Inflammatory mediator bradykinin increases population of sensory neurons expressing functional T-type Ca2+ channels

T-type Ca2+ channels are important regulators of peripheral sensory neuron excitability. Accordingly, T-type Ca2+ currents are often increased in various pathological pain conditions, such as inflammation or nerve injury. Here we investigated effects of inflammation on functional expression of T-type Ca2+ channels in small-diameter cultured dorsal root ganglion (DRG) neurons. We found that overnight treatment of DRG cultures with a cocktail of inflammatory mediators bradykinin (BK), adenosine triphosphate (ATP), norepinephrine (NE) and prostaglandin E2 (PGE2) strongly increased the population size of the small-diameter neurons displaying low-voltage activated (LVA, T-type) Ca2+ currents while having no effect on the peak LVA current amplitude. When applied individually, BK and ATP also increased the population size of LVA-positive neurons while NE and PGE2 had no effect. The PLC inhibitor U-73122 and B2 receptor antagonist, Hoe-140, both abolished the increase of the population of LVA-positive DRG neurons. Inflammatory treatment did not affect CaV3.2 mRNA or protein levels in DRG cultures. Furthermore, an ubiquitination inhibitor, MG132, did not increase the population of LVA-positive neurons. Our data suggest that inflammatory mediators BK and ATP increase the abundance of LVA-positive DRG neurons in total neuronal population by stimulating the recruitment of a 'reserve pool' of CaV3.2 channels, particularly in neurons that do not display measurable LVA currents under control conditions

Loss-of-function of the Voltage-gated Sodium Channel NaV1.5 (Channelopathies) in Patients with Irritable Bowel Syndrome.

Background & Aims SCN5A encodes the α-subunit of the voltage-gated sodium channel NaV1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of NaV1.5. Methods We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without IBS (controls). Mutant forms of SCN5A were expressed in human embryonic kidney-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls. Results Missense mutations were found in SCN5A in 13 of 584 patients (2.2%, probands). Diarrhea-predominant IBS was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (31%) than diarrhea-predominant IBS (10%; P <.05). Electrophysiologic analysis showed that 10 of 13 detected mutations disrupted NaV1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-NaV1.5 had the greatest effect in reducing NaV1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current and administration of mexiletine to 1 carrier of this mutation (who had constipation-predominant IBS) normalized their bowel habits. In the genome-wide association study and 4 replicated studies, the SCN5A locus was strongly associated with IBS. Conclusions About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt Na V1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options

The G-Protein β3 subunit 825 TT genotype is associated with epigastric pain syndrome-like dyspepsia

<p>Abstract</p> <p>Background</p> <p>Although familial clustering of functional dyspepsia (FD) has been reported, the role of genetics in the susceptibility to FD is still not well understood. Several reports indicate an association between FD and G-protein β3 (GNB3) subunit gene polymorphism (C825T); however, these studies had small sample sizes and the findings are inconclusive. In the present study we clarified the association between GNB3 gene polymorphism and dyspepsia in a large population of Japanese subjects who visited a hospital for annual health check-up.</p> <p>Methods</p> <p>Subjects with significant upper gastrointestinal findings were excluded. Subjects with dyspeptic symptoms were divided into either a postprandial distress syndrome (PDS) group or an epigastric pain syndrome (EPS) group according to the Rome III criteria. The presence of the GNB3 C825T polymorphism was then evaluated and logistic regression analysis was used to test all variables.</p> <p>Results</p> <p>The GNB3 genotype distribution in subjects without dyspepsia was 191 CC (25.1%), 368 TC (48.4%), and 202 TT (26.5%) and 17 CC (25.0%), 29 TC (42.6%), and 22 TT (32.4%) in subjects with dyspepsia. No significant correlation was found between the GNB3 825TT genotype and dyspepsia. However, the TT genotype was significantly associated with subjects with EPS-like symptoms (odds ratio (OR) = 2.00, 95% confidence interval (CI); 1.07-3.76) compared to the CT/CC genotype adjusted for gender and age. No significant correlation was found between GNB3 polymorphism and PDS-like symptoms (OR = 0.68, 95% CI; 0.31-1.51). With the exclusion of subjects with both EPS- and PDS-like symptoms, only the TT genotype was significantly associated with EPS-like symptoms (OR = 2.73, 95% CI; 1.23-5.91).</p> <p>Conclusion</p> <p>The homozygous GNB3 825T allele influences the susceptibility to EPS-like dyspepsia.</p

Structural and thermal studies of silver nanoparticles and electrical transport study of their thin films

This work reports the preparation and characterization of silver nanoparticles synthesized through wet chemical solution method and of silver films deposited by dip-coating method. X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), field emission transmission electron microscopy (FETEM), high-resolution transmission electron microscopy (HRTEM), selected area electron diffraction (SAED), and energy dispersive spectroscopy (EDX) have been used to characterize the prepared silver nanoparticles and thin film. The morphology and crystal structure of silver nanoparticles have been determined by FESEM, HRTEM, and FETEM. The average grain size of silver nanoparticles is found to be 17.5 nm. The peaks in XRD pattern are in good agreement with that of face-centered-cubic form of metallic silver. TGA/DTA results confirmed the weight loss and the exothermic reaction due to desorption of chemisorbed water. The temperature dependence of resistivity of silver thin film, determined in the temperature range of 100-300 K, exhibit semiconducting behavior of the sample. The sample shows the activated variable range hopping in the localized states near the Fermi level

Theoretical Analysis the Optical Properties of Multi-coupled Silver Nanoshell Particles

The surface plasmon resonances of silver nanoshell particles are studied by Green’s function. The nanoshell system of plasmon resonances results from the coupling of the inner and outer shell surface plasmon. The shift of the nanoshell plasmon resonances wavelength is plotted against with different dielectric environments, several different dielectric cores, the ratio of the inner and outer radius, and also its assemblies. The results show that a red- and blue-shifted localized surface plasmon can be tuned over an extended wavelength range by varying dielectric environments, the dielectric constants and the radius of nanoshell core respectively. In addition, the separation distances, the distribution of electrical field intensity, the incident directions and its polarizations are also investigated. The study is useful to broaden the application scopes of Raman spectroscopy and nano-optics

Plant Identity Influences Decomposition through More Than One Mechanism

Plant litter decomposition is a critical ecosystem process representing a major pathway for carbon flux, but little is known about how it is affected by changes in plant composition and diversity. Single plant functional groups (graminoids, legumes, non-leguminous forbs) were removed from a grassland in northern Canada to examine the impacts of functional group identity on decomposition. Removals were conducted within two different environmental contexts (fertilization and fungicide application) to examine the context-dependency of these identity effects. We examined two different mechanisms by which the loss of plant functional groups may impact decomposition: effects of the living plant community on the decomposition microenvironment, and changes in the species composition of the decomposing litter, as well as the interaction between these mechanisms. We show that the identity of the plant functional group removed affects decomposition through both mechanisms. Removal of both graminoids and forbs slowed decomposition through changes in the decomposition microenvironment. We found non-additive effects of litter mixing, with both the direction and identity of the functional group responsible depending on year; in 2004 graminoids positively influenced decomposition whereas in 2006 forbs negatively influenced decomposition rate. Although these two mechanisms act independently, their effects may be additive if both mechanisms are considered simultaneously. It is essential to understand the variety of mechanisms through which even a single ecosystem property is affected if we are to predict the future consequences of biodiversity loss

Lactate Produced by Glycogenolysis in Astrocytes Regulates Memory Processing

When administered either systemically or centrally, glucose is a potent enhancer of memory processes. Measures of glucose levels in extracellular fluid in the rat hippocampus during memory tests reveal that these levels are dynamic, decreasing in response to memory tasks and loads; exogenous glucose blocks these decreases and enhances memory. The present experiments test the hypothesis that glucose enhancement of memory is mediated by glycogen storage and then metabolism to lactate in astrocytes, which provide lactate to neurons as an energy substrate. Sensitive bioprobes were used to measure brain glucose and lactate levels in 1-sec samples. Extracellular glucose decreased and lactate increased while rats performed a spatial working memory task. Intrahippocampal infusions of lactate enhanced memory in this task. In addition, pharmacological inhibition of astrocytic glycogenolysis impaired memory and this impairment was reversed by administration of lactate or glucose, both of which can provide lactate to neurons in the absence of glycogenolysis. Pharmacological block of the monocarboxylate transporter responsible for lactate uptake into neurons also impaired memory and this impairment was not reversed by either glucose or lactate. These findings support the view that astrocytes regulate memory formation by controlling the provision of lactate to support neuronal functions

Gut microbiota and sirtuins in obesity-related inflammation and bowel dysfunction

Obesity is a chronic disease characterized by persistent low-grade inflammation with alterations in gut motility. Motor abnormalities suggest that obesity has effects on the enteric nervous system (ENS), which controls virtually all gut functions. Recent studies have revealed that the gut microbiota can affect obesity and increase inflammatory tone by modulating mucosal barrier function. Furthermore, the observation that inflammatory conditions influence the excitability of enteric neurons may add to the gut dysfunction in obesity. In this article, we discuss recent advances in understanding the role of gut microbiota and inflammation in the pathogenesis of obesity and obesity-related gastrointestinal dysfunction. The potential contribution of sirtuins in protecting or regulating the circuitry of the ENS under inflamed states is also considered

Anisotropic nanomaterials: structure, growth, assembly, and functions

Comprehensive knowledge over the shape of nanomaterials is a critical factor in designing devices with desired functions. Due to this reason, systematic efforts have been made to synthesize materials of diverse shape in the nanoscale regime. Anisotropic nanomaterials are a class of materials in which their properties are direction-dependent and more than one structural parameter is needed to describe them. Their unique and fine-tuned physical and chemical properties make them ideal candidates for devising new applications. In addition, the assembly of ordered one-dimensional (1D), two-dimensional (2D), and three-dimensional (3D) arrays of anisotropic nanoparticles brings novel properties into the resulting system, which would be entirely different from the properties of individual nanoparticles. This review presents an overview of current research in the area of anisotropic nanomaterials in general and noble metal nanoparticles in particular. We begin with an introduction to the advancements in this area followed by general aspects of the growth of anisotropic nanoparticles. Then we describe several important synthetic protocols for making anisotropic nanomaterials, followed by a summary of their assemblies, and conclude with major applications