CDN1163, a SERCA activator, causes intracellular Ca leak, mitochondrial hyperpolarization and cell cycle arrest in mouse neuronal N2A cells.

Objective: Activity or expression of sarcoplasmic/endoplasmic reticulum Ca ATPase (SERCA) is diminished in some disease states such as cardiac failure and diabetes mellitus. A newly developed activator of SERCA, CDN1163, reportedly rescued or alleviated pathological conditions attributed to dysfunctional SERCA. We examined whether CDN1163 could relieve mouse neuronal N2A cell growth inhibition caused by cyclopiazonic acid (CPA, SERCA inhibitor).

Sensitivity of Ca-sensing receptor-transient receptor potential-mediated Ca influx to extracellular acidity in bEND.3 endothelial cells.

Ca-sensing receptors (CaSRs) are G protein-coupled receptors activated by elevated concentrations of extracellular Ca. In our previous works, we showed protein and functional expression of CaSR in mouse cerebral endothelial cell (EC) (bEND.3); the CaSR response (high Ca-elicited cytosolic [Ca] elevation) was unaffected by suppression of phospholipase C but in part involved Ca influx through transient receptor potential V1 (TRPV1) channels.

Afatinib triggers a Ni -resistant Ca influx pathway in A549 non-small cell lung cancer cells.

Afatinib is used to treat non-small cell lung cancer cells (NSCLC), and its mechanism involves irreversible inhibition of epidermal growth factor receptor (EGFR) tyrosine kinase. In this study, we examined if afatinib had cytotoxic action against NSCLC other than inhibition of tyrosine kinase. Afatinib (1-30 μM) caused apoptotic death in A549 NSCLC in a concentration-dependent manner.

Suppression of Ca oscillations by SERCA inhibition in human alveolar type 2 A549 cells: rescue by ochratoxin A but not CDN1163.

Aims: Lung type 2 alveolar cells, by secreting surfactant to lower surface tension, contribute to enhance lung compliance. Stretching, as a result of lung expansion, triggers type 1 alveolar cell to release ATP, which in turn stimulates Ca-dependent surfactant secretion by neighboring type 2 cells. In this report, we studied ATP-triggered Ca signaling in human alveolar type 2 A549 cells.

Propofol Causes Sustained Ca2+ Elevation in Endothelial Cells by Stimulating Ryanodine Receptor and Suppressing Plasmalemmal Ca2+ Pump.

Propofol, a general anesthetic administered intravenously, may cause pain at the injection site. The pain is in part due to irritation of vascular endothelial cells. We here investigated the effects of propofol on Ca2+ transport and pain mediator release in human umbilical vein endothelial cells (EA.

A basal level of γ-linolenic acid depletes Ca stores and induces endoplasmic reticulum and oxidative stresses to cause death of breast cancer BT-474 cells.

Gamma-linolenic acid (GLA), a natural fatty acid obtained from oils of various vegetables and seeds, has been demonstrated as an anticancer agent. In this work, we investigated the anticancer effects of GLA on breast cancer BT-474 cells. GLA at 30 μM, a concentration reportedly within the range of circulating concentrations in clinical studies, caused apoptotic cell death.

High-Throughput Screening to Identify Small Molecules That Selectively Inhibit APOL1 Protein Level in Podocytes.

High-throughput phenotypic screening is a key driver for the identification of novel chemical matter in drug discovery for challenging targets, especially for those with an unclear mechanism of pathology. For toxic or gain-of-function proteins, small-molecule suppressors are a targeting/therapeutic strategy that has been successfully applied. As with other high-throughput screens, the screening strategy and proper assays are critical for successfully identifying selective suppressors of the target of interest.

Characterization of Ca-Sensing Receptor-Mediated Ca Influx in Microvascular bEND.3 Endothelial Cells.

Ca-sensing receptors (CaSR), activated by elevated concentrations of extracellular Ca, have been known to regulate functions of thyroid cells, neurons, and endothelial cells (EC). In this report, we studied CaSR-mediated Ca influx in mouse cerebral microvascular EC (bEND.3 cells).

Perturbation of Ca stores and store-operated Ca influx by lidocaine in neuronal N2A and NG108-15 cells.

In this report we examined the effects of lidocaine on Ca homeostasis of neuronal cells using microfluorimetric measurement of cytosolic Ca with fura 2 as probe. In mouse neuroblastoma N2A cells, 10 mM lidocaine caused Ca release from the cyclopiazonic acid (CPA)-dischargeable pool and abolished ATP-triggered Ca release. Lidocaine-triggered Ca release was not affected by xestospongin C (XeC), an inositol 1,4,5-trisphosphate receptor (IP3R) inhibitor.

Tannic acid, a vasodilator present in wines and beverages, stimulates Ca influx via TRP channels in bEND.3 endothelial cells.

Tannic acid (TA) is a polyphenol compound present in wines and many beverages. Although previous works have shown that TA could cause vasodilation in an endothelial cell (EC)-dependent manner, there is hitherto no report showing whether TA could raise EC cytosolic Ca concentration. In this work we examined the effects of TA on cytosolic Ca of mouse brain bEND.

Polyamine stimulation perturbs intracellular Ca2+ homeostasis and decreases viability of breast cancer BT474 cells.

Intracellular polyamines such as spermine and spermidine are essential to cell growth in normal and especially in cancer cells. However, whether extracellular polyamines affect cancer cell survival is unknown. We therefore examined the actions of extracellular polyamines on breast cancer BT474 cells.

Quercetin depletes intracellular Ca stores and blunts ATP-triggered Ca signaling in bEnd.3 endothelial cells.

Quercetin is a flavonol polyphenol widely found in many vegetables, grains, and fruits. Quercetin has been shown to inhibit proliferation and invasion of various glioma cells and is regarded as a potential anticancer agent against glioma. However, whether and how this drug could affect brain blood vessels and endothelial cells (EC) are less understood.

ARC 118925XX stimulates cation influx in bEND.3 endothelial cells.

In a previous publication when we studied the purinergic receptor with which ATP interacted in mouse brain bEND.3 endothelial cells, we observed addition of 3 μm ARC 118925XX (ARC; selective P2Y antagonist) strongly suppressed ATP-triggered Ca release, suggesting the response was mediated via P2Y receptors. We here report ARC unexpectedly promoted substantial Ca influx even when ATP-triggered Ca release was largely inhibited.

Antagonism of Ca-sensing receptors by NPS 2143 is transiently masked by p38 activation in mouse brain bEND.3 endothelial cells.

Ca-sensing receptors (CaSR) are G protein-coupled receptors which are activated by a rise in extracellular Ca. CaSR activation has been known to inhibit parathyroid hormone release and stimulate calcitonin release from parathyroid glands and thyroid parafollicular C cells, respectively. The roles of CaSR in other cell types including endothelial cells (EC) are much less understood.

Enhancing tetrandrine cytotoxicity in human lung carcinoma A549 cells by suppressing mitochondrial ATP production.

ATP depletion induced by inhibiting glycolysis or mitochondrial ATP production has been demonstrated to cause cancer cell death. Whether ATP depletion can enhance the efficacy and potency of anti-cancer effects of herbal compounds is so far unknown. We examined the enhancing effect of ATP depletion on anti-cancer actions of tetrandrine (TET) in human lung carcinoma A549 cells.

Lysophosphatidylcholine-induced cytotoxicity and protection by heparin in mouse brain bEND.3 endothelial cells.

A pathological feature in atherosclerosis is the dysfunction and death of vascular endothelial cells (EC). Oxidized low-density lipoprotein (LDL), known to accumulate in the atherosclerotic arterial walls, impairs endothelium-dependent relaxation and causes EC apoptosis. A major bioactive ingredient of the oxidized LDL is lysophosphatidylcholine (LPC), which at higher concentrations causes apoptosis and necrosis in various EC.

Valproic acid inhibits ATP-triggered Ca release via a p38-dependent mechanism in bEND.3 endothelial cells.

Valproic acid (VA) is currently used to treat epilepsy and bipolar disorder. It has also been demonstrated to promote neuroprotection and neurogenesis. Although beneficial actions of VA on brain blood vessels have also been demonstrated, the effects of VA on brain endothelial cell (EC) Ca signaling are hitherto unreported.

Eicosapentaenoic acid triggers Ca release and Ca influx in mouse cerebral cortex endothelial bEND.3 cells.

Eicosapentaenoic acid (EPA), an omega-3 fatty acid abundant in fish oil, protects endothelial cells (EC) from lipotoxicity and triggers EC NO release. The latter is related to an elevation of cytosolic Ca. Although EPA has been shown to cause human EC cytosolic Ca elevation, the mechanism is unclear.

Discovery of MK-4409, a Novel Oxazole FAAH Inhibitor for the Treatment of Inflammatory and Neuropathic Pain.

We report herein the identification of MK-4409, a potent and selective fatty acid amide hydrolase (FAAH) inhibitor. Starting from a high throughput screening (HTS) hit, medicinal chemistry efforts focused on optimizing of FAAH inhibition in vitro potency, improving the pharmacokinetic (PK) profile, and increasing in vivo efficacy in rodent inflammatory and neuropathic pain assays.

Discovery of MK-3168: A PET Tracer for Imaging Brain Fatty Acid Amide Hydrolase.

We report herein the discovery of a fatty acid amide hydrolase (FAAH) positron emission tomography (PET) tracer. Starting from a pyrazole lead, medicinal chemistry efforts directed toward reducing lipophilicity led to the synthesis of a series of imidazole analogues. Compound 6 was chosen for further profiling due to its appropriate physical chemical properties and excellent FAAH inhibition potency across species.

Taking stock of Myanmar's progress toward the health-related Millennium Development Goals: current roadblocks, paths ahead.

Myanmar is a developing country with considerable humanitarian needs, rendering its pursuit of the Millennium Development Goals (MDGs) an especially high priority. Yet progress to date remains under-examined on key fronts. Particularly within the three health-related MDGs (MDGs 4, 5, and 6), the limited data reported point to patchy levels of achievement.

Adverse birth outcomes among native-born and foreign-born mothers in Taiwan: a population-based birth cohort study.

Background: The number of children born to foreign-born mothers in Taiwan has significantly increased since the 1990s. These foreign-born mothers are mainly from China and Southeast Asia. Children born to foreign-born mothers, according to media reports, are subject to inferior health.

Migration of health workers in the Pacific Islands: a bottleneck to health development.

Human resources for health (HRH) are a crucial component of a well-functioning health system. Problems in the global HRH supply and distribution are an obstacle to achieving the health-related Millennium Development Goals and other health outcomes. The Pacific Island region, covering 20,000 to 30,000 islands in the South Pacific Ocean, is suffering a serious HRH crisis.

Unaltered graft survival and intragraft lymphocytes infiltration in the cardiac allograft of Cxcr3-/- mouse recipients.

Previous studies showed that absence of chemokine receptor Cxcr3 or its blockade prolong mouse cardiac allograft survival. We evaluated the effect of the CXCR3 receptor antagonist MRL-957 on cardiac allograft survival, and also examined the impact of anti-CXCR3 mAb in human CXCR3 knock-in mice. We found only a moderate increase in graft survival (10.

Generation of mice expressing the human glucagon receptor with a direct replacement vector.

The process of evaluating the in vivo efficacy of non-peptidyl receptor antagonists in animal models is frequently complicated by failure of compounds displaying high affinity against the human receptors to show measurable affinity at the corresponding rodent receptors. In order to generate a suitable animal model in which to evaluate the in vivo activity of non-peptidyl glucagon receptor antagonists, we have utilized a direct targeting approach to replace the murine glucagon receptor with the human glucagon receptor gene by homologous recombination. Specific expression of the human glucagon receptor (GR) in the livers of transgenic mice was confirmed with an RNase protection assay, and the pharmacology of the human GRs expressed in the livers of these mice parallels that of human GR in a recombinant CHO cell line with respect to both binding of 125I-glucagon and the ability of glucagon to stimulate cAMP production.