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In this paper, a CMOS wideband low-pass filter is proposed. In the wide band active filter design, the unit gain frequency (GBW) of OPAMP should be larger than GHz. The GBW of the proposed OPAMP is around 2.3 GHz. Additionally, the OPAMP with a complementary structure in signal and common mode feedback is proposed and has a wide operating voltage range at the input and output. The 1-dB gain compression point (P1dB) at the output is 4.9 dBm. A source follower is employed for driving 50 Ω output impedance without degrading the bandwidth and linearity of the filter. The power consumption is 27 mW from a 1-V supply voltage. The 3 dB bandwidth of the filter ranges from 330 MHz to 660 MHz with 3-bit cap tuning. This work is implemented in a 65-nm CMOS process, with a chip area of 0.18 mm2.

Recently, highly spatially dense air quality monitoring networks using low-cost sensors have been attempted worldwide. However, the quality of data from these sensor networks remains to be validated. This study assessed the potential of low-cost sensors for spatially dense air quality monitoring. Thirty sets of air quality sensor nodes for CO, NO2, O3, PM2.5, and PM10 were custom-built to evaluate their consistency in measurement, both among the sensor nodes and between the sensor node and instruments that use Federal Reference/Equivalent Methods (FRMs/FEMs) in the real atmosphere under two distinctly differing meteorological conditions (summer and winter) in Seoul and Busan, Korea. We found that commercially available low-cost sensors possess great potential as monitors for short-term air quality studies in urban areas, at least for one-month periods, given that (1) the self-consistency among the 30 sensors was high (R2 > 0.93), (2) the consistency between the sensors and the FRM/FEM instruments was reasonably high (R2 > 0.87 overall for the periods of comparison ), and (3) the consistency both among the sensors and between the sensors and the FRM/FEM instruments remained stable throughout the summer and the winter. However, vigorous data post-processing is needed to obtain reliable air quality data. For longer-term or temporally discontinuous monitoring, several issues must be addressed, including the limited lifetime of sensors, the degradation in sensor performance over time, and the long warm-up times for gaseous pollutant sensors. The O3 sensors required minimal post-processing correction, and the particulate matter and CO sensors agreed well with the FEM instruments after appropriate scale correction, but the NO2 sensors required additional efforts to correct for the effects of meteorological conditions and interfering materials. Overall, our results suggest that when investigating spatiotemporally heterogeneous distributions of air pollutants in various urban environments, a three-dimensional sensor network can be a useful tool for short-term monitoring, as long as data are corrected properly.

Islets are highly vascularized for prompt insulin secretion. Although angiopoietin-1 (Ang1) is a well-known angiogenic factor, its role in glucose homeostasis remains largely unknown. The objective of this study was to investigate whether and how Ang1 contributes to glucose homeostasis in response to metabolic challenge. We used inducible systemic Ang1 knockout (Ang1sys−/−) and β-cell–specific Ang1 knockout (Ang1β-cell−/−) mice fed a high-fat diet for 24 weeks. Although the degree of insulin sensitivity did not differ between Ang1sys−/− and Ang1sys+/+ mice, serum insulin levels were lower in Ang1sys−/− mice, resulting in significant glucose intolerance. Similar results were observed in Ang1β-cell−/− mice, suggesting a critical role of β-cell–derived Ang1 in glucose homeostasis. There were no differences in β-cell area or vasculature density, but glucose-stimulated insulin secretion was significantly decreased, and PDX-1 expression and GLUT2 localization were altered in Ang1β-cell−/− compared with Ang1β-cell+/+ mice. These effects were associated with less pericyte coverage, disorganized endothelial cell ultrastructure, and enhanced infiltration of inflammatory cells and upregulation of adhesion molecules in the islets of Ang1β-cell−/− mice. In conclusion, β-cell–derived Ang1 regulates insulin secretion and glucose homeostasis by stabilizing the blood vessels in the islet and may be a novel therapeutic target for diabetes treatment in the future.

Cluster of differentiation 93 (CD93) is a glycoprotein expressed in activated endothelial cells. The extracellular portion of CD93 can be secreted as a soluble form (sCD93) under inflammatory conditions. As diabetic nephropathy (DN) is a well-known inflammatory disease, we hypothesized that sCD93 would be a new biomarker for DN. We prospectively enrolled 97 patients with type 2 diabetes and evaluated the association between serum sCD93 and DN prevalence. The association between CD93 and development of DN was investigated using human umbilical cord endothelial cells (HUVECs) in vitro and diabetic db/db mice in vivo. Subjects with higher sCD93 levels had a lower estimated glomerular filtration rate (eGFR). The sCD93 level was an independent determinant of both the albumin-to-creatinine ratio (ACR) and the eGFR. The risk of prevalent DN was higher in the high sCD93 group (adjusted odds ratio 7.212, 95% confidence interval 1.244&ndash, 41.796, p = 0.028). In vitro, CD93 was highly expressed in HUVECs and both CD93 expression and secretion were upregulated after lipopolysaccharides (LPS) stimulation. In vivo, peritoneal and urine sCD93 levels and the renal glomerular expression of CD93 were significantly higher in the db/db mice than in the control db/m+ mice. These results suggest the potential of sCD93 as a candidate biomarker associated with DN.

To investigate the spatial and temporal variability of air quality (CO, NO2, O3, and PM2.5) with a high spatial resolution in various adjacent micro-environments, 30 sets of sensor-nodes were deployed within an 800 × 800 m monitoring domain in the center of the largest megacity (Seoul) in South Korea. The sensor network was operated in summer and winter. The daily variation in air pollutant concentrations revealed a similar trend, with discernible concentration differences among monitoring sub-sites and a government-operated air quality monitoring station. These differences in pollutant levels (except PM2.5) among the sub-sites were pronounced in the daytime with high volumes of traffic. The coefficient of divergence and Pearson correlation coefficient showed that spatial and temporal variability was more significant in summer than winter. Ozone displayed the greatest spatial variability, with little temporal variability among the sub-sites and a negative correlation with NO2, implying that ozone concentrations were primarily determined by vehicular NOX emissions due to NO titration effects under the urban canopy. The PM2.5 concentration displayed homogeneous spatial and temporal distributions over the entire monitoring period, implying that PM2.5 monitoring with at least a 1 × 1 km resolution is sufficient to examine the spatial and temporal heterogeneity in urban areas.

Objective: CD93 is a glycoprotein that is known to enhance phagocytosis. The extracellular portion of CD93 can be enzymatically cleaved and secreted to the serum as a soluble form (sCD93). Diabetic nephropathy (DN) is a well-known inflammatory disease that commonly progresses to end stage renal disease (ESRD) in diabetes. Although albuminuria and estimated glomerular filtration rate (eGFR) is currently used for the diagnosis and the prognostication of DN, the prognostic value of the two parameters is modest at best. Here, we hypothesized that sCD93 would be a new biomarker for DN. Methods: We registered 97 human subjects with type 2 diabetes and evaluated the association between serum sCD93 and DN. The underlying mechanism of CD93 regulation was elucidated using human umbilical cord endothelial cell (HUVEC) in vitro and diabetic db/db mice in vivo. Results: The group with higher sCD93 has lower eGFR level and higher prevalence of CKD defined by eGFR. The log(sCD93) was significantly associated with albumin-to-creatinine ratio (ACR) (r=0.229, p=0.028) and the sCD93 level was an independent determinant of ACR and eGFR. The odds ratio of having DN was higher in the high serum sCD93 group even after adjusting for other covariates (adjusted odds ratio 7.283, 95% CI 1.255-42.268, p=0.027). In vitro, CD93 was highly expressed in HUVEC and both CD93 expression and sCD93 secretion was upregulated after LPS stimulation. In db/db mice, sCD93 level was much higher in the peritoneal fluid compared to the db/m mice. The db/db mice showed significantly higher CD93 expression in the renal glomerulus compared to that of the db/m mice suggesting that the elevated sCD93 according to the degree of DN progression might be associated with upregulated expression of CD93 in glomerulus. Conclusion: Based on these human and rodent data, we conclude that sCD93 could be a candidate molecule associated with DN. Disclosure S. Lee: None. H. Park: None. M. Lee: None. A. Choi: None. J. Park: None. C. Ahn: None. S. Lee: None. S. Kang: None. Funding Korean National Research Foundation (2014R1A1A3051221)

The carbon nanofibers (CNFs) and Si-CNFs composite were synthesized using a chemical vapor deposition (CVD) method with an iron-copper catalyst and silicon-covered Ni foam. Acetylene as a carbon source was flowed into the quartz reactor of a tubular furnace heated to 600 degrees C. This temperature was maintained for 10 min to synthesize the CNFs. The morphologies, compositions, and crystal quality of the prepared CNFs were characterized by Scanning electron microscopy (SEM), Energy dispersive spectroscopy (EDS), X-ray Diffraction (XRD), Raman spectroscopy, and X-ray photoelectron spectroscopy (XPS). The electrochemical characteristics of the Si-CNFs composite as an anode of the Li secondary batteries were investigated using a three-electrode cell. The as-deposited Si-CNF composite on the Ni foam was directly employed as an working electrode without any binder, and lithium foil was used as the counter and reference electrode. A glass fiber separator was used as the separator membrane. Two kinds of electrolytes were employed; 1) 1 M LiPF6 was dissolved in a mixture of EC (ethylene carbonate): PC (propylene carbonate): EMC (Ethyl methyl carbonate) in a 1:1:1 volume ratio and 2) 1 M LiClO4 was dissolved in a mixture of propylene carbonate (PC): ethylene carbonate (EC) in a 1:1 volume ratio. The galvanostatic charge-discharge cycling and cyclic voltammetry measurements were carried out at room temperature by using a battery tester. The resulting Si-CNFs composite achieved the large discharge capacity of 613 mAh/g and much improved cycle-ability with the retention rate of 87% after 20 cycles.

Objective The ligand-activated transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) is a key factor in adipogenesis, insulin sensitivity, and cell cycle regulation. Activated PPARγ might also have anti-inflammatory and antiatherogenic properties. We tested whether lobeglitazone, a new PPARγ agonist, might protect against atherosclerosis. Methods A rat model of balloon injury to the carotid artery, and high-fat, high-cholesterol diet-fed apolipoprotein E gene knockout (ApoE −/− ) mice were studied. Results After the balloon injury, lobeglitazone treatment (0.3 and 0.9 mg/kg) caused a significant decrease in the intima-media ratio compared with control rats (2.2 ± 0.9, 1.8 ± 0.8, vs. 3.3 ± 1.2, P −/− mice fed a high-fat diet, lobeglitazone treatment (1, 3, and 10 mg/kg) for 8 weeks reduced atherosclerotic lesion sizes in the aorta compared with the control mice in a dose-dependent manner. Treatment of vascular smooth muscle cells with lobeglitazone inhibited proliferation and migration and blocked the cell cycle G 0 /G 1 to S phase progression dose-dependently. In response to lobeglitazone, tumor necrosis factor alpha (TNFα)-induced monocyte-endothelial cell adhesion was decreased by downregulating the levels of adhesion molecules. TNFα-induced nuclear factor kappa-B (NF-κB) p65 translocation into the nucleus was also blocked in endothelial cells. Insulin resistance was decreased by lobeglitazone treatment. Circulating levels of high sensitivity C-reactive protein and monocyte chemoattractant protein-1 were decreased while adiponectin levels were increased by lobeglitazone in the high-fat diet-fed ApoE −/− mice. Conclusion Lobeglitazone has antiatherosclerotic properties and has potential for treating patients with diabetes and cardiovascular risk.

Transplantation of stem cell-derived insulin producing cells (IPCs) has been proposed as an alternative to islet transplantation for the treatment of diabetes mellitus. However, current IPC differentiation protocols are focused on generating functional cells from the pluripotent stem cells and tend to rely on multistep, long-term exposure to various exogenous factors. In this study, we addressed the observation that under stress, pancreatic β-cells release essential components that direct the differentiation of the bone marrow nucleated cells (BMNCs) into IPCs. Without any supplementation with known differentiation-inducing factors, IPCs can be generated from BMNCs by in vitro priming for 6 days with conditioned media (CM) from the β-cells. In vitro primed BMNCs expressed the β-cell-specific transcription factors, as well as insulin, and improved hyperglycemia and glucose intolerance after transplantation into the streptozotocin-induced diabetic mice. Furthermore, we have found that components of the CM which trigger the differentiation were enclosed by or integrated into micro particles (MPs), rather than being secreted as soluble factors. Identification of these differentiation-directing factors might enable us to develop novel technologies required for the production of clinically applicable IPCs.

The diagnosis of myocarditis traditionally relies on invasive endomyocardial biopsy but none of the imaging studies so far are specific for infiltration of the inflammatory cells itself. We synthesized Ga-68-2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) mannosylated human serum albumin (MSA) by conjugating human serum albumin with mannose, followed by conjugation with NOTA and labeling it with Ga-68. The efficacy of Ga-68-NOTA-MSA positron emission tomography (PET) for imaging myocardial inflammation was tested in a rat myocarditis model. A significant number of mannose receptor-positive inflammatory cells infiltrated the myocardium in both human and rat myocarditis tissue. Ga-68-NOTA-MSA uptake was upregulated in organs of macrophage accumulation, such as liver, spleen, bone marrow and myocardium (0.32 (0.31 similar to 0.33) for normal versus 1.02 (0.86 similar to 1.06) for myocarditis (median (range), SUV); n=4 similar to 6 per group, p-value=0.01). Ga-68-NOTA-MSA uptake in the left ventricle was upregulated in myocarditis compared with normal rats (2.29 (1.42 similar to 3.40) for normal versus 4.18 (3.43 similar to 6.15) for myocarditis (median (range), average standard uptake value ratio against paraspinal muscle); n=6 per group, p-value < 0.01), which was downregulated in rats with cyclosporine-A treated myocarditis (3.69 (2.59 similar to 3.86) for myocarditis versus 2.28 (1.76 similar to 2.60) for cyclosporine-A treated myocarditis; n=6 per group, p-value < 0.01). The specificity of the tracer was verified by administration of excess non-labeled MSA. Ga-68-NOTA-MSA uptake was significantly enhanced earlier in the evolution of myocarditis before any signs of inflammation could be seen on echocardiography. These results demonstrate the potential utility of visualizing infiltration of mannose receptor-positive macrophages with Ga-68-NOTA-MSA PET in the early diagnosis of as well as in the monitoring of treatment response of myocar

This study investigated carbon nanofibers (CNFs) grown on reticulated vitreous carbon (RVC) foam through catalytic deposition of ethylene. Before growing the CNFs, Co(II) on the RVC foam was expected to act as a catalyst by deposition. The preparation of the CNFs was a two-step process. The first step was preparing the RVC from polyurethane (PU) foam. Changes in weight over time were evaluated using two kinds of resol. The change in the mass and state of the sample with the change in temperature was studied during the carbonization process. The second step was to prepare the CNFs. An OH group was attached by the oxidation of the RVC foam. A change in the shape and mass of the sample was observed due to a change in nitric acid concentration and oxidation time. Then, cobalt was deposited to grow CNFs on the RVC foam. Hydrolysis helped to deposit the Co(ll) on the RVC foam. The appropriate time and temperature were investigated for the reduction process. In the last step, CNFs were prepared by the introducing ethylene gas. The resulting samples were analyzed using scanning electron microscopy, energy dispersive spectroscopy, N2-sorption, and X-ray photoelectron spectroscopy.

This research was conducted to synthesize carbon nanofibers on C-fiber textiles by thermal CVD using Fe catalyst. The substrate which was a carbon textile consisting of non woven carbon fibers and attached graphite particles, was oxidized by nitric acid before the deposition process. Hydroxyl groups were created on the C-fiber textile due to the oxidization step. Fe (III) hydroxide was subsequently deposited on the oxidized surface of the C-fiber textile. To deposit ferric particles two different methods were tested: i) deposition-precipitation, ii) dip-coating. For the experiments using both type of catalyst deposition the weight ratio of Fe to C-fiber textile was also varied. Ferric particles were reduced to iron after deposition by using H2/N2gas and CNFs were grown by flowing ethylene gas. Properties of carbon nanofibers created like this were analyzed through Scanning Electron Microscopy (SEM), Energy Dispersive Spectroscopy (EDS), N2-sorption (BET), X-Ray Diffraction (XRD), and X-ray Photoelectron Spectoscopy (XPS). In the case of deposition-precipitation method the result shows that the diameter of carbon nanofibers grew up to 40~60nm and 30~55nm at which the weight ratios of Fe catalyst to C-fiber textiles are 1:30 and 1:70 respectively. If Fe particles were deposited by dip-coating method, the diameter of carbon nanofibers grew up to 40~60nm and 25~30nm for the ratios of Fe catalyst to C-fiber textiles 1:10 and 1:30.

Post-translational modification by bonding of small ubiquitin-like modifier (SUMO) peptides influences various cellular functions, and is regulated by SUMO-specific proteases (SENPs). Several proteins have been suggested to have diverse impact on insulin synthesis and secretion through SUMO modification in β cells. However, the role of SUMO modification in β cell mass has not been established. Here, we examined the changes in expression of Senp in INS1 cells and pancreatic islets under diabetes-relevant stress conditions and associated changes in β cell mass. Treatment with 25 mM glucose for 72 h induced Senp2 mRNA expression but not that of Senp1 in INS1 cells. Immunohistochemical staining with anti-SENP2 antibody on human pancreas sections revealed that SENP2 was localized in the nucleus. Moreover, in a patient with type 2 diabetes, SENP2 levels were enhanced, especially in the cytoplasm. Senp2 cytoplasmic levels were also increased in islet cells in obese diabetic mice. Cell number peaked earlier in INS1 cells cultured in high-glucose conditions compared to those cultured in control media. This finding was associated with increased Ccnd1 mRNA expression in high-glucose conditions, and siRNA-mediated Senp2 suppression abrogated it. Mafa expression, unlike Pdx1, was also dependent on Senp2 expression during high-glucose conditions. In conclusion, Senp2 may play a role in β cell mass in response to chronic high-glucose through Cyclin D1 and Mafa.

We have performed a study on the electrochemical and structural characteristics of CNFs-Si composites which are active anode material for lithium secondary batteries. Carbon nanofibers (CNFs) have been synthesized by Chemical Vapor Deposition (CVD) using Co and Cu catalysts. The CNFs on the surface of the Si particle can provide a flexible space to relieve the volumetric expansion during a charge. Therefore, the CNFs composites on Si particles were prepared on the basis of the following two processes: (1) CNFs were grown on the simple mechanical mixture of Si particles and catalysts (CNFs/Si); (2) CNFs were grown on the surface of a pyrolytic carbon that was coated with Si particles (CNFs/PC/Si). The morphology and composition of CNFs-Si composites were analyzed by SEM and EDS measurements. Crystallinity and amorphicity were investigated using XRD and Raman spectroscopy. The characteristics of the synthesized CNFs-Si composites were analyzed through XPS, TGA, and BET. The two different CNFs-Si composite materials were evaluated as the anodic material in three different electrode cells. We found that the initial capacity of the CNFs/PC/Si composite electrode was 1,361 mAh/g with retention rate of 28.4%, which was better than the retention rate of 4.9% with the CNFs/Si electrode.

Reticulated polyurethane foams are often used as templates for the processing of metal and ceramic foams, since polyurethane foams with a high homogeneity and uniformity of pores and a wide variety of porosities and pore sizes are commercially available. Current conventional methods to pyrolyse polyurethane have brought attention to issues such as long processing time, high costs and high contents of carbon residue. Microwave hybrid heating, as a new pyrolysis method, has been investigated in this research to overcome these issues. Two microwave hybrid and one conventional heating process as comparison were performed to pyrolyse binder and polyurethane for the processing of NiCr8020 foams, which were fabricated by dip-coating method in a powder metallurgical route. Compared to the conventional process, the processing time and residual carbon content of the pyrolysed and pre-sintered foams can be reduced significantly by utilizing microwave hybrid heating techniques, whereas the stability of microwave hybrid heating must be improved and a compromise must be made between the heating rate and the residual carbon content due to the formation of burst holes during the rapid decomposition of polyurethane.

Carbon nanofibers were synthesized on transition metal (Fe, Co, Cu) catalysts by Chemical Vapor Deposition (CVD). The variations of thickness and surface of the fibers were investigated according to the concentration of the transition metal. In order to prepare the metal catalysts for synthesis, transition metal nitrate and copper nitrate at a weight ratio were dissolved in distilled water. The obtained catalyst precipitates were filtered and then dried for more than 24 hours at 110 degrees C. Carbon nanofibers were synthesized by using ethylene gas of carbon source by CVD after pulverization of the fully-dried catalyst precipitates. They were characterized by SEM, EDS, Raman, XRD, XPS and TG/DTA, and their specific surface area was measured by BET. The characteristics of the synthesized carbon nanofibers were greatly influenced by the concentration ratio of the metal catalysts. Especially, uniform carbon nanofibers grew when the concentration ratio of Fe and Cu was 7:3, and that of Co and Cu was 6:4. Carbon nanofibers synthesized under such concentration conditions had the best crystallizability, compared to carbon nanofibers synthesized with metal catalysts of different concentration ratios, and revealed high amorphicity as well as high specific surface area.

Aims The association between hyperhomocysteinaemia and cardiovascular disease has been attributed to low levels of S -adenosylmethionine (SAM), a metabolic intermediate of homocysteine. However, the role of SAM in the development of restenosis has not been explored. Therefore, we investigated the effects of SAM on neointimal formation after balloon injury in obese diabetic rats and cultured cells. Methods and results Otsuka Long–Evans Tokushima fatty rats were divided into the following three groups: control (normal saline); SAM15; and SAM30 (15 and 30 mg/kg per day, respectively; n = 10 per group). SAM was administered orally from 1week before carotid injury to 2weeks thereafter. SAM treatment for 3weeks caused a significant dose-dependent reduction in the intima-to-media ratio. SAM treatment significantly reduced the proliferation of vascular smooth muscle cells (VSMCs) and induced more apoptosis than was observed in the control group. This effect was accompanied by reduced circulating levels of high-sensitivity C-reactive protein and monocyte chemoattractant protein-1, reduced urine 8-hydroxy-2′-deoxyguanosine (8-OHdG), and increased adiponectin. Intima-to-media ratio correlated significantly with the levels of inflammatory markers, adiponectin, and 8-OHdG. In vitro experiments demonstrated that VSMC proliferation and migration and the adhesion of monocytes decreased in response to SAM. SAM treatment also reduced tumour necrosis factor-α-induced reactive oxygen species and tunicamycin-induced GRP78 expression in VSMCs. Conclusion These findings suggest that SAM exerts protective effects against restenosis after balloon injury in a rat model of type 2 diabetes by reducing the proliferation and inducing the apoptosis of VSMCs, modifying the inflammatory processes and reducing oxidative and endoplasmic reticulum stresses.

OBJECTIVE Peroxisome proliferator–activated receptor (PPAR)-α/γ dual agonists have been developed to alleviate metabolic disorders. However, several PPARα/γ dual agonists are accompanied with unwanted side effects, including body weight gain, edema, and tissue failure. This study investigated the effects of a novel PPARα/γ dual agonist, CG301269, on metabolic disorders both in vitro and in vivo. RESEARCH DESIGN AND METHODS Function of CG301269 as a PPARα/γ dual agonist was assessed in vitro by luciferase reporter assay, mammalian one-hybrid assay, and analyses of PPAR target genes. In vitro profiles on fatty acid oxidation and inflammatory responses were acquired by fatty acid oxidation assay and quantitative (q)RT-PCR of proinflammatory genes. In vivo effect of CG301269 was examined in db/db mice. Total body weight and various tissue weights were measured, and hepatic lipid profiles were analyzed. Systemic glucose and insulin tolerance were measured, and the in vivo effect of CG301269 on metabolic genes and proinflammatory genes was examined by qRT-PCR. RESULTS CG301269 selectively stimulated the transcriptional activities of PPARα and PPARγ. CG301269 enhanced fatty acid oxidation in vitro and ameliorated insulin resistance and hyperlipidemia in vivo. In db/db mice, CG301269 reduced inflammatory responses and fatty liver, without body weight gain. CONCLUSIONS We demonstrate that CG301269 exhibits beneficial effects on glucose and lipid metabolism by simultaneous activation of both PPARα and PPARγ. Our data suggest that CG301269 would be a potential lead compound against obesity and related metabolic disorders.

Here, we demonstrate that SENP2, a desumoylating enzyme, plays a critical role in the control of adipogenesis. SENP2 expression was markedly increased upon the induction of adipocyte differentiation, and this increase was dependent on protein kinase A activation. Remarkably, knockdown of SENP2 led to a dramatic attenuation of adipogenesis with a marked decrease in PPARgamma and C/EBPalpha mRNA levels. Knockdown of SENP2 also caused a marked reduction in the level of C/EBPbeta protein but not in that of C/EBPbeta mRNA. Interestingly, sumoylation of C/EBPbeta dramatically increased its ubiquitination and destabilization, and this increase could be reversed by SENP2. In addition, overexpression of C/EBPbeta could overcome the inhibitory effect of SENP2 knockdown on adipogenesis. Furthermore, SENP2 was absolutely required for adipogenesis of preadipocytes implanted into mice. These results establish a critical role for SENP2 in the regulation of adipogenesis by desumoylation and stabilization of C/EBPbeta and in turn by promoting the expression of its downstream effectors, such as PPARgamma and C/EBPalpha.

To investigate whether or not antiaminoacyl-tRNA synthetase (aaRS) autoantibodies could be detected in patients with type 1 diabetes mellitus (DM) and be used as a diagnostic marker for type 1 DM, autoantibodies against aaRSs were measured in the plasma of normal subjects, patients with type 1 DM and patients with type 2 DM.An enzyme-linked immunosorbent assay was performed to detect anti-aaRS autoantibodies in the plasma of normal subjects, and patients with type 1 DM, and patients with type 2 DM.From the 65 (normal), 58 (type 1 DM) and 57 (type 2 DM) subjects, anti-aaRS autoantibodies were found in 37.9% of patients with type 1 DM compared with 1.54% of the non-diabetic controls, and 5.26% of the patients with type 2 DM (p0.0001). In addition, anti-aaRS autoantibodies were identified in 30% of patients with type 1 DM without classical type 1 DM autoantibodies.Anti-aaRS autoantibodies were identified in 37.9% of patients with type 1 DM. The results of this study demonstrate for the first time that autoantibodies against aaRSs are specifically associated with type 1 DM.

Glucose homeostasis is maintained by the orchestration of peripheral glucose utilization and hepatic glucose production, mainly by insulin. In this study, we found by utilizing a combined parallel chromatography mass profiling approach that lysophosphatidylcholine (LPC) regulates glucose levels. LPC was found to stimulate glucose uptake in 3T3-L1 adipocytes dose- and time-dependently, and this activity was found to be sensitive to variations in acyl chain lengths and to polar head group types in LPC. Treatment with LPC resulted in a significant increase in the level of GLUT4 at the plasma membranes of 3T3-L1 adipocytes. Moreover, LPC did not affect IRS-1 and AKT2 phosphorylations, and LPC-induced glucose uptake was not influenced by pretreatment with the PI 3-kinase inhibitor LY294002. However, glucose uptake stimulation by LPC was abrogated both by rottlerin (a protein kinase Cdelta inhibitor) and by the adenoviral expression of dominant negative protein kinase Cdelta. In line with its determined cellular functions, LPC was found to lower blood glucose levels in normal mice. Furthermore, LPC improved blood glucose levels in mouse models of type 1 and 2 diabetes. These results suggest that an understanding of the mode of action of LPC may provide a new perspective of glucose homeostasis.

Extracts of ginseng species show antihyperglycemic activity. We evaluated the antihyperglycemic and antiobesity effects of ginsam, a component of Panax ginseng produced by vinegar extraction, which is enriched in the ginsenoside Rg3. Otsuka Long-Evans Tokushima Fatty rats, an obese insulin-resistant rat model, were assigned into 1 of 3 groups (n = 8 each): controls (isotonic sodium chloride solution, 5 mL/d), rats given 300 mg/(kg d) ginsam, and rats given 500 mg/(kg d) ginsam. An intraperitoneal 2-hour glucose tolerance test was performed at the end of the 6-week treatment. After 8 weeks, body and liver weights, visceral fat measured by computed tomography, and fasting glucose and insulin concentrations and lipid profiles were recorded. Insulin-resistant rats treated with ginsam had lower fasting and postprandial glucose concentrations compared with vehicle-treated rats. Importantly, overall glucose excursion during the intraperitoneal 2-hour glucose tolerance test decreased by 21.5% (P < .01) in the treated rats, indicating improved glucose tolerance. Plasma insulin concentration was significantly lower in ginsam-treated rats. These changes may be related to increased glucose transporter 4 expression in skeletal muscle. Interestingly, when the data from both ginsam-treated groups were combined, body weight was 60% lower in the ginsam-treated rats than in the controls (P < .01). Liver weight and serum alanine aminotransferase concentrations were also lower in the ginsam-treated rats. These effects were associated with increased peroxisome proliferator-activated receptor gamma expression and adenosine monophosphate-activated protein kinase phosphorylation in liver and muscle. Our data suggest that ginsam has distinct beneficial effects on glucose metabolism and body weight control in an obese animal model of insulin resistance by changing the expression of genes involved in glucose and fatty acid metabolism.

Lysophosphatidic acid (LPA) is known to have diverse cellular effects, but although LPA is present in many biological fluids, including blood, its effects on glucose metabolism have not been elucidated. In this study, we investigated whether LPA stimulation is related to glucose regulation. LPA was found to enhance glucose uptake in a dose-dependent manner both in L6 GLUT4myc myotubes and 3T3-L1 adipocytes by triggering GLUT4 translocation to the plasma membrane. Moreover, the effect of LPA on glucose uptake was completely inhibited by pretreating both cells with LPA receptor antagonist Ki16425 and Gi inhibitor pertussis toxin. In addition, LPA increased the phosphorylation of AKT-1 with no effects on IRS-1, and LPA-induced glucose uptake was abrogated by pretreatment with the PI 3-kinase inhibitor LY294002. When low concentration of insulin and LPA were treated simultaneously, an additive effect on glucose uptake was observed in both cell types. In line with its cellular functions, LPA significantly lowered blood glucose levels in normal mice but did not affect insulin secretion. LPA also had a glucose-lowering effect in streptozotocin-treated type 1 diabetic mice. In combination, these results suggest that LPA is involved in the regulation of glucose homeostasis in muscle and adipose tissues.

Adipose tissue is a highly versatile system in which mitochondria in adipocytes undergo significant changes during active tissue remodelling. BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) is a mitochondrial protein and a known mitochondrial quality regulator. In this study, we investigated the role of BNIP3 in adipocytes, specifically under conditions of peroxisome proliferator-activated receptor-γ (PPARγ)-induced adipose tissue remodelling. The expression of BNIP3 was evaluated in 3T3-L1 adipocytes in vitro, C57BL/6 mice fed a high-fat diet and db/db mice in vivo. Mitochondrial bioenergetics was investigated in BNIP3-knockdown adipocytes after rosiglitazone treatment. A putative peroxisome proliferator hormone responsive element (PPRE) was characterised by promoter assay and electrophoretic mobility shift assay (EMSA). The protein BNIP3 was more abundant in brown adipose tissue than white adipose tissue. Furthermore, BNIP3 expression was upregulated by 3T3-L1 pre-adipocyte differentiation, starvation and rosiglitazone treatment. Conversely, BNIP3 expression in adipocytes decreased under various conditions associated with insulin resistance. This downregulation of BNIP3 was restored by rosiglitazone treatment. Knockdown of BNIP3 in adipocytes inhibited rosiglitazone-induced mitochondrial biogenesis and function, partially mediated by the 5′ AMP-activated protein kinase (AMPK)–peroxisome proliferator-activated receptor γ, co-activator 1 α (PGC1α) signalling pathway. Rosiglitazone treatment increased the transcription level of Bnip3 in the reporter assay and the presence of the PPRE site in the Bnip3 promoter was demonstrated by EMSA. The protein BNIP3 contributes to the improvement of mitochondrial bioenergetics that occurs on exposure to rosiglitazone. It may be a novel therapeutic target for restoring mitochondrial dysfunction under insulin-resistant conditions.

Objective— There is still debate as to whether antiatherosclerotic effect of PPARγ ligands is dependant on PPARγ gene itself or some other pathway. Methods and Results— To investigate the effect of PPARγ gene modulation on neointima formation after balloon injury, we delivered adenoviral vectors expressing the wild-type (WT) dominant negative (DN) PPARγ, or a control gene (β-galactosidase [BG]) into carotid artery after balloon injury in rosiglitazone (a PPARγ ligand)-treated (R+) (3 mg/kg/d) and nontreated (R−) rats. Two weeks after gene delivery, in both R+ and R− animals, the PPARγ-WT gene transfer showed a significantly lower intima-media ratio (IMR) than control group. Moreover, the delivery of a PPARγ-DN form showed the highest IMR (in R+WT, 0.51±0.15; R+BG, 0.89±0.14; R+DN, 1.20±0.18, P P Conclusions— In vivo transfer of the PPARγ-WT gene was found to inhibit smooth muscle proliferation, sustain apoptosis, and reduce neointima formation after balloon injury irrespective of rosiglitazone treatment. These results indicate that PPARγ overexpression itself has a protective role against restenosis after balloon injury.

Selective inhibition of glycogen synthase kinase-3 (GSK3) has been targeted as a novel therapeutic strategy for diabetes mellitus. We investigated the anti-diabetic efficacy and molecular mechanisms of KICG1338 (2-(4-fluoro-phenyl)-3H-imidazo[4,5-b]pyridine-7-carboxylic acid(4-methyl-pyridin-3-yl)-amide), a GSK3β inhibitor, in three animal models: Otsuka Long-Evans Tokushima Fatty (OLETF) rats, leptin receptors-deficient db/db mice, and diet-induced obese (DIO) mice. Biochemical parameters including glucose tolerance tests and gene expressions associated with glucose metabolism were investigated. Glucose excursion decreased significantly by KICG1338-treated OLETF rats, accompanied by increase in insulin receptor substrate-1 and glucose transporter (GLUT)-4 expressions in muscle and decreased GLUT-2 expression in liver. Glucose-lowering effects were similarly observed in KICG1338-treated db/db and DIO mice. KICG1338 treatment increased adiponectin levels and decreased TNF-α levels. KICG1338 therapy also led to greater β-cell preservation and less hepatic fat infiltration with decreased expressions of genes involved in inflammation and endoplasmic reticulum stress. These data demonstrate anti-diabetic efficacy of KICG1338, a novel GSK3β inhibitor.

A new processing route for porous b-Si3N4 –ceramics suitable as substrates for Si3N4 functionally graded materials, FGM`s with an environmental barrier coating, EBC, is described. Such materials could be useful for operation at temperatures up to 1650°C in combustion engines, where oxidation and corrosion under hydrothermal conditions cause severe damage of known dense Si3N4-ceramics. The new process is based on microwave sintering of a-Si3N4–Yb-silicate green parts to obtain up to 60% open porous b-Si3N4 pre-forms equilibrated at high temperature with respect to the RE-silicate content, followed by Si-melt infiltration. A sufficient wetting by molten silicon is achieved by coating the inner surface of the porous pre-form with amorphous carbon prior to infiltration. The influence of different green processing parameters and different heating methods - microwave heating and conventional heating – on the porosity of the pre-form is reported. Infiltration is performed by microwave heating of the carbon coated pre-forms, whereas for nitridation both heating processes are combined.

Distribution of electrical field gradients developing upon microwave heating glass parts immersed in an alkaline salt melt is analyzed by simulation. It is assumed that such gradients influence the process of ion exchange between the molten salt and the silicate glass immersed in it. It is shown that strong E-field gradients exist between the melt and the solid glass which could enhance ion transport due to an electro-migration effect superimposing the concentration gradient. In addition, interaction of the solid glass with microwave radiation could facilitate stress relaxation in the glass, which upon thermally induced ion exchange is retarding diffusion of alkali ions. A special microwave applicator has been developed which enables equilibration of inhomogeneous electromagnetic field distribution by mechanical movement of the samples subjected to ion exchange in order to analyze the overall effect of electromagnetic filed influence on ion exchange phenomena.

The work evaluates the effect of heating rate in microwave sintering, and the effect of particle size of 316L powders in microwave and conventional sintering processes. The powders of 316L stainless steel were compacted by uniaxial press at 700 MPa, and sintered at 1250 degrees C for 1 h by means of conventional sintering and microwave sintering. The sintering atmospheres were Ar/H-2 95/5% for conventional sintering and Ar/H-2 90/10% for microwave sintering. Mechanical properties were evaluated using tensile tests. The samples were characterized by optical microscopy and SEM. The porosity levels were determined using image analysis software. Microwave sintering yields fully recrystallized microstructure different from conventional sintering, however no difference in distribution and shape of pores was noticed. Heating rate in microwave sintering affects densification, tensile strength and elongation. Moreover, the use of fine powders improves physical and mechanical properties of the samples sintered by both methods. (C) 2014 Elsevier B.V. All rights reserved.

The successful islet transplantation, for the treatment of type 1 diabetes, depends on the quantity and the quality of transplanted islets. Previously, it has reported that the significant loss of isolated islet mass could be prevented by sphingolipid metabolite, sphinogosine 1-phophate (S1P). This study was performed to elucidate whether the beneficial effects of S1P maintaining isolated pancreatic islets ex vivo are mimicked by modulation of intracellular S1P. We tested the in vitro effect of various agents that modulate intracellular S1P levels in insulinoma cell lines and isolated islets to compare their anti-apoptotic effects with that of S1P. As results, we discovered that 4-deoxypyridoxine (DOP), which inhibits the degradation of intracellular S1P by inhibiting S1P lyase (SPL) activity, minimized the chemically induced apoptosis of insulinoma cell lines as S1P did. Also, supplementation of DOP in the culture media protected the regression of isolated islets that have been maintained ex vivo at least for 18 h providing the evidence of increasing viability of isolated islets with DOP, which impaired SPL activity. In conclusion, these results suggest that the application of SPL inhibitors could be considered as a supplement for the maintenance of viable islets isolated from donor sources in the process of islet transplantation.

BackgroundRecently, it has been suggested that enhancement of incretin effect improves cardiac function. We investigated the effect of a DPP-IV inhibitor, des-fluoro-sitagliptin, in reducing occurrence of restenosis in carotid artery in response to balloon injury and the related mechanisms.Methods and findingsOtsuka Long-Evans Tokushima Fatty rats were grouped into four: control (normal saline) and sitagliptin 100, 250 and 500 mg/kg per day (n = 10 per group). Sitagliptin or normal saline were given orally from 1 week before to 2 weeks after carotid injury. After 3 weeks of treatment, sitagliptin treatment caused a significant and dose-dependent reduction in intima-media ratio (IMR) in obese diabetic rats. This effect was accompanied by improved glucose homeostasis, decreased circulating levels of high-sensitivity C-reactive protein (hsCRP) and increased adiponectin level. Moreover, decreased IMR was correlated significantly with reduced hsCRP, tumor necrosis factor-α and monocyte chemoattractant protein-1 levels and plasminogen activator inhibitor-1 activity. In vitro evidence with vascular smooth muscle cells (VSMCs) demonstrated that proliferation and migration were decreased significantly after sitagliptin treatment. In addition, sitagliptin increased caspase-3 activity and decreased monocyte adhesion and NFκB activation in VSMCs.ConclusionsSitagliptin has protective properties against restenosis after carotid injury and therapeutic implications for treating macrovascular complications of diabetes.

Background Treatment with trimetazidine (TMZ), 1-[2,3,4-trimethoxybenzyl] piperazine, dihydrochloride, improves cardiac function and ameliorates endothelial dysfunction. However, its potential efficacy against restenosis after balloon injury has not been addressed. We investigated the effect of TMZ on reducing the occurrence of restenosis in the carotid artery in response to balloon injury and explored potential mechanisms for the effects. Material and methods Streptozotocin (40mg/kg)-injected Sprague–Dawley rats and Otsuka Long–Evans Tokushima Fatty rats were used for type 1 and type 2 diabetes models, respectively. Both types of rats were divided into three groups: control and TMZ treatment 10 and 20mg/kg per day ( n =10 per group). TMZ or normal saline was given orally from 2weeks before to 2weeks after carotid injury. Results Four weeks of TMZ treatment resulted in a significant and dose-dependent reduction in the intima-media ratio in diabetic rats. This effect was accompanied by decreased proliferation of vascular smooth muscle cells (VSMCs) and accelerated re-endothelialization after carotid balloon injury. In vitro study with VSMCs decreased proliferation and migration, while human umbilical vein endothelial cells (HUVECs) increased proliferation and decreased apoptosis after TMZ treatment. Antioxidative effects of TMZ were observed in both VSMCs and HUVECs. Conclusions Reduction of restenosis by TMZ treatment involved changes in antioxidative and anti-inflammatory properties, which are cell-specific effects on either survival or apoptosis. The specific actions and physiological effects of TMZ may contribute to better understanding of the pathogenesis of atherosclerosis, which is a major complication of diabetes mellitus.

Background EGb761, a standardized Ginkgo biloba extract, has antioxidant and antiplatelet aggregation and thus might protect against atherosclerosis. However, molecular and functional properties of EGb761 and its major subcomponents have not been well characterized. We investigated the effect of EGb761 and its major subcomponents (bilobalide, kaemferol, and quercetin) on preventing atherosclerosis in vitro, and in a rat model of type 2 diabetes. Methods and Results EGb761 (100 and 200 mg/kg) or normal saline (control) were administered to Otsuka Long-Evans Tokushima Fatty rats, an obese insulin-resistant rat model, for 6 weeks (from 3 weeks before to 3 weeks after carotid artery injury). Immunohistochemical staining was performed to investigate cell proliferation and apoptosis in the injured arteries. Cell migration, caspase-3 activity and DNA fragmentation, monocyte adhesion, and ICAM-1/VCAM-1 levels were explored in vitro. Treatment with EGb761 dose-dependently reduced intima-media ratio, proliferation of vascular smooth muscle cells (VSMCs) and induced greater apoptosis than the controls. Proliferation and migration of VSMCs in vitro were also decreased by the treatment of EGb761. Glucose homeostasis and circulating adiponectin levels were improved, and plasma hsCRP concentrations were decreased in the treatment groups. Caspase-3 activity and DNA fragmentation increased while monocyte adhesion and ICAM-1/VCAM-1 levels decreased significantly. Among subcomponents of EGb761, kaemferol and quercetin reduced VSMC migration and increased caspase activity. Conclusions EGb761 has a protective role in the development of atherosclerosis and is a potential therapeutic agent for preventing atherosclerosis.

Industrial scale high temperature microwave processing of materials, like e.g., dielectric heating for sintering or heat treatment of powder metals and ceramics has not been successful yet, mainly because of lack of suitable equipment. The paper presents results of antenna development aiming at 2.45 GHz microwave transmission into hot processing chambers, with minimum heat loss because only minor cooling of windows or transmission lines is required. High power microwave coupling is enabled by an array of high temperature resistant rod antennas. The design is performed in two steps: first simulation (FDTD) and experimental validation is done for a single antenna, than the results are transferred into the design of a 6 antenna array. This antenna array is capable of transmitting up to 36 kW 2.45 GHz radiation into a 1m3 volume process chamber at temperatures up to 1500°C. The homogeneity of E-H-field distribution in the chamber and the limitations of material selection for the antenna array are discussed.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor regulating inflammation, atherosclerosis, insulin sensitivity and adipogenesis. Recently, it has been discovered that modification by the small ubiquitin-like modifier (SUMO) plays an important role in PPARgamma activity. In the present study, we investigated the effect of sumoylation on the antiatherogenic property of PPARgamma. PPARgamma-K107R sumoylation mutant, PPARgamma-wild type (WT) and control genes were transfected on vascular smooth muscle cells (VSMCs) to compare their effect on the proliferation and migration. Adenoviral vectors expressing the PPARgamma-K107R, PPARgamma-WT or control gene were delivered into the carotid arteries of rats after balloon injury. The PPARgamma-K107R increased the transcriptional activity of peroxisome proliferator response element (PPRE) and had a more potent transcriptional repression activity on the inducible nitric oxide synthase (iNOS) promoter as compared to the other sumoylation mutants or WT. PPARgamma-K107R or WT gene transfer inhibited VSMCs proliferation and migration to a greater extent than the control. The PPARgamma-K107R had more potent activity than PPARgamma-WT in this regard. PPARgamma-K107R or WT transfer showed a significantly lower intima-media ratio (IMR) than the control after balloon injury in rats. Again, the delivery of the PPARgamma-K107R decreased IMR further compared to PPARgamma-WT. In addition, the PPARgamma-K107R transfer showed a lower proliferation index and a higher apoptotic index than PPARgamma-WT. In conclusion, the PPARgamma sumoylation mutant K107R strongly inhibited VSMCs proliferation and migration, sustained apoptosis, and reduced neointimal formation after balloon injury. These results indicate that desumoylation at K107 in PPARgamma might play an important role against atherosclerosis.

Lysophosphatidylserine (LPS) is known to have diverse cellular effects, but although LPS is present in many biological fluids, its in vivo effects have not been elucidated. In the present study, we investigated the effects of LPS on glucose metabolism in vivo, and how skeletal muscle cells respond to LPS stimulation. LPS enhanced glucose uptake in a dose- and time-dependent manner in L6 GLUT4myc myotubes, and this effect of LPS on glucose uptake was mediated by a Gαi and PI 3-kinase dependent signal pathway. LPS increased the level of GLUT4 on the cell surface of L6 GLUT4myc myotubes, and enhanced glucose uptake in 3T3-L1 adipocytes. In line with its cellular functions, LPS lowered blood glucose levels in normal mice, while leaving insulin secretion unaffected. LPS also had a glucose-lowering effect in STZ-treated type 1 diabetic mice and in obese db/db type 2 diabetic mice. This study shows that LPS-stimulated glucose transport both in skeletal muscle cells and adipocytes, and significantly lowered blood glucose levels both in type 1 and 2 diabetic mice. Our results suggest that LPS is involved in the regulation of glucose homeostasis in skeletal muscle and adipose tissue.

O-GlcNAcylation is a kind of post-translational modification and many nuclear and cytoplasmic proteins are O-GlcNAcylated. In this study, we demonstrated that thiazolidinediones (TZDs), which are used as insulin sensitizer, specifically inhibited the O-GlcNAcylation of Sp1 but did not affect the O-GlcNAcylation of the total proteins in cell culture systems and mouse models. This effect was mediated by peroxisome proliferator activated receptor gamma (PPARgamma) activation and probably by synthesis of a specific protein induced by PPARgamma activation. In addition, we demonstrated that the O-GlcNAcylation sites in the zinc-finger domain were involved in the transcriptional activation of Sp1 and that rosiglitazone, a member of TZDs, affected Sp1 transcriptional activity partially by regulating the O-GlcNAcylation level of these sites. Considering the role of hexosamine biosynthesis pathway in hyperglycemia-induced insulin resistance and Sp1 in the hyperglycemia-induced gene expression, the regulation of Sp1 O-GlcNAcylation by TZDs may help to explain the function of TZDs as a treatment for insulin resistance and diabetes.

Production scale inert atmosphere microwave sintering has not been successful yet, mainly because of lack of suitable equipment. For sintering in air microwave furnaces are available at different industrial scale, e.g., gas-microwave hybrid heated batch kilns or microwave “adiabatic casket” tunnel kiln [1]. Inert atmosphere furnaces require vacuum and gastight coupling of microwave energy. In the State of the Art technology, microwave-coupling windows represent a heat sink inside the sintering furnace. Although, radiation heat loss at temperatures > 1600 °C can be reduced by using a thermally insulating casket inside the microwave furnace, heat loss and temperature gradients caused by the microwave transparent windows are still not acceptable. Therefore, a new concept was developed assisted heating in inert atmosphere sintering furnaces, enabling high power microwave coupling by means of high temperature resistant antennas [2]. This paper presents microwave sintering results of commercial powder metallurgical (PM)-parts, details of the antenna system and the processing technology.