Search Results (834)

Background/Objectives: Glucagon-like peptide-1 (GLP-1), which is released by enteroendocrine L-cells, is the primary incretin hormone and plays a pivotal role in glucose regulation, appetite control, and metabolic health. While GLP-1 receptor agonists offer significant therapeutic benefits, there is a growing interest in identifying foods that can increase endogenous GLP-1 production through physiological processes. However, the physiological impact of modulating GLP-1 through diet is modest compared with activating GLP-1 receptors pharmacologically. This narrative review summarizes the latest reports on how specific food matrices and gut microbiota-dependent pathways influence GLP-1 release, emphasizing their importance in precision nutrition. Methods: Literature published between 2001 and 2026 was reviewed, including experimental, clinical, and translational studies examining the effects of foods on GLP-1 secretion, L-cell activation, nutrient-sensing receptors, microbial metabolites, and metabolic outcomes. Evidence was synthesized for food categories such as fermented dairy products, fermented vegetables, whole grains, legumes, fiber-rich root vegetables, berries, grapes, green tea, turmeric and oily fish. Results: Foods modulate endogenous GLP-1 secretion through complementary pathways involving L-cell stimulation and the activation of receptors, including FFAR2, FFAR3, GPR119, TGR5 and FFAR4 (GPR120), as well as the production of microbial metabolites. Fermented dairy products, kimchi, kefir, Jerusalem artichokes, chicory root, oats, garlic, onions, berries, grapes, green tea and oily fish support incretin regulation through microbial fermentation, the generation of short-chain fatty acids (SCFAs), bile acid signalling and the release of bioactive compounds. These food matrices shape metabolite profiles more effectively than isolated nutrients, highlighting the importance of the interaction between whole foods and the gut microbiota. Conclusions: Foods rich in fermentable substrates, polyphenols, bioactive peptides and omega-3 fatty acids are promising dietary modulators of physiological GLP-1 activity. Taking into account microbiome characteristics, metabolic phenotype and individual postprandial responses could facilitate the development of personalized nutrition strategies to help prevent and manage obesity, type 2 diabetes and related cardiometabolic disorders. Full article

Background: Diabetes mellitus is a chronic metabolic disorder often accompanied by psychological distress, including stress, anxiety, and depression. Such emotional symptoms can influence self-care behaviours and metabolic control. In Saudi Arabia, cultural and religious practices may mitigate the effects of psychological distress on glycaemic regulation. Limited evidence exists regarding the simultaneous assessment of depression, anxiety, and stress in relation to objective glycaemic indicators such as HbA1c among adults with diabetes in Saudi Arabia. This study aimed to determine the association between psychological distress and glycaemic control among adults with diabetes, while exploring the influence of demographic and biochemical factors. Methods: A cross-sectional study was conducted from 21 January 2026 to 19 April 2026 among 546 adults diagnosed with diabetes in multiple healthcare settings in Riyadh, Saudi Arabia. Psychological distress was assessed using the DASS-21 questionnaire, while glycaemic control was measured using HbA1c, categorised as controlled (<7%) or uncontrolled (≥7%). Demographic, anthropometric, and biochemical parameters including BMI, blood pressure, and lipid profile were collected from medical records and standardized assessments. Associations were examined using chi-square tests and multiple linear regression analysis was performed including psychological distress scores, BMI, blood pressure measurements, and lipid profile parameters to identify factors associated with HbA1c variation. Results Psychological distress was prevalent; however, stress (6.2–10.7%), anxiety, and depression were significantly associated with variation in HbA1c levels. In contrast, nationality, total cholesterol, LDL, triglycerides, and systolic blood pressure were significantly associated with HbA1c. Multiple regression showed that stress (B = 0.09, p = 0.015), systolic blood pressure (B = 0.146, p = 0.006), and total cholesterol (B = 0.229, p < 0.001) were independent predictors, collectively explaining 14.8% of HbA1c variance. Multiple regression analysis identified stress, systolic blood pressure, and total cholesterol as significant factors associated with variation in HbA1c levels. Conclusions: While psychological distress is common among adults with diabetes, its direct impact on HbA1c may be attenuated in populations with strong religious and cultural coping practices. Conversely, metabolic factors, particularly total cholesterol and systolic blood pressure, alongside stress, showed stronger associations with HbA1c levels in this study population. These findings underscore the importance of integrating physiological, psychological, and culturally contextualised strategies in diabetes management to optimize outcomes. Full article

Copper is a redox-active transition metal that is essential for the assembly and catalytic function of cytochrome c oxidase (Complex IV), the terminal enzyme of the mitochondrial electron transport chain and a principal site of physiological oxygen reduction. Elevated Complex IV activity and respiratory chain uncoupling are among the most consistently replicated biological findings in autism spectrum disorder (ASD), yet the interaction between mitochondrial copper delivery, respiration, and cellular oxidant handling in ASD has not been systematically defined. We treated dermal fibroblasts from 9 children with ASD and 10 typically developing controls with the copper(I)–niacin complex Cunermuspir (0, 50, or 100 µM for 1 or 24 h exposure) and challenged them with graded concentrations (0–5.0 µM) of the redox-cycling agent 2,3-dimethoxy-1,4-naphthoquinone (DMNQ). Mitochondrial respiration was profiled by Seahorse XF respirometry (2133 observations across 28 experiments), and cellular reactive oxygen species (CellROX™ Green) and mitochondrial mass/polarization (MitoTracker™ Deep Red) were quantified by fluorescence imaging. ASD fibroblasts displayed a hypermetabolic, uncoupled respiratory phenotype (~73% higher baseline respiration; ~109% higher proton leak; reduced coupling efficiency). Linear mixed models with polynomial dose terms revealed significant ASD × Cunermuspir complex interactions (ASD × Cunermuspir and/or their higher-order interactions with DMNQ and treatment) for four respiratory parameters. ASD cells exhibited lower steady-state oxidation-dependent CellROX™ Green fluorescence than controls despite greater respiratory uncoupling, as well as lower steady-state MitoTracker™ Deep Red fluorescence; Cunermuspir reshaped the MitoTracker™ DMNQ dose–response in an ASD-selective manner. These findings identify the Cunermuspir-associated modulation of the ASD mitochondrial and oxidant handling phenotype and motivate further mechanistic and translational evaluation. Full article

Background/Objectives: Hypothyroidism may influence lactation physiology, but evidence regarding its association with mature human milk composition remains limited. This cross-sectional study evaluated macronutrient composition and apparent thyroid-stimulating hormone (TSH) concentration in 24 h composite mature milk samples from women with a documented history/diagnosis of treated or clinically managed hypothyroidism attending lactation counseling and human milk-bank consultation, compared with controls without known thyroid disorders. Methods: Sixty-six lactating women attending the Human Milk Bank in Toruń, Poland, were enrolled (31 with hypothyroidism, including six with Hashimoto’s disease; 35 controls). Thyroid characterization was based on diagnoses and laboratory results documented during routine preconception or early-pregnancy/perinatal care; the study did not include contemporaneous maternal serum TSH/FT4 testing at milk collection in either group. Composite 24 h milk samples were analyzed using the MIRIS Human Milk Analyzer for fat, crude protein, true protein, carbohydrates, total solids, and energy. Milk TSH was measured using a third-generation ELFA assay. Because this serum/plasma assay was not formally validated for the human milk matrix, values are reported as exploratory apparent milk TSH concentrations. Results: No statistically significant between-group differences were observed in macronutrient composition in the analyses performed. For example, the HG-CG mean difference for energy content was −3.47 kcal/100 mL (95% CI: −8.45 to 1.52; p = 0.169; q = 0.814), and all confidence intervals for milk-composition outcomes included zero. Median apparent milk TSH concentration was 0.0180 [IQR 0.0130–0.0208] µIU/mL in controls and 0.0155 [IQR 0.0093–0.0210] µIU/mL in the hypothyroidism group (Mann–Whitney U = 459.0, p = 0.286). Hyperlactation was frequent in this selected cohort and was more common in controls (27/35; 77.1%) than in the hypothyroidism group (16/31; 51.6%). Exploratory analyses of pre-pregnancy BMI and Hashimoto’s disease were limited by small subgroup sizes. Conclusions: In this small selected cohort, a documented diagnosis/history of treated or clinically managed hypothyroidism was not associated with statistically significant differences in mature milk macronutrient composition or apparent milk TSH concentration. These findings are exploratory and should not be interpreted as evidence of equivalence, confirmed euthyroidism at sampling, or exclusion of smaller effects. Full article

Background: Temporomandibular disorders constitute multifaced systemic impairments capable of compromising overall physiological homeostasis. This study compares oxidative and nitrosative stress biomarkers between patients with temporomandibular myofascial pain with referral and healthy controls. Methods: We enrolled 44 individuals with temporomandibular myofascial pain with referrals and 44 controls. The procedure involved clinical examination based on the Diagnostic Criteria for Temporomandibular Disorders and saliva collection. Biochemical determination involved advanced glycation end products (AGEs), advanced oxidation protein products (AOPPs), thiobarbituric-acid-reactive substances (TBARS), and total nitric oxide (NO). Results: Median concentrations of TBARS and total NO were significantly elevated in the study group relative to the controls (TBARS: 6.078 vs. 1.486; total NO: 138.6 vs. 23.82), whereas the concentration of AOPPs was significantly lower (151.1 vs. 505.3). Multiple regression revealed that myofascial pain was an independent predictor of the observed differences, even after we adjusted for age and salivary flow rate (TBARS: β = 4.78 [95% CI: 2.020, 7.541], _adjp = 0.0018; total NO β = 128.4 [95% CI: 82.70, 174.1] _adjp = 0.0004; AOPP β = −755.7 [95% CI: −1228, −283.5] _adjp-value = 0.0028. Conclusions: Myofascial pain with referral is independently associated with oxidative imbalance, highlighting the relevance of TBARS and total NO as promising severity biomarkers. The unexpected decrease in AGE and AOPP levels requires standardized studies to confirm diagnostic utility. Full article

As a core organ responsible for metabolism and homeostatic regulation, the kidney performs physiological functions that encompass material excretion, fluid balance, electrolyte regulation, and endocrine control; and serves as a critical hub for maintaining the coordinated functioning of multiple organ systems. Kidney injury not only leads to disturbances in these core physiological functions but also generates systemic complications such as cardiovascular disease, hypertension, and diabetes mellitus through an “injury–inflammation–metabolic disorder” cascade. Epidemiologic studies and clinical statistics have revealed that acute kidney injury (AKI) may progress to chronic kidney disease (CKD) because of maladaptive repair, impaired regeneration, and other factors. During this process, macrophages—particularly certain functionally specialized macrophage subtypes—engage in complex intercellular communication with neighboring cells that include renal tubular epithelial cells, endothelial cells, fibroblasts, and platelets, thereby forming pathological signaling networks that collectively drive persistent inflammation and the progression of renal fibrosis. Macrophages thus play complex and dynamic dual regulatory roles throughout the initiation, progression, and repair of kidney injury, and their functional polarization and phenotypic transformation directly influence the pathological progression of kidney diseases. We herein aimed to elucidate the roles of AKI-to-CKD transition-associated macrophages, especially the subtypes with specialized functions in kidney diseases and to systematically review current research progress, thus to provide a reference for advancing basic research and clinical diagnostic and therapeutic strategies for kidney diseases. Full article

Alzheimer’s disease (AD) is a neurodegenerative disorder, which is characterized by several features, such as the deposition of amyloid β (Aβ) fibrils in the brain, leading to the formation of plaques and secondly tau-associated neurofibrillary tangles, resulting in the degeneration of the brain cells. Another feature of AD is mitochondrial dysfunction and oxidative stress, which are linked to the excessive production of reactive oxygen species (ROS). Under physiological conditions, ROS homeostasis is well controlled by the ROS generating system and the cellular antioxidant network. This antioxidant network is in part controlled by nuclear factor erythroid 2-related factor 2 (Nrf2), and its activation protects tissues against oxidative stress and chronic inflammation. Since oxidative stress, inflammation, and impaired proteostasis are significantly involved in the pathogenesis of AD, the KEAP1-Nrf2 system has emerged as a promising therapeutic target for the disease. Caenorhabditis elegans is an invaluable model organism among others for neurodegenerative disease research, due to its short life cycle, transparent body, and fully mapped nervous system and many transgenic C. elegans models have been developed to study different aspects of AD. This review attempts to provide comprehensive understanding of the molecular characteristics and pathological basis of AD, including the altered Nrf2-ARE signaling in AD and the molecular architecture and regulation of the Nrf2-SKN-1 pathway in C. elegans. An overview of plant-derived natural products and their effect on Nrf2/SKN-1 activation. Several classical and novel transgenic strains are described, translating findings from C. elegans to mammalian models and humans, including clinical translations and ongoing trials, as well as personalized medicinal approaches are discussed. Full article

Asthma is a heterogeneous disease that often begins in childhood and frequently occurs alongside allergic conditions. In asthma research, it is important to focus on proteins that are the primary regulators of cellular physiology. The differences in the proteome between children with asthma and those with an atopic background remain poorly understood. The present study included 130 serum samples from four groups of pediatric patients under the age of five: (1) with asthma and IgE-dependent allergies; (2) with non-atopic asthma; (3) non-asthmatics with IgE-dependent allergy; and (4) a control group without asthma and IgE-dependent allergies. The serum samples were used for protein–peptide profiling and proteomic identification using nanoLC-MALDI-TOF/TOF MS/MS. The obtained data were analyzed using univariate statistics and the STRING tool v12.0 to identify protein–protein potential interactions. A total of seven proteins were identified as discriminative between the study groups: A2M, AACT, IgG3, C3, ITIH2, IgG3 and IGK. All of them were upregulated in patients with IgE-dependent allergy compared to other study groups. STRING analysis identified functional associations among four proteins (AACT, A2M, C3, and ITIH2) with discriminatory potential for distinguishing between non-atopic asthma and non-asthmatic patients with IgE-dependent allergy. The results suggest that the identified putative protein markers overlap in cellular pathways, including those associated with the pathophysiology of asthma and allergic disorders. These findings provide further insight into the overall proteomic profile of pediatric patients with asthma and IgE-dependent allergy, highlighting its heterogeneity across the analyzed groups. Full article

The heart–kidney axis has emerged as a central framework for understanding the bidirectional interactions that drive cardiorenal syndrome and broader cardiovascular–kidney–metabolic (CKM) disease. However, existing interpretations have often emphasized hemodynamic and neurohormonal mechanisms without fully integrating the growing evidence for endocrine, inflammatory, and metabolic mediators that coordinate injury across organs. This Review was therefore undertaken to provide an updated and clinically relevant synthesis of the physiological basis of heart–kidney communication, the mechanisms underlying its disruption, and the therapeutic implications of these insights. To achieve this aim, we performed a systematic narrative review of the literature using PubMed, Embase, Web of Science, and Scopus for studies, supplemented by manual screening of reference lists. Priority was given to original studies, large cohort analyses, randomized controlled trials, meta-analyses, and authoritative reviews. We integrated evidence spanning physiological regulation, maladaptive signaling pathways, emerging mediators, experimental models, and evolving treatment strategies. The reviewed evidence indicates that heart–kidney crosstalk is driven not only by altered perfusion and venous congestion, but also by sustained activation of the renin–angiotensin–aldosterone system (RAAS) and sympathetic nervous system (SNS), inflammation, oxidative stress, mitochondrial dysfunction, anemia, uremic toxins, and disordered mineral metabolism. Among novel mediators, fibroblast growth factor 23 (FGF23) emerges as a major bone-derived, chronic kidney disease (CKD)-associated endocrine mediator linking renal injury to cardiac hypertrophy, fibrosis, calcium mishandling, and diastolic dysfunction, whereas Klotho appears to exert counter-regulatory protective effects. Heart-derived natriuretic peptides, including atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), remain important modulators of renal blood flow, natriuresis, and volume homeostasis. We further highlight the translational relevance of newer biomarkers and therapies, including sodium–glucose cotransporter 2 inhibitors (SGLT2is), glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists), and mineralocorticoid receptor antagonists (MRAs), which may help address cardiac and renal dysfunction in parallel. Overall, this Review supports a revised conceptual model in which the heart–kidney axis is governed by multidirectional hemodynamic, neurohormonal, immune, and endocrine signaling networks. A more integrated understanding of these mechanisms may improve biomarker discovery, refine risk stratification, and promote therapies that target both organs simultaneously. Full article

Acute pancreatitis is a common and heterogeneous inflammatory disorder whose clinical course ranges from a self-limited illness to persistent organ failure, infected pancreatic necrosis, and prolonged critical illness. Contemporary management has moved away from protocolised aggressive fluid loading, prolonged fasting, prophylactic antibiotics, and early open necrosectomy. Instead, current care emphasises repeated physiological assessment, moderate goal-directed resuscitation, early enteral or oral nutrition, organ-specific support, antimicrobial stewardship, and delayed minimally invasive intervention within a multidisciplinary step-up strategy. This narrative review examines acute pancreatitis from an intensive care perspective. Particular attention is given to early risk stratification, intensive care unit triage, haemodynamic and respiratory support, acute kidney injury, intra-abdominal hypertension, nutrition, biliary source control, diagnosis and treatment of infected necrosis, and the timing and selection of endoscopic, radiological, and surgical interventions. The implications of obesity, pregnancy, advanced age, and multimorbidity are also discussed. Recent randomised trials have clarified several clinically important questions: aggressive hydration increases fluid overload without improving outcomes; routine urgent endoscopic retrograde cholangiopancreatography is not beneficial in predicted severe biliary pancreatitis without cholangitis; postponed drainage may avoid invasive intervention in a substantial proportion of patients with infected necrosis; and endoscopic or minimally invasive approaches reduce treatment burden compared with primary open surgery. Persistent organ failure remains the principal determinant of mortality, while infected necrosis further increases risk and complexity. Future progress will depend on dynamic prediction models, biomarker-guided antimicrobial decisions, personalised haemodynamic strategies, phenotype-directed immunomodulation, and regionalised multidisciplinary care. Full article

Stanniocalcin-1 (STC-1) is a multifunctional glycoprotein; however, its role in protecting intestinal epithelial cells against oxidative injury has not been completely elucidated. This study investigated the cytoprotective effects and underlying molecular mechanisms of STC-1 overexpression in porcine intestinal epithelial (IPEC-J2) cells subjected to tert-butyl hydroperoxide (TBHP)-induced oxidative stress. IPEC-J2 cells were transfected with pcDNA3.1/STC-1 prior to TBHP challenge. STC-1 overexpression markedly rescued cells from TBHP-induced cytotoxicity and cell death, and was associated with a reduced Bax/Bcl-2 ratio. Concurrently, elevated STC-1 expression dramatically suppressed intracellular reactive oxygen species and mitochondrial superoxide accumulation while preserving the mitochondrial membrane potential. These physiological improvements were accompanied by enhanced total antioxidant capacity and activities of key antioxidant enzymes. Mechanistically, STC-1 overexpression enhanced autophagic flux and promoted Pink1/Parkin-mediated mitophagy to eliminate dysfunctional mitochondria. Furthermore, STC-1 upregulation potentiated the AMPK–Nrf2/Sirt1 signaling axis and the subsequent transcriptional upregulation of mitochondrial quality control markers, including FoxO1, PGC-1α, and TFAM, under stress conditions. Collectively, these findings demonstrate that STC-1 safeguards porcine intestinal cells against oxidative injury by orchestrating a cooperative defense network encompassing ROS scavenging, mitochondrial homeostasis, and antioxidant defense amplification via the AMPK–Nrf2/Sirt1 pathway, highlighting a potential therapeutic target for preventing stress-associated intestinal disorders in piglets. Full article

Microplastics have emerged as a persistent and prevalent threat to human health and the marine environment due to their widespread use and poor management, including low recycling rates, inadequate waste management, improper disposal, and inadequate control of plastic leakage into the environment. Plastic pollution is transported to the marine ecosystem through both ocean-based and land-based pathways and can be fragmented into microplastics (<5 mm) and nanoplastics (<1 µm). The study explains the sources, distribution, mechanisms of degradation, and transport pathways to the marine environment. Land-based activities are recognized as the dominant source, causing approximately 70–80% of marine plastic pollution. Domestic greywater is highlighted as a significant and common source of microplastics due to the release of microbeads and synthetic fibers from different sources, such as laundry, washbasins, and personal care products (PCPs). Similarly, greywater release from maritime vessels and cruise ships significantly contributes to marine microplastic pollution. The study discusses the biotic and abiotic degradation mechanisms. The health and environmental effects of microplastics are measured across different trophic levels. Ingestion and bioaccumulation of microplastics can cause physiological and reproductive disturbances. Human exposure through seafood consumption and inhalation may result in skin infections, cardiovascular complications, gastrointestinal disorders, and respiratory problems. The mitigation and control measures include improvements in wastewater treatment, public awareness, policy regulations, and biodegradable alternatives to support sustainable protection of the marine environment. Full article

Background/Objectives: Pregnancy is associated with profound hormonal, hemodynamic, and metabolic changes that may affect the auditory and vestibular systems. However, evidence regarding pregnancy-related audiological disturbances remains limited due to the low incidence of these conditions and the scarcity of dedicated studies. The study aimed to identify the most commonly reported audiological changes occurring during pregnancy and the postpartum period with an emphasis on sudden sensorineural hearing loss (SSNHL), its risk factors, clinical presentation, and treatment methods. Methods: A literature search was conducted in PubMed, Embase, Web of Science, and Google Scholar from database inception to November 2025 using combinations of the keywords “pregnancy”, “hearing loss”, and “audiological changes”. The review is based on twenty-four original articles that met the preselected criteria. Results: Current evidence does not support pregnancy as an independent risk factor for SSNHL; the prevalence in obstetric patients is lower than in the control groups. Most cases occur during the third trimester or the postpartum period. Pre-pregnancy obesity and elevated blood pressure were identified as potential risk factors. Higher income levels and rural residency are associated with an increased incidence of SSNHL, whereas gestational diabetes, pre-eclampsia, and pregnancy-related weight gain showed no consistent association with SSNHL. Audiometric studies demonstrated mild, predominantly low-frequency, hearing threshold elevations that were generally transient and resolved after delivery. Tinnitus, nausea, aural fullness, dizziness, and vertigo were the most common ear-related complaints. Most of these disorders resolve spontaneously, but some studies suggest steroid treatment should be introduced. Intratympanic corticosteroid therapy was the most frequently investigated treatment for SSNHL and was associated with favorable hearing outcomes in most reported cases. Limited evidence suggests that Dextran 40 may improve hearing outcomes when used as an adjunctive therapy. Conclusions: Potentially transient cochleovestibular impairment during pregnancy and the postpartum period should not be underestimated and requires further evaluation. Pregnancy-related physiological adaptations may contribute to transient auditory and vestibular disturbances, particularly during late pregnancy and the postpartum period. Although current evidence does not indicate an increased risk of SSNHL during pregnancy, prompt recognition and management remain important to prevent long-term hearing impairment. Further high-quality studies are required to clarify the underlying mechanisms and establish evidence-based treatment recommendations for pregnant patients with SSNHL. Full article

During protein synthesis, ribosome stalling, collision, and aberrant elongation can lead to the accumulation of defective nascent polypeptides and compromise cellular homeostasis. To counteract such translational disturbances, eukaryotic cells have evolved a highly conserved translational quality control network, in which the ribosome-associated quality control (RQC) pathway plays a central role in the recognition and elimination of aberrant translation complexes. Zinc Finger Protein 598 (ZNF598), a key E3 ubiquitin ligase in mammalian cells, functions as an essential factor in the early recognition and signal transduction steps of the RQC pathway. Accumulating evidence indicates that ZNF598 senses aberrant translational states, and particularly in the context of ribosome collision, mediates site-specific ubiquitination of 40S ribosomal proteins, thereby promoting ribosome splitting, nascent chain clearance, and subsequent processing of defective mRNAs. Beyond its canonical role in RQC, ZNF598 has also been implicated in the translational repression of defective mRNAs, regulation of inflammatory signaling, antiviral responses, and control of toxic translation products associated with neurodegenerative disorders. In this review, we summarize the structural features, molecular mechanisms, regulatory networks, and physiological as well as pathological functions of ZNF598. We also discuss current controversies and future directions in the field, with the aim of providing a broader framework for understanding translational quality control and its therapeutic potential. Full article

Background: Population aging is driving a convergent rise in three disorders historically managed in isolation: cardiovascular disease, neurocognitive decline, and osteoporotic bone loss. Mechanistic data indicate that these systems are coupled through shared regulators of calcium trafficking, inflammation resolution, vascular integrity, and inflammaging. On this basis, a “Heart–Brain–Bone” axis has been proposed; it should be understood as an integrative conceptual framework that organizes evidence drawn from three separate studies, not as a validated physiological entity with agreed diagnostic criteria or demonstrated modifiability. Three lipid-soluble nutrients—long-chain omega-3 polyunsaturated fatty acids (EPA/DHA), vitamin D3 (cholecalciferol), and vitamin K2 (menaquinone-7 [MK-7])—act on overlapping nodes of this network. Methods: We performed a structured narrative review. PubMed/MEDLINE, Embase, the Cochrane Library, and Web of Science were searched from database inception to 25 June 2026 using predefined term blocks for each nutrient, each organ domain, and each candidate mechanism, and the search was updated on 7 August 2026. Records were screened against prespecified inclusion and exclusion criteria by two authors independently, with disagreements resolved by a third. The strength of evidence for each nutrient–organ relationship was graded with an explicitly defined four-level scheme ((−) to (+++)) applied separately to preclinical, observational, randomized and meta-analytic evidence. Results: Vitamin K2-dependent gamma-carboxylation of matrix Gla protein (MGP) and osteocalcin has been proposed to influence whether calcium is incorporated into the bone matrix or deposited in the arterial wall, offering a candidate mechanistic account of the “calcium paradox” associated with isolated vitamin D3 supplementation; EPA/DHA-derived specialized pro-resolving mediators may support resolution of endothelial and neuronal inflammation; and bone-, vascular- and brain-derived signals (osteocalcin, FGF23, the neurovascular unit) interconnect the three organs. These mechanisms are biologically plausible but remain insufficiently confirmed in humans. The clinical evidence is heterogeneous, formulation- and population-dependent, and comprises positive, neutral and null results: cardiovascular omega-3 trials are discordant (REDUCE-IT, which used icosapent ethyl [an EPA ethyl ester], positive; VITAL/STRENGTH/ASCEND null, predominantly in lower-risk or replete cohorts); cognitive trials are largely null or subgroup-dependent (MAPT, DO-HEALTH, VITAL); and MK-7 improves surrogate bone and calcification biomarkers and slowed coronary artery calcification in one recent randomized imaging trial (VitaK-CAC), whereas combined MK-7 plus vitamin D3 did not slow aortic valve or coronary calcification in AVADEC and MK-7 did not reduce bone loss in early menopausal women. Recognized safety signals include a dose-dependent increase in atrial fibrillation with high-dose omega-3, adverse skeletal effects of high-dose or bolus vitamin D, and clinically relevant interference of even low-dose MK-7 with vitamin K antagonist therapy. Conclusions: No adequately powered randomized trial has demonstrated that the combination of long-chain omega-3, vitamin D3 and MK-7 is superior to its individual components or to placebo for any clinical endpoint. The combined regimen is therefore mechanistically rational and hypothesis-generating rather than clinically established; benefit appears most plausible in individuals with elevated risk or demonstrable nutritional insufficiency, and least in replete, low-risk populations. Findings should be interpreted within a broader healthy-aging context that includes lifestyle and psychosocial factors. Adequately powered factorial randomized controlled trials stratified by baseline Omega-3 index, 25(OH)D and vitamin K status, with prespecified mechanistic biomarkers and hard endpoints, are required. Full article