Search Results (37,765)

Background/Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, yet the association between folic acid (FA) intake and CRC risk remains controversial. This study investigated the effects of varying dietary FA levels on colorectal carcinogenesis and the underlying mechanisms. Methods: BALB/c mice were fed diets containing FA at <0.1, 2.0, 6.0, 8.0, or 20.0 mg/kg for 14 weeks. After 4 weeks, colorectal tumorigenesis was induced using the azoxymethane/dextran sulfate sodium (AOM/DSS) protocol. Tumor multiplicity, maximum tumor diameter, tumor volume, colorectal length, histopathology, and cell proliferation were assessed. Mechanistic assessments included uracil misincorporation, thymidylate synthase (TS), telomere attrition, genome-wide DNA methylation, RAP1 signaling, immune-related markers, and inflammatory cytokines in colorectal tissues. Results: Both FA deficiency (<0.1 mg/kg) and excess (8.0/20.0 mg/kg) increased colorectal tumor burden, with increased tumor number, larger maximum diameter, greater tumor volume, shortened colorectal length, and enhanced cell proliferation, whereas the 6.0 mg/kg diet group showed the lowest tumor burden. FA deficiency reduced TS expression, elevated deoxyuridine monophosphate (dUMP) levels, decreased deoxythymidine monophosphate (dTMP) levels, increased uracil misincorporation, and exacerbated telomere attrition, as evidenced by shortened telomeres and increased damage. In contrast, excessive FA intake induced Rap1 GTPase-activating protein (RAP1GAP) hypermethylation, reduced Rap1GAP expression, enhanced RAP1 activity, and upregulated programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) expression. Conclusions: Dietary FA can exhibit a U-shaped association with colorectal carcinogenesis, with protective effects observed within an optimal range. FA deficiency and excess may drive tumor development through distinct molecular pathways involving uracil misincorporation-induced telomere attrition and DNA methylation-mediated immunosuppression, respectively. Full article

Coronavirus infections pose a significant threat to both human and animal health, causing widespread morbidity, mortality, and substantial economic losses. While vaccines are crucial for prevention, their efficacy is often limited by the high mutation rate of these viruses. This underscores the urgent need for anti-coronavirus drugs, particularly broad-spectrum antiviral agents. In this study, we demonstrated for the first time that Biochanin A (BCA), a bioactive isoflavonoid found in legumes, exhibits broad-spectrum antiviral activity against coronaviruses. BCA potently inhibits porcine epidemic diarrhea virus (PEDV), as well as human coronaviruses HCoV-OC43 and HCoV-229E in vitro, with EC₅₀ values of 6.90, 2.80 and 15.4 μM, respectively. In a lethal mouse model of HCoV-OC43-induced encephalitis, oral administration of BCA (40–60 mg/kg) significantly improved animal survival and reduced cerebral viral loads. Mechanistic studies revealed that BCA upregulates the AMPK/Nrf2 signaling pathway, thereby increasing expression of the glutamate-cysteine ligase catalytic subunit (GCLC) and enhancing glutathione (GSH) biosynthesis. Our findings identify BCA as a promising host-directed antiviral agent and highlight its therapeutic potential against coronavirus infections. Full article

Background: Aralia echinocaulis has therapeutic effects on rheumatoid arthritis (RA), with total polysaccharide and glycoside (TPGs) as main active components. RA pathogenesis involves gut microbiota dysbiosis and immune‒metabolic crosstalk, but the role of microbiota-derived succinate in RA remains unclear. Objective: This study explored the role of succinate-GPR91 signaling in intestinal dendritic cells (DCs) in the context of RA and the therapeutic mechanism of A. echinocaulis TPGs. Methods: Collagen-induced arthritis (CIA) mice were treated with TPGs or exogenous succinate. Paw edema, inflammation, gut succinate levels, the Th17/regulatory T (Treg) balance, and DC activation via succinate-GPR91 were detected, and GPR91-targeting siRNA and CD4+ T-cell coculture assays for verification. Results: TPGs alleviated symptoms in CIA mice and restored the Th17/Treg balance by reducing intestinal succinate levels. Succinate activated DCs via GPR91 to promote Th17 differentiation, while TPGs suppressed DC maturation and Th17-driven inflammation, supporting the involvement of a gut-centric immunometabolic axis in RA. Conclusion: TPGs ameliorate RA by targeting the succinate-GPR91-Th17 pathway, identifying succinate as a novel RA target and TPGs as a potential microbiota-modulating agent. Full article

A high-fat (HF) diet disrupts metabolic homeostasis and impairs peripheral circadian rhythms in key metabolic tissues. β-Hydroxybutyrate (BHB), a major circulating ketone body, functions not only as an energy substrate but also as a signaling metabolite regulating nutrient-sensing and inflammatory pathways. However, its role in modulating metabolic–circadian interactions under conditions of nutrient excess remains unclear. In this study, we investigated whether BHB supplementation influences metabolic signaling and circadian clock oscillations in liver, skeletal muscle and adipose tissue under chow and HF conditions. Male C57BL/6 mice were fed chow or HF with or without BHB supplementation (500 mg/kg body weight in the diet) for 7 weeks. Metabolic parameters were assessed by indirect calorimetry, and tissues were collected every 4 h across the circadian cycle. HF feeding increased body weight and adiposity (p < 0.01), reduced AMPK activation, enhanced AKT/mTOR signaling, elevated NF-κB levels and dampened clock gene rhythmicity. BHB supplementation significantly decreased food intake in HF-fed mice (p < 0.01) and partially reversed several molecular alterations in a tissue-specific manner. In skeletal muscle and adipose tissue, BHB increased AMPK activation and reduced mTOR and NF-κB signaling (p < 0.05), whereas hepatic effects were more modest. Notably, BHB modulated circadian gene expression, restoring aspects of rhythmic amplitude and/or phase, particularly in adipose tissue. These findings may indicate that BHB supplementation modulates nutrient-sensing pathways and partially restores peripheral circadian rhythms under HF conditions. While some effects may be influenced by reduced energy intake, BHB may serve as a metabolic signal linking nutrient status to circadian regulation. Full article

Idiopathic pulmonary fibrosis (IPF) is characterised by progressive parenchymal remodelling, driven by epithelial dysfunction, fibroblast activation, and altered immune regulation within the distal lung. Alveolar macrophages (AMs) reside in a surfactant-rich environment and are specialised for continuous lipid handling, yet the significance of this metabolic role for macrophage heterogeneity and fibrotic progression has remained incompletely integrated across studies. In this review, we synthesise evidence from human lung tissue, experimental models, lipidomic analyses, and clinical investigations to place macrophage populations described in IPF—including FABP4-high homeostatic cells and SPP1-associated disease-enriched states—within a unified lipid-metabolic context. We show that macrophage heterogeneity in IPF can be understood as a variation within a core lipid-handling programme rather than the emergence of distinct macrophage lineages. Profibrotic macrophage states are characterised by altered lipid processing and signalling, including dysregulated sterol handling, lysophospholipid pathways, and eicosanoid balance, which impair surfactant turnover and contribute to fibroblast activation. Importantly, experimental and clinical data indicate that macrophage lipid-metabolic programmes remain modifiable, although definitive disease-modifying efficacy in IPF has yet to be established. Framing macrophage states within a lipid-metabolic framework provides a coherent basis for interpreting heterogeneous datasets and supports the rationale for therapeutic strategies aimed at stabilising or restoring macrophage lipid handling in fibrotic lung disease. Full article

Background: Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries and one of the few solid tumors with a steadily rising incidence, paralleling global trends in obesity and insulin resistance. Its strong epidemiologic association with systemic metabolic dysfunction positions EC as a uniquely accessible model for metabolically informed chemoprevention. Methods: This narrative review was conducted through a systematic search of PubMed/MEDLINE and Embase using the following terms: “endometrial cancer” AND (“insulin resistance” OR “metabolic syndrome” OR “PI3K” OR “chemoprevention” OR “bariatric surgery” OR “metformin” OR “cellular senescence”). Searches were limited to English-language publications; no date restriction was applied for foundational molecular studies, while clinical and translational evidence was reviewed from 2000 to 2025. Additional references were identified through manual review of reference lists of included articles. Results: We examine metabolic amplification as a conceptual framework in which hyperinsulinemia, inflammatory reinforcement, and redox-epigenetic modulation intensify proliferative signaling in biologically susceptible endometrial tissue, particularly within molecular subtypes enriched for PI3K pathway activation such as tumors lacking a specific molecular profile (NSMP). Bariatric surgery offers the strongest human evidence supporting the principle that durable metabolic correction can substantially reduce EC incidence. In contrast, pharmacologic interventions including metformin, anti-inflammatory agents, and nutraceutical compounds demonstrate variable or limited preventive efficacy, and short-term biomarker modulation cannot substitute for validated reduction in cancer risk. The endometrial intraepithelial neoplasia (EIN) model provides a uniquely accessible platform for biomarker-guided intervention. Conclusions: Integration of genomic subtype classification with metabolic profiling may enable precision prevention strategies in clearly defined high-risk populations. Effective chemoprevention will require molecular enrichment, confirmation of tissue-level target engagement, and clinically meaningful endpoints, while acknowledging the translational limits of pathway-directed approaches. Full article

The high incidence of thrombosis in lymphoma is largely due to chronic inflammation and endothelial dysfunction. To elucidate the mechanisms underlying thrombus formation and fibrinolysis, we investigated interactions between circulating endothelial cells and peripheral blood mononuclear cells (MNCs), along with inflammatory signaling pathways, in patients with follicular lymphoma (FL), Hodgkin lymphoma (HL), and diffuse large B-cell lymphoma (DLBCL), independent of the presence of thrombosis, compared to healthy controls by flow cytometry, immunoblotting, and fluorometric assays. We observed increased tissue factor (TF) expression on CD31+ endothelial cells in DLBCL and FL. In DLBCL, inducible nitric oxide synthase expression was elevated in MNCs, while reduced nitrite levels correlated with an advanced clinical stage in patients with thrombosis. In lymphoma, nuclear factor kappa B (NFκB) signaling was activated in MNCs, while signal transducer and activator of transcription 3 (STAT3) activation was increased in DLBCL with thrombosis. Trans-endothelial migration of MNC was enhanced in HL, FL and DLBCL with thrombosis and reduced by inflammatory cytokine tumor necrosis factor alpha (TNF-α) that promoted platelet aggregation like interleukin-6 (IL-6) in HL and FL. Fibrinolytic analyses showed reduced tissue type plasminogen activator in lymphoma, whereas increased urokinase-type plasminogen activator (uPA) was linked to poorer total survival in DLBCL with thrombosis, suggesting a compensatory role in early thrombus resolution. These findings indicate that chronic inflammation promotes endothelial activation, dysregulated fibrinolysis, and increased vascular permeability, contributing to heightened thrombotic risk. This study provides mechanistic insight into lymphoma-associated thrombosis and identifies TF, uPA, and the inflammatory signaling pathways as potential biomarkers and therapeutic targets. Full article

Objectives: This study aimed to investigated the role of Giardia extracellular vesicles (EVs) in intercellular communication and to evaluated their potential as vaccine candidates. Methods: The immunomodulatory effects of Giardia EVs were assessed in mouse macrophages and human monocyte-derived dendritic cells (Mo-DCs), with a particular focus on key inflammatory signaling pathways. In vivo immunogenicity was evaluated following EV administration, and the antigenic composition of EV cargo was characterized by proteomic analysis. Results: Giardia EVs activated pro-inflammatory signaling pathways in mouse macrphages, including SAPK/JNK, ERK1/2, and NF-κB. This activation was associated with IκB-α degradation and nuclear translocation of p65. Furthermore, EV stimulation significantly upregulated the expression of pro-inflammatory genes, including Il1β, Il6, Il4, Ptgs2, Nos2, and Tnf, with log₂ fold changes ranging from 3.9 to 15.8. Consistently, EVs increased iNOS protein expression (28–45%) and nitrite production (9.6–12.3-fold). In human Mo-DCs, Giardia EVs promoted cellular maturation, as evidenced by increased expression of MHC-II, CD80, and CD86, and enhanced T-cell proliferation with a Th1-skewed profile. In vivo immunization induced antigen-specific antibody responses, with IgG subclass distribution indicative of a balanced Th1/Th2 response. Proteomic analysis identified immunoreactive EV-associated proteins, including elongation factor 1-alpha, α-7.3 giardin, tubulin, and variant surface proteins (VSPs), which are well-established antigens in Giardia infection, with prominent bands observed at approximately 22 kDa and 50 kDa. Conclusions: Collectively, these findings demonstrate that Giardia EVs modulate innate immune responses in vitro, elicit antigen-specific humoral immunity in vivo, and contain conserved immunogenic proteins. These properties support their potential as a promising cell-free vaccine platform against giardiasis. Full article

(1) Background: The “Bider” marking refers to the symmetrical black stripes distributed on the shoulder blades of Dun Mongolian horses, representing an ancestral trait of significant genetic value. However, the molecular mechanisms underlying its formation remain unclear. This study aims to elucidate the molecular basis of these markings by comparing transcriptomic differences in skin tissues from variously pigmented areas of Mongolian horses’ “Bider” patterns. (2) Methods: Using three Dun Mongolian horses as subjects, skin tissue samples were collected from their shoulders (dark-marked and light-marked areas), dorsal midline, and croup regions for transcriptome sequencing. Differentially expressed genes were identified based on sequencing data, followed by Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Key findings were validated through quantitative reverse transcription polymerase chain reaction (qRT-PCR). (3) Results: The sequencing yielded approximately 893 million high-quality clean reads, with an overall alignment rate exceeding 96%. A total of 140 to 775 differentially expressed genes were identified. GO enrichment analysis revealed that these genes were significantly enriched in biological processes related to pigment metabolism, skin and hair follicle development, signal transduction (including calcium and cyclic guanosine monophosphate (cGMP) signaling), and immune regulation. KEGG analysis further indicated that multiple pathways closely associated with pigment regulation, including the calcium signaling pathway, tyrosine metabolism, cyclic adenosine monophosphate (cAMP) signaling pathway, and melanoma pathway, were significantly enriched across different tissue comparison groups, suggesting their potential key roles in coat color phenotype formation. The reliability of the sequencing data was corroborated by the results of qRT-PCR validation. (4) Conclusions: This study conducted a transcriptome analysis of skin samples from various pigmented regions of the Dun Mongolian horse’s Bider marking, revealing that the formation of this marking is associated with the differential expression of numerous genes and is co-regulated by multiple pigment-related signaling pathways. Full article

Particulate matter (PM) is a complex mixture of airborne solid particles and liquid droplets originating from various environmental sources, and it has been implicated in the initiation, development, and progression of pulmonary inflammation and respiratory diseases. However, the underlying associated molecular mechanisms remain unclear. Adenophora divaricate Franch. & Sav. (AD) is a medicinal herb classified within the Campanulaceae family and genus Adenophora, with a broad geographic distribution across East Asia, including Korea, Asia, and Russia. In this study, we investigated the mechanisms underlying the effects of AD on PM-induced lung inflammation in both PM-stimulated RAW264.7 cells and PM-exposed mice. Considering that the reactive oxygen species (ROS)-mediated thioredoxin-interacting protein (TXNIP) and NOD-like receptor pyrin domain containing (NLRP3) inflammasome pathway plays a role in PM-induced inflammatory responses, we focused on determining whether AD exerts its anti-inflammatory effects through modulation of this signaling pathway. The anti-inflammatory properties of the methanolic extract of AD were evaluated using PM-stimulated RAW264.7 cells and PM-exposed mice. PM was administered intranasally to mice for 7 days, whereas AD or dexamethasone was orally administered for the same duration. AD treatment significantly attenuated pulmonary inflammation, as evidenced by reduced inflammatory cell counts and decreased cytokine levels in bronchoalveolar lavage fluid. In addition, AD decreased oxidative stress marker (ROS and thiobarbituric acid reactive substances) while increasing glutathione content, leading to suppression of TXNIP/NLRP3 inflammasome expression. Histopathological analysis revealed a marked alleviation of inflammatory responses in lung tissue, characterized by diminished inflammatory cell infiltration and reduced alveolar wall thickening. Collectively, these findings suggest ROS-mediated TXNIP serves as a key regulatory factor, and AD may serve as a potential therapeutic agent for pulmonary inflammation. Full article

Restless legs syndrome (RLS) is one of the most prevalent sleep disorders, yet its diagnosis continues to rely almost entirely on subjective symptom descriptions. This persistent dependence on phenomenology reflects the absence of reliable biological markers to aid in the process of diagnosis or monitoring. However, there is accumulating molecular evidence that suggests that RLS is associated with systemic biological alterations. These extend beyond the traditional paradigm of iron deficiency. The present scoping review synthesizes the current research on circulating serum biomarkers investigated in RLS outside classical iron indices. A comprehensive search of PubMed, Scopus, and Web of Science databases identified 1050 records, of which 50 studies met eligibility criteria and were included. In the processing of data, clusters emerged into several recurring biological domains, including dysregulated iron regulatory signaling (hepcidin), low-grade immune activation, oxidative stress, and neuroaxonal injury markers. High-throughput omics studies reveal molecular network perturbations involving inflammatory pathways, complement activation, metabolic signaling, and cellular stress responses. Biomarker associations appear stronger when linked to objective motor burden. These findings suggest that RLS may involve multifarious molecular changes detectable in the serum. Consequently, this can support the transition from symptom-based diagnosis toward biomarker-informed stratification, which may enable more precise disease characterization and improved diagnostic accuracy. Full article

Ultraviolet (UV) irradiation induces complex skin damage, including hyperpigmentation, oxidative stress, and alterations in proteins related to keratinocyte differentiation and epidermal barrier-associated status. This study investigated the multifunctional protective effects of Padina arborescens ethanolic extract (PAEE) against skin damage in melanocytes, keratinocytes, and zebrafish. In alpha-melanocyte-stimulating hormone (α-MSH)-stimulated B16F10 cells, PAEE effectively suppressed the protein kinase A (PKA)/cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) signaling pathway, which was associated with reduced expression of microphthalmia-associated transcription factor (MITF) and tyrosinase, leading to decreased melanin synthesis. PAEE also exhibited photoprotective properties by reducing reactive oxygen species (ROS), inhibiting interleukin-1 beta (IL-1β), and attenuating matrix metalloproteinase-1 (MMP-1) upregulation associated with UVB (ultraviolet B)-induced photodamage in HaCaT keratinocytes. Notably, PAEE restored the UVB-reduced expression of filaggrin and involucrin, representative markers of keratinocyte differentiation and epidermal barrier-associated status, in HaCaT keratinocytes. In zebrafish embryos, PAEE suppressed α-MSH-induced melanin accumulation and UVB-induced ROS generation at non-toxic concentrations. Taken together, these results suggest that PAEE exerts anti-melanogenic and photoprotective effects in cellular and zebrasfish models and may serve as a promising marine-derived ingredient for cosmeceutical applications targeting UVB-related skin damage. Full article

Sphingosine 1-phosphate (S1P) is a potent bioactive sphingolipid that plays essential roles in regulating various immune responses, including lymphocyte trafficking, immune cell differentiation, and immunosurveillance. Different immune responses to S1P arise from the diverse Sphingosine 1-phosphate receptors (S1PRs) expressed on the cell surface, shaping unique, context-dependent responses to S1P. Beyond surface receptor engagement, intracellular S1P signaling is also being recognized as a crucial modulator of immune cell responses. Furthermore, the multifaceted S1P signaling axis has emerged as a key regulator of immune responses within the tumor microenvironment (TME), influencing both innate and adaptive immune cell behavior to facilitate tumor progression. A deeper mechanistic understanding of S1P signaling and its impact on immune cell fate is essential for developing novel therapeutic strategies to enhance anti-tumor responses. This review summarizes our current knowledge of how S1P influences immune cell function, with a specific focus on S1PR-dependent and S1PR-independent cellular signaling pathways. We also examine the alterations in immune cell responses that occur within the TME and current therapeutic strategies targeting S1P signaling. Full article

Colorectal cancer (CRC) persists as a significant public health burden due to its high morbidity and mortality rates worldwide, yet the molecular events that govern its initiation and progression remain incompletely understood. We recently conducted microRNA (miRNA) profiling and identified multiple dysregulated miRNAs in CRC compared to adjacent normal tissue. Among those, miR-138-5p emerged as a potential tumor suppressor due to its marked downregulation in CRC tissue; however, the stage-specific expression of this miRNA during CRC progression and underlying molecular mechanisms remains to be unraveled. In this study, we performed differential expression profiling of healthy colon, adenomatous polyp (AP), and CRC tissues based on public datasets, revealing significant downregulation of miR-138-5p in CRC compared to controls, but not during the AP stage, suggesting a role in later stages of malignant progression. Forced expression of miR-138-5p in HCT116 and HT-29 CRC models suppressed clonogenic survival, proliferation, and migration while inducing cell death. Additionally, miR-138-5p significantly inhibited tumor formation under three-dimensional culture settings, reinforcing its tumor-suppressive function in a physiologically relevant context. Transcriptomic profiling of miR-138-5p-overexpressing CRC models revealed widespread changes in the pathways related to zinc ion binding, cilium morphogenesis, smoothened signaling, and nuclear transport. Integrated computational and experimental analyses identified 41 potential gene targets, among which TCF3, UBE2C, EIF4EBP1, LYPLA1, and CD44 were validated as potential miR-138-5p-regulated genes. Collectively, these findings establish miR-138-5p as a stage-specific tumor suppressor in CRC, acting through coordinated regulation of oncogenic networks across multiple pathways. Downregulation of miR-138-5p appears to be a late oncogenic event, conferring proliferative, survival, and invasive advantages to tumor cells. Restoration of miR-138-5p or therapeutic targeting of its downstream effectors may represent promising avenues for CRC therapeutic intervention. Full article

Jujube (Ziziphus jujuba Mill.) is a functional food with both edible and medicinal properties. It is rich in various bioactive compounds and holds significant development value and application prospects in food nutrition, medicine, and health. This review systematically summarizes the research progress on the synthesis mechanism and pharmacological activities of phenolic compounds in jujube fruits, clarifies the composition of their main components, sorts out the research advances in extraction technologies of jujube phenolic compounds, and focuses on analyzing the content differences and distribution patterns across cultivars and tissue parts. On this basis, it examines the regulatory mechanisms of phenolic compound synthesis in depth, with a particular focus on elucidating the regulatory networks of genes and transcription factors involved in flavonoid biosynthesis. Meanwhile, this review comprehensively summarizes the pharmacological activities of phenolic compounds in jujube fruits, including antioxidant, anticancer, antibacterial, anti-inflammatory, and hypoglycemic effects. It also elucidates the molecular mechanisms underlying these bioactivities, such as regulating signaling pathways and scavenging free radicals. Finally, it analyzes the limitations of current research and proposes key directions for future development. This review provides theoretical support and a scientific basis for the in-depth development and utilization of jujube phenolic compounds as well as for the research and development of related functional foods and drugs. Full article