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Aim: A prospective cohort study in a Japanese urban general population was performed to investigate whether triglyceride (TG) and its related indices were associated with the risk for the incidence of ischemic cardiovascular disease (CVD) after the adjustment for low-density lipoprotein cholesterol (LDL-C) in Asian community dwellers. Methods: A 15.1-year prospective cohort study was performed in 6,684 Japanese community dwellers aged 30–79 years without a history of CVD and whose fasting TG levels were ＜400 mg/dL. After adjusting for covariates, including LDL-C, the multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of the deciles (D) of TG and those of 1-standard deviation (SD) increment of log-transformed TG (1-SD of TG) according to LDL-C level (≥ 140 and ＜140 mg/dL) for ischemic CVD incidence were estimated. The multivariable-adjusted HRs and 95%CIs of the quintiles (Q) of TG, TG/HDL-C, and the cardiometabolic index (CMI) for ischemic CVD were also estimated. Results: In 101,230 person-years, 464 ischemic CVD cases occurred. For D 10 of TG, the HR (95%CI) was 1.56 (1.05–2.32), and for 1-SD of TG, it was 1.30 (1.00–1.70) in participants with LDL-C ＜140 mg/dL and 1.07 (0.77–1.50) in those with LDL-C ≥ 140 mg/dL. For Q 5 of the CMI, the multivariable-adjusted HR was higher than those of TG and TG/HDL-C. Conclusions: Fasting TG was an independent predictor for ischemic CVD incidence after adjusting for LDL-C in Japanese community dwellers with TG ＜400 mg/dL. Among TG, TG/HDL-C, and the CMI, the CMI could be the most powerful predictor for ischemic CVD.

We previously identified seven peptides in serum that are associated with hypertensive disorders of pregnancy (HDP). However, the significance of these peptides in the general population is unknown. The aim of this study was to clarify the relationships of HDP-associated peptides with hypertension and other cardiovascular risks in adult men. We investigated the relationships of peptide levels with cardiovascular risk factors, including adiposity, blood pressure, blood lipids and glycemic status, in men (mean age: 46.4 years) who were receiving annual health checkups at their workplace. The concentrations of the abovementioned seven peptides in serum were measured simultaneously using a mass spectrometer. Among the seven peptides, only a peptide with m/z 2091 (P-2091) derived from fibrinogen-α showed a significant correlation with diastolic blood pressure (Spearman's rank correlation coefficient [r], -0.446). Another peptide with m/z 2378 (P-2378) originating from complement component 4 showed a significant positive correlation with body mass index (r, 0.273) and a significant inverse correlation with HDL cholesterol (r, -0.336). In addition, a peptide with m/z 3156 (P-3156) derived from an inter-α-trypsin inhibitor showed significant inverse correlations with body mass index (r, -0.258) and triglycerides (r, -0.334). There was no significant correlation of the levels of any of the seven peptides with hemoglobin A1c. Among the seven peptides related to HDP, P-2091, P-2378 and P-3156 were inversely associated with diastolic blood pressure, HDL cholesterol and triglycerides, respectively. Therefore, these peptides are possible biomarkers for discriminating cardiovascular risk in a general population.

Background Urinary liver-type fatty acid-binding protein (L-FABP) is a well-known marker of proximal tubular impairment. We evaluated the relationship between cardiovascular disease (CVD) risk factors and levels of L-FABP in a cross-sectional community-based study. Participants with normoalbuminuria and normal estimated glomerular filtration rate (eGFR), that is, non-chronic kidney disease (non-CKD), were enrolled in this study. To the best of our knowledge, this is the first study to focus on the association between CVD risk factors and a proximal tubular marker in the Japanese general population with normoalbuminuria and normal eGFR. Methods The present study is part of the Sasayama study. The participants included 1000 community residents (447 men and 553 women) aged 40–64 years without a history of CVD or renal dysfunction. Out of these participants 375 men and 477 women, defined as non-CKD, were included for further analysis. In each sex, the highest quintile group was considered to have high-normal L-FABP levels. A multiple logistic regression model was used to evaluate the relationship between risk factors for CVD and high-normal L-FABP levels in the non-CKD participants. We performed a similar analysis using the high-normal urinary albumin to creatinine ratio (UACR) as a dependent variable instead of L-FABP. Results Among the non-CKD participants, in the highest quintile group (Q5, top 20%), L-FABP was ≥2.17 μg/gCre in men and ≥ 2.83 μg/gCre in women. In women, the multivariate odds ratio was 3.62 (1.45–9.00) for high-normal L-FABP in the presence of diabetes mellitus (DM) compared with that in the group without DM. However, the relationship between DM and the UACR level was not significant. In men, DM was significantly associated with high-normal UACR. However, the relationship with L-FABP levels was not significant. Conclusions The presence of DM was more strongly related to high-normal L-FABP levels than to high-normal UACR in women even at the stage of normoalbuminuria and normal eGFR. Our results were also consistent with the findings of a previous study where women were more prone to nonalbuminuric renal impairment compared to men, although further studies are required to confirm the results.

Light-to-moderate alcohol drinking reduces the risk of ischemic heart disease, and this effect of alcohol is mainly explained by alcohol-induced elevation of HDL cholesterol. Hypo-HDL cholesterolemia is a potent risk factor for cardiovascular disease. The aim of this study was to clarify how alcohol relates to cardiovascular risk factors in men with hypo-HDL-cholesterolemia.The subjects were middle-aged men with hypo-HDL cholesterolemia (40 mg/dl), and they were divided into four groups by daily alcohol consumption (non-; light,22 g ethanol/day; moderate, ≥22 g ethanol and44 g ethanol/day; heavy drinkers, ≥44 g ethanol/day). Each risk factor was compared among the groups after adjustment for age and histories of smoking and regular exercise.Systolic and diastolic blood pressure levels, log-transformed lipid accumulation product and log-transformed cardio-metabolic index were significantly higher in moderate and heavy drinkers than in nondrinkers. Log-transformed triglycerides and triglycerides-to-HDL cholesterol ratio were significantly higher in light, moderate and heavy drinkers than in nondrinkers and tended to be higher with an increase of alcohol intake. LDL cholesterol and LDL cholesterol-to-HDL cholesterol ratio were significantly lower in light, moderate and heavy drinkers than in nondrinkers and tended to be lower with an increase of alcohol intake. The above trends for the relationships of alcohol drinking with the cardiovascular risk factors were also found in multivariate logistic regression analysis.In men with hypo-HDL cholesterolemia, alcohol drinking shows positive associations with blood pressure and triglycerides and an inverse association with LDL cholesterol.

Background The ratio of triglycerides to HDL cholesterol (TG/HDL-C ratio) is known as a good predictor for cardiovascular disease. The purpose of this study was to compare discrimination for cardiovascular risk by different cut-off values of the TG/HDL-C ratio. Methods Receiver operating characteristic (ROC) analysis was performed for the relationship between TG/HDL-C ratio and accumulation of cardio-metabolic risk factors including visceral obesity, hypertension and diabetes. Logistic regression analysis was performed for the relationships of TG/HDL-C ratio with cardio-metabolic risk factors using the cut-off values obtained by ROC analysis and conventional cut-off values (men, 3.75; women, 3.00). Results In ROC analysis, the optimal cut-off values for TG/HDL-C ratio were 2.967 in men and 2.237 in women, which were much smaller than the conventional cut-of values. Odds ratios for multiple cardio-metabolic risk factors of subjects with vs. subjects without a high TG/HDL-C ratio in men and women were 5.75 (4.43–7.46) and 18.76 (10.32–34.13), respectively, by using the new cut-off values and they were 5.03 (3.96–6.39) and 16.11 (9.20–28.20), respectively, by using the conventional cut-off values. The odds ratios for visceral obesity, hypertension and diabetes were comparable when using these two different cut-off values. Conclusion Cut-off values should be ideally calculated by ROC analysis. However, the discrimination power of cut-off values for the TG/HDL-C ratio calculated by ROC analysis for cardio-metabolic risk was similar to those by using the conventional cut-off values. Further studies using cardiovascular events as outcomes in the analysis may be needed to determine more suitable cut-off values of the TG/HDL-C ratio.

Background Smoking is a major risk factor for dyslipidemia. However, it remains to be clarified whether light smoking in Asian women affects lipid profiles and lipid-related indices. The aim of this study was to determine the relationships between lipid-related indices and smoking in Japanese women. Alcohol drinking influences blood lipid levels and is a potent confounder for the relationship between smoking and blood lipids. Thus, analysis for the relationships between smoking and blood lipid-related indices was also performed after stratification of drinking status. Methods The participants were 18,793 Japanese women aged 35–70 years. A cross-sectional study was performed using a local population-based database. The relationships of smoking with each index were investigated by using analysis of covariance and logistic regression analysis with adjustment for age and other lifestyle factors such as alcohol drinking and regular exercise. Results In multivariate logistic regression analysis, odds ratios of smokers vs. nonsmokers for high ratio of LDL cholesterol to HDL cholesterol (LDL-C/HDL-C), high ratio of triglycerides to HDL cholesterol (TG/HDL-C), high lipid accumulation product (LAP) and high cardio metabolic index (CMI) were significantly higher than the reference level of 1.00 in overall participants (2.17 [1.78–2.66], 1.70 [1.47–1.97], 1.17 [1.08–1.27] and 1.41 [1.30–1.53], respectively), nondrinking participants (2.29 [1.80–2.91], 1.68 [1.39–2.02], 1.21 [1.08–1.36] and 1.46 [1.30–1.63], respectively), and drinking participants (1.96 [1.35–2.85], 1.76 [1.39–2.21], 1.13 [1.01–1.27] and 1.38 [1.22–1.55], respectively). In overall participants, nondrinking participants, and drinking participants, LDL-C/HDL-C, TG/HDL-C, LAP and CMI were significantly higher in smokers than in nonsmokers. In nondrinking participants, triglycerides and LDL cholesterol were significantly higher in smokers than in nonsmokers, while the ratio of waist circumference to height and HDL cholesterol were significantly lower in smokers than in nonsmokers. Conclusion In women, all of the four lipid-related indices tested were higher in smokers than in nonsmokers, and these associations were independent of alcohol drinking. The high levels of the lipid-related indices in smokers result from the detrimental effects of smoking on levels of blood lipids such as triglycerides, HDL cholesterol and LDL cholesterol.

Background. Habitual alcohol drinking has been shown to be associated with incidental diabetes and glycemic status. The aim of this study was to determine the relationships between alcohol drinking and peripheral blood cell counts in patients with diabetes. Methods. The participants (n = 333) were Japanese male workers with diabetes aged 32–65 years (mean age: 52.9 years). Relationships of frequency of habitual alcohol drinking with peripheral blood cell-related variables were investigated in middle-aged men with diabetes. Results. Erythrocyte and leukocyte counts were significantly lower in regular drinkers than in nondrinkers, while platelet count, hemoglobin concentration and hematocrit were not significantly different between regular drinkers and nondrinkers. Mean corpuscular hemoglobin and mean corpuscular volume were sig-nificantly higher in regular drinkers than in nondrinkers. Both serum γ-glutamyl transpeptidase and HDL cholesterol levels tended to be higher with an increase of frequency of drinking. Conclusions: There are inverse associations of habitual alcohol drinking with erythrocyte count and leukocyte counts but not with platelet count in men with diabetes.

BackgroundResveratrol has been shown to inhibit platelet aggregation. However, the mechanism for this action of resveratrol remains to be clarified. The purpose of this study was to elucidate the Ca2+-related mechanism for the inhibitory action of resveratrol on platelet aggregation.MethodsCa2+entry and subsequent aggregation of human platelets induced by different stimulants including thrombin, thapsigargin, and 1-oleoyl-2-acetylglycerol (OAG) were measured by the fluorescence method and light transmittance method, respectively. Each stimulant was added to a nominally Ca2+-free medium containing platelets, and then CaCl2was added to the medium to induce Ca2+influx into platelets.ResultsThapsigargin-induced Ca2+entry into platelets and subsequent platelet aggregation were significantly inhibited in the presence of resveratrol at 6.25 μM or higher concentrations, while OAG-induced Ca2+entry and subsequent platelet aggregation were not affected by resveratrol at concentrations up to 50 μM. In the nominally Ca2+-free medium, thrombin induced a small transient increase in intracellular Ca2+concentrations, which was attenuated in the presence of resveratrol at 12.5 μM or higher concentrations. Thrombin-induced Ca2+entry into platelets and subsequent platelet aggregation were significantly inhibited in the presence of resveratrol at 12.5 μM or higher concentrations.ConclusionsThe results suggest that resveratrol inhibits thrombin-induced platelet aggregation through decreasing Ca2+release from its stores and inhibiting store-operated Ca2+influx into platelets.

Background: Anemia is induced by chronic alcohol abuse. However, it remains to be clarified whether a habitual alcohol intake affects erythrocyte-related indices in a general population. Methods: The subjects were 16,014 Japanese male workers aged 30–65 years. The subjects were divided into non-, occasional, and regular drinkers based on the frequency of alcohol consumption. Regular drinkers were further quantitatively divided based on their daily alcohol consumption into light, moderate, and heavy drinkers. Relationships between alcohol drinking and erythrocyte-related indices were investigated. Results: Erythrocyte counts and hemoglobin levels tended to be lower and higher, respectively, with increases in the frequency and amount of drinking. In logistic regression analysis, the odds ratios (OR) for abnormally low erythrocyte counts of moderate and heavy drinkers vs. nondrinkers were significantly higher than the reference level of 1.00 and the values tended to be higher with an increase in the alcohol intake. The OR vs. nondrinkers for abnormally low levels of hemoglobin and hematocrit were significantly lower than the reference level in all of the drinker groups and they were lowest in light drinkers among the drinker groups. Conclusion: A habitual alcohol intake has different associations with erythrocyte counts and hemoglobin and with low erythrocyte counts and low hemoglobin. Thus, alcohol is thought to have diverse effects on erythropoiesis.

Non-small cell lung cancer (NSCLC) accounts for over 80% of all diagnosed lung cancer cases. Lung cancer is the leading cause of cancer-related deaths worldwide. Most NSCLC cells overexpress vascular endothelial growth factor-A (VEGF-A) which plays a pivotal role in tumour angiogenesis. Anti-angiogenic therapies including VEGF-A neutralisation have significantly improved the response rates, progression-free survival and overall survival of patients with NSCLC. However, the median survival of these patients is shorter than 18 months, suggesting that NSCLC cells secrete VEGF-independent angiogenic factors, which remain unknown. We aimed to explore these factors in human NSCLC cell lines, A549, Lu99 and EBC-1 using serum-free culture, to which only EBC-1 cells could adapt. By mass spectrometry, we identified 1,007 proteins in the culture supernatant derived from EBC-1 cells. Among the identified proteins, interleukin-8 (IL-8), macrophage migration inhibitory factor (MIF), galectin-1, midkine (MK), IL-18, galectin-3, VEGF-A, hepatoma-derived growth factor (HDGF), osteopontin (OPN), connective tissue growth factor (CTGF) and granulin (GRN) are known to be involved in angiogenesis. Tube formation, neutralisation and RNA interference assays revealed that VEGF-A and HDGF function as angiogenic factors in EBC-1 cells. To confirm whether VEGF-A and HDGF also regulate angiogenesis in the other NSCLC cell lines, we established a novel culture method. NSCLC cells were embedded in collagen gel and cultured three-dimensionally. Tube formation, neutralisation and RNA interference assays using the three-dimensional (3D) culture supernatant showed that VEGF-A and HDGF were not angiogenic factors in Lu99 cells. By gene microarray in EBC-1 and Lu99 cells, we identified 61 mRNAs expressed only in Lu99 cells. Among these mRNAs, brain-derived neurotrophic factor (BDNF), fibroblast growth factor-2 (FGF-2) and FGF-5 are known to be involved in angiogenesis. Tube formation and neutralisation assays clarified that FGF-2 functions as an angiogenic factor in Lu99 cells. These results indicate that HDGF enhances VEGF-dependent angiogenesis and that FGF-2 is a VEGF-independent angiogenic factor in human NSCLC cells.

Cardiometabolic index (CMI), calculated as the product of waist-to-height ratio and triglycerides-to-HDL cholesterol ratio, has been proposed as a discriminator of diabetes and has been reported to be associated with progression of atherosclerosis. The purpose of this study was to determine the relationship between alcohol drinking and CMI in men with diabetes.The subjects were Japanese male workers aged from 35 to 65 years with diabetes mellitus (n = 1411). The subjects were divided by average daily alcohol consumption (g ethanol/day) into 4 categories of alcohol drinking (nondrinkers; light drinkers,22; moderate drinkers, ≥ 22 and44; heavy drinkers, ≥ 44). CMI and variables comprising CMI were compared in the nondrinker and each of the drinker groups. Age, habits of smoking and regular exercise, and a present history of medication therapy for diabetes were adjusted in each analysis.Log-transformed CMI was significantly lower in light and moderate drinkers than in nondrinkers. Waist-to-height ratio was significantly lower in moderate drinkers than in nondrinkers, while log-transformed triglycerides was significantly higher in heavy drinkers than in nondrinkers. HDL cholesterol tended to be higher with an increase of alcohol consumption. Odds ratios with their 95% confidence intervals vs. nondrinkers for high CMI were 0.53 (0.36-0.78) in light drinkers, 0.61 (0.46-0.80) in moderate drinkers, and 0.74 (0.55-1.00) in heavy drinkers.In men with diabetes, CMI is lower in light-to-moderate drinkers than in nondrinkers, and this results mainly from a positive association between alcohol drinking and HDL cholesterol.

Blood HDL cholesterol and LDL cholesterol levels are known to be higher and lower, respectively, in drinkers than in nondrinkers, and the beneficial effects of alcohol on cholesterol metabolism are thought to mainly explain the lower risk for ischemic heart disease in light-to-moderate drinkers than in nondrinkers. However, it remains unknown whether sensitivities of HDL and LDL cholesterol levels to alcohol are different or not. The subjects of this study were 21,572 middle-aged Japanese men, and they were divided into three tertile groups for blood HDL cholesterol levels. The relationships between habitual alcohol intake and LDL cholesterol levels were investigated in each tertile for HDL cholesterol. In all of the tertile groups for HDL cholesterol, mean LDL cholesterol levels were significantly lower in the drinking subgroups than in the nondrinking subgroup and tended to be lower with an increase of alcohol intake. In all of the tertile groups for HDL cholesterol, odds ratios for high LDL cholesterol of each drinking subgroup vs. the nondrinking subgroup were significantly lower than the reference level of 1.00, and also tended to be lower with an increase of alcohol intake. The odds ratios of each drinking subgroup tended to be lower in the 1st tertile group for HDL cholesterol than in the 3rd tertile group. Drinkers in the 1st tertile for HDL cholesterol are thought to have relatively low sensitivity of HDL cholesterol to alcohol, but clearly showed lower LDL cholesterol levels than those found in nondrinkers. Therefore, the sensitivity of LDL cholesterol level to alcohol is different from the sensitivity of HDL cholesterol level to alcohol.

The aim of this study was to clarify the relationship between drinking and metabolically healthy status in men with normal weight, overweight and obesity.The subjects were Japanese men aged from 35 to 60 years (n=31781) and they were divided by daily amount of drinking (g ethanol) into light (22), moderate (≥22 and44), heavy (≥44 and66) and very heavy (≥66) drinkers. Metabolically healthy subjects were defined as those without hypertension, dyslipidemia and diabetes.The percentage of metabolically healthy subjects was much lower in the overweight (BMI≥25 and30) and obese (BMI≥30) groups than in the normal weight group (BMI≥18.5 and25) and was much lower in the obese group than in the overweight group. In each of the normal weight and overweight groups, percentages of metabolically healthy subjects were significantly lower in heavy and very heavy drinkers than in nondrinkers and were marginally significantly higher in light drinkers than in nondrinkers. The above associations between drinking and metabolically healthy status were confirmed by logistic regression analysis. In the obese group, the percentage of metabolically healthy subjects was significantly lower in regular drinkers (including all drinker categories) than in nondrinkers, and metabolically healthy subjects were rare (0.56%) among regular drinkers.Regardless of absence and presence of overweight or obesity, excessive alcohol drinking is inversely associated with metabolically healthy status and should be avoided for prevention of cardiovascular disease.

Alcohol inhibits platelet function, and platelet count is often reduced in individuals with alcohol use disorder. However, the relation of habitual alcohol drinking with platelet count in a general population remains to be determined. The participants were 6508 men (30 ~ 69 years old) who had received annual health checkup examinations, and most of them (98.6%) were nondrinkers or drinkers with an average ethanol intake of less than 66 g per day. Relationships of platelet count with alcohol intake were investigated by using analysis of covariance and multivariate linear and logistic regression analyses. Platelet count was significantly correlated with age, smoking, γ-glutamyl transpeptidase, body mass index and leukocyte count, which were thus used as explanatory variables in the multivariate analyses. Mean platelet counts in light (

Aim: We investigated the relationships of serum uric acid levels with the progression of atherosclerosis in patients with peripheral arterial disease (PAD) after treatment. Methods: Subjects were male patients diagnosed with PAD. Atherosclerosis at the common carotid artery was evaluated based on its intima-media thickness (IMT). Leg arterial flow was evaluated by measuring ankle-brachial index (ABI) and exercise-induced decrease in ABI. Results: Among various risk factors including age, blood pressure, adiposity, estimated glomerular filtration rate, and blood lipid, blood glucose, uric acid, fibrinogen and C-reactive protein levels, only uric acid levels showed significant correlations with ABI [Pearson's correlation coefficient, −0.292 (p < 0.01)] and leg exercise-induced decrease in ABI [Pearson's correlation coefficient, 0.236 (p < 0.05)]. However, there was no significant correlation between uric acid levels and maximum or mean IMT. Odds ratios of subjects with the 3rd tertile versus subjects with the 1st tertile for uric acid levels were significantly higher than the reference level of 1.00 for low ABI [4.44 (95% confidence interval, 1.45–13.65, p < 0.01)] and for high % decrease in ABI after exercise [4.31 (95% confidence interval, 1.34–13.82, p < 0.05)]. The associations of uric acid levels with the indicators of leg ischemia were also found after adjustment for age, history of revascularization therapy, diabetes, smoking, alcohol consumption, body mass index, triglyceride levels, and renal function. Conclusion: Uric acid levels are associated with the degree of leg ischemia in patients with PAD. Further interventional studies are needed to determine whether the correction of uric acid levels is effective in preventing the progression of PAD.

Alcohol is known to inhibit blood coagulation. Patients with diabetes mellitus are prone to show hypercoagulability. However, it remains to be clarified whether and how habitual alcohol drinking affects coagulability in patients with diabetes. The purpose of this study was to determine the relationship between alcohol intake and d-dimer, a sensitive marker of blood coagulation, in patients with diabetes. We investigated the relationship between alcohol intake and d-dimer in plasma of 269 patients with type 2 diabetes by using analysis of covariance and logistic regression analysis after adjustment for age, gender, body mass index, hemoglobin A1c, and histories of smoking and anti-coagulation therapy. Log-transformed d-dimer and HDL cholesterol were significantly lower and higher, respectively, in regular drinkers than in nondrinkers, while there were no significant differences in log-transformed d-dimer and HDL cholesterol in occasional drinkers and nondrinkers. Odds ratios of regular drinkers vs. nondrinkers for high d-dimer (0.46 [0.21-0.98]) and low HDL cholesterol (0.20 [0.08-0.50]) were significantly lower than the reference level, while the odds ratios of occasional drinkers for high d-dimer (1.24 [0.41-3.73]) and low HDL cholesterol (0.43 [0.15-1.25]) were not significantly different from the reference level. HDL cholesterol showed a significant inverse correlation with log-transformed d-dimer both in overall subjects and in nondrinkers. Regular drinking, but not occasional drinking, was associated with lower d-dimer levels, suggesting that habitual alcohol drinking suppresses hypercoagulability in patients with diabetes. There is an alcohol intake-independent inverse association between HDL cholesterol and d-dimer.

Aims The risk of thromboatherosclerotic disease is lower in moderate drinkers than in non-drinkers. We investigated the effects of ethanol on platelet aggregation under a condition with shear stress. Short summary Shear stress-induced formation of platelet thrombi is inhibited by ethanol at its attainable concentrations after drinking. This effect is prominent at the early stage of thrombus formation, being in agreement with inhibitory actions of ethanol on the initial steps of platelet activation such as Ca2+ entry and phospholipase A2 activation. Methods Platelet aggregation was evaluated by using a total thrombus-formation analysis system, and shear rates of 1000 s-1 (low), 1500 s-1 (middle) and 2000 s-1 (high) were loaded to whole blood. The times required to generate increases in flow pressure of 10 kPa (T10), 30 kPa (T30) and 50 kPa (T50) in microchips containing the blood, which depend on the degree of thrombus generation, were recorded. Results Under the conditions of the low-grade and middle-grade shear rates, T10 and T30 were significantly longer in the presence of ethanol at 0.25-1% than in the absence of ethanol. T10 under the condition of the low-grade shear rate and T30 under the conditions of the low-grade and middle-grade shear rates were also significantly longer in the presence of ethanol at 0.125% than in the absence of ethanol. On the other hand, T50 under the conditions of the low-grade and middle-grade shear rates was not significantly different in the absence and presence of ethanol at 0.125, 0.25 and 0.5%. Under the condition of the high-grade shear rate, T10, T30 and T50 were not significantly different in the absence and presence of ethanol at its lower concentrations. Conclusions Ethanol at attainable concentrations inhibits platelet thrombus formation induced by shear stress, and the inhibitory effect of ethanol is prominent at the early stage of thrombus formation.

There is limited information on characterization of individuals with hyper-high-density lipoprotein (HDL) cholesterolemia.The purpose of this study was to investigate the cardiometabolic profile of individuals with hyper-HDL cholesterolemia in comparison with the profile of individuals with normo-HDL cholesterolemia.The subjects were Japanese men and women who had hyper-HDL cholesterolemia (≥100 mg/dL) and their control subjects who had normal HDL cholesterol levels (≥40 and80 mg/dL) and were matched for age or age and alcohol consumption. The cardiometabolic profiles were compared between the hyper- and normo-HDL cholesterolemic groups.Both in men and women, body mass index, waist-to-height ratio, triglycerides, low-density lipoprotein cholesterol, and hemoglobin A1c were significantly lower in subjects with hyper-HDL cholesterolemia than in subjects with normo-HDL cholesterolemia, whereas systolic and diastolic blood pressure levels were not significantly different between the 2 groups. In generalized estimating equation with adjustment for smoking and regular exercise, odds ratios of the hyper- vs normo-HDL cholesterolemic groups were significantly lower than the reference level of 1.00 for high body mass index, high waist-to-height ratio, hypertriglyceridemia, hyper-low-density lipoprotein cholesterolemia, high lipid accumulation product, and metabolic syndrome. The previously mentioned results were obtained both in age-matched analysis and in age- and alcohol intake-matched analysis, although the percentage of regular drinkers was significantly higher in the hyper-HDL cholesterolemic group than in the age-matched control group.Hyper-HDL cholesterolemia was inversely associated with obesity, dyslipidemia, and metabolic syndrome in the analysis using alcohol intake-matched subject groups. Therefore, the association of hyper-HDL cholesterolemia with lower cardiometabolic risk is thought to be independent of habitual alcohol drinking.

Cardiometabolic index (CMI), calculated as a product of waist-to-height ratio and triglycerides-to-HDL cholesterol ratio, is a new index for discriminating diabetes mellitus. Patients with peripheral arterial disease (PAD) are prone to have other atherosclerotic diseases such as coronary artery disease and stroke. The purpose of this study was to clarify the relationships between CMI and indicators of atherosclerotic progression in patients with PAD.The subjects were 63 outpatients with PAD. Relationships of CMI with variables related to atherosclerotic progression were investigated using multivariate linear regression analysis and analysis of covariance with adjustment for age, sex and histories of smoking and alcohol drinking.Log-transformed CMI was significantly correlated with mean intima-media thickness of the common carotid artery (IMT) (standardized regression coefficient: 0.350, p0.01) and % decrease in ankle-brachial systolic pressure index (ABI) after treadmill exercise (standardized regression coefficient: 0.365, p0.01). Mean IMT and % decrease in ABI by treadmill exercise were significantly higher (p0.01) in the group of the 3rd tertile for CMI than in the group of its 1st tertile (mean ± SE: mean IMT (mm), 0.94 ± 0.06 (1st tertile) vs. 0.94 ± 0.06 (2nd tertile) vs. 1.19 ± 0.06 (3rd tertile); % decrease in ABI, 14.1 ± 3.4 [1st tertile] vs. 26.0 ± 3.5 [2nd tertile] vs. 30.0 ± 3.5 [3rd tertile]).CMI was shown to be associated with the degrees of atherosclerosis in the common carotid artery and ischemia in leg arteries and is therefore a useful discriminator of atherosclerotic progression in patients with PAD.

BACKGROUND Plasma concentration of n-3 polyunsaturated fatty acids (PUFAs) has been reported to be associated with renal function in Western populations. However, few studies have investigated the association between serum long-chain n-3 and n-6 PUFA profiles and renal function in a Japanese population with high marine-derived long-chain n-3 PUFA intake. METHODS A cross-sectional study was performed in 549 Japanese rural community-dwellers aged 40 to 64 years. In adjusted analysis of covariance, we assessed the relationship between estimated glomerular filtration rate (eGFR) and tertiles of serum long-chain n-3 and n-6 PUFA profiles ([eicosapentaenoic acid {EPA} + docosahexaenoic acid {DHA}]:arachidonic acid [AA]). GFR was estimated by Japanese specific equations using serum creatinine and cystatin C (eGFRcre and eGFRcys). Using multivariate-adjusted linear regression models, we also assessed the relationships between eGFRs and several n-3 and n-6 PUFAs, which have been suggested to be associated with renal function. RESULTS In all participants, higher dietary fish intake as assessed by a semi-quantitative questionnaire was associated with higher serum value of (EPA+DHA):AA. Participants in the higher (EPA+DHA):AA tertiles had non-significantly higher eGFRcre and significantly higher eGFRcys (P = 0.016). In addition, eGFRcys in T2+T3 of (EPA+DHA):AA was significantly higher than that in T1 (adjusted mean eGFRcys, T1: 87 ml/min/1.73 m(2), T2+T3: 91 ml/min/1.73 m(2); P < 0.01). Among the PUFAs, only (EPA+DHA) was significantly associated with eGFRcys. CONCLUSIONS Serum (EPA+DHA):AA, which reflects an individual's fish intake, might be associated with eGFRcys in Japanese community-dwellers.

Peripheral arterial disease (PAD) is an atherosclerotic obstructive disease of the arteries in lower extremities. Patients with PAD show high rates of mortality from coronary artery disease (CAD) and stroke. Smoking as well as diabetes is an important risk factor for PAD. A lesion of PAD in the lower extremities tends to be more proximal in smokers than in nonsmokers and to be more distal in patients with diabetes than in nondiabetics. By a systematic review, the odds ratio for PAD of smokers vs nonsmokers has been reported to be in the range of 1.7-7.4. Previous epidemiological studies suggest a stronger association of smoking with PAD than that with CAD. Nitric oxide (NO) is an important molecule suppressing the progression of atherosclerosis, but this function is compromised by smoking. Smoking decreases the bioactivity of NO and the expression level of NO synthase. In addition, smoking results in deteriorations of risk factors for atherosclerosis such as decreases in blood HDL (high-density lipoprotein) cholesterol and tissue plasminogen activator levels and increases in the levels of blood triglycerides, LDL (low-density lipoprotein) cholesterol, fibrinogen and the von Willebrand factor. Thus, smoking increases blood coagulability and deteriorates the blood lipid profile, resulting in thrombogenetic proneness and dyslipidemia. Smoking also increases the generation of atherogenic oxidized LDL in blood and decreases antiatherogenic prostacyclin production in the vascular endothelium. Smoking cessation is important for the prevention and therapy of PAD, and to this end, counseling by physicians and nicotine replacement therapy are useful and strongly recommended for patients with PAD.

Background Although ethanol is known to inhibit platelet aggregation, the effects of another variant of alcohol, methanol, have not been reported. The purpose of this study was to determine whether methanol and its metabolite, formic acid, affect Ca2+ entry into and subsequent aggregation of platelets in vitro. Methods Ca2+ entry into and aggregation of human platelets were measured by spectrofluorometry using Fura-2/AM as an indicator and the light transmission method, respectively. Results Thrombin-induced platelet aggregation was significantly augmented by methanol at pharmacological concentrations (0.5–2%) in a concentration-dependent manner. Methanol at 2% significantly attenuated thapsigargin-induced platelet aggregation, which was not significantly affected by lower concentrations (0.5 and 1%) of methanol. Methanol (0.5–2%) did not significantly affect platelet aggregation induced by 1-oleoyl-2-acetyl-sn-glycerol (OAG), or Ca2+ entry into platelets induced by thrombin, thapsigargin, or OAG. Platelet aggregation induced by thrombin, thapsigargin, or OAG was significantly inhibited by formic acid at toxic concentrations (0.01% or higher). Ca2+ entry into platelets induced by thrombin or thapsigargin was also significantly inhibited by formic acid at 0.01% or higher, while that induced by OAG was not affected by formic acid at 0.005 and 0.01% and augmented by that at 0.02%. Conclusions Methanol at pharmacological doses has diverse effects on platelet aggregation, depending on the aggregation stimuli, without affecting Ca2+ entry into platelets. Formic acid at toxic concentrations has an inhibitory action on platelets aggregation, which was partly explained by the reduction of Ca2+ entry into platelets.

Thrombomodulin (TM), a transmembrane glycoprotein on vascular endothelial cells, is a naturally occurring anticoagulant. Recombinant human soluble TM (rTM), composed of the extracellular domain of TM, also shows anti-coagulant and anti-inflammatory activity, but the effects of rTM on microangiopathy remain unclear. We reported that FK506 induced endothelial dysfunction through inactivation of Akt and extracellular-regulated kinase 1/2 using a three-dimensional culture blood vessel model. In the present study, we examined the effects of rTM on FK506-induced endothelial dysfunction. We found that rTM suppressed FK506-induced endothelial cell death, but not the breakdown of capillary-like tube structures. rTM prevented FK506-induced inactivation of Akt, but not of extracellular-regulated kinase 1/2. Akt inhibition by LY294002 abrogated the preventive effect of rTM on FK506-induced Akt inactivation and the suppressive effect of rTM on FK506-induced cell death. These results suggest that rTM attenuates FK506-induced endothelial dysfunction through prevention of Akt inactivation.

Dysfunction of the innate immune system has been reported to cause intestinal inflammation. Vitamin D3 is known to be an important immune system regulator and exerts anti-inflammatory effects. We investigated in vitro effects of vitamin D3 and its derivatives on the innate immune system in HT-29 cells, a line of human colon adenocarcinoma cells. Among the innate immune-related receptors such as Toll-like receptor (TLR) 1, 2, 4, 6, and CD14 examined by flow cytometry, only CD14 was up-regulated by vitamin D3 derivatives. Release of soluble form CD14 (sCD14) was also increased by vitamin D3 derivatives. The 1α,25-dihydroxy-22-oxavitamin D3 (Oxa-D3) induced-sCD14 release was inhibited by U0126 (a specific inhibitor of extracellular signal-regulated kinase; ERK1/2) but not by SB203580 (a specific inhibitor of p38 MAPK), and ERK1/2 phosphorylation was accelerated by Oxa-D3. These results indicate that Oxa-D3 facilitates the release of sCD14 through ERK1/2 activation. IL-8 production stimulated with LPS was diminished by vitamin D3 derivatives. Recombinant sCD14 also lowered the LPS-stimulated IL-8 production, suggesting neutralization of LPS by sCD14. The anti-inflammatory effect of vitamin D3 derivatives was thus associated with diminution of IL-8 production due to increased release of sCD14.

Light-to-moderate alcohol consumption is known to reduce the risk of coronary artery disease.The purpose of this study was to investigate relationships of alcohol intake with atherogenic indices, such as the ratio of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol (LDL-C/HDL-C ratio) and the ratio of triglycerides to high-density lipoprotein cholesterol (TG/HDL-C ratio), in women.Subjects (14,067 women, 20-45 years) were divided by alcohol intake into three groups of nondrinkers, occasional drinkers, and regular drinkers, and each drinker group was further divided into lower- (22 g ethanol/drinking day) and greater- (≥ 22 g ethanol/drinking day) quantity drinkers. Atherogenic indices were compared among the alcohol groups.Odds ratio (OR) for high LDL-C/HDL-C ratio or high TG/HDL-C ratio calculated after adjustment for age, body mass index, smoking, and habitual exercise was significantly lower (P.05) than a reference level of 1.00 in regular or occasional lower- and higher quantity drinkers vs. nondrinkers (OR for high LDL-C/HDL-C ratio, 0.28 (95% confidence interval [95% CI], 0.18-0.44) in regular lower-quantity drinkers, 0.18 (95% CI, 0.12-0.28) in regular higher quantity drinkers, 0.71 (95% CI, 0.61-0.83) in occasional lower-quantity drinkers, and 0.53 (95% CI, 0.44-0.64) in occasional higher quantity drinkers; OR for high TG/HDL-C ratio, 0.52 (95% CI, 0.32-0.85) in regular lower-quantity drinkers, 0.67 (95% CI, 0.47-0.96) in regular higher-quantity drinkers, 0.61 (95% CI, 0.50-0.76) in occasional lower-quantity drinkers, and 0.63 (95% CI, 0.50-0.79) in occasional higher-quantity drinkers. Both LDL-C/HDL-C ratio and log-transformed TG/HDL-C ratio were significantly greater in smokers than in nonsmokers. Both in smokers and nonsmokers, LDL-C/HDL-C ratio and log-transformed TG/HDL-C ratio were significantly lower in regular lower- and higher-quantity drinkers than in nondrinkers. In nonsmokers, LDL-C/HDL-C ratio and log-transformed TG/HDL-C ratio tended to be lower and greater, respectively, in regular greater-quantity drinkers than in regular lower-quantity drinkers.In women, alcohol drinking is inversely associated with atherogenic indices irrespective of smoking status, and the inverse association of alcohol drinking with LDL-C/HDL-C ratio is stronger than that with TG/HDL-C ratio.

Although diacylglycerol kinase (DGK) is known to be expressed in vascular smooth muscle cell, its functional significance remains to be clarified. We hypothesized that DGK is involved in the pathway of cytokine-induced nitric oxide (NO) production in vascular smooth muscle cells. The purpose of this study was to investigate the effects of R59949, a diacylglycerol kinase inhibitor, on inducible nitric oxide production in vascular smooth muscle cell. Cultured rat aortic smooth muscle cells (RASMCs) were used to elucidate the effects of R59949 on basal and interleukin-1β (IL-1β)-induced NO production. The effects of R59949 on protein and mRNA expression of induced nitric oxide synthase (iNOS) and on transplasmalemmal l-arginine uptake were also evaluated using RASMCs. Treatment of RASMCs with R59949 (10 μM) inhibited IL-1β (10 ng/ml)-induced NO production but not basal NO production. Neither protein nor mRNA expression level of iNOS after stimulation with IL-1β was significantly affected by R59949. Estimated enzymatic activities of iNOS in RASMCs were comparable in the absence and presence of R59949. Stimulation of RASMCs with IL-1β caused a marked increase in transplasmalemmal l-arginine uptake into RASMCs. l-Arginine uptake in the presence of IL-1β was markedly inhibited by R59949, while basal l-arginine uptake was not significantly affected by R59949. Both IL-1β-induced NO production and l-arginine uptake were abolished in the presence of cycloheximide (1 μM). The results indicate that R59949 inhibits inducible NO production through decreasing transplasmalemmal l-arginine uptake. DGK is suggested to be involved in cytokine-stimulated l-arginine transport and regulate its intracellular concentration in vascular smooth muscle cell.

TG/HDL ratio has been proposed to be a good predictor of cardiovascular disease. The aim of this study was to determine whether TG/HDL ratio and its association with adiposity index are modified by age and gender. Subjects were younger (35-40 years) and older (60-70 years) Japanese men and women (n=16,825) receiving health checkup examinations. TG/HDL ratio and its relationship with adiposity index such as waist-to-height ratio (WHtR) were compared between the age pair and between the gender pair. Log-transformed TG/HDL ratio was significantly higher in older women than in younger women, while log-transformed TG/HDL ratio was comparable in younger and older men. The odds ratio (OR) for high TG/HDL ratio in subjects with vs. subjects without high WHtR was significantly lower in older men and women than in younger men and women, respectively. The OR was significantly lower in younger men than in younger women [4.08 (3.63-4.58) (younger men) vs. 8.42 (5.55-12.78) (younger women), p

The aim of this study was to clarify the role of diacylglycerol kinase (DGK)γ in vascular endothelial cells. The mRNA and protein expression of DGKγ and inducible nitric oxide synthase (iNOS) in rat aortic endothelial cells (RAECs) were investigated using RT-PCR, immunocytochemical, and immunoblot analyses. In RAECs, immunoreactivity of DGKγ was detected in the cytoplasm as a tubular or reticular structure. DGKγ immunoreactivity colocalized with those for GM130 and Golgin 97 but not with that for protein disulfide isomerase (PDI). In the presence of brefeldin A, DGKγ immunoreactivity was markedly decreased and displayed an aggregation-like pattern. After treatment of RAECs with nocodazole, DGKγ immunoreactivity was detected in Golgi stacks, which were severely segmented and appeared in vesicular shape. Stimulation with IL-1β increased mRNA expression of DGKγ, which was strongly attenuated by SB203580, a p38 MAPK inhibitor. IL-1β also induced expression of iNOS, which was observed as a tubular structure, and this distribution coincided with DGKγ immunoreactivity. Brefeldin A reduced both iNOS immunoreactivity and DGKγ immunoreactivity. iNOS expression was impaired by DGK inhibitors, R59022 and R59949. These results suggest that DGKγ is upregulated by IL-1β through the p38 MAPK pathway and may be involved in protein trafficking of iNOS in vascular endothelial cells.

Objectives The aim of this study was to determine whether diacylglycerol kinase (DGK) is involved in transplasmalemmal Ca2+ influx of platelets. Methods Effects of R59949, an inhibitor of diacylglycerol kinase, on intracellular Ca2+ concentration ([Ca2+]i) and mRNA expression of DGK isozymes were investigated using washed human platelet suspensions. Key findings Thrombin-induced increase in [Ca2+]i was significantly inhibited by pretreatment of platelets with R59949, while thapsigargin-induced increase in [Ca2+]i was comparable in platelets with and without R59949 pretreatment. Thapsigargin-induced increase in [Ca2+]i was markedly attenuated in the presence of SKF-96365. In the presence of SKF-96365, thrombin-induced increase in [Ca2+]i was significantly attenuated, and additional treatment with R59949 caused a further decrease in [Ca2+]i. Pretreatment of platelets with 1-butanol significantly attenuated thrombin-induced increase in [Ca2+]i, while thrombin-induced increase in [Ca2+]i was augmented in the presence of propranolol. mRNA expression of DGK-α and DGK-γ, which are known to be inhibited by R59949, in platelets was confirmed by RT-PCR analysis. Conclusions R59949 inhibited a store-depletion-insensitive component of transplasmalemmal Ca2+ entry induced by thrombin, while store-operated Ca2+ entry was not affected by R59949. The results of this study suggest that phosphatidic acid is involved in thrombin-induced Ca2+ influx of platelets.

Objective: The aim of this study was to determine whether obesity influences relationships between habitual alcohol drinking and hemoglobin A1C (HbA1C) level. Methods: Japanese men (35–70 years old, n = 24858) were divided into non-, light (1C were investigated in overall subjects and subjects of quartile groups for degree of obesity. Results: HbA1C tended to be higher as quartiles of BMI and waist-to-height ratio increased. HbA1C was significantly lower in light, moderate and heavy drinkers than in nondrinkers. These associations in overall subjects were also found in all of the quartiles of BMI and waist-to-height ratio, except for light drinkers in the 3rd and 4th quartiles of BMI and the 4th quartile of waist-to-height ratio. Odds ratios versus nondrinkers for high HbA1C were significantly lower than a reference level of 1.0 in all drinker groups, and these associations were not altered after adjustment for age, history of smoking, and BMI or waist-to-height ratio. Conclusion: The results suggest that alcohol consumption is associated with lower HbA1C level independent of degree of obesity.

Summary Cellulose acetate (CA) beads are often used for leucocyte apheresis therapy against inflammatory bowel disease. In order to clarify the mechanism of the anti-inflammatory effects of CA, global analysis of the molecules generated in blood by the interaction with CA beads was performed in this study. An activated medium was collected from whole blood that had been preincubated with CA beads, and the effects of the CA-activated medium on leucocyte function were investigated. Fresh blood was stimulated with lipopolysaccharide (LPS) or interferon (IFN)-β in the presence of the activated medium, and levels of chemokines and cytokines, including CXCL10 (IFN-inducible protein-10), and phosphorylated STAT1 (signal transducer and activator of transcription 1), which is known to be essential for CXCL10 production in leucocytes, were measured. IFN-β- or LPS-induced CXCL10 production, expression of CXCL10 mRNA and phosphorylation of STAT1 were significantly reduced in the presence of the medium pretreated with CA beads compared with the control without the CA bead treatment. The factors inhibiting CXCL10 production were identified as the C3 and C4 fragments by mass spectrometry. The monomeric C3bi and C4b proteins were abundant in the medium pretreated with CA beads. Furthermore, purified C3bi and C4b were found to inhibit IFN-β-induced CXCL10 production and STAT1 phosphorylation. Thus, STAT1-mediated CXCL10 production induced by stimulation with LPS or IFN was potently inhibited by monomeric C3bi and C4b generated by the interaction of blood with CA beads. These mechanisms mediated by monomeric C3bi and C4b may be involved in the anti-inflammatory effects of CA.

Alcohol and tobacco are important modifiable risk factors for prevention of atherosclerosis and cardiovascular disease. There is a strong association between habitual alcohol drinking and smoking. Alcohol shows diverse effects on progression of atherosclerosis mainly through its blood pressure–elevating and high-density lipoprotein (HDL) cholesterol–raising actions. In addition to atherogenic actions, smoking modifies associations between alcohol consumption and cardiovascular risk factors. A positive association of alcohol consumption with blood pressure and inverse associations of alcohol consumption with low-density lipoprotein (LDL) cholesterol and non-HDL cholesterol were more prominent in smokers than in nonsmokers. Both in smokers and nonsmokers, HDL cholesterol tended to be higher with an increase in alcohol consumption. Therefore, blood pressure elevation and LDL cholesterol reduction by drinking are suggested to be greater in smokers than in nonsmokers. Further prospective studies on whether and how smoking influences associations of alcohol consumption with atherosclerotic risk factors and cardiovascular events are needed.

The aim of this study was to determine the relationships of risk factors for atherosclerosis with oxidized low-density lipoprotein (OxLDL) evaluated by a new enzyme immunoassay for measurement of LOX-1 (lectin-like OxLDL receptor) ligand.Subjects were 236 healthy men aged 33-62 years. LOX-1 ligand containing apoB (LAB) was measured by an enzyme-immunoassay using immobilized recombinant LOX-1 and anti-ApoB monoclonal antibody.In simple regression analysis, log-converted LAB showed significant positive correlations with history of smoking, waist circumference, diastolic blood pressure, LDL cholesterol, log-converted triglycerides, uric acid and white blood cell count and showed a significant negative correlation with HDL cholesterol. In multiple regression analysis using history of smoking, history of drinking, waist circumference, diastolic blood pressure, HDL cholesterol, log-converted triglycerides and uric acid as explanatory variables, log-converted LAB showed significant correlations only with history of smoking and log-converted triglycerides. Log-converted LAB was significantly higher in heavy smokers (≥20 cigarettes per day) than in nonsmokers and light smokers (20 cigarettes per day), while no difference in log-converted LAB was found between nonsmokers and light smokers. Log-converted LAB was significantly higher in subjects with hypertriglyceridemia (≥150 mg/dl), large waist circumference (≥85 cm), high diastolic blood pressure (≥85 mmHg), or metabolic syndrome defined by the NCEP-ATP III criteria than in subjects without each risk factor or metabolic syndrome.Hypertriglyceridemia and smoking are determinants of LOX-1 ligand activity in healthy men and are thus thought to be crucial risk factors for initiation of atherosclerotic progression through generation of OxLDL.

Eur J Clin Invest 2011 Abstract Background and objectives Habitual alcohol drinking influences blood cholesterol profile, and dyslipidaemia often accompanies obesity. The aim of this study was to determine whether obesity modifies relationships between alcohol intake and blood cholesterol profile. Methods Japanese men aged 35–60 years (n = 23 834) were divided into two groups by body mass index (BMI) (normal BMI: ≥ 18·5 and

The aim of this study was to determine the relationship of alcohol intake with metabolic syndrome in obese people.Japanese men (35-65 years, n = 7250) who showed high body mass index (25 kg/m(2) or over) were divided into four groups by alcohol intake [non-, light (22 g ethanol/day), heavy (≥22 and44 g ethanol/day) and very heavy (≥ 44 g ethanol/day) drinkers]. Odds ratios for metabolic syndrome were calculated after adjustment for age and history of smoking.Prevalence of metabolic syndrome was significantly higher in very heavy drinkers than in nondrinkers and was significantly lower in light drinkers than in heavy and very heavy drinkers. The odds ratio vs. nondrinkers for metabolic syndrome was significantly low in light drinkers (odds ratio [OR] = 0.84, 95% confidence interval [CI]: 0.71-0.98, p0.05), was not significant in heavy drinkers (OR = 1.01, 95% CI: 0.90-1.13), and was significantly high in very heavy drinkers (OR = 1.23, 95% CI: 1.08-1.40, p0.01).In Japanese men with overweight or obesity, there are significant inverse and positive associations of light and excessive alcohol consumption, respectively, with metabolic syndrome.

Background: Relationships between alcohol consumption and risks for metabolic syndrome in general populations are very controversial. It is unknown whether age influences the relationship between alcohol intake and the prevalence of metabolic syndrome. Objective: The purpose of this study was to determine whether age influences the relationship between alcohol consumption and metabolic syndrome. Methods: Men aged ≧35 and Results: Both in the younger and older groups, ORs for high blood pressure and low HDL cholesterol were significantly high and low, respectively, in all drinker groups. In younger subjects, the OR for large waist circumference was significantly low in light drinkers, and the OR for high hemoglobin A1c was significantly low in light and heavy drinkers, while these associations were not found in older subjects. The OR for metabolic syndrome was significantly low in light and heavy drinkers in the younger subjects but was not significant in any drinker groups in older subjects. Conclusion: Age influences the relationships between alcohol consumption and atherosclerotic risk factors, and there is a significant association between alcohol intake and a lower risk for metabolic syndrome in young men but not in elderly men.

Aim: Results of previous studies on the relationship between habitual alcohol drinking and metabolic syndrome in a general population are not consistent, and this relationship in patients with diabetes is unknown. The aim of this study was to clarify the relationship of alcohol consumption with meta-bolic syndrome in patients with diabetes.Methods: Japanese male workers with diabetes (n = 1960) were divided into non-, light (< 22 g ethanol/day), heavy (≥ 22 and < 44 g ethanol/day) and very heavy (≥ 44 g ethanol/day) drinkers. Re-lationships of alcohol consumption with visceral obesity evaluated by waist circumference, high blood pressure, dyslipidemia (high triglycerides and/or low HDL cholesterol), hyperglycemia, and metabolic syndrome (3 or more of these risk factors by the NCEP-ATP III criteria) were investigated.Results: Odds ratio vs. nondrinkers for high blood pressure was significantly high in all drinker groups, while odds ratio vs. nondrinkers for low HDL cholesterol was significantly low in all drinker groups. Odds ratio vs. nondrinkers for high triglycerides was significantly low in light drinkers and was significantly high in very heavy drinkers. Odds ratio vs. the nondrinker group for large waist circumference was not significant in any drinker groups. Odds ratio vs. nondrinkers for metabolic syndrome was significantly high in very heavy drinkers but was not significant in light and heavy drinkers.Conclusion: Excessive alcohol intake is associated with a higher risk for metabolic syndrome through elevations of blood pressure and triglycerides in Japanese male patients with diabetes.

This study investigated relationships between alcohol intake and multiple risk factors for atherosclerosis in smokers and nonsmokers. Men aged 35 to 54 years (n = 27 005) were divided into 6 groups by ethanol intake. The prevalence of multiple (≥3 or ≥4) risk factors, including obesity, high blood pressure, high total cholesterol, triglyceride and fasting blood glucose, and low high-density lipoprotein (HDL) cholesterol, was compared among the groups in smokers and nonsmokers. Smokers and nonsmokers showed U- and J-shaped relationships, respectively, between alcohol intake and prevalence of multiple risk factors. Odds ratios of drinkers versus nondrinkers for multiple risk factors were significantly low in very light, light, moderate, and heavy drinkers in smokers and were significantly low in light and moderate drinkers but not in very low and heavy drinkers in nonsmokers. There is a U- or J-shaped relationship between alcohol consumption and multiple risk factors for atherosclerosis, and this relationship is modified by smoking.

Serum non-HDL cholesterol is a strong predictor of cardiovascular diseases. We studied the relationship between habitual alcohol drinking and non-HDL cholesterol.Healthy male subjects (n = 27,005) and female subjects (n = 16,805) were divided into 5 groups by average daily ethanol intake. Serum non-HDL cholesterol level and prevalence of serum high non-HDL cholesterol (or = 170 mg/dl) were compared among the groups.Non-HDL cholesterol level and prevalence of high non-HDL cholesterol became lower as alcohol intake increased. The threshold alcohol intake in the drinker groups showing significantly lower non-HDL cholesterol level and significantly lower prevalence of high non-HDL cholesterol, compared with those in non-drinkers, was lower in women (10 g/d) than in men (or = 10 and20 g/d). Odds ratios of each drinker group vs. the non-drinker group for high non-HDL cholesterol became lower as alcohol intake increased. The odds ratio of each drinker group vs. the non-drinker group for high non-HDL cholesterol tended to be lower in women than in men.The results suggest that even light drinking is sufficient to significantly lower serum non-HDL cholesterol and that this effect of alcohol drinking on non-HDL cholesterol is more pronounced in women than in men.

The expression pattern of diacylglycerol kinase (DGK) and the biological significance of DGKepsilon in vascular smooth muscle cells were investigated. mRNA expression for DGKalpha, DGKepsilon, and DGKzeta was detected in isolated rat aortic smooth muscle cells (RASMCs) and A7r5 cells by reverse transcription with polymerase chain reaction analysis. An immunocytochemical study revealed intense DGKepsilon in a filamentous pattern, parallel to the long axis of cell, and on actin stress fibers as shown by double-staining with fluorescent phalloidin. DGKalpha was detected sparsely in the cytoplasm and nucleus, and DGKzeta was observed as a granular pattern in the nucleus. In order to elucidate the functional significance of DGKepsilon, its immunoreactivity was examined in RASMCs incubated with serotonin, a vasoconstrictive agonist. When RASMCs were stimulated with serotonin, the cells lost their polarization and shortened, i.e., contracted. In RASMCs contracted by serotonin, DGKepsilon was detected diffusely in the cytoplasm without a filamentous stress fiber pattern. Protein and mRNA expression of DGKepsilon in RASMCs was significantly increased by stimulation with serotonin. Inhibition of Rho-associated kinases by Y-27632 or inhibition of actin polymerization by cytochalasin B resulted in a decrease in the intensity of DGKepsilon immunoreactivity on stress fibers. The results suggest that DGKepsilon interacts with actin stress fibers and is involved in their stability in vascular smooth muscle cells.

Alcohol intake and smoking have been reported to influence atherosclerotic progression.The purpose of this study was to determine whether the associations of alcohol intake with blood pressure (BP) and serum lipid concentrations are modified by smoking in Japanese women.Eligible subjects were healthy female Japanese workers aged 35 to55 years who had received periodic health examinations at workplaces in Yamagata Prefecture in Japan. Subjects were classified as smokers or nonsmokers and subclassified into 3 subgroups based on average daily reported alcohol intake: nondrinkers, light drinkers (15 g/d), and heavy drinkers (-15 g/d). The means of each variable (systolic and diastolic BP [SBP and DBP, respectively] and serum concentrations of total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides) were compared among the 2 groups of smoking history and 3 subgroups of alcohol intake after adjusting for age and body mass index.A total of 16,805 healthy women were enrolled (14,695 nonsmokers, 2110 smokers). In smokers, SBP was significantly higher in heavy drinkers than in nondrinkers, and DBP was significantly higher in light drinkers and heavy drinkers than in nondrinkers (all, P0.01). In nonsmokers, SBP was not significantly higher in light drinkers and heavy drinkers versus nondrinkers, and the difference in DBP between heavy drinkers and nondrinkers was significant (P0.01), but that between light drinkers and nondrinkers was not. In smokers but not in nonsmokers, serum TC concentration was significantly lower in heavy drinkers than in nondrinkers. In smokers and nonsmokers, LDL-C was significantly lower in light and heavy drinkers than in nondrinkers (all, P0.01), and serum HDL-C was significantly higher in light and heavy drinkers than in nondrinkers (all, P0.01). The differences in mean LDL-C between light and heavy drinkers versus nondrinkers were numerically greater in smokers than in nonsmokers.In this sample of women in Japan, serum LDL-C concentration was significantly lower in drinkers than in nondrinkers, and smoking might increase this association between alcohol intake and lowered LDL-C.

Aims: The reduction of habitual alcohol drinking is recommended for the prevention of hypertension. Daily or weekly alcohol consumption, which is used for evaluation of the effects of alcohol drinking on blood pressure, is usually not corrected by body weight. In this study, the influence of body weight on the relationship between alcohol intake and blood pressure was investigated. Methods: The subjects (27,005 healthy men at ages of 35–54 years) were divided into four groups by average daily ethanol intake [non-, light (

BACKGROUND The purpose of this study was to determine whether gender influences the association of alcohol drinking with blood pressure. METHODS The subjects (43,810 healthy men and women at ages of 35-54 years) were divided into five groups by average daily ethanol intake (non-, very light (

Using hippocampal slices, we found that chronic ethanol consumption by rats induces tolerance to the impairing effects of acute ethanol treatment on induction of long-term potentiation (LTP) in CA1 neurons. In hippocampal slices from pair-fed control rats, stable LTP was induced by tetanic stimulation consisting of 25 or more pulses at 100 Hz, but not by tetanic stimulation of 15 pulses at 100 Hz, and LTP induction was blocked if the tetanus was delivered in the presence of 8.6 mM ethanol, 1 microM muscimol, a gamma-aminobutyric acid (GABA) A receptor agonist, or 2.5 microM dl-2-amino-5-phosphonovaleric acid (AP5), an N-methyl-d-aspartate (NMDA) receptor antagonist. In hippocampal slices from rats chronically fed a liquid diet containing ethanol, a tetanus consisting of 15 pulses at 100 Hz did induce stable LTP, indicating a decrease in the stimulation threshold for inducing LTP. Application of ethanol, muscimol, or AP5 did not affect LTP induction in these cells, suggesting that the effects of chronic ethanol exposure on LTP induction are mediated by a reduction in GABAergic inhibition or an increase in NMDA receptor activity in hippocampal CA1 neurons.

Effects of docetaxel, a taxane-derivative anti-cancer drug, on lipopolysaccharide (LPS)-induced nitric oxide (NO) synthesis were investigated in alveolar macrophages isolated from rats. LPS-induced NO production and inducible NO synthase (iNOS) expression were significantly enhanced in the macrophages isolated from rats injected intraperitoneally with docetaxel (4 mg/kg body weight per day for 5 consecutive days) compared with those in macrophages from control rats administrated a vehicle. In vivo administration of docetaxel augmented LPS-induced p38 activation but not extracellular signal-related kinase (ERK) activation in isolated macrophages. On the other hand, in vitro treatment of macrophages with docetaxel (5 and 10 microg/ml) inhibited LPS-induced NO production and iNOS expression. Levels of lactate dehydrogenase released from macrophages were neither affected by in vitro treatment with docetaxel (up to 10 microg/ml) nor by its in vivo administration. These results suggest that docetaxel has an enhancing action in vivo on LPS-induced iNOS expression and subsequent NO production through stimulation of p38 activity in alveolar macrophages.

Habitual alcohol drinking affects both blood pressure and serum lipids. I investigated the relationships among alcohol drinking, blood pressure and atherogenic index defined by serum total and HDL cholesterol levels in young women.The subjects were young (20-39 y) healthy female workers (n=7887) receiving annual health checkups. Blood pressure was compared in subjects divided into groups according to average daily alcohol consumption (non-drinkers; light drinkers,15 g/day ethanol; moderate-to-heavy drinkers,or =15 g/day ethanol) and in subjects divided into tertile groups of atherogenic index calculated as (total cholesterol-HDL cholesterol)/HDL cholesterol.When overall subjects were analyzed, systolic and diastolic blood pressure in light and moderate-to-heavy drinkers was not significantly different from that in non-drinkers. Total cholesterol levels and atherogenic index were significantly lower and HDL cholesterol was significantly higher in the light and moderate-to-heavy drinker groups than in the non-drinker group. Atherogenic index and HDL cholesterol were also significantly lower and higher, respectively, in the moderate-to-heavy drinker group than in the light drinker group. In the lowest tertile group of atherogenic index, systolic and diastolic blood pressure after adjustment for age, body mass index, smoking history and atherogenic index was significantly higher in the moderate-to-heavy drinker groups than in the non-drinker group, while systolic and diastolic blood pressure was not different among the 3 alcohol consumption groups in the highest tertile group of atherogenic index. In non-, light and moderate-to-heavy drinker groups, systolic and diastolic blood pressure was significantly higher in the highest tertile group of atherogenic index than in the lowest and middle tertile groups.Habitual alcohol drinking is related to blood pressure in young women with low atherogenic index but not in those with high atherogenic index, while blood pressure is associated with atherogenic index independently of alcohol drinking.

Hypo-HDL cholesterolemia is a potent cardiovascular risk factor, and HDL cholesterol level is influenced by lifestyles including alcohol drinking, smoking and regular exercise. The aim of this study was to clarify the relationships between hypo-HDL cholesterolemia and cardiovascular risk factors and to determine whether or not these relationships depend on the above-mentioned lifestyles.The subjects were 3456 men and 2510 women (35-60 years of age) showing low HDL cholesterol levels (40mg/dl for men and50mg/dl for women) and their age-matched control subjects showing normal HDL cholesterol levels. Each cardiometabolic risk factor was compared between the groups with and without hypo-HDL cholesterolemia. Data for hypo-HDL cholesterolemic subjects not having habits of alcohol drinking, smoking and regular exercise (men, n=333; women, n=1410) and their age-matched control subjects were also analysed.Both in men and in women of overall subjects and subjects without histories of alcohol drinking, smoking and regular exercise, odds ratios of subjects with hypo-HDL cholesterolemia vs. subjects with normo-HDL cholesterolemia for high body mass index, high waist-to-height ratio, high triglycerides, high lipid accumulation product and multiple risk factors (three or more out of obesity, hypertension, dyslipidaemia and diabetes) were significantly higher than the reference level of 1.00. These associations in overall subjects were found when the above habits were adjusted.Hypo-HDL cholesterolemic men and women have adverse cardiovascular profiles, such as obesity, hypertriglyceridemia and multiple risk factors, independently of age, alcohol drinking, smoking and regular exercise.

Cardiometabolic index (CMI) is a new index for discriminating diabetes mellitus and has been demonstrated to be associated with the degree of atherosclerosis in patients with peripheral arterial disease. The purpose of this study was to clarify the relationship of CMI with smoking, a major risk factor for atherosclerotic disease.The subjects included 31,742 Japanese men (35 - 60 years old) receiving health-checkup examinations at their workplaces. CMI was calculated as a product of waist-to-height ratio and triglycerides-to-HDL cholesterol ratio. Relationships between CMI and smoking were investigated by using analysis of covariance and logistic regression analysis after adjusting for age and histories of alcohol drinking and regular exercise.Odds ratios (with their confidence intervals) vs. nonsmokers for high CMI (1.748) were 1.16 (1.10 - 1.23, p0.01) in light smokers (or = 20 cigarettes/day), 1.60 (1.49 - 1.70, p0.01) in heavy smokers (20 and 5 40 cigarettes/day), and 2.34 (1.77 - 3.09, p0.01) in very heavy smokers (40 cigarettes/day). CMI was significantly higher in each smoker group than in the nonsmoker group and tended to be higher with an increase in amount of smoking. The odds ratio (with its confidence interval) for diabetes of subjects with vs. those without high CMI was 2.27 (2.06 - 2.50, p0.01) in overall subjects and was not significantly different in each smoker group compared with the odds ratio in the nonsmoker group.There was a dose-dependent relationship between CMI and amount of smoking, while the association between CMI and diabetes was not different in smokers and nonsmokers. Thus, CMI was suggested to be useful for discriminating diabetes both in smokers and nonsmokers.