Food & Function最新文献

γ-Oryzanol, a mixture of phytosteryl ferulates present in rice bran, has gained attention for its cholesterol-lowering properties, likely due to its interaction with the pharmacological target enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR). Our study explores the individual contributions of the four major γ-oryzanol constituents, namely cycloartenyl ferulate, campesteryl ferulate, β-sitosteryl ferulate, and 24-methylenecycloartenyl ferulate, to cholesterol synthesis and efflux/excretion. First, according to a concerted approach involving molecular docking, surface plasmon resonance binding studies, and enzyme inhibition assays, we determined the binding affinities and inhibitory activities of each constituent toward HMGCR. Additionally, we evaluated their impact on cholesterol metabolism in HepG2 cells by assessing the cellular cholesterol levels and the expression of selected biomarkers of cholesterol metabolism pathways under non-cytotoxic conditions. The major components of γ-oryzanol, cycloartenyl ferulate (CAF) and 24-methylenecycloartenyl ferulate (24MCAF) significantly affected cholesterol metabolism and reduced cellular cholesterol levels via distinct mechanisms, despite their highly conserved chemical structures. Specifically, CAF reduced the total and free cholesterol levels, consequently triggering a compensatory activation of the SREBP-2 pathway, marked by increased HMGCR and LDL receptor expression, whereas 24MCAF moderately lowered cholesterol and enhanced its clearance primarily by upregulating the cholesterol efflux transporter ABCG1. Instead, both CAF and 24MCAF comparably affected ABCA1, another cholesterol efflux regulatory protein, and CYP7A1, essential for converting cholesterol into bile acids. Together, these dynamics reveal a dual modulation that supports the lipid-lowering effects of γ-oryzanol components and highlights their potential as therapeutic agents in cholesterol management.

Postmenopausal women are approximately twice as likely to develop cardiometabolic diseases (CMDs) as premenopausal women. Plant-based diets rich in fruits and vegetables, due to their high content of bioactive compounds such as (poly)phenols, represent a promising strategy to reduce the risk of CMDs in this population. However, the cardioprotective effects of (poly)phenols depend largely on inter-individual variability, which is strongly influenced by the gut microbiota composition. Menopause is often associated with gut dysbiosis, characterized by a reduced microbial diversity and a lower abundance of beneficial bacteria. This imbalance in the gut microbiota profile of postmenopausal women could influence (poly)phenol metabolism and, consequently, the health benefits attributed to (poly)phenol-rich food (PP-rich food) consumption. Therefore, this study aimed to assess the impact of a daily consumption of PP-rich foods (dark chocolate, green tea and fruit juice) for 2 months on the urinary phenolic profile in postmenopausal women at high cardiometabolic risk. To this end, 116 urinary phenolic metabolites were determined using UHPLC-ESI-QqQ-MS/MS. Dietary intervention with PP-rich foods led to a significant increase in the urinary excretion of phenolic metabolites derived from gut microbiota activity and phase II metabolism. Notably, there was a significant increase in the excretion of glucuronidated and/or sulfated conjugates of phenyl-γ-valerolactones, phenylvaleric acids, phenylacetic acids, benzoic acids, and urolithins. It is expected that these phenolic metabolites could be the bioactive compounds responsible for the potential beneficial effects derived from the daily intake of dark chocolate, green tea, and fruit juice on the reduction of the risk of CMDs in postmenopausal women.

Rhodomyrtus tomentosa fruit is an edible berry with diverse bioactivities. However, its antidepressant effects remain unexplored. The purpose of this study was to evaluate the impact of Rhodomyrtus tomentosa fruit ethanol extract (RTEE) on depressive-like behaviors resulting from chronic unpredictable mild stress (CUMS) exposure in mice and to investigate the underlying molecular mechanisms. The results demonstrated that RTEE significantly ameliorated depressive-like behaviors in CUMS-challenged mice, as indicated by increased total distance traveled, velocity, and central zone entries (in the open field test), enhanced sucrose preference (in the sucrose preference test), and decreased immobility time (in the forced swim and tail suspension tests). Meanwhile, RTEE significantly reduced the number of Iba-1⁺ and GFAP⁺ cells and down-regulated COX-2, TNF-α, and IL-6 expression in the hippocampus by suppressing the TLR4/MyD88/NF-κB signaling axis, thus alleviating neuroinflammation. In addition, RTEE significantly reduced the number of TUNEL⁺ cells in the dentate gyrus (DG), thus attenuating hippocampal apoptosis. Moreover, RTEE significantly increased the number of DCX⁺ and BrdU⁺ cells, up-regulated PSD95 expression, and restored the AMPK/BDNF/CREB and Wnt/β-catenin signaling axes in the hippocampus, thus rescuing hippocampal neurogenesis. These findings indicated that RTEE ameliorated depressive-like behaviors in CUMS-challenged mice by alleviating hippocampal neuroinflammation and apoptosis and rescuing neurogenesis. Therefore, this study establishes a mechanistic basis for the potential of Rhodomyrtus tomentosa fruit as an innovative nutritional therapy for depression.

Long-chain polyunsaturated fatty acids (LC-PUFAs) are vital for brain health, with cis9, trans11-conjugated linoleic acid (c9, t11-CLA) showing neuroprotective effects. This study investigated the impact of c9, t11-CLA on offspring cognitive development in an ω-3 PUFA deficiency model. c9, t11-CLA supplementation during gestation and lactation improved episodic-like memory and learning ability, as evidenced by a 63% increase in novel object recognition time and reduced Morris water maze latency. c9, t11-CLA altered brain lipid profiles and promoted myelination in the prefrontal cortex of pubescent offspring mice by upregulating the protein levels of myelin-associated glycoprotein (MAG) and platelet-derived growth factor receptor alpha (PDGFRα). In addition, although proteomic KEGG analysis and western blotting verified that c9, t11-CLA supplementation appears to modulate the PTEN/AKT signaling pathway in the hippocampus, its relationship with synaptic plasticity remains speculative. Western blot validation further revealed that c9, t11-CLA supplementation enhanced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activation and trafficking through increased phosphorylation of Ca/calmodulin-dependent protein kinase II alpha (CaMKIIα) at Thr286, ultimately strengthening synaptic plasticity as evidenced by significant upregulation of postsynaptic density protein 95 (PSD95), p-CaMKIIα/CaMKIIα, and glutamate ionotropic receptor AMPA type subunit 1 (GluA1). These findings highlight the potential of c9, t11-CLA as a nutritional intervention for neurodevelopment and provide preliminary insights into the mechanisms by which c9, t11-CLA supplementation may regulate cognitive function.

TMAO has been linked to various cardiometabolic diseases and all-cause mortality risk. A major dietary precursor of TMAO is L-carnitine. L-Carnitine is metabolised by microbiota to γ-butyrobetaine (γ-BB), followed by trimethylamine (TMA), and is then oxidised to TMAO in the liver. Previously, we have shown that a polyphenol-rich pomegranate extract dose-dependently inhibited the production of γ-BB and TMA from L-carnitine. Here, we further investigated the effects of the pomegranate extract and its individual constituents/metabolites (polyphenols, spray-drying agent gum Arabic, and urolithins) on the microbial metabolism of L-carnitine to γ-BB and TMA using a high-throughput in vitro model of the human colon. A small-scale, high-throughput colon model was inoculated with L-carnitine, individual constituents of the extract (2 mg mL^-1), and 1% human faecal inoculum, while continuously monitoring pH. Samples were collected over 48 hours, and methylamines were quantified using LC-MS/MS with isotopically labelled internal standards. Punicalagin, but not the other constituents, inhibited the conversion of L-carnitine to γ-BB (p < 0.001) and almost completely blocked TMA production compared to the control (p < 0.003). Furthermore, including the whole pomegranate extract in the high-throughput colon model significantly reduced the pH and completely inhibited L-carnitine metabolism, suggesting that acidification may also inhibit microbial L-carnitine metabolism. Here it was shown that, of all the tested phenolic and non-phenolic components of the pomegranate extract, only punicalagin inhibited TMA production from L-carnitine, highlighting it as a promising inhibitor of TMA and potentially TMAO formation.

Sarcopenia, an aging-related disorder characterized by progressive loss of skeletal muscle mass and function, lacks well-defined mechanisms and specific therapeutics. This study investigated the therapeutic effects of yeast protein (YP) on dexamethasone (DEX)-induced muscle atrophy in C57BL/6J mice using transcriptomic and metabolomic approaches. High-dose (2 g per kg bodyweight) YP (H-YP) significantly ameliorated muscle histopathology, increased serum CAT and SOD activity, enhanced grip strength and hanging endurance, elevated muscle ATP and IGF-1 levels, and reduced MSTN expression (P < 0.05). Multi-omics integration revealed that H-YP improved sarcopenia primarily by modulating protein anabolism, energy metabolism, oxidative stress, lipid metabolism, and inflammatory pathways. Key upregulated targets included the Prkag3 gene and metabolites (L-histidine, L-leucine, L-tyrosine, and guanidinoacetate). Mechanistically, H-YP synergistically activated both the IGF-1/PI3K/Akt/FOXO pathway and CaMKK/AMPK axis, collectively improving insulin sensitivity, mitochondrial function, and protein homeostasis. These findings provide a strategic foundation for sarcopenia intervention.

Background and aims: Currently, there is a paucity of systematic research investigating the association between betaine and its related metabolites in breast milk and infant neurodevelopment. To address this gap, this study aimed to examine the relationship between concentrations of betaine, choline, trimethylamine N-oxide (TMAO), and L-carnitine in breast milk and infant neurodevelopment. Methods: A prospective birth cohort study was conducted, enrolling 158 mother-infant pairs. Breast milk samples were collected at 42 days postpartum, and concentrations of the target metabolites were quantified using high-performance liquid chromatography-tandem mass spectrometry. Infant neurodevelopment was evaluated at 6 months of age using the "Child Developmental Scale (0-6 Years)", from which developmental quotients (DQ) across multiple domains were derived. Generalized linear models and Bayesian Kernel Machine Regression (BKMR) were employed to assess both individual and combined effects of the four metabolites on infant development. Results: Breast milk betaine levels were significantly positively associated with DQ scores in gross motor, fine motor, adaptability, and social behavior domains. Choline concentrations showed positive association with fine motor and adaptability DQ. In contrast, higher TMAO and L-carnitine levels were linked to lower adaptability and gross motor DQ, respectively. BKMR analysis identified betaine as the predominant contributor to overall developmental DQ among the four metabolites, with the strongest influence observed for the fine motor domain (posterior inclusion probability = 0.880). No significant pairwise interactions between metabolites were detected. Conclusion: This study offers comprehensive evidence regarding the relationships between breast milk levels of betaine, choline, TMAO, and L-carnitine and infant neurodevelopment at 6 months of age. These findings may inform personalized nutritional strategies during lactation to support optimal infant neurodevelopment. Clinical Trial Registry number: ChCTR2200055202.

Prospective evidence linking n-3 polyunsaturated fatty acid (PUFA) supplementation to non-alcoholic fatty liver disease (NAFLD) risk remains limited. In this cohort study of 488 888 UK Biobank participants, we evaluated associations of fish oil supplementation (a key source of n-3 PUFAs) with severe NAFLD incidence using Cox proportional hazards models. Mediation analysis evaluated the roles of serum metabolic and inflammatory biomarkers. Genetic interaction analyses included polymorphisms linked to n-3 PUFA metabolism. Over 12.3 years of follow-up, 5671 participants developed severe NAFLD. Fish oil supplementation was associated with a 7% lower risk of severe NAFLD (HR 0.93, 95% CI 0.87-0.99; P = 0.022). Mediation analyses revealed that C-reactive protein (CRP) (8.8% mediated), high-density lipoprotein cholesterol (HDL-C) (7.5%), and cystatin C (10.0%) partially explained this association. No significant interactions were observed between supplementation and genetic variants (all P > 0.05). These findings support the use of n-3 PUFA supplements in the primary prevention of severe NAFLD.

Urinary tract infections (UTIs) are among the most prevalent urological diseases worldwide, characterized by high morbidity and recurrence rates. Uropathogenic Escherichia coli (UPEC) is the predominant etiological agent of UTIs. It adheres to epithelial cells in the urethra or bladder via adhesins, followed by local colonization, proliferation, and induction of uroepithelial tissue damage and inflammation. However, the widespread use of antibiotics has led to increasing resistance in UPEC, posing significant challenges to the treatment of UTIs. In the present study, we successfully isolated and identified M-3-Gal as an antibacterial compound from cranberries. Research data indicated that oral administration of M-3-Gal before and after modeling in C57BL/6 mice significantly reduced bacterial loads in the urine, bladder, and kidneys of UTI mice, thereby alleviating UPEC-associated UTIs and reducing inflammatory and oxidative stress levels. In vitro experiments further revealed that M-3-Gal inhibits bacterial adhesion and invasion by suppressing the expression of bacterial adhesins, disrupting pilus structures, and downregulating the expression of cellular integrins.

Plants produce a diverse array of secondary metabolites, with hydroxytyrosol (HT) and its derivatives distinguished by their antioxidant and chemopreventive properties. Upon dietary consumption, native HT undergoes extensive biotransformation, initially facilitated by the gut microbiota. Increasing evidence suggests that several of these downstream products, rather than the parent molecule, are responsible for the most significant biological effects in mammalian cells. The identification of novel metabolites may reveal unknown metabolic pathways, more particularly in distinct pathological contexts such as cancer. The in vitro simulated gastrointestinal digestion (INFOGEST method) of HT, followed by bioavailability in the tumoral metabolically active intestinal Caco-2 cells (50 µM HT for 2, 4, and 6 h), was performed. Subsequently, an untargeted metabolomic analysis on the supernatant revealed novel HT-derived entities compared with water. Among these, ethoxy phenylacetic acid sulfates (4, 5), ethyl hydroxyphenylacetate acid sulfate (6) and ethoxy hydroxyphenylacetic acid or ethyl hydroxyphenylacetate glucuronide were described for the first time in a study and confirmed by MS/MS fragmentation. These accumulated ethylated forms were undetectable in non-tumoral plasma samples from HT-supplemented humans (60 mg day^-1 HT for 28 days) and mice (50 mg kg^-1 day^-1 HT for 2 months), suggesting a tumour-specific or, at the very least, tumour-favoured biotransformation pathway. These findings not only expand the diversity of HT metabolites but also propose ethoxy-phenylacetic acid and its sulfate conjugate as potential biomarkers for cancer detection.