Iron deficiency anemia (IDA) remains a prevalent health issue, especially among Japanese women, and may be influenced by dietary patterns and lipid metabolism. This study aimed to investigate the association between circulating bile acid (BA) concentrations and iron-related biomarkers in young Japanese women. Blood biochemical and anthropometric data were collected from 33 healthy young women aged 20. The participants can be divided into two groups based on the levels of total-iron binding capacity (TIBC), although their hemoglobin and ferritin levels were in the normal ranges. When participants were divided based on TIBC, the low TIBC group showed significantly higher levels of 12-hydoxylated, non-12-hydoxylated, and total BAs, as well as significantly lower blood glucose levels compared to the normal group (p < 0.05). Positive correlations were observed between TIBC and specific BA species, such as glycolithocholic acid (p = 0.3993, p < 0.0288), cholic acid (p = 0.4767, p < 0.0077), and taurocholic acid (p = 0.4423, p < 0.0144). Additionally, transferrin levels were positively correlated with glycholithocholic acid (p = 0.3649, p < 0.0474). These findings suggest that TIBC may serve as an early indicator of hypoglycemia, reflecting preclinical metabolic disturbance, in addition to being a latent IDA marker.
Radon inhalation as well as voluntary exercise increase antioxidant function in experimental animals. However, the combined effects of radon inhalation and exercise on antioxidant functions have not yet been investigated. In this study, we examined the effects of combined voluntary wheel running (VWR) and radon inhalation on antioxidant functions in various organs of mice. Mice were individually housed in cages equipped with running wheels, and allowed voluntary exercise for 5, 15, or 25 days, followed by radon inhalation at 2,000 Bq/m3 for 24 h. Antioxidant function was enhanced by the combined treatment in the kidneys, pancreas, spleen, and stomach, with responses varying according to exercise duration. In contrast, antioxidant function was reduced in the lungs and heart. No clear interaction effects of the combined treatment were observed in the liver, small intestine, colon, and brain. These findings suggest that the combined effects of voluntary exercise and radon inhalation on antioxidant functions are organ-specific and can be categorized into distinct response patterns across tissues.
Mongolian Lycium ruthenicum (LR) are rich in anthocyanins and oligomeric proanthocyanidins, which possess potent antioxidant and anti-inflammatory properties. However, their therapeutic potential in inflammatory skin diseases, such as atopic dermatitis (AD), remains unclear. This study investigated the antioxidant and anti-inflammatory properties of topical LR extract and its therapeutic potential in experimental models of AD. Antioxidant activity was assessed in UVB-irradiated human keratinocytes (HaCaT) by measuring intracellular reactive oxygen species (ROS) and the expression of Nrf2 and HO-1. Anti-inflammatory effects were examined in TNF-α/IFN-γ-stimulated HaCaT and LPS-induced DC2.4 cells. In vivo efficacy was evaluated in NC/nga and HR-1 mouse models of AD. LR extract significantly suppressed UVB-induced ROS production and enhanced Nrf2 and HO-1 expression. It reduced pro-inflammatory cytokine and chemokine levels by inhibiting ERK phosphorylation in HaCaT cells. Topical LR treatment in vivo attenuated trans-epidermal water loss, epidermal hyperplasia and immune cell infiltration, and Th2 cytokine levels in the lymph nodes. Dorsal root ganglion calcium imaging revealed decreased neuronal responsiveness to pruritogens following LR application. Topical application of LR extract ameliorated AD-like inflammation and pruritus through antioxidative and immunomodulatory mechanisms. These findings highlight LR as a natural therapeutic agent for managing oxidative stress-related skin inflammation and barrier dysfunction.
This study aimed to investigate the molecular targets and anti-tumor mechanisms of cordycepin in gastric cancer (GC). Bioinformatics analysis was performed using the GSE65801 dataset to identify differentially expressed genes (DEGs) in GC. Potential cordycepin targets were screened from the CTD database, and the key gene was identified by intersecting these targets with GC DEGs and constructing a PPI network. The expression of fibronectin 1 (FN1) in GC was validated using public databases (TIMER, GEPIA and Ualcan) and in vitro experiments in GC cell lines (AGS and HGC-27). The functional effects of cordycepin, alone or in combination with FN1 overexpression, on cell proliferation (CCK8 and colony formation assay), apoptosis (flow cytometry), and the PI3K/AKT pathway (western blot) were assessed. A total of 649 DEGs were identified in GC and 336 potential targets of cordycepin were screened. FN1 was screened as a key intersection target of cordycepin and GC, and was found to be significantly upregulated in GC tissues and cells. High FN1 expression was associated with poor patient survival. Cordycepin treatment significantly inhibited the viability of GC cells and downregulated FN1 protein expression. Functionally, cordycepin suppressed cell proliferation and induced apoptosis by the inhibition of the PI3K/AKT pathway, and these effects were reversed by overexpression of FN1. In conclusion, cordycepin inhibited GC cell growth partially through the downregulation of FN1 and inactivation of the PI3K/AKT pathway, suggesting that FN1 was a novel potential target for cordycepin in the treatment of GC.
Oxidative stress is a central mechanism in metabolic, cardiovascular, and neurodegenerative diseases, contributing to inflammation, mitochondrial dysfunction, and apoptosis. Consequently, redox-modulating therapies are increasingly explored as potential therapeutic strategies. This review evaluates the mechanistic basis, experimental evidence, and clinical applicability of hydrogen-rich water (HRW) in oxidative stress-related diseases. A structured literature search identified mechanistic, preclinical, and clinical studies investigating HRW or molecular hydrogen (H2) on oxidative stress, inflammation, mitochondrial regulation, and disease-related outcomes. Due to substantial methodological heterogeneity, findings were synthesized qualitatively. HRW has been proposed to selectively neutralize highly reactive species such as hydroxyl radicals (•OH) and peroxynitrite (ONOO-) while preserving physiological reactive oxygen species signalling. Mechanistic studies demonstrate activation of nuclear factor erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE) pathways, suppression of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) inflammatory cascades, modulation of JAK/STAT signalling, preservation of mitochondrial bioenergetics, and enhancement of autophagic regulation. Preclinical and clinical studies report improvements in glycaemic control, endothelial function, cardiometabolic health, neuroprotection, exercise performance, and treatment-related fatigue. Despite an excellent safety profile, standardization of HRW preparation and large multicentre randomized controlled trials (RCTs) remain necessary to establish clinical efficacy and translational potential.
Triple-negative breast cancer (TNBC) is characterized by its aggressive phenotype and limited therapeutic options. FOXO1, a member of the O-class of forkhead transcription factors, has been implicated in various oncogenic processes, yet its specific role in TNBC remains to be fully elucidated. This study aimed to investigate the effects of the FOXO1-selective inhibitor, AS1842856, on the proliferation of the human TNBC cell line MDA-MB-231 and to identify the underlying molecular mechanisms. Treatment with AS1842856 significantly suppressed the proliferation of MDA-MB-231 cells in a dose-dependent manner. Additionally, AS1842856 suppressed the expression of lysyl oxidase-like 4 (LOXL4). Given LOXL4 is known to be involved in extracellular matrix remodeling and is frequently associated with cancer progression and metastasis, AS8142856 has been considered to suppress MDA-MB-231 cell migration. Interestingly, however, the knockdown of FOXO1 did not lead to a significant reduction in LOXL4 expression levels, suggesting that AS1842856 suppresses LOXL4 expression through FOXO1-independent mechanisms. We found that AS1842856-mediated ERK activation and intracellular reactive oxygen species are crucial in reducing LOXL4. Furthermore, the combined action of pharmacological inhibition of ERK pathways and AS1842856 suppressed MDA-MB-231 cell migration. These findings demonstrate that the ERK-LOXL4 signaling axis may play a critical role in the proliferation of TNBC cells. In conclusion, targeting the LOXL4 and ERK pathways pharmacologically could provide a novel therapeutic strategy for the treatment of aggressive breast cancers.
High-resolution manometry (HRM) is essential for evaluating esophageal motility, and the Chicago Classification ver. 4.0 recommends measurements in both supine and upright positions. However, the impact of body position on HRM metrics and their relationship with symptoms has not been fully clarified. In this retrospective observational study, 287 patients undergoing HRM were categorized into postoperative, disorders of esophagogastric junction outflow (DEO), peristaltic disorders, and normal motility groups. Integrated relaxation pressure (IRP), distal contractile integral (DCI), and intrabolus pressure (IBP) were assessed in both positions, and symptom severity was evaluated using the Eckardt score, Gastroesophageal Reflux Disease Questionnaire (GerdQ), and Hospital Anxiety and Depression Scale (HADS). IRP and DCI were significantly lower in the upright position, whereas IBP showed no positional difference. In the DEO group, IRP correlated with the Eckardt score in both positions, with a slightly stronger correlation in the supine position. Reflux and anxiety symptoms also correlated with the Eckardt score, suggesting interactions between motility impairment, reflux, and psychological factors. Although HRM metrics varied by position, neither position was clearly superior for explaining symptoms. HRM in both supine and upright positions remains essential for comprehensive clinical assessment.
Klotho, an anti-aging protein, controls the insulin-like growth factor-1 (IGF-1) and suppresses inflammation implicated in senescence. We previously reported that glycyrrhizin (GL), a medicinal ingredient of licorice root, significantly attenuates inflammatory responses by inhibiting high-mobility group box 1 (HMGB1). In this study, we investigated whether GL is effective in suppressing the decline in Klotho levels and aging-induced frailty. After oral administration of GL three times a week for 12 months, the following effects were observed: reductions in the increases in blood fats, steatoses, obesity, and kidney aging; maintenance of activity level and rotarod test performance. Furthermore, we found beneficial effects of GL on the blood levels of functional proteins; upregulation of anti-aging factors, IGF-1 and Klotho; decrease in cystatin-C, an indicator of declining kidney function; and decreases in IL-6 and TNF-α, inflammatory cytokines. GL also seemed to increase superoxide dismutase 2, an antioxidant enzyme, in the liver and kidneys. As GL can inhibit HMGB1, it may attenuate this inflammatory amplification loop, reducing the systemic senescence-associated secretory phenotype and thus mitigating multiple aging phenotypes by maintaining Klotho levels.
Environmental factors are crucial causes of polycystic ovary syndrome (PCOS). There is growing evidence of an association between circadian rhythm disturbance and PCOS, but the underlying molecular mechanisms This study aimed to explore the molecular mechanism of PCOS induced by circadian rhythm disturbance and evaluate the therapeutic potential of melatonin. A rat model of circadian rhythm disturbance was established via 24-h continuous light exposure. Rats were randomly divided into the Control group (normal circadian rhythm), Model group (continuous light exposure), and Model + Melatonin treatment group (continuous light exposure + melatonin). Reproductive endocrine indicators, ovarian histomorphology, and ovarian granulosa cell (GC) function were assessed. Additionally, circadian rhythms of serum hormones, autophagy-related markers (LC3), and hypothalamic clock genes were detected at six zeitgeber time (ZT) points. Autophagy and apoptosis levels in GCs, as well as the activation of MAPK and PI3K/Akt/mTOR pathways, were also detected. Continuous light exposure induced PCOS-like phenotypes in rats, characterized by disrupted estrous cycles, cystic ovarian changes, and loss of circadian rhythms in serum hormones, autophagy marker LC3, and hypothalamic clock genes. Moreover, continuous light exposure reduced GC viability, increased GC autophagy and apoptosis, activated the MAPK pathway, and inhibited the PI3K/Akt/mTOR pathway in GCs. Melatonin treatment significantly ameliorated these PCOS-like phenotypes. Our study showed circadian rhythm disturbance induced PCOS via MAPKs and PI3K/Akt/mTOR signaling pathways and increased autophagy level in rat ovarian GCs. Melatonin had a therapeutic effect on PCOS by reversing these signaling pathway abnormalities and reducing autophagy and apoptosis levels in GCs.
Trace elements such as copper, zinc, and magnesium are essential for antioxidant defense, insulin action and glucose homeostasis, yet their clinical utility as biomarkers in childhood type 1 diabetes mellitus remains uncertain. We conducted a case-control study of 199 Egyptian children aged 5-18 years (100 with type 1 diabetes mellitus and 99 non-diabetic controls) attending the National Nutrition Center. Anthropometry, lifestyle characteristics and biochemistry were assessed, and serum copper, zinc, and magnesium were measured by atomic absorption; the copper to zinc ratio was calculated. Children with type 1 diabetes mellitus had significantly lower zinc and magnesium concentrations and higher copper to zinc ratios than controls, while mean copper levels did not differ significantly. Lower magnesium and zinc, higher body mass index, elevated triglycerides, and reduced physical activity were independently associated with type 1 diabetes mellitus. In receiver operating characteristic analyses, magnesium showed the best discriminative performance between diabetic and control children, whereas zinc and the copper to zinc ratio were highly specific markers of poor glycemic control, and zinc deficiency and reduced estimated glomerular filtration rate were consistently associated with microvascular complications. These findings support trace-element monitoring to refine risk stratification and management in pediatric type 1 diabetes mellitus.
Oxidative stress has long been implicated in the pathogenesis of a wide range of chronic diseases; however, systemic antioxidant therapies have yielded limited clinical benefits, partly due to their non-selective distribution and interference with physiological redox signaling. Increasing evidence suggests that the intestine plays a central role in amplifying systemic inflammation, yet the causal contribution of intestinal reactive oxygen species (ROS) has remained unclear. In this review, we summarize a series of studies demonstrating that selective scavenging of intestinal ROS, achieved by orally administered, non-absorbable antioxidant nanoparticles, exerts profound effects on whole-body pathophysiology without systemic drug exposure. These gut-localized antioxidants remain confined to the intestinal lumen, effectively suppressing oxidative damage to the intestinal barrier while avoiding adverse effects associated with intracellular or mitochondrial ROS depletion. Experimental evidence across multiple disease models shows that attenuation of intestinal oxidative stress prevents systemic inflammation, reduces circulating pro-inflammatory cytokines such as interleukin-6, and improves diverse pathological outcomes, including exercise-induced organ damage, depression-like behaviors via the gut-brain axis, and muscle wasting in cancer cachexia. Collectively, these findings establish intestinal oxidative stress as an upstream driver of systemic disease progression and highlight gut-confined antioxidant intervention as a safe and mechanistically distinct therapeutic strategy. This concept provides a new framework for re-evaluating oral antioxidant therapy from the perspective of intestinal redox control and its clinical implications.
Neonatal sepsis (NS) is one of the leading causes of neonatal mortality. The nonspecific clinical manifestations and the limited timeliness of existing biomarkers (such as C-reactive protein) highlight the urgent need for highly accurate diagnostic tools. Neutrophils, as key effector cells of innate immunity, are closely involved in the progression of NS. This study integrated training (GSE69686) and validation (GSE25504) datasets from the GEO database. Neutrophil infiltration characteristics were analyzed utilizing CIBERSORT, and weighted gene co-expression network analysis (WGCNA) was introduced to determine neutrophil-related co-expression modules. Three machine learning algorithms-LASSO, SVM-RFE, and RF-were implemented to cross-screen core diagnostic genes. A combined diagnostic model was distributed based on these genes. NetworkAnalyst was utilized to predict miRNA-TF regulatory networks, and GSVA was conducted to interpret biological functions. Three algorithms identified IL1R2 and METTL7B as core diagnostic genes; the model showed strong reliability. IL1R2 high expression correlated with reduced CD8(+) T cells, regulatory T cells, and neutrophils (p < 0.05). METTL7B high expression linked positively to B cells and negatively to NK cells/neutrophils. The two genes synergistically cause immune cell dysfunction. Six miRNAs and 15 transcription factors (e.g., NFKB1/RELA, STAT3) regulating these genes were found, involved in inflammation and metabolic reprogramming. Integrating neutrophil infiltration and triple-machine-learning, this study first proposed an IL1R2/METTL7B two-gene panel. The model had high accuracy and generalizability, potentially contributing to NS pathogenesis via immune dysfunction and metabolic reprogramming, supporting rapid diagnostics and targeted interventions.
Dietary carotenoids (lutein and zeaxanthin) and anthocyanins show retinal protective potential, yet their clinical efficacy in healthy children's developing visual systems remains unclear. We aimed to investigate whether lutein, zeaxanthin, and anthocyanin (LA) supplementation enhances visual function and vision protection in healthy school-aged children (6-10 years). Sixty-four participants were randomized to control or treatment (received LA supplementation daily) groups. Macular pigment optical density (MPOD), central foveal thickness (CFT), minimum foveal thickness (MFT), axial length (AL), spherical equivalent refraction (SER) and contrast sensitivity function (CSF) after LA supplementation were examined at baseline, 1, 3 and 6 months. ASQ-11 questionnaire was used to evaluate eye fatigue. Compared with control group, from baseline to 1, 3 and 6 months, MPOD levels were increased in treatment group, with the most significant increase at the 6-month follow-up. CFT and MFT levels were also elevated with time. Moreover, AL remarkably increased at 1, 3, and 6 months, considering it is a physiological increase caused by growth and development of children. At 6 months, the change in AL was prominently reduced in the treatment group. Besides, the reduction of SER levels was less in treatment group than that in control group. Additionally, CSF of control group and treatment group increased during the 6-month follow-up. CSF at spatial frequency 3c/d in the treatment group was markedly higher than that in the control group at the sixth month follow-up. Furthermore, LA notably improved visual fatigue symptoms. Collectively, LA supplementation enhances visual function and vision protection in healthy school-aged children. Registration number (TRN): ChiCTR2500100376
DNA-protein crosslinks are bulky lesions that block DNA replication and transcription and are increasingly recognized in metabolic disorders characterized by carbonyl stress. Glyceraldehyde is a highly reactive triose that forms advanced glycation end-products, but its contribution to nuclear DNA-protein crosslink formation has not been defined. We examined glyceraldehyde-induced DNA-protein crosslinks in rat cardiomyoblast-derived H9c2 cells using an advanced recovery of potassium sodium dodecyl sulfate precipitates (ARK) assay combined with liquid chromatography-tandem mass spectrometry. Glyceraldehyde exposure modestly but significantly increased DNA-protein crosslink levels and generated nuclear high-molecular-weight complexes enriched in glycation adducts. Proteomic profiling of the DNA-tethered protein fraction revealed non-muscle myosin heavy chain isoforms 9 and 10 among the most abundant components. Liquid chromatography-tandem mass spectrometry mapping identified glycation adducts on multiple arginine residues within the coiled-coil rod and non-helical tail regions of non-muscle myosin heavy chains, including N δ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine and argpyrimidine. These modifications coincided with detergent-insoluble, high-molecular-weight myosin species in nuclear fractions. Our data identify glycated non-muscle myosins as major constituents of glyceraldehyde-induced, DNA-tethered DPC-associated assemblies and suggest a link between carbonyl stress and DNA damage associated with nuclear protein aggregation in cardiomyoblasts.
This study aims to investigate the regulatory effects and underlying mechanisms of enteral nutrition (EN) on colorectal cancer (CRC). An inflammatory colorectal tumor model was established in mice using the azoxymethane-dextran sulfate sodium method. The mice were divided into groups including a model group and groups treated with EN or EN plus the Toll-like receptor 4 (TLR4) activator lipopolysaccharide. The T follicular helper/T follicular regulatory (Tfh/Tfr) cell ratios in splenic tissues were analyzed by flow cytometry. Protein expression related to the TLR4 pathway and cytokines in colonic tissues was assessed by Western blotting and quantitative real-time polymerase chain reaction. Histopathological changes were evaluated using hematoxylin-eosin staining. The proportion of Tfh cells to Tfr cells is significantly imbalanced in CRC, and this imbalance was corrected following EN treatment. This correction of Tfh/Tfr imbalance was found to inhibit tumor growth, suggesting that the regulatory effect of EN on CRC may be mediated through the modulation of the Tfh/Tfr cell balance. At the molecular level, we discovered that EN was found to suppress the activation of the TLR4 signaling pathway. Furthermore, the addition of lipopolysaccharide abolished the effects of EN, indicating that the regulation of the Tfh/Tfr cell ratio by EN is mediated through the TLR4 signaling pathway. This study provides evidence that EN can inhibit the progression of CRC, potentially by regulating Tfh/Tfr immune imbalance via the TLR4 signaling pathway. These findings highlight the potential of EN as a therapeutic strategy for CRC treatment.
Chronic kidney disease (CKD), affecting 8-16% of the global population, presents substantial public health burdens. While constituting only 5% of daily dietary intake, minerals critically influence physiological processes. This study investigates associations between dietary mineral intake and CKD risk; utilizing publicly available data from the National Health and Nutrition Examination Survey (NHANES), we employed multivariate logistic regression, restricted cubic spline (RCS), weighted quantile sum (WQS), quantile-based g-computation (QGcomp), and Bayesian kernel machine regression (BKMR) models to assess CKD-mineral relationships; multivariate logistic regression revealed significant inverse associations between CKD risk and calcium (OR = 0.72), phosphorus (OR = 0.69), magnesium (OR = 0.65), copper (OR = 0.81), potassium (OR = 0.85), and zinc (OR = 0.88). RCS analysis demonstrated linear protective trends for calcium, phosphorus, zinc, potassium, and selenium, while magnesium, iron, and copper exhibited U-shaped dose-response patterns. WQS regression identified a protective mineral mixture (weighted index OR = 0.83), with magnesium (35.2%) and calcium (28.1%) as primary contributors. QGcomp analysis highlighted magnesium's protective effect (-0.21 risk score) contrasting with iron's adverse association (+0.18). BKMR modeling confirmed magnesium's significant protection (PIP = 0.92) and sodium's risk elevation (PIP = 0.87); magnesium and calcium emerge as robust protective factors against CKD, while sodium intake increases disease risk. Phosphorus, potassium, zinc, and copper demonstrate potential benefits, whereas iron shows context-dependent effects. These findings emphasize mineral-specific dietary strategies for CKD prevention.
