Deletion of vitamin D receptor leads to premature emphysema/COPD by increased matrix metalloproteinases and lymphoid aggregates formation

Deficiency of vitamin D is associated with accelerated decline in lung function. Vitamin D is a ligand for nuclear hormone vitamin D receptor (VDR), and upon binding it modulates various cellular functions. The level of VDR is reduced in lungs of patients with chronic obstructive pulmonary disease (COPD) which led us to hypothesize that deficiency of VDR leads to significant alterations in lung phenotype that are characteristics of COPD/emphysema associated with increased inflammatory response. We found that VDR knock-out (VDR(−/−)) mice had increased influx of inflammatory cells, phospho-acetylation of nuclear factor-kappaB (NF-κB) associated with increased proinflammatory mediators, and up-regulation of matrix metalloproteinases (MMPs) MMP-2, MMP-9, and MMP-12 in the lung. This was associated with emphysema and decline in lung function associated with lymphoid aggregates formation compared to WT mice. These findings suggest that deficiency of VDR in mouse lung can lead to an early onset of emphysema/COPD because of chronic inflammation, immune dysregulation, and lung destruction

The Effect of Welding Residual Stress for Making Artificial Stress Corrosion Crack in the STS 304 Pipe

The stress corrosion crack is one of the fracture phenomena for the major structure components in nuclear power plant. During the operation of a power plant, stress corrosion cracks are initiated and grown especially in dissimilar weldment of primary loop components. In particular, stress corrosion crack usually occurs when the following three factors exist at the same time: susceptible material, corrosive environment, and tensile stress (residual stress included). Thus, residual stress becomes a critical factor for stress corrosion crack when it is difficult to improve the material corrosivity of the components and their environment under operating conditions. In this study, stress corrosion cracks were artificially produced on STS 304 pipe itself by control of welding residual stress. We used the instrumented indentation technique and 3D FEM analysis (using ANSYS 12) to evaluate the residual stress values in the GTAW area. We used the custom-made device for fabricating the stress corrosion crack in the inner STS 304 pipe wall. As the result of both FEM analysis and experiment, the stress corrosion crack was quickly generated and could be reproduced, and it could be controlled by welding residual stress

Emphysema is associated with increased inflammation in lungs of atherosclerosis-prone mice by cigarette smoke:implications in comorbidities of COPD

<p>Abstract</p> <p>Background</p> <p>Chronic obstructive pulmonary disease is associated with numerous vascular effects including endothelial dysfunction, arterial stiffness and atherogenesis. It is also known that a decline in lung function is associated with increased cardiovascular comorbidity in smokers. The mechanism of this cardiopulmonary dual risk by cigarette smoke (CS) is not known. We studied the molecular mechanisms involved in development of emphysema in atherosclerosis-prone apolipoprotein E-deficient (ApoE^-/-) mice in response to CS exposure.</p> <p>Methods</p> <p>Adult male and female wild-type (WT) mice of genetic background C57BL/6J and ApoE^-/-mice were exposed to CS, and lung inflammatory responses, oxidative stress (lipid peroxidation products), mechanical properties as well as airspace enlargement were assessed.</p> <p>Results and Discussion</p> <p>The lungs of ApoE^-/-mice showed augmented inflammatory response and increased oxidative stress with development of distal airspace enlargement which was accompanied with decline in lung function. Interestingly, the levels and activities of matrix metalloproteinases (MMP-9 and MMP-12) were increased, whereas the level of eNOS was decreased in lungs of CS-exposed ApoE^-/-mice as compared to air-exposed ApoE^-/-mice or CS-exposed WT mice.</p> <p>Conclusion</p> <p>These findings suggest that CS causes premature emphysema and a decline of lung function in mice susceptible to cardiovascular abnormalities via abnormal lung inflammation, increased oxidative stress and alterations in levels of MMPs and eNOS.</p

Nonlocality of Hardy type in experiments using independent particle sources

By applying Hardy's argument, we demonstrate the violation of local realism in a gedanken experiment using independent and separated particle sources.Comment: 9 pages, 1 fig, revtex, title change

Black rice (Oryza sativa L.) extract attenuates hepatic steatosis in C57BL/6 J mice fed a high-fat diet via fatty acid oxidation

<p>Abstract</p> <p>Background</p> <p>Two major risk factors for the onset of fatty liver disease are excessive alcohol intake and obesity, the latter being associated with non-alcoholic fatty liver disease (NAFLD). The aim of this study was to examine the effects of black rice extract (BRE) on hepatic steatosis and insulin resistance in high-fat diet-fed mice, providing a model of NAFLD.</p> <p>Methods</p> <p>Twenty-four mice were randomly divided into three groups (n = 8 in each group): normal fat diet (ND), high fat diet (HF), and high fat diet supplemented with 1% (w/w) BRE (HF +1% BRE). The experimental diets were fed for seven weeks.</p> <p>Results</p> <p>A HF induced hepatic steatosis with significant increases in the serum levels of free fatty acids (FFAs), triglyceride (TG), total cholesterol (TC), and insulin. By contrast, supplementary BRE (10 g/kg of diet) included in the HF alleviated hepatic steatosis and significantly decreased serum TG and TC levels (p < 0.01 for both). Dietary BRE also increased expression of fatty acid metabolism-related genes, including carnitine palmitoyltransferase (CPT1A), acyl-CoA oxidase (ACO), cytochrome P450 (CYP4A10), and peroxisome proliferator activated receptor (PPAR)-α (p < 0.05 for all).</p> <p>Conclusions</p> <p>Dietary BRE supplementation improved serum lipid profiles and significantly enhanced mRNA expression levels of fatty acid metabolism-related genes, primarily via β-oxidation and ω-oxidation in the liver. Taken together, these findings suggest that a BRE-supplemented diet could be useful in reducing the risks of hepatic steatosis and related disorders, including hyperlipidemia and hyperglycemia.</p

NF-kappa B Inducing Kinase, NIK Mediates Cigarette Smoke/TNF alpha-Induced Histone Acetylation and Inflammation through Differential Activation of IKKs

Peer reviewe

Highly Efficient Generation of Heritable Zebrafish Gene Mutations Using Homo- and Heterodimeric TALENs

Transcription activator-like effector nucleases (TALENs) are powerful new research tools that enable targeted gene disruption in a wide variety of model organisms. Recent work has shown that TALENs can induce mutations in endogenous zebrafish genes, but to date only four genes have been altered, and larger-scale tests of the success rate, mutation efficiencies and germline transmission rates have not been described. Here, we constructed homodimeric TALENs to 10 different targets in various endogenous zebrafish genes and found that 7 nuclease pairs induced targeted indel mutations with high efficiencies ranging from 2 to 76%. We also tested obligate heterodimeric TALENs and found that these nucleases induce mutations with comparable or higher frequencies and have better toxicity profiles than their homodimeric counterparts. Importantly, mutations induced by both homodimeric and heterodimeric TALENs are passed efficiently through the germline, in some cases reaching 100% transmission. For one target gene sequence, we observed substantially reduced mutagenesis efficiency for a variant site bearing two mismatched nucleotides, raising the possibility that TALENs might be used to perform allele-specific gene disruption. Our results suggest that construction of one to two heterodimeric TALEN pairs for any given gene will, in most cases, enable researchers to rapidly generate knockout zebrafish

Nrf2 deficiency influences susceptibility to steroid resistance via HDAC2 reduction

Abnormal lung inflammation and oxidant burden are associated with a significant reduction in histone deacetylase 2 (HDAC2) abundance and steroid resistance. We hypothesized that Nrf2 regulates steroid sensitivity via HDAC2 in response to inflammation in mouse lung. Furthermore, HDAC2 deficiency leads to steroid resistance in attenuating lung inflammatory response, which may be due to oxidant/antioxidant imbalance. Loss of antioxidant transcription factor Nrf2 resulted in decreased HDAC2 in lung, and increased inflammatory lung response which was not reversed by steroid. Thus, steroid resistance or inability of steroids to control lung inflammatory response is dependent on Nrf2-HDAC2 axis. These findings have implications in steroid resistance, particularly during the conditions of oxidative stress when the lungs are more susceptible to inflammatory response, which is seen in patients with chronic obstructive pulmonary disease, asthma, rheumatoid arthritis, and inflammatory bowel disease

Inhibitory Effect of Inflexinol on Nitric Oxide Generation and iNOS Expression via Inhibition of NF-κB Activation

Inflexinol, an ent-kaurane diterpenoid, was isolated from the leaves of Isodon excisus. Many diterpenoids isolated from the genus Isodon (Labiatae) have antitumor and antiinflammatory activities. We investigated the antiinflammatory effect of inflexinol in RAW 264.7 cells and astrocytes. As a result, we found that inflexinol (1, 5, 10 μM) suppressed the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) as well as the production of nitric oxide (NO) in LPS-stimulated RAW 264.7 cells and astrocytes. Consistent with the inhibitory effect on iNOS and COX-2 expression, inflexinol also inhibited transcriptional and DNA binding activity of NF-κB via inhibition of IκB degradation as well as p50 and p65 translocation into nucleus. These results suggest that inflexinol inhibits iNOS and COX-2 expression through inhibition of NF-κB activation, thereby inhibits generation of inflammatory mediators in RAW 264.7 cells and astrocytes, and may be useful for treatment of inflammatory diseases

Rad51 Interacts with Non-structural 3 Protein of Hepatitis C Virus and Regulates Viral Production

Hepatitis C virus (HCV) is a leading cause of chronic liver disease affecting over 170 million people worldwide. Chronic infection with HCV progresses to liver fibrosis, cirrhosis, and hepatocellular carcinoma. HCV exploits host cellular factors for viral propagation. To investigate the cellular factors required for HCV propagation, we screened a siRNA library targeting human cell cycle genes using cell culture grown HCV-infected cells. In the present study, we selected and characterized a gene encoding Rad51. Rad51, a member of a conserved recombinase family, is an essential factor for homologous recombination and repair of double-strand DNA breaks. We demonstrated that siRNA-mediated knockdown of Rad51 significantly inhibited HCV propagation without affecting HCV RNA replication. Silencing of Rad51 impaired secretion of infectious HCV particles and thus intracellular viruses were accumulated. We showed that HCV NS3 specifically interacted with Rad51 and accumulated Rad51 in the cytosol. Furthermore, Rad51 was coprecipitated with NS3 and HCV RNA. By employing membrane flotation and protease protection assays, we also demonstrated that Rad51 was co-fractionated with HCV NS3 on the lipid raft. These data indicate that Rad51 may be a component of the HCV RNA replication complex. Collectively, these data suggest that HCV may exploit cellular Rad51 to promote viral propagation and thus Rad51 may be a potential therapeutic target for HCV