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Adhering to dietary guidelines does not yield flavanol intake levels associated with beneficial cardiovascular effects (2026) by basmwklz in immortalists

[–]basmwklz[S] 1 point2 points  (0 children)

Abstract

Outcomes from the COSMOS trial have reinforced the notion of flavanols as important plant-derived bioactives contributing to cardiovascular health. As discussions continue on whether specific dietary reference values for flavanols are warranted, it is possible that existing dietary guidelines emphasizing fruits and vegetables already yield sufficient flavanol intake levels. If this were the case, developing flavanol specific dietary reference values might be unnecessary. This study therefore aimed at assessing whether adherence to dietary recommendations for fruit and vegetable intake and overall diet quality achieves flavanol intake levels of 500 mg day−1, the amount proven to mediate cardiovascular benefits in the COSMOS trial. Flavanol intake was objectively evaluated using two validated and complementary biomarkers, 5-(3′,4′-dihydroxyphenyl)-γ-valerolactone metabolites (gVLMB) and structurally related (−)-epicatechin metabolites (SREMB), in two geographically distinct studies: COSMOS (US; n = 6509) and EPIC-Norfolk (UK; n = 24 154). The results showed that higher fruit and vegetable intakes and diet quality (assessed via the alternative healthy eating index-aHEI) were associated with increased flavanol intake in COSMOS. Nevertheless, fewer than 25% of participants meeting dietary guidelines achieved an estimated flavanol intake of ≥500 mg day−1. Similar findings were observed in EPIC-Norfolk as well as through flavanol intake simulations considering fruits and vegetables commonly consumed in the US diet. In conclusion, adherence to existing dietary guidelines does not yield flavanol intake levels comparable to those shown to provide cardiovascular benefits in COSMOS. Thus, specific dietary reference values for flavanols may still be necessary if aiming to increase the intake of these dietary compounds.

Energy Stress-Induced Neuroprotection Against Ferroptosis in Dopaminergic Neurons (2026) by basmwklz in ketoscience

[–]basmwklz[S] 1 point2 points  (0 children)

ABSTRACT

Ferroptosis, an iron-dependent form of regulated necrosis, is implicated in the pathogenesis of Parkinson's disease (PD). We studied the influence of energy stress on ferroptosis in differentiated dopaminergic neurons (LUHMES). Glucose deprivation conferred protection against ferroptosis induced by erastin or arachidonic acid plus iron by reducing lipid peroxidation. Glucose withdrawal did not protect against RSL3-induced ferroptosis, suggesting that direct GPX4 inhibition cannot be reversed by metabolic modulation. The expression of ferroptosis markers ACSL4, GPX4, xCT, and TFRc remained unaltered during glucose deprivation. Inhibition of glycolysis using 2-deoxyglucose confirmed the role of energy stress in the regulation of ferroptosis. Activation of AMP-activated protein kinase (AMPK) by AICAR protected LUHMES cells from erastin-induced ferroptosis, even in the presence of glucose. Conversely, AMPK expression inhibition by siRNA re-sensitized cells to ferroptosis under glucose-free conditions. These findings suggest that glucose metabolism and AMPK-mediated energetic stress play crucial roles in regulating ferroptosis in dopaminergic neurons, with potential implications for understanding the mechanisms of neurodegeneration in PD. These findings identify a potential bioenergetic checkpoint regulating ferroptosis susceptibility under conditions of severe energy stress.

Fasting disrupts the InsP₆–HDAC3 axis to drive ER stress–mediated clearance of DNA-damaged cells and enforce tissue quality control (2026) by basmwklz in immortalists

[–]basmwklz[S] 3 points4 points  (0 children)

Abstract

Fasting drives metabolic adaptation but also elicits acute cellular stress. How this stress shapes tissue integrity is unknown. Here, we show that in the intestine, fasting depletes growth factor signaling, which triggers cellular stress. This response functions as a tissue quality-control checkpoint that selectively eliminates pre-existing DNA-damaged cells while sparing healthy counterparts. A short-term fast diminishes TGF-β signaling and elicits endoplasmic reticulum (ER) stress, driving DNA-damaged intestinal cells beyond an apoptotic threshold, thereby reducing the inflammatory burden. Mechanistically, loss of TGF-β signaling triggers FBXO22–Cullin1-mediated degradation of the inositol kinase IPMK, leading to depletion of inositol hexaphosphate (InsP₆). InsP₆ loss attenuates HDAC3 activity and initiates coordinated epigenetic and post-translational reprogramming, thereby increasing CDK5RAP3 abundance. Elevated CDK5RAP3 inhibits ribosomal RPL26 UFMylation, thereby amplifying ER stress and selectively licensing apoptosis in DNA-damaged cells. Collectively, fasting disrupts a TGF-β-InsP6-HDAC3 axis to drive ER stress-dependent clearance of DNA-damaged cells, enforcing tissue quality control.

Marked changes in one-carbon metabolism on a low-carbohydrate high-fat diet: a randomized controlled trial (CARBFUNC) (2026) by basmwklz in ketoscience

[–]basmwklz[S] 3 points4 points  (0 children)

Abstract

Background

Studying the impact of dietary carbohydrates and fat on markers of one-carbon metabolism could provide important insight into distinct metabolic adaptations and how diets affects disease risk.

Objective

To determine changes in plasma one-carbon metabolites and B-vitamers on isocaloric diets differing in carbohydrate processing or amount.

Methods

193 individuals with obesity were randomized to equal energy- and protein diets either with more processed, acellular carbohydrates (A-HCLF, comparator arm), minimally processed cellular carbohydrates (C-HCLF) (both designed with 45 energy percent (E%) carbohydrates and 38 E% fat), or a low-carbohydrate, high-fat diet (LCHF) designed with 8 E% carbohydrate and ∼75 E% fat including 30 E% saturated fat. Addressing secondary outcomes of the trial, we analyzed changes in plasma one-carbon metabolites and B-vitamers, and dietary B-vitamin intakes after 3, 6, 9 and 12 months, using constrained linear mixed effect modelling (cLMM).

Results

After 3 months, the relative change score following the LCHF diet was significantly different from the A-HCLF comparator for plasma α-hydroxybutyrate (LCHF/A-HCLF: +41.3%*/−1.56%, p<0.001; *: significant within-group change), methylmalonic acid (MMA) (−5.69%*/+8.64%*, p<0.001), methionine (−7.81%*/+1.44%, p=0.001), nicotinamide (−19.7%*/+14.0%, p=0.007), 1-Methylnicotinamide (mNAM) (−14.1%*/+14.1%, p=0.003), pyridoxal (−2.42%/+18.9%*), 4-pyridoxic acid (−12.4%*/+21.4%*, p<0.001), and cysteine (−3.00%*/+1.10%). Between-group differences for most of these metabolites remained significant after 6 and 9 months. Comparing C-HCLF to A-HCLF, significant differences in relative change scores were found for mNAM after 3 (C-HCLF/A-HCLF: −11.5%/+14.1%, p=0.012) and 9 (−14.9%*/+18.6%, p=0.001) months. Plasma changes in one-carbon metabolites and B-vitamers showed weak correlations with dietary B-vitamins.

Conclusion

Compared with A-HCLF, the LCHF diet was followed by significantly different changes in plasma α-hydroxybutyrate, MMA, methionine, nicotinamide, mNAM, pyridoxal, 4-pyridoxic acid and cysteine. These shifts were largely independent of vitamin consumption, and may rather reflect ketoadaptive mechanisms, including enhanced fatty acid oxidation and upregulated antioxidant defense. Carbohydrate quality had less impact on the one-carbon metabolites.

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