Elevation Of Ca Concentration Research Articles

Levetiracetam, Calcium Antagonism, and Bipolar Disorder.

Hyperactive intracellular calcium ion (Ca) signaling in peripheral cells has been a reliable finding in bipolar disorder. Some established mood stabilizing medications, such as lithium and carbamazepine, have been found to normalize elevated intracellular Ca concentrations ([Ca]i) in platelets and lymphocytes from bipolar disorder patients, and some medications the primary effect of which is to attenuate increased [Ca]i have been reported to have mood stabilizing properties.Hyperactive intracellular Ca signaling has also been implicated in epilepsy, and some anticonvulsants have calcium antagonist properties. This study demonstrated that levetiracetam, an anticonvulsant that has been shown to block N and P/Q-type calcium channels in animal studies does not alter elevated [Ca]i in blood platelets of patients with bipolar disorder. Review of published clinical trials revealed no controlled evidence of efficacy as a mood stabilizer.This study underscores the possibility that pharmacologic actions of a medication in animals and normal subjects may not necessarily predict its pharmacologic or clinical effects in actual patients. Effects of treatments on pathophysiology that is demonstrated in clinical subtypes may be more likely to predict effectiveness in those subtypes than choosing medications based on structural similarities to established treatments.

Plasma Membrane Ca2+-Permeable Channels are Differentially Regulated by Ethylene and Hydrogen Peroxide to Generate Persistent Plumes of Elevated Cytosolic Ca2+ During Transfer Cell Trans-Differentiation.

The enhanced transport capability of transfer cells (TCs) arises from their ingrowth wall architecture comprised of a uniform wall on which wall ingrowths are deposited. The wall ingrowth papillae provide scaffolds to amplify plasma membranes that are enriched in nutrient transporters. Using Vicia faba cotyledons, whose adaxial epidermal cells spontaneously and rapidly (hours) undergo a synchronous TC trans-differentiation upon transfer to culture, has led to the discovery of a cascade of inductive signals orchestrating deposition of ingrowth wall papillae. Auxin-induced ethylene biosynthesis initiates the cascade. This in turn drives a burst in extracellular H2O2 production that triggers uniform wall deposition. Thereafter, a persistent and elevated cytosolic Ca(2+) concentration, resulting from Ca(2+) influx through plasma membrane Ca(2+)-permeable channels, generates a Ca(2+) signal that directs formation of wall ingrowth papillae to specific loci. We now report how these Ca(2+)-permeable channels are regulated using the proportionate responses in cytosolic Ca(2+) concentration as a proxy measure of their transport activity. Culturing cotyledons on various combinations of pharmacological agents allowed the regulatory influence of each upstream signal on Ca(2+) channel activity to be evaluated. The findings demonstrated that Ca(2+)-permeable channel activity was insensitive to auxin, but up-regulated by ethylene through two independent routes. In one route ethylene acts directly on Ca(2+)-permeable channel activity at the transcriptional and post-translational levels, through an ethylene receptor-dependent pathway. The other route is mediated by an ethylene-induced production of extracellular H2O2 which then acts translationally and post-translationally to up-regulate Ca(2+)-permeable channel activity. A model describing the differential regulation of Ca(2+)-permeable channel activity is presented.

Uraniferous paleoplacers of the Mesoarchean Mahagiri Quartzite, Singhbhum craton, India: Depositional controls, nature and source of > 3.0 Ga detrital uraninites

The quartz-pebble conglomerate (QPC)-hosted detrital uranium mineralization is unique in character in terms of their restricted distribution before 2.2Ga atmosphere during pre-Great Oxidation Event (pre-GOE). Such QPC paleoplacer deposits over the world are good targets for moderate to high tonnage and low grade uranium deposits and more importantly for their gold content. The Mahagiri Quartzite, dated c. 3.02Ga for their youngest detrital zircon population, is developed unconformably over the Mesoarchean Singhbhum Granite (3.44Ga to 3.1Ga). The Mahagiri Quartzite includes a conglomerate-pebbly sandstone dominated subaerial alluvial fan to coastal braided plain sequence in the lower parts and shallow marine mature quartz arenite in the upper parts. The alluvial fan-braided plain deposits in the lower parts host a number of pyritiferous and uraniferous conglomerate and pebbly sandstone beds. The uraninite grains are rounded to subrounded in outline suggesting mechanical transport and detrital origin. Together with detrital pyrite and uraninite constitute the example of >3.0Ga paleoplacer closely comparable to the Witwatersrand Au–U deposits. EPMA and SEM-EDS studies suggest that the uraninite grains are rich in Th (>4wt.%), S and REE-Y. Chemical formula calculations from EPMA analyses suggest uraninite grains belong to two populations with different oxidation states as revealed from Y/REE and cation U4+: U6+ [apfu] ratios. The U contents of the detrital uraninite grains from Mahagiri are significantly lower than that of the ideal stoichiometric composition of UO2. This is mainly due to higher amount of heterovalent cationic substitution by Th, REE, Y, Pb, and Ca in Mahagiri QPC uraninite structures, and partial alteration and metamictization of uraninites. Alteration due to metamictization resulted in elevated concentration of Si, Al, P, and Ca in more altered and metamict uraninite grains. The REE pattern is typically flat with comparable LREE–HREE concentration. The high Th content flat REE-pattern suggests that the uraninitere presents high temperature phases (>350°C) and are magmatic in origin. The Mahagiri detrital uraninite grains suggest existence of highly felsic and K-rich (richer than TTG) granodiorite–granite–monzogranite suites (GGM) of rocks older than 3.1Ga in the Singhbhum craton.

Impact of the Red Mud Disposal on Several Floodplain Lagoons of the Lower Orinoco River

This paper identifies the effects of red mud spills on several lagoons of the Orinoco River located surrounding the red mud deposits. Chemical and mineralogical analyses of sediments indicate that the geochemical signature of red mud is evident in Los Caribes and Guadita lagoons, with elevated concentrations of Fe, Al, and Na and the presence of goethite and hematite as the major mineral phases. Water quality analyses indicate that these lagoons have elevated values of dissolved oxygen, pH, conductivity, and dissolved Ca, Na, Ni, and Al. Also, elevated concentrations of Ca, Mg, and Mn in sediments suggest the precipitation of calcite, brucite a Mn-oxyhydroxides due to high pH values. Although Los Cardonales lagoon also showed evidence of red mud deposition, the enrichment of Mn, Zn, Ni, and Cd in sediments from this lagoon could be associated with wastewaters coming from landfills. The absence of vascular plants and the low abundance of fish communities in several lagoons can be related with the high pH values and the elevated concentrations of dissolved Al. The high concentrations of Fe and Mn in sediments of these lagoons can have adverse effects on benthic organisms, according to International Guidelines. Even though this lagunar system is impacted by red mud spills, hyperalkaline conditions (pH > 13) were not found in superficial waters. Thus, dissolved trace element concentrations (Fe, Zn, Mn, Cr, Cu, Cd, and Pb) in waters were not high, mainly due to trace elements are immobilized by sorption or coprecipitation at circum-neutral pH.

Applications of chemostratigraphy in Cretaceous sediments encountered in the North Central Rub’ al-Khali Basin, Saudi Arabia

The following study was undertaken on inorganic geochemical data acquired for 832 core and cuttings samples taken from Cretaceous sediments encountered in 11 wells in the North Central Rub’ al-Khali Basin, Saudi Arabia. The study sections extend from Khafji Member at the base of the Wasia Formation to the basal part of the Aruma Formation. The principal objective of the study was to produce a chemostratigraphic scheme for these wells, though a comparison was also made with a previous lithostratigraphic scheme.Although ICP–OES (Inductively Coupled Plasma–Optical Emission Spectrometry) and ICP–MS (Inductively Coupled Plasma–Mass Spectrometry) were used to acquire data for 50 elements, the chemostratigraphic scheme is based on changes in the following ‘key’ elements and ratios: Ca, Al, Zr, P/Y, Zr/P, Zr/Y, Zr/Nb, Mo and Zr. The scheme comprises a hierarchical order of five zones, 18 subzones and four divisions, with the zones labelled C1, C2, C3, C4 and C5 in ascending stratigraphic order. The definition of these zones are mainly based on changes in Ca and Al reflecting variations in bulk lithology as a response to changes in base level. Zone C1 is dominated by elevated Al and low Ca concentrations and represents calcareous mudrocks deposited in a lagoonal–prodelta environment. An increase in base level led to the formation of highly calcareous rudistic limestones deposited in a shallow marine environment, with a further increase in base level resulting in the deposition of calcareous mudrocks with high Al values in zone C3. Zone C4 comprises rudistic limestones (with elevated Ca and low Al) deposited in shallow marine conditions, while C5 is dominated by calcareous mudrocks and argillaceous limestones deposited in a prodeltaic paleoenvironment. Although the definition of zones mainly relates to changes in base level/bulk lithology, more subtle changes in provenance are modelled using the P/Y, Zr/P, Zr/Y and Zr/Nb ratios which are used to define most subzones and divisions. Variations in this ratio are almost entirely dependent on changes in source/provenance.Although all of the zones and most of the subzones are correlative between the study wells it is noted that different criteria are used to define the zone C2 and C4 subzones in the eastern and western wells of the study area. This suggests that separate sediment sources were responsible for the delivery of clastic material to these carbonate ‘reefs’ during the deposition of these subzones.One important conclusion from this study is that there are close links between the chemostratigraphic and lithostratigraphic correlations but the former offers a much higher level of resolution.

Exposure of 304L and 310S in chlorinating gasification environments

This work examines the difference in behaviour between two austenitic steels, 304L and 310S, in a simulated environment with carbon and oxygen activities typical of the syngas cooler of a steam blown gasifier. The cyclic exposures were performed with and without addition of 500 ppm HCl for a total duration of 960 h. The oxide layers (200–600 nm) were studied using TEM, a focused ion beam microscope with EDX (FIB-EDX), electron back scattered diffraction (EBSD), SEM and X-ray diffraction (XRD). For 304L, a Cr and Ni depleted zone with a ferritic structure was observed below the oxide layer and a thin, manganese rich layer at the metal/oxide interface. For 310S, circular oxide patches were observed on the surface after exposure with HCl. These displayed elevated concentration of Al, Ca and Si, typical of inclusions. Results indicate that the addition of HCl results in a difference in oxide quality and structure but that HCl at the level of this study has little impact on the sound metal thickness.

The antidepressant bupropion exerts alleviating properties in an ovariectomized osteoporotic rat model.

Depression is a risk factor for impaired bone mass and micro-architecture, but several antidepressants were found to increase the incidence of osteoporotic fractures. In the present study we used ovariectomized (OVX) rats as a model of osteoporosis to investigate the effects of the antidepressant bupropion on the femoral bones. OVX animals were treated with bupropion (30, 60 mg·kg(-1)·d(-1)) for six weeks. Bone turnover biomarkers (urinary DPD/Cr ratio, serum BALP, OC, TRAcP 5b, CTX and sRANKL levels) and inflammatory cytokines (TNF-α, IL-1β and IL-6) were determined using ELISA. Inductively coupled plasma mass spectroscopy (ICP-MS) was used to determine the femoral bone mineral concentrations. The cortical and trabecular morphometric parameters of femoral bones were determined using micro-CT scan and histopathology. In OVX rats, the levels of bone turnover biomarkers and inflammatory cytokines were significantly elevated and femoral bone Ca(2+) and PO4(3-) concentrations were significantly reduced. Moreover, cortical and trabecular morphometric parameters and histopathology of femoral bones were severely altered by ovariectomy. Bupropion dose-dependently inhibited the increases in bone turnover biomarkers and inflammatory cytokines. OVX rats treated with the high dose of bupropion showed normal mineral concentrations in femoral bones. The altered morphometric parameters and histopathology of femoral bones were markedly attenuated by the treatment. Bupropion exerts osteo-protective action in OVX rats through suppressing osteoclastogenesis-inducing factors and inflammation, which stabilize the osteoclasts and decrease bone matrix degradation or resorption.

Soil type influences crop mineral composition in Malawi

Food supply and composition data can be combined to estimate micronutrient intakes and deficiency risks among populations. These estimates can be improved by using local crop composition data that can capture environmental influences including soil type. This study aimed to provide spatially resolved crop composition data for Malawi, where information is currently limited.Six hundred and fifty-two plant samples, representing 97 edible food items, were sampled from >150 sites in Malawi between 2011 and 2013. Samples were analysed by ICP-MS for up to 58 elements, including the essential minerals calcium (Ca), copper (Cu), iron (Fe), magnesium (Mg), selenium (Se) and zinc (Zn).Maize grain Ca, Cu, Fe, Mg, Se and Zn concentrations were greater from plants grown on calcareous soils than those from the more widespread low-pH soils. Leafy vegetables from calcareous soils had elevated leaf Ca, Cu, Fe and Se concentrations, but lower Zn concentrations. Several foods were found to accumulate high levels of Se, including the leaves of Moringa, a crop not previously been reported in East African food composition data sets.New estimates of national dietary mineral supplies were obtained for non-calcareous and calcareous soils. High risks of Ca (100%), Se (100%) and Zn (57%) dietary deficiencies are likely on non-calcareous soils. Deficiency risks on calcareous soils are high for Ca (97%), but lower for Se (34%) and Zn (31%). Risks of Cu, Fe and Mg deficiencies appear to be low on the basis of dietary supply levels.

Oxidation of cardiolipin is involved in functional impairment and disintegration of liver mitochondria by hypoxia/reoxygenation in the presence of increased Ca²⁺ concentrations.

The aim of this study was to investigate the interrelationship between the mitochondrial phospholipid cardiolipin (CL), mitochondrial respiration and morphology in dependence on hypoxia/reoxygenation and Ca(2+). Therefore, we subjected rat liver mitochondria to hypoxia/reoxygenation at different extramitochondrial Ca(2+) concentrations and analysed mitochondrial respiration, morphology, CL content, the composition of molecular CL species, oxidation of CL and two mono-lyso-CL species. Hypoxia/reoxygenation in the presence of elevated extramitochondrial Ca(2+) concentration caused dramatic impairment of mitochondrial respiration and morphology. Concomitantly, increased amounts of oxidised CL were detected in the incubation medium after the treatment. Hypoxia/reoxygenation alone caused degradation of CL. The treatments had no effect on the composition of molecular CL species. Our data support the hypothesis that CL oxidation and CL degradation are involved in mitochondrial injury caused by hypoxia/reoxygenation and Ca(2+). Our results further suggest that prevention of CL oxidation by modification of CL composition may support the beneficial action of antioxidants during hypoxia/reoxygenation in the presence of elevated Ca(2+) concentrations.

Intracellular Calcium Attenuates Persistent Current Conducted by Mutant Human Cardiac Sodium Channels in Long-QT Syndrome

Mutation in the cardiac voltage-gated sodium channel NaV1.5 can cause congenital long-QT syndrome type 3 (LQT3). Most NaV1.5 mutations associated with LQT3 promote a mode of sodium channel gating in which some channels fail to inactivate, contributing to sustained or persistent sodium current (INa,P), which is directly responsible for delayed repolarization and prolongation of the QT interval. LQT3 patients have highest risk of arrhythmia during sleep or during periods of slow heart rate. During exercise (high heart rate), there is an increase in the steady-state intracellular free calcium (Ca) concentration. We hypothesized that higher levels of intracellular Ca may act in some way to lower arrhythmia risk in LQT3 subjects. We tested this idea by examining the effects of varying intracellular Ca concentrations on the level of INa,P in cells expressing a typical LQT3 mutation, delKPQ. We found that elevated intracellular Ca concentration significantly reduced INa,P conducted by delKPQ channels but not wild-type channels. INa,P measured 200-ms after the peak transient current (expressed as % of peak current) for mutant channels was 2.6±0.4% in low Ca and 0.6±0.1% in high Ca (p<0.001). This attenuation of INa,P in delKPQ expressing cells by Ca remained in the presence of KN-93 indicating it was not due to CaM kinase II activation (2.2±0.2% in low Ca and 0.9±0.3% in high Ca; p<0.001). We conclude that intracellular Ca contributes to the regulation of INa,P conducted by a LQT3 mutant and propose that, during excitation-contraction coupling, the increase of intracellular free Ca may contribute to suppression of mutant channel current and protect cells from delayed repolarization. These findings help explain the increased arrhythmia risk in LQT3 during slow heart rate.

Injection and Monitoring at the Wallula Basalt Pilot Project

Abstract Continental flood basalts represent one of the largest geologic structures on earth but have received comparatively little attention for geologic storage of CO2. Flood basalt lava flows have flow tops that are porous, permeable, and have large potential capacity for storage of CO2. In appropriate geologic settings, interbedded sediment layers and dense low-permeability basalt rock flow interior sections may act as effective seals allowing time for mineralization reactions to occur. Previous laboratory experiments showed the relatively rapid chemical reaction of CO2-saturated pore water with basalts to form stable carbonate minerals. However, recent laboratory tests with water-saturated supercritical CO2 show that mineralization reactions occur in this phase as well, providing a second and potentially more important mineralization pathway than was previously understood. Field testing of these concepts is proceeding with drilling of the world's first supercritical CO2 injection well in flood basalt being completed in May 2009 near the township of Wallula in Washington State and corresponding CO2 injection permit granted by the State of Washington in March 2011. Injection of a nominal 1000 MT of CO2 was completed in August 2013 and site monitoring is in progress. Well logging conducted immediately after injection termination confirmed the presence of CO2 predominantly within the upper flow top region, and showed no evidence of vertical CO2 migration outside the well casing. Shallow soil gas samples collected around the injection well show no evidence of leakage and fluid and gas samples collected from the injection zone show strongly elevated concentrations of Ca, Mg, Mn, and Fe and 13C/18O isotopic shifts that are consistent with basalt-water chemical reactions. If proven viable by this field test and others that are in progress or being planned, major flood basalts in the U.S., India, and perhaps Australia would provide significant additional CO2 storage capacity and additional geologic sequestration options in regions of these countries where conventional storage options are limited.

Serum carbohydrate antigen 19-9 and prognosis of patients with gastric cancer

Previous studies have assessed the prognostic role of serum carbohydrate antigen 19-9 (CA 19-9) concentration in patients with gastric cancer, but the findings from those studies were inconsistent. We searched the PubMed and Web of Science databases to find eligible studies assessing the prognostic role of CA 19-9 in patients with gastric cancer. Twelve studies with a total of 5,072 gastric cancer patients were finally included into the meta-analysis. The pooled hazard ratio (HR) with corresponding 95 % confidence interval (95 % CI) for overall survival were calculated to assess the prognostic role of CA 19-9 in patients with gastric cancer. Overall, elevated serum concentration of CA 19-9 (>37 U/mL) was associated with poorer overall survival in patients with gastric cancer (fixed-effects HR = 1.36, 95 % CI 1.24-1.48, P < 0.001). Subgroup analysis by study design further showed that elevated serum concentration of CA 19-9 was associated with poorer overall survival in patients with gastric cancer. There was no obvious risk of publication bias. Elevated concentration of serum CA 19-9 is associated with poorer overall survival in patients with gastric cancer.

Role of ASIC1 in the development of chronic hypoxia-induced pulmonary hypertension.

Chronic hypoxia (CH) associated with respiratory disease results in elevated pulmonary vascular intracellular Ca(2+) concentration, which elicits enhanced vasoconstriction and promotes vascular arterial remodeling and thus has important implications in the development of pulmonary hypertension (PH). Store-operated Ca(2+) entry (SOCE) contributes to this elevated intracellular Ca(2+) concentration and has also been linked to acute hypoxic pulmonary vasoconstriction (HPV). Since our laboratory has recently demonstrated an important role for acid-sensing ion channel 1 (ASIC1) in mediating SOCE, we hypothesized that ASIC1 contributes to both HPV and the development of CH-induced PH. To test this hypothesis, we examined responses to acute hypoxia in isolated lungs and assessed the effects of CH on indexes of PH, arterial remodeling, and vasoconstrictor reactivity in wild-type (ASIC1(+/+)) and ASIC1 knockout (ASIC1(-/-)) mice. Restoration of ASIC1 expression in pulmonary arterial smooth muscle cells from ASIC1(-/-) mice rescued SOCE, confirming the requirement for ASIC1 in this response. HPV responses were blunted in lungs from ASIC1(-/-) mice. Both SOCE and receptor-mediated Ca(2+) entry, along with agonist-dependent vasoconstrictor responses, were diminished in small pulmonary arteries from control ASIC(-/-) mice compared with ASIC(+/+) mice. The effects of CH to augment receptor-mediated vasoconstrictor and SOCE responses in vessels from ASIC1(+/+) mice were not observed after CH in ASIC1(-/-) mice. In addition, ASIC1(-/-) mice exhibited diminished right ventricular systolic pressure, right ventricular hypertrophy, and arterial remodeling in response to CH compared with ASIC1(+/+) mice. Taken together, these data demonstrate an important role for ASIC1 in both HPV and the development of CH-induced PH.

18beta-Glycyrrhetinic acid induces apoptosis in pituitary adenoma cells via ROS/MAPKs-mediated pathway

The purpose of the present study was to evaluate the anti-tumor effects of 18beta-glycyrrhetinic acid (GA), a natural compound extracted from liquorice, against pituitary adenoma and its underlying mechanisms in cultured cells and mouse model of xenografted tumor. GA induced cellular damage in rat pituitary adenoma-derived MMQ and GH3 cells, manifested as reduced cell viability, increased lactate dehydrogenase release, elevated intracellular reactive oxygen species (ROS) and Ca(2+) concentration. GA also caused G0/G1 phase arrest, increased apoptosis rate and increased mitochondrial membrane permeabilization by suppressing the mitochondrial membrane potential and down-regulating a ratio of B cell lymphoma 2 (Bcl-2) and Bax. GA activated calcium/calmodulin-dependent protein kinase II (CaMKII), c-Jun N-terminal kinase (JNK) and P38; but these activating effects were attenuated by pretreatment with N-acetyl-L-cysteine, a ROS inhibitor. Pretreatment with KN93, a CaMKII inhibitor, also abolished the GA activation of JNK and P38. GA remarkably inhibited growth of pituitary adenoma grafted on nude mice. These results suggest that the anti-pituitary adenoma effect of GA is associated with its apoptotic actions by activating mitochondria-mediated ROS/mitogen-activated protein kinase pathways in particular CaMKII that may serve a linkage between ROS accumulation and the activation of JNK and P38. This study provides experimental evidence in the support of further developing GA as a chemotherapeutic agent for pituitary adenoma.

How Does the Cell Overcome LCP Nanoparticle-Induced Calcium Toxicity?

To address the question of how cells respond to the possible Ca(2+) toxicity caused by the release of Ca(2+) into the cytoplasm by LCP nanoparticles, a series of in vitro and in vivo studies using Ca(2+) pump inhibitors were conducted. The results indicated that two major Ca(2+) pumps on the plasma membrane and the mitochondrial membrane, respectively, were able to rapidly respond to the elevated cytosolic Ca(2+) concentration and prevent Ca(2+)-induced apoptosis or necrosis. However, exposure to specific inhibitors of calcium pumps would cause LCP-treated H460 cells to undergo necrosis both in vitro and in vivo. These results demonstrated that the Ca(2+) delivered by LCP was not toxic to cells when the cells contain functional Ca(2+) pumps.

Application of Hyaluronic Acid Sodium Salt and Vitamin C in the Therapy of Dogs with Hypertrophic Osteodystrophy

Abstract Radiographic examination of the distal radius and ulna of dogs showed changes in metaphyseal areas of both bones characteristic of hypertrophic osteodystrophy (HOD). The serum of the patients showed increased activity of alkaline phosphatase (ALKP) and elevated concentrations of Ca and P. Oral application of vitamin C and injection of sodium salt of hyaluronic acid in the bolus caused a reduction in swelling, disappearance of pain symptoms around the joints, and increased appetite. Radiographic examinations performed on the 60th d of treatment revealed the withdrawal of the changes characteristic for HOD. The chosen biochemical parameters tested during the treatment showed a decrease in comparison to the values before treatment, namely: ALKP by 27.7%, Ca by 22.2%, P by 12.3%, and Mg by 2.4%. Clinical condition of the animals was defined as good or very good. The use of hyaluronic acid and vitamin C in the treatment of HOD in the first stage of the disease proved to be highly successful, resulting in the inhibition of the disease course.

Noradrenaline stimulates cell proliferation by suppressing potassium channels via Gi/o‐protein‐coupled α1B‐adrenoceptors in human osteoblasts

Recent studies demonstrated that the sympathetic nervous system regulates bone metabolism via β(2) -adrenoceptors. Although α-adrenoceptors are also expressed in osteogenic cells, their functions in bone metabolism have been less studied. We previously demonstrated that noradrenaline suppressed potassium currents via α(1B) -adrenoceptors in the human osteoblast SaM-1 cell line. The aim of this study was to investigate the signal transduction pathway and the physiological role of noradrenaline in human osteoblasts in more detail. To investigate signal transduction through α(1B) -adrenoceptors, we used whole-cell patch clamp recording and Ca fluorescence imaging. Potassium channels regulate membrane potential and cell proliferation activity in non-excitable cells, so we evaluated cell proliferation activity by BrdU incorporation and WST assay. In SaM-1 cells, bath-applied noradrenaline elevated intracellular Ca(2+) concentration and this effect was abolished by both chloroethylclonidine, an α(1B) -adrenoceptor antagonist, and U73122, a PLC inhibitor. However, the inhibitory effect of noradrenaline on whole-cell current was unaffected by U73122. In contrast, in cells pretreated with either Pertussis toxin, a G(i/o) -protein-coupled receptor inhibitor, or gallein, a Gβγ-protein inhibitor, the inhibitory effect of noradrenaline on whole-cell current was significantly suppressed. Noradrenaline-induced enhancement of cell proliferation was inhibited by CsCl, a non-selective potassium channel blocker, gallein and H89, a PKA inhibitor, but not by U73122. Noradrenaline facilitated cell proliferation by regulation of potassium currents in human osteoblasts via G(i/o) -protein-coupled α(1B) -adrenoceptors, not via coupling to Gq-proteins.

Clinical Usefulness of Cancer Antigen 15-3 in Breast Cancer Patients Before and After Surgery

Background: Cancer Antigen 15-3 (CA 15-3) is a tumor-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 retrospectively evaluate CA 15-3 as a prognostic factor in early detection of breast cancer relapse as well as to analyze the statistical correlation between CA 15-3 levels and clinical-pathological parameters including staging, grading, estrogen and progesterone receptors. Methods: Sera of 726 women with breast carcinoma obtained preoperatively and postoperatively were assayed for CA 15- 3 by chemoluminescent immunometric assay. Results: We found that the mean serum CA 15-3 levels in patients before surgery were significantly higher (36.59 U/ml) compared with those of CA 15-3 after surgery (27.11 U/ml). We also found that elevated preoperative serum levels of CA 15-3 were significantly correlated with the presence of metastatic disease. In particular, among 305/700 patients (43,6%) that displayed over cut-off (>40U/ml) preoperative levels of CA 15-3, 94 patients (30,8%) developed advanced disease (metastases to distant sites). By contrast, in a subgroup of 395/700 patients (56.4%) with CA 15.3 serum levels < 40U/ml, only 32/305 patients (8%) showed signs of advanced disease during follow-up. Cox regression analysis revealed that only the presence of metastasis and the increased serum levels of CA 15-3 after surgery are significant risk factors for relapse of disease. Conclusion: Elevated preoperative concentrations of CA 15-3 may be a useful predictive factor for cancer progression in postoperative patients.

Lanthanum Induced Primary Neuronal Apoptosis Through Mitochondrial Dysfunction Modulated by Ca2+ and Bcl-2 Family

As a representative element of lanthanide, lanthanum has been widely used in various fields and eventually entered environment and accumulated in human body. Epidemiological and experimental evidences indicated that lanthanum has neurotoxicity; however, the detailed mechanism is still elusive. Here, we chose primary cerebral cortical neurons as model in vitro to investigate the mechanism underlying the toxic effects of lanthanum chloride (LaCl3). This study revealed the following findings: (1) LaCl3 treatment (0.01, 0.1, and 1.0mM for 24h) reduced the viability of cortical neurons and elevated apoptotic rate significantly in a dose-dependent manner. (2) LaCl3 triggered mitochondrial apoptotic pathway in cortical neurons, characterized with collapsed mitochondrial membrane potential, release of cytochrome c into cytosol, and increasing expression of activated caspase-3. (3) LaCl3 elevated intracellular Ca(2+) concentration, promoted reactive oxygen species generation, and upregulated pro-apoptotic Bax, whereas it downregulated anti-apoptotic Bcl-2 expression and consequently altered Bax/Bcl-2 ratio, which ultimately lead to neuronal mitochondrial apoptosis. Our results demonstrated that toxicity of lanthanum in cortical neurons perhaps partly attributed to enhanced mitochondrial apoptosis due to mitochondrial dysfunction modulated by Ca(2+) and Bcl-2 family.

Novel insights into TRPV4 function in the kidney

Kidneys are complex highly organized paired organs of nearly one million nephrons each. They rigorously process about 180l of plasma daily to keep whole body homeostasis. To effectively perform such a titanic work, kidneys rely on mechanisms able to sense dynamic changes in composition and flow rates of protourine along the renal tubule. It is envisioned that Ca(2+)-permeable transient receptor potential (TRP) channels, and specifically mechanosensitive TRPV4, can serve to interpret these external mechanical cues in the form of elevated intracellular Ca(2+) concentration. This, in turn, initiates multiple cellular responses and adaptation mechanisms. The current review summarizes up-to-date knowledge about the sites of TRPV4 expression in renal tissue as well as discusses the functional role of the channel in cellular responses to hypotonicity and tubular flow. We will also provide insights as to how TRPV4 fits into classical polycystin mechanosensory complex in cilia and will speculate about previously underappreciated clinical implication of pharmacological TRPV4 targeting in treatment of polycystic kidney disease.