Synthesis of Macrocyclic Hexaoxazole (6OTD) Dimers, Containing Guanidine and Amine Functionalized Side Chains, and an Evaluation of Their Telomeric G4 Stabilizing Properties

Structure-activity relationship studies were carried out on macrocyclic hexaoxazole (6OTD) dimers, whose core structure stabilizes telomeric G-quadruplexes (G4). Two new 6OTD dimers having side chain amine and guanidine functional groups were synthesized and evaluated for their stabilizing ability against a telomeric G4 DNA sequence. The results show that the 6OTD dimers interact with the DNA to form 1:1 complexes and stabilize the antiparallel G4 structure of DNA in the presence of potassium cation. The guanidine functionalized dimer displays a potent stabilizing ability of the G4 structure, as determined by using a FRET melting assay (ΔTm = 14°C)

Self-reported speed of eating and 7-year risk of type 2 diabetes mellitus in middle-aged Japanese men

Objective: This cohort study investigated the association between eating speed and the incidence of type 2 diabetes in middle-aged Japanese men. Materials/Methods: Participants were 2,050 male employees of a metal products factory in Japan. We measured self-reported categorical eating speed. The incidence of diabetes was determined in annual medical examinations over a 7-year period. The association between eating speed and the incidence of diabetes adjusted for multiple variables (age, family history of diabetes, smoking, alcohol drinking, habitual exercise, and presence of hypertension and hyperlipidemia) was evaluated using Cox proportional hazards models. Results: The prevalence of obesity (BMI ≥ 25 kg/m 2) across the categories of eating speed (slow, medium, and fast) was 14.6, 23.3, and 34.8%, respectively, and a faster eating speed was associated with a higher prevalence of obesity. During the study, 177 participants developed diabetes. Crude incidence rates (/1,000 person-years) across the three categories of eating speed were 9.9, 15.6, and 17.3, respectively. Multivariate-adjusted hazard ratios (95% CI) across the categories were 1.00 (reference), 1.68 (0.93-3.02), and 1.97 (1.10-3.55), respectively, and eating speed was associated with the risk of diabetes (p for trend = 0.030). After further adjustment for BMI, a significant association was not observed. Conclusions: Eating speed was associated with the incidence of diabetes. Since these associations were not significant after adjusting for BMI, eating speed may act via its effect on body weight. Eating speed is a controllable risk factor, and eating slowly could be an acceptable lifestyle intervention for the prevention of diabetes mellitus. © 2012 Elsevier Inc. All rights reserved

Family history of diabetes, lifestyle factors, and the 7-year incident risk of type 2 diabetes mellitus in middle-aged Japanese men and women

Aims/Introduction: This cohort study of middle-aged Japanese participants investigated the relationship between family history of diabetes, the incident risk of type 2 diabetes and the interaction of these variables with other factors. Materials and Methods: Study participants were 3,517 employees (2,037 men and 1,480 women) of a metal products factory in Japan. Baseline health examinations included questions about medical history, physical examination, anthropometric measurements, questions about lifestyle factors, such as smoking, alcohol consumption and habitual exercise, and a self-administered diet history questionnaire. Family history of diabetes was defined as having at least one-first-degree relative with diabetes. The incidence of diabetes was determined in annual medical examinations over a 7-year period. Hazard ratios (HRs) for type 2 diabetes were estimated by Cox proportional hazards analysis. Results: Of the 3,517 participants, 630 (18%) had a family history of diabetes mellitus. During the study, 228 participants developed diabetes. The age and sex-adjusted HR for type 2 diabetes in participants with a family history of diabetes was 1.82 (95% confidence interval 1.36-2.43) as compared with those without a family history of diabetes. HRs did not change after adjustment for body mass index and lifestyle factors. We found no interactions with body mass index, insulin resistance, pancreatic β-cell function or lifestyle factors. Conclusions: Family history of diabetes was associated with the incident risk of diabetes, and these associations were independent of other risk factors, such as obesity, insulin resistance, and lifestyle factors in Japanese men and women. © 2013 Asian Association for the Study of Diabetes and Wiley Publishing Asia Pty Ltd

Sugar-sweetened beverage and diet soda consumption and the 7-year risk for type 2 diabetes mellitus in middle-aged Japanese men

Purpose: This cohort study investigated the association between sugar-sweetened beverage (SSB) and diet soda consumption and the incidence of type 2 diabetes in Japanese men. Methods: The participants were 2,037 employees of a factory in Japan. We measured consumption of SSB and diet soda using a self-administered diet history questionnaire. The incidence of diabetes was determined in annual medical examinations over a 7-year period. Hazard ratios (HRs) with 95 % confidence intervals (CIs) for diabetes were estimated after adjusting for age, body mass index, family history, and dietary and other lifestyle factors. Results: During the study, 170 participants developed diabetes. The crude incidence rates (/1,000 person-years) across participants who were rare/never SSB consumers, <1 serving/week, ≥1 serving/week and <1 serving/day, and ≥1 serving/day were 15.5, 12.7, 14.9, and 17.4, respectively. The multivariate-adjusted HR compared to rare/never SSB consumers was 1.35 (95 % CI 0.80-2.27) for participants who consumed ≥1 serving/day SSB. Diet soda consumption was significantly associated with the incident risk of diabetes (P for trend = 0.013), and multivariate-adjusted HRs compared to rare/never diet soda consumers were 1.05 (0.62-1.78) and 1.70 (1.13-2.55), respectively, for participants who consumed <1 serving/week and ≥1 serving/week. Conclusions: Consumption of diet soda was significantly associated with an increased risk for diabetes in Japanese men. Diet soda is not always effective at preventing type 2 diabetes even though it is a zero-calorie drink. © 2013 Springer-Verlag Berlin Heidelberg

Dietary carbohydrate intake, presence of obesity and the incident risk of type 2 diabetes in Japanese men

The present cohort study assessed the risk among Japanese men for developing type 2 diabetes, based on the percentage of energy intake from carbohydrates and degree of obesity. Participants and Methods: The participants were 2,006 male factory employees, and the macronutrient intake of each patient was measured using a self-administered diet history questionnaire. The incidence of diabetes was determined in annual blood examinations over a 10-year period. Results: During the study, 232 participants developed diabetes. The crude incidence rates (/1,000 person-years) for different levels of carbohydrate intake as a percentage of calories consumed (65.0% of energy intake) were 16.5, 14.4, 12.7 and 17.6. Overall, carbohydrate intake was not associated with the risk of diabetes. However, there was significant interaction between carbohydrate intake and degree of obesity on the incidence of diabetes (P for interaction = 0.024). Higher carbohydrate intake was associated with elevated risk for diabetes among participants with a body mass index ≥25.0 kg/m2 (P for trend = 0.034). For obese participants, the multivariate-adjusted hazard ratio for those with carbohydrate intakes >65% energy was 2.01 (95% confidence interval 1.08-3.71), which was significantly higher than that of participants with carbohydrate intakes 50.0-57.4% energy. Conclusions: Higher carbohydrate intake was associated with higher risk of diabetes in obese participants, but not in non-obese participants. Obese participants with carbohydrate intakes >65% energy should reduce their intakes to levels within the desirable carbohydrate energy proportion for Japanese (50-65% energy) to prevent development of type 2 diabetes. © 2016 Asian Association for the Study of Diabetes and John Wiley & Sons Australia, Ltd

Population Attributable Fraction of Smoking and Metabolic Syndrome on Cardiovascular Disease Mortality in Japan: a 15-Year Follow Up of NIPPON DATA90

<p>Abstract</p> <p>Background</p> <p>Smoking and metabolic syndrome are known to be related to cardiovascular diseases (CVD) risk. In Asian countries, prevalence of obesity has increased and smoking rate in men is still high. We investigated the attribution of the combination of smoking and metabolic syndrome (or obesity) to excess CVD deaths in Japan.</p> <p>Methods</p> <p>A cohort of nationwide representative Japanese samples, a total of 6650 men and women aged 30-70 at baseline without history of CVD was followed for 15 years. Multivariate-adjusted hazard ratio for CVD death according to the combination of smoking status and metabolic syndrome (or obesity) was calculated using Cox proportional hazard model. Population attributable fraction (PAF) of CVD deaths was calculated using the hazard ratios.</p> <p>Results</p> <p>During the follow-up period, 87 men and 61 women died due to CVD. The PAF component of CVD deaths in non-obese smokers was 36.8% in men and 11.3% in women, which were higher than those in obese smokers (9.1% in men and 5.2% in women). The PAF component of CVD deaths in smokers without metabolic syndrome was 40.9% in men and 11.9% in women, which were also higher than those in smokers with metabolic syndrome (7.1% in men and 3.9% in women).</p> <p>Conclusion</p> <p>Our results indicated that a large proportion of excess CVD deaths was observed in smokers without metabolic syndrome or obesity, especially in men. These findings suggest that intervention targeting on smokers, irrespective of the presence of metabolic syndrome, is still important for the prevention of CVD in Asian countries.</p

Long-chain n-3 polyunsaturated fatty acids intake and cardiovascular disease mortality risk in Japanese: a 24-year follow-up of NIPPON DATA80

Background:Dietary intake of long-chain n-3 PUFA (LCn3FA) among Japanese is generally higher than that in Western populations. However, little is known whether an inverse association of LCn3FA with cardiovascular disease (CVD) risk exists in a population with higher LCn3FA intake.Objective:To investigate the association between LCn3FA intake and the long-term risk of CVDs in a Japanese general population.Methods:We followed-up a total of 9190 individuals (56.2% women, mean age 50.0 years) randomly selected from 300 areas across Japan and free from CVDs at baseline. Dietary LCn3FA intake was estimated using household weighed food records. Cox models were used to calculate multivariate-adjusted hazard ratios (HR) and confidence intervals (CI) according to sex specific quartiles of LCn3FA intake.Results:During 24-year follow-up (192,897 person-years), 879 cardiovascular deaths were observed. The median daily intake of LCn3FA was 0.37% kcal (0.86 g/day). Adjusted HR for CVD mortality was lower in the highest quartile of LCn3FA intake (HR 0.80; 95% CI 0.66-0.96) compared with the lowest quartile, and the trend was statistically significant (P = 0.038). The similar but statistically non-significant trends were observed for coronary heart disease death and stroke death. In analyses by age groups, the inverse associations of LCn3FA intake with the risk of total CVD death and stroke death were significant in younger individuals (30-59 years at baseline).Conclusion:LCn3FA intake was inversely and independently associated the long-term risk of total CVD mortality in a representative sample of Japanese with high LCn3FA intake

G-quadruplexes as potential therapeutic targets for embryonal tumors

Embryonal tumors include a heterogeneous group of highly malignant neoplasms that primarily affect infants and children and are characterized by a high rate of mortality and treatment-related morbidity, hence improved therapies are clearly needed. G-quadruplexes are special secondary structures adopted in guanine (G)-rich DNA sequences that are often present in biologically important regions, e.g. at the end of telomeres and in the regulatory regions of oncogenes such as MYC. Owing to the significant roles that both telomeres and MYC play in cancer cell biology, G-quadruplexes have been viewed as emerging therapeutic targets in oncology and as tools for novel anticancer drug design. Several compounds that target these structures have shown promising anticancer activity in tumor xenograft models and some of them have entered Phase II clinical trials. In this review we examine approaches to DNA targeted cancer therapy, summarize the recent developments of G-quadruplex ligands as anticancer drugs and speculate on the future direction of such structures as a potential novel therapeutic strategy for embryonal tumors of the nervous system