Search Results (2,389)

Background/Objectives: Calcium–phosphorus metabolism is critical for skeletal development in weaned piglets. This study evaluated the effects of dietary 25-hydroxyvitamin D₃ (25-OH-VD₃) in combination with phytase and probiotics on mineral metabolism, bone development, and related molecular mechanisms in weaned piglets. Methods: Sixty 28-day-old weaned piglets (7.1 ± 1.30 kg) were randomly assigned to four dietary treatments for 31 days (including 3 days of acclimation): CON (basal diet + 50 µg/kg 25-OH-VD₃), HI (CON + 50 mg/kg phytase), CY (CON +10 mg/kg probiotics), HICY (CON + 50 mg/kg phytase + 10 mg/kg probiotics). Apparent calcium digestibility, serum biochemical indices, bone mineral density (BMD), and mRNA and protein expression of calcium–phosphorus transport- and metabolism-related genes in jejunal mucosa and kidney were assessed. Results: Compared with CON, piglets in the HI, CY, and HICY groups showed higher apparent calcium digestibility (p < 0.05). Serum transforming growth factor-β was elevated in CY and HICY (p < 0.05). HI enhanced metatarsal and toe BMD (p < 0.05) and upregulated jejunal solute carrier family 34, member 2 (SLC34A2) and SLC34A3 mRNA expression (p < 0.05). In contrast, HICY reduced mRNA expression of transient receptor potential cation channel subfamily V member 6 and calcium-binding protein D28k, as well as of calcium-binding protein D9k and cytochrome P450 27B1 in the kidney (p < 0.05). Renal calcium-sensing receptor protein abundance increased in CY (p < 0.05). Conclusions: Supplementation of 25-OH-VD₃ with phytase and/or probiotics improved calcium utilization and modulated key transport pathways, contributing to enhanced bone development in weaned piglets. These findings highlight coordinated nutritional regulation of mineral metabolism during early post-weaning growth. Full article

Background/Objectives: Type 1 diabetes (T1D) and multiple sclerosis (MS) are autoimmune, multifactorial, organ-specific disorders mediated by immune cells. Their co-occurrence has been partially attributed to shared genetics and environmental factors. We aimed to dissect the shared genetic architecture between T1D and MS using large-scale genome-wide association studies (GWASs) and colocalization analyses. Methods: We applied a Bayesian colocalization framework to two large-scale GWAS data sets: a T1D study comprising 18,942 cases and 501,638 controls, and an MS GWAS including 14,802 cases and 26,703 controls. Results: We identified 26 shared colocalizing association signals between T1D and MS. Among them, seven loci (EOMES, RGS14, DLL1, ZNF438/ZEB1, SESN3, WARS1/SLC25A47, and IRF8) were novel for T1D and two (UBAC2 and LAT) for MS. Several signals showed supportive evidence in additional datasets and demonstrated functional annotation characteristics consistent with disease involvement. Conclusions: Colocalization can be a powerful discovery tool for disorders with co-divided genetic architecture, as prioritizing shared rather than individual causal variants may enhance the detection of novel loci. Our findings indicate that T1D and MS predominantly share general autoimmune susceptibility signals (17/26), rather than disease-specific (private), often with opposite direction of effect (9/26), underscoring their immunological heterogeneity. Full article

This study examines the impact of Sustainable Livelihood Capital (SLC) on women’s participation in production activities in Vietnam’s mangrove areas, using a gender-focused approach to advance gender-sensitive livelihood theory. Employing binary Logit regression and cross-tabulation analysis, model robustness was confirmed via the Bayesian Information Criterion (BIC). Findings identify financial and human capital as core factors influencing participation, with access to credit emerging as the factor exhibiting the strongest correlation. Livelihood stability and practical vocational training support women’s long-term productive engagement. The study highlights the livelihood paradox and resource lock-in effects: over-reliance on mangrove income reduces participation, limiting diversification, while over-exploitation correlates positively with participation as a survival strategy, exerting short-term environmental pressure. Conversely, owning traditional assets like fishing boats negatively affects participation, showing traditional factors hinder economic restructuring. The findings of heterogeneity analysis emphasize the necessity of policy intervention. For example, women under 56 are primarily financially driven; those over 56 exhibit lower participation and face severe human capital bottlenecks, especially education. Larger households face significant financial barriers despite having abundant human capital. Married women face dual constraints from financial and traditional physical capital, while single/divorced women hold advantages in education and opportunities. Furthermore, In areas far from fishing ports, financial and human capital are core drivers. This research provides quantitative evidence on the complex, heterogeneous effects of SLC on women’s productive engagement, offering a scientific foundation for multi-dimensional, targeted policy measures to foster sustainable livelihood diversification. Full article

Ferroptosis is an iron-dependent form of regulated cell death characterized by lipid peroxidation and failure of cellular antioxidant defenses. Increasing evidence indicates that ferroptosis contributes to the biological effects of radiotherapy and influences both tumor radiosensitivity and normal tissue injury. Because radiotherapy is a central treatment modality for many head and neck cancers, understanding how ferroptosis interacts with radiation responses has important translational implications. Ionizing radiation can induce ferroptosis through reactive oxygen species generation, disruption of glutathione metabolism, suppression of the SLC7A11–GSH–GPX4 antioxidant axis, and remodeling of membrane lipid composition. Conversely, tumor cells frequently develop radioresistance by reinforcing ferroptosis-suppressive pathways, including enhanced cystine transport, lipid desaturation, and metabolic adaptation. In head and neck cancers such as head and neck squamous cell carcinoma, nasopharyngeal carcinoma, oral squamous cell carcinoma, and thyroid malignancies, experimental studies show that modulation of ferroptosis significantly alters radiation response. Strategies that promote ferroptosis—including inhibition of antioxidant defenses, targeting of lipid metabolism, and modulation of iron homeostasis—have demonstrated radiosensitizing effects in preclinical models. However, ferroptosis may also contribute to radiation-induced normal tissue injury, particularly in oxidative stress-sensitive organs such as the salivary glands. This review summarizes the molecular basis of ferroptosis in radiotherapy, examines its role in radiosensitivity and radioresistance in head and neck cancers, and discusses therapeutic strategies to exploit ferroptosis while minimizing normal tissue toxicity. Full article

Colorectal cancer (CRC) remains a major cause of cancer-related death, and resistance to chemotherapy and radiotherapy continues to limit durable disease control. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has therefore emerged as a potential therapeutic strategy. However, models focused solely on glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) do not fully explain why CRC cells differ in their sensitivity to ferroptosis. In this review, we examine how ferroptosis in CRC is shaped by iron trafficking and selenium-dependent antioxidant defense. We first discuss the poly(rC)-binding proteins 1 and 2 (PCBP1/2)-nuclear receptor coactivator 4 (NCOA4) axis, which regulates iron storage, trafficking, and ferritinophagy. We then review the AlkB homolog 8 (ALKBH8)-directed selenoprotein network, which supports the detoxification of lipid peroxides and maintenance of redox homeostasis. We next consider how these two systems intersect and how their interplay influences ferroptosis sensitivity. We also discuss why concurrent disruption of iron handling and selenium-dependent defense mechanisms may enhance therapeutic efficacy. Finally, we outline potential clinical applications, including combination strategies and biomarker development. Full article

Ankylosing spondylitis (AS) is a chronic immune-mediated inflammatory disease affecting the axial skeleton, characterized by progressive structural damage and functional impairment. Although biologic therapies targeting tumor necrosis factor and interleukin-17 have improved clinical outcomes, a substantial proportion of patients fail to achieve sustained disease control. Emerging evidence suggests that metabolic alterations may contribute to AS pathogenesis; however, systematic characterization of metabolism-related biomarkers and their regulatory networks remains limited, and the interplay between metabolic dysfunction and immune dysregulation in AS is poorly understood. Two whole-blood GEO datasets (GSE25101, GSE73754; n = 104) were integrated as the primary analytical cohort. A third dataset (GSE11886, n = 18; monocyte-derived macrophages) was included for exploratory cross-tissue analysis. Differential expression analysis identified 847 DEGs, which were refined to 16 metabolism-related genes through weighted gene co-expression network analysis (WGCNA) and GeneCards database filtering. Eleven machine learning algorithms with 5-fold cross-validation were applied to construct diagnostic models and identify hub genes. Validation analyses included immune cell infiltration estimation using CIBERSORT, metabolic pathway activity assessment via ssGSEA, single-cell transcriptomics from GSE268839, functional enrichment through GSEA/GSVA, and chromosomal localization analysis. A competing endogenous RNA (ceRNA) regulatory network was constructed to map post-transcriptional regulation. Natural compounds from 66 AS-treating traditional Chinese medicines were screened against hub genes using deep learning-based binding prediction. Multiple machine learning algorithms achieved comparable cross-validated performance (CV AUC range 0.741–0.836; top five models: 0.805–0.836) using the six hub genes (MFN2, SLC27A3, RHOB, SMG7, AKR1B1, LCOR) identified through SHAP-based feature importance analysis of the PLS model. Leave-one-dataset-out validation between the two whole-blood cohorts showed that all algorithms exceeded an AUC of 0.77 in Round 1 (validate: GSE73754, n = 72; best AUC 0.861), while Round 2 (validate: GSE25101, n = 32) yielded more modest performance (best AUC, 0.715) reflecting the smaller validation sample. Exploratory application to GSE11886 (macrophage-derived samples) showed near-chance performance, consistent with the tissue-source discrepancy. AS patients exhibited significant downregulation of oxidative phosphorylation, TCA cycle, and glycolysis pathways (p < 0.01), accompanied by elevated glutathione metabolism (p < 0.001). Immune cell deconvolution revealed reduced CD8+ T cell proportions correlating with MFN2 downregulation, and increased neutrophil frequencies correlating with SLC27A3 upregulation. Exploratory single-cell analysis indicated that RHOB expression was relatively enriched in border-associated macrophages and fibroblasts, while AKR1B1 was more prominently expressed in vascular endothelial cells and plasmacytoid dendritic cells. The ceRNA network identified 21 miRNAs and 65 lncRNAs forming 86 regulatory interactions, with four key regulatory axes (SATB1-AS1/miR-539-5p/LCOR, FAM95B1/miR-223-3p/RHOB, LINC01106/miR-106a-5p/MFN2, AATBC/miR-185-5p/SMG7) predicted to regulate hub gene expression. Compound screening identified betaine, pyruvic acid, citric acid, etc., as top-ranking candidates, with MFN2 showing the highest binding capacity among hub genes. This study provides an integrative framework linking metabolic reprogramming with immune dysfunction in AS. The six-gene diagnostic signature showed preliminary discriminatory ability in the available datasets, while the ceRNA regulatory network and natural compound screening results prioritize candidate regulatory pathways and compounds for future validation. These findings advance our understanding of AS pathogenesis and may guide future biomarker development and targeted intervention strategies. Full article

The aim of this study was to assess the effect of sertraline on the gene expression of placental transporters for hormones, folates, nutrients and drugs over the course of pregnancy in rats. The studies were conducted on gestational days (GDs) 16 and 20 following oral treatment with 10 mg/kg/day sertraline or the vehicle, administered from weaning onward. The weight and area of the fetuses and placentas were analyzed, and maternal plasma sertraline concentrations were measured. Gene expression of ATP-binding cassette transporter b1a and b1b (Abcb1a and Abcb1b), organic anion-transporting polypeptide 4a1(Slco4A1/Oatp4a1), folate receptor-α (Folr1), reduced folate carrier (Slc19A1/Rfc), and L-type amino acid transporter (Slc7A5/Lat1) was evaluated in the placenta. Sertraline reduced fetal weight (p < 0.001) and fetal area (p < 0.01) at GD 16, while no significant differences were observed in placental weight or area between exposed and unexposed groups. Sertraline concentration was significantly lower at GD20 than at GD16 (p < 0.001). At GD 16, sertraline reduced the expression of Abcb1a (p = 0.027), Abcb1b (p < 0.01), and Oatp4a1 (p = 0.037) compared with controls. Conversely, sertraline induced Folr1 expression in both GDs and increased Rfc expression at GD 20, while Lat1 was not affected. These findings indicate that sertraline alters placental drug transporter gene expression and may impair nutrient transfer to the fetus. Full article

Chronic pain, a complex multidimensional disorder, remains a major healthcare issue and a therapeutic challenge. Neuropathic pain is a chronic pain condition that results from damage or dysfunction in the nervous system. While mechanisms of neuropathic pain at the peripheral and spinal cord level have been extensively studied, pain mechanisms in the brain remain underexplored. The amygdala, a limbic brain region, has emerged as a critical brain area for the emotional–affective dimension of pain and pain modulation. Amygdala neuroplasticity has been associated with pain states, but the exact molecular and cellular mechanisms underlying these states and the transition from acute to chronic pain are not well understood. Here, we used the spinal nerve ligation (SNL) model of neuropathic pain in male rats to investigate changes in gene expression in the amygdala at the chronic pain stage using RNA sequencing (RNA-Seq). Two amygdala nuclei, the basolateral (BLA) and central (CeA), were investigated in a hemisphere-dependent manner. We used an integrative approach that focuses on functional significance and cell-type specificity of differentially expressed genes (DEGs) to nominate mechanistic targets for central regulation of chronic pain. Our integrative transcriptomic and bioinformatic analyses identified individual genes (e.g., Cxcl10, Cxcl12, Mbp, Plp1, Mag, Mog, Slc17a6, Gad1, and Sst), molecular pathways (e.g., cytokine-mediated signaling pathway), biological processes (e.g., myelination, synaptic transmission), and specific cell types (e.g., oligodendrocytes, glutamatergic, and GABAergic neurons) affected by chronic pain. Our results also provide some evidence for the emerging concept of hemispheric lateralization of pain processing in the amygdala. Overall, our study proposes oligodendrocyte dysfunction in the amygdala, neuroimmune signaling in the CeA, and glutamatergic neurotransmission in the BLA as key processes and potential therapeutic targets for the management of chronic neuropathic pain. Full article

Cancer progression is influenced by the dynamic interplay between tumor cells and the surrounding stromal microenvironment. Therapy-induced senescence (TIS) of stromal fibroblasts represents a common outcome of anticancer treatments, contributing to tumor progression through the senescence-associated secretory phenotype (SASP). While SASP cytokines promote cancer malignancy, the contribution of secreted metabolites from senescent cells remains poorly understood. Here, we investigate the role of senescent stromal metabolism in regulating prostate and ovarian cancer cell invasion. Conditioned media (CM) from TIS-induced human prostate (HPFs) and ovarian fibroblasts (HOFs) promote enhanced invasion of cancer cells. Invasion is partially preserved after exposure to boiled CM, suggesting a role for heat-stable metabolic factors. Metabolomic profiling of senescent fibroblasts-derived CM reveals a significant increase in Glutamine (Gln) levels, identifying senescent stromal fibroblasts as a previously unrecognized source of extracellular Gln in the tumor microenvironment (TME). Exposure of cancer cells to senescent CM increases Gln uptake, together with upregulation of the transporter SLC1A5 and increased intracellular Gln. This metabolic adaptation is associated with increased malignant phenotype including epithelial-to-mesenchymal transition (EMT) and stemness features. Extracellular Gln depletion, pharmacological inhibition of glutaminase-1 (GLS1) in cancer cells, or Gln synthetase (GS) silencing in fibroblasts markedly impair senescent fibroblasts CM-induced invasion, EMT markers expression, and stemness features in cancer cells. Stromal-derived Gln is associated with increased cancer cell invasion through activation of a redox-dependent NRF2/ETS1 signaling axis. Analysis of patient-derived transcriptomic datasets further suggests chemotherapy-associated upregulation of Gln metabolism and ETS1 expression. These findings identify senescent stromal-derived Gln as a key metabolic driver of prostate and ovarian cancer aggressiveness and reveal a TIS-associated metabolic vulnerability that could be explored in future preclinical studies. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) remains a major malignancy with high incidence and mortality, in part due to its diverse etiology and intratumoral heterogeneity, which contributes to drug resistance and frequent recurrence. SALL1 (Spalt-Like Transcription Factor 1), a zinc-finger transcription factor, was reported to function as a tumor suppressor in several cancers, including breast cancer and glioma, and accumulating evidence support its involvement in tumor biology. In this study, the role of SALL1 in HCC was examined. Methods: Public RNA and protein databases derived from human HCC were interrogated. Western blotting quantification of clinical HCC for SALL1 levels was carried out. Cell culture and xenograft studies were performed using genetically modified HCC tumor cells. Results: As revealed by pubic RNA and protein database analysis and further western blotting quantification of clinical samples of HCC, SALL1 is decreased in human HCC. The effect of reduced SALL1 expression on the tumorigenic properties and transcriptional regulation in HCC was then examined. Knockdown of SALL1 in the HCC cell lines Huh7 and Hep3B, enhanced cell proliferation in vitro and accelerated tumor growth in a xenograft mouse model, suggesting that lower SALL1 expression increases cell proliferation and tumorigenesis in HCC. RNA-seq and ChIP analyses further identified three novel candidate target genes (SLC6A14, GABRG1, and AKR1B10), suggesting that SALL1 may exert a tumor-suppressive effect, at least in part, through negative regulation of these genes. Conclusions: These findings establish SALL1 as a possible tumor suppressor and provide new insights into the biological significance of SALL1 downregulation in HCC. SALL1 could be a candidate prognostic marker and a potential therapeutic target. Full article

Circular RNAs (circRNAs) exhibit significant sex- and development stage-specific expression patterns in the gonads of various fish species, yet their functions and regulatory mechanisms in male reproductive development remain largely unexplored in crucian carp (Carassius auratus). In this study, we characterized the expression features and biological functions of circSPEF2, a circular RNA derived from the reproduction-related gene spef2. Our results showed that circSPEF2 expression was markedly elevated in mature testes and progressively upregulated during gonadal maturation. Functional studies suggested that circSPEF2 likely does not act through a ceRNA-dependent mechanism. Transcriptome sequencing following circSPEF2 overexpression identified 45 upregulated and 70 downregulated differentially expressed genes, with GO and KEGG enrichment analyses revealing significant alterations in multiple gonadal development-related genes and signaling pathways. Subsequent siRNA-mediated knockdown of circSPEF2, combined with qRT-PCR validation, confirmed that circSPEF2 positively regulates the expression of genes associated with cell maturation and differentiation, including prdm1a, lamc2, and slc25a27, while concurrently suppressing that of proliferation- and apoptosis-related genes such as wnt8b, cpeb3, and bcl2l11. Furthermore, RNA pull-down combined with mass spectrometry identified three candidate circSPEF2-binding proteins, namely, hnRNP A/B, SRSF2, and CFAP263. Collectively, these findings indicate that circSPEF2 plays an important role in male gonadal development in fish and provide new insights into the post-transcriptional regulatory mechanisms underlying vertebrate male reproduction. Full article

Heart failure (HF) is frequently associated with iron deficiency and anemia, negatively impacting patient outcomes. This study aimed to investigate the contribution of genetic variation in iron metabolism-related genes to biochemical and hematological phenotypes in HF. An HF population of 182 patients with functional iron deficiency (ID) and anemia was stratified by sex and heart failure subtype, including HF with reduced ejection fraction (HFrEF) and HF with non-reduced ejection fraction (HFnrEF). Genetic variants in HFE (rs1799945), SLC40A1 (rs1439816, rs2304704), and TMPRSS6 (rs855791) were evaluated. Variants in HFE and SLC40A1 were associated with differences in serum iron, ferritin, transferrin saturation, hemoglobin, and RDW. The phenotypic impact of these variants was modulated by sex and heart failure subtype, highlighting the influence of iron availability, inflammatory burden, and erythropoietic demand. In contrast, no significant associations were observed for the TMPRSS6 variant. In conclusion, genetic variation in key regulators of iron metabolism contributes to the heterogeneity of iron-related biochemical and hematological phenotypes in HF. These findings emphasize the interplay between genetic background, sex, and heart failure physiology and support the relevance of personalized approaches to iron assessment and management in heart failure. Full article

Targeted delivery systems offer a promising approach for selectively modulating cellular processes; yet the intracellular consequences of targeted nutrient delivery to trophoblast cells remain poorly defined. Here, we investigated a previously validated placenta-targeting peptide conjugated to liposomes encapsulating stable isotope-labelled L-arginine and L-lysine to examine cellular uptake and downstream molecular responses in a trophoblast-like cell model. Peptide-dependent uptake of fluorescently labelled liposomes was confirmed in BeWo cells, demonstrating selective internalisation compared with non-targeted controls. Encapsulation of isotope-labelled amino acids enabled direct quantification of intracellular delivery and incorporation into the cellular proteome using stable isotope labelling by amino acids in cell culture (SILAC). Quantitative proteomic analysis revealed coordinated changes in proteins associated with translation, metabolism, and nitric oxide synthase regulation following targeted liposomal uptake. Notably, V-type proton ATPase subunit G1 (ATP6V1G1) and large neutral amino acid transporter small subunit 1 (SLC7A5) showed increased incorporation of labelled amino acids and were independently validated by Western blotting. Together, these findings establish a proof-of-concept platform for targeted intracellular amino acid delivery to trophoblast-like cells and define the resulting proteomic responses. This work provides mechanistic insight into intracellular amino acid utilisation and a framework for future studies in placental cell biology. Full article

Protein turnover and extracellular proteolysis continuously generate diverse peptide fragments within biological systems, yet the metabolic and pharmacological implications of these peptides remain incompletely understood. Among these transporters, members of the solute carrier family 15 (SLC15), including peptide transporter 1 (PEPT1/SLC15A1) and peptide transporter 2 (PEPT2/SLC15A2), mediate the proton-coupled uptake of dipeptides, tripeptides, and structurally related compounds across cellular membranes. While these transporters have been extensively studied in the context of intestinal peptide absorption and drug delivery, their potential roles in cancer biology remain incompletely understood. Tumor microenvironments are characterized by extensive proteolysis and dynamic metabolic remodeling, processes that can generate diverse peptide fragments derived from extracellular matrix proteins and intracellular protein turnover. These peptides may accumulate locally and potentially serve as substrates for cellular peptide transport systems. Once internalized through peptide transporters, dipeptides are typically hydrolyzed into free amino acids that can support biosynthetic pathways, energy metabolism, and cellular growth. In addition to their potential metabolic roles, certain endogenous dipeptides have also been reported to influence cellular signaling pathways and redox homeostasis. The broad substrate specificity of peptide transporters has also attracted significant interest in pharmacology because numerous clinically used drugs exploit these transport systems for efficient cellular uptake. This property raises the possibility that peptide transporters may be utilized for transporter-mediated drug delivery strategies, including the development of peptide-modified prodrugs or dipeptide–drug conjugates. In this review, we summarize the molecular characteristics and physiological functions of dipeptide transport systems with a particular focus on the SLC15 transporter family. We then discuss emerging evidence linking peptide transporters to tumor metabolism and the tumor microenvironment. Finally, we highlight current progress and future perspectives in exploiting peptide transport systems for transporter-mediated drug delivery and therapeutic targeting in cancer. Full article

Acute mountain sickness (AMS) arises from hypobaric hypoxia at high altitude and still lacks effective pharmacological treatments. Although hypoxic preconditioning via gradual ascent prevents AMS, the underlying molecular adaptations have not yielded therapeutics. Here, inspired by metabolic reprogramming during stepwise altitude adaptation, we screened for anti-hypoxia compounds and identified H0802 (N-(pyridin-2-yl) pyridine-2-carbothioamide) as the most promising candidate. H0802 markedly enhances hypoxic tolerance in mice, prolongs survival under acute hypoxia, improves survival during simulated high-altitude exposure, and attenuates hypoxia-induced lung injury, accompanied by combined anti-inflammatory and antioxidant effects. Transcriptomic profiling shows that H0802 elicits a gene expression signature resembling hypoxia, including key hypoxia-related genes (Edn1, Angptl4, Mt1, Gdf15, Slc7a5, and Hif-3α) involved in glucose and oxygen metabolism. Mechanistically, H0802 stabilizes endogenous hypoxia-inducible factor (HIF) proteins under normoxia by preventing ubiquitin-dependent degradation, thereby activating hypoxia-responsive genes. In vivo, H0802 pretreatment lowers circulating glucose and hepatic glycogen while increasing brain glucose uptake, suggesting a metabolic shift that preserves cerebral energy during acute hypoxic stress; it also modulates whole-body oxygen consumption. H0802 represents a candidate for anti-AMS therapy, and phenotypic optimization of H0802 provides a potential route for drug discovery. Full article