Search Results (154)

Background/Objectives: Maternal vitamin D deficiency has been associated with preeclampsia, but evidence regarding preconception partner-specific vitamin D biomarkers is limited. We evaluated associations between preconception maternal and paternal vitamin D biomarkers and the odds of preeclampsia. Methods: This secondary prospective cohort analysis used data from the Folic Acid and Zinc Supplementation Trial (FAZST), a multicenter study conducted in the United States between 2013 and 2017. Of the 2370 enrolled couples who were seeking infertility treatment, 1054 couples achieved a documented pregnancy. Because preeclampsia can only be ascertained among pregnancies progressing beyond 20 weeks of gestation, the primary analytic population was restricted to 826 pregnancies that reached ≥20 weeks, including 98 with preeclampsia and 728 without preeclampsia. Preconception serum total 25-hydroxyvitamin D (25(OH)D), vitamin D-binding globulin (VDBG), albumin, free 25(OH)D, and bioavailable 25(OH)D were assessed in both partners. Multivariable logistic regression models estimated adjusted odds ratios (aORs) and 95% confidence intervals (CIs). Results: In categorical analyses, maternal total 25(OH)D findings were consistent with a possible U-shaped pattern. Compared with concentrations of 30–< 50 ng/mL, concentrations ≤20 ng/mL were associated with higher odds of preeclampsia (aOR = 2.58, 95% CI: 1.13–5.88), as were concentrations ≥50 ng/mL (aOR = 5.45, 95% CI: 1.71–17.41). Similar categorical patterns were observed for maternal free 25(OH)D, with higher odds at concentrations ≤8.25 pg/mL (aOR = 2.23, 95% CI: 1.13–4.43) and ≥12.5 pg/mL (aOR = 4.71, 95% CI: 1.97–11.29), and for maternal bioavailable 25(OH)D concentrations ≤3.5 ng/mL (aOR = 2.61, 95% CI: 1.19–5.72) and ≥5.0 ng/mL (aOR = 5.38, 95% CI: 2.15–13.46). Lower paternal bioavailable 25(OH)D was associated with lower odds of preeclampsia in the fully adjusted model (aOR = 0.50, 95% CI: 0.28–0.89); however, this finding should be considered exploratory. Conclusions: Among pregnancies progressing to ≥20 weeks, lower and higher categories of maternal total, free, and bioavailable 25(OH)D were associated with the odds of preeclampsia relative to intermediate categories. These categorical findings are consistent with a possible U-shaped pattern but do not establish a nonlinear dose–response relationship. Paternal findings were limited and should be considered exploratory. Full article

Neuropathic pain is a chronic, difficult-to-treat condition arising from injury or disease of the somatosensory nervous system. Current pharmacological treatments provide limited relief for many patients and are often associated with adverse effects, highlighting the need for complementary mechanism-based strategies. Neuroinflammation and oxidative stress are pivotal and interdependent drivers of neuropathic pain, promoting glial activation, cytokine release, mitochondrial dysfunction, redox imbalance, ion channel sensitization, and peripheral and central sensitization. Nutraceuticals and dietary bioactive compounds have gained attention because of their pleiotropic actions, i.e., multiple pharmacological activities, on inflammatory, oxidative, metabolic, mitochondrial, and neuroimmune pathways. This review summarizes the mechanistic roles of neuroinflammation and oxidative stress in neuropathic pain and discusses evidence supporting nutraceutical-based interventions, including polyphenols, terpenoids, alkaloids, fatty acids and lipid-derived compounds, antioxidant nutraceuticals, vitamins, and micronutrients. Preclinical studies indicate that these compounds can attenuate pain-related behaviors by modulating redox-sensitive inflammatory signaling, glial reactivity, mitochondrial function, nociceptive ion channels, and endogenous antioxidant defenses. Although clinical evidence remains limited, selected compounds, including alpha-lipoic acid, palmitoylethanolamide, omega-3 fatty acids, B-complex vitamins, vitamin D, and capsaicin, show translational promise. Future studies should prioritize standardized formulations, bioavailability, dosing, safety, mechanistic biomarkers, and robust randomized trials to clarify their clinical role as complementary, multi-target strategies for neuropathic pain management. Full article

Background/Objectives: Interest in alternative, non-animal sources of vitamin D has increased due to the global prevalence of its deficiency and the growing demand for plant-based dietary options. Mushrooms and algae have emerged as potential sustainable sources of vitamin D₂ and, in selected cases, vitamin D₃ following ultraviolet (UV) exposure. However, the comparative bioavailability and clinical effectiveness of vitamin D₂ relative to vitamin D₃ remain controversial. This review aims to evaluate the content of vitamin D₂ in mushrooms and algae, the impact of UV irradiation on its synthesis, and the effectiveness of vitamin D₂ supplementation compared with vitamin D₃ in humans. Methods: PubMed, ScienceDirect, and Google Scholar were searched (1996–2026). Only human intervention studies were included when assessing clinical efficacy. Data on natural sources and pharmaceutical formulations were analyzed. Results: UV irradiation markedly increases vitamin D₂ content in mushrooms, as compared to cultivated products. Algal vitamin D content varies, depending on species and UV exposure, with no robust clinical trials confirming improvement of serum 25(OH)D after algal supplementation. Across multiple randomized controlled trials, vitamin D₂ consistently increased circulating 25(OH)D₂ but frequently reduced 25(OH)D₃ and demonstrated lower efficacy in raising total 25(OH)D compared with vitamin D₃, as confirmed by a recent meta-analysis. Conclusions: Although UV-enhanced mushrooms represent a quantifiable dietary source of vitamin D₂, clinical evidence consistently indicates lower efficacy of vitamin D₂ compared with vitamin D₃. Algae cannot currently be considered a validated source of vitamin D for improving human vitamin D status. Further mechanistic and long-term clinical studies are required. Full article

Background: Shifting toward more plant-based diets is promoted for health, environmental, and ethical reasons. However, the nutritional consequences of reducing animal-based foods, particularly across age groups with specific dietary needs, remain insufficiently understood. Methods: In this simulation study, we used dietary intake data from 3570 participants in the Dutch National Food Consumption Survey (2019–2021) to evaluate how replacing animal-based foods with plant-based alternatives affects the intake of protein, essential amino acids (EAAs), vitamins, and minerals across different age groups. Two substitution scenarios were modeled: a nutritionally conscious and a less conscious plant-based dietary pattern. Results: Total protein intake decreased in both scenarios, with the strongest reductions observed in elderly individuals (71–79 years). Vitamin intake, particularly B vitamins and vitamin A, declined in most age groups, and vitamin D remained chronically low. Mineral intake also decreased, notably for calcium, iron, iodine, selenium, and zinc, especially among women and adolescents. Conclusions: These results underscore the importance of dietary planning and targeted fortification when promoting plant-based eating patterns. Future research should refine bioavailability estimates and evaluate the long-term health effects of such dietary transitions across life stages. Full article

Supplements are widely perceived as safe and beneficial; yet in oncology, this assumption is questionable. Clinical trials over the past few decades have often produced disappointing results, raising a critical question: are these agents used correctly, or could they inadvertently cause harm? This review examines supplements frequently used in cancer care—such as oral vitamin C, berberine, N-acetylcysteine, vitamin D, vitamin E, melatonin, polyphenols, alpha-lipoic acid, selenium, and coenzyme Q10—which can act as tumor suppressors or promoters depending on dose, route, and disease stage. We examine their dual antioxidant and pro-oxidant properties, revealing that therapeutic outcomes are shaped not only by the molecule itself, but also by bioavailability, dosing thresholds, and the tumor redox environment. Building on these insights, we propose that four factors may be considered to guide clinical use: ensure that anticancer effects are not overshadowed by antioxidant activity, achieve sufficient bioavailability, confirm pro-oxidant concentrations where possible, and prioritize supplements that target the respiration-supported non-OxPhos pathways. By framing supplements as context-dependent redox modulators rather than universally beneficial agents, this review provides a mechanistically grounded framework for informing future research and safer, more effective integrative oncology strategies. Full article

Background: Vitamin D has traditionally been recognized for its role in calcium homeostasis and skeletal health, but vitamin D receptor expression and vitamin D-metabolizing enzymes have also been identified in extra-skeletal tissues, including components of the male reproductive tract. Observational evidence has suggested associations between vitamin D status and androgen-related markers; however, whether vitamin D supplementation has a measurable effect on androgen bioavailability remains uncertain. Objective: This systematic review and meta-analysis evaluated the effects of vitamin D supplementation on total testosterone (TT) and androgen bioavailability markers in adult men, including sex hormone-binding globulin (SHBG), free androgen index (FAI), calculated free testosterone (calculated FT), and bioactive testosterone (BAT) where methodologically compatible. Methods: The review was registered in PROSPERO (CRD420261365005) and conducted according to PRISMA 2020 and Cochrane methodological guidance. Searches were conducted from database inception to April 2026 in PubMed, Web of Science, Scopus, ClinicalTrials.gov, and the WHO ICTRP. Embase was initially planned but was not searched because institutional access was unavailable; this amendment was made before screening, extraction, risk-of-bias assessment, and synthesis. Records were deduplicated in Zotero, screened in a structured matrix, and converted from report-level records into independent comparison-level datasets where appropriate. Meta-analyses used random-effects REML models with Hartung–Knapp adjustment. Results: The official search set comprised 2854 records, of which 703 duplicates were removed, leaving 2151 records for title and abstract screening. The full-text screening file was reconciled to 162 PRISMA-countable reports/records: 135 reports were assessed, 27 reports could not be assessed because the full text was unavailable or had not been obtained for review, and 27 reports/studies were retained for qualitative synthesis. Eighteen reports were considered candidate sources for quantitative synthesis and were operationalized into 21 comparison-level records. The primary TT model included 11 comparisons and showed no clear effect of vitamin D supplementation on final TT (MD 0.47 nmol/L, 95% CI −0.50 to 1.44; I² = 24.1%). No clear effects were observed for SHBG (MD 0.27 nmol/L, 95% CI −2.14 to 2.68), FAI (MD −0.37, 95% CI −4.28 to 3.55), calculated FT sensitivity evidence (MD −0.0096 nmol/L, 95% CI −0.0525 to 0.0332), or BAT exploratory evidence (MD −0.47 nmol/L, 95% CI −1.77 to 0.83). GRADE certainty was low for TT, SHBG, and FAI, and very low for calculated FT and BAT. Conclusions: Current randomized evidence does not demonstrate a statistically clear or reproducible effect of vitamin D supplementation on total testosterone or androgen bioavailability markers in adult men. GRADE certainty was low for total testosterone, SHBG, and FAI, and very low for calculated free testosterone and bioactive testosterone. Because directly measured and calculated free testosterone are not analytically equivalent, free testosterone was not pooled as a primary outcome; method-compatible calculated FT was handled as sensitivity evidence and BAT as exploratory evidence. Full article

Edible and medicinal mushrooms are widely studied for their bioactive compounds, yet their role as sources of essential vitamins remains inadequately defined and often overestimated. This review provides a critical assessment of vitamin composition in edible and medicinal mushrooms, with an emphasis on B-group vitamins and vitamin D₂, focusing on variability, bioavailability, and limitations for nutritional applications. Current evidence indicates that mushrooms can contribute to the intake of selected B vitamins, particularly riboflavin (B₂) and thiamine (B₁), at levels comparable to common plant foods. However, their relevance as a source of vitamin B₁₂ is highly uncertain due to pronounced compositional variability, the frequent occurrence of inactive corrinoid analogues, and limited evidence of physiological bioavailability. In contrast, vitamin D₂ represents a distinctive and technologically controllable feature of mushrooms, formed via the ultraviolet-induced conversion of ergosterol. Post-harvest UV exposure can substantially enhance vitamin D₂ content, enabling targeted biofortification strategies. Nevertheless, the nutritional significance of mushroom-derived vitamins is constrained by inconsistencies in reported concentrations, lack of standardized analytical methodologies, and insufficient clinical evidence. Overall, edible and medicinal mushrooms should not be regarded as universal natural sources of vitamins; rather, their nutritional relevance depends on species, cultivation conditions, post-harvest processing, analytical verification, and, particularly in the case of vitamin D₂, controlled UV-induced biofortification. Future research should prioritize standardized analytical approaches and well-designed human studies to support evidence-based nutritional applications. Full article

Background/Objectives: Vitamin D is a nutrient-related secosteroid system with endocrine, paracrine, immunological, and neurodevelopmental actions relevant to nutritional psychiatry. Psychiatric research has often treated vitamin D either as a cross-sectional correlate of depression or as a non-specific supplement expected to act across heterogeneous diagnostic categories. This narrative review aimed to develop a more discriminating framework in which vitamin D is considered a lifespan neuroimmune and immunometabolic signal whose psychiatric relevance depends on developmental timing, biological context, and phenotype. Methods: Evidence was integrated from developmental epidemiology, neonatal dried-blood-spot studies, randomized trials, meta-analyses, Mendelian randomization studies, clinical guidelines, and mechanistic neuroscience. The review focuses on prenatal and neonatal 25-hydroxyvitamin D, vitamin D-binding protein, free and bioavailable vitamin D, vitamin D receptor signaling, immune and microglial pathways, neurotransmitter systems, neurotrophic signaling, mitochondrial function, oxidative stress, hypothalamic–pituitary–adrenal-axis regulation, and the gut–microbiota–immune–brain axis. Results: The available evidence does not support vitamin D as a universal treatment for psychiatric disorders. Instead, vitamin D deficiency and altered vitamin D biology appear most relevant in biologically and clinically defined risk states, including neurodevelopmental vulnerability, inflammatory depression, psychosis liability, severe mental illness with nutritional deprivation, metabolic comorbidity, and cognitive frailty. Mechanistic data support plausible links with cytokine biology, the tryptophan–kynurenine pathway, dopaminergic and serotonergic systems, stress regulation, and neuroimmune homeostasis. Conclusions: Vitamin D should be conceptualized in psychiatry as a context-dependent neuroimmune and immunometabolic signal rather than a generic psychotropic intervention. Future studies should prioritize biomarker-enriched, developmentally timed, nutrition-centered models of precision prevention and adjunctive care. Full article

The pathophysiological basis of Parkinson’s disease (PD) remains incompletely understood. However, the influence of environmental factors, such as continuous cadmium exposure, requires further investigation. Notably, common comorbidities such as iron deficiency anemia (IDA), chronic obstructive pulmonary disease (COPD), and zinc deficiency are linked with increased cadmium bioavailability, and elevated blood cadmium levels have been reported in individuals with PD. Cd (II) deposits in the midbrain, causing the accumulation of inflammatory lipids, which promote neuronal destruction. Cd-treated animals develop Parkinson-like syndromes, and cadmium exposure is associated with neuronal loss and disruption of dopaminergic receptor expression. Neurofilament light chain (NfL), a biomarker of neurodegeneration, has been found to be elevated in patients with Parkinson’s disease and correlates with Cd blood concentrations. Iron deficiency promotes the secretion of FGF-23, which depletes vitamin D levels, further increasing the risk of PD. Moreover, COPD and IDA are two well-known examples of systemic hypoxia, which attracts metals bound to transferrin, such as cadmium and iron, leading to increased metal accumulation in various tissues, including the brain. Lead levels are also elevated in individuals with IDA, contributing to the risk of PD. Additionally, Cd exposure is associated with a reduced abundance of Lachnospiraceae in stool and decreased levels of butyrate, both of which are characteristic features of patients with Parkinson’s disease. Therefore, this review aims to explore how COPD, IDA, and zinc deficiency—known risk factors for Parkinson’s disease—lead to an increased cadmium burden and contribute to the onset and progression of the disease. Full article

Methylglyoxal (MG) is a reactive dicarbonyl compound generated mainly as a byproduct of glycolysis. Excess accumulation of MG can promote protein glycation and the formation of advanced glycation end-products (AGEs), which have been associated with oxidative stress, inflammation, mitochondrial dysfunction, and cellular damage. These processes are implicated in the development of several chronic conditions, including diabetes, neurodegenerative disorders, cardiovascular disease, and age-related decline. The glyoxalase system, comprising Glyoxalase I (Glo1) and Glyoxalase II (Glo2), serves as a key cellular defense mechanism that detoxifies MG and helps maintain dicarbonyl homeostasis. Among these enzymes, Glo1 catalyzes the conversion of MG into less reactive intermediates in a glutathione (GSH)-dependent manner. A range of natural compounds and dietary phytochemicals, including sulforaphane, resveratrol, α-lipoic acid, selenium, vitamin D3, and N-acetylcysteine, have been reported to modulate Glo1 activity through transcriptional regulation, antioxidant effects, or support of intracellular GSH levels. Evidence from preclinical and limited human studies suggests that these compounds may help reduce MG burden and AGE formation, although their effects are often indirect and context-dependent. However, several challenges remain, including variable bioavailability, dose-dependent responses, disease-specific differences in Glo1 regulation, and the lack of standardized biomarkers and adequate clinical validation. This review examines the MG–Glo1 axis as a mechanistic framework linking metabolic stress to disease and evaluates natural compounds as context-dependent modulators of this pathway. By integrating mechanistic insights with emerging in vivo and clinical evidence, this work highlights the potential, while acknowledging the limitations, of targeting Glo1 as a translational strategy for managing glycation-associated disorders. Full article

Ergosterol is a fungal sterol with broad pharmacological activities, including anticancer, anti-inflammatory, cholesterol- and uric acid-lowering effects, and serves as the precursor of vitamin D₂. Despite its therapeutic potential, poor aqueous solubility, physicochemical instability, and low oral bioavailability severely limit its clinical application. This review provides an integrative overview of the physicochemical properties, biosynthesis, biological activities, underlying molecular mechanisms, pharmacokinetics, and safety profiles of ergosterol and its major derivatives. A structured literature search was conducted in PubMed, Web of Science, Scopus and CNKI up to February 2026, with findings critically synthesized across preclinical models. Current evidence links ergosterol-related interventions to changes in signaling pathways such as PI3K/Akt, NF-κB, and Wnt/β-catenin, although direct target-engagement evidence remains limited for many disease models. The review concludes that while ergosterol represents a promising natural scaffold for drug development, translational progress is constrained by limited human pharmacokinetic data and insufficient exposure–response validation. Future research should prioritize metabolite profiling, clinically relevant dosing strategies, and formulation optimization to better define the translational potential of ergosterol-based compounds. Full article

Background/Objectives: Natural multi-component nutraceutical formulations may modulate interconnected pathways involved in metabolic and bone health. This study evaluated, using in vitro models, the effects of a standardized botanical–vitamin formulation on intestinal barrier integrity, osteoblastic activity, and osteoclast differentiation, focusing on intestinal-bone crosstalk, redox-inflammatory signalling, and potential synergistic interactions among components. Methods: A combined in vitro approach using intestinal, osteoblastic, and osteoclastic cell models was applied to assess a formulation containing characterized plant extracts and vitamin D₃. The study evaluated cytocompatibility, intestinal barrier function, cellular uptake, and the modulation of markers related to osteogenesis and osteoclastogenesis, using biochemical, molecular, and enzymatic assays, as well as oxidative stress measurements and synergy analysis. Results: The formulation maintained intestinal barrier integrity and bioavailability without cytotoxicity, promoted osteoblastic differentiation and reduced oxidative stress, while inhibiting osteoclast differentiation and resorptive activity. These effects were associated with modulation of inflammatory and redox-related signalling pathways and showed additive to synergistic interactions among components. Conclusions: These findings support a multi-target nutraceutical approach that can concurrently influence intestinal barrier and bone remodelling in vitro, offering mechanistic evidence for its role in modulating the gut–bone axis, and highlight the need for further studies in advanced models and clinical trials. Full article

Background/Objectives: Acute high-intensity exercise may transiently alter circulating vitamin D metabolites. However, the effects of training status, supplementation dose, and vitamin D-binding protein (VDBP) on the exercise-induced redistribution and bioavailability of vitamin D remain unclear. This pilot study examined whether training status and vitamin D₃ supplementation dose modulate vitamin D status, anaerobic performance, and acute post-exercise changes in vitamin D metabolites and VDBP. Methods: Thirty-four healthy young men participated, comprising 22 mixed martial arts (MMA) athletes and 12 untrained controls. MMA athletes received either 3500 or 6000 IU/day of vitamin D₃ for four weeks, while untrained participants received 3500 IU/day or a placebo. Before and after the intervention, participants performed a supramaximal anaerobic exercise protocol (3 × 30 s Wingate tests). Blood samples were collected at rest and 30 min and 24 h post-exercise to assess vitamin D metabolites, VDBP, bioavailable and free 25(OH)D₃, interleukin-6, and lactate. Results: Supplementation with 3500 IU/day significantly increased serum 25(OH)D₃ in untrained men (p = 0.003) but not in MMA athletes. In contrast, 6000 IU/day increased 25(OH)D₃ in MMA athletes to a sufficient concentration (p = 0.001) and improved maximal power (+7.5%), mean power (+4.9%), and total work (+5.0%). Acute exercise increased circulating vitamin D metabolites in trained athletes but reduced them in untrained men supplemented with vitamin D. Conclusions: The efficacy of vitamin D₃ supplementation and the acute exercise-induced vitamin D responses appear to be training-dependent. A daily dose of 6000 IU is more effective in achieving vitamin D sufficiency and performance benefits in MMA athletes, whereas 3500 IU is sufficient for untrained men. Full article

Background: Obesity is commonly seen as a condition of overnutrition; however, it is paradoxically associated with micronutrient deficiencies. These deficiencies are clinically relevant and may contribute to the progression of obesity-related comorbidities through interconnected pathways, including chronic low-grade inflammation, oxidative stress, gut dysbiosis, and impaired nutrient absorption. Objectives: This narrative review aims to summarize current evidence regarding the prevalence, underlying mechanisms, and clinical consequences of micronutrient deficiencies in individuals with obesity, with particular emphasis on their metabolic implications and potential therapeutic strategies. Results: Among individuals with obesity, iron, zinc, magnesium, calcium, vitamin D, vitamin B12, and folate are the most frequently reported deficiencies. These deficiencies arise from multiple mechanisms, including poor diet quality, increased metabolic demands, and compromised gastrointestinal absorption. In addition, obesity-related alterations in pharmacokinetics may further interfere with micronutrient distribution and bioavailability. Together, these mechanisms may lead to various clinical outcomes, such as anemia, immune, metabolic, and cardiovascular dysfunctions, along with cognitive impairment. Although several studies suggest that correcting these deficiencies may improve clinical outcomes, findings remain inconsistent, highlighting the complex and multifactorial pathophysiology underlying micronutrient imbalance in obesity. Conclusions: Micronutrient deficiencies represent frequently overlooked contributors to metabolic dysregulation in obesity. Their identification and correction should be considered a central part of the obesity management strategy. A personalized supplementation approach, based on clinical, biological, and pathophysiological characteristics, may provide a complementary support for weight-management treatments. Full article

Background: Alzheimer’s disease (AD) remains a major public health challenge. Observational associations between dietary patterns and reduced dementia risk have prompted investigations of dietary bioactives (DBs) as cognitive nutraceuticals. Methods: This critical narrative review examines interventional trials for nine prominent DBs relevant to AD: docosahexaenoic acid (DHA), curcumin, resveratrol, epigallocatechin gallate (EGCG), nicotinamide riboside (NR), tricaprilin, vitamin E (α-tocopherol), cannabinoids, and NIC5-15 (D-pinitol). Trials were identified through ClinicalTrials.gov (search date: December 2024) and supplemented by PubMed searches for published results. Data were extracted on trial phase, design, cognitive/functional endpoints, biomarker outcomes, and development status. Findings are synthesized qualitatively; no formal meta-analysis or risk of bias assessment was conducted. Results: None of the nine bioactives demonstrated consistent cognitive efficacy in AD. Phase III trials of DHA, curcumin, and tricaprilin did not meet primary cognitive endpoints. Resveratrol reduced CSF Aβ40 without cognitive benefit. Cannabinoids improved behavioral symptoms but showed no measurable cognitive effects. High-dose vitamin E slowed functional decline, while cognition remained unchanged. In contrast, trials in preclinical or at-risk populations reported preliminary cognitive signals for EGCG and biomarker engagement for NR, suggesting potential for early intervention. Conclusions: Current clinical evidence does not support high-dose DBs supplementation as an effective treatment for AD. Predominantly negative late-phase findings highlight limitations, with potential contributors including limited bioavailability, late intervention, insufficient target engagement, and biological heterogeneity. Future research may benefit from early biomarker-defined populations, optimized formulations, multi-nutrient or dietary approaches, and precision nutrition strategies considering genetic risk and baseline nutrient status. DBs may be better positioned for prevention or early-stage intervention rather than late-stage therapy. Full article