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BACKGROUND Type 2 diabetes is a risk factor for atherosclerosis. Oxidative stress, which is a causative factor in insulin resistance, leads to atherosclerosis in patients with diabetes. Xanthine oxidoreductase (XOR) is an enzyme that catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid and is related to oxidative stress. We aimed to examine the influence of plasma XOR activity on arterial stiffness in patients with type 2 diabetes. METHODS In total, 458 patients with type 2 diabetes not receiving antihyperuricemic agents were enrolled and their clinical parameters including plasma XOR activity and the cardio-ankle vascular index (CAVI) were measured. Patients were divided into the liver dysfunction and absence of liver dysfunction groups. Multiple regression analysis was performed. RESULTS The median plasma XOR activity level was 64.3 pmol/h/mL (33.3-147.3 pmol/h/mL). Plasma XOR activity was correlated significantly and positively with aspartate transaminase and alanine transaminase (ρ > 0.5). The level of plasma XOR activity in the liver dysfunction group was eight-fold higher than that in the absence of liver dysfunction group. A significant positive correlation was observed between plasma XOR activity and the CAVI only in the liver dysfunction group (ρ = 0.3968, P < 0.0043). Multiple regression models demonstrated that plasma XOR activity was an independent predictor of the CAVI in the liver dysfunction group (P = 0.0055). CONCLUSIONS Our results suggest that plasma XOR activity is associated with arterial stiffness and may have a role in atherosclerosis development in patients with type 2 diabetes and liver dysfunction.

OBJECTIVE: Bariatric surgery (BS) improves glycemic control in type 2 diabetes; however, some patients show insufficient improvement. Understanding the pathophysiology of type 2 diabetes in obese patients can facilitate appropriate treatment for type 2 diabetes after BS. The homeostatic model assessment (HOMA) 2 enables the calculation of the values from C-peptide data and evaluation of insulin users. We aimed to evaluate the pathophysiology of type 2 diabetes using pre- and postoperative parameters and HOMA2 in obese patients who underwent BS. METHODS: We retrospectively reviewed data from 45 obese patients with type 2 diabetes who underwent BS. They were followed-up for 12 months. The relationship between the HOMA2 score and complete remission (CR) of type 2 diabetes after BS was analyzed. Patients with and without CR were assigned to the CR and non-CR groups, respectively. Multiple regression analysis was used to identify factors associated with improvement in type 2 diabetes after BS. RESULTS: BS significantly improved body weight and glucose metabolism. The preoperative glycosylated hemoglobin A1c level and insulin secretion (HOMA2-%B) significantly differed between the CR and non-CR groups. Postoperative weight reduction and improved insulin sensitivity correlated significantly with CR; multiple regression showed that the preoperative HOMA 2-%B independently predicted CR of type 2 diabetes after BS. CONCLUSION: Preoperative insulin secretion, improvement in insulin sensitivity, and weight reduction after BS are related to CR of type 2 diabetes after BS. The results better reveal the pathophysiology of and treatment for type 2 diabetes in obese patients who undergo BS.

Presepsin is a diagnostic and prognostic biomarker of sepsis; however, elevated presepsin levels have also been documented without sepsis. This study aims to retrospectively analyze the laboratory parameters and Sequential Organ Failure Assessment (SOFA) score affecting presepsin levels in 567 patients. Some patients with elevated presepsin levels exhibited renal dysfunction or elevation of biliary enzymes despite a low SOFA score. The univariate regression analysis revealed a close correlation between presepsin levels and SOFA score, serum creatinine (CRE), blood urea nitrogen, and biliary enzymes. In addition, a multivariate regression analysis revealed that SOFA score, alkaline phosphatase (ALP), and CRE independently affected presepsin levels significantly. The analysis of covariance (ANCOVA) revealed that presepsin levels were significantly higher in patients with hepatobiliary disease. Besides, we found that patients who presented with the dilatation of intra- or extrahepatic bile ducts and the elevation of ALP or total bilirubin exhibited remarkable high presepsin levels in the bile. Furthermore, the presepsin production in the liver’s Kupffer cells was established by immunostaining in patients who received surgical liver resection. Overall, this study elucidates that biliary enzymes’ elevation affects presepsin levels, presepsin exists in high concentrations in the bile, and is positive in Kupffer cells.

Statins have been reported to increase the plasma concentration of arachidonic acid (AA), an omega-6 long chain polyunsaturated fatty acid (LCPUFA) in several clinical studies indicating that statins affect the endogenous synthesis of LCUFAs. In the present study, we investigated the roles of the intrinsic mevalonate cascade and Rho-dependent pathway in LCPUFA synthesis, especially focusing on fatty acid desaturases (Fads) 2, using the human hepatocellular carcinoma cell line HepG2. Cell number and the activity of caspase-3 and 7 (caspase-3/7) was measured using a commercial kit. Gene expression was analyzed by quantitative real-time PCR. Protein expression was detected by Western blot analysis. Atorvastatin decreased cell viability and increased caspase-3/7 activity in a dose-dependent manner. At lower concentrations, atorvastatin stimulated both mRNA and protein expression of Fads2, and increased mRNA expression of FADS1 and ELVOL5. Both mevalonate and geranylgeranyl-pyrophosphate (GGPP), but not cholesterol, fully reversed atorvastatin-induced upregulation of Fads2, and mevalonate-effected reversal was inhibited by treatment with the Rho-associated protein kinase inhibitor Y-27632. These data clearly demonstrated that in human HepG2 cells, statins affect the endogenous synthesis of LCPUFAs by regulation of not only Fads2, but also Fads1 and Elovl5, through the GGPP-dependent Rho kinase pathway.

Objectives: Obesity is one of the causes of metabolic disorders. Laparoscopic sleeve gastrectomy (LSG) confers beneficial effects not only on body weight (BW) but also on metabolic disorders. The lipoprotein lipase (LPL) level in preheparin serum is associated with visceral adipose tissue and reflects insulin resistance. However, the change in serum preheparin LPL levels after LSG remains unclear. This study aimed to examine the effect of LSG on preheparin LPL level in obese patients compared with nonsurgical treatment. Methods: We retrospectively reviewed a total of 100 obese patients who were treated for obesity and had preheparin LPL levels measured before and 12 months after LSG or after 12 months of nonsurgical treatment. Fifty-six patients received LSG (LSG group), and 44 patients had no surgical treatment (nonsurgical group). We compared clinical parameters such as body mass index (BMI), hemoglobin A1c (HbA1c), and preheparin LPL level before and 12 months after treatment. Results: BMI and HbA1c decreased significantly in both groups, but decreases in both parameters were greater in the LSG group than in the nonsurgical group. Estimated glomerular filtration was significantly improved only in the LSG group. Preheparin LPL level increased significantly only in the LSG group (from 45.8 ± 21.6 to 75.0 ± 34.9 ng/mL, p < 0.001). Multiple regression identified LSG and decreased BMI as independent predictors of preheparin LPL level increase. Conclusions: These results suggest that LSG independently increases pre­heparin LPL level beyond BW reduction in obese patients.

Background: The plasma concentration of arachidonic acid, one of the omega-6 long-chain polyunsaturated fatty acids (LCPUFAs), was increased by the treatment of statin in several clinical studies indicating that statin affects the endogenous synthesis of LCPUFAs, which is regulated by the action of the fatty acid desaturases (FADSs) and elongation of very long-chain fatty acids (ELOVLs). Aims: We investigated the roles of the intrinsic mevalonate cascade and rho-dependent pathway in the statin-induced regulation of these desaturases and elongases using human hepatocellular carcinoma cell line HepG2 cells. Methods: Cell viability was assessed by measuring mitochondrial activity of WST-8, and the activity of caspase-3 and -7 (caspase-3/7) was measured. Gene expression was analyzed by quantitative real-time PCR. Protein expressions were detected by Western blot analysis. Results: Although atorvastatin decreased the cell viability with increasing activity of caspase-3/7 in a dose-dependent manner, both mRNA and protein expression of FADS2 were stimulated by atorvastatin at lower dose of 12.5 and 25 uM, where mRNA expression of FADS1 and Elovl5 also increased. Both mevalonate and geranylgeranyl-pyrophosphate (GGPP), not cholesterol, fully restored the atorvastatin-induced inhibition of cell viability, and the atorvastatin-induced upregulation of mRNA and protein of FADS2. The Rho-associated protein kinase (ROCK) inhibitor Y-27632 inhibits the restoration of mevalonate and GGPP. Both EPA and DHA, but not AA, significantly suppressed the atorvastatin-induced upregulation of gene expression of FADS1, FADS2 and Elovl5. Conclusions: These data demonstrated that statin may affect the endogenous synthesis of LCPUFAs by the regulation of these desaturases and elongases through GGPP-dependent rho kinase pathway in HepG2 cells. Disclosure I. Tatsuno: None. S. Tanaka: None. N. Ishihara: None.

Numerous clinical studies have reported that statins increase the plasma concentration of arachidonic acid, which is an ω-6 long-chain polyunsaturated fatty acid (LCPUFA), and decrease the concentrations of eicosapentaenoic acid and docosahexaenoic acid, which are ω‑3 LCPUFAs. These findings indicate that statins may affect the endogenous synthesis of LCPUFAs, which is regulated by fatty acid desaturases (FADSs) and elongation of very long‑chain fatty acids proteins (ELOVLs). The present study aimed to investigate the roles of the intrinsic mevalonate cascade and Rho‑dependent pathway in statin‑induced regulation of these desaturases and elongases, as well as cell viability using mouse 3T3‑L1 cells. mRNA expression was analyzed by quantitative polymerase chain reaction. Treatment with atorvastatin decreased cell viability and increased the mRNA expression levels of Fads1, Fads2 and ELOVL fatty acid elongase 5 (Elovl5) in a dose‑dependent manner. Mevalonate and geranylgeranyl pyrophosphate (GGPP), but not cholesterol, fully reversed the atorvastatin‑induced downregulation of cell viability and upregulation of gene expression; however, mevalonate itself did not affect cell viability and gene expression. The Rho‑associated protein kinase inhibitor Y‑27632 inhibited the mevalonate‑ and GGPP‑mediated reversal of atorvastatin‑induced upregulation of Fads1, Fads2 and Elovl5. These findings indicated that statins may affect the endogenous synthesis of LCPUFAs by regulating Fads1, Fads2 and Elovl5 gene expression via the GGPP‑dependent Rho kinase pathway in mouse 3T3-L1 cells.

In recent years, natural and synthetic estrogens have been recognized as endocrine disruptors in aquatic organisms. Although natural and synthetic estrogens are known to be degraded by microbes, only limited information about their degradation pathways is available. Here, we studied the degradation pathways of a natural estrogen, 17β-estradiol, by the nitrifying microorganism Nitrosomonas europaea, and we determined whether the degradation products of 17β-estradiol had estrogenic activity. To identify the degradation products, we subjected the culture solution to solid-phase extraction, and the extract was analyzed by gas chromatography–mass spectrometry. The potential estrogenic activity of the degradation products was investigated by means of a yeast two-hybrid assay. 1,3,5(10),16-Estratetraen-3-ol (estratetraenol) was newly identified as a degradation intermediate produced by dehydration of 17β-estradiol. Estratetraenol was also degraded by N. europaea, and its degradation rate was faster than that of 17β-estradiol. The two-hybrid assay confirmed that estratetraenol acted as a ligand for the estrogen receptor; estratetraenol thus has potential estrogenic activity. N. europaea eliminated the estrogenic activity derived from 17β-estradiol. This paper is the first to report dehydration as a mechanism of microbial estrogen degradation.

近年，III種地盤では共振しにくい橋として，多点固定橋が適用されている．しかし，多点固定橋では，温度変化やクリープ等による桁の伸縮に起因する不静定力により，地震時の挙動に影響を及ぼす．PC多点固定橋では，不静定量のうちクリープ等の影響は地震時の設計に見込まれているが，温度変化の影響は見込まれていない．本論文ではPC多点固定橋を対象に，温度変化による桁収縮が地震時に及ぼす影響を評価した．検討結果より，PC多点固定橋では地震時応答への不静定量の影響は大きいものの，温度変化の影響は大きくないことが明らかとなった．これは，常時状態で不静定量により橋脚断面が決定されており，不静定量に占める温度変化の影響はクリープ等に比べて小さいためである．

This paper describes the loss and recovery in the hydrophobicity of unfilled high temperature vulcanized silicone rubber (HTV-SR) resulting from corona discharge. In this study, HTV-SR specimens were exposed to corona stress generated by a parallel needle–plane electrode system, and physicochemical analyses on the surface layer of SR before and after corona discharge treatment were carried out by using Fourier transform infra-red (FTIR) spectroscopy, scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). It is demonstrated that hydrophilic OH groups that are by-products of ageing can be formed instead of hydrophobic CH3 groups on the surface of aged SR and the corona discharge plays an important role on the temporary loss of hydrophobicity. After a substantial period of ‘rest’, the hydrophobic recovery of SR results from the diffusion of low-molecular weight (LMW) silicone fluid from the bulk onto the aged layer.

This paper describes the results of experiments and simulations made to examine the corona discharges from water droplets on a polymer surface exposed to electrical stress. In this study, water droplets with different conductivities and volumes were placed on the surface of plate-shaped high temperature vulcanized silicone rubber (HTV-SR) energized with ac voltage, and the corona discharge phenomena were observed by a high-speed camera with an image intensifier. The electric-field distributions were calculated by the finite element method (FEM). It is demonstrated that the electric field is intensified at the triple junction of the water droplet, air and the insulating material due to the difference in their permittivities, which can ionize the surrounding air and trigger a corona discharge. It can also be confirmed that the contact angle, volume, conductivity and number of water droplets are shown to have a marked effect on the mode of the corona discharge development.