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We report that a Lewis acidic silane, Me2SiHCl, can mediate the direct cross-coupling of a wide range of carbonyl compounds with alcohols to form dialkyl ethers. The reaction is operationally simple, tolerates a range of polar functional groups, can be utilized to make sterically hindered ethers, and is extendable to sulfur and nitrogen nucleo­philes.

This study investigated the effect of a co-solvent on the lithium metal negative electrode to understand the growth of dendritic lithium and the battery performance. An electrolyte was prepared by adding a dimethyl carbonate (DMC) co-solvent in a propylene carbonate (PC) solvent. Adding DMC, considerably improved the unstable and low cyclic efficiency in the PC only electrolyte was considerably improved. Scanning electron microscopy showed that the growth of dendritic lithium was affected by the quantity of DMC. The more DMC was added, the more the dendritic lithium formation was suppressed. Fourier transform infrared spectroscopy revealed that the surface component of the deposited lithium was different, depending on the quantity of DMC added. This study successfully demonstrated that DMC co-solvent could suppress dendritic lithium.

Methylglyoxal (MG) is a reactive dicarbonyl intermediate and a precursor of advanced glycation end products (AGEs). The authors investigated the role played by AGEs in muscle myopathy and the amelioration of its effects by curcumin and gingerol. In addition to producing phenotypical changes, MG increased oxidative stress and reduced myotube formation in C2C12 cells. RAGE (receptor for AGEs) expression was up-regulated and MYOD and myogenin (MYOG) expressions were concomitantly down-regulated in MG-treated cells. Interestingly, AGE levels were higher in plasma (~32 fold) and muscle (~26 fold) of diabetic mice than in control mice. RAGE knock-down (RAGEkd) reduced the expressions of MYOD and MYOG and myotube formation in C2C12 cells. In silico studies of interactions between curcumin or gingerol and myostatin (MSTN; an inhibitor of myogenesis) and their observed affinities for activin receptor type IIB (ACVRIIB) suggested curcumin and gingerol reduce the interaction between MSTN and ACVRIIB. The findings of this study suggest enhanced AGE production and subsequent RAGE-AGE interaction obstruct the muscle development program, and that curcumin and gingerol attenuate the effect of AGEs on myoblasts.

Impaired diastolic heart function has been observed in persons with non-alcoholic fatty liver disease (NAFLD) and/or with type 2 diabetes mellitus (T2DM). However, it is unclear whether NAFLD fibrotic progression, i.e., non-alcoholic steatohepatitis, poses an independent risk for diastolic dysfunction in T2DM. We investigated the association between liver fibrosis and left ventricular (LV) diastolic dysfunction in T2DM.We analyzed 606 patients with T2DM, aged ≥50 years, who had undergone liver ultrasonography and pulsed-wave Doppler echocardiography. Insulin sensitivity was measured by short insulin tolerance test. Presence of NAFLD and/or advanced liver fibrosis was determined by abdominal ultrasonography and NAFLD fibrosis score (NFS). LV diastolic dysfunction was defined according to transmitral peak early to late ventricular filling (E/A) ratio and deceleration time, using echocardiography.LV diastolic dysfunction was significantly more prevalent in the NAFLD versus non-NAFLD group (59.7% vs. 49.0%,Liver fibrosis was associated with LV diastolic dysfunction in patients with T2DM and may be an independent risk factor for diastolic dysfunction, especially in patients without systemic insulin resistance.

Neither lowering of blood lipid levels nor treatment with statins definitively improves renal outcomes. Ezetimibe, a non-statin antilipidemic agent, is known to not only decrease blood lipid levels but also reduce inflammatory response and activate autophagy. We evaluated the effect of adding ezetimibe to a statin on renal outcome compared with statin monotherapy by analyzing longitudinal data of 4537 patients treated with simvastatin 20 mg plus ezetimibe 10 mg (S + E) or simvastatin 20 mg alone (S) for more than 180 days. A propensity-score-based process was used to match baseline characteristics, medical history, and estimated glomerular filtration rate (eGFR) between S + E and S groups. Changes in serum creatinine and incidence of renal events, defined as doubling of serum creatinine to &ge, 1.5 mg/dL or occurrence of end-stage renal disease after the first day of treatment initiation, were compared between the groups. Among 3104 well-matched patients with a median follow-up of 4.2 years, the S + E group showed a significantly lower risk of renal events than the S group (hazard ratio 0.58, 95% CI 0.35-0.95, P = 0.032). In addition, the S + E group tended to preserve renal function compared with the S group throughout follow-up, as assessed by serum creatinine changes (P-values for time&ndash, group interactions &lt, 0.001). These data support the beneficial effects on renal function when combining ezetimibe with a statin.

OBJECTIVE To assess the effects of empagliflozin, a selective sodium–glucose cotransporter 2 (SGLT2) inhibitor, on broad biological systems through proteomics. RESEARCH DESIGN AND METHODS Aptamer-based proteomics was used to quantify 3,713 proteins in 144 paired plasma samples obtained from 72 participants across the spectrum of glucose tolerance before and after 4 weeks of empagliflozin 25 mg/day. The biology of the plasma proteins significantly changed by empagliflozin (at false discovery rate–corrected P < 0.05) was discerned through Ingenuity Pathway Analysis. RESULTS Empagliflozin significantly affected levels of 43 proteins, 6 related to cardiomyocyte function (fatty acid–binding protein 3 and 4 [FABPA], neurotrophic receptor tyrosine kinase, renin, thrombospondin 4, and leptin receptor), 5 to iron handling (ferritin heavy chain 1, transferrin receptor protein 1, neogenin, growth differentiation factor 2 [GDF2], and β2-microglobulin), and 1 to sphingosine/ceramide metabolism (neutral ceramidase), a known pathway of cardiovascular disease. Among the protein changes achieving the strongest statistical significance, insulin-like binding factor protein-1 (IGFBP-1), transgelin-2, FABPA, GDF15, and sulphydryl oxidase 2 precursor were increased, while ferritin, thrombospondin 3, and Rearranged during Transfection (RET) were decreased by empagliflozin administration. CONCLUSIONS SGLT2 inhibition is associated, directly or indirectly, with multiple biological effects, including changes in markers of cardiomyocyte contraction/relaxation, iron handling, and other metabolic and renal targets. The most significant differences were detected in protein species (GDF15, ferritin, IGFBP-1, and FABP) potentially related to the clinical and metabolic changes that were actually measured in the same patients. These novel results may inform further studies using targeted proteomics and a prospective design.

The association of specific urinary proteins other than albumin with cardiovascular (CV) outcomes in patients with type 2 diabetes (T2D) has been shown. In this respect, CV outcomes may differ in non-albuminuric T2D patients who were considered as a low risk group, according to the presence of proteinuria. We investigated the association between proteinuria and atherosclerosis assessed by carotid artery intima-media thickness (CIMT) in non-albuminuric T2D patients. 2047 T2D patients whose urine albumin-to-creatinine ratio was below 30 mg/g were recruited and classified into a non-proteinuria (NP, uPCR &lt, 150 mg/g, n = 1865) group and a non-albuminuric proteinuria (NAP, uPCR &ge, 150 mg/g, n = 182) group. CIMT was compared between the two groups and logistic regression analysis was conducted to verify whether proteinuria could predict deteriorated CIMT status. In this cross-sectional study, mean CIMT of the NAP group were significantly thicker than those of the NP group (0.73 &plusmn, 0.16 vs. 0.70 &plusmn, 0.14, p = 0.016). The presence of proteinuria is associated with deteriorated CIMT after the adjustment for conventional risk factors (odds ratio, 2.342, 95% confidence interval, 1.082&ndash, 5.070, p = 0.030) in regression analysis. We postulated that the measurement of urinary protein in conjunction with albumin might be helpful for predicting atherosclerosis, especially for non-albuminuric patients.

Despite the benefits of pioglitazone in the treatment of non-alcoholic fatty liver disease (NAFLD), many treated patients continue to experience disease progression. We aimed to investigate the additive effect of ipragliflozin on NAFLD in patients with type 2 diabetes treated with metformin and pioglitazone. In this 24-week randomized controlled trial, 44 patients with type 2 diabetes and comorbid NAFLD were either randomized to receive 50 mg/day of ipragliflozin as an add-on treatment (n = 29) or maintained on metformin and pioglitazone (n = 15). The fatty burden was assessed using the fatty liver index, NAFLD liver fat score, and controlled attenuation parameter (CAP). Changes in fat and muscle depots were measured by dual-energy x-ray absorptiometry and abdominal computed tomography scans. The enrolled patients were relatively controlled (mean baseline glycated hemoglobin of 6.6% &plusmn, 0.6%) and centrally obese (mean waist circumference of 101.6 &plusmn, 10.9 cm). At week 24, patients in the ipragliflozin add-on group exhibited reduced hepatic fat content (fatty liver index: &minus, 9.8 &plusmn, 1.9, p = 0.002, NAFLD liver fat score: &minus, 0.5 &plusmn, 0.2, p = 0.049, CAP: &minus, 8.2 &plusmn, 7.8 dB/m2, p = 0.133). Ipragliflozin add-on therapy also reduced whole-body visceral fat and the ratio of visceral to subcutaneous fat (change in whole-body visceral fat: &minus, 69.6 &plusmn, 21.5 g, change in abdominal visceral fat: &minus, 26.2 &plusmn, 3.7 cm2, abdominal visceral to subcutaneous fat ratio: &minus, 0.15 &plusmn, 0.04, all p &lt, 0.05). In conclusion, ipragliflozin treatment significantly ameliorates liver steatosis and reduces excessive fat in euglycemic patients with type 2 diabetes and NAFLD taking metformin and pioglitazone.

We describe a general strategy for the intermolecular synthesis of polysubstituted cyclopentenones using palladium catalysis. Overall, this reaction is achieved via a molecular shuffling process involving an alkyne, an alpha,beta-unsaturated acid chloride, which serves as both the alkene and carbon monoxide source, and a hydrosilane to create three new C-C bonds. This new carbon monoxide-free pathway delivers the products with excellent yields. Furthermore, the regioselectivity is complementary to conventional methods for cyclopentenone synthesis. In addition, a set of regio- and chemodivergent reactions are presented to emphasize the synthetic potential of this novel strategy., Journal of the American Chemical Society, 142 (50), ISSN:0002-7863, ISSN:1520-5126

Lipotoxicity, induced by saturated fatty acid (SFA)-mediated cell death, plays an important role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). The KEAP1 (kelch like ECH associated protein 1)-NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2) pathway is a pivotal defense mechanism against lipotoxicity. We previously reported that SQSTM1/p62 has a cytoprotective role against lipotoxicity through activation of the noncanonical KEAP1- NFE2L2 pathway in hepatocytes. However, the underlying mechanisms and physiological relevance of this pathway have not been clearly defined. Here, we demonstrate that NFE2L2-mediated induction of SQSTM1 activates the noncanonical KEAP1-NFE2L2 pathway under lipotoxic conditions. Furthermore, we identified that SQSTM1 induces ULK1 (unc-51 like autophagy activating kinase 1) phosphorylation by facilitating the interaction between AMPK (AMP-activated protein kinase) and ULK1, leading to macroautophagy/autophagy induction, followed by KEAP1 degradation and NFE2L2 activation. Accordingly, the activity of this SQSTM1-mediated noncanonical KEAP1-NFE2L2 pathway conferred hepatoprotection against lipotoxicity in the livers of conventional sqstm1- and liver-specific sqstm1-knockout mice. Moreover, this pathway activity was evident in the livers of patients with nonalcoholic fatty liver. This axis could thus represent a novel target for NAFLD treatment. Abbreviations: ACACA: acetyl-CoA carboxylase alpha; ACTB: actin beta; BafA1: bafilomycin A1; CM-H2DCFDA:5-(and-6)-chloromethyl-2ʹ,7ʹ-dichlorodihydrofluorescein diacetate; CQ: chloroquine; CUL3: cullin 3; DMSO: dimethyl sulfoxide; FASN: fatty acid synthase; GSTA1: glutathione S-transferase A1; HA: hemagglutinin; Hepa1c1c7: mouse hepatoma cells; HMOX1/HO-1: heme oxygenase 1; KEAP1: kelch like ECH associated protein 1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; MTORC1: mechanistic target of rapamycin kinase complex 1; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NAC: N-acetyl-L-cysteine; NAFLD: nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; NFE2L2/NRF2: nuclear factor, erythroid 2 like 2; NQO1: NAD(P)H quinone dehydrogenase 1; PA: palmitic acid; PARP: poly (ADP-ribose) polymerase 1; PRKAA1/2: protein kinase AMP-activated catalytic subunits alpha1/2; RBX1: ring-box 1; ROS: reactive oxygen species; SESN2: sestrin 2; SFA: saturated fatty acid; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; SREBF1: sterol regulatory element binding transcription factor 1; TBK1: TANK binding kinase 1; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; ULK1: unc-51 like autophagy activating kinase.

The Axion Resonant InterAction Detection Experiment (ARIADNE) is a collaborative effort to search for the QCD axion using nuclear magnetic resonance (NMR), where the axion acts as a mediator of spin-dependent forces between an unpolarized tungsten source mass and a sample of polarized helium-3 gas. Since the experiment involves precision measurement of a small magnetization, it relies on limiting ordinary magnetic noise with superconducting magnetic shielding. In addition to the shielding, proper characterization of the noise level from other sources is crucial. We investigate one such noise source in detail: the magnetic noise due to impurities and Johnson noise in the tungsten source mass.

Skeletal muscle, the largest part of the total body mass, influences energy and protein metabolism as well as maintaining homeostasis. Herein, we demonstrate that during murine muscle satellite cell and myoblast differentiation, transthyretin (TTR) can exocytose via exosomes and enter cells as TTR- thyroxine (T4) complex, which consecutively induces the intracellular triiodothyronine (T3) level, followed by T3 secretion out of the cell through the exosomes. The decrease in T3 with the TTR level in 26-week-old mouse muscle, compared to that in 16-week-old muscle, suggests an association of TTR with old muscle. Subsequent studies, including microarray analysis, demonstrated that T3-regulated genes, such as FNDC5 (Fibronectin type III domain containing 5, irisin) and RXR&gamma, (Retinoid X receptor gamma), are influenced by TTR knockdown, implying that thyroid hormones and TTR coordinate with each other with respect to muscle growth and development. These results suggest that, in addition to utilizing T4, skeletal muscle also distributes generated T3 to other tissues and has a vital role in sensing the intracellular T4 level. Furthermore, the results of TTR function with T4 in differentiation will be highly useful in the strategic development of novel therapeutics related to muscle homeostasis and regeneration.

The effects of an intermittent fasting diet (IFD) in the general population are still controversial. In this study, we aimed to systematically evaluate the effectiveness of an IFD to reduce body mass index and glucose metabolism in the general population without diabetes mellitus. Cochrane, PubMed, and Embase databases were searched to identify randomized controlled trials and controlled clinical trials that compared an IFD with a regular diet or a continuous calorie restriction diet. The effectiveness of an IFD was estimated by the weighted mean difference (WMD) for several variables associated with glucometabolic parameters including body mass index (BMI) and fasting glucose. The pooled mean differences of outcomes were calculated using a random effects model. From 2814 studies identified through a literature search, we finally selected 12 articles (545 participants). Compared with a control diet, an IFD was associated with a significant decline in BMI (WMD, &minus, 0.75 kg/m2, 95% CI, &minus, 1.44 to &minus, 0.06), fasting glucose level (WMD, &minus, 4.16 mg/dL, 6.92 to &minus, 1.40), and homeostatic model assessment of insulin resistance (WMD, &minus, 0.54, 1.05 to &minus, 0.03). Fat mass (WMD, &minus, 0.98 kg, 2.32 to 0.36) tended to decrease in the IFD group with a significant increase in adiponectin (WMD, 1008.9 ng/mL, 95% CI, 140.5 to 1877.3) and a decrease in leptin (WMD, &minus, 0.51 ng/mL, 0.77 to &minus, 0.24) levels. An IFD may provide a significant metabolic benefit by improving glycemic control, insulin resistance, and adipokine concentration with a reduction of BMI in adults.

Two spotted spider mite, Tetranychus urticae, is a polyphagous pest to a variety of plants and they are hard to be controlled due to occurrence of resistance to acaricides. In this study, biochemical evaluation after ethyl formate (EF) and phosphine (PH3) fumigation towards T. urticae might help officials to control them in quarantine purposes. PH3 fumigation controlled eggs (LC50; 0.158 mg/L), nymphs (LC50; 0.030 mg/L), and adults (LC50; 0.059 mg/L) of T. urticae, and EF effectively affected nymphs (LC50; 2.826 mg/L) rather than eggs (LC50; 6.797 mg/L) and adults (LC50; 5.836 mg/L). In a longer exposure time of 20 h, PH3 fumigation was 94.2-fold more effective tool for control of T. urticae than EF fumigant. EF and PH3 inhibited cytochrome c oxidase (COX) activity differently in both nymphs and adults of T. urticae. It confirmed COX is one of target sites of these fumigants in T. urticae and COX is involved in the respiratory chain as complex IV. Molecular approaches showed that EF fumigation completely down-regulated the expression of cox11 gene at the concentration of LC10 value, while PH3 up-regulated several genes greater than twofold in T. urticae nymphs treated with the concentration of LC50 value. These increased genes by PH3 fumigation are ndufv1, atpB, para, and ace, responsible for the expression of NADH dehydrogenase [ubiquinone] flavoprotein 1, ATP synthase, and acetylcholinesterase in insects, respectively. Lipidomic analyses exhibited a significant difference between two fumigants-exposed groups and the control, especially an ion with 815.46 m/z was analyzed less than twofold in the fumigants-treated group. It was identified as PI(15:1/18:3) and it may be used as a biomarker to EF and PH3 toxicity. These findings may contribute to set an effective control strategy on T. urticae by methyl bromide alternatives such as EF and PH3 because they have shared target sites on the respiratory chain in the pest.

BACKGROUND AND OBJECTIVES We sought to investigate an anti-atherosclerotic and anti-inflammatory effect of sodium-glucose cotransporter-2 (SGLT-2) inhibitors in normoglycemic atherosclerotic rabbit model. METHODS Male New Zealand white rabbits (n=26) were fed with a 1% high-cholesterol diet for 7 weeks followed by normal diet for 2 weeks. After balloon catheter injury, the rabbits were administered with the Dapagliflozin (1mg/kg/day) or control-medium for 8 weeks (n=13 for each group). All lesions were assessed with angiography, optical coherence tomography (OCT), and histological assessment. RESULTS Atheroma burden (38.51±3.16% vs. 21.91±1.22%, p

Recent epidemiological studies have suggested an association between sarcopenia and non-alcoholic fatty liver disease (NAFLD) in the general population, prompting our investigation into the gender-specific association between sarcopenia and NAFLD in patients with type 2 diabetes mellitus (T2DM).In this cross-sectional study, 4210 patients with T2DM were recruited from the Seoul Metabolic Syndrome Cohort. Appendicular skeletal muscle mass (ASM) was estimated from bioimpedance analysis measurements, and the skeletal muscle mass index (SMI) was calculated by dividing the sum of ASM by body weight. Sarcopenia was defined as a gender-specific SMI value2 standard deviations (SDs) below the mean for healthy young adults. NAFLD was defined as the presence of hepatic steatosis on ultrasonography with no other causes of chronic liver disease.Among the entire study population (mean age: 57.4±10.8 years), 1278 (30.4%) had NAFLD and 1240 (29.5%) had sarcopenia, and the prevalence of NAFLD was significantly higher in those with sarcopenia: 46.2% vs 25.1% (P0.001) in men; 38.3% vs 25.4% (P0.001) in women. Sarcopenia was significantly associated with higher risk of NAFLD in men (adjusted odds ratio [OR]: 1.58, 95% confidence interval [CI]: 1.15-2.17), whereas the association was attenuated in women after adjusting for clinical risk factors.Sarcopenia is independently associated with NAFLD in men with T2DM, which suggests that sarcopenia may be a risk factor for NAFLD in men with T2DM.

The proton electric dipole moment (pEDM) experiment is proposed to be done with two counter-rotating beams in an all-electric storage ring. Radial magnetic field is one of the most critical systematic errors in the experiment as it mimics the EDM signal. Its secondary effect is a vertical split between the counter-rotating beams. According to the proposal of the pEDM experiment, that split should be monitored and compensated to picometer level by the beam position monitoring systems (BPM). We propose a BPM using Superconducting QUantum Interference Devices or SQUIDs to measure the beam splitting with such resolution that corresponds to magnetic field measurement with $10^{-18}$ T (aT) resolution. In this paper we experimentally demonstrate that the white noise of such magnetometers and SQUID read-out electronics can be decreased by more than two orders of magnitude down to 25 aT$\sqrt{\text{Hz}}$ by using 5 hour signal averaging. It demonstrates very high long-time stability and low intrinsic fluctuation level in the instrument. We expect that our next BPM version will be able to reach

Objective: Ketones may be regarded as a thrifty fuel for peripheral tissues, but their clinical prognostic significance still remains unclear. We investigated the association between spontaneous fasting ketonuria and incident diabetes in conjunction with changes in metabolic parameters in a large population-based, observational study. Research Design and Methods: We analyzed a total of 8,703 individuals free of diabetes at baseline in the Korean Genome and Epidemiology Study, a community-based, 12-year prospective study. Subjects with (n=195) or without fasting ketonuria were 1:4 matched by propensity score. Incident diabetes was defined as: fasting plasma glucose ≥126 mg/dL, 2-hour glucose ≥200 mg/dL on biennial 75g oral glucose tolerance test, or current antidiabetic medication. Using Cox regression models, hazard ratios for developing diabetes associated with the presence of ketonuria at baseline were analyzed. Results: Over 12 years, of the 925 subjects in the propensity score matched cohort, 190 (20.5%) developed diabetes. The incidence rate of diabetes was significantly lower in subjects with spontaneous ketonuria compared to those without ketonuria (adjusted hazard ratio 0.64 [95% confidence interval=0.42-0.99]. This result was replicated in the whole cohort (HR 0.67 [95% CI: 0.46-0.98] after multivariate adjustment). During follow-up, subjects with ketonuria at baseline maintained lower 1-hour and 2-hour glucose levels, and a higher insulinogenic index during follow-up despite comparable baseline values. Conclusions: The presence of spontaneous fasting ketonuria was significantly associated with a reduced incidence rate of diabetes, independently of metabolic parameters. Our findings suggest spontaneous fasting ketonuria is a stable phenotype and a novel signature in the modulation of glucose metabolism. Disclosure S.J. Cho: None. I. Lee: None. S. Lee: None. E. Kang: None. E. Ferrannini: None. Y. Lee: None. G. Kim: None. B. Cha: None.

Background: Sarcopenia, an age-related decline in skeletal muscle mass, leads to metabolic and vascular abnormalities. However, little is known regarding the independent relationship between skeletal muscle mass and atherosclerosis in patients with type 2 diabetes mellitus (T2DM). The purpose of this study was to evaluate the association of skeletal muscle mass with markers of carotid atherosclerosis, carotid intima-media thickness (CIMT) and carotid artery plaque, in men and women with T2DM. Methods: In this cross-sectional study, a total of 8,918 patients (4,520 men and 4,398 women) with T2DM were recruited from the outpatient clinic of Huh’s Diabetes Center from 2003 to 2016. Skeletal muscle mass was estimated from bioimpedance analysis measurements and skeletal muscle mass index (SMI, %) was defined as skeletal muscle mass (kg)/total body weight (kg) × 100. Carotid ultrasonography was performed to measure mean CIMT of both common carotid arteries. Carotid artery plaque was defined as a focal structure protruding into the lumen of the vessel of ≥50% than the surrounding area. Results: In both men and women, the presence of carotid artery plaque was higher with decreasing SMI quartiles. In men, this association remained significant after adjustment for additional risk factors (ptrend Conclusion: Low muscle mass is associated with the presence of carotid artery plaque in men with T2DM. Disclosure M. Nam: None. D. Seo: None. M. Jung: None. S. Ahn: None. S. Hong: None. Y. Lee: None. Y. Choi: None. B. Huh: None. K. Huh: None. S. Kim: None. Funding National Research Foundation of Korea (2017R1D-1A1B03034581)

Background: Obese individuals with normal metabolic profiles, so-called “metabolically healthy obese (MHO)” status has shown better clinical outcomes via previous studies. However, studies dealing with the association between MHO and dementia, which is deeply associated with metabolic disorders, were still insufficient. We designed this study to assess the association between MHO and the risk of incident dementia. Methods: The present study is a retrospective cohort study, including 5,669,488 patients aged 60 years old or over without any history of dementia, by using the National Health Insurance System of South Korea. Subjects were divided into 4 groups based on their metabolic health and obesity status. Metabolic health was determined based on the criteria of metabolic syndrome by Adult Treatment Panel-III. Obesity was judged based on the baseline body mass index. The incidence of dementia was checked and compared longitudinally between 4 groups. Results: When we put the metabolically healthy non-obese group to the reference value (hazard ratio (HR) = 1), MHO group showed the lowest incidence of dementia (HR 0.87, 95% confidence interval (CI) 0.86-0.88). This trend was more prominent when we followed up the risk of Alzheimer’s disease as a subgroup analysis (HR 0.85, 95% CI 0.83-0.86). Non-obese subjects with metabolic syndrome showed significantly increased risk for overall dementia (HR 1.20, 95% CI 1.19-1.21), especially for vascular dementia (HR 1.41, 95% CI 1.38-1.45). Conclusion: MHO status was associated with lower risk for dementia, especially for Alzheimer’s disease. Disclosure J. Bae: None. J. Lee: None. Y. Cho: None. M. Lee: None. S. Lee: None. I. Lee: None. E. Kang: None. S.J. Cho: None. K. Han: None. B. Cha: None. Y. Lee: None.

Caspase 8 is a central player in the apoptotic cell death pathway and is also essential for cytokine processing. The critical role of this protease in cell death pathways has generated research interest because its activation has also been linked with neural cell death. Thus, blocking the activity of caspase 8 is considered a potential therapy for neurodegenerative diseases. To extend the repertoire of caspase 8 inhibitors, we employed several computational approaches to identify potential caspase 8 inhibitors. Based on the structural information of reported inhibitors, we designed several individual and consensus pharmacophore models and then screened the ZINC database, which contains 105,480 compounds. Screening generated 5332 candidates, but after applying stringent criteria only two candidate compounds, ZINC19370490 and ZINC04534268, were evaluated by molecular dynamics simulations and subjected to Molecular Mechanics/Poisson Boltzmann Surface Area (MM-PBSA) analysis. These compounds were stable throughout simulations and interacted with targeted protein by forming hydrogen and van der Waal bonds. MM-PBSA analysis showed that these compounds were comparable or better than reported caspase 8 inhibitors. Furthermore, their physical properties were found to be acceptable, and they are non-toxic according to the ADMET online server. We suggest that the inhibitory efficacies of ZINC19370490 and ZINC04534268 be subjected to experimental validation.

Rationale: Transverse myelitis (TM) is a spinal cord inflammatory myelopathy that causes motor/sensory loss and urinary retention below the level of the affected spinal cord. Although a few case reports have described the control of neuropathic pain in patients with TM via spinal cord stimulation, no documented case regarding the control of severe allodynia following TM via intrathecal pump has been described. Patient concerns: A 37-year-old woman was referred to a pain clinic for severe intractable pain below the T5 level followed by Sjögren's syndrome-induced TM. Diagnoses: A neurological examination revealed paresthesia and allodynia below the T5 level. The sensory evaluation was limited by extreme pain and jerking movements. The muscle strength of both lower limbs was grade 3. Interventions: Intrathecal pump was inserted into the left lower abdomen. Catheter tip was placed at the midline of the T8 level. Outcomes: The numeric rating scale (NRS) for pain score decreased from 10 to 5. Functional Independence Measure score increased from 67 before implantation to 92 at the time of discharge, while the patient's Barthel score increased from 31 to 46. Lessons: Neuropathic pain due to Sjögren's syndrome-related TM could be controlled effectively using the intrathecal morphine pump.

Sodium glucose co-transporter 2 (SGLT2) inhibitors increase urinary glucose excretion (UGE) by reducing the renal threshold for glucose excretion, which results in decreased serum glucose concentrations in patients with type 2 diabetes mellitus (T2D). However, no study to date has determined whether larger increases in UGE after SGLT2 inhibitor treatment correspond to larger reductions in glycated hemoglobin (HbA1C). We enrolled participants who were newly prescribed an SGLT2 inhibitor (dapagliflozin 10 mg or ipragliflozin 50 mg, once daily) as an add-on therapy. Patients were tested for HbA1C and first morning spot urinary-creatinine and -glucose concentrations immediately prior to administration of the SGLT2 inhibitor and at a 12-week follow-up appointment. We investigated the relationship between increases in morning spot UGE and decreases in HbA1C. A total of 101 participants with T2D were enrolled. The median age and diabetes duration were 61.0 and 12.8 years, respectively, and the median HbA1C was 8.10%. SGLT2 inhibitors significantly lowered the HbA1C level, with a median change from baseline to week 12 of −0.60% (p

Relationship on new statin use and the risk of hepatocellular carcinoma (HCC) in patients with incident type 2 diabetes mellitus (T2DM), who might be at the risk of developing HCC, is uncertained. A nationwide population–based nested case–control study was conducted within the National Health Insurance Service National Sample Cohort 2002–2013 in Korea. Newly prescribed statin after newly diagnosed T2DM was defined as statin use. Controls were matched to case patients on age, sex, follow–up time, and the date of diabetes diagnosis at a five–to–one ratio. Odds ratios (ORs) for associations of statin use with HCC were calculated using conditional logistic regression. After at least a 5-year HCC–free period, there were 229 incident HCC cases and 1,145 matched controls from 47,738 patients with incident diabetes. Of these 229 incident HCC cases, 27 (11.8%) were statin users, whereas 378 (33.0%) were statin users among 1,145 controls. Statin use was associated with a reduced risk of HCC development (adjusted OR [AOR]= 0.36, 95% confidence interval [CI] 0.22–0.60) after adjustment for chronic viral hepatitis, liver cirrhosis, alcoholic liver disease, previous cancer, aspirin use, insulin use, sulfonylurea use, metformin use, thiazolidinedione use, history of chronic obstructive pulmonary disease, Charlson comorbidity score, household income level, and residential area. Risk reduction was accentuated with an increase of cumulative defined daily doses (cDDD) compared with non–users (AORs 0.53, 0.36, 0.32, and 0.26 in ≤60, 60–180, 181–365, and >365cDDD, respectively; P for trend

Background Insulin resistance (IR) is a major factor associated with type 2 diabetes. By using homeostasis model assessment of insulin resistance (HOMA-IR), we aimed to elucidate the factors associated with IR risk, especially the cumulative effect of obesity and sarcopenia on IR. Methods A total of 8,707 adults from the 4th and 5th Korean National Health and Examination Surveys were studied. Laboratory, anthropometric, and lifestyle factors were analyzed to reveal their association with HOMA-IR and IR risk. Subjects were divided into four groups according to the presence of obesity and sarcopenia to identify their effect on IR risk. Results We found that high triglycerides and alanine aminotransferase, low high-density lipoprotein cholesterol, obesity, and sarcopenia were independent risk factors for IR in both sexes. Obese men with sarcopenia had a significantly higher risk of IR than men who were obese or sarcopenic (but not both). The additive effect of sarcopenia with obesity on IR risk was not observed in women. Cutoffs of HOMA-IR for determining IR were calculated as 75 percentile value of young healthy subpopulation, 2.19 in men and 2.18 in women. These cutoffs could distinguish individuals with impaired fasting glucose from normal ones, with a sensitivity of 65.4% (men) and 73.3% (women), and a specificity of 68.8% (men) and 69.4% (women). Conclusion These data showed that obese men with sarcopenia exhibited a significantly higher IR risk than non-sarcopenic obese men. In women, body composition did not affect IR if they were already obese. This article is protected by copyright. All rights reserved.

Although sarcopenia is associated with metabolic disorders, its influence on albuminuria has not been determined. The aim of this study was to identify the relationship between sarcopenia and albuminuria in the general population.This was a population-based, cross-sectional study using a nationally representative sample of 2326 subjects aged ≥20years from the Korea National Health and Nutrition Examination Surveys of 2008-2011. Appendicular skeletal muscle (ASM) measured by dual-energy X-ray absorptiometry was used to assess sarcopenia, which was defined as ASM divided by body mass index, as recommended by the international consensus meeting of the National Institutes of Health. Albuminuria was defined as an albumin-to-creatinine ratio of ≥30mg/g using random spot urine samples.A total of 385 (16.5%) subjects were classified as having albuminuria. Sarcopenic subjects showed a higher proportion of albuminuria than subjects without sarcopenia (odds ratios [ORs]=2.17-3.26, all P0.05) after stratification based on the presence of hypertension, diabetes, or metabolic syndrome and a higher homeostasis model assessment of insulin resistance (all P0.001). The albuminuria risk was comparable between insulin-sensitive subjects with sarcopenia and insulin-resistant subjects with preserved muscle mass. A multiple logistic regression analysis also demonstrated that sarcopenia was independently associated with albuminuria (OR=1.61, 95% confidence interval [CI]=1.04-2.48, P0.05). The association between sarcopenia and albuminuria remained strong in the elderly population (ORs=1.80-2.68, P0.05), whereas it lost its significance in the younger age group. Furthermore, the risk of albuminuria was much higher in sarcopenic obese subjects than in other groups (OR=4.90, 95% CI=3.23-7.43, P0.001).Sarcopenia was associated with an increased risk of albuminuria independent of hypertension, diabetes, and metabolic syndrome. Sarcopenia and obesity had a synergistic impact on the increased risk of albuminuria. This suggests that sarcopenic obesity as well as sarcopenia alone may be considered as novel risk factors for albuminuria.

Oxidative stress is important for the pathogenesis of nonalcoholic fatty liver disease (NAFLD), a chronic disease that ranges from hepatic steatosis to nonalcoholic steatohepatitis (NASH). The nuclear factor erythroid 2-related factor 2-Kelch-like ECH associated protein 1 (Nrf2-Keap1) pathway is essential for cytoprotection against oxidative stress. In this study, we found that oxidative stress or inflammatory biomarkers and TUNEL positive cells were markedly increased in NASH patients compared to normal or simple steatosis. In addition, we identified that the hepatic mRNA levels of Nrf2 target genes such as Nqo-1 and GSTA-1 were significantly increased in NASH patients. Ezetimibe, a drug approved by the Food and Drug Administration for the treatment of hypercholesterolemia, improves NAFLD and alleviates oxidative stress. However, the precise mechanism of its antioxidant function remains largely unknown. We now demonstrate that ezetimibe activates Nrf2-Keap1 pathway which was dependent of autophagy adaptor protein p62, without causing cytotoxicity. Ezetimibe activates AMP-activated protein kinase (AMPK), which in turn phosphorylates p62 (p-S351) via their direct interaction. Correspondingly, Ezetimibe protected liver cells from saturated fatty acid-induced apoptotic cell death through p62-dependent Nrf2 activation. Furthermore, its role as an Nrf2 activator was supported by methione- and choline- deficient (MCD) diet-induced NASH mouse model, showing that ezetimibe decreased the susceptibility of the liver to oxidative injury. These data demonstrate that the molecular mechanisms underlying ezetimibe's antioxidant role in the pathogenesis of NASH.

A series of symmetric and nonsymmetric tetrahydroindenyl zirconium complexes was obtained by the reaction of ZrCl4 or (CpTMS)ZrCl3 with lithium salts of the corresponding tetrahydroindenes. Activated with methylalumoxane, these complexes exhibit high activity in polymerization of ethylene (up to 6.8∙106 g PE (mol Zr h)–1), as well as in copolymerization of ethylene and hex-1-ene (up to 8.6∙106 g PE (mol Zr h)–1).

This study was performed to understand how chlorpyrifos (CHL) affects zebrafish (Danio rerio) embryos and adults, by exposing this model organism to various concentrations of the insecticide. The 96-h acute toxicity test to determine the effect of CHL on adult zebrafish yielded a LC50 of 709.43μg/L(-1). Small molecular weight proteins less than 25kDa and phospholipids were analyzed with MALDI-TOF MS/MS in order to compare expression patterns, revealing that some peaks were dramatically altered after CHL treatment. Whereas no acute toxicity was detected in the embryo toxicity test, malformation of zebrafish larvae was observed, with many individuals harboring curved spines. In an angiogenesis test on larvae of transgenic zebrafish, CHL did not have an inhibitory effect. Relative gene expression analyses using real-time polymerase chain reaction (RT-PCR) of DNA from zebrafish embryos revealed that different subtypes of cytochrome P450 (CYP450), such as CYP1A and CYP3A, were significantly up-regulated in response to CHL at a concentration of 400μg/L(-1) compared to the control. The expression level of NR1I2, a CYP gene transcriptional regulator, UGT1a1, and MDR1 were all up-regulated in the CHL-treated embryos. Finally, the expression level of acetylcholinesterase (AChE) and catalase (CAT) decreased, whereas that of superoxide dismutase (SOD) did not differ significantly. Our results suggest that the up-regulation of metabolic enzymes including CYP450 and MDR1 may be involved in CHL resistance in zebrafish.