats were randomly divided into three groups: control (sham surgery) group, untreated MCAO group and EA-treated MCAO+EA group. Rats in the MCAO and MCAO+EA groups underwent modelling of poststroke cognitive impairment by MCAO surgery. EA was performed for 30 min daily at GV20 and GV24 (1-20 Hz) for 1 week. The Morris water maze experiment was used to assess cognitive function. 2,3,5-triphenyl tetrazolium chloride staining was used to measure infarct volume. The intracellular Ca 2+ content in the Cornu Ammonis (CA)1 area of the hippocampus was assessed by laser confocal scanning microscopy. ELISA was performed to evaluate the concentration of glutamate (Glu) in the hippocampus, and the protein expression of two Glu receptors (N-methyl-D-aspartic acid receptor (NMDAR) 2A and NMDAR2B) were analysed by Western blotting., Results: Compared with the untreated MCAO group, EA effectively ameliorated cognitive impairment (P=0.01) and shrunk the infarct volume (P=0.032). The content of intracellular Ca 2+ , Glu and NMDAR2B in the hippocampus was significantly raised by MCAO (P=0.031-0.043), while EA abrogated these effects. NMDAR2A was decreased by MCAO (P=0.015) but increased by EA (P=0.033)., Conclusions: EA had a beneficial effect on cognitive repair after cerebral I/R, and its mechanism of action likely involves a reduction of Ca 2+ influx via inhibition of Glu neurotoxicity and downregulation of NMDAR2B expression., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

β-Hydroxy-β-methylbutyrate (HMB) is a leucine metabolite available in calcium salt (CaHMB) and free acid forms as a sports nutrition ergogenic aid. HMB has also been used to support muscle health in the elderly and other populations needing to maintain muscle mass. Several human studies have reported safety data for CaHMB, and rodent sub-chronic toxicity studies have been conducted; however, there are no published genotoxicity studies for HMB. Therefore, three studies (a bacterial reverse mutation test, an in vitro mammalian chromosomal aberration test, and an in vivo mammalian cell micronucleus test) were performed. In the Ames test, no changes in revertant colonies or background were noted with CaHMB concentrations up to 5000 μg per plate, either with or without metabolic activation in five bacterial strains. In the chromosomal aberration test, the number of aberrations associated with up to 2.5 mM CaHMB (long-term) or 10.0 mM (short-term) were similar to those observed for negative controls (<5%), and no polyploidy was observed. Lastly, in the mammalian micronucleus test, no changes in immature erythrocyte or micronuclei frequencies were observed in animals treated with up to 2000 mg·kg -1 body weight CaHMB. In conclusion, CaHMB was determined to have no genotoxic effects., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Fibroblast growth factor 23 (FGF23) is associated with mortality in patients with CKD. However, the mechanisms underlying stimulation of FGF23 remain to be investigated. We examined whether hypercalcemia induced by continuous intravenous (CIV) calcium (Ca) infusion regulates FGF23 levels in normal rats (Normal) and 5/6 nephrectomized uremic rats (Nx). Microinfusion pumps were implanted in the Normal and Nx rats for CIV Ca infusion, and blood, urine, kidney, and tibia were collected. The results showed an increase in serum Ca-stimulated FGF23 independently of serum phosphate (P) and creatinine levels in Normal and Nx rats. FGF23 mRNA from the tibia was also increased by the Ca infusion. Despite high FGF23 levels after Ca infusion, urinary P excretion was decreased. Renal α-Klotho expression was significantly reduced by Ca infusion. These results suggest that intravenous Ca loading might stimulate FGF23 production from bone in normal and uremic rats. Reduction of renal P excretion suggests that the bioactivity of FGF23 is inhibited, and the decrease in renal α-Klotho expression might have a role in this pathological process. In conclusion, CIV Ca loading increased FGF23 in normal and uremic rats, and renal α-Klotho is necessary to maintain the bioactivity of FGF23 as a phosphaturic factor.

Formation water (FoW) is a by-product from oil and gas production and usually has high concentrations of soluble salts and metals. Calcium (Ca) and magnesium (Mg) have been shown to reduce the toxicity of metals to aquatic animals, and previous study showed that high waterborne Ca exerts mild effect against disturbances on Na + regulation in Amazonian armored catfish tamoatá (Hoplosternum littorale) acutely exposed to high Fe, Mn, and Ba levels. Here, we hypothesized that high Mg levels might also reduce the toxic effects of these metals on Na + regulation of tamoatá. The exposure to 5% FoW promoted an increase in Na + uptake and a rapid accumulation of Na + in all tissues analyzed (kidney+ -ATPase in fish. High waterborne Mg lowered Na + efflux rates and markedly inhibited Na + uptake, and also reduced both NKA activity and newly Na + accumulation in gills of fish. High Fe levels increased Na + net losses and inhibited Na + uptake in tamoatá. The diffusive Na + losses and the newly accumulated Na + in gills were reduced in fish exposed to high Mn and Ba. High waterborne Ba also inhibited NKA in gills, while both high Mn and Ba inhibited v-type H + -ATPase in kidney of tamoatá. High Mg did not lessen the toxic effect of Fe on Na + net fluxes, and reduced even more Na + uptake and the newly Na + accumulation in gills and plasma, and did not prevent the inhibition of both NKA and v-type H + -ATPases in kidney. Furthermore, Mg did not attenuate the effect of Mn on inhibition Na + uptake, keeping the activity of v-type H + -ATPase in kidney significantly lowered. High Mg levels mildly attenuated the effects of Ba in Na + balance by increasing the new accumulation of Na + in liver, and restore the activity of both NKA and v-type H + -ATPase in gills of tamoatá. Overall, high waterborne Mg does not have a strong contribution to, or have only minor effects, in protecting tamoatá against disruptions in Na + regulation mediated by high Fe, Mn, and Ba levels.

The dorsal Lateral Geniculate Nucleus (dLGN) is the primary image-forming target of the retina and shares a reciprocal connection with primary visual cortex (V1). Previous studies showed that corticothalamic input is essential for the development of thalamocortical projections, but less is known about the potential role of this reciprocal connection in the development of retinal projections. Here, we show a deficit of retinal innervation in the dLGN around E18.5 in Tra2β conditional knockout (cKO) "cortexless" mice, an age when apoptosis occurs along the thalamocortical tract and in some dLGN neurons. In vivo electrophysiology experiments in the dLGN further confirmed the loss of functional retinal input. Experiments with N-methyl-d-aspartic acid-induced V1 lesion as well as Fezf2 cKO mice confirmed that the disruption of connections between the dLGN and V1 lead to abnormal retinal projections to the dLGN. Interestingly, retinal projections to the ventral Lateral Geniculate Nucleus (vLGN) and Superior Colliculus (SC) were normal in all 3 mice models. Finally, we show that the cortexless mice had worse performance than control mice in a go-no go task with visual cues. Our results provide evidence that the wiring of visual circuit from the retina to the dLGN and V1 thereafter is coordinated at a surprisingly early stage of circuit development.

It is thought that tissue damage at advanced age is mainly caused by ROS (reactive oxygen species, O 2 - , H 2 O 2 , and ·OH). However, it was found that acrolein (CH 2 =CH-CHO) is more toxic than ROS, and is mainly produced from spermine (SPM), one of the polyamines, rather than from unsaturated fatty acids. Significant amounts of SPM are present normally as SPM-ribosome complexes, and contribute to protein synthesis. However, SPM was released from ribosomes due to the degradation of ribosomal RNA by ·OH or the binding of Ca 2+ to ribosomes, and acrolein was produced from free SPM by polyamine oxidases, particularly by SPM oxidase. Acrolein inactivated several proteins such as GAPDH (glycelaldehyde-3-phosphate dehydrogenase), and also stimulated MMP-9 (matrix metalloproteinase-9) activity. Acrolein-conjugated GAPDH translocated to nucleus, and caused apoptosis like nitrosylated GAPDH. Through acrolein conjugation with several proteins, acrolein causes tissue damage during brain stroke, dementia, renal failure, and primary Sjögren's syndrome. Thus, development of acrolein scavengers with less side effects is very important to maintain QOL (quality of life) of elderly people.

Based on previous research on the acute toxicity of major ions (Na + , K + , Ca 2+ , Mg 2+ , Cl - , SO 4 2- , and HCO 3 - /CO 3 2- ) to Ceriodaphnia dubia, a mathematical model was developed for predicting the median lethal concentration (LC50) for any ion mixture, excepting those dominated by K-specific toxicity. One component of the model describes a mechanism of general ion toxicity to which all ions contribute and predicts LC50s as a function of osmolarity and Ca activity. The other component describes Mg/Ca-specific toxicity to apply when such toxicity exceeds the general ion toxicity and predicts LC50s as a function of Mg and Ca activities. This model not only tracks well the observed LC50s from past research used for model development but also successfully predicts LC50s from new toxicity tests on synthetic mixtures of ions emulating chemistries of various ion-enriched effluents and receiving waters. It also performs better than a previously published model for major ion toxicity. Because of the complexities of estimating chemical activities and osmolarity, a simplified model based directly on ion concentrations was also developed and found to provide useful predictions. Environ Toxicol Chem 2018;37:247-259. Published 2017 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America., (Published 2017 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.)

The cellular prion protein (PrP C ) whose conformational misfolding leads to the production of deadly prions, has a still-unclarified cellular function despite decades of intensive research. Following our recent finding that PrP C limits Ca 2+ entry via store-operated Ca 2+ channels in neurons, we investigated whether the protein could also control the activity of ionotropic glutamate receptors (iGluRs). To this end, we compared local Ca 2+ movements in primary cerebellar granule neurons and cortical neurons transduced with genetically encoded Ca 2+ probes and expressing, or not expressing, PrP C Our investigation demonstrated that PrP C downregulates Ca 2+ entry through each specific agonist-stimulated iGluR and after stimulation by glutamate. We found that, although PrP-knockout (KO) mitochondria were displaced from the plasma membrane, glutamate addition resulted in a higher mitochondrial Ca 2+ uptake in PrP-KO neurons than in their PrP C -expressing counterpart. This was because the increased Ca 2+ entry through iGluRs in PrP-KO neurons led to a parallel increase in Ca 2+ -induced Ca 2+ release via ryanodine receptor channels. These data thus suggest that PrP C takes part in the cell apparatus controlling Ca 2+ homeostasis, and that PrP C is involved in protecting neurons from toxic Ca 2+ overloads., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2017. Published by The Company of Biologists Ltd.)

At excess levels, zinc (Zn) disrupts mitochondrial functional integrity and induces oxidative stress in aquatic organisms. Although much is known about the modulation of Zn toxicity by calcium (Ca) in fish, their interactions at the mitochondrial level have scarcely been investigated. Here we assessed the individual and combined effects of Zn and Ca on the relationship between mitochondrial respiration, ROS and membrane potential (ΔΨ mt ) in rainbow trout liver mitochondria. We tested if cation uptake through the mitochondrial calcium uniporter (MCU) is a prerequisite for Zn- and/or Ca-induced alteration of mitochondrial function. Furthermore, using our recently developed real-time multi-parametric method, we investigated the changes in respiration, ΔΨ mt , and reactive oxygen species (ROS, as hydrogen peroxide (H 2 O 2 )) release associated with Ca-induced mitochondrial depolarization imposed by transient and permanent openings of the mitochondrial permeability transition pore (mPTP). We found that independent of the MCU, Zn precipitated an immediate depolarization of the ΔΨ mt that was associated with relatively slow enhancement of H 2 O 2 release, inhibition of respiration and reversal of the positive correlation between ROS and ΔΨ mt . In contrast, an equitoxic dose of Ca caused transient depolarization, and stimulation of both respiration and H 2 O 2 release, effects that were completely abolished when the MCU was blocked. Contrary to our expectation that mitochondrial transition ROS Spike (mTRS) would be sensitive to both Zn and Ca, only Ca suppressed it. Moreover, Zn and Ca in combination immediately depolarized the ΔΨ mt , and caused transient and sustained stimulation of respiration and H 2 O 2 release, respectively. Lastly, we uncovered and characterized an mPTP-independent Ca-induced depolarization spike that was associated with exposure to moderately elevated levels of Ca. Importantly, we showed the stimulation of ROS release associated with highly elevated but not unrealistic Ca loads was not the cause but a result of mPTP opening in the high conductance mode., (Copyright © 2017 Elsevier B.V. All rights reserved.)

FabG performs the NADPH-dependent reduction of β-keto acyl-acyl carrier protein substrates in the elongation cycle of fatty acid synthesis. We report the characterization of a temperature-sensitive mutation ( fabG Δ 8 ) in Escherichia coli fabG that results from an in-frame 8-amino-acid residue deletion in the α6/α7 subdomain. This region forms part of one of the two dimerization interfaces of this tetrameric enzyme and is reported to undergo significant conformational changes upon cofactor binding, which define the entrance to the active-site cleft. The activity of the mutant enzyme is extremely thermolabile and is deficient in forming homodimers at nonpermissive temperatures with a corresponding decrease in fatty acid synthesis both in vivo and in vitro Surprisingly, the fabG Δ 8 strain reverts to temperature resistance at a rate reminiscent of that of a point mutant with intragenic pseudorevertants located either on the 2-fold axes of symmetry or at the mouth of the active-site cleft. The fabG Δ 8 mutation also confers resistance to the calmodulin inhibitor trifluoperazine and renders the enzyme extremely sensitive to Ca 2+ in vitro We also observed a significant alteration in the lipid A fatty acid composition of fabG Δ 8 strains but only in an lpxC background, probably due to alterations in the permeability of the outer membrane. These observations provide insights into the structural dynamics of FabG and hint at yet another point of regulation between fatty acid and lipid A biosynthesis. IMPORTANCE Membrane lipid homeostasis and its plasticity in a variety of environments are essential for bacterial survival. Since lipid biosynthesis in bacteria and plants is fundamentally distinct from that in animals, it is an ideal target for the development of antibacterial therapeutics. FabG, the subject of this study, catalyzes the first cofactor-dependent reduction in this pathway and is active only as a tetramer. This study examines the interactions responsible for tetramerization through the biochemical characterization of a novel temperature-sensitive mutation caused by a short deletion in an important helix-turn-helix motif. The mutant strain has altered phospholipid and lipid A compositions and is resistant to trifluoperazine, an inhibitor of mammalian calmodulin. Understanding its structural dynamics and its influence on lipid A synthesis also allows us to explore lipid homeostasis as a mechanism for antibiotic resistance., (Copyright © 2017 American Society for Microbiology.)

This systematic review with meta-analysis, performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines, aims at evaluating the potential correlation between magnesium and calcium concentration in drinking waters and the risk of cardiovascular diseases (CVD), which impose a considerable burden in high-income countries. Included studies were of the case-control studies type. From an initial list of 643 potentially eligible articles, seven studies were finally retained in the quantitative analysis. Since each one of them assessed different ion concentrations, subjects exposed to the highest concentration versus those exposed to the lowest concentration were compared. By including an overall figure of 44,000 subjects, the result suggests a protective effect of the ions on CVD prevention, with an effect-size (ES) of 0.82 (95% confidence interval CI = [0.70-0.95], p-value = 0.008) for calcium, and ES = 0.75 (95% CI = [0.66-0.86], p-value = 0.000) for magnesium. Hard water consumption seems to be protective against CVD. However, the high heterogeneity (I 2 = 75.24, p-value = 0.001 for calcium; I 2 = 72.96, p-value = 0.0024 for magnesium) and the existence of publication bias limits the robustness and generalizability of these findings. Further high-quality studies are needed to reproduce and confirm these results.

Active surveillance has emerged as an alternative to immediate treatment for men with low-risk prostate cancer. Accordingly, identification of environmental factors that facilitate progression to more aggressive stages is critical for disease prevention. Although calcium-enriched diets have been speculated to increase prostate cancer risk, their impact on early-stage tumors remains unexplored. In this study, we addressed this issue with a large interventional animal study. Mouse models of fully penetrant and slowly evolving prostate tumorigenesis showed that a high calcium diet dramatically accelerated the progression of prostate intraepithelial neoplasia, by promoting cell proliferation, micro-invasion, tissue inflammation, and expression of acknowledged prostate cancer markers. Strikingly, dietary vitamin D prevented these calcium-triggered tumorigenic effects. Expression profiling and in vitro mechanistic studies showed that stimulation of PC-3 cells with extracellular Ca 2+ resulted in an increase in cell proliferation rate, store-operated calcium entry (SOCE) amplitude, cationic channel TRPC6, and calcium sensing receptor (CaSR) expression. Notably, administration of the active vitamin D metabolite calcitriol reversed all these effects. Silencing CaSR or TRPC6 expression in calcium-stimulated PC3 cells decreased cell proliferation and SOCE. Overall, our results demonstrate the protective effects of vitamin D supplementation in blocking the progression of early-stage prostate lesions induced by a calcium-rich diet. Cancer Res; 77(2); 355-65. ©2016 AACR., (©2016 American Association for Cancer Research.)

Pretreatments such as low temperature blanching and/or calcium soaking affect the cooked texture of vegetal food. In the work, lotus rhizomes (Nelumbo nucifera Gaertn.) were pretreated using the following 4 treatments, blanching at 40°C, blanching at 90°C, soaking in 0.5% CaCl2, and blanching at 40°C followed by immersion in 0.5% CaCl2. Subsequently, the cell wall material of pretreated samples was isolated and fractioned to identify changes in the degree of esterification (DE) and monosaccharide content of each section, and the texture of the lotus rhizomes in different pre-treatments was determined after thermal processing with different time. The results showed that the greatest hardness was obtained after blanching at 40°C in CaCl2, possibly attributing to the formation of a pectate calcium network, which maintains the integrity of cell walls. Furthermore, the content of galactose, rhamnose and arabinose decreased due to the breakage of sugar backbones and subsequent damage to cell walls. Our results may provide a reference for lotus rhizome processing., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

This study determined the effects of glutamate on the Ca(2+) paradoxical heart, which is a model for Ca(2+) overload-induced injury during myocardial ischaemia and reperfusion, and evaluated its effect on a known mediator of injury, calpain. An isolated rat heart was retrogradely perfused in a Langendorff apparatus. Ca(2+) paradox was elicited via perfusion with a Ca(2+) -free Krebs-Henseleit (KH) solution for 3 minutes followed by Ca(2+) -containing normal KH solution for 30 minutes. The Ca(2+) paradoxical heart exhibited almost no viable tissue on triphenyltetrazolium chloride staining and markedly increased LDH release, caspase-3 activity, cytosolic cytochrome c content, and apoptotic index. These hearts also displayed significantly increased LVEDP and a disappearance of LVDP. Glutamate (5 and 20 mmol/L) significantly alleviated Ca(2+) paradox-induced injury. In contrast, 20 mmol/L mannitol had no effect on Ca(2+) paradox. Ca(2+) paradox significantly increased the extent of the translocation of μ-calpain to the sarcolemmal membrane and the proteolysis of α-fodrin, which suggests calpain activation. Glutamate also blocked these effects. A non-selective inhibitor of glutamate transporters, dl-TBOA (10 μmol/L), had no effect on control hearts, but it reversed glutamate-induced cardioprotection and reduction in calpain activity. Glutamate treatment significantly increased intracellular glutamate content in the Ca(2+) paradoxical heart, which was also blocked by dl-TBOA. We conclude that glutamate protects the heart against Ca(2+) overload-induced injury via glutamate transporters, and the inhibition of calpain activity is involved in this process., (© 2016 John Wiley & Sons Australia, Ltd.)

Alternatives for the treatment of amyotrophic lateral sclerosis (ALS) are scarce and controversial. The etiology of neuronal vulnerability in ALS is being studied in motor neuron-like NSC-34 cells to determine the underlying mechanisms leading to selective loss of motor neurons. One such mechanism is associated with mitochondrial oxidative stress, Ca(2+) overload, and low expression of Ca(2+)-buffering proteins. Therefore, in order to elicit neuronal death in ALS, NSC-34 cells were exposed to the following cytotoxic agents: (1) a mixture of oligomycin 10 µM and rotenone 30 µM (O/R), or (2) phenylarsine oxide 1 µM (PAO) (to mimic excess free radical production during mitochondrial dysfunction), and (3) veratridine 100 µM (VTD) (to induce overload of Na(+) and Ca(2+) and to alter distribution of Ca(2+)-buffering proteins [parvalbumin and calbindin-D28k]). Thus, the aim of the study was to test the novel neuroprotective compound ITH33/IQM9.21 (ITH33) and to compare it with riluzole on in vitro models of neurotoxicity. Cell viability measured with MTT showed that only ITH33 protected against O/R at 3 μM and PAO at 10 μM, but not riluzole. ITH33 and riluzole were neuroprotective against VTD, blocked the maximum peak and the number of [Ca(2+)]c oscillations per cell, and restored the effect on parvalbumin. However, only riluzole reversed the effect on calbindin-D28k levels. Therefore, ITH33 was neuroprotective against oxidative stress and Na(+)/Ca(2+) overload, both of which are involved in ALS.

Calcium has an important role in regulating numerous cellular activities. However, extremely high levels of intracellular calcium can lead to neurotoxicity, a process commonly associated with degenerative diseases. Despite the clear role of calcium cytotoxicity in mediating neuronal cell death in this context, the pathological mechanisms remain controversial. We used a well-established Drosophila model of retinal degeneration, which involves the constitutively active TRP(P365) channels, to study calcium-induced neurotoxicity. We found that the disruption of mitochondrial function was associated with the degenerative process. Further, increasing autophagy flux prevented cell death in Trp(P365) mutant flies, and this depended on the PINK1/Parkin pathway. In addition, the retinal degeneration process was also suppressed by the coexpression of PINK1 and Parkin. Our results provide genetic evidence that mitochondrial dysfunction has a key role in the pathology of cellular calcium neurotoxicity. In addition, the results demonstrated that maintaining mitochondrial homeostasis via PINK1/Parkin-dependent mitochondrial quality control can potentially alleviate cell death in a wide range of neurodegenerative diseases.

Acid rain (AR) impacts forest health by leaching calcium (Ca) away from soils and plants. Ca is an essential element and participates in various plant physiological responses. In the present study, the protective role of exogenous Ca in alleviating AR stress in Liquidambar formosana Hance at the physiological and proteomic levels was examined. Our results showed that low Ca condition resulted in the chlorophyll content and photosynthesis decreasing significantly in L. formosana leaves; however, these effects could be reversed by high Ca supplementation. Further proteomic analyses successfully identified 81 differentially expressed proteins in AR-treated L. formosana under different Ca levels. In particular, some of the proteins are involved in primary metabolism, photosynthesis, energy production, antioxidant defense, transcription, and translation. Moreover, quantitative real time polymerase chain reaction (qRT-PCR) results indicated that low Ca significantly increased the expression level of the investigated Ca-related genes, which can be reversed by high Ca supplementation under AR stress. Further, Western blotting analysis revealed that exogenous Ca supply reduced AR damage by elevating the expression of proteins involved in the Calvin cycle, reactive oxygen species (ROS) scavenging system. These findings allowed us to better understand how woody plants respond to AR stress at various Ca levels and the protective role of exogenous Ca against AR stress in forest tree species.

The Clinch and Powell Rivers (Virginia, USA) support diverse mussel assemblages. Extensive coal mining occurs in both watersheds. In large reaches of both rivers, major ion concentrations are elevated and mussels have been extirpated or are declining. We conducted a laboratory study to assess major ion effects on growth and survival of juvenile Villosa iris. Mussels were exposed to pond water and diluted pond water with environmentally relevant major ion mixtures for 55 days. Two treatments were tested to mimic low-flow concentrations of Ca(2+), Mg(2+), [Formula: see text] , [Formula: see text] , K(+) and Cl(-) in the Clinch and Powell Rivers, total ion concentrations of 419 mg/L and 942 mg/L, respectively. Mussel survival (>90%) and growth in the two treatments showed little variation, and were not significantly different than in diluted pond water (control). Results suggest that major ion chronic toxicity is not the primary cause for mussel declines in the Clinch and Powell Rivers., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Mitochondrial Ca(2+) overload is a critical, preceding event in neuronal damage encountered during neurodegenerative and ischemic insults. We found that loss of PTEN-induced putative kinase 1 (PINK1) function, implicated in Parkinson disease, inhibits the mitochondrial Na(+)/Ca(2+) exchanger (NCLX), leading to impaired mitochondrial Ca(2+) extrusion. NCLX activity was, however, fully rescued by activation of the protein kinase A (PKA) pathway. We further show that PKA rescues NCLX activity by phosphorylating serine 258, a putative regulatory NCLX site. Remarkably, a constitutively active phosphomimetic mutant of NCLX (NCLX(S258D)) prevents mitochondrial Ca(2+) overload and mitochondrial depolarization in PINK1 knockout neurons, thereby enhancing neuronal survival. Our results identify an mitochondrial Ca(2+) transport regulatory pathway that protects against mitochondrial Ca(2+) overload. Because mitochondrial Ca(2+) dyshomeostasis is a prominent feature of multiple disorders, the link between NCLX and PKA may offer a therapeutic target., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)