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BACKGROUND & AIMS: Previous studies have shown that antioxidants may be associated with risk of Alzheimer's disease (AD). However, some findings have failed to demonstrate a significant correlation. To rigorously evaluate this relationship, a comprehensive review and meta-analysis were conducted. METHODS: All relevant cohort studies reporting association between antioxidants intake (diet and/or supplement use) and AD risk were searched in 9 electronic databases and 4 registration platforms from their inception up to March 15, 2023. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using either a fixed-effects or random-effects model. Heterogeneity was assessed using I2 statistics. Furthermore, a dose-response meta-analysis was conducted to explore potential dose-response relationships. RESULTS: Eleven cohort studies were included. The pooled HRs of AD were 0.90 (95% CI = 0.60-1.34) and 0.94 (95% CI = 0.75-1.17) for the dietary intake of vitamin E, 0.90 (95% CI = 0.76-1.07) for the vitamin E supplement use. The pooled HRs of AD were 0.84 (95% CI = 0.76-0.93) and 0.60 (95% CI = 0.35-1.02) for the dietary intake of vitamin C, 0.85 (95% CI = 0.72-1.00) for the vitamin C supplement use. The pooled HRs of AD were 1.02 (95% CI = 0.85-1.22) and 0.86 (95% CI = 0.68-1.07) for the dietary intake of beta-carotene. Notably, no significant dose-response relationship was observed. CONCLUSIONS: A high dietary intake of vitamin C (≥ 75 mg/d) was found to have a statistically significant impact on reducing the risk of AD. However, no significant association was observed between dietary intake of vitamin E or beta-carotene, or the use of vitamin E or vitamin C supplement use, and the risk of AD. © 2024. The Author(s).

The efficacy of functional lipids with antioxidant properties in reducing cardiovascular risk has not been consistent. Randomized controlled trials (RCTs) reporting estimates for the effects of antioxidant functional lipid supplementations on cardiometabolic risk factors were searched up to 1 May 2024. Overall, antioxidant lipid supplementations, compared with placebo, had favorable effects on systolic blood pressure (lycopene: -1.95 [-3.54, -0.36] mmHg), low-density lipoprotein cholesterol (n6 fatty acid: -0.39 [-0.71, -0.06] mmol/L; astaxanthin: -0.11 [-0.21, -0.01] mmol/L), high-density lipoprotein cholesterol (n3 fatty acid: 0.20 [0.13, 0.27] mmol/L; n6 fatty acid: 0.08 [0.01, 0.14] mmol/L; astaxanthin: 0.13 [0.05, 0.21] mmol/L), total cholesterol (n6 fatty acid: -0.24 [-0.37, -0.11] mmol/L; astaxanthin: -0.22 [-0.32, -0.12] mmol/L; beta-carotene: -0.13 [-0.23, -0.04] mmol/L), triglyceride (n3 fatty acid: -0.37 [-0.47, -0.28] mmol/L; astaxanthin: -0.46 [-0.83, -0.10] mmol/L), and fasting blood insulin (astaxanthin: -2.66 [-3.98, -1.34] pmol/L). The benefits of antioxidant lipid supplementations appeared to be most evident in blood pressure and blood lipids in participants with different cardiometabolic health statuses. Notably, n9 fatty acid increased triglyceride and hemoglobin A1C in the total population, which increases CVD risk. Antioxidant lipid supplementations ameliorate cardiometabolic risk factors, while their effect may depend on type and cardiometabolic health status. Long-term RCTs are needed to corroborate risk-benefit ratios across different antioxidant functional lipid supplementation settings.

The impact of beta-carotene on cattle fertility has been investigated in various studies; however, consensus on this issue has not been reached. In the present study, we systematically reviewed and meta-analysed 29 publications conducted between 1984 and 2022, focusing on seven fertility measures, clinical mastitis and milk yield in cows. We did not find statistically significant results in 8 out of 11 parameters (p > .05). Statistically significant results were observed for milk yield (MD: 216.25 kg in 305 days, p = .01, CI: 50.73-381.77), pregnancy at first service (OR: 1.38 CI: 1.08-1.76, p = .01) and clinical mastitis (OR: 0.59, CI: 0.44-0.80, p = .006) in favour of beta-carotene supplementation. The meta-regression revealed significant effects of 'plasma beta-carotene levels' on 'service to per pregnancy' and dose on 'milk yield' (p = .04 and p = 0). In binary outcomes, 'dose × day' and 'plasma beta-carotene concentration in the control group' positively influenced pregnancy at first service (p = .02 and .03). In conclusion, given the positive point direction observed for some variables and insignificant results for others, there is a need for more studies. We note the very high heterogeneity of outcomes and suggest caution in interpreting results. © 2024 Wiley‐VCH GmbH. Published by John Wiley & Sons Ltd.

BACKGROUND AND OBJECTIVE: Given the potential association between oxidative stress, periodontitis and dental caries, whether dietary supplementation with antioxidants is beneficial for periodontitis and dental caries has been widely reported, but remains controversial. This study aims to clarify these relationships through two-sample Mendelian randomization (MR) analysis. METHODS: Circulating antioxidants (copper, selenium, zinc, ascorbate, β-carotene, lycopene, retinol and vitamin E) were derived from absolute circulating antioxidants and circulating antioxidant metabolites. Summary data of periodontitis and dental caries were obtained from two separate databases, respectively. We performed inverse-variance weighted (IVW) analysis separately in different databases, followed by meta-analysis. The robustness of results was examined by sensitivity analyses, including three complementary MR methods, heterogeneity and pleiotropy tests, and PhenoScanner query. RESULTS: IVW analysis showed that elevated levels of absolute circulating retinol reduced the risk of periodontitis (GLIDE: OR = 0.41, 95% CI = 0.18-0.95, p = .038, power = 100%; FinnGen: OR = 0.15, 95% CI = 0.04-0.54, p = .004, power = 100%). The pooled OR for periodontitis risk per unit increase of retinol is 0.30 (95% CI = 0.15-0.61, p = .001, I2 = 40.3%, power = 100%). No significant associations were noted for genetically predicted circulating antioxidants and dental caries risk. The sensitivity analyses yielded similar estimates. CONCLUSION: This study demonstrates that a negative causality between circulating retinol and periodontitis risk, and null linkage between circulating antioxidants and dental caries risk, suggesting potential strategies for the prevention and control of periodontitis. © 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

BACKGROUND: Gastric cancer is characterized by high invasiveness, heterogeneity, and late diagnosis, leading to high incidence and mortality rates. It is a significant public health concern globally. Early prevention is crucial in reducing the occurrence of gastric cancer, and dietary prevention, particularly focusing on carotenoids, has been considered a convenient and effective approach. However, the association between carotenoid intake and gastric cancer incidence remains controversial. METHODS: A systematic search was conducted in PubMed, Ovid Embase, Web of Science, and Cochrane databases from inception to January 5, 2023. Two reviewers independently screened search results, extracted relevant data, and evaluated study quality. Statistical analysis was performed using the "metan" command in STATA 16 software. Random-effects or fixed-effects models were chosen based on the magnitude of heterogeneity among studies. RESULTS: This study included a total of 35 publications, consisting of 23 case-control studies and 12 cohort studies. Meta-analysis of case-control studies showed that alpha-carotene (OR = 0.71, 95% CI: 0.55-0.92), beta-carotene (OR = 0.62, 95% CI: 0.53-0.72), and lutein (OR = 0.82, 95% CI: 0.69-0.97) significantly reduced the risk of gastric cancer, while beta-cryptoxanthin (OR = 0.88, 95% CI: 0.75-1.04) and lycopene (OR = 0.86, 95% CI: 0.73-1.00) showed no significant correlation. Meta-analysis of cohort studies indicated no significant associations between any of the five carotenoids and gastric cancer incidence (alpha-carotene: RR = 0.81, 95% CI: 0.54-1.23; beta-carotene: RR = 0.86, 95% CI: 0.64-1.16; beta-cryptoxanthin: RR = 0.86, 95% CI: 0.64-1.16; lutein: RR = 0.94, 95% CI: 0.69-1.29; lycopene: RR = 0.89, 95% CI: 0.69-1.14). CONCLUSIONS: The relationship between carotenoids and gastric cancer incidence may vary depending on the type of study conducted. Considering that evidence from cohort studies is generally considered stronger than evidence from case-control studies, and high-quality randomized controlled trials show no significant association between carotenoids and gastric cancer incidence, current evidence does not support the supplem

BACKGROUND: Gastric cancer is characterized by high invasiveness, heterogeneity, and late diagnosis, leading to high incidence and mortality rates. It is a significant public health concern globally. Early prevention is crucial in reducing the occurrence of gastric cancer, and dietary prevention, particularly focusing on carotenoids, has been considered a convenient and effective approach. However, the association between carotenoid intake and gastric cancer incidence remains controversial. METHODS: A systematic search was conducted in PubMed, Ovid Embase, Web of Science, and Cochrane databases from inception to January 5, 2023. Two reviewers independently screened search results, extracted relevant data, and evaluated study quality. Statistical analysis was performed using the "metan" command in STATA 16 software. Random-effects or fixed-effects models were chosen based on the magnitude of heterogeneity among studies. RESULTS: This study included a total of 35 publications, consisting of 23 case-control studies and 12 cohort studies. Meta-analysis of case-control studies showed that alpha-carotene (OR = 0.71, 95% CI: 0.55-0.92), beta-carotene (OR = 0.62, 95% CI: 0.53-0.72), and lutein (OR = 0.82, 95% CI: 0.69-0.97) significantly reduced the risk of gastric cancer, while beta-cryptoxanthin (OR = 0.88, 95% CI: 0.75-1.04) and lycopene (OR = 0.86, 95% CI: 0.73-1.00) showed no significant correlation. Meta-analysis of cohort studies indicated no significant associations between any of the five carotenoids and gastric cancer incidence (alpha-carotene: RR = 0.81, 95% CI: 0.54-1.23; beta-carotene: RR = 0.86, 95% CI: 0.64-1.16; beta-cryptoxanthin: RR = 0.86, 95% CI: 0.64-1.16; lutein: RR = 0.94, 95% CI: 0.69-1.29; lycopene: RR = 0.89, 95% CI: 0.69-1.14). CONCLUSIONS: The relationship between carotenoids and gastric cancer incidence may vary depending on the type of study conducted. Considering that evidence from cohort studies is generally considered stronger than evidence from case-control studies, and high-quality randomized controlled trials show no significant association between carotenoids and gastric cancer incidence, current evidence does not support the supplem

Carrots are main dietary sources of several potential anti-cancer compounds, including polyacetylenes, while β-carotene has shown no benefits in controlled cancer trials. Accordingly, associations between carrot intake and cancer incidence were quantified, where necessary using α-carotene as a non-causal biomarker of carrot consumption, by searching for studies published before June 2022 reporting risk estimates for relationships of cancer incidence with carrot intake or α-carotene intake or α-carotene plasma concentration, supplemented with hand searches of included studies and reviews. Meta-analyses comparing highest and lowest reported intakes in prospective studies using a random-effects model estimated summary relative risks (RRs) with 95% confidence intervals (CIs), separately for carrot intake or α-carotene plasma concentration, and the corresponding dose-responses. Of 198 observational studies, in 50 prospective studies with 52000 cases recording carrot intake, the cancer-risk was substantially reduced (RR 0.90, 95% CI 0.87-0.94, p ˂ 0·00004). In 30 prospective studies with 9331 cases reporting plasma α-carotene levels, summary RR was 0.80 (0.72-0.89, p ˂ 0·00006). For both exposure types, inter-study heterogeneity was moderate, interaction with cancer types insignificant, and the dose-response significant (p ˂ 0·01). In conclusion, carrot consumption is robustly associated with decreased cancer-risk; carrot consumption should be encouraged, and the causal mechanisms further investigated.

CONTEXT: β-Carotene, which is derived from most fruits and vegetables, is the most common type of carotenes. Existing studies have demonstrated that β-carotene is associated with some positive health outcomes. However, results about the effects of supplemental β-carotene on cancer are inconsistent. OBJECTIVE: To determine the association between supplemental β-carotene intake and the risk of cancers. DATA SOURCES: Eight databases (PubMed, Web of Science, Embase, Cochrane, China National Knowledge Infrastructure, Wangfang, China Science and Technology Journal Database, and Chinese Biomedical Literature Database) were systematically searched until September 2022. DATA EXTRACTION: Only reports from randomized controlled trials in which an association between supplemental β-carotene intake and the risk of cancer was found were included in the meta-analysis. DATA ANALYSIS: A total of 18 eligible studies based on 8 different randomized controlled trials were included in the meta-analysis, with varying sample sizes from 391 to 39 876 participants. There was no significant association between supplemental β-carotene intake and overall cancer incidence rate after synthesizing all the results (risk ratio [RR]: 1.02; 95% confidence interval [CI], 0.99-1.05). Results from subgroup analysis indicated that intake of supplemental β-carotene significantly increased the risk of lung cancer (RR: 1.19; 95%CI: 1.08-1.32), whereas no significant associations were observed for other site-specific cancers. In addition, smokers and the subgroup of participants with only low-dose β-carotene intake had a risk increment of cancer if they took supplemental β-carotene (RR: 1.16; 95%CI: 1.05-1.29). CONCLUSION: β-Carotene supplementation has no beneficial or harmful effect on cancer incidence; moreover, it might have potentially harmful effects on lung cancer, especially for people who smoke. On the basis of the evidence from this study, supplemental intake of β-carotene is not recommended for preventing cancer, and the establishment of a tolerable upper intake level of β-carotene should be considered. © The Author(s) 2023. Published by Oxford University Press on behalf of the International

BACKGROUND: Antioxidants, as scavengers of free radicals, have been proposed as potential targets for the prevention and treatment of rheumatoid arthritis (RA), however, the causal associations between antioxidants and RA are still in debate. OBJECTIVE: This study aims to evaluate this causal association with two-sample Mendelian randomization (MR) analysis. METHODS: Inverse-variance weighted was used as the major analysis method of MR. Genetic variants associated with dietary antioxidants including vitamin E (α- and γ-tocopherol), β-carotene, lycopene, vitamin C (L-ascorbic acid or ascorbate), and retinol, and their circulating metabolites were used as instrumental variables. The causal effects of the antioxidants were assessed in genome-wide association study datasets of RA from a previous publication (Okada Y. et al.) and Finngen consortium and combined with meta-analysis. RESULTS: We observed that the levels of circulating retinol metabolite negatively correlates with the risk of overall RA in the dataset from Okada Y. et al. (odds ratio [OR]=0.952, 95% confidence interval [CI]=0.911-0.996, p = 0.031) and Finngen (OR=0.946, 95%CI=0.903-0.991, p = 0.020). The causal association remained consistent in the meta-analysis (OR=0.949, 95%CI=0.919-0.98, p = 0.002). Increased levels of circulating retinol metabolite also suggestively decreased the risk of seropositive RA (OR=0.936, 95%CI=0.884-0.992, p = 0.025) but not seronegative RA (OR=0.996, 95%CI=0.921-1.076, p = 0.913). No causal effects of other dietary antioxidants on RA were identified in our analyses. CONCLUSIONS: Our study suggested a protective effect of circulating retinol metabolites, but not other antioxidants, on overall RA and seropositive RA. Dietary supplementation of retinol may be an effective measure for the primary prevention of RA.

Lung cancer is one of the most common neoplasms globally, with about 2.2 million new cases and 1.8 million deaths annually. Although the most important factor in reducing lung cancer risk is lifestyle change, most patients favour the use of supplements, for example, rather than quitting smoking or following a healthy diet. To better understand the efficacy of such interventions, a systematic review was performed of data from randomized controlled trials concerning the influence of beta-carotene supplementation on lung cancer risk in subjects with no lung cancer before the intervention. The search corpus comprised a number of databases and eight studies involving 167,141 participants, published by November 2021. The findings indicate that beta-carotene supplementation was associated with an increased risk of lung cancer (RR = 1.16, 95% CI = 1.06-1.26). This effect was even more noticeable among smokers and asbestos workers (RR = 1.21, 95% CI = 1.08-1.35) and non-medics (RR = 1.18, 95% CI = 1.07-1.29). A meta-regression found no relationship between the beta-carotene supplementation dose and the size of the negative effect associated with lung cancer risk. Our findings indicate that beta-carotene supplementation has no effect on lung cancer risk. Moreover, when used as the primary chemoprevention, beta-carotene may, in fact, increase the risk of lung cancer.

BACKGROUND: Adequate intake of carotenoids and vitamin E supports healthy aging, yet evidence is limited on whether multivitamin-multimineral (MVM) supplementation changes serum concentrations over time. OBJECTIVE: The aim of this investigation was to evaluate the effect of daily MVM supplementation among older adults on serum carotenoid and vitamin E concentrations over a 2-year period. DESIGN: The COcoa Supplement and Multivitamin Outcomes Study is a large-scale, randomized, placebo-controlled, 2 × 2 factorial trial, designed to test the effects of daily MVM and cocoa extract supplementation for chronic disease prevention. Participants completed semiannual questionnaires and provided optional biospecimen samples at baseline, 1-year, and 2-year follow-up. PARTICIPANTS AND SETTING: Between 2015 and 2020, US adults (women aged 65 years and older, men aged 60 years and older) without major cardiovascular disease or recent cancer were enrolled in the COcoa Supplement and Multivitamin Outcomes Study. This analysis included biospecimen substudy participants with blood samples provided at baseline and ≥1 follow-up timepoint (n = 400; 1 excluded due to unusable sample; final N = 399). INTERVENTION: Participants were randomized to receive daily MVM supplementation or a placebo, with or without cocoa extract. MAIN OUTCOME MEASURES: Changes in serum carotenoids and α-tocopherol concentrations were evaluated over the 2-year follow-up. STATISTICAL ANALYSES: Multivariable linear mixed models estimated changes in serum biomarker concentrations, comparing MVM with placebo, adjusting for covariates (age, sex, and cocoa extract intervention). RESULTS: Increases in serum carotenoids and α-tocopherol levels with MVM supplementation emerged at year 1 and persisted through year 2. MVM supplementation led to significantly higher serum concentrations of total carotenoids (percent change: 15.5%; 95% CI, 8.72 to 22.70), lutein (percent change: 17.17%; 95% CI, 7.53 to 27.66), beta carotene (percent change: 46.96%; 95% CI, 35.10 to 59.85), and α-tocopherol (percent change: 29.50%; 95% CI, 22.88 to 36.47) over 2 years compared with placebo. No significant differences were observed for lyco

BACKGROUND: Specific metabolites detected in biofluids after food intake have been proposed as objective markers to address limitations with traditional dietary assessment methods. Although hundreds of metabolites have been associated with foods or food groups, they require validation. OBJECTIVES: The aim of this study was to develop a panel from the proposed biomarkers of dietary intake reflecting major food groups and compare them against known and self-reported dietary intakes. METHODS: A randomized crossover trial of 3 interventions, including a day of foods consumed under observation, was performed. Each feeding day was of 3 food groups (e.g., whole grains, dairy, and fish) with optional snacks (e.g., fruit, chicken, and legumes) but absent of 3 other food groups (e.g., meat, vegetables, nuts, and seeds). Fasted whole blood and 24-h urine samples were analyzed by liquid chromatography mass spectrometry to detect previously proposed biomarkers of food intake. Urinary sodium was measured. Pairwise correlation coefficients and generalized linear modeling (GLM) considered relationships between biomarkers and food groups. Comparisons were drawn between self-reported and known dietary intakes. RESULTS: Twenty-one participants [mean age 24.8, standard deviation (SD) 6.0 y, body mass index: 24.1; SD: 4.0] completed the trial. GLM coefficients indicated fish intake was associated with 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid [62.15 (95% confidence interval: 35.00, 89.29)], wholegrain intake with 3,5-dihydroxybenzoic acid [87.32 (24.28, 150.35)] and fruit intake with fructose [5.39 (2.53, 8.25)], and s-methylcysteine [5.91 (1.24, 10.58)]. GLM rate ratios indicated chicken intake was associated with 3-methylhistidine [0.19 (0.07, 0.31)], anserine [0.21 (0.05, 0.37)], and carnosine [0.11 (0.03, 0.19)], legume intake with glycine betaine [0.21 (0.02, 0.40)] and vegetable intake with sulforaphane [0.30 (0.20, 0.47)], S-methylcysteine [0.23 (0.14, 0.45)], methoxytyramine [0.21 (0.08, 0.35)], and β-carotene [0.05 (0.02, 0.08)]. There was no association between 24-h urinary sodium and known sodium intake [0.11 (-0.06, 0.28)]. Self-reported dietary intake was associ

PURPOSE: The aim of the MultiVeg study, a double-blind, randomised controlled trial (RCT), was to investigate the nutritional status of healthy vegans following 4 months of multinutrient supplementation. METHODS: A double-blind, RCT was conducted with 72 vegan adults (19-57 years) in Germany. Data on anthropometric parameters, dietary nutrient intake, and nutritional status were collected. The nutritional status of the participants was assessed at baseline and after 4 months. The results were compared between groups using ANCOVA. The results for vitamins and choline are presented here. RESULTS: After adjustment for baseline values, age, sex, and multiple testing, no significant between-group differences in biomarker concentration changes from baseline to 4 months were observed for vitamin A, retinol-binding protein, transthyretin, beta-carotene, methylmalonic acid, homocysteine, choline, total osteocalcin, carboxylated and undercarboxylated osteocalcin, and folate. In contrast, significant between-group differences in changes were observed for flavin adenine dinucleotide (FAD), serum vitamin B12, holotranscobalamin, and the combined vitamin B12 status indicator (cB12) after adjustment. CONCLUSION: A multinutrient supplement containing 82 µg of vitamin B12 per day significantly positively affected vitamin B12 blood biomarkers in healthy vegans. REGISTRATION: This study was registered in the German Clinical Trials Register (DRKS00028151). © 2025. The Author(s).

OBJECTIVES: Two infant formulas with unique combinations of 1,3-dioleoyl-2-palmitoyl-sn-glycerol sn2 palmitate, galactooligosaccharide, polydextrose, fructooligosaccharide, β-carotene, lutein, α-lactalbumin, osteopontin, and lactoferrin were evaluated for non-inferiority compared to a commercially available formula. METHODS: In a randomized, controlled, parallel-arm, double-blind, multicenter, non-inferiority study, eligible infants were enrolled to receive an experimental (BBN-001 [Part 1; N = 129], BBN-102 [Part 2; N = 117]) formula or commercial formula (Brand; N = 143) for 120 days (Clinical Trials.gov NCT03331276). Infants were considered eligible if they were healthy, term (≥ 37 and ≤ 42 weeks of gestation), singleton newborns, with a birth weight of at least 2,500 g, and no more than 14 postnatal days-of-age. Anthropometric growth, formula intake, gastrointestinal tolerance, and adverse events were measured throughout the study, and fecal soap fatty acids were measured at the end. The primary endpoint was weight gain at the end of the trial, with treatment groups to be considered non-inferior if their weight gain was > -3 g/d compared to the control group. RESULTS: Both experimental formulas were non-inferior to the Brand formula according to anthropometric outcomes. Formula intake, total adverse events, and stool frequency and consistency were similar to Brand formulas. Some measures of gassiness and fussiness improved in the experimental formulas (P < 0.05). Fecal calcium increased and fecal palmitic acid soaps decreased in both experimental formulas (all P ≤ 0.045), and total soap fatty acids were decreased in the BBN-102 group compared to the Brand group (P = 0.020). CONCLUSIONS: The experimental formulas were well tolerated and deemed non-inferior to those of a Brand formula. The experimental formulas improved some measures of gastrointestinal tolerance compared to standard commercially available infant formulas. TRIAL REGISTRATION: ClinicalTrials.gov NCT03331276. Copyright: © 2025 Fleming et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and r

Emerging evidence suggests a bidirectional relationship between vitamin A deficiency (VAD) and gut microbiota, with implications to host health. This double-blind randomised controlled trial (NCT03256123) aims to investigate the effects of 6-month red palm olein (RPO)-enriched biscuit supplementation on gut microbiota of 328 vitamin A-deficient primary schoolchildren (aged 8-12 years) in rural Malaysia, randomised to receive either RPO-enriched biscuits (experimental group, n = 145) or palm olein (PO)-enriched biscuits (control group, n = 183). Stool samples are collected at baseline, 3-month and 6-month of supplementation, and analysed using 16S rRNA gene sequencing. The primary outcome is the changes in gut microbiota composition, while secondary outcomes include alteration in gut microbiota diversity, correlations with blood biomarkers, and microbial network structure. Compared to the control group, the experimental group shows significant reductions in alpha diversity indices (e.g., observed ASVs and chao1, P < 0.001), and increased abundance of potentially beneficial gut bacteria, such as Anaerostipes, UCG-010 and Lachnospiraceae_NK4A136_group (Padj < 0.05), which also positively correlate with improvements in alpha-carotene, beta-carotene, alpha-tocopherol, packed cell volume, and mean corpuscular volume (Padj < 0.05). Microbial network analysis reveals that the experimental group exhibits a more cohesive and stable network, evidenced by higher average degree and clustering coefficient values, and lower average path lengths (P < 0.001). Our findings shed light on the potential of RPO-enriched biscuit supplementation in modulating gut microbiota in vitamin A-deficient children by enhancing microbial network cohesiveness and enriching potentially beneficial bacterial taxa which are linked to enhanced micronutrient and haematological outcomes. These findings lay a valuable foundation and expand the existing evidence base for understanding the relationship between provitamin A carotenoids and gut microbiota. © 2025. The Author(s).

Erratum in JAMA Intern Med. 2026 Jul 1;186(7):915. doi: 10.1001/jamainternmed.2026.2377. IMPORTANCE: Programs to improve access to healthy foods for people with diabetes exist in some jurisdictions but not others, and their effects on disease control are not established. OBJECTIVE: To measure the effect of a monthly grocery store voucher that allows access to healthy foods on diabetes control in patients experiencing food insecurity. DESIGN, SETTING, AND PARTICIPANTS: This randomized parallel-arm clinical trial was conducted from March 21, 2023, to April 1, 2025, at 7 sites in Toronto, Canada. Patients were randomly allocated to a monthly voucher or usual access to healthy foods. Eligibility required hemoglobin A1c (HbA1c) levels from 6.0% to 11% and food insecurity. Data analysis was conducted in May 2025. INTERVENTION: A $65 monthly voucher ($85 for those in households with 6 or more individuals) for 6 months. MAIN OUTCOMES AND MEASURES: The primary outcome was change in HbA1c levels from baseline to 6 months. Secondary outcomes included levels of β-carotene and ascorbic acid, self-reported fruit and vegetable consumption, financial security, food security, and general health. RESULTS: Of 1061 patients approached, 390 were enrolled (mean [SD] age, 60 [13] years; 191 [49%] men, 198 [51%] women); 81 (21%) identified as Black, 93 (24%) identified as South Asian, and 105 (27%) identified as White. Overall, 194 (50%) were randomly allocated to receive the voucher and 196 (50%) to control. The nonsignificant mean difference between voucher and control in the change in HbA1c was -0.18% (95% CI, -0.41 to 0.05; P = .13; mean difference adjusted for baseline HbA1c, age, sex, household size, and condition, -0.10%; 95% CI, -0.33 to 0.12; P = .35). The voucher improved self-reported vegetable consumption (44.7% vs 21.5% 2 or more times per day), fruit consumption (42.6% vs 22.7% 2 or more times per day), food insecurity (risk difference, -0.10; 95% CI, -0.18 to -0.02), and general health (odds ratio, 1.6; 95% CI, 1.1-2.3) but not financial insecurity (risk difference, -0.07; 95% CI, -0.16 to 0.02) or β-carotene level (mean difference, 0.01 µmol/L; 95% CI, -0.08 to 0.06) a

BACKGROUND/OBJECTIVES: The high cost of healthy foods makes it difficult for people with a low income to manage diabetes. This study examined the effects of a monthly grocery voucher on the dietary intake, assessed through the Canadian Diet History Questionnaire III, of diabetes patients facing food or financial insecurity. We also assessed the impact on levels of hemoglobin A1c, beta-carotene, and ascorbic acid. METHODS: Participants were randomly selected from a larger clinical trial and completed the survey at 6-month follow-up. RESULTS: Voucher recipients consumed more whole fruit (mean difference in daily servings, MD 0.8; 95% CI [0.1, 1.6]) and fewer refined grains (MD -1.0; 95% CI [-1.9, -0.1]). For other food groups, the confidence intervals for the difference included null effect. Mean HEFI-2019 score was 51.7 out of 80, with voucher recipients averaging 52.4 vs. 51.0 for controls (MD 1.4; 95% CI [-3.6, 6.1]). The voucher group showed a slight HbA1c decrease (MD -0.4; 95% CI [-1.4, 0.5]). CONCLUSIONS: A voucher providing access to healthy foods for people with diabetes or prediabetes slightly increased intake of fruits and decreased intake of refined grains. Larger interventional studies are needed to determine the effects of vouchers on dietary intake among this population.

BACKGROUND: Alzheimer disease (AD) prevention is a public health priority, yet the impact of dietary carotenoids on cognitive decline, particularly in apolipoprotein E (APOE) ε4 carriers, remains unclear. OBJECTIVES: The objective of this study was to examine whether the APOE ε4 genotype modifies the relationship between blood carotenoid concentrations and global cognition. METHODS: This study was conducted within the Mediterranean-Dietary Approaches to Stop Hypertension intervention for neurodegenerative delay trial, a 3-y randomized controlled trial comparing the effects of the Mediterranean-Dietary Approaches to Stop Hypertension intervention for neurodegenerative delay diet with the usual diet on global cognition in older adults. Eligible participants were ≥65 y, had a body mass index (in kg/m2) >25, a family history of AD, suboptimal diets, and a Montreal cognitive assessment score ≥22. The primary outcome was 3-y change in global cognitive function, assessed using a validated composite cognitive score converted to standardized units (SUs). Baseline plasma carotenoid concentrations were measured in a subgroup of participants (n = 442). Mixed-effects models were used to test the interaction between APOE ε4 status and baseline carotenoid concentrations on cognitive trajectories. RESULTS: The mean age was 70.0 y for noncarriers (n = 308) and 69.4 y for APOE ε4 carriers (n = 134). Among APOE ε4 carriers, a 1-unit increment in plasma total carotenoids at baseline was associated with higher global cognitive scores [β = 0.17 SU; 95% confidence interval (CI): 0.06, 0.28 SU; P = 0.009]. Similar associations were observed for β-carotene (β = 0.13 SU; 95% CI: 0.05, 0.21 SU; P = 0.001), α-carotene (β = 0.09 SU; 95% CI: 0.02, 0.15 SU; P = 0.008), lutein plus zeaxanthin (β = 0.14 SU; 95% CI: 0.04, 0.25 SU; P = 0.008), lycopene (β = 0.17 SU; 95% CI: 0.07, 0.28 SU; P = 0.005), and β-cryptoxanthin (β = 0.13 SU; 95% CI: 0.05, 0.21 SU; P = 0.03). Associations in noncarriers were weaker or nonsignificant. CONCLUSIONS: Higher plasma carotenoid concentrations were associated with slower cognitive decline in APOE ε4 carriers, potentially mitigating genetic risk. This trial was re

BACKGROUND/OBJECTIVES: UV radiation is a primary cause of skin damage and photoaging. β-carotene, a potent antioxidant, aids in mitigating UV-induced oxidative stress and enhancing skin photoprotection. This research aimed to evaluate the efficacy of a nutraceutical product designed to prevent photoaging. METHODS: The product consists of a blend of hemp seed oil and banana (Musa AA), formulated as a chewable tablet. Healthy male participants aged 35-50 years were enrolled in a randomized, parallel, single-blind, placebo-controlled clinical trial. Participants received either the chewable nutraceutical (five tablets after meals in the morning and evening, equivalent to 8 ± 2 mg/day of β-carotene and 400 mg/day of PUFA) or a chewable placebo for 16 weeks. A total of thirty-six participants successfully completed the entire 16-week study. RESULTS: Administration of the nutraceutical resulted in a significant reduction (p < 0.05) in UV solar light stimulator-induced erythema on the dorsal skin at week 4, with a mean value of 3.76 ± 0.46 AU, compared to the initial value of 4.88 ± 0.62 AU at week 0. Additionally, serum β-carotene concentration significantly increased from 0.45 ± 0.02 µg/mL at week 0 to 0.61 ± 0.06 µg/mL at week 16 (p < 0.05). Moreover, skin intensity in the sun-exposed arm area also significantly improved at week 16, increasing from 71.33 ± 3.50 at week 0 to 81.80 ± 4.45 (p < 0.05). CONCLUSIONS: The results indicate that the developed nutraceutical may offer effective protection against erythema, making it a promising option for preventing photoaging.

PURPOSE: To determine whether oral micronutrient supplementation slows geographic atrophy (GA) progression in age-related macular degeneration (AMD). DESIGN: Post hoc analysis of Age-Related Eye Disease Study (AREDS) and AREDS2, multicenter randomized placebo-controlled trials of oral micronutrient supplementation, each with 2 × 2 factorial design. PARTICIPANTS: A total of 392 eyes (318 participants) with GA in AREDS and 1210 eyes (891 participants) with GA in AREDS2. METHODS: The AREDS participants were randomly assigned to oral antioxidants (500 mg vitamin C, 400 IU vitamin E, 15 mg β-carotene), 80 mg zinc, combination, or placebo. The AREDS2 participants were randomly assigned to 10 mg lutein/2 mg zeaxanthin, 350 mg docosahexaenoic acid/650 mg eicosapentaenoic acid, combination, or placebo. Consenting AREDS2 participants were also randomly assigned to alternative AREDS formulations: original; no beta-carotene; 25 mg zinc instead of 80 mg; both. MAIN OUTCOME MEASURES: (1) Change in GA proximity to central macula over time and (2) change in square root GA area over time, each measured from color fundus photographs at annual visits and analyzed by mixed-model regression according to randomized assignments. RESULTS: In AREDS eyes with noncentral GA (n = 208), proximity-based progression toward the central macula was significantly slower with randomization to antioxidants versus none, at 50.7 μm/year (95% confidence interval [CI], 38.0-63.4 μm/year) versus 72.9 μm/year (95% CI, 61.3-84.5 μm/year; P = 0.012), respectively. In AREDS2 eyes with noncentral GA, in participants assigned to AREDS antioxidants without β-carotene (n = 325 eyes), proximity-based progression was significantly slower with randomization to lutein/zeaxanthin versus none, at 80.1 μm/year (95% CI, 60.9-99.3 μm/year) versus 114.4 μm/year (95% CI, 96.2-132.7 μm/year; P = 0.011), respectively. In AREDS eyes with any GA (n = 392), area-based progression was not significantly different with randomization to antioxidants versus none (P = 0.63). In AREDS2 eyes with any GA, in participants assigned to AREDS antioxidants without β-carotene (n = 505 eyes), area-based progression was not significantly diffe

The antioxidant capacity and mechanism of a binary mixture of natural antioxidants β-carotene, γ-oryzanol, and β-sitosterol were evaluated using purified walnut oil as a substrate. Synergistic effects were identified using Rancimat method, while free radical generation was examined by ESR. Dynamic changes in antioxidants and oxidation products were analyzed by GC-MS and HPLC. Results indicated that interaction effects were influenced by different ratios and concentrations. Notably, β-carotene and γ-oryzanol exhibited a significant synergism during oxidation. Specifically, γ-oryzanol not only scavenges lipid radicals but also has the potential to regenerate β-carotene, thereby restoring its antioxidant function. In addition, γ-oryzanol produces oxidation products with antioxidant activity that further contribute to radical inhibition. Daily storage tests also confirmed that the synergistic antioxidant binaries effectively extended edible oil shelf life.

Food additives are chemical substances that are added to processed food to improve its flavor, texture, or appearance. Food additives can inhibit intestinal transporters, such as breast cancer resistance protein (BCRP), multidrug resistance associated protein 2 (MRP2), organic anion transporting polypeptide 2B1 (OATP2B1), and P-glycoprotein (P-gp). This inhibition could potentially affect the absorption of their substrate drugs and cause unwanted food-drug interactions. In this study, 22 food additives were evaluated for their impact on BCRP, MRP2, OATP2B1, and P-gp transport. The inhibition potency toward intestinal transporters was first studied using membrane vesicles and HEK293 cells. In these assays, four food additives (beta-carotene, butylated hydroxytoluene, dodecyl gallate, and octyl gallate) were identified as inhibitors. Seven food additives (allura red AC, beta-carotene, brilliant blue FCF, carmoisine, neohesperidin DC, sunset yellow FCF, and tartrazine), which were identified as inhibitors either in the current study or in our previous studies, were selected for Caco-2 permeability studies to further evaluate their possible effect on drug absorption. None of the selected food additives showed any effect on sulfasalazine permeability. These results suggest that the selected food additives are inhibitors of the studied transporters but are unlikely to cause clinically significant intestinal transporter-mediated drug interactions.

This in vivo study performed in rat adjuvant arthritis aims to advance the understanding of astaxanthin's therapeutic properties for the possible treatment of rheumatoid arthritis (RA) in monotherapy and along with the standard RA treatment, methotrexate (MTX), in combination therapy. The main goal was to elucidate astaxanthin's full therapeutic potential, evaluate its dose dependency, and compare its effects in monotherapy with other carotenoids such as β-carotene and β-cryptoxanthin (KXAN). Moreover, potential differences in therapeutic activity caused by using different sources of astaxanthin, synthetic (ASYN) versus isolated from Blakeslea trispora (ASTAP), were evaluated using one-way ANOVA (Tukey-Kramer post hoc test). KXAN was the most effective in reducing plasma MMP-9 levels in monotherapy, significantly better than MTX, and in reducing hind paw swelling. The differences in the action of ASTAP and ASYN have been observed across various biometric, anti-inflammatory, and antioxidative parameters. In combined therapy with MTX, the ASYN + MTX combination proved to be better. These findings, especially the significant anti-arthritic effect of KXAN and ASYN + MTX, could be the basis for further preclinical studies.

In this study, N-Methyl-N-nitrosourea (MNU) was intraperitoneally injected to construct a mouse retinitis pigmentosa (RP) model to evaluate the protective effect of chitosan and β-carotene on RP. The results demonstrated that chitosan synergized with β-carotene significantly reduced retinal histopathological structural damage in RP mice. The co-treatment group of β-carotene and chitosan restored the retinal thickness and outer nuclear layer thickness better than the group treated with the two alone, and the thickness reached the normal level. The content of β-carotene and retinoids in the liver of chitosan and β-carotene co-treated group increased by 46.75 % and 20.69 %, respectively, compared to the β-carotene group. Chitosan and β-carotene supplement suppressed the expressions of Bax, Calpain2, Caspase3, NF-κB, TNF-α, IL-6, and IL-1β, and promoted the up-regulation of Bcl2. Chitosan and β-carotene interventions remarkably contributed to the content of SCFAs and enhanced the abundance of Ruminococcaceae, Rikenellaceae, Odoribacteraceae and Helicobacteraceae. Correlation analysis demonstrated a strong association between gut microbiota and improvement in retinitis pigmentosa. This study will provide a reference for the study of the gut-eye axis.

Background: Osteoporosis (OS) is a pathological condition that makes bones susceptible to fractures by affecting the balance between bone formation and resorption. Recent literature uncovered the possible potential of bioactive compounds with antioxidant mechanisms to counter the issue. Cowpea (CP) isoflavones based on our previous study, vitamin D and natural antioxidant β-carotene for its pleotropic protective effects were assessed alone and in combination. Aim: The study aims to assess the antioxidant and osteoblast differentiation abilities of cowpea isoflavones alone and in combination of vitamin D (VD) and β-carotene (BC) in the human osteosarcoma cell line Saos2. Methods: Saos2 cells were maintained in cell culture conditions and concentrations of CP extract (genistein + daidzein), BC and VD required to increase cell proliferation were estimated using MTT assay. Upon treating cells with the EC50 concentrations, lysates were prepared and levels of alkaline phosphatase (ALP) and osteocalcin were evaluated using ELISA. Oxidative stress parameters and osteoblast differentiation markers were evaluated. Results: CP extract (genistein + daidzein), BC and VD concentrations which enhanced the cell proliferation rate were determined and elevated levels of ALP and osteocalcin upon treatment was observed. Anti-oxidant stress parameters studied showed an increase in cells upon treatment compared to control. Significant alterations in levels of protein involved in osteoblast differentiation are observed upon treatment. Conclusion: Cowpea isoflavones has shown a significant activity against OS by elevating antioxidant parameters and inducing osteoblast differentiation in the present study.

Puerarin, a bioactive flavonoid found in the root of Pueraria lobata, is claimed to possess various medicinal properties. However, application of puerarin in functional foods is currently limited by its poor bioaccessibility. Existing delivery systems that guarantee puerarin bioaccessibility involve complex preparation steps and safety issues. Therefore, this study aimed to use meat protein and olive oil to efficiently and economically fabricate a food grade high internal phase Pickering emulsion (HIPPE) with co-encapsulated puerarin and β-carotene to improve the bioaccessibility of puerarin. Moreover, the impact on lipid digestibility and puerarin bioaccessibility was verified using a simulated in vitro gastrointestinal tract. Co-encapsulating puerarin and β-carotene in HIPPE increased puerarin bioaccessibility (85.17%) compared to that achieved with only puerarin in HIPPE (62.66%). This increased bioaccessibility may have been due to the personalized formulation and the exceptional structure of the HIPPE, which slowed down lipid digestion and inhibited puerarin degradation. A synergistic interaction occurred between β-carotene and HIPPE to improve puerarin bioaccessibility. Our results have important implications for the design of effective delivery systems for encapsulation of puerarin and other bioactive components.

The purpose of the present study was to determine for the first time the volatile constituents, the antioxidant and antimicrobial activities of the essential oil (EO) of the endemic Moroccan Linaria ventricosa, alone or in combination with four known antibiotics. The major constituents were 2-methoxy-4-vinylphenol (17.4%), α-terpinene (13.64%) and 3,5-dimethylphenyl isocyanate (12.21%). The EO had moderate antioxidant potency, as measured by DPPH free radical scavenging (1.233 ± 0.031 mg/mL), ferric reducing antioxidant power assay (0.373 ± 0.019 mg/mL) and β-carotene/linoleic acid (0.922 ± 0.026 mg/mL). EO showed microbicidal activity against all microorganisms tested. The highest effectiveness was recorded against Candida albicans (IZ = 24 mm, MIC = 4.87 mg/mL and MMC = 9.75 mg/mL) and Candida glabrata (IZ = 22 mm, MIC = MMC = 4.87 mg/mL). Gram negative bacteria were the most resistant (MIC = MMC = 39 mg/mL). The combination of EO at sub-inhibitory concentrations with antibiotics showed a significant decrease in their individual MICs from 2 to 128 fold, being the best for ciprofloxacin and fluconazole against E. coli and C. albicans and C. glabrata, respectively. © 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Carotenoids in food substances are believed to have health benefits by lowering the risk of diseases. Lutein, a carotenoid compound, is one of the essential nutrients available in green leafy vegetables (kale, broccoli, spinach, lettuce, and peas), along with other foods, such as eggs. As nutrition plays a pivotal role in maintaining human health, lutein, as a nutritional substance, confers promising benefits against numerous health issues, including neurological disorders, eye diseases, skin irritation, etc. This review describes the in-depth health beneficial effects of lutein. As yet, a minimal amount of literature has been undertaken to consider all its promising bioactivities. The step-by-step biosynthesis of lutein has also been taken into account in this review. Besides, this review demonstrates the drug interactions of lutein with β-carotene, as well as safety concerns and dosage. The potential benefits of lutein have been assessed against neurological disorders, eye diseases, cardiac complications, microbial infections, skin irritation, bone decay, etc. Additionally, recent studies ascertained the significance of lutein nanoformulations in the amelioration of eye disorders, which are also considered in this review. Moreover, a possible approach for the use of lutein in bioactive functional foods will be discussed.

Phenolic acids (caffeic acid, p-coumaric acid,) and carotenes (β-carotene, lycopene) were mixed in different ratios to investigate antioxidant interactions on H2O2-induced H9c2 cells with ezetimibe (inhibitor of carotenes membrane transporters). Cellular uptake of carotenes, expression of membrane transporters, reactive oxygen species (ROS), nuclear factor erythroid 2-related factor 2 (Nrf2), NAD(P)H dehydrogenase quinone1 (NQO1), heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit (GCLC) were analyzed. Results revealed that phenolic acids increased cellular uptake of carotenes and expression of their membrane transporters. Combination groups contained more phenolic acids showed synergistic effects. For example, β-carotene: caffeic acid = 1:2 significantly suppressed the intracellular ROS (+EZT, 66.34 ± 51.53%) and enhanced the accumulation of nucleus-Nrf2 (+EZT, 30.23 ± 5.30) compared to the groups contained more β-carotene (+EZT, ROS: 75.48 ± 2.55%, nucleus-Nrf2: 19.48 ± 4.22). This study provided an implication of functional foods formulation and demonstrated that antioxidant synergism may due to the up-regulation of carotenes membrane transporters by phenolic acids.

Neuroblastoma is the most common extracranial solid tumor in childhood. The different treatments available for neuroblastoma are challenged by high rates of resistance, recurrence, and progression, most notably in advanced cases and highly malignant tumors. Therefore, the development of more targeted therapies, which are biocompatible and without undesired side effects, is highly desirable. The mechanisms of actions of platinum nanoparticles (PtNPs) and retinoic acid (RA) in neuroblastoma have remained unclear. In this study, the anticancer effects of PtNPs and RA on neuroblastoma were assessed. We demonstrated that treatment of SH-SY5Y cells with the combination of PtNPs and RA resulted in improved anticancer effects. The anticancer effects of the two compounds were mediated by cytotoxicity, oxidative stress (OS), mitochondrial dysfunction, endoplasmic reticulum stress (ERS), and apoptosis-associated networks. Cytotoxicity was confirmed by leakage of lactate dehydrogenase (LDH) and intracellular protease, and oxidative stress increased the level of reactive oxygen species (ROS), 4-hydroxynonenal (HNE), malondialdehyde (MDA), and nitric oxide (NO), and protein carbonyl content (PCC). The combination of PtNPs and RA caused mitochondrial dysfunction by decreasing the mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) content, number of mitochondria, and expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Endoplasmic reticulum-mediated stress and apoptosis were confirmed by upregulation of protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6), activating transcription factor 4 (ATF4), p53, Bax, and caspase-3 and down regulation of B-cell lymphoma 2 (BCl-2). PtNPs and RA induced apoptosis, and oxidative DNA damage was evident by the accumulation of 8-hydroxy-2-deoxyguanosine (8-OHdG) and 8-hydroxyguanosine (8-OHG). Finally, PtNPs and RA increased the differentiation and expression of differentiation markers. Differentiated SH-SY5Y cells pre-treated with PtNPs or RA or the combination of both were more sensitive to the cytotox

This study explores the sustainable valorization of grape pomace digestate as a biofertilizer for the cultivation of Calendula officinalis L., a medicinal and edible flower with significant functional potential. Grape pomace, a major byproduct of winemaking, was subjected to anaerobic digestion to produce a nutrient-rich digestate applied at 0, 10, 20, and 30% concentrations under four irrigation regimes (57-232 mL day-1). Two seasonal greenhouse experiments evaluated agronomic performance, flower yield, and biochemical composition. Moderate to high digestate applications (20-30%) markedly enhanced flower yield and aerial biomass, while promoting the accumulation of proteins, lipids, soluble sugars, carotenoids, and phenolic compounds. Flowers grown under these conditions exhibited elevated β-carotene levels (80.97 mg 100 g-1) and strong antioxidant activity (>1300 μmol TEAC 100 g-1), supporting their potential in functional foods, nutraceuticals, and natural colorants. Seasonal variation influenced metabolic responses, with summer enhancing sugar and carotenoid synthesis and winter favoring pigment stability. The digestate was free from toxic elements and improved substrate fertility, confirming its agronomic safety and efficiency. A sustainability evaluation yielded an EcoScale score of 89.8, substantially higher than values reported in comparable literature, underscoring the high environmental performance and process greenness of this approach. Overall, this work presents a scalable, eco-efficient strategy to convert winery residues into high-value floral biomass, advancing circular bioeconomy principles and sustainable agricultural practices. © 2026 The Authors. Published by American Chemical Society.

Improving and sustaining the health and productivity of dairy cows require integrated strategies that combine management and appropriate nutrition. This review adopts two complementary perspectives: optimizing periparturient management to support high productivity without compromising animal health and improving gestational nutrition to produce healthy replacement heifers. Several studies have examined how maternal nutritional and metabolic status before and after calving influence postpartum reproduction, productivity, placental development, and offspring health. Prepartum energy status is a key determinant of early postpartum ovarian function, with a timely first ovulation associated with adequate insulin-like growth factor-I exposure during follicular development. Insufficient β-carotene intake in energy-prioritized feeding systems adversely affects ovarian resumption. Uterine recovery is also nutrition-sensitive; cows with endometritis exhibit signs of impaired liver function, whereas delayed uterine involution is associated with inefficient ruminal nitrogen utilization. Supplementation with lysine, the first limiting amino acid in corn-based diets, further promotes uterine recovery. From a developmental perspective, maternal insulin resistance is associated with low birth weight and altered endocrine profiles in calves, which are indicative of long-term metabolic vulnerability. In contrast, lysine supplementation during the dry period supports neonatal protein synthesis and growth. Furthermore, in growing primiparous cows, greater milk yield during early pregnancy was associated with reduced anti-Müllerian hormone concentrations in female calves, suggesting a lower ovarian reserve. Collectively, these findings highlight the importance of gestational and peripartum nutritional management not only for improving dairy cow fertility and productivity but also for optimizing the health and reproductive potential of the next generation.

BACKGROUND: Withania somnifera (Ashwagandha) is a widely used medicinal plant known for its neuroprotective, hepatoprotective, fertility-enhancing, and anti-inflammatory properties. Although it has a long history of use in traditional medicine, a detailed understanding of its phytochemical constituents and associated biological activities remains limited. AIM: To perform comprehensive metabolomic profiling of Withania somnifera and identify its major bioactive secondary metabolites, with a focus on compounds contributing to neuroprotection, liver health, reproductive support, and inflammation modulation. METHODS: Root extracts of Withania somnifera (Ashwagandha) were subjected to methanol-based organic phase extraction followed by LC-MS/MS analysis, resulting in the characterization of 1,020 metabolites. Among these, 1,010 compounds were classified as putatively annotated (MSI Level 2/3 annotations) metabolites based on MS1 data, while 10 highly abundant metabolites were further confirmed by MS/MS fragmentation and assigned MSI Level 2 annotations. Relative abundance analysis was performed to determine the predominant phytochemical constituents of the extract. Key metabolites identified through this approach were subsequently correlated with the known pharmacological properties of Ashwagandha, including its immunomodulatory, anti-inflammatory, antioxidant, adaptogenic, and neuroprotective effects. RESULTS: The analysis identified a diverse array of secondary metabolites, many present at low individual abundance ( < 0.30% ). Notable compounds included the alkaloids Gentianaine ( 8.44% ) and Sauroxine ( 2.94% ), phenolics such as Mulberrofuran A ( 14.58% ) and Sulphuretin ( 9.61% ), and terpenoids including Pinocarvone and Ergosterol. (% of total annotated metabolites) These compounds were associated with anti-oxidative, neuro-regenerative, hepatoprotective, and anti-inflammatory effects. Additional metabolites, including Gomphrenin-I, Sitosterol, Pfaffic acid, and β -Carotene, were linked to reproductive health. Embelin and Kievitone were noted for their potential roles in enhancing oxidative stress responses. Despite the low abundance of individual compounds, th