Search Results (1,455)

Pathogen manipulation of host behavior is a widespread evolutionary strategy to enhance its transmission, yet whether different pathogens elicit distinct behavioral and molecular responses in the same host remains poorly understood. We performed parallel behavioral assays and comparative transcriptomic analyses on third-instar Lymantria dispar larvae infected with Lymantria dispar multiple nucleopolyhedrovirus (LdMNPV, virus), Staphylococcus aureus (bacterium) and Metarhizium anisopliae (fungus). Climbing height was recorded over 72 h post-infection, and gene expression pattern was profiled using RNA-seq at 72 h. Only LdMNPV infection induced significant, sustained upward climbing behavior among the three pathogen infection groups. All three pathogens activated Toll and IMD immune pathways, but LdMNPV triggered substantially broader transcriptomic reprogramming. Notably, the virus specifically upregulated multiple energy metabolism pathways (nicotinate/nicotinamide metabolism, pyruvate metabolism, TCA cycle and oxidative phosphorylation) and the neuroactive ligand-receptor interaction pathway—a pattern absent in bacterial and fungal infections. LdMNPV drove tree-top disease through a virus-specific, multi-system manipulation strategy that couples metabolic activation with neural signaling modulation. This comparative study reveals fundamental differences in behavioral manipulation across pathogen kingdoms and provides candidate pathways for functional validation. Full article

Nicotinamide mononucleotide (NMN), a direct precursor of the essential coenzyme nicotinamide adenine dinucleotide (NAD⁺), confers anti-aging effects and multiple health benefits. Engineered microorganisms represent a promising platform for sustainable industrial production of NMN. Here, the previously reported NMN-producing strain NMN008 was engineered to co-utilize glucose and glycerol for the biosynthesis of NMN from nicotinamide (NAM). First, the glycolytic genes pgi and pykA/pykF were sequentially deleted to disrupt glucose catabolism through the glycolytic pathway, thereby potentially improving precursor availability for NMN biosynthesis. Second, a feedback-resistant glycerol kinase mutant (glpK*) was introduced to enhance glycerol utilization, aiming to compensate for the growth defects associated with impaired glycolysis. These modifications enabled glycerol to primarily support cell growth and energy metabolism, while improving glucose allocation toward NMN biosynthesis by reducing its competitive consumption through glycolysis. As a result, the final strain achieved an NMN titer of 32.92 g/L in a 2 L bioreactor, representing a 26.28% increase in NMN production and a substantial 34.48% improvement in carbon conversion efficiency. Our research provides an effective strategy to achieve industrial-scale production of NMN, laying a foundation for the widespread application of NMN. Full article

Background/Objective: Delaying muscle fatigue could alleviate economic and food security, and welfare concerns associated with transporting market-weight pigs to harvest. Previous research demonstrates barrow nicotinamide riboside (NR) supplementation at varying doses during the last 10 d of finishing shows to be a countermeasure to muscle fatigue by reducing muscle fiber recruitment and increasing mitochondrial DNA expression in a dose-dependent manner. Therefore, this study aims to determine if a greater NR dose further enhances barrow fatigue resistance and characterize muscle mitochondria content and efficiency. Methods: Barrows (N = 87) were assigned to one of two dietary NR supplementation doses (TRT): 0 (0NR) or 150 (150NR) mg/kg body weigh NR administered during the last 14 d of finishing. Muscle (MUS) biopsies were collected on supplementation d (DAY) 0, 7 and 14 from three hind-leg muscles for NAD+ quantification and mitochondrial DNA expression and efficiency. On days 15 and 16, barrows were subjected to a performance test until they were subjectively exhausted. Electromyography data collection during the performance test were divided into five periods (PER) and included normalized root mean square (nRMS) from the same muscles. Results: There were no three-way interaction for nRMS (p > 0.83), but there were MUS × TRT and PER × TRT interactions (p < 0.05). During performance testing, 150NR had greater nRMS than 0NR in the bicep femoris (BF) and tensor fasciae latae (TFL; p < 0.01), but there were no differences in the semitendinosus (ST; p = 0.77). Treatments did not differ during PER 1 and 2 (p > 0.14) but 150NR had greater nRMS than 0NR during PER 3, 4 and 5 (p < 0.01) across all muscles. There was no three-way interaction for normalized (nNAD+; p = 0.14), but there was a DAY × TRT interaction (p < 0.05). There were no differences between 0NR and 150NR at d 0 (p = 0.95); however, by d 7 and 14, 150NR muscles had greater nNAD+ than 0NR muscles (p < 0.01). There tended to be a three-way interaction for mitochondrial DNA expression (p = 0.09). At supplementation d 14, all 150NR muscles had greater mitochondrial DNA expression and electron transport chain complex I and II activities (p < 0.01). When normalized to citrate synthase activity, electron transport chain complex I and II activity did not differ (p > 0.05). Conclusions: Large-dose NR supplementation appears to support sustained muscle fiber recruitment during prolonged activity and enhance fatigue resilience, primarily through increased NAD+ and mitochondrial biomarkers abundance and not through mitochondrial efficiency. Full article

Nicotinamide adenine dinucleotide (NAD⁺) is essential for maintaining homeostasis in all types of cells, including endothelium, and depletion of its pool can impair bioenergetics and stress response, contributing to cardiovascular disorders. Nicotinamide riboside (NR) effectively restores the intracellular NAD⁺ pool, supporting endothelial integrity, but the molecular mechanisms remain incompletely elucidated, particularly regarding extracellular adenine nucleotide catabolism, purinergic signaling, and their effects on immune cell adhesion. In this study, we aimed to investigate the effects of NR on intracellular nucleotides, extracellular adenine nucleotide catabolism, and adhesive properties in the cultured murine (H5V) and human (HMEC-1) microvascular endothelial cell line. We demonstrated that NR treatment significantly increased intracellular NAD⁺ concentrations without changes in the energy status of endothelial cells. We also showed that NR treatment accelerated extracellular hydrolysis of ATP and AMP and decreased the rate of adenosine deamination in endothelial cells. Moreover, we observed CD73 activity and adenosine-related reduced adhesion of T-lymphocytes, monocytes and platelets to the NR-treated endothelial monolayer. Our findings highlight a previously unrecognized role of NR in maintaining endothelial homeostasis, showing that NR is not only a potent intracellular NAD⁺ booster in endothelial cells but also affects extracellular nucleotide metabolism in a way that promotes cytoprotective adenosine formation. Full article

The fruit of Aronia melanocarpa (Michx.) Elliott is a berry with multiple properties and was included as a new raw food material by the National Health Commission of China (NHC) in September 2018. This study focused on the immune regulatory properties and underlying mechanism of polysaccharides extracted from Aronia melanocarpa fruit (AMFP) by undertaking an integrated analysis of multiple endogenous metabolic pathways. An improvement in AMFP in immunosuppressed model mice at three levels of immune organs, immune cells, and immune factors was determined. The immunomodulatory role of AMFP was assessed through measurement of metabolomic and lipidomic profilings by UPLC-Q-TOF/MS. A total of 53 differential endogenous metabolites in the urinary, serum, and lipid metabolomics were identified, followed by KEGG pathway enrichment. Furthermore, the underlying mechanisms were elucidated by an integrated analysis of multiple metabolomics and lipidomics. Primarily, we found regulation of immune-related metabolic pathways, including nicotinate and nicotinamide metabolism, sphingolipid metabolism, glycerophospholipid metabolism, purine metabolism, steroid hormone biosynthesis, and arachidonic acid metabolism. The results also demonstrated the mutual validation of key pathways and mechanisms. AMFP potentiated both humoral and cellular immunity responses and protected the immune system from oxidative damage. This research provides a reference and a basis for the development and application of AMFP in the field of health foods that regulate immunity. Full article

Cosmetic dermatology has largely focused on topical applications targeting the stratum corneum. However, emerging evidence suggests that visible aging is a systemic readout of internal “organ clocks” and molecular dysregulation across the epidermis and dermis. This review proposes an “inside–out strategy” that seeks to re-conceptualize aesthetic vitality as a measurable indicator of systemic physiological resilience. The author describes theoretically proposed organ–skin axes, including the role of molecular signaling of kidney-derived klotho (KL1 fragment) via FGFR1-α–klotho complexes and muscle-derived irisin through the AMPK/PGC-1-α pathway in modulating skin homeostasis. Drawing on recent breakthroughs in non-human primate models (2023–2025), this synthesis explores the potential of systemic interventions—including nicotinamide adenine dinucleotide (NAD+) precursors (sirtuin 1 SIRT1 activators), senolytics (targeting BCL-2/p16), and glucagon-like peptide-1 (GLP-1) receptor agonists—as candidates to potentially synchronize these internal clocks. Furthermore, the review identifies direct regenerative interventions, such as retinoids (RAR/RXR signaling), chemical peels (HIF-1-α induction), exosomes (miR-21/29 delivery), and poly-L-lactic acid PLLA (mechanotransduction via YAP/TAZ), positioning them as potential physical and chemical epigenetic modulators that may support the restoration of cellular transcriptional fidelity. This article proposes a new paradigm for regenerative aesthetics that focuses on restoring the youthful phenotype by optimizing systemic molecular crosstalk and epigenetic transcriptional fidelity. Full article

Zearalenone (ZEN) is a widely distributed estrogenic mycotoxin that compromises intestinal health in pigs, but its spatial difference ZEN and niche-specific regulatory effects on the intestinal microbiota remain largely unelucidated. In this study, 12 healthy three-way crossbred weaned piglets (Duroc × Landrace × Yorkshire) were randomly divided into two treatments. The control group (CON) was fed with the basal diet, and the treatment group (ZEN) was supplemented with 1.5 mg ZEA/kg of the basal diet for 28 days. Chyme and mucosal microorganisms in the duodenum, jejunum, ileum, colon and cecum were profiled by using 16S rDNA sequencing. The results indicated that ZEN significantly reduced the α-diversity of ileal chyme, while the abnormal increase in α-diversity of ileal and cecal mucosa represented a pathological signature of intestinal mucosal barrier damage induced by ZEN, which was detrimental to intestinal health. β-Diversity analysis revealed ZEN altered the microbial community composition of the cecal chyme. LEfSe analysis revealed gut segment-specific and niche-specific biomarker taxa among the groups, and functional prediction further indicated that ZEN exposure significantly perturbed key metabolic pathways: it downregulated nicotinate and nicotinamide metabolism as well as the citrate cycle in ileal chyme and upregulated the pentose and glucuronate interconversions pathway in cecal chyme. Collectively, this study demonstrated the effects of ZEN on the intestinal microbiota across spatial difference and ecological niches in weaned piglets, providing a basis for elucidating the microecological mechanisms underlying ZEN-induced intestinal injury in pigs. Full article

Abiotic stresses severely constrain crop productivity by disrupting cellular redox homeostasis and hormone signaling. Although individual stresses differ in origin, plant responses converge on a conserved regulatory system centered on reactive oxygen species (ROS) and phytohormone crosstalk. Controlled ROS production in chloroplasts, mitochondria and the apoplast functions as a signaling mechanism that interacts dynamically with abscisic acid, auxin, ethylene, jasmonate and cytokinin pathways through shared regulatory nodes, including nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and redox-sensitive transcriptional cascades. Endogenous metabolites, including phenolics, terpenoids, carotenoids, alkaloids, polyamines, glutathione and signaling peptides, are embedded within this network and modulate its amplitude and sensitivity. In parallel, non-microbial biostimulants derived from seaweeds, higher plants, protein hydrolysates and humic substances have been widely reported to enhance crop performance under abiotic stress. However, mechanistic integration between biostimulant research and plant stress signaling remains limited. In this review, we propose that terrestrial plant- and algal-derived biostimulants act not as external substitutes for hormones or antioxidants but as modulators of endogenous ROS–hormone signaling hubs. We first synthesize the current understanding of redox–hormone integration under abiotic stress, then examine endogenous metabolites as intrinsic regulators of this network, followed by an analysis of biostimulants in relation to shared regulatory nodes. By positioning biostimulant action within the established redox–hormone network, we provide a mechanistic framework that links stress biology with agronomic application and supports rational strategies to enhance crop resilience. Full article

Background/Objectives: Oral squamous cell carcinoma (OSCC) is a major cause of human cancer. The enzyme, nicotinamide N-methyltransferase (NNMT), is overexpressed in a variety of human cancers, including OSCC. Our objective was to target NNMT with novel inhibitors and determine their anti-cancer efficacy while shedding light on their possible mechanism of action. Methods: We identified two small molecule inhibitors of NNMT (AG-670 and AO-022) based on a pharmacophore of the in silico nicotinamide binding site. These inhibitors were investigated for (i) potency to inhibit the activity of the isolated NNMT enzyme (EC₅₀ values), (ii) cytotoxicity (IC₅₀ values) against the human OSCC cell line, SCC-4, and (iii) ability to affect cellular energy metabolism, as measured by oxygen consumption, in SCC-4 cells (plus dysplastic oral keratinocytes (DOK) cells and breast cancer MCF-7 cells). Immunoblotting was used to determine whether NNMT was expressed in the aforementioned cells. Results: NNMT is expressed in SCC-4 and DOK cells (and primary human oral keratinocytes) but not MCF 7 cells. The NNMT inhibitors inhibit isolated NNMT enzyme activity and were cytotoxic to SCC-4 cells (EC₅₀ and IC₅₀ values in the micromolar range). Sublethal doses of the inhibitors were demonstrated to inhibit in situ mitochondrial oxygen consumption in SCC-4 and DOK cells but not in MCF-7 cells. It was demonstrated that the NNMT inhibitors do not directly inhibit mitochondrial electron transport chain activity. Thus, we deduce that the NNMT inhibitors affect mitochondrial activity indirectly via NNMT. Conclusions: It is concluded that NNMT is a potential drug target for oral cancer. Full article

Background: Glucocorticoids (GCs) are a key pathogenic factor in steroid-induced avascular necrosis of the femoral head (SANFH). GCs can directly damage bone microvascular endothelial cells (BMECs), leading to impaired intraosseous blood supply. Recent studies suggest the Hippo signaling pathway may be involved in the pathogenesis of SANFH; however, its role in vascular endothelial repair and angiogenesis remains unclear. This study aims to investigate the therapeutic effects of human umbilical cord mesenchymal stem cells (hUC-MSCs) on SANFH, with a particular focus on their protective or reparative mechanisms on BMECs. Methods: In vivo, a SANFH mouse model is established and divided into NC, MPS, and hUC-MSCs groups, followed by Micro-CT imagin, hematoxylin and eosin (HE) staining and immunohistochemistry (IHC) (n = 8 per group). In vitro, BMECs are divided into NC, dexamethasone (Dex), hUC-MSCs, and Fer-1 groups to analyze cellular biological behaviors. Target protein expression is assessed using Western blotting and immunofluorescence microscopy. Ferroptosis-related markers are detected via biochemical assays. Mitochondrial ultrastructural changes are observed using transmission electron microscopy. Results: In vivo, the MPS group exhibited significant bone cavitation, sparse trabeculae, and disrupted trabecular architecture in the femoral head. The hUC-MSCs group showed marked improvement in bone microstructure, HE staining showed a significant decrease in the empty lacunae rate in the femoral head, and IHC results revealed markedly increased expression of cluster of differentiation 31 (CD31) and vascular endothelial growth factor (VEGF). In vitro, Dex stimulation suppressed BMECs proliferation. In Dex-treated cells, levels of intracellular reactive oxygen species (ROS), lipid peroxides, ferrous ion (Fe²⁺), malondialdehyde (MDA), acyl-CoA synthetase long chain family member 4 (ACSL4) and nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) were all increased, while expression of glutathione (GSH) and glutathione Peroxidase 4 (GPX4) was reduced. Transmission electron microscopy revealed plasma membrane rupture and reduction or loss of mitochondrial cristae. Furthermore, Dex promoted Hippo-mediated phosphorylation of Yes-associated protein (YAP)/Transcriptional coactivator with PDZ-binding motif (TAZ), upregulated NOX4 expression, and suppressed CD31 and VEGF expression. Following hUC-MSCs treatment, BMECs demonstrated enhanced proliferation, migration, and tube-forming capacity. Cellular GSH and GPX4 levels increased, antioxidant capacity was restored, peroxide accumulation decreased, and cells were protected from ferroptosis-effects comparable to those in the Fer-1 group. Additionally, hUC-MSCs inhibited YAP/TAZ phosphorylation and promoted elevated expression of CD31 and VEGF. Conclusions: These findings suggest that hUC-MSCs may attenuate Dex-induced ferroptosis in BMECs, enhance BMEC migration and angiogenesis, and improve femoral head microstructure in SANFH through modulation of the Hippo-YAP/TAZ signaling pathway. This study provides novel insights into the therapeutic potential of hUC-MSCs for SANFH. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is becoming increasingly prevalent worldwide, particularly among individuals with obesity and type 2 diabetes (T2D). MASLD remains potentially reversible in the early phases but, without timely intervention, it can progress to metabolic dysfunction-associated steatohepatitis (MASH) and hepatic fibrosis, which in turn may advance to cirrhosis and hepatocellular carcinoma over time. With no pharmacological treatments specifically indicated for MASLD, current therapeutic strategies include lifestyle modifications, including dietary modifications. Niacin and its molecular derivatives (collectively belonging to the vitamin B3 group) play a central role in metabolic processes, especially through their involvement in the biosynthesis of the oxidized form of nicotinamide adenine dinucleotide (NAD⁺). A growing body of preclinical evidence suggests that reduced NAD⁺ levels are a hallmark of MASLD, and that NAD⁺ precursors may help attenuate disease progression through multiple mechanisms, including sirtuin 1 (SIRT1)-mediated inhibition of hepatic lipogenesis. Although these findings from experimental models suggest a potential role for niacin and related molecular derivatives as a modulators of MASLD-related pathways, evidence from human studies remains limited and inconsistent. For instance, interventional studies evaluating niacin or molecular derivatives supplementation have reported variable findings, with several trials showing limited meaningful benefits on MASLD-related outcomes. Consequently, further well-designed, controlled trials are needed to clarify therapeutic efficacy, dose–response relationship, and the feasibility of integrating niacin derivatives into dietary or therapeutic strategies aimed at reducing liver fat and improving adverse metabolic outcomes. This review aims to (i) summarize mechanistic insights on the role of niacin as a source of NAD⁺ on experimental MASLD and (ii) critically evaluate the available human evidence on the effect of supplemental niacin and derivatives in the prevention of MASLD development and its progression to MASH and fibrosis. Full article

Type 2 Diabetes Mellitus (T2DM) is a widespread metabolic disorder that can affect brain health, primarily through the damaging effects of prolonged hyperglycemia. This condition increases oxidative stress (OS), neuroinflammation, and neuroapoptosis, ultimately impairing cognitive function. Acrylamide (ACY), a neurotoxicant formed during high-temperature food processing and present in cigarette smoke, may further aggravate these neurological disturbances. The present experiment examined the exacerbating effects of T2DM and ACY exposure on cognitive function, neurodegeneration, OS, neuroinflammation, and neuroapoptosis in diabetic rats. T2DM was induced via intraperitoneal injections of nicotinamide and streptozotocin, followed by daily oral doses of ACY for a month. Behavioral assessments (EPM, NOR, and Y-maze) evaluated cognitive performance. Brain tissues were analyzed for biochemical markers of neurodegeneration (GSK-3β, AChE, BACE1), OS (MDA, GSH, Catalase), neuroinflammation (NF-κB, TNF-α, PGE2, COX-2), and neuroapoptosis (Bcl-2, Bax, Caspase-3). Immunohistochemistry of Bcl-2, Bcl-6, CD138, and NF assessed structural brain changes. Results indicated that T2DM and ACY exposure significantly increased the incidence of neurological disturbances. Notably, through increased COX-2, PGE2, MDA, Bax, Bcl-6, Caspase-3, and cognitive decline deficits. This study highlights the harmful neurotoxic amplification of T2DM and ACY exposure, emphasizing the importance of public health measures to reduce ACY exposure through dietary and lifestyle changes, particularly among T2DM populations. Further research into neuroprotective strategies and underlying mechanisms is necessary. Full article

Glaucoma is a multifaceted optic neuropathy, characterized by the progressive loss of retinal ganglion cells. This damage frequently continues even after intraocular pressure (IOP) has been effectively lowered. This resistance to conventional IOP-lowering therapy underscores the critical role of interacting IOP-independent mechanisms; specifically metabolic failure and systemic mitochondrial dysfunction have emerged as key parallel drivers. This review analyzes the paradigm shift from a pressure-centric model to a bioenergetic one, focusing on mitochondrial function, peripheral blood mononuclear cell (PBMC) biomarkers, and oxygen consumption dynamics. We synthesize evidence demonstrating that glaucoma patients exhibit a metabolic vulnerability, characterized by lower PBMC oxygen consumption rates and depleted systemic nicotinamide adenine dinucleotide levels relative to healthy individuals. Furthermore, compromised systemic respiratory performance correlates with more rapid worsening of visual fields and structural thinning, independent of IOP status. Moreover, we delineate the role of Complex I defects, SARM1-mediated axonal degeneration, and proteomic alterations, which indicate defective mitophagy. These findings establish systemic metabolic profiling as a valuable supplementary tool for assessing patient risk and support the clinical translation of neuroprotective therapies targeting mitochondrial bioenergetics, specifically nicotinamide, pyruvate, coenzyme Q₁₀, and metformin. Full article

Hydrogen peroxide (H₂O₂) is a key extracellular redox signaling molecule that regulates diverse physiological processes, including immune cell activation and proliferation. However, its role in maintaining extracellular redox balance and mediating intercellular signaling remains underexplored. In this study, we investigated how extracellular depletion of H₂O₂ by catalase modulates intracellular signaling pathways in macrophages. Catalase treatment effectively depleted extracellular H₂O₂ in a concentration- and time-dependent manner, leading to activation of mitogen-activated protein kinase (MAPK) pathways, including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38, as well as nuclear translocation of the nuclear factor κB (NF-κB) p65 subunit. Perturbation of extracellular redox status resulted in robust upregulation of inflammatory and oxidative stress–related genes, including cyclooxygenase-2 (COX-2), C-C motif chemokine ligand 5 (CCL5), inducible nitric oxide synthase (iNOS), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. This transcriptional response was accompanied by increased nitric oxide (NO) production and enhanced nuclear translocation and DNA-binding activity of nuclear factor erythroid 2–related factor 2 (Nrf2). Mechanistically, our data suggest that NO-mediated S-nitrosylation contributes to activation of the cellular antioxidant response. In addition, catalase-mediated depletion of extracellular H₂O₂ significantly (p < 0.05) suppressed 5-bromo-2′-deoxyuridine (BrdU) incorporation, indicating inhibition of macrophage proliferation. Together, these findings demonstrate that extracellular H₂O₂ functions as a physiological redox signal that maintains cellular homeostasis, and that its removal triggers a coordinated intracellular response involving both inflammatory activation and antioxidant defense. This study highlights the critical role of extracellular redox balance in shaping macrophage function and provides mechanistic insight into how changes in the oxidative environment regulate downstream immune signaling pathways. 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