Biomarkers and Gene Polymorphisms in Members of Long- and Short-lived Families: A Longevity Study.

BACKGROUND: The influence of biomarkers in human lifespan has been investigated but with no clear results yet. MATERIALS AND METHODS: Lipids, Uric Acid (UA), Adiponectin (ADIPOQ), Insulin-like Growth Factor (IGF-1), cholesteryl ester transfer protein (CETP) and angiotensin-converting enzyme (ACE) proteins, as well as CETP, ADIPOQ, insulin-like growth factor binding protein-3 (IGFBP3) and ACE-gene polymorphisms were evaluated in 149 Greek individuals. The Long-Lived Families (LON) (n=84) comprised of 3 generations: long-lived aged ≥90 years (P), offspring (FL1) and their grandchildren (FL2), while the Short-Lived Families (EAD) (n=65) where both parents died <75 years, comprised of 2 generations: middle-aged (FD1) and children (FD2). RESULTS: Serum CETP and IGF-1 levels were lower, whereas AdipoQ concentrations were higher in P compared with FL1 and FL2 members (CETP: p = 0.03 for both comparisons; IGF-1 p < 0.001 for both comparisons and ADIPOQ: p = 0.001 and p = 0.004, respectively). Furthermore, serum triglycerides, UA and glucose concentrations were higher in FD1 compared with FD2 subjects (p=0.001, 0.02 and ≤0.001, respectively). In FD2 and FL2, CETP levels were lower in individuals with B2B2 compared with B1B1 genotype (p=0.007). Additionally, ACE concentrations were higher in individuals with DD compared with II genotype in both Families (p=0.001). After adjustment for age and gender, CETP levels were lower in P and FL2 individuals with B2B2 compared with the B1B1 genotype (p=0.004 and 0.007, respectively). CONCLUSION: Increase serum TGs, UA and GL concentrations were higher in the middle-aged individuals compared with their children in families independently of their lifespan. The serum adiponectin concentration was the highest in the oldest old individuals implying beneficial influence on lifespan. Independently of family's lifespan history, the youngest individuals with CETPB2B2 genotype, compared with individuals with CETPB1B1 genotypes, had lower serum CETP concentrations. The knowledge of the unfavourable gene(s)influencing human lifespan may be helpful in encouraging individuals to follow healthier lifestyle habits and better control their high-risk biomarkers.

A "healthy diet-optimal sleep" lifestyle pattern is inversely associated with liver stiffness and insulin resistance in patients with nonalcoholic fatty liver disease.

Several lifestyle habits have been described as risk factors for nonalcoholic fatty liver disease (NAFLD). Given that both healthy and unhealthy habits tend to cluster, the aim of this study was to identify lifestyle patterns and explore their potential associations with clinical characteristics of individuals with NAFLD. One hundred and thirty-six consecutive patients with ultrasound-proven NAFLD were included. Diet and physical activity level were assessed through appropriate questionnaires. Habitual night sleep hours and duration of midday naps were recorded. Optimal sleep duration was defined as sleep hours ≥ 7 and ≤ 9 h/day. Lifestyle patterns were identified using principal component analysis. Eight components were derived explaining 67% of total variation of lifestyle characteristics. Lifestyle pattern 3, namely high consumption of low-fat dairy products, vegetables, fish, and optimal sleep duration was negatively associated with insulin resistance (ß = -1.66, P = 0.008) and liver stiffness (ß = -1.62, P = 0.05) after controlling for age, sex, body mass index, energy intake, smoking habits, adiponectin, and tumor necrosis factor-α. Lifestyle pattern 1, namely high consumption of full-fat dairy products, refined cereals, potatoes, red meat, and high television viewing time was positively associated with insulin resistance (ß = 1.66, P = 0.005), although this association was weakened after adjusting for adiponectin and tumor necrosis factor-α. A "healthy diet-optimal sleep" lifestyle pattern was beneficially associated with insulin resistance and liver stiffness in NAFLD patients independent of body weight status and energy intake.

Associations Between Lifestyle Characteristics and the Presence of Nonalcoholic Fatty Liver Disease: A Case-Control Study.

BACKGROUND: Dietary and physical activity (PA) habits have been suggested as important factors for nonalcoholic fatty liver disease (NAFLD). Published data are mainly focused on the effect of either diet or exercise, whereas data on other aspects like sleep remain sparse. The aim of this study was to explore potential associations between dietary intake, PA, and sleeping habits, and the presence of NAFLD. METHODS: One hundred patients with ultrasound-proven NAFLD and 55 healthy controls matched for age, sex, and body mass index were included. Dietary habits were assessed through a semiquantitative validated food frequency questionnaire. PA level was assessed with a validated questionnaire. Total night sleep hours and duration of midday rest were also recorded. Optimal sleep duration was defined as sleep hours ≥7 and ≤9 hr/day. RESULTS: Patients compared to controls consumed less vegetables and nuts, more sweets, drank less coffee and alcohol (all P < 0.05), and exhibited a lower level of PA (P = 0.006). PA level [odds ratio (OR) per 100 metabolic equivalent of task-min/day = 0.74, 95% confidence interval (CI) 0.61-0.89, P = 0.002] was associated with lower probability of having NAFLD, whereas sweets consumption (OR = 2.13, 95% CI 1.22-3.71, P = 0.008) was associated with increased probability, after adjusting for several confounders, including body weight status. Optimal sleep duration was marginally and inversely associated with NAFLD presence (OR = 0.38, 95% CI 0.14-1.01, P = 0.05). CONCLUSION: Higher PA level and optimal sleep duration are associated with lower likelihood, whereas sweets consumption is associated with higher likelihood of having NAFLD. These associations are independent of body weight status and energy intake.

Reduced circulating adiponectin levels are associated with the metabolic syndrome independently of obesity, lipid indices and serum insulin levels: a cross-sectional study.

BACKGROUND: Given the increasing rate of overweight and the burden of metabolic syndrome (MetS) on cardiovascular disease development, better understanding of the syndrome is of great importance. Therefore, the objectives were to examine whether interleukin-6 (IL-6) and adiponectin are associated with MetS, and whether this association is mediated by components of the MetS. METHODS: During 2011-2012, 284 individuals (159 men, 53 ± 9 years, 125 women 52 ± 9 years) without cardiovascular disease, type 1 diabetes mellitus, high-grade inflammatory disease, living in the greater Athens area, Greece, participated in clinical examination. Adiponectin and IL-6 were measured in fasting plasma samples. MetS was defined according to the International Diabetes Federation (IDF) and the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) criteria. RESULTS: MetS was present in 37 % (IDF) and 33 % (AHA/NHLBI) of the study population (P < 0.001). Adiponectin was inversely associated with MetS (odds ratio, 95 % confidence interval: 0.829, 0.762- 0.902 for MetS-IDF, and 0.840, 0.772- 0.914 for MetS-AHA/NHLBI). Body mass index (BMI), waist circumference, high density lipoprotein (HDL)-cholesterol, triglyceride and insulin concentration mediated the association between adiponectin and MetS-IDF (z-test, standard error, P-value: 2.898, 0.012, 0.004, for BMI; 2.732, 0.012, 0.006 for waist circumference; 2.388, 0.011, 0.017 for HDL-cholesterol; 2.163, 0.010, 0.031 for triglyceride; 2.539, 0.010, 0.011 for insulin). Similarly, BMI, waist circumference, HDL-cholesterol and insulin concentration mediated the association between adiponectin and MetS-AHA/NHLBI (z-test, standard error, P-value: 2.633, 0.011, 0.008 for BMI; 2.441, 0.011, 0.015 for waist circumference; 1.980, 0.010, 0.048 for HDL-cholesterol; 2.225, 0.009, 0.026 for insulin). However, adiponectin remained significantly associated with MetS. IL-6 was not significantly associated with MetS. CONCLUSION: MetS components, in particular obesity and lipid indices, as well as serum insulin levels, mediate the association between adiponectin and MetS as defined by both the IDF and AHA/NHLBI criteria.

Synthesis of new nebularine analogues and their inhibitory activity against adenosine deaminase.

A number of new 2,6-disubstituted-1-deazanebularine analogues as well as two structurally related pyrazole-fused tricyclic nucleosides were prepared. Their synthesis was carried out by the conversion of 6-amino-2-picoline to a suitable 1-deazapurine, followed by a Vorbrüggen type glycosylation and subsequent elaboration of the condensed pyrazole ring. The synthesized nebularine analogues proved to be weak adenosine deaminase inhibitors.

Blood redox status is associated with the likelihood of nonalcoholic fatty liver disease irrespectively of diet's total antioxidant capacity.

It is well established that oxidative stress is implicated in nonalcoholic fatty liver disease pathogenesis, whereas the dietary intake of antioxidants has been reported to be low in patients with the disease. We hypothesized that blood redox status measurements would be associated with nonalcoholic fatty liver disease presence and severity, and that diet's total antioxidant capacity could moderate the aforementioned association. The study sample consisted of 73 patients with nonalcoholic fatty liver disease, of which 58 were matched by age, sex, and body mass index with 58 controls. Diet's total antioxidant capacity was estimated through the ferric-reducing antioxidant power, the total radical-trapping antioxidant parameter, and the Trolox equivalent antioxidant capacity scores, whereas blood redox status was assessed by measuring thiobarbituric acid reactive substances levels, the enzymatic activity of glutathione peroxidase, and serum resistance to oxidation. Diet's total antioxidant capacity scores and glutathione peroxidase activity were not significantly associated with the disease presence or severity. Both thiobarbituric acid reactive substances and serum resistance to oxidation were significantly associated with the likelihood of nonalcoholic fatty liver disease (odds ratios [ORs], 7.769 [P= .007] and 0.936 [P= .033], respectively), independently of abdominal fat level, degree of insulin resistance, blood lipid levels, markers of subclinical inflammation, and diet's total antioxidant capacity, but not with the disease histologic severity or stage. Our results support the association between blood redox status and the likelihood of nonalcoholic fatty liver disease regardless of diet's total antioxidant capacity.

The impact of cereal grain consumption on the development and severity of non-alcoholic fatty liver disease.

PURPOSE: There is evidence that dietary habits contribute to the presence and severity of non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to explore any associations between consumption of grains and the development and severity of NAFLD. METHODS: Seventy-three consecutive NAFLD patients were enrolled. Additionally, 58 controls matched for age, sex and body mass index with 58 patients were also included. Consumption of grains was estimated through a semi-quantitative food frequency questionnaire. Medical history, anthropometric indices, body composition analysis, physical activity data, biochemical and inflammatory markers were available for all the participants. Liver stiffness measurement by transient elastography was performed in 58 and liver biopsy in 34 patients. RESULTS: In patients, consumption of whole grains was associated with lower abdominal fat level (ß = -0.24, p = 0.02) and lower levels of insulin resistance index (ß = -0.28, p = 0.009), while it also correlated inversely with interleukin-6 levels (ρ = -0.23, p = 0.05). Consumption of whole grains was associated with lower likelihood of having histological steatohepatitis (OR 0.97, 95% CI 0.94-1.000), after adjusting for sex and energy intake, but the association became weaker after further adjusting for abdominal fat or interleukin-6 levels. In the case-control analysis, consumption of refined grains was associated with higher odds of having NAFLD (OR 1.021, 95% CI 1.001-1.042), after adjusting for age, sex, energy intake, abdominal fat level, HOMA-IR, LDL, adiponectin and TNF-α. CONCLUSIONS: Although refined grain consumption increased the likelihood of having NAFLD, whole-grain consumption favorably affected clinical characteristics of patients with NAFLD and tended to be associated with less severe disease.

Adherence to the Mediterranean diet is associated with the severity of non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Nutrition has been proposed as a potential environmental factor affecting the risk of non-alcoholic fatty liver disease (NAFLD). In the present study, the impact of adherence to the Mediterranean diet (MD) on the presence and severity of NAFLD was explored. METHODS: Seventy-three consecutive adult patients with recent NAFLD diagnosis were included. Adherence to the MD was estimated with MedDietScore. Demographic and anthropometric data, body composition analysis and several biochemical and inflammatory markers were estimated. Liver stiffness measurements by transient elastography were available in 58 patients and liver biopsies in 34 patients. Fifty-eight patients were matched with 58 healthy controls in terms of age, sex and body mass index. RESULTS: MedDietScore was negatively correlated to patients' serum alanine aminotransferase (p = 0.03) and insulin levels (p = 0.001), insulin resistance index (p = 0.005) and severity of steatosis (p = 0.006) and positively to serum adiponectin levels (p = 0.04). Patients with non-alcoholic steatohepatitis (NASH) exhibited lower adherence to MD (29.3 ± 3.2 vs. 34.1 ± 4.4, p = 0.004) compared to those with simple fatty liver. Logistic regression analysis revealed that one unit increase in the MedDietScore was associated with 36% lower likelihood of having NASH (odds ratio: 0.64, 95% confidence interval: 0.45-0.92), after adjusting for sex and abdominal fat level. No difference in the MedDietScore was observed between patients and controls. CONCLUSIONS: Higher adherence to the Mediterranean diet is not associated with lower likelihood of having NAFLD, but it is associated with less degree of insulin resistance and less severe liver disease among patients with NAFLD.

Cognitive function and oxidative stress after carotid endarterectomy: comparison of propofol to sevoflurane anesthesia.

OBJECTIVE: To examine the antioxidant role of propofol in ischemia-reperfusion during carotid endarterectomy (CEA) and its influence on cognitive dysfunction after CEA. DESIGN: A randomized prospective study. SETTING: Single-center study in a university hospital. PARTICIPANTS: Forty-four patients. INTERVENTIONS: Patients underwent elective CEA under general anesthesia with either sevoflurane (group S, n = 21) or propofol (group P, n = 23). MEASUREMENTS AND MAIN RESULTS: Cognitive function was assessed with the Mini-Mental State Examination (MMSE) before CEA, 1 hour after CEA, and 24 hours after CEA. Blood samples from the radial artery and the internal jugular vein were drawn before carotid clamping and 5 minutes following unclamping, and peripheral blood was obtained 24 hours postoperatively. Samples were analyzed for lactate, S100B, and P-selectin concentrations and for the antioxidative markers malondialdehyde/low-density lipoprotein ratio and nitrate + nitrite concentrations. Compared with group S, patients in group P exhibited a greater increase in their MMSE values 24 hours postoperatively. Patients who had their MMSE performance reduced at 24 hours also were significantly fewer in group P (13% v 43% in group S, p<0.05). Significantly lower levels of lactate and S100B were observed in arterial and jugular vein samples in group P. In addition, the jugular vein-arterial differences of malondialdehyde-to-low-density lipoprotein ratio and nitrates + nitrites concentrations were lower during propofol anesthesia. CONCLUSIONS: Propofol seemed to improve cognitive performance after CEA. This improvement was associated with decreased indices of ischemic cerebral damage and seemed to be due to antioxidative effect in the ischemic cerebral circulation.

Oral supplementation with L-aspartate and L-glutamate inhibits atherogenesis and fatty liver disease in cholesterol-fed rabbit.

Previous studies have shown that dietary supplementation with L-aspartate and L-glutamate inhibits fatty streak initiation in cholesterol-fed rabbit. The present study investigates the role of dicarboxylic amino acids on the progression of fatty streaks and the development of fatty liver disease, which were caused in New Zealand White rabbits after a 0.5% w/w cholesterol diet for 7 weeks. A group of animals additionally received a combination of 12.5 mM L-aspartate and 12.5 mM L-glutamate per day through drinking water. Total cholesterol (TC), high-density lipoproteins cholesterol (HDLC), non-HDLC and triacylglycerol (TAG) concentrations were measured in plasma. Serum gamma-glutamyl transferase (gamma-GT), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were also determined. At the end of dietary intervention, animals were sacrificed. Aortic, hepatic and brain lesions were evaluated after staining with hematoxylin and eosin. Supplementation with dicarboxylic amino acids inhibited the progression of aortic intima thickness (P < 0.05) and the development of liver lesions (P < 0.05). TC, non-HDLC and TAG were similarly increased in both cholesterol-fed groups. Serum gamma-GT and AST activities elevated during the study in all cholesterol-fed animals but the elevation of gamma-GT was milder and significantly lower in rabbits treated with L-aspartate and L-glutamate (P < 0.05). ALT activity was not affected by cholesterol feeding. In conclusion, oral supplementation with L-aspartate and L-glutamate inhibits the progression of atherogenesis and the development of fatty liver disease in the animal model of cholesterol-fed rabbit. The beneficial effects of dicarboxylic amino acids reflect the limited elevation of serum gamma-GT activity.

Platelet activating factor (PAF) and activity of its biosynthetic and catabolic enzymes in blood and leukocytes of male patients with newly diagnosed heart failure.

OBJECTIVES: To evaluate platelet activating factor (PAF) levels, its metabolic enzymes activity and its associations with other inflammatory markers in heart failure (HF) patients. DESIGN AND METHODS: PAF, and two of its key biosynthetic enzymes [lyso-PAF acetyltransferase (lyso-PAF-AT) and DTT-insensitive CDP-choline:1-alkyl-2-acetyl-sn-glycerol cholinephosphotransferase (PAF-CPT)] along with its catabolic enzymes [PAF-acetylhydrolase (PAF-AH) and lipoprotein-associated phospholipase-A(2) (Lp-PLA(2))] were measured in serum and leukocytes of twelve newly diagnosed male HF patients. Serum CRP, TNF-alpha, IL-6, sCD14 and CD40L were also determined. RESULTS: PAF ranged from 0.03 to 5.6 pmol/mL. Median lyso-PAF-AT, PAF-CPT, PAF-AH and Lp-PLA(2) activities were 4.1, 68.42, 644.44 pmol/min/mg protein and 51.42 pmol/min/microL correspondingly. Lyso-PAF-AT and PAF-CPT activities positively correlated with CRP, IL-6 and with each other, whereas PAF-CPT activity correlated with sCD14 and CD40L (P<0.05). CONCLUSIONS: PAF's biosynthetic enzyme activities correlated with inflammatory and immunologic molecules, which are activated in HF. Our study indicates a potential role of PAF in HF patients.