Expression of the peroxisome proliferator activated receptor γ gene is repressed by DNA methylation in visceral adipose tissue of mouse models of diabetes

<p>Abstract</p> <p>Background</p> <p>Adipose tissues serve not only as a store for energy in the form of lipid, but also as endocrine tissues that regulates metabolic activities of the organism by secreting various kinds of hormones. Peroxisome proliferator activated receptor γ (PPARγ) is a key regulator of adipocyte differentiation that induces the expression of adipocyte-specific genes in preadipocytes and mediates their differentiation into adipocytes. Furthermore, PPARγ has an important role to maintain the physiological function of mature adipocyte by controlling expressions of various genes properly. Therefore, any reduction in amount and activity of PPARγ is linked to the pathogenesis of metabolic syndrome.</p> <p>Results</p> <p>In this study, we investigated the contribution of epigenetic transcriptional regulatory mechanisms, such as DNA methylation, to the expression of the PPARγ gene, and further evaluated the contribution of such epigenetic regulatory mechanisms to the pathogenesis of metabolic syndrome. In 3T3-L1 preadipocytes, the promoter of the PPARγ2 gene was hypermethylated, but was progressively demethylated upon induction of differentiation, which was accompanied by an increase of mRNA expression. Moreover, treatment of cells with 5'-aza-cytideine, an inhibitor of DNA methylation, increased expression of the PPARγ gene in a dose-dependent manner. Methylation <it>in vitro </it>of a PPARγ promoter-driven reporter construct also repressed the transcription of a downstream reporter gene. These results suggest that the expression of the PPARγ gene is inhibited by methylation of its promoter. We next compared the methylation status of the PPARγ promoters in adipocytes from wild-type (WT) mice with those from two diabetic mouse models: <it>+Lepr</it>^<it>db</it><it>/+Lepr</it>^{<it>db </it>}and diet-induced obesity mice. Interestingly, we found increased methylation of the PPARγ promoter in visceral adipose tissues (VAT) of the mouse models of diabetes, compared to that observed in wild-type mice. We observed a concomitant decrease in the level of PPARγ mRNA in the diabetic mice compared to the WT mice.</p> <p>Conclusion</p> <p>We conclude that the expression of PPARγ gene is regulated by DNA methylation of its promoter region and propose that reduced expression of PPARγ owing to DNA methylation in adipocytes of the VAT may contribute to the pathogenesis of metabolic syndrome.</p

OTUD1 deubiquitinase regulates NF-κB- and KEAP1-mediated inflammatory responses and reactive oxygen species-associated cell death pathways

Deubiquitinating enzymes (DUBs) regulate numerous cellular functions by removing ubiquitin modifications. We examined the effects of 88 human DUBs on linear ubiquitin chain assembly complex (LUBAC)-induced NF-κB activation, and identified OTUD1 as a potent suppressor. OTUD1 regulates the canonical NF-κB pathway by hydrolyzing K63-linked ubiquitin chains from NF-κB signaling factors, including LUBAC. OTUD1 negatively regulates the canonical NF-κB activation, apoptosis, and necroptosis, whereas OTUD1 upregulates the interferon (IFN) antiviral pathway. Mass spectrometric analysis showed that OTUD1 binds KEAP1, and the N-terminal intrinsically disordered region of OTUD1, which contains an ETGE motif, is indispensable for the KEAP1-binding. Indeed, OTUD1 is involved in the KEAP1-mediated antioxidant response and reactive oxygen species (ROS)-induced cell death, oxeiptosis. In Otud1−/−-mice, inflammation, oxidative damage, and cell death were enhanced in inflammatory bowel disease, acute hepatitis, and sepsis models. Thus, OTUD1 is a crucial regulator for the inflammatory, innate immune, and oxidative stress responses and ROS-associated cell death pathways

Protein phosphatase 4 catalytic subunit regulates Cdk1 activity and microtubule organization via NDEL1 dephosphorylation

Protein phosphatase 4 catalytic subunit (PP4c) is a PP2A-related protein serine/threonine phosphatase with important functions in a variety of cellular processes, including microtubule (MT) growth/organization, apoptosis, and tumor necrosis factor signaling. In this study, we report that NDEL1 is a substrate of PP4c, and PP4c selectively dephosphorylates NDEL1 at Cdk1 sites. We also demonstrate that PP4c negatively regulates Cdk1 activity at the centrosome. Targeted disruption of PP4c reveals disorganization of MTs and disorganized MT array. Loss of PP4c leads to an unscheduled activation of Cdk1 in interphase, which results in the abnormal phosphorylation of NDEL1. In addition, abnormal NDEL1 phosphorylation facilitates excessive recruitment of katanin p60 to the centrosome, suggesting that MT defects may be attributed to katanin p60 in excess. Inhibition of Cdk1, NDEL1, or katanin p60 rescues the defective MT organization caused by PP4 inhibition. Our work uncovers a unique regulatory mechanism of MT organization by PP4c through its targets Cdk1 and NDEL1 via regulation of katanin p60 distribution

Hemostasis of Gastric Variceal Hemorrhage by Transileocoecal and Transhepatic Obliteration

Obliteration for gastric or duodenal variceal hemorrhage was performed via transileocoecal or transhepatic portal catheterization in 8 patients with portal hypertension. The patients were 6 men and 2 women, whose average age was 59 years. All of the patients had cirrhosis of the liver. The obliteration was performed as an emergency procedure in 6 cases, and 2 patients were electively treated. Transileocoecal obliteration (TIO) and transhepatic obliteration (PTO) were selected for 6, and 2 patients, respectively. Variceal bleeding was successfully controlled in all patients after completion of the therapy. One patient died after 3 months when duodenal variceal bleeding recurred. Elective surgical operations were performed on 2 patients after the initial therapy, because the vein feeding toward the varices remained. Six of the patients have survived to date without bleeding. Transient oliguria and jaundice after the therapy were noticed in 2 patients. Histological examination revealed cast formation of polymerized cyanoacrylate in the obliterated gastric varices of 2 patients. TIO and PTO seem to be safe, effective procedures to stop bleeding from ectopic varices, gastric or duodenal. This therapy is useful either to obtain accurate information about the varices or to obliterate the collateral veins in patients with ruptured ectopic varices.</p

Effect of CYP2C19 Polymorphism on Treatment Success in Lansoprazole-Based 7-Day Treatment Regimen for Cure of H. pylori Infection in Japan

Recently, Helicobacter pylori (H. pylori)-positive peptic ulcer patients were treated by a 1-week triple therapy [lansoprazole (LPZ) 30 mg, amoxicillin 750 mg and clarithromycin 200 or 400 mg, each twice daily] without the checking CYP2C19 genotype in Japan. This regimen was done to obtain sufficient cure rates for H. pylori infection using a high dose of LPZ (60 mg/day) without the great cost of having to determine the genotype. However, the failure rate for eradicating H. pylori was reported to be 12.5%. The reasons for this were studied in 33 Japanese patients with H. pylori-positive gastric or duodenal ulcer. Blood samples of the patients were collected to determine the genotype of CYP2C19 and plasma concentrations of LPZ and its metabolites at 3 h postdose on the morning of the 7th day of treatment. H. pylori infection was cured in 25 of the 33 patients (75.8%). The cure rate was highest in the group of poor metabolizers (PM), intermediate in the group of extensive metabolizers of the heterozygous type (htEM) and lowest in the group of extensive metabolizers of the homozygous type (hmEM). The relative ratio of mean plasma concentration for LPZ among the 3 groups was 1.00:1.43:2.93 (hmEM:htEM:PM groups). Our data suggest that success of the eradication is dependent on the CYP2C19-related genotypic status or the plasma concentrations of LPZ in a steady state condition after a multiple dosing regimen; that is to say, checking CYP2C19 is necessary even on occasions when treatment is done by H. pylori eradication methods as performed in Japan

JEPX spot prices forecasting system using GIS

Japan Electric Power Exchange (JEPX) is the only electricity market in Japan that allows transactions for electric power established in 2005. Several commodities are traded there, such as the spot market and the forward market. In particular, the spot market is a major trading market. The price of the spot market changes depending on the relationship between supply and demand. Therefore, it is important to forecast spot market prices to make a supply and demand plan for the next day. This research focused on the factors that determine supply and demand are related to geospatial information—first, deriving the explanatory variables for JEPX spot prices using Geographic Information System (GIS). Then, constructing the spot price forecasting system by machine learning using the derived explanatory variables. By using this system, it is possible to forecast electricity prices with higher accuracy than existing methods

GIS based JEPX spot prices forecasting system using solar power generation focusing on lowest prices

In recent years, the proportion of solar power generation in Japan's power generation facilities has been increasing. The amount of solar power generation affects the JEPX (Japan Electric Power Exchange) spot prices. When the amount of solar power generation is excessive during the low demand period, the lowest prices sometimes appear in the spot market. On the other hand the existing forecasting method cannot forecast the lowest prices; hence the forecasting error of the existing method is large. In this study, the authors focused on the appearance of the lowest prices and analyzed the conditions under which the lowest prices are likely to appear. As a result, the authors identified the conditions where the lowest price is likely to appear by comparing with the season and past forecasted solar power generation. Then, the JEPX spot prices forecasting system was developed considering the appearance of the lowest prices. The system combined these conditions, and the authors developed the JEPX spot prices forecasting system. This system can accurately forecast the appearance of the lowest prices and spot prices

Construction of PHEV driving support system using GIS for optimal operation

Plug-in Hybrid Vehicles (PHEVs) have multiple driving modes, and it is possible to proper driving energy management by a combination of driving modes. In this research, the authors obtained driving data and made it possible to estimate the driving energy consumption for each driving mode. The authors focused on the difference in power generation efficiency depending on the driving road by driving the series hybrid mode. Therefore, pre-charging method on roads with high power generation efficiency was proposed for reducing fuel consumption. Finally, the PHEV energy management system using the Geographic Information System (GIS) was constructed to optimal energy consumption and driving cost by the combination of multiple driving modes. The authors showed that fuel consumption and driving cost are reduced compared to not using this system