Discovery of Novel 7-[(1R,5S)-1-Amino-5-fluoro-3-azabicyclo[3.3.0]octan-3-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropane]-8-(methoxy or methyl)quinolones.

A series of 8-methoxy or 8-methylquinolones bearing novel 3-aminooctahydrocyclopenta[c]pyrrole derivatives at the C-7 position was synthesized, and the pharmacological, physicochemical, and toxicological properties of the individual compounds were evaluated. Novel 8-methylquinolone 7, which includes a 3-amino-7-fluorooctahydrocyclopenta[c]pyrrole moiety at the C-7 position, showed potent antibacterial activity against both Gram-positive and negative pathogens. Compound 7 also demonstrated favorable pharmacokinetic and pharmacodynamic properties and an acceptably safe toxicological profile. Consequently, compound 7 was selected as a clinical candidate.

Positive linear dose-response relationships, but no J-shaped relationship, between drinking habits and estimated glomerular filtration rate in middle-aged Japanese men.

The relationship between drinking frequency and amount of alcohol consumption (i.e., drinking habits) and the risk of chronic kidney disease (CKD) remains unclear. We aimed to clarify either a linear or J-shaped dose-response relationship between drinking habits and estimated glomerular filtration rate (eGFR) as a biomarker for identifying individuals at high risk of CKD. In a large-scale cross-sectional study, 403 men and 121 women with an eGFR of 30-60 mL/min per 1.73 m(2) were defined as cases, and 1209 men and 363 women with ≥60 mL/min/1.73 m(2) were randomly extracted as controls (one case subject was matched with three control subjects, matched according to age and season of data collection). We calculated multivariate-adjusted CKD risk and the corresponding mean eGFR according to drinking habits. In men, negative and positive linear relationships with drinking habits were found for CKD risk and mean eGFR (p < 0.001 for all linear terms), respectively, but there were no corresponding J-shaped relationships (not significant for all quadratic terms). In regard to the mean eGFR, however, positive linear relationships were only shown in men in the highest eGFR quartile (p < 0.05 and p < 0.01 for drinking frequency and amount of alcohol consumption, respectively). In women, no association was found. Regarding each drinking habit, we found a positive linear dose-response relationship to eGFR in middle-aged men with an eGFR ≥30 mL/min/1.73 m(2).

Serum Fatty Acid Binding Protein 4 Concentrations Are Positively and Independently Associated with Blood Pressure and Abdominal Fat among Parameters in Health Check-Ups in Ordinary Middle-Aged Japanese Males.

We wished to examine potential associations among blood concentrations of fatty acid-binding protein (FABP) 4 and parameters in health check-ups such as abdominal fat area (AFA) and blood pressure (BP) in middle-aged Japanese males. We conducted a cross-sectional study of males who participated in health check-ups in Japan. We excluded participants diagnosed with metabolic diseases by the time of their check-up. A total of 305 subjects (30-64 [mean±standard deviation, 47.3±8.5] y) were recruited. Areas of total-abdominal, visceral and subcutaneous fat were measured using computed tomography. We compared the association of serum concentrations of FABP4 with various clinical parameters by Pearson product-moment correlation coefficient (PPMCC) analyses, and by step-wise multivariate linear regression analyses (MLRA). PPMCC analyses showed that blood concentrations of FABP4 were positively associated with: body mass index; areas of fat (total abdominal, visceral, subcutaneous); systolic BP; diastolic BP; total cholesterol; low-density lipoprotein-cholesterol; triacylglycerol; activities of γ-glutamyl transpeptidase, aspartate aminotransferase and alanine aminotransferase; white blood cell count; and levels of creatinine. Step-wise MLRA showed that AFAs (visceral and subcutaneous) and diastolic BP were positively and independently associated with serum concentrations of FABP4 among the parameters tested. These data suggest that serum concentrations of FABP4 are independently and positively associated with BP and AFA among parameters measured in health check-ups in middle-aged Japanese males.

Plasma TNF-α Is Associated with Inflammation and Nutrition Status in Community-Dwelling Japanese Elderly.

Inflammation has been suggested to play an important role in age-related chronic diseases and disability, and it is associated with nutritional status including obesity and malnutrition. While numerous studies have examined the validity of inflammatory markers in the population studies in Caucasian elderly people, very little information is available for the factors affecting inflammatory markers in Asian elderly people. Among inflammatory markers frequently used for the studies of aging, tumor necrosis factor α (TNF-α) is produced mainly by macrophages, and contributes to production of interleukin-6 (IL-6) and C-reactive protein (CRP), thus directing a chronic inflammatory process in the body. In the present study, we examined the associations between plasma TNF-α level and several factors related to nutrition status, including BMI, albumin, and energy intake in community-dwelling Japanese elderly. We conducted a cross-sectional study of 390 men and women aged 70-86 y (average 73.5 y), who participated in health check-ups. Associations between plasma TNF-α levels, other clinical parameters, and lifestyle factors were analyzed using Spearman's rank correlation coefficient analysis and multiple linear regression analysis. In elderly men, plasma TNF-α level was positively associated with age, white blood cell count, monocyte count, plasma CRP level, serum creatinine, ureic acid, and triacylglycerol levels, and negatively associated with albumin/globulin ratio, eGFR, and serum HDL-cholesterol level. In elderly women, plasma TNF-α level was positively associated with age, plasma CRP level, and serum triacylglycerol level, and negatively associated with serum albumin and HDL-cholesterol levels. The results of this study suggest that plasma TNF-α is associated with inflammation and insulin resistance in both Japanese elderly men and women, and a prominent association of TNF-α with malnutrition status was observed in elderly women.

Self-reported faster eating is positively associated with accumulation of visceral fat in middle-aged apparently healthy Japanese men.

PURPOSE: Faster eating is positively associated with body mass index in apparently healthy Japanese populations. In the present study, we examined the associations between self-reported rate of eating and visceral and subcutaneous fat areas in apparently healthy middle-aged Japanese men. METHODS: We conducted a cross-sectional study of men who participated in health checkups in Japan. We removed participants who were diagnosed with metabolic diseases by the time of their health checkups. A total of 320 subjects aged 30-64 years (mean ± standard deviation, 47.4 ± 8.6 years) were selected. We compared the associations between rate of eating and various clinical parameters including visceral and subcutaneous fat areas, using analysis of covariance (ANCOVA), which was adjusted by age and lifestyle factors such as alcohol intake, energy intake, smoking, and physical activity. Multivariate logistic regression analyses (MLRA) were performed with visceral fat area (cm(2)) as the dependent variable and independent variables that included self-reported rate of eating. RESULTS: Tukey's multiple test following ANCOVA showed that self-reported rate of eating was positively associated with visceral fat area (cm(2)), but not with subcutaneous fat area (cm(2)). MLRA showed that the odds ratio of rate of eating for visceral fat area in tertile (T) 3 (>100 cm(2)) compared with T1 (≤70 cm(2)) was 1.99 (95% CI 1.40-2.90, P < 0.01), and the association remained after adjustment for the subcutaneous fat area. CONCLUSIONS: The present results show that self-reported faster eating is positively associated with visceral fat accumulation, independently of subcutaneous fat accumulation, in apparently healthy Japanese men.

Self-reported faster eating associated with higher ALT activity in middle-aged, apparently healthy Japanese women.

OBJECTIVE: Faster eating and elevated circulating activity of alanine aminotransferase (ALT), a marker for liver injury, are risk factors for the development of obesity and type 2 diabetes mellitus, and their complications. The aim of this study was to examine the association between self-reported eating rate and circulating ALT activity in apparently healthy middle-aged Japanese women. METHODS: We conducted a cross-sectional study of 900 apparently healthy women ages 40 to 64 y (mean ± SD, 53.1 ± 7.1 y) who participated in health check-ups in Japan. We analyzed their clinical serum parameters and lifestyle factors, including self-reported eating rate. Associations between liver injury markers (ALT, γ-glutamyl transpeptidase [GTP], and aspartate aminotransferase [AST]), other clinical parameters and lifestyle factors were analyzed using Tukey's multiple range test following analysis of variance and analysis of covariance for three groups, divided by self-reported eating rates. The associations between self-reported faster eating and ALT activity and lifestyle factors were analyzed by multivariate logistic regression analyses. RESULTS: ALT activity, but not γ-GTP or AST activities, was higher in participants who reported relatively fast/very fast eating than in those who reported medium eating after adjusting for age, alcohol intake, energy intake, smoking, and physical activity. The odds ratio of eating rate for ALT activity in T3 (18-128 U/L) compared with T1 (3-12 U/L) was 1.67 (P < 0.01), but the association disappeared after adjustment for body mass index (BMI). CONCLUSIONS: ALT activity is positively associated with faster eating, but is dependent on BMI in middle-aged, apparently healthy Japanese women.

Serum γ-GTP activity is closely associated with serum CRP levels in non-overweight and overweight middle-aged Japanese men.

The relationship between γ-glutamyltransferase (γ-GTP) and C-reactive protein (CRP) has not been established, particularly in the lean or non-overweight population. In the present study, we examined the associations between γ-GTP and CRP in non-overweight and overweight middle-aged Japanese men. We conducted a cross-sectional study of 4,271 apparently healthy men aged 40 to 64 y (mean±SD, 50.5±6.6 y) who participated in health checkups. Associations between serum CRP levels, other clinical parameters, and lifestyle factors were analyzed using Spearman's rank correlation coefficient analysis and multiple linear regression analysis in the non-overweight (body mass index [BMI]<25 kg/m(2)) and overweight (BMI≥25 kg/m(2)) men. Associations between serum γ-GTP activity and serum CRP levels were analyzed using analysis of covariance by comparisons of serum CRP levels of four subgroups according to γ-GTP status. In non-overweight men, BMI, high-density lipoprotein cholesterol, triacylglycerols, fasting blood glucose, aspartate aminotransferase, γ-GTP, and smoking habit were positively associated with serum CRP levels. In overweight men, BMI, diastolic blood pressure, triacylglycerols, and γ-GTP were positively associated with serum CRP levels. After adjustment for age, BMI, smoking status, and alcohol intake, dose-response relationships were observed between γ-GTP and CRP levels in both overweight and non-overweight men. The results of this study indicate that an increase in serum γ-GTP activity is closely associated with elevated CRP levels in both non-overweight and overweight middle-aged Japanese men.

Design, synthesis, and biological evaluations of novel 7-[7-amino-7-methyl-5-azaspiro[2.4]heptan-5-yl]-8-methoxyquinolines with potent antibacterial activity against respiratory pathogens.

Novel 7-[7-amino-7-methyl-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]- 8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 2a and 2b were designed and synthesized to obtain potent antibacterial drugs for the treatment of respiratory tract infections. Among these, compound 2a possessing (S)-configuration for the asymmetrical carbon on the pyrolidine moiety at the C-7 position of the quinolone scaffold exhibited potent in vitro antibacterial activity against respiratory pathogens including gram-positive (Streptococcus pneumoniae and Staphylococcus aureus), gram-negative (Haemophilus influenzae and Moraxcella catarrhalis), and atypical strains (Chalmydia pneumoniae and Mycoplasma pneumoniae), as well as multidrug-resistant Streptococcus pneumoniae and quinolone-resistant and methicillin-resistant Staphylococcus aureus). Furthermore, compound 2a showed excellent in vivo activity against the experimental murine pneumonia model due to multidrug resistant Streptococcus pneumoniae (MDRSP) and favorable profiles in preliminary toxicological and nonclinical pharmacokinetic studies.

Plasma sE-selectin level is positively correlated with neutrophil count and diastolic blood pressure in Japanese men.

Increased levels of circulating soluble type of E-selectin (sE-selectin), neutrophil counts and blood pressure are associated with the development of cardiovascular diseases (CVD). In this study, we conducted a cross-sectional study of men who participated in health check-ups, and selected those who were not diagnosed with or being treated for metabolic diseases such as diabetes, hypertension and lipid abnormality according to the health check-ups. We measured their basic clinical parameters including blood pressure and neutrophil count, plasma sE-selectin concentration and lifestyle factors, and assessed their interrelations by multivariate linear regression (MLR) analysis. A total of 351 subjects aged 47.5±8.41 (range, 30-64) y were recruited. Significantly correlated with sE-selectin concentration were neutrophil count, diastolic blood pressure (DBP), and systolic blood pressure (SBP) (Pearson's correlation coefficient, 0.194, 0.220 and 0.175, respectively). MLR analysis showed that sE-selectin concentration was independently positively related with DBP and neutrophil count, whereas neutrophil count was positively associated with sE-selectin concentration but not DBP. DBP, but not SBP, was independently positively correlated with sE-selectin concentration but not neutrophil count. These results indicate that circulating sE-selectin concentration may be a biomarker for indicating subsequent development of metabolic diseases, in particular CVD, from a healthy state.

Circulating interleukin-1ß concentrations are independently-positively associated with γ-glutamyltransferase activity within the normal range in middle-aged apparently healthy Japanese women.

We previously demonstrated that the circulating concentrations of interleukin (IL)-1ß, which is known to induce the development and progression of type 2 diabetes and its complications, were positively associated with γ-glutamyltransferase (γ-GTP) activity in middle-aged apparently healthy Japanese men. It was still unknown if the association between IL-1ß concentrations and γ-GTP activity is within the normal range in apparently healthy Japanese women. In this study, we conducted a cross-sectional study of 824 apparently healthy women aged 40-64 y [mean±standard deviation age, 53.1±7.1 y; body mass index (BMI), 22.0±3.1 kg/m(2)] who participated in health checkups in Japan, and whose γ-GTP activity was within the normal range (<38 U/L). Associations of γ-GTP with IL-1ß and other clinical or lifestyle factors were determined using analysis of variance (ANOVA) and one-way analysis of covariance (ANCOVA) followed by Tukey's multiple-range test. Multivariate logistic regression analyses (MLRA) were performed with γ-GTP activity as the dependent variable; independent variables included IL-1ß plus clinical and lifestyle factors. ANOVA and ANCOVA indicated that IL-1ß concentrations were positively associated with γ-GTP activity. MLRA showed that γ-GTP activity showed trends for higher IL-1ß concentrations after adjusting for age, BMI, energy intake, alcohol intake, and smoking status. Together, IL-1ß concentrations are positively associated with γ-GTP activity within the normal range in middle-aged apparently healthy Japanese women. Our results suggest that γ-GTP activity would be useful for assessing inflammation from the healthy state in Japanese women.

Self-reported rate of eating is associated with higher circulating ALT activity in middle-aged apparently healthy Japanese men.

PURPOSE: Elevated circulating activities of alanine aminotransferase (ALT), a marker for liver injury, and the lifestyle of a higher rate of eating in healthy and preclinical subjects are associated with increased risk of obesity and diabetes. In this study, we examined the associations between self-reported rate of eating and circulating ALT activity in middle-aged apparently healthy Japanese men. METHODS: We conducted a cross-sectional study of 3,929 apparently healthy men aged 40-59 years (mean ± SD age, 49.2 ± 5.8 years; BMI, 23.5 ± 2.8 kg/m²) who participated in health checkups in Japan. We analyzed their clinical serum parameters and lifestyle factors, including self-reported rate of eating. Associations between self-reported rate of eating and liver injury markers [ALT, γ-glutamyl transpeptidase (GTP), and aspartate aminotransferase (AST)], other clinical parameters or lifestyle factors were determined using analysis of variance followed by Tukey's test. Multivariate logistic regression analyses (MLRA) were performed with ALT activity as the dependent variable and independent variables that included self-reported rate of eating. RESULTS: MLRA showed that ALT activity showed trends for higher self-reported rate of eating after adjustment for age, energy intake, and smoking status. The association between ALT activity and self-reported rate of eating disappeared after adjustment for BMI. CONCLUSION: The results of this study show that ALT activity is positively associated with self-reported rate of eating in middle-aged apparently healthy Japanese men.

Principal component 1 score calculated from metabolic syndrome diagnostic parameters is a possible marker for the development of metabolic syndrome in middle-aged Japanese men without treatment for metabolic diseases.

PURPOSE: The risk of metabolic syndrome (MetS) is assessed based on the presence of risk factors that include dyslipidemia, hyperglycemia, hypertension and obesity. In this study, we assessed the risk of MetS using principle component (PC) analysis of MetS diagnostic parameters and examined whether the resulting eigenvalues are associated with the circulating concentrations of inflammatory cytokines [interleukin (IL)-1ß and IL-6] and a marker for insulin sensitivity (adiponectin) in middle-aged Japanese men without treatment for metabolic diseases. MATERIALS: We conducted a cross-sectional study of 308 Japanese men without treatment for metabolic diseases aged 40-69 years who participated in health checkups in Japan. We calculated the PC1 score from the following MetS diagnostic parameters: body mass index (BMI), fasting blood glucose, diastolic blood pressure, triacylglycerol and high-density lipoprotein cholesterol. We compared the relationship between PC1 scores and other clinical parameters, including IL-1ß, IL-6 and adiponectin, by Spearman's rank correlation coefficient analyses and Jonckheere-Terpstra test. RESULTS: The associations for most clinical parameters were higher with the PC1 score than with other MetS diagnostic parameters. Homeostasis model assessment-insulin resistance, an index of insulin resistance, showed stronger associations with PC1 score than with MetS diagnostic parameters. Significant associations for IL-1ß, IL-6 and adiponectin were observed with the PC1 score, BMI and triacylglycerol; these associations were higher with the PC1 score than with BMI and triacylglycerol. CONCLUSIONS: The present results show that the PC1 score is closely associated with parameters of MetS, inflammation and insulin resistance.

Associations between leukocyte counts and cardiovascular disease risk factors in apparently healthy Japanese men.

Increased leukocyte counts, particularly white blood cell and neutrophil counts, are reportedly associated with increased incidence of cardiovascular diseases (CVD) and mortality in subjects with acute and moderate coronary diseases. However, few reports have determined the associations between leukocyte subset (i.e., white blood cells, neutrophils, monocytes, lymphocytes, basophils and eosinophils) counts and CVD risk factors. In this study, we examined the associations between leukocyte subset counts and CVD risk factors in apparently healthy Japanese men. We conducted a cross-sectional study of men who participated in health checkups, and selected those who were not being treated for metabolic diseases. We determined associations between leukocyte subset counts and CVD risk factors by multivariate linear regression (MLR) analysis and analysis of covariance (ANCOVA). Overall, 3,576 subjects aged 49.3±5.75 (range, 40-59) y were recruited. MLR and ANCOVA showed that white blood cell, neutrophil, monocyte counts are associated with decreased high-density lipoprotein cholesterol (HDL-C) and increased C-reactive protein levels, the lymphocyte count is positively associated with lipid abnormalities (i.e., decreased HDL-C, increased low-density lipoprotein cholesterol and increased triacylglycerol (TG)), and the basophil count is associated with increased TG and liver injury marker levels (i.e., alanine aminotransferase). Our results in this study demonstrated that leukocyte subset counts showed differential associations with CVD risk factors in apparently healthy Japanese men.

A higher rate of eating is associated with higher circulating interluekin-1ß concentrations in Japanese men not being treated for metabolic diseases.

OBJECTIVE: In this study, we examined the relations between the rate of eating and circulating interleukin (IL)-1ß and IL-6 levels in Japanese men not being treated for metabolic diseases. METHODS: We conducted a cross-sectional study of 170 men 40 to 59 y old (mean ± standard deviation, 51.4 ± 5.7 y old) who participated in health checkups in Japan and were not being treated for metabolic diseases. We measured clinical serum parameters and plasma IL-1ß and IL-6 concentrations and assessed by questionnaire lifestyle factors such as the dietary intake of food/nutrition and the rate of eating. Using multivariate linear regression analysis, we analyzed the relations between the rate of eating and IL-1ß and IL-6 concentrations, clinical parameters, and lifestyle factors. RESULTS: Significant Spearman correlation coefficients with the rate of eating were observed for IL-1ß and IL-6 (0.250 and 0.195, respectively). The rate of eating was positively associated with IL-1ß independently of IL-6, body mass index, homeostasis model assessment for insulin resistance, alcohol intake, energy intake, smoking status, and physical activity. CONCLUSIONS: These results indicate that a higher rate of eating is positively and independently associated with circulating IL-1ß concentrations in Japanese men not being treated for metabolic diseases.

Accumulation of visceral fat is positively associated with serum ALT and γ-GTP activities in healthy and preclinical middle-aged Japanese men.

Elevated circulating alanine aminotransferase (ALT) and γ-glutamyltransferase (γ-GTP) activities, and the accumulation of fat, particularly visceral fat, in healthy and preclinical subjects reportedly increase the risk for metabolic diseases such as diabetes. In the present study, we examined the associations between these hepatic enzymes and the total visceral and subcutaneous fat area, and for both regions of fat independently, in healthy and preclinical middle-aged Japanese men. We conducted a cross-sectional study of men who participated in health check-ups in Japan. We removed participants, who were diagnosed with metabolic diseases at the time of the health check-up. Three hundred fifteen subjects aged 40-64 y (mean±SD, 50.5±6.9 y) were selected. We compared associations between the total visceral and subcutaneous fat area, and for both regions independently, with various clinical parameters, including hepatic enzyme markers, using Spearman's rank correlation coefficient analysis and multiple linear regression analysis. The total visceral and subcutaneous fat area and both regions independently were positively associated with body mass index, systolic and diastolic blood pressure, fasting blood glucose, total cholesterol, low-density lipoprotein cholesterol, aspartate aminotransferase, ALT and γ-GTP. ALT and γ-GTP activities were the strongest explanatory variables for increased visceral fat area, independent of the subcutaneous fat area. In contrast, these hepatic enzymes were not explanatory variables for increased subcutaneous fat area. The results of the present study show that the accumulation of visceral fat is positively associated with ALT and γ-GTP activities independently of subcutaneous fat area in healthy and preclinical Japanese men.

The combination of genetic variations in the PRDX3 gene and dietary fat intake contribute to obesity risk.

Oxidative stress is caused by an imbalance between the production of reactive oxygen species (ROS) and the antioxidant capacity of the cell. This imbalance and an excess of ROS induce tissue/cellular damage, which are implicated in chronic inflammation disorders such as obesity, insulin resistance, and metabolic syndromes. Peroxiredoxins (Prxs) are the most abundant and ancient cellular antioxidant proteins that help to control intracellular peroxide levels and ROS-dependent signaling. Of the six mammalian isoforms, Prx III is specifically localized in mitochondria. In this study, we detected novel associations between genetic variations of the PRDX3 gene and BMI and obesity risk in the general Japanese population. In addition, these associations were observed only in the subjects with high dietary fat intake, but not in the subjects with low dietary fat intake. These findings indicate that the interaction between genetic variations in the PRDX3 gene and dietary fat intake is important for modulation of BMI and obesity risk.

Circulating interleukin-1ß and interleukin-6 concentrations are closely associated with γ-glutamyltranspeptidase activity in middle-aged Japanese men without obvious cardiovascular diseases.

Interleukin (IL)-1ß and IL-6 expressions are known to be induced by oxidant stress. In the present study, we examined the relationships between these interleukins and the activity of γ-glutamyltranspeptidase (γ-GTP), which was recently reported as a source of oxidant stress production, in the circulating blood of middle-aged Japanese men without obvious cardiovascular diseases. We conducted a cross-sectional study of 317 Japanese men without obvious cardiovascular diseases aged 40 to 69 years (mean ± SD, 58.6 ± 7.6 years) who participated in health checkups in Japan. We analyzed their clinical parameters in serum, lifestyle factors, and plasma IL-1ß and IL-6 concentrations. We compared the relationships between these interleukin concentrations and the clinical parameters and lifestyle factors by Spearman correlation coefficients. Stepwise multiple linear regression analyses for interleukins based on the other parameters and γ-GTP, which were classified into 3 groups according to the concentrations, were performed. Interleukin-1ß and IL-6 concentrations were closely associated with γ-GTP activity but less associated with alanine aminotransferase and aspartate aminotransferase activities by Spearman correlation coefficients. Stepwise multiple linear regression analyses showed that γ-GTP activity was the explanatory variable for elevated IL-1ß and IL-6 concentrations. As natural logarithms, the IL-1ß and IL-6 concentrations were estimated to be 1.734- and 1.157-fold higher, respectively, in subjects with high γ-GTP activity ranges than in subjects with a low γ-GTP activity range. The present results show that circulating IL-1ß and IL-6 concentrations are strongly and independently associated with γ-GTP activity in middle-aged Japanese men without obvious cardiovascular diseases.

Associations between markers of liver injury and cytokine markers for insulin sensitivity and inflammation in middle-aged Japanese men not being treated for metabolic diseases.

Elevated circulating alanine aminotransferase (ALT) and γ-glutamyltranspeptidase (γ-GTP) activities in healthy and preclinical subjects are associated with increased risk for obesity, diabetes and related complications. In the present study, we examined the associations between these hepatic enzymes and circulating cytokines as markers for insulin sensitivity (adiponectin) and inflammation [interleukin-6 (IL-6)] in middle-aged Japanese men not being treated for metabolic diseases. We conducted a cross-sectional study of 310 Japanese men aged 40-69 y (mean ± SD, 58.8 ± 7.6 y) who were not being treated for metabolic diseases and who participated in health checkups in Japan. We analyzed their lifestyle factors, clinical factors, and plasma adiponectin and IL-6 concentrations. We determined associations between the concentrations of these cytokines and the clinical and lifestyle factors using Spearman's correlation analysis, Jonckheere-Terpstra's test and multiple linear regression. ALT activity was negatively associated with adiponectin (r=-0.302, p<0.001) but not with IL-6. γ-GTP activity was positively associated with IL-6 (r=0.335, p<0.001) and negatively associated with adiponectin (r=-0.129, p<0.05). Aspartate aminotransferase (AST) activity was positively associated with IL-6 (r=0.131, p<0.05) and negatively associated with adiponectin (r=-0.125, p<0.05). Multiple linear regression analyses showed that adiponectin was independently and negatively associated with ALT activity, while IL-6 was independently and positively associated with γ-GTP activity. Adiponectin and IL-6 were not independently associated with AST activity. The results of this study indicate that circulating ALT activity is negatively associated with adiponectin concentration, γ-GTP is positively associated with increased IL-6 concentration, and AST is not associated with these cytokines in middle-aged Japanese men not being treated for metabolic diseases.

Plasma interleukin-1ß concentrations are closely associated with fasting blood glucose levels in healthy and preclinical middle-aged nonoverweight and overweight Japanese men.

Plasma interleukin (IL)-1ß and IL-6 are markers that predict the risk of inflammation in diabetes. In the current study, we examined the relationship between fasting glucose and plasma inflammatory cytokines (IL-1ß and IL-6) concentrations in healthy and preclinical middle-aged Japanese men (mean ± SD, 58.7 ± 7.8 years old) divided according to body mass index (<25 kg/m(2), nonoverweight group; ≥25 kg/m(2), overweight group). We conducted a cross-sectional study of 413 healthy and preclinical men aged 40 to 69 years who participated in health checkups in Japan. We measured their clinical parameters, lifestyle factors, and plasma IL-1ß and IL-6 concentrations. Participants were classified according to their fasting blood glucose levels, and we compared their plasma cytokine levels. Plasma IL-1ß and IL-6 levels in nonoverweight subjects were positively and strongly associated with fasting blood glucose and hemoglobin A(1c); in contrast, these cytokines were strongly associated with homeostasis model assessment of insulin resistance and fasting glucose in overweight subjects. Significant positive associations between plasma IL-1ß and glucose concentrations were observed within the groups classified according to glucose concentrations, after adjustment for age and body mass index. The results of our current study show that plasma IL-1ß levels are strongly associated with fasting blood glucose concentrations in healthy and preclinical nonoverweight and overweight Japanese men.

Design, synthesis and biological evaluations of novel 7-[3-(1-aminocycloalkyl)pyrrolidin-1-yl]-6-desfluoro-8-methoxyquinolones with potent antibacterial activity against multi-drug resistant Gram-positive bacteria.

A series of novel 6-desfluoro [des-F(6)] and 6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methoxyquinolones bearing 3-(1-aminocycloalkyl)pyrrolidin-1-yl substituents at the C-7 position (1-6) was synthesized to obtain potent drugs for nosocomial infections caused by Gram-positive pathogens. The des-F(6) compounds 4-6 exhibited at least four times more potent activity against representative Gram-positive bacteria than ciprofloxacin or moxifloxacin. Among the derivatives, 7-[(3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl] derivative 4, which showed favorable profiles in preliminary toxicological and non-clinical pharmacokinetic studies, exhibited potent antibacterial activity against clinically isolated Gram-positive pathogens that had become resistant to one or more antibiotics.