Increased evidence suggests that moderate activation of the mitochondrial unfolded protein response (UPRmt) can delay aging and ameliorate neurodegenerative pathologies. Stevioside (Ste), a natural zero-calorie sweetener extracted from Stevia rebaudiana, has gained global acceptance as a sugar substitute in the food industry. Accumulated studies indicate that stevioside exhibits a wide spectrum of biological effects, including anti-hyperglycemic, anti-hypertensive, anti-inflammatory, and antimicrobial activities. However, its potential roles in aging and neurodegenerative diseases remain poorly understood. In this study, the lifespan of Caenorhabditis elegans was found to be prolonged upon exposure to (1, 10, and 100 μM) stevioside in a dose-dependent manner. Furthermore, we found that stevioside extended the lifespan and healthspan in C. elegans via activation of the ATFS-1-mediated UPRmt pathway. Intriguingly, the amelioration of Alzheimer's disease-related phenotypes by stevioside was also mediated through the ATFS-1 pathway. Additionally, we found that stevioside increased the resistance of oxidative stress and reduced ROS levels and upregulated superoxide dismutase (SOD) activity in C. elegans via the ATFS-1 pathway. These results demonstrated that both the anti-aging and neuroprotective effects of stevioside in C. elegans required a functional ATFS-1-dependent mitochondrial unfolded protein response. Collectively, our work highlighted that stevioside might be a viable candidate for the prevention and treatment of aging and age-related diseases.

Exercise is widely recognized for its substantial health benefits in promoting well-being and preventing disease across diverse populations; however, inappropriate training intensity combined with insufficient recovery can lead to overtraining syndrome (OTS), characterized by sustained performance decline, physiological maladaptation, and psychological disturbances. Probiotics have emerged as a promising nutritional strategy for modulating host metabolism and the gut microbiota, yet effective interventions for OTS remain limited. In the present study, a well-established OTS-like mouse model induced by a progressive treadmill protocol was used to evaluate the effects of Lactobacillus kefiranofaciens K6 supplementation on performance decline, physiological maladaptation, psychological disturbances, and gut microbiota dysbiosis. Mice were randomly assigned to Sedentary, Exercise, OTS, and OTS-K6 groups and received the designated interventions for 10 weeks. K6 supplementation was associated with attenuation of OTS-induced reductions in body weight, appetite, body composition, endurance performance, glucose tolerance, and tissue glycogen content, as well as improvements in peripheral fatigue biomarkers, including muscle injury markers (CK and LDH) and energy metabolism indicators (glucose, lactate, and ammonia). In addition, K6 administration was associated with improved intestinal barrier-related gene expression (Claudin-1, ZO-1, and ZO-2), reduced tissue and systemic inflammatory responses (TNF-α, IL-6, neutrophil counts, PLR, and NLR), and support of immune function as indicated by lymphocyte levels. K6 supplementation also alleviated OTS-induced anxiety-like behaviors. Furthermore, gut microbiota composition was altered by exercise, OTS induction, and K6 supplementation, with K6 modulating OTS-related dysbiosis by reducing Heminiphilus faecis and increasing Paramuribaculum intestinale. Moreover, changes in Duncaniella dubosii and P. intestinale may also provide potential benefits in the Exercise group. Excessive training stress in this experimental OTS-like mouse model was associated with multiple metabolic, inflammatory, behavioral, and microbiota-related disturbances, whereas K6 supplementation was associated with attenuation of several OTS-related alterations. These findings suggest that microbiota-targeted nutritional strategies may support physiological resilience under excessive training stress; however, the results should be interpreted as associative and hypothesis-generating, as mechanistic relationships were not directly examined.

Barley is rich in fermentable dietary fiber and phenolic compounds, both of which have recognized benefits for gut health and whose functionality is influenced by processing. Here, four barley genotypes differing in β-glucan content, type of starch, and phenolic profiles were extruded to obtain ready-to-eat products, which were then evaluated using a combined in vitro digestion-colonic fermentation model. The gastrointestinal fate of β-glucans and phenolics, short-chain fatty acids production, phenolic metabolite formation, and gut microbiota composition were assessed. After digestion, substantial amounts of β-glucans and phenolics remained in the non-bioaccessible fraction, supporting their relevance as substrates for colonic fermentation. During fermentation, the β-glucan-rich genotypes Annapurna® and Hilose® showed the strongest butyrogenic response, while the purple-grain genotype DHL-151340, characterized by a flavone- and anthocyanin-rich profile, showed an earlier and more pronounced accumulation of low-molecular-weight phenolic catabolites. Compared with the control, barley extrudates induced time-dependent shifts in microbiota composition, although community profiles tended to converge at later fermentation stages. Overall, genotype- and processing-driven differences translated into distinct fermentation and phenolic biotransformation footprints, highlighting the relevance of barley matrix composition in shaping the colonic fate of cereal bioactive compounds.

Brain-derived neurotrophic factor (BDNF) is a growth factor that has a central role in sustaining brain function. Besides the brain, BDNF is also expressed in immune cells. In preclinical models, anthocyanins (AC) consumption has been associated with benefits in BDNF homeostasis. This study investigated in healthy adults if the simultaneous consumption of a high-fat meal (HFM) with a cyanidin/delphinidin-rich extract (CDRE) could affect circulating BDNF, and BDNF expression in peripheral blood mononuclear cells (PBMCs). Underlying mechanisms were investigated in Jurkat T cells. While the HFM did not affect serum BDNF in the placebo group, simultaneous CDRE consumption caused a significant cumulative (1-3 h) BDNF increase, peaking at 2 h post-meal. The area under the curve (AUC) for the most abundant phenolic acids measured in serum, i.e., 4-hydroxyhippuric acid (HA) and 4-hydroxy-3-methoxybenzoic acid (vanillic acid, VA)-3-O-glucuronide correlated with the AUC for serum BDNF. As evaluated in Jurkat T cells, this could be due to HA and VA's capacity to increase cytosolic calcium. The CDRE also increased BDNF expression in PBMCs 3 h post-consumption. In vitro and molecular modeling evidence point to two mechanisms of action: (i) indirect protection of BDNF expression through CDRE anti-inflammatory actions, and (ii) a direct capacity of HA and VA to activate the β2-adrenergic receptor and downstream cAMP/PKA/CREB-mediated increased BDNF gene expression. While the short-term effects of CDRE consumption can be due to HA and VA presence in the extract, AC and phenolic acid metabolism by the microbiota would later generate HA and VA and consequently benefit BDNF homeostasis.

Triple-negative breast cancer (TNBC) presents a major therapeutic challenge due to its aggressive behavior and a microenvironment characterized by a dysregulated axis linking inflammation to tumor progression. As a selenium-biofortified edible vegetable, selenium-enriched rapeseed shoots (SeRS) are a promising dietary source of methylselenocysteine (MSC), highlighting their potential in "medicine-food homology" strategies. This study aimed to investigate the chemo-preventive efficacy of selenium-enriched SeRS as a dietary intervention in TNBC, building upon its previously documented anti-inflammatory and antioxidant properties, and to elucidate its underlying mechanism of action. We first demonstrated that SeRS aqueous extract significantly inhibited the migration and invasion of 4T1 TNBC cells in vitro. Subsequently, in a preventive dietary intervention study, administration of SeRS potently suppressed orthotopic tumor growth and metastasis in a 4T1 syngeneic mouse model. Concomitantly, SeRS treatment favorably remodeled the tumor immune microenvironment, as evidenced by increased infiltration of CD4+ and CD8+ T cells and a decrease in exhausted PD-1+/LAG-3+ T cell subsets. Integrated metabolomic and transcriptomic analyses identified resolvin D5 (RvD5), a specialized pro-resolving mediator, as a key endogenous metabolite upregulated by SeRS, and revealed the pro-inflammatory IL-17 signaling pathway as a potential target. Molecular docking confirmed high-affinity binding between RvD5 and IL-17A. Functionally, both SeRS and purified RvD5 suppressed IL-17 pathway activation, as evidenced by reduced phospho-p65 and downregulation of IL-17 receptor (IL-17RA) and ACT-1. Critically, rescue experiments established that RvD5 could reverse IL-17A-induced pro-tumorigenic effects. Our findings elucidate a coordinated mechanism in which SeRS, via upregulation of RvD5, suppresses the IL-17 signaling pathway-a key driver of chronic inflammation and immune dysfunction in TNBC-thereby exerting anti-TNBC effects. This work provides a scientific basis for developing selenium-enriched agricultural products into functional foods for cancer prevention through targeted nutritional modulation.

Obesity is associated with impaired intestinal barrier integrity, gut dysbiosis, and adipose tissue dysfunction, leading to endotoxemia and metabolic disturbances. We previously observed that grape pomace extract (GPE), rich in phenolic compounds, protected mice from high-fat diet (HFD)-induced endotoxemia and hepatic steatosis. This study aimed to evaluate the effect of GPE on intestinal permeability, gut microbiota composition, and the associated metabolic alterations in HFD-fed mice. Mice were assigned to four experimental groups and fed for 13 weeks with either a standard diet or HFD (approximately 60% total calories from fat) with or without GPE supplementation (300 mg of GPE per kg body weight per day). DNA was extracted from the cecal and colon contents and gut microbiota was analyzed using 16S rRNA gene sequencing. Mice fed a HFD developed obesity, increased adipose tissue mass, adipocyte hypertrophy, brown adipose tissue (BAT) whitening, and metabolic alterations. These changes were associated with endotoxemia, partial alterations in tight junction (TJ) protein expression, activation of inflammatory signaling pathways involved in TJ opening (IKK phosphorylation, and extracellular signal-regulated kinase (ERK 1/2)) in the colon. Additionally, HFD altered microbial diversity compared to control groups. GPE supplementation mitigated HFD-induced obesity, metabolic disturbances, and endotoxemia while also restoring specific aspects of colon morphology and intestinal barrier integrity. Notably, GPE led to a selective modulation of specific gut bacteria. Overall, GPE supplementation partially improved intestinal barrier markers and altered gut microbiota composition in HFD-fed mice. In addition, GPE reduced endotoxemia and improves obesity-related metabolic alterations, supporting its potential as a dietary strategy to mitigate HFD-induced metabolic disturbances.

Fermented foods are staples in diets worldwide and are known for their health benefits. Microorganisms are the key to fermented food production as they convert raw substrates into digestible, nutritious, and health-promoting products. While microbes are essential for fermented food production, their contribution to the dietary protein profile of the final food product in terms of microbial biomass is largely unknown. We analyzed proteins from 17 fermented foods using metaproteomics to identify and quantify microbial and food-derived proteins. We found that microbial proteins contribute up to 11% of the total protein content in fermented foods and comprise as much as 60% of the total number of identified proteins. These microbial proteins included many for central functions in microbial cells, such as glycolysis enzymes, translation machinery, and chaperones, as well as proteins for specialized functions that are important for the ecological niches in food fermentation, such as carbohydrate degrading enzymes and proteases. Some of these microbial proteins, such as proteases, could impact gut physiology. These findings highlight the substantial contribution of microbial proteins to the nutritional and functional profile of fermented foods, which may have important implications for interactions with the gut microbiota and health outcomes.

Background: Metabolic flexibility is characterized by a complex response in blood markers rapidly returning to baseline after a high-saturated-fat, high-refined-carbohydrate meal, and this adaptability is progressively lost as chronic metabolic dysfunction develops. Objective: To comprehensively profile the postprandial response and identify novel potential biomarkers related to defense, oxidative stress and other processes, to better define metabolic flexibility. Methods: Conventional methods as well as metabolomics and proteomics were used to profile the response in 12 healthy men to a high-saturated-fat, high-refined-carbohydrate meal, at hourly time points both before and after consumption. Results: In addition to the expected changes in glucose, insulin, triglycerides, fatty acids and myeloperoxidase, we observed multiple previously unreported changes in the plasma proteome, including a compromised "cellular oxidant detoxification" pathway (55 proteins) at 4 and 5 hours after the meal. Between individuals, the magnitude of the decrease in Cu-Zn-superoxide dismutase protein was associated with plasma postprandial glucose area-under-the-curve (r = -0.767, p = 0.004). In contrast, the peripheral blood mononuclear cell proteome showed minimal changes over 6 hours. Through plasma metabolomic analysis, we observed many novel postprandial changes with potential use as biomarkers, most notably increases in oxidative stress-related products such as myeloperoxidase putative products L-methionine S-oxide, 3-(4-hydroxyphenyl)pyruvate, and L-homocitrulline and in gut microbiota metabolites such as hydroxy-isocaproic acid, as well as a sustained elevation of phenylalanine, tyrosine, and branched chain amino acids at 6 hours. Conclusion: These data indicate a complex diminution of plasma defense proteins after a high-saturated fat high-refined carbohydrate meal, and then a return to baseline reflecting metabolic flexibility in the cohort of healthy young men. However, the data also show that some risk markers and stress products are still elevated 6 hours after the meal. The data provide a valuable resource for future postprandial metabolomic studies assessing the protective effect of nutrients and phytochemicals on postprandial stresses, and enabling comparisons between healthy and compromised populations. The clinical trial registry number is ACTRN12619000929101 (www.anzctr.org.au).

Ulcerative colitis (UC) involves chronic intestinal inflammation, epithelial barrier disruption, and microbial dysbiosis. Theabrownin (TB), a major bioactive compound derived from Pu-erh tea, has demonstrated anti-inflammatory properties, yet its role in intestinal barrier protection and underlying mechanisms remain unclear. In this study, TB (1 g per kg BW) was administered to dextran sulfate sodium salt (DSS)-induced colitis mice, leading to a marked alleviation in body weight loss and colon injury. TB significantly enhanced goblet cell function and mucus layer integrity, thereby supporting microbial homeostasis and epithelial defense. 16S rDNA sequencing revealed that TB restored microbial balance by enriching Prevotellaceae_UCG-001 while suppressing Eubacterium and Parasutterella. Mechanistically, TB upregulated ST6GalNAc6, reduced sialyl-Tn (STn) expression, and normalized MUC2 sialylation; inhibition of ST6GalNAc6 with 3Fax-Neu5Ac abrogated these protective effects. Collectively, these findings demonstrate that TB enhances intestinal barrier integrity and microbiota balance through modulation of the ST6GalNAc6-STn-MUC2 axis, highlighting its potential as a functional food ingredient for gut health management.

Quinoa (Chenopodium quinoa Willd.) is globally recognized as a "superfood" with superior nutritional value. Quinoa bran, the nutrient-dense outer layer of the grain, is increasingly utilized as a high-value ingredient in the food industry. Epidemiological evidence has linked the consumption of whole grains to a reduced risk of colorectal cancer (CRC). Our previous studies have confirmed that triterpenoids enriched in quinoa bran (QBT) exhibit significant anti-CRC activity, yet the underlying molecular mechanisms remain unclear. In this study, we demonstrate that QBT exerts potent tumor-suppressive effects in vitro and in vivo without inducing toxicity in major murine organs, indicating a favorable safety profile. Mechanistically, QBT acts as an apoptosis inducer by triggering lethal reactive oxygen species (ROS) accumulation in CRC cells, resulting in mitochondrial dysfunction and caspase-dependent apoptosis. Concurrently, QBT functions as an immunosensitizer by activating endoplasmic reticulum stress, thereby converting oxidative cell death into immunogenic cell death (ICD), as evidenced by enhanced calreticulin exposure and the release of ATP and high mobility group box 1 (HMGB1), eliciting a robust "vaccine-like effect". Consequently, QBT effectively promotes dendritic cell maturation and CD8+ T cell infiltration. Collectively, this study reveals that QBT suppresses CRC through a dual mechanism involving direct apoptosis induction and immune activation via ICD. These results support QBT as a promising functional food ingredient for the prevention and adjuvant treatment of CRC.