Free fatty acids (FFAs), in addition to glucose, have been shown to stimulate insulin release through the G protein-coupled receptor (GPCR)40 receptor in pancreatic beta-cells. Intracellular free calcium concentration ([Ca(2+)](i)) in beta-cells is elevated by FFAs, although the mechanism underlying the [Ca(2+)](i) increase is still unknown. In this study, we investigated the action of linoleic acid on voltage-gated K(+) currents. Nystatin-perforated recordings were performed on identified rat beta-cells. In the presence of nifedipine, tetrodotoxin, and tolbutamide, voltage-gated K(+) currents were observed. The transient current represents less than 5%, whereas the delayed rectifier current comprises more than 95%, of the total K(+) currents. A long-chain unsaturated FFA, linoleic acid (10 microm), reversibly decreased the amplitude of K(+) currents (to less than 10%). This reduction was abolished by the cAMP/protein kinase A system inhibitors H89 (1 microm) and Rp-cAMP (10 microm) but was not affected by protein kinase C inhibitor. In addition, forskolin and 8'-bromo-cAMP induced a similar reduction in the K(+) current as that evoked by linoleic acid. Insulin secretion and cAMP accumulation in beta-cells were also increased by linoleic acid. Methyl linoleate, which has a similar structure to linoleic acid but no binding affinity to GPR40, did not change K(+) currents. Treatment of cultured cells with GPR40-specific small interfering RNA significantly reduced the decrease in K(+) current induced by linoleic acid, whereas the cAMP-induced reduction of K(+) current was not affected. We conclude that linoleic acid reduces the voltage-gated K(+) current in rat beta-cells through GPR40 and the cAMP-protein kinase A system, leading to an increase in [Ca(2+)](i) and insulin secretion.

BackgroundGlutamate is a major neurotransmitter in the central nervous system (CNS). Large amount of glutamate can overstimulate N-methyl-D-aspartate receptor (NMDAR), causing neuronal injury and death. Recently, NMDAR has been reported to be found in the lungs. The aim of this study is to examine the effects of memantine, a NMDAR channel blocker, on bleomycin-induced lung injury mice.MethodsC57BL/6 mice were intratracheally injected with bleomycin (BLM) to induce lung injury. Mice were randomized to receive saline, memantine (Me), BLM, BLM plus Me. Lungs and BALF were harvested on day 3 or 7 for further evaluation.ResultsBLM caused leukocyte infiltration, pulmonary edema and increase in cytokines, and imposed significant oxidative stress (MDA as a marker) in lungs. Memantine significantly mitigated the oxidative stress, lung inflammatory response and acute lung injury caused by BLM. Moreover, activation of NMDAR enhances CD11b expression on neutrophils.ConclusionsMemantine mitigates oxidative stress, lung inflammatory response and acute lung injury in BLM challenged mice.

Idiopathic pulmonary fibrosis (IPF) is a major cause of respiratory failure in critically ill patients and common outcome of various lung interstitial diseases. Its mortality remains high, and no effective pharmacotherapy, in addition to artificial ventilation and transplantation, exists. As such, the administration of mesenchymal stem or stromal cells (MSCs) is currently investigated as a new therapeutic method for pulmonary fibrosis. Clinical trials on MSC-based therapy as a potential treatment for lung injury and fibrosis are also performed. MSCs can migrate to injured sites and secrete multiple paracrine factors and then regulate endothelial and epithelial permeability, decrease inflammation, enhance tissue repair, and inhibit bacterial growth. In this review, recent studies on stem cells, particularly MSCs, involved in alleviating lung inflammation and fibrosis and their potential MSC-induced mechanisms, including migration and differentiation, soluble factor and extracellular vesicle secretion, and endogenous regulatory functions, were summarized.

In the nervous system, excessive activation of NMDA receptors causes neuronal injury. Although activation of NMDARs has been proposed to contribute to the progress of diabetes, little is known about the effect of excessive long-term activation of NMDARs on β-cells, especially under the challenge of hyperglycemia. Here we thoroughly investigated whether endogenous glutamate aggravated β-cell dysfunction under chronic exposure to high-glucose via activation of NMDARs. The glutamate level was increased in plasma of diabetic mice or patients and in the supernatant of β-cell lines after treatment with high-glucose for 72 h. Decomposing the released glutamate improved GSIS of β-cells under chronic high-glucose exposure. Long-term treatment of β-cells with NMDA inhibited cell viability and decreased GSIS. These effects were eliminated by GluN1 knockout. The NMDAR antagonist MK-801 or GluN1 knockout prevented high-glucose-induced dysfunction in β-cells. MK-801 also decreased the expression of pro-inflammatory cytokines, and inhibited I-κB degradation, ROS generation and NLRP3 inflammasome expression in β-cells exposed to high-glucose. Furthermore, another NMDAR antagonist, Memantine, improved β-cells function in diabetic mice. Taken together, these findings indicate that an increase of glutamate may contribute to the development of diabetes through excessive activation of NMDARs in β-cells, accelerating β-cells dysfunction and apoptosis induced by hyperglycemia.

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