Changes in Oxidative Damage, Inflammation and [NAD(H)] with Age in Cerebrospinal Fluid

An extensive body of evidence indicates that oxidative stress and inflammation play a central role in the degenerative changes of systemic tissues in aging. However a comparatively limited amount of data is available to verify whether these processes also contribute to normal aging within the brain. High levels of oxidative damage results in key cellular changes including a reduction in available nicotinamide adenine dinucleotide (NAD+), an essential molecule required for a number of vital cellular processes including DNA repair, immune signaling and epigenetic processing. In this study we quantified changes in [NAD(H)] and markers of inflammation and oxidative damage (F2-isoprostanes, 8-OHdG, total antioxidant capacity) in the cerebrospinal fluid (CSF) of healthy humans across a wide age range (24–91 years). CSF was collected from consenting patients who required a spinal tap for the administration of anesthetic. CSF of participants aged .45 years was found to contain increased levels of lipid peroxidation (F2-isoprostanes) (p = 0.04) and inflammation (IL-6) (p = 0.00) and decreased levels of both total antioxidant capacity (p = 0.00) and NAD(H) (p = 0.05), compared to their younger counterparts. A positive association was also observed between plasma [NAD(H)] and CSF NAD(H) levels (p = 0.03). Furtheranalysis of the data identified a relationship between alcohol intake and CSF [NAD(H)] and markers of inflammation. The CSF of participants who consumed .1 standard drink of alcohol per day contained lower levels of NAD(H) compared to those who consumed no alcohol (p,0.05). An increase in CSF IL-6 was observed in participants who reported drinking .0–1 (p,0.05) and .1 (p,0.05) standard alcoholic drinks per day compared to those who did not drink alcohol. Taken together these data suggest a progressive age associated increase in oxidative damage, inflammation and reduced [NAD(H)] in the brain which may be exacerbated by alcohol intake

Chronic nitrite treatment activates adenosine monophosphate-activated protein kinase-endothelial nitric oxide synthase pathway in human aortic endothelial cells

Endothelial dysfunction, with impaired bioavailability and/or bioactivity of the vasoprotective molecule, nitric oxide, appears to be a vital step in the initiation of atherosclerosis. Several studies have shown that dietary nitrate/nitrite can have significant benefits on human cardiovascular homeostasis. Although serum nitrite concentrations can reach micromolar levels, the physiological significance of nitrate/nitrite in normal tissues has not been fully elucidated. We investigated in vitro the chronic effects of nitrate/nitrite on endothelial nitric oxide synthase (eNOS) to determine the potential vasoprotective effects of nitrate/nitrite and the underlying molecular mechanisms. Our results demonstrate the expression of phosphorylated eNOS at Ser1177 and phosphorylated adenosine monophosphate activated protein kinase (AMPK) at Thr172 in human aortic endothelial cells were increased after nitrite treatment. We suggest that nitrite stimulation may enhance eNOS activation, which is due, in part, to AMPK activation. The AMPK–eNOS activation by nitrite may be a possible molecular mechanism underlying the vascular protective effects of dietary nitrate

Rescue of glucocorticoid-programmed adipocyte inflammation by omega-3 fatty acid supplementation in the rat

BACKGROUND: Adverse fetal environments predispose offspring to pathologies associated with the metabolic syndrome. Previously we demonstrated that adult offspring of dexamethasone-treated mothers had elevated plasma insulin and pro-inflammatory cytokines, effects prevented by a postnatal diet enriched with omega (n)-3 fatty acids. Here we tested whether prenatal glucocorticoid excess also programmed the adipose tissue phenotype, and whether this outcome is rescued by dietary n-3 fatty acids. METHODS: Offspring of control and dexamethasone-treated mothers (0.75 μg/ml in drinking water, day 13 to term) were cross-fostered to mothers on a standard (Std) or high n-3 (Hn3) diet at birth. Offspring remained on these diets post-weaning, and serum and retroperitoneal fat were obtained at 6 months of age (n = 5-8 per group). Serum was analysed for blood lipids and fatty acid profiles, adipocyte cross sectional area was measured by unbiased stereological analysis and adipose expression of markers of inflammation, glucocorticoid sensitivity and lipid metabolism were determined by RT-qPCR analysis. RESULTS: Serum total fatty acid levels were elevated (P < 0.01) in male offspring of dexamethasone-treated mothers, an effect prevented by Hn3 consumption. Prenatal dexamethasone also programmed increased adipose expression of Il6, Il1b (both P < 0.05) and Tnfa (P < 0.001) mRNAs regardless of fetal sex, but again this effect was prevented (for Il6 and Il1b) by Hn3 consumption. Offspring of dexamethasone-treated mothers had increased adipose expression of Gr (P = 0.008) and Ppara (P < 0.05) regardless of sex or postnatal diet, while 11bHsd1 was upregulated in males only. The Hn3 diet increased Ppard expression and reduced adipocyte size in all offspring (both P < 0.05) irrespective of prenatal treatment. CONCLUSIONS: Prenatal glucocorticoid exposure programmed increased expression of inflammatory markers and enhanced glucocorticoid sensitivity of adipose tissue. Partial prevention of this phenotype by high n-3 consumption indicates that postnatal dietary manipulations can limit adverse fetal programming effects on adipose tissue

N-Acetylcysteine prevents but does not reverse dexamethasone-induced hypertension

1. We have shown previously that N-acetylcysteine (NAC) prevents the increase in blood pressure induced by adrenocorticotropin treatment. The present study investigated the effect of NAC on dexamethasone (Dex)-induced hypertension. 2. Male Sprague-Dawle

Relationship between dietary intake and erythrocyte PUFA in adolescents from a Western Australian cohort

Background: Population-based studies show that the intake of omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFA) are associated with a range of health conditions. Therefore, the reliability of food frequency questionnaires (FFQ) as rapid and easily accessible screening tools for PUFA intake deserve investigation. Objective: We aimed to assess the relationship between erythrocyte fatty acids and fatty acid intake collected using the Commonwealth Scientific and Industrial Research Organisation (CSIRO) food frequency questionnaire in an adolescent cohort. Design: A cross-sectional study using data from 1155 young adolescents participating in the 14-year follow-up of the Raine Study. Bland–Altman plots were used to determine the agreement between dietary intake and erythrocyte levels of each fatty acid. Results: The main dietary source of n-3 long-chain (LC) PUFA was ‘fresh fish’ (53% of total n-3 LC-PUFA). Docosahexaenoic acid (DHA) showed the strongest correlation between erythrocyte and diet assessment (r = 0.274; p \u3c 0.001), whilst linoleic acid (LA) (r = 0.103; p \u3c 0.001) and arachidonic acid (AA) (r = − 0.06; p = 0.042) showed weaker correlations, with limits of agreement relatively narrow. Bland–Altman plots showed a dose-dependent bias between the FFQ fatty acid data and corresponding erythrocyte data. Conclusions: For the major n-3 and n-6 PUFA, dietary intakes derived from the FFQ showed weaker correlations and poorer agreement with erythrocyte levels, and the deviation between the two increased with higher intake levels

Changes in dairy food and nutrient intakes in Australian adolescents

Dairy nutrients, such as calcium, are particularly important in adolescence, a critical time for growth and development. There are limited Australian data following individuals through adolescence, evaluating changes in dairy nutrient and dairy product consumption. We used a validated food frequency questionnaire to investigate consumption in adolescents participating in both the 14 and 17 year follow-ups of the Western Australian Pregnancy Cohort (Raine) Study. Most adolescents did not reach age and gender specific recommended daily intakes for calcium or magnesium at 14 years, and this decreased as they aged to 17 years (from 33.0% to 29.2% meeting for calcium, P \u3c 0.05, and from 33.6% to 20.5% meeting for magnesium, P \u3c 0.01). Mean intakes of calcium, potassium, riboflavin and vitamin A also decreased with age (P \u3c 0.01). Mean dairy intake decreased from 536 ± 343 g/day to 464 ± 339 g/day (P \u3c 0.01), due mostly to a decrease in regular milk, although flavoured milk consumption increased in boys. Cheese and butter were the only products to show a significantly increased consumption over the period. Girls decreased from 2.2 to 1.9 serves/day of dairy, while boys remained relatively steady at 2.9 to 2.8 serves/day. Our findings suggest that dairy product consumption decreases over adolescence. This may have implications for bone mass, development and later health

Sex differences in the association of phospholipids with components of the metabolic syndrome in young adults

BACKGROUND: There are differences in the prevalence and severity of diseases between males, females not taking hormonal contraceptives (non-HC females) and females taking hormonal contraceptives (HC females). The aim of this study was to identify sex-specific differences in the metabolome and its relation to components of the metabolic syndrome in a young adult population. METHODS: The subjects analysed are from the 20-year follow-up of the Western Australian Pregnancy Cohort (Raine) Study. Two hundred fifteen plasma metabolites were analysed in 1021 fasted plasma samples by a targeted liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) metabolomics approach. Principal component analysis between males (n = 550), non-HC females (n = 199) and HC females (n = 269) was applied. Regression analysis with a sex x metabolite concentration interaction was performed on components of the MetS, namely waist circumference, systolic blood pressure, and plasma HDL-C, triglycerides and glucose concentration, as outcome to select the significant metabolites of the interaction. Those selected metabolites were used as predictors in a sex group stratified analysis to compare the different beta coefficients and therefore the sex group-dependent associations. RESULTS: Principal component analysis between males, non-HC females, and HC females showed a general discriminating trend between males and HC females. One hundred twenty-seven metabolites were significantly different between males and non-HC females, whereas 97 differed between non-HC females and HC females. Males and non-HC females mainly differed in sphingomyelin, lyso-phosphatidylcholine, acyl-carnitine and amino acid species, whilst non-HC females and HC females mainly differed in phosphatidylcholine, lyso-phosphatidylcholine and acyl-carnitine concentrations. Forty-one metabolites (phosphatidylcholines, sphingomyelines, lyso-phosphatidylcholine) were significantly differently associated with the MetS factors in the different groups. CONCLUSIONS: We have shown clear differences between plasma metabolite concentrations in males, and HC or non-HC females, especially in lyso-phosphatidylcholine, sphingomyelin and phosphatidylcholine, which have been shown to associate with obesity in other studies. The association of these metabolites differed between sexes with components of the metabolic syndrome, which means that development of diseases like obesity and diabetes may differ between the sexes. Our findings highlight the importance of considering sex differences when conducting a metabolomics study and the need to account for the effect of HC usage in females in future studies

Oral contraceptive use in girls and alcohol consumption in boys are associated with increased blood pressure in late adolescence

Aims: Lifestyle behaviours established during adolescence may adversely affect blood pressure (BP) and contribute to gender differences in cardiovascular risk in adulthood. We aimed to assess the association of health behaviours with BP in adolescents, using data from the Western Australian Pregnancy (Raine) Study. Methods: Cross-sectional analysis on 1248 Raine Study adolescents aged 17 years, to examine associations between lifestyle factors and BP. Results: Boys had 8.97 mmHg higher systolic BP, as compared with girls. The 30% of girls using oral contraceptives (OC) had 3.27 and 1.74 mmHg higher systolic and diastolic BP, respectively, compared with non-users. Alcohol consumption in boys, increasing body mass index (BMI) and the sodium-potassium ratio were associated with systolic BP. We found a continuous relationship between BMI and systolic BP in both genders; however, the gradient of this relationship was significantly steeper in boys, compared with girls not taking OC. In boys, systolic BP was 5.7 mmHg greater in alcohol consumers who were in the upper quartile of BMI and the urinary sodium-potassium ratio compared with teetotallers in the lowest quartile. In girls, systolic BP was 5.5 mmHg higher in those taking OC, in the highest BMI and urinary sodium-potassium ratio quartile as compared to those not taking the OC pill and in the lowest quartile. Conclusion: In addition to gender-related differences in the effects of adiposity on BP, we found lifestyle-related health behaviours such as high salt intake for both sexes, consumption of alcohol in boys, and OC use in girls were important factors associated with BP measurements in late adolescence. This suggests that gender-specific behavioural modification in adolescence may prevent adult hypertension

Fetal growth trajectories and measures of insulin resistance in young adults

Context: Events during gestation greatly influence the risk of cardiometabolic diseases including diabetes in offspring during later life. Objective: This study aimed to investigate relationships between serial ultrasound-derived fetal growth trajectories and markers of insulin resistance in young adults in the Raine Study, an Australian pregnancy cohort. Methods: Linear mixed modeling examined the relationship between fetal growth trajectory groups, constructed using serial ultrasound-based abdominal circumference (AC), femur length (FL), and head circumference (HC) from 1333 mother-fetal pairs, and offspring Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), as a marker of diabetes risk, at 20 (n = 414), 22 (n = 385), and 27 (n = 431) years. Analyses were adjusted for age, sex, ethnicity, socioeconomic status, adult lifestyle factors, and maternal factors during pregnancy. Results: The study identified 7 AC, 5 FL, and 5 HC growth trajectory groups. Compared to the average-stable (reference) group, a low-falling AC growth trajectory (26%; P = .005) and 2 low HC growth trajectories (20%; P = .006% and 8%; P = .021) were associated with higher adult HOMA-IR. Trajectories representing a high-stable FL and a rising HC were associated with 12% (P = .002) and 9% (P = .021) lower adult HOMA-IR, respectively, compared to the reference group. Conclusion: Restricted fetal HC and AC from early pregnancy are associated with higher relative insulin resistance in the offspring during adulthood. These data strengthen our understanding of the importance of the intrauterine environment and its effect on the risk of predisposition to adult diabetes and related metabolic disorders

The effects of alcohol on plasma lipid mediators of inflammation resolution in patients with Type 2 diabetes mellitus

Background Type 2 diabetes mellitus is characterized by peripheral insulin resistance and low-grade systemic inflammation. Inflammation resolution is recognised as an important process driven by specialised pro-resolving mediators of inflammation (SPMs) and has the potential to moderate chronic inflammation. Alcohol has the potential to affect synthesis of SPMs by altering key enzymes involved in SPM synthesis and may influence ongoing inflammation associated with Type 2 diabetes mellitus. Aims (i) To examine the effects of alcohol consumed as red wine on plasma SPM in men and women with Type 2 diabetes in a randomised controlled trial and (ii) compare baseline plasma SPM levels in the same patients with those of healthy volunteers. Methods Twenty-four patients with Type 2 diabetes mellitus were randomized to a three-period crossover study with men drinking red wine 300 ml/day (∼31 g alcohol/day) and women drinking red wine 230 ml/day (∼24 g alcohol/day), or equivalent volumes of dealcoholized red wine (DRW) or water, each for 4 weeks. The SPM 18-hydroxyeicosapentaenoic acid (18-HEPE), E-series resolvins (Rv) (RvE1-RvE3), 17-hydroxydocosahexaenoic acid (17-HDHA), and D-series resolvins (RvD1, 17R-RvD1, RvD2, RvD5), 14-hydroxydocosahexaenoic acid (14-HDHA) and Maresin 1 were measured at the end of each period. A baseline comparison of plasma SPM, hs CRP, lipids and glucose was made with healthy volunteers. Results Red wine did not differentially affect any of the SPM measured when compared with DRW or water. Baseline levels of the hs-CRP and the SPM 18-HEPE, 17-HDHA, RvD1 and 17R-RvD1 in patients with Type 2 diabetes mellitus were all significantly elevated compared with healthy controls and remained so after adjusting for age and gender. Conclusion Moderate alcohol consumption as red wine does not alter plasma SPM in patients with Type 2 diabetes mellitus. The elevation of SPM levels compared with healthy volunteers may be a homeostatic response to counter ongoing inflammation