Elevation Of Ca Concentration Research Articles

Indigenous microbes induced fluoride release from aquifer sediments

Release of fluoride from Quaternary sediments produces F-contaminated groundwater which threatens the health of millions of people worldwide. Despite the mechanisms of fluoride release from sediments are documented by numerous studies, it remains poorly understood that whether indigenous microbes participate in or not for the formation of F-rich groundwater by releasing fluoride from aquifer sediments. A microcosm-based approach, geochemistry and techniques of microbiology and molecular ecology were conducted together to investigate these mechanisms. Results show that microbes are abundant in high [F] groundwater containing at least 1129 operational taxonomic units (OTUs), and indigenous microbes can have an essential role in the mobilization of fluoride in sediments collected from aquifers in a typical fluorosis area in China. It also shows that for the sediments in this study, fluoride release (ca. 2 mg/L) is coupled with elevated concentrations of Ca (△ = 75 mg/L), Mg (△ = 33 mg/L), Al (△ = 0.2 mg/L) and Mn (△ = 1.4 mg/L). This suggests that the fluoride may source from the dissolution of F-bearing carbonate minerals and/or Al-Mn hydroxides in a local acidic environment. The findings provide additional insights into the biogeochemical circulation of fluoride in natural environment, especially in groundwater system and the development of effective strategies for the management of F-contaminated groundwater worldwide.

Precipitation-dissolution behaviors of rare earth ions in H3PO4[sbnd]Ca(H2PO4)2 solutions

In order to achieve deeper understanding of rare earth elements (REEs) behaviors during phosphate rock processing with H3PO4. The solubility of REEs in Ca(H2PO4)2H3PO4 solutions with various concentrations of Ca(H2PO4)2 at different temperatures were tested. The results demonstrate that REEs solubility decreases sharply with the increasing concentration of Ca(H2PO4)2. Equations between [REE3+] and [H+], [H+] and [Ca2+] in Ca(H2PO4)2H3PO4 solutions were built based on the precipitation-dissolution equilibrium of rare earth phosphates and the ionization equilibrium of H3PO4. According to the equations, the decreasing mechanism of REEs solubility caused by elevated concentration of Ca(H2PO4)2 was determined. The mechanism can be illustrated as that the elevated concentration of [H2PO4–] decreases the concentration of hydrogen ion by retarding the ionization process of H3PO4 and directly promotes the precipitation of rare earth phosphates. Furthermore, it can be easy deduced that similar effect would be caused by the other cation impurities (Fe3+, Al3+, etc.) on REEs solubility based on the mechanism. In addition, superimposed reduction effect on REEs solubility caused by the elevated concentration of Ca(H2PO4)2 and the elevated temperature is found. This superimposed effect leads to a super low solubility of REEs in Ca(H2PO4)2H3PO4 solution. On the basis of the experimental study, outlooks and suggestions for further development of REEs recovery method are given.

Mycorrhizae and Rhizobacteria on Precambrian Rocky Gold Mine Tailings: II. Mine-Adapted Symbionts Alleviate Soil Element Imbalance for a Better Nutritional Status of White Spruce Seedlings

In the context of a phytorestoration project, the purpose of this study was to assess the respective contribution to the nutritional status of Picea glauca seedlings of ectomycorrhizae and rhizobacteria native or not to the Sigma-Lamaque gold mine wastes in northern Quebec, Canada. In a glasshouse experiment, inoculated plants were grown for 32 weeks on coarse waste rocks or fine tailings obtained from the mining site. The survival, health, growth, and nutritional status of plants were better on coarse waste rocks than on fine tailings. Fe and Ca were especially found at high levels in plant tissues but at much lower concentrations on waste rocks. Interestingly, inoculation of microsymbionts had only minimal effects on N, P, K, and Mg plant status that were indeed close or within the concentration range encountered in healthy seedlings. However, both fungal and bacterial treatments improved Fe and Ca concentrations in plant tissues. Fe concentration in the foliage of plants inoculated with the fungi Tricholoma scalpturatum Tri. scalp. MBN0213 GenBank #KC840613 and Cadophora finlandia Cad. fin. MBN0213 GenBank #KC840625 was reduced by >50%. Both fungi were isolated from the mining site. The rhizobacteria, Azotobacter chroococcum, also improved plant Fe level in some cases. Regarding Ca nutritional status, the native bacterial strain Pseudomonas putida MBN0213 GenBank #AY391278 was the only symbiont that reduced foliar content by up to 23%. Ca concentration was negatively correlated with the fungal mycorrhization rate of seedling roots. This relation was especially strong (r = -0.66, p-value ≤ 0.0001) in the case of C. finlandia. Also, a similar relationship existed with root Fe concentration (r = -0.44, p-value ≤ 0.0001). In fact, results showed that seedling performance was more correlated with elevated Ca and Fe concentration in planta than with nutrient deficiency. Also, native microsymbionts were capable of regulating seedling nutrition in the poor substrate of the Sigma-Lamaque gold mine tailings.

The study of prognostic significance of CA 15-3 in breast cancer

Background: Cancer Antigen 15-3 (CA 15-3) is a tumour-associated antigen used as serum marker for breast cancer surveillance in patients and for monitoring the response to treatment. Aim of this study was to prospectively evaluate CA 15-3 as a prognostic factor in early detection of breast cancer relapse, recurrence and early detection of distant metastasis as well as to analyse the statistical correlation between CA 15-3 levels and clinical-pathological parameters including tumour size, lymph node, histological type, grading, hormonal receptors.Methods: Sera of 85 women with breast carcinoma obtained pre-treatment, post-treatment and follow-up at 6 months were assayed for CA 15-3 by solid phase enzyme-linked immunosorbent assay (ELISA).Results: Author founds that the mean serum CA 15-3 levels in patients before treatment were significantly higher (50.59U/ml) compared with those of CA 15-3 after treatment (24.07U/ml) and follow-up at 6 months (21.07U/ml). Author also found that elevated pre-treatment serum levels of CA 15-3 were significantly correlated with poor prognosis of patients. In particular, among 16/85 patients (18.8%) that displayed over cut-off (>24.95U/ml) pre-treatment levels of CA 15-3, 2 patients (2.35%) developed recurrence,2 patients (2.35%) developed residual tumour, 2 patients (2.35%) developed advanced disease (metastases to distant sites) and 10 (11.76%) patients expired during and after study. Chi-square correlation analysis revealed that the presences of increased serum levels of CA 15-3 after treatment are significant risk factors for poor prognosis in patients.Conclusions: Elevated pre-treatment concentrations of CA 15-3 may be a useful prognostic factor for cancer progression in patients.

Low incidence of hypercalcemia following combined calcipotriol hydrate/betamethasone dipropionate ointment treatment in Japanese patients with severe psoriasis vulgaris

Purpose: Topical active vitamin D3 application alone or in combination with topical steroid application is widely used to treat psoriasis. In Japan, combined calcipotriol hydrate/betamethasone dipropionate ointment has been used for patients with psoriasis vulgaris since September 2014. Current evidence regarding the incidence of hypercalcemia due to the use of this combination product, however, is insufficient. We evaluated the incidence of hypercalcemia following combined calcipotriol hydrate/betamethasone dipropionate ointment in patients with severe psoriasis vulgaris.Methods: Japanese patients (n = 22) with extensive plaque psoriasis (body surface area: 20–30%) applied the combined calcipotriol hydrate/betamethasone dipropionate ointment once daily for 8 weeks, and their serum Ca concentrations were measured periodically.Results: The mean serum Ca concentration changed only marginally, from 9.04 ± 0.34 mg/dL before treatment to 9.08 ± 0.39 mg/dL after 8 weeks of treatment. None of the patients had an elevated serum Ca concentration throughout the study. No cases of hypercalcemia were reported as an adverse event. No correlation was detected between the amount of the combined calcipotriol hydrate/betamethasone dipropionate ointment applied and changes in the serum Ca concentration.Conclusion: The incidence of hypercalcemia due to topical application of a combined calcipotriol hydrate/betamethasone dipropionate ointment is low in Japanese patients with severe psoriasis vulgaris.

GROUNDWATER QUALITY AND FATE OF PUBLIC HEALTH IN NEW KARACHI TOWN, KARACHI, PAKISTAN

The aim of present study was to evaluate the groundwater quality and its potential impacts by drinking on the health of New Karachi Town residents. For this purpose, a total of 25 groundwater samples were randomly collected through boring wells at a depth range of 961 meters from the study area. Data revealed that all the chemical parameters exceeded their guideline values of WHO for drinking purpose in most of the wells. TDS content of groundwater is very high (mean: 4781.6 mg/L) which exceeded the WHO limit (500 mg/L) for drinking purpose. Highly elevated concentration of Na (mean: 1397mg/L), K (mean: 39.72 mg/L), Ca (mean: 308.7 mg/L), Mg (mean: 1408.65 mg/L), Cl (mean: 2502.345 mg/L), HCO3 (mean: 441 mg/L) and SO4 (mean: 332.4376 mg/L) is reported in more than 85% wells which is against the corresponding WHO guideline for drinking purpose. Very high concentration of these major ions (Mg, K, Ca, Na, Cl, SO4 and HCO3) is indicating the sewage mixing with groundwater in study area. Groundwater in New Karachi town is not suitable for drinking purpose and may cause serious health impacts of acute and chronic nature.

Fluorides and Fluorcarbonates in Rocks of the Katugin Complex, Eastern Siberia: Indicators of Geochemical Mineral Formation Conditions

The paper discusses the chemical composition and parageneses of fluorides and fluorcarbonates in rocks of the Katugin Complex, with which a unique deposit of REE–Nb–Ta ore with cryolite is associated. In mineralogy and chemical composition, the rocks correspond to biotite, biotite–amphibole, arfvedsonite, and aegirine–arfvedsonite granites, which were regarded in earlier publications as granite-like metasomatic rocks. Aegirine–arfvedsonite granite contains a cryolite–gagarinite assemblage, which reflects depletion of Ca in the mineral-forming medium and enrichment in Na and F. Arfvedsonite granite is characterized by intergrowth of yttrofluorite with fluocerite and gagarinite, which indicates a relative enrichment in Ca and low CO2 content. Biotite granite is characterized by an assemblage of fluorite with titanite, apatite, and monazite as evidence for an elevated Ca concentration along with moderate F and P contents in the system. Neighborite, coulsellite, gagarinite, fluocerite, and tveitite-(Y) appear in biotite–amphibole granite along with replacement of annite with riebeckite and development of albite after microcline. All this indicates that a moderately alkaline Na-fluoride solution with a low Ca concentration affects biotite granite.

Preoperative serum levels of YKL 40 and CA125 as a prognostic indicators in patients with endometrial cancer

ObjectiveTo evaluate the utility of YKL-40 and CA125 in endometrial cancer (EC) patients, and to determine their prognostic value in assessing the disease-free survival (DFS) and overall survival (OS). MethodsWe analyzed seventy-four EC patients, treated at a single institution and 25 healthy individuals. CA 125 serum level was evaluated in the Cobas 6000 system and YKL-40, using the ELISA method. ResultsSignificantly increased serum level of YKL-40 and CA125 was in EC patients in FIGO I-IB when compared to healthy controls. CA125 was significantly higher in patients with more advanced FIGO stage vs. FIGO I, and also in patients with lymph node metastases vs. patients with no metastases. The obtained AUC for YKL-40 was higher than for CA125. There was, however, higher diagnostic sensitivity for YKL-40 in comparison to CA125, both in patients with type I and type II tumours. In patients who had disease progression, both the percentage of elevated concentration of CA 125 and YKL-40 was higher than in patients with remission. The Chi2 test demonstrated the statistically significant differences. The predictive value of CA125 in an aspect of DFS and OS was demonstrated. ConclusionsA high diagnostic sensitivity of YKL-40 in the early stages of the disease suggests the possibility of using this biomarker at an early diagnostic phase of patients with EC. The patients with increased levels of YKL-40 before treatment are also at the higher risk of relapse. The determination of CA125 before surgery may be helpful in the evaluation of the regional lymph nodes, and is a poor prognostic factor for OS and DFS.

Calcium-sensing receptor-ERK signaling promotes odontoblastic differentiation of human dental pulp cells

Activation of the G protein-coupled calcium-sensing receptor (CaSR) has crucial roles in skeletal development and bone turnover. Our recent study has identified a role for activated CaSR in the osteogenic differentiation of human periodontal ligament stem cells. Furthermore, odontoblasts residing inside the tooth pulp chamber play a central role in dentin formation. However, it remains unclear how CaSR activation affects the odontoblastic differentiation of human dental pulp cells (HDPCs). We have investigated the odontoblastic differentiation of HDPCs exposed to elevated levels of extracellular calcium (Ca) and strontium (Sr), and the contribution of CaSR and the L-type voltage-dependent calcium channel (L-VDCC) to this process. Immunochemical staining of rat dental pulp tissue demonstrated that CaSR was expressed at high levels in the odontoblastic layer, moderate levels in the sublayer, and low levels in the central pulp tissue. Although normal HDPCs expressed low levels of CaSR, stimulation with Ca or Sr promoted both CaSR expression and odontoblastic differentiation of HDPCs along with increased expression of odontoblastic makers. These effects were inhibited by treatment with a CaSR antagonist, whereas treatment with an L-VDCC inhibitor had no effect. Additionally, knockdown of CaSR with siRNA suppressed odontoblastic differentiation of Ca- and Sr-treated HDPCs. ERK1/2 phosphorylation was observed in Ca- and Sr-treated HDPCs, whereas CaSR antagonist treatment or CaSR knockdown blocked ERK1/2 phosphorylation. Furthermore, inhibition of ERK1/2 suppressed mineralization of Ca- and Sr-treated HDPCs. These results suggest that elevated concentrations of extracellular Ca and Sr induce odontoblastic differentiation of HDPCs through CaSR activation and the ERK1/2 phosphorylation.

Maintenance and regulation of asymmetric phospholipid distribution in human erythrocyte membranes: implications for erythrocyte functions.

The article summarizes new insights into the molecular mechanisms for the maintenance and regulation of the asymmetric distribution of phospholipids in human erythrocyte membranes. We focus on phosphatidylserine, which is primarily found in the inner leaflet of the membrane lipid bilayer under low Ca conditions (<1 μmol/l) and is exposed to the outer leaflet under elevated Ca concentrations (>1 μmol/l), when cells become senescent. Clarification of the molecular basis of phosphatidylserine flipping and scrambling is important for addressing long-standing questions regarding phosphatidylserine functions. ATP11C, a P-IV ATPase, has been identified as a major flippase in analyses of patient erythrocytes with a 90% reduction in flippase activity. Phospholipid scramblase 1 (PLSCR1) has been defined as a Ca-activated scramblase that is completely suppressed by membrane cholesterol under low Ca concentrations. For survival, phosphatidylserine surface exposure is prevented by cholesterol-mediated suppression of PLSCR1 under low Ca concentrations, irrespective of flipping by ATP11C. In senescent erythrocytes, PLSCR1 is activated by elevated Ca, resulting in phosphatidylserine exposure, allowing macrophage phagocytosis. These recent molecular findings establish the importance of the maintenance and regulation of phosphatidylserine distribution for both the survival and death of human erythrocytes.

Accumulation of trace elements in edible crops and poplar grown on a titanium ore landfill.

Urban gardening has recently experienced rapid development; however, the risk of the transfer of toxic elements from neighboring industry needs to be evaluated. We performed a multi-elemental analysis with several common edible crops (cucumber, pepper, cabbage, and lettuce) and poplar grown directly on a titanium ore landfill as a maximized scenario of exposure. Despite elevated concentrations of soil Ca, Fe, Mn, and Ti resulting from the industrial process, we did not register higher accumulation of these elements in the edible parts of crops or in poplar leaves grown on red gypsum compared with the control soil. Only S concentrations were higher in plants grown on the red gypsum, especially for cabbage. The principal component analysis among elements for plants grown on red gypsum indicated that S and Mn were accumulated by different plant species than Cd, Cu, and Zn. The poplar clone had a significantly higher transfer of S and Cr than the control and is a suitable tree species for monitoring element transfer to vegetation in this industrial context. By comparing our data with tolerable daily intake (TDI) recommendations, we demonstrated the low risk of cultivating edible crops directly on an industrial substrate in a maximized scenario of exposure, except for Cr, for which the toxicity depends on the bioavailable form. However, we did not consider the cumulative effects of the various elements because there are no current guidelines, and further research is needed to address this question.

Composition and conditions of crystallization of zircon from the rare-metal ores of the Gremyakha–Vyrmes Massif, Kola Peninsula

The first data on the composition and inner structure of zircon, one of the main ore minerals of the rare-metal metasomatites of the Gremyakha–Vyrmes alkaline-ultramafic massif, are reported. Early zircon generations are enriched in Y and REE and contain numerous inclusions of rock-forming and accessory minerals of metasomatites, as well as syngenetic fluid inclusions of calcite, thorite and thorianite. Late generations differ in the elevated Hf content and contain no inclusions. The elevated concentrations of Ca and Th in the central zones of crystals are related to the presence of numerous micron-sized inclusions of calcite and thorium phases. All zircon varieties have extremely low U and Pb contents. Concentrations and distribution patterns of incompatible and rare-earth elements in zircon from the metasomatites of the Gremyakha–Vyrmes Massif are similar to those of syenite pegmatites and magmatic carbonatites around the world. Mineral from these associations shows a positive Ce anomaly and elevated HREE contents. According to the compositions of zircon and thorite inclusion in it and experimental data on the simultaneous synthesis of these minerals, the crystallization temperature of zircon was 700–750°С. Using Ti-in-zircon temperature dependence, late zurcon was formed at temperature of 700–750°С. The rare-metal metasomatites are formed at the final stages of the massif formation, presumably after foidolites. Carbonatites could initiate metasomatic reworking of foidolites and accumulation of trace metals in them. The evolution of the primary alkaline–ultramafic melt toward the enrichment in trace elements was mainly controlled by crystallization differentiation.

Crystallization of Nano‐Calcium Carbonate: The Influence of Process Parameters

AbstractPrecipitated calcium carbonate was synthesized by carbonation of calcium hydroxide in the presence and absence of ultrasound (conventional stirring) at atmospheric as well as at elevated pressures and different initial concentrations of Ca(OH)2. Spherical morphology of the formed calcite was favored at high Ca(OH)2 concentrations and low CO2 pressures. The presence of ultrasound did not show any influence on the reaction rate in case of efficient mixing. A small increase of the reaction rate was observed at lower CO2 pressures. Elevated pressures in combination with ultrasound did not lead to notable changes of reaction rate or particle morphology.

2,3,7,8-tetrachlorodibenzo-p-dioxin exposure influence the expression of glutamate transporter GLT-1 in C6 glioma cells via the Ca(2+) /protein kinase C pathway.

The widespread environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), is considered one of the most toxic dioxin-like compounds. Although epidemiological studies have shown that TCDD exposure is linked to some neurological and neurophysiological disorders, the underlying mechanism of TCDD-mediated neurotoxicity has remained unclear. Astrocytes are the most abundant cells in the nervous systems, and are recognized as the important mediators of normal brain functions as well as neurological, neurodevelopmental and neurodegenerative brain diseases. In this study, we investigated the role of TCDD in regulating the expression of glutamate transporter GLT-1 in astrocytes. TCDD, at concentrations of 0.1-100 nm, had no significantly harmful effect on the viability of C6 glioma cells. However, the expression of GLT-1 in C6 glioma cells was downregulated in a dose- and time-dependent manner. TCDD also caused activation of protein kinase C (PKC), as TCDD induced translocation of the PKC from the cytoplasm or perinuclear to the membrane. The translocation of PKC was inhibited by one Ca(2+) blocker, nifedipine, suggesting that the effects are triggered by the initial elevated intracellular concentration of free Ca(2+) . Finally, we showed that inhibition of the PKC activity reverses the TCDD-triggered reduction of GLT-1. In summary, our results suggested that TCDD exposure could downregulate the expression of GLT-1 in C6 via Ca(2+) /PKC pathway. The downregulation of GLT-1 might participate in TCDD-mediated neurotoxicity. Copyright © 2016 John Wiley & Sons, Ltd.

Chemical shift assignments of calmodulin constructs with EF hand mutations.

Calmodulin (CaM) is a ubiquitous cytosolic Ca(2+)-binding protein able to bind and regulate hundreds of different proteins. It consists of two globular domains joined by a flexible central linker region. Each one of these domains contains two EF hand pairs capable of binding to Ca(2+). Upon Ca(2+) binding CaM undergoes a conformational change exposing hydrophobic patches that interact with its intracellular target proteins. CaM is able to bind to target proteins in the Ca(2+)-replete and Ca(2+)-deplete forms. To study the Ca(2+)-dependent/independent properties of binding and activation of target proteins by CaM, CaM constructs with Ca(2+) binding disrupting mutations of Asp to Ala at position one of each EF hand have been used. One target protein of CaM is nitric oxide synthase, which catalyzes the production of nitric oxide. At elevated Ca(2+) concentrations, CaM binds to neuronal NOS and endothelial NOS, making them the Ca(2+)-dependent NOS enzymes. In contrast, inducible NOS is transcriptionally regulated in vivo and binds to CaM at basal levels of Ca(2+). Here we report the NMR backbone and sidechain resonance assignments of C-lobe Ca(2+)-replete and deplete CaM12, N-lobe Ca(2+)-replete and deplete CaM34, CaM1234 in the absence of Ca(2+) and N-lobe Ca(2+)-replete CaM34 with the iNOS CaM-binding domain peptide.

Gap junction blockage promotes cadmium-induced apoptosis in BRL 3A derived from Buffalo rat liver cells.

Gap junctions mediate direct communication between cells; however, toxicological cascade triggered by nonessential metals can abrogate cellular signaling mediated by gap junctions. Although cadmium (Cd) is known to induce apoptosis in organs and tissues, the mechanisms that underlie gap junction activity in Cd-induced apoptosis in BRL 3A rat liver cells has yet to be established. In this study, we showed that Cd treatment decreased the cell index (a measure of cellular electrical impedance) in BRL 3A cells. Mechanistically, we found that Cd exposure decreased expression of connexin 43 (Cx43), increased expression of p-Cx43 and elevated intracellular free Ca2+ concentration, corresponding to a decrease in gap junctional intercellular communication. Gap junction blockage pretreatment with 18β-glycyrrhizic acid (GA) promoted Cd-induced apoptosis, involving changes in expression of Bax, Bcl-2, caspase-3 and the mitochondrial transmembrane electrical potential (Δψm). Additionally, GA was found to enhance ERK and p38 activation during Cd-induced activation of mitogen-activated protein kinases, but had no significant effect on JNK activation. Our results indicated the apoptosis-related proteins and the ERK and p38 signaling pathways may participate in gap junction blockage promoting Cd-induced apoptosis in BRL 3A cells.

EMRE Is a Matrix Ca(2+) Sensor that Governs Gatekeeping of the Mitochondrial Ca(2+) Uniporter.

The mitochondrial uniporter (MCU) is an ion channel that mediates Ca(2+) uptake into the matrix to regulate metabolism, cell death, and cytoplasmic Ca(2+) signaling. Matrix Ca(2+) concentration is similar to that in cytoplasm, despite an enormous driving force for entry, but the mechanisms that prevent mitochondrial Ca(2+) overload are unclear. Here, we show that MCU channel activity is governed by matrix Ca(2+) concentration through EMRE. Deletion or charge neutralization of its matrix-localized acidic C terminus abolishes matrix Ca(2+) inhibition of MCU Ca(2+) currents, resulting in MCU channel activation, enhanced mitochondrial Ca(2+) uptake, and constitutively elevated matrix Ca(2+) concentration. EMRE-dependent regulation of MCU channel activity requires intermembrane space-localized MICU1, MICU2, and cytoplasmic Ca(2+). Thus, mitochondria are protected from Ca(2+) depletion and Ca(2+) overload by a unique molecular complex that involves Ca(2+) sensors on both sides of the inner mitochondrial membrane, coupled through EMRE.

Panaxydol, a component of Panax ginseng, induces apoptosis in cancer cells through EGFR activation and ER stress and inhibits tumor growth in mouse models.

We reported previously that panaxydol, a component of Panax ginseng roots, induced mitochondria-mediated apoptosis preferentially in transformed cells. This study demonstrates that EGFR activation and the resulting ER stress mediate panaxydol-induced apoptosis, and that panaxydol suppresses in vivo tumor growth in syngeneic and xenogeneic mouse tumor models. In addition, we elucidated that CaMKII and TGF-β-activated kinase (TAK1) participate in p38/JNK activation by elevated cytoplasmic Ca(2+) concentration ([Ca(2+)]c). In MCF-7 cells, EGFR was activated immediately after exposure to panaxydol, and this activation was necessary for induction of apoptosis, suggesting that panaxydol might be a promising anticancer candidate, especially for EGFR-addicted cancer. Activation of PLCγ followed EGFR activation, resulting in Ca(2+) release from the endoplasmic reticulum (ER) via inositol triphosphate and ryanodine receptors. ER Ca(2+) release triggered mitochondrial Ca(2+) uptake indirectly through oxidative stress and ensuing ER stress. Elevated [Ca(2+)]c triggered sequential activation of calmodulin/CaMKII, TAK1 and p38/JNK. As shown previously, p38 and JNK activate NADPH oxidase. Here, it was shown that the resulting oxidative stress triggered ER stress. Among the three signaling branches of the unfolded protein response, protein kinase R-like ER kinase (PERK), but not inositol-requiring enzyme 1 or activating transcription factor 6, played a role in transmitting the apoptosis signal. PERK induced C/EBP homologous protein (CHOP), and CHOP elevated Bim expression, initiating mitochondrial Ca(2+) uptake and apoptosis. In summary, we identified roles of EGFR, the CAMKII-TAK1-p38/JNK pathway, and ER stress in panaxydol-induced apoptosis and demonstrated the in vivo anticancer effect of panaxydol.

Pathophysiological insights of methylglyoxal induced type-2 diabetes.

Diabetes mellitus is a metabolic disorder constituting a major health problem whose prevalence has gradually increased worldwide over the past few decades. Type 2 diabetes mellitus (T2DM) remains more complex and heterogeneous and arises as a combination of insulin resistance and inadequate functional β-cell mass and comprises about 90% of all diabetic cases. Appropriate experimental animal models are essential for understanding the molecular basis, pathogenesis of complications, and the utility of therapeutic agents to abrogate this multifaceted disorder. Currently, animal models for T2DM are obtained as spontaneously developed diabetes or diabetes induced by chemicals or dietary manipulations or through surgical or genetic methods. The currently used diabetogenic agents have certain limitations. Recently, methylglyoxal (MG), a highly reactive compound derived mainly from glucose and fructose metabolism has been implicated in diabetic complications. MG is a major precursor of the advanced glycation end product (AGE) and promotes impaired functions of insulin signaling, GLUT transporters, anion channels, kinases, and endothelial cells and is finally involved in apoptosis. Recent array of literature also cited that higher concentrations of MG causes rapid depolarization, elevated intracellular Ca(2+) concentration, and acidification in pancreatic β-cells. This review henceforth highlights the mechanism of action of MG and its implications in the pathophysiology of experimental diabetes.

Membrane Docking of the Synaptotagmin 7 C2A Domain: Computation Reveals Interplay between Electrostatic and Hydrophobic Contributions.

The C2A domain of synaptotagmin 7 (Syt7) is a Ca(2+) and membrane binding module that docks and inserts into cellular membranes in response to elevated intracellular Ca(2+) concentrations. Like other C2 domains, Syt7 C2A binds Ca(2+) and membranes primarily through three loop regions; however, it docks at Ca(2+) concentrations much lower than those required for other Syt C2A domains. To probe structural components of its unusually strong membrane docking, we conducted atomistic molecular dynamics simulations of Syt7 C2A under three conditions: in aqueous solution, in the proximity of a lipid bilayer membrane, and embedded in the membrane. The simulations of membrane-free protein indicate that Syt7 C2A likely binds three Ca(2+) ions in aqueous solution, consistent with prior experimental reports. Upon membrane docking, the outermost Ca(2+) ion interacts directly with lipid headgroups, while the other two Ca(2+) ions remain chelated by the protein. The membrane-bound domain was observed to exhibit large-amplitude swinging motions relative to the membrane surface, varying by up to 70° between a more parallel and a more perpendicular orientation, both during and after insertion of the Ca(2+) binding loops into the membrane. The computed orientation of the membrane-bound protein correlates well with experimental electron paramagnetic resonance measurements presented in the preceding paper ( DOI: 10.1021/acs.biochem.5b00421 ). In particular, the strictly conserved residue Phe229 inserted stably ∼4 Å below the average depth of lipid phosphate groups, providing critical hydrophobic interactions anchoring the domain in the membrane. Overall, the position and orientation of Syt7 C2A with respect to the membrane are consistent with experiments.