The mechanisms underlying non-alcoholic steatohepatitis (NASH) are not completely elucidated. In the current study we integrated gene expression profiling of liver biopsies from NASH patients with ...translational studies in mouse models of steatohepatitis and pharmacological interventions in isolated hepatocytes to identify new molecular targets in NASH.
Using oligonucleotide microarray analysis we identified a significant enrichment of genes involved in the multi-step catalysis of long-chain polyunsaturated fatty acids, namely, Δ-5 desaturase (Δ5D) and Δ6D in NASH. Increased expression of Δ5D and Δ6D at both mRNA and protein level were confirmed in livers from mice with high-fat diet-induced obesity and NASH. Gas chromatography analysis revealed impaired desaturation fluxes toward the ω-6 and ω-3 pathways resulting in increased ω-6 to ω-3 ratio and reduced ω-3 index in human and mouse fatty livers. Restoration of hepatic ω-3 content in transgenic fat-1 mice expressing an ω-3 desaturase, which allows the endogenous conversion of ω-6 into ω-3 fatty acids, produced a significant reduction in hepatic insulin resistance, steatosis, macrophage infiltration, necroinflammation and lipid peroxidation, accompanied by attenuated expression of genes involved in inflammation, fatty acid uptake and lipogenesis. These results were mostly reproduced by feeding obese mice with an exogenous ω-3-enriched diet. A combined Δ5D/Δ6D inhibitor, CP-24879, significantly reduced intracellular lipid accumulation and inflammatory injury in hepatocytes. Interestingly, CP-24879 exhibited superior antisteatotic and anti-inflammatory actions in fat-1 and ω-3-treated hepatocytes.
These findings indicate that impaired hepatic fatty acid desaturation and unbalanced ω-6 to ω-3 ratio play a role in the pathogenesis of NASH.
Diabetic retinopathy (DR) is a devastating complication of individuals with type 2 diabetes mellitus. The retina is rich in long-chain ω-3 polyunsaturated fatty acids (LCω3PUFAs), which are substrate ...for oxylipins with anti-inflammatory and antiangiogenic properties. Experimental models support dietary LCω3PUFA protection against DR, but clinical data are lacking.
To determine whether LCω3PUFA intake relates to a decreased incidence of sight-threatening DR in individuals with type 2 diabetes older than 55 years.
In late 2015, we conceived a prospective study within the randomized clinical trial Prevención con Dieta Mediterránea (PREDIMED), testing Mediterranean diets supplemented with extra virgin olive oil or nuts vs a control diet for primary cardiovascular prevention. The trial was conducted in primary health care centers in Spain. From 2003 to 2009, 3614 individuals aged 55 to 80 years with a previous diagnosis of type 2 diabetes were recruited. Full data were available for 3482 participants (48% men; mean age 67 years).
Meeting the dietary LCω3PUFA recommendation of at least 500 mg/d for primary cardiovascular prevention, as assessed by a validated food-frequency questionnaire.
The main outcome was incident DR requiring laser photocoagulation, vitrectomy, and/or antiangiogenic therapy confirmed by an external adjudication committee.
Of the 3482 participants, 48% were men and the mean age was 67 years. A total of 2611 participants (75%) met target LCω3PUFA recommendation. During a median follow-up of 6 years, we documented 69 new events. After adjusting for age, sex, intervention group, and lifestyle and clinical variables, participants meeting the LCω3PUFA recommendation at baseline (≥500 mg/d) compared with those not fulfilling this recommendation (<500 mg/d) showed a 48% relatively reduced risk of incident sight-threatening DR, with a hazard ratio of 0.52 (95% CI, 0.31-0.88; P = .001). This association was slightly stronger for yearly updated LCω3PUFA intake (relative risk, 0.48; 95% CI, 0.28-0.82; P = .007).
In middle-aged and older individuals with type 2 diabetes, intake of at least 500 mg/d of dietary LCω3PUFA, easily achievable with 2 weekly servings of oily fish, is associated with a decreased risk of sight-threatening DR. Our results concur with findings from experimental models and the current model of DR pathogenesis.
clinicaltrials.gov Identifier: http://www.controlled-trials.com/ISRCTN35739639.
Purpose
Epidemiological studies and clinical trials support the association of nut consumption with a lower risk of prevalent non-communicable diseases, particularly cardiovascular disease. However, ...the molecular mechanisms underlying nut benefits remain to be fully described. MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression and play a pivotal role in health and disease. Exosomes are extracellular vesicles released from cells and mediate intercellular communication. Whether nut consumption modulates circulating miRNAs (c-miRNAs) transported in exosomes is poorly described.
Methods
Cognitively healthy elderly subjects were randomized to either control (
n
= 110, abstaining from walnuts) or daily supplementation with walnuts (15% of their total energy, ≈30–60 g/day,
n
= 101) for 1-year. C-miRNAs were screened in exosomes isolated from 10 samples, before and after supplementation, and identified c-miRNA candidates were validated in the whole cohort. In addition, nanoparticle tracking analysis and lipidomics were assessed in pooled exosomes from the whole cohort.
Results
Exosomal hsa-miR-32-5p and hsa-miR-29b-3p were consistently induced by walnut consumption. No major changes in exosomal lipids, nanoparticle concentration or size were found.
Conclusion
Our results provide novel evidence that certain c-miRNAs transported in exosomes are modulated by walnut consumption. The extent to which this finding contributes to the benefits of walnuts deserves further research.
Walnut consumption counteracts oxidative stress and inflammation, 2 drivers of cognitive decline. Clinical data concerning effects on cognition are lacking.
The Walnuts And Healthy Aging study is a ...2-center (Barcelona, Spain; Loma Linda, CA) randomized controlled trial examining the cognitive effects of a 2-y walnut intervention in cognitively healthy elders.
We randomly allocated 708 free-living elders (63–79 y, 68% women) to a diet enriched with walnuts at ∼15% energy (30–60 g/d) or a control diet (abstention from walnuts). We administered a comprehensive neurocognitive test battery at baseline and 2 y. Change in the global cognition composite was the primary outcome. We performed repeated structural and functional brain MRI in 108 Barcelona participants.
A total of 636 participants completed the intervention. Besides differences in nutrient intake, participants from Barcelona smoked more, were less educated, and had lower baseline neuropsychological test scores than those from Loma Linda. Walnuts were well tolerated and compliance was good. Modified intention-to-treat analyses (n = 657) uncovered no between-group differences in the global cognitive composite, with mean changes of −0.072 (95% CI: −0.100, −0.043) in the walnut diet group and −0.086 (95% CI: −0.115, −0.057) in the control diet group (P = 0.491). Post hoc analyses revealed significant differences in the Barcelona cohort, with unadjusted changes of −0.037 (95% CI: −0.077, 0.002) in the walnut group and −0.097 (95% CI: −0.137, −0.057) in controls (P = 0.040). Results of brain fMRI in a subset of Barcelona participants indicated greater functional network recruitment in a working memory task in controls.
Walnut supplementation for 2 y had no effect on cognition in healthy elders. However, brain fMRI and post hoc analyses by site suggest that walnuts might delay cognitive decline in subgroups at higher risk. These encouraging but inconclusive results warrant further investigation, particularly targeting disadvantaged populations, in whom greatest benefit could be expected. This trial was registered at clinicaltrials.gov as NCT01634841.
Purpose
Information on the association between diet and cardiovascular disease (CVD) in type 1 diabetes (T1D) is scarce. We assessed the association between biomarkers of fatty acid (FA) intake and ...the presence of carotid plaques (a surrogate marker of future CVD events) in this high-risk population.
Methods
Cross-sectional study in 167 consecutive T1D patients without CVD and with at least one of the following: ≥ 40 years, diabetic nephropathy, or ≥ 10 years of T1D duration with another CVD risk factor. The FA profile of erythrocyte membranes was determined by gas chromatography, and the number of carotid plaques (intima-media thickness ≥ 1.5 mm) was assessed by ultrasonography. Regression models were constructed adjusting for classical (age, gender, blood pressure, smoking habit, LDL-cholesterol, body mass index and statins) and T1D-specific risk factors (diabetes duration, HbA1c and chronic complications).
Results
A total of 58.7% were men (mean age 48.3 ± 10.3 years, T1D duration 27.2 ± 10.1 years). Sixty-one patients (36.5%) showed carotid plaque. Linoleic acid decreased and all-C18:1
trans
increased with the number of carotid plaques (none, 1–2, ≥ 3 plaques;
p
for trend < 0.05). In multivariate regression models, linoleic acid remained inversely associated with the presence of plaque 1% increase of total FAs; OR 0.71 (0.53–0.95),
p
= 0.021 and ≥ 2 plaques OR 0.70 (0.51–0.98),
p
= 0.039; whereas, all-C18:1
trans
was positively associated with ≥ 3 plaques (0.1% increase of total FAs; OR 1.51 1.05–2.16, p = 0.026).
Conclusions
Erythrocyte FA composition, as a biomarker of FA intake, was independently associated with preclinical atherosclerosis in T1DM. Our data support the potential role of an unfavorable pattern of fat intake and CVD risk in this population.
Diabetic subjects are at increased risk of cardiovascular disease. Atherosclerosis, the common soil of most of the cardiovascular complications, is more prevalent and extensive in this population due ...not only to hyperglycemia, insulin resistance, and dyslipidemia, but also to inflammation and oxidative stress. Lycopenes are bioactive compounds with antioxidant and anti-inflammatory activities mostly supplied by tomato and tomato byproducts. We investigated the association between circulating lycopenes and carotid plaque burden in diabetic patients, in a cross-sectional study in 105 newly diagnosed diabetic subjects. Atheroma plaque (wall thickness ≥ 1.5 mm), number of plaques, and plaque burden (sum of maximum heights of all plaques) were assessed by sonographic evaluation of carotid arteries. Plasma lycopenes (5-
-, 9-
-, 13-
-, and
-lycopene) were quantified by high performance liquid chromatography-mass spectrometry HPLC-MS. Atheroma plaque was observed in 75 participants, from which 38 presented one plaque and 37 two or more carotid plaques. No differences were observed in the plasmatic concentrations of lycopenes between subjects with and without atherosclerotic plaque presence. However, plaque burden was inversely associated with 5-
-lycopene, all
-lycopene isomers,
-lycopene, and total lycopene isomers (all,
< 0.05). High plasma levels of lycopenes inversely relate to atherosclerotic burden. We provide novel evidence that suggests that the consumption of compounds found in tomato and tomato byproducts might be beneficial for the prevention of atherosclerosis.
Accumulating evidence links nut consumption with an improved risk of metabolic syndrome (MetS); however, long-term trials are lacking. We examined the effects of a daily dose of walnuts for two years ...on MetS in a large elderly cohort. A total of 698 healthy elderly participants were randomly assigned to either a walnut supplemented or a control diet. The participants in the walnut group were provided with packaged walnuts (1, 1.5, or 2 oz. or ~15% of energy) and asked to incorporate them into their daily habitual diet. The participants in the control group were asked to continue with their habitual diet and abstain from eating walnuts and other tree nuts. Intake of n-3 fatty acid supplements was not permitted in either group. Fasting blood chemistries, blood pressure, and anthropometric measurements were obtained at baseline and at the end of intervention. A total of 625 participants (67% women, mean age 69.1 y) completed this two-year study (90% retention rate). Triglycerides decreased in both walnut (-0.94 mg/dl) and control (-0.96 mg/dl) groups, with no significant between-group differences. There was a non-significant decrease in systolic and diastolic blood pressure in the walnut group (-1.30 and -0.71 mm Hg, respectively) and no change in the control group. Fasting blood glucose decreased by ~1 point in both the walnut and control groups. There were no significant between-group differences in the development or reversion of MetS. In conclusion, supplementing the diet of older adults with a daily dose of walnuts had no effect on MetS status or any of its components, although the walnut group tended to have lower blood pressure.
The identification of nutritional patterns associated with the development of type 2 diabetes (T2D) might help lead the way to a more efficient and personalized nutritional intervention. Our study is ...aimed at evaluating the association between fatty acids (FA) in red blood cell (RBC) membranes, as a quantitative biomarker of regular dietary fat intake, and incident type 2 diabetes in a Spanish population. We included 1032 adult Spaniards (57% women, age 49 ± 15 years, 18% prediabetes), without diabetes at study entry, from the Di@bet.es cohort. Incident diabetes was diagnosed at the end of the study follow-up. The FA percentage in RBC was determined at baseline by gas chromatography. Participants were followed on average 7.5 ± 0.6 years. Lower percentages of linoleic acid (LA), α-linolenic (ALA), and eicosapentaenoic acid (EPA), and higher percentages of docosahexaenoic acid (DHA) in RBC membranes were associated, independently of classical risk factors, with worse glucose metabolism at the end of the study follow-up. In addition, higher percentages of ALA and EPA, and moderate percentages of DHA, were associated with lower risk of diabetes. No significant associations were found for LA and diabetes risk. Dietary patterns rich in vegetables are independently associated with lower risk of both deterioration of glucose regulation and incident diabetes, and should be reinforced for the prevention of diabetes.
During development of cardiovascular disease (CVD), interferon-γ-mediated inflammation accelerates degradation of tryptophan into downstream metabolites. A Mediterranean diet (MedDiet) consisting of ...a high intake of extra-virgin olive oil (EVOO), nuts, fruits, vegetables, and cereals has been demonstrated to lower the risk of CVD. The longitudinal relation between tryptophan and its downstream metabolites and CVD in the context of a MedDiet is unstudied.
We sought to investigate the relation between metabolites in the tryptophan-kynurenine pathway and CVD in the context of a MedDiet pattern.
We used a case-cohort design nested in the Prevención con Dieta Mediterránea randomized controlled trial. There were 231 CVD cases (stroke, myocardial infarction, cardiovascular death) among 985 participants over a median of 4.7 y of follow-up mean ± SD age: 67.6 ± 6.1 y; 53.7% women; mean ± SD body mass index (in kg/m
): 29.7 ± 3.7. We assessed plasma tryptophan, kynurenine, kynurenic acid, 3-hydroxyanthranilic acid, and quinolinic acid concentrations at baseline and after 1 y of intervention with a MedDiet. We combined these metabolites in a kynurenine risk score (KRS) by weighting each metabolite by the adjusted coefficient of its associations with CVD. Cox models were used in the primary analysis.
Increases in tryptophan after 1 y were associated with a lower risk of composite CVD (HR per SD: 0.79; 95% CI: 0.63, 0.98). The baseline kynurenic acid concentration was associated with a higher risk of myocardial infarction and coronary artery disease death but not stroke. A higher KRS was more strongly associated with CVD in the control group than in the 2 intervention groups (
-interaction = 0.003). Adjustment for changes in plasma tryptophan attenuated the inverse association between MedDiet+EVOO and CVD.
An increase in the plasma tryptophan concentration was significantly associated with a decreased risk of CVD. A MedDiet may counteract the deleterious effects of a high kynurenine risk score.
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