The influence of circulating polyunsaturated fatty acids (PUFAs) on alopecia areata (AA) development remains poorly understood, with inconsistent results reported. Our study aims to evaluate their causal associations using the bidirectional Mendelian randomization method. European ancestry genome-wide association studies were used to analyze the genetic associations between PUFAs and AA (n = 211,428). Sample sizes for PUFAs were 13,527, 13,506, 114,999, 7818, and 13,549 for plasma linoleic acid (LA), omega-6, omega-3, docosahexaenoic acid (DHA), and PUFAs other than 18:2 (otPUFA), respectively. The causal associations were primarily determined by the inverse variance weighted (IVW) method. Circulating omega-6 (IVW odds ratio [OR] = 1.64, 95% confidence interval [CI] = 1.15-2.33, P = .0059) and LA (IVW OR = 1.49, 95% CI = 1.05-2.13, P = .0257) were positively associated with AA risk. Conversely, AA was negatively correlated with circulating DHA (IVW OR = 0.99, 95% CI = 0.99-1.00, P = .0324). Elevated circulating omega-6 and LA are correlated with an increased AA risk. Furthermore, AA was negatively associated with circulating DHA. These findings provide insights into the potential biological mechanisms underlying the development of AA, offering potential implications for dietary recommendations and treatment options.

OBJECTIVES:To investigate the in vitro and in vivo antiviral efficacy and underlying mechanism of regorafenib against Enterovirus 71 (EV71), as no licensed direct-acting antivirals are available for severe cases. METHODS:The inhibitory effect of regorafenib against EV71 was evaluated using qRT‒PCR, Western blot, IF, and CPE assays. The stage of the viral life cycle targeted by regorafenib was determined via time-of-addition, binding and entry assays. In vivo efficacy was assessed in an EV71-infected murine model by monitoring body weight, clinical scores, and viral RNA loads in tissues. The mechanism of action was elucidated by analyzing the effect of regorafenib on the MEK/ERK phosphorylation in the host mitogen-activated protein kinase (MAPK) pathway. A potential interaction with the EV71 capsid protein VP1 was investigated using molecular docking. RESULTS:Regorafenib demonstrated potent, dose-dependent antiviral activity against EV71 in vitro and exhibited broad-spectrum efficacy against multiple human enteroviruses. In an EV71-infected murine model, oral administration of regorafenib at doses of 1.25 or 2.5 mg/kg/day significantly alleviated infection-associated symptoms and reduced viral loads in key organs. Mechanistic investigations revealed that regorafenib suppressed viral replication by inhibiting the phosphorylation of MEK and ERK in the MAPK pathway. Molecular docking studies further predicted that regorafenib binds to the viral capsid protein VP1, providing a potential structural basis for its antiviral effect. CONCLUSIONS:Our findings establish that regorafenib exhibits inhibitory activity against EV71 in vitro and in vivo, which warrants further preclinical evaluation as a candidate lead compound.

Background: Research demonstrates that pyroptosis is a critical factor in the progression of cardiovascular diseases and their related complications. Nevertheless, the precise association between this particular cell death process and the pathophysiological characteristics of atrial fibrillation (AF) remains uncertain. This exploratory study investigates the association between pyroptosis-related genes (PRGs), predicted immune-cell enrichment, and AF using a systems biology approach. Methods: Two datasets obtained from the Gene Expression Omnibus, along with a dataset from GeneCards pertaining to pyroptosis-related genes (PRGs), were utilized in this study. Following this, 18 AF-PRGs acquired from the GSE41177 dataset and PRGs were analyzed for functional enrichment using Gene Ontology (GO) annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and gene set enrichment analysis (GSEA). Subsequently, the validation dataset was employed to assess the 18 AF-PRGs, leading to the identification of seven candidate genes for exploratory validation. Then, interaction networks were developed to elucidate potential regulatory relationships among PRGs, miRNAs, transcription factors, and drugs. Finally, single-sample GSEA was used to estimate predicted immune-cell enrichment in AF. Results: The KEGG pathway analysis indicated that AF-related PRGs are significantly enriched in pathways linked to NOD-like receptor signaling, lipid metabolism, and bacterial infection, highlighting the potential role of inflammation in the pathogenesis of AF. After validation, we identified seven additional reliable genes: S100A9, S100A4, MPEG1, NAIP, CDK9, S100A8, and S100A12. Additionally, 177 miRNAs were predicted to regulate these seven genes, while 50 transcription factors (TFs) were identified to regulate six of them, and 38 drugs were predicted to target six genes as hypothesis-generating interactions. In assessing predicted immune-cell enrichment, we observed significant differences between AF and sinus rhythm atrial tissues. Conclusion: This exploratory study suggests that pyroptosis-related inflammatory gene signatures may be associated with AF and provides hypotheses for future mechanistic and translational validation.

Background Lung cancer remains one of the most lethal malignancies worldwide, with therapeutic resistance and low response rates representing major clinical challenges. The biosynthetic enzyme NFS1 has been implicated in tumour progression across various cancer types. PANoptosis is a recently identified type of cell death that can increase antitumour immunity, resulting in effective tumour suppression. Platycodin D (PD), a triterpenoid saponin isolated from the traditional Chinese medicine Platycodon grandiflorus, has demonstrated anticancer effects through mechanisms such as apoptosis induction and autophagy regulation. Purpose This study aimed to investigate the mechanism by which PD targets NFS1 to induce PANoptosis and increase antitumour immunity in lung cancer. Methods The antiproliferative effect of PD was assessed using a CCK-8 assay. Changes in the expression of key PANoptosis-related proteins were analysed by Western blotting, and YP1/PI et al were used to visualize different modes of cell death. CETSAs and DARTSs were performed to validate the direct interaction between PD and NFS1. ELISA and flow cytometry were used to measure the release of ICD-related molecules and DCs maturation, respectively. Mouse models were established to evaluate the in vivo antitumour efficacy and immunomodulatory effects of PD, both alone and in combination with NFS1 siRNA. Results PD inhibited lung cancer cell proliferation in a dose-dependent manner. Mechanistically, PD directly bound to NFS1, downregulated its expression, and induced significant accumulation of ROS, leading to the activation of PANoptosis. Furthermore, PD treatment triggered the release of ATP and HMGB1, and promoted DCs maturation. In vivo studies confirmed that PD significantly suppressed tumour growth and acted synergistically with NFS1 knockdown to promote antitumour immunity. Conclusion Our findings demonstrate that PD targets NFS1 to trigger ROS-dependent PANoptosis and activate antitumour immune responses, providing a novel immunotherapy sensitization strategy for lung cancer patients.

ETHNOPHARMACOLOGICAL RELEVANCE:Chronic hepatic injury is a liver disease that poses a threat to human health with increasing morbidity. Chinese herb pairs are the fundamental and concise form of traditional Chinese medicine (TCM) prescriptions, which can effectively explain their underlying concepts. Curcumae rhizoma (Ezhu) and Atractylodis macrocephalae rhizoma (Baizhu) herb-pair (PW) have been frequently used in TCM prescriptions for hundreds of years, which derived from the renowned traditional Chinese medical classic "Yixue Zhongzhong Canxi Lu", primarily to treat liver-related conditions such as hypochondriac pain, abdominal mass, amassment and accumulation that are closely associated with liver diseases including hepatic injury and hepatic fibrosis in modern medicine. As a classic drug pair of invigorating Qi and promoting blood circulation, they align with the TCM syndrome characteristics of chronic hepatic injury with qi deficiency and blood stasis. However, the specific mechanism of the therapeutic effects of PW against chronic hepatic injury remains unclear. AIM OF THE STUDY:The study aimed to assess the enhanced efficacy, underlying targets, and the potential mechanism of PW in treating chronic hepatic injury. MATERIALS AND METHODS:UPLC-MS/MS analysis was performed to identify the active components of PW. Subsequently, the therapeutic efficacy as well as latent action mechanisms of PW upon chronic hepatic injury were examined in vivo study in rats with chronic hepatic injury and in vitro in LX-2 cells. A network pharmacology method was used to prognosticate the mechanisms by which PW treats chronic hepatic injury. Integrated application of pharmacokinetic analysis and metabolomics approaches was employed to identify and characterize critical active ingredients and regulatory signaling pathways. Western blot assays and molecular docking were conducted to reveal the primary mechanisms of action. RESULTS:Totally 1059 metabolites were identified, including 662 detected in positive ion mode and additional 397 detected in negative ion mode. Network pharmacology suggested that the protective effect against chronic hepatic injury of PW may be closely relevant to PI3K/AKT/mTOR signaling pathway. Pharmacodynamics assessment indicated that PW effectively inhibited chronic HI progression in vivo compared with the two herbs alone. PW significantly improved lipid deposition, hepatic function, inflammation and histopathological injury. Additionally, PW significantly decreased the serum AST, ALT and ALP activity levels and effectively reduced the expression level of α-SMA in the liver, significantly inhibited the phosphorylation level of the PI3K/AKT/mTOR pathway. The results of pharmacokinetics and tissue distribution studies showed that PW may increase the concentration of potential bioactive compounds like Curcumol, Curdione, Germacrone, Furanodiene, Atractylenolide III and Atractylon, thereby enhancing the effect of anti-chronic hepatic injury. Combined metabolomics and WB analysis of rat liver tissue revealed that the enhanced anti-chronic hepatic injury effect of PW may be associated with PI3K/AKT/mTOR signaling pathway. Experiments on LX-2 cells indicated that the combination of Curdione and Atractylolide III exerted a hepatoprotective effect by reducing the phosphorylation levels of proteins in the PI3K/AKT/mTOR pathway. CONCLUSION:PW significantly increases the plasma exposure of potential active compounds and the liver distribution level. It emerges as a potential therapeutic strategy for chronic HI, thereby exerting an enhanced anti-chronic hepatic injury effect accompanying fibrotic lesions through the modulation of PI3K/AKT/mTOR signaling pathway.

Atherosclerosis (AS), the fundamental pathological basis of most cardiovascular diseases, is a chronic and progressive inflammatory disorder characterized by lipid deposition and plaque formation within the arterial wall. Despite significant advances in pharmacological and interventional therapies, the global burden of AS remains substantial, emphasizing the need to identify novel molecular regulators and therapeutic targets. Caveolin-1 (Cav-1), a key scaffolding protein of plasma membrane caveolae, has emerged as a context-dependent modulator of lipid handling and vascular homeostasis in AS. Evidence from experimental and clinical studies indicates that Cav-1 participates in endothelial low-density lipoprotein (LDL) transcytosis and barrier function in endothelial cells (ECs), regulates cholesterol efflux and inflammatory signaling in macrophages (MΦs), and influences phenotypic plasticity in vascular smooth muscle cells (VSMCs). These coordinated actions position Cav-1 at the intersection of lipid metabolism and vascular inflammation. Notably, while global Cav-1 deficiency markedly attenuates atherosclerotic lesion formation in animal models, the cell type-specific and stage-dependent mechanisms underlying these effects remain incompletely understood. Cav-1 activity is further modulated by post-translational modifications (PTMs), particularly tyrosine-14 phosphorylation, which can influence its membrane localization, stability, and protein–protein interactions. In addition, emerging evidence suggests dynamic interplay between Cav-1 and autophagy-related pathways, highlighting its role in maintaining lipid and cellular homeostasis under metabolic stress. In this review, we systematically summarize current evidence regarding Cav-1 and caveolae across vascular cell types, delineate existing controversies and knowledge gaps, and evaluate the translational potential of targeting Cav-1–associated lipid regulatory pathways in AS.

Cardiovascular diseases (CVDs) pose a major global health challenge due to their high associated morbidity and mortality. The pathogenesis of CVDs is intricately linked to aberrant histone post-translational modifications (PTMs), such as methylation, acetylation, crotonylation, and lactylation, which are pivotal regulators of chromatin structure and gene expression. These reversible chemical modifications dynamically orchestrate transcriptional programs without altering the DNA sequence. This review comprehensively elucidates the mechanistic roles of histone PTMs in CVD pathophysiology, highlighting their dynamic regulation of disease progression through interactions with key signaling pathways. We further explore the translational potential of targeting PTMs and their modifying enzymes for therapy. Finally, we discuss emerging epigenetic therapeutic strategies and assess their current challenges and future clinical prospects.

Sex-control technologies that alter offspring sex ratios can markedly improve the economic efficiency of dairy production. Recent studies have demonstrated that treatment with the TLR7/8 agonist R848 enables successful in vitro separation of X- and Y-bearing spermatozoa in mice, cattle, and goats. This is because high-quality semen is essential for successful artificial insemination, especially during chilled storage. In this study, X/Y sperm-specific activation and sorting methods were used to isolate sperm from dairy goats, and the effectiveness of sperm isolation was evaluated using TLR7 immunofluorescence staining. Different concentrations of ginsenoside Rc were added to the semen diluent as a natural preservative, and the lower-layer X-bearing sperm recovered from the sorting system were subjected to chilled storage. The effects of ginsenoside Rc on chilled storage performance were then assessed. Among the tested concentrations, 150 μg/mL of ginsenoside Rc exhibited the most potent protective effect, significantly improving the quality, mitochondrial function, antioxidant capacity and the relative protein abundance of SIRT1, PGC-1α, and Nrf1 of the lower-layer X-bearing sperm after chilled storage for 7 days. In summary, supplementation with ginsenoside Rc in the chilled extender improved the quality of lower-layer X-bearing dairy goat spermatozoa during chilled storage by maintaining mitochondrial function, enhancing antioxidant defense, and reducing oxidative damage, facilitating the application of lower-layer X-bearing sperm-selected sperm in production.

As an essential amino acid, tryptophan (Trp) serves as a pivotal mediator in gut-brain axis (GBA) communication through three primary metabolic pathways: kynurenine (Kyn), indole, and serotonin (5-HT), which together regulate neuroimmune and neuroendocrine homeostasis via the vagus and spinal afferent nerves, circulatory system, and hypothalamic-pituitary-adrenal (HPA) axis. This review systematically examines Trp metabolism’s critical roles in GBA, emphasizing molecular pathways, rate-limiting enzymes, and receptor-mediated signaling. We discuss the bidirectional interplay between gut microbiota and host Trp metabolism, encompassing microbial modulation of host enzyme activities such as indoleamine 2,3-dioxygenase and direct production of bioactive indole derivatives like indole-3-propionic acid. Characteristic disruptions in Trp metabolism patterns are identified across GBA-associated disorders including irritable bowel syndrome, inflammatory bowel disease, depression, Alzheimer’s disease, schizophrenia and Parkinson’s disease, marked by aberrant neurotoxic to neuroprotective metabolite ratios and enzymatic dysregulation. The aryl hydrocarbon receptor (AhR) emerges as a molecular hub connecting Trp metabolites to GBA functions, with distinct metabolites eliciting opposing effects through AhR activation. Therapeutic strategies targeting Trp metabolism are critically evaluated, including fecal microbiota transplantation, probiotic supplementation, metabolite administration, and enzyme inhibitors. Future research directions address mechanistic gaps and translational challenges in restoring GBA homeostasis via Trp pathway modulation.

BackgroundAtherosclerosis (AS) is a widespread cardiovascular disorder that constitutes a major contributor to global morbidity and mortality, thereby imposing significant economic burdens on healthcare systems worldwide. Efferocytosis, the phagocytic removal of apoptotic cells, serves as a fundamental mechanism for maintaining tissue homeostasis during normal physiological function and for restoring equilibrium following pathological insults.MethodsThis study systematically investigated the functional roles of efferocytosis across specific cell types using single-cell datasets. By integrating differential expression analysis, weighted gene co-expression network analysis (WGCNA), and machine learning approaches, six key genes were identified. Gene set variation analysis (GSVA) was subsequently performed to elucidate the biological pathways in which these genes are involved. Furthermore, the ssGSEA algorithm was applied to assess the association between these genes and immune cell infiltration levels. To evaluate their diagnostic potential, a nomogram was constructed based on the gene signature. Unsupervised consensus clustering revealed two distinct molecular subtypes of atherosclerosis. Finally, the protein expression levels of core EFRGs in atherosclerosis were analyzed using Western blotting.ResultsSingle-cell data analysis demonstrates that macrophages, vascular smooth muscle cells, and endothelial cells play potential functional roles in efferocytosis. Utilizing bulk RNA sequencing, six core efferocytosis-related genes (STAB1, ANO5, GULP1, LGR6, SCARF1, and CAMK2G) were identified, which exhibit significant diagnostic potential in atherosclerosis. Based on the expression profiles of these six genes, atherosclerosis can be stratified into two distinct molecular subtypes—subtypes A and B—with subtype B being characterized by its association with unstable plaque formation. Western blot analysis confirmed the expression trends of five proteins (ANO5, GULP1, LGR6, SCARF1, and CAMK2G) among the candidates.ConclusionThis study has revealed the potential value of efferocytosis-related biomarkers in the diagnosis of atherosclerosis (AS) and the optimization of treatment strategies, providing new theoretical basis and research perspectives for precise intervention in cardiovascular diseases.

The degree of processing of the Paofupian (PFP) directly determines their clinical safety and effectiveness, but currently, there is a lack of relevant research, and actual production relies solely on subjective judgment based on experience, lacking objective standards and quality control measures. This study employs computer vision and Fourier Transform Near-Infrared (FT-NIR) spectroscopy for rapid, non-destructive, and accurate evaluation of the processing degrees of Paofupian. Machine learning techniques, including Optimizable Tree, Linear Support Vector Machine (Linear SVM), Cosine K-Nearest Neighbors (Cosine KNN), and Partial Least Squares Regression (PLSR), were used to develop models for qualitative identification and quantitative prediction of PFP. Initial results show poor classification accuracy using only RGB or GLCM features. However, fusing these features with the original near-infrared spectra improved accuracy significantly, achieving 77.5% for Optimizable Tree and Linear SVM, and 60.0% for Cosine KNN. Despite this, the models remained below high precision standards. After preprocessing the original spectral data with Multivariate Scatter Correction, classification accuracy surged to 100% for Optimizable Tree and Linear SVM, and to 90.0% for Cosine KNN, demonstrating the efficacy of spectral preprocessing combined with machine learning. Furthermore, characteristic wavelengths were selected using algorithms such as Competitive Adaptive Reweighted Sampling (CARS), leading to a PLSR model for predicting the five alkaloid components in PFP. The five alkaloid models exhibited different levels of predictive performance. The mesaconitine model showed strong predictive performance, with an R2p of 0.93555 and an RPDp of 4.0237. The models for benzoylmesaconitine, benzoylaconine, benzoylhypaconine, and hypaconitine yielded RPDp values between 2.6560 and 2.9208, indicating potential for rapid screening or approximate quantification. Further validation using additional independent batches is required before these models can be applied as alternatives to conventional reference analysis.

Gastrodia elata (G. elata) is recognized as a plant with both medicinal and edible values, and its modern processing is predominantly performed through steaming; therefore, precise control of the steaming procedure is required to ensure consistency and controllability in clinical application. In this study, Hyperspectral (HSI) data of G. elata subjected to different steaming degrees were acquired over the spectral range of 350–2500 nm. Partial least-squares regression (PLSR) was employed as the modeling framework, in combination with multiple spectral preprocessing and feature-wavelength selection methods, to achieve quantitative prediction of the contents of major active ingredients including gastrodin (GAS), p-hydroxybenzyl alcohol (HBA), parishin E (PE), parishin C (PC), and parishin A (PA). The optimal modeling strategies for the six target compounds were GAS-SNV+1d, HBA-SG + ICO, PE-SG + CARS, PB-1d + ICO, PC-SNV+1d + VISSA, and PA-1d + VISSA. The RPD values of all models were greater than 2.5, indicating good predictive ability and stability. In summary, this study has provided a viable methodological approach for rapid and precise quality monitoring and process standardization in traditional Chinese medicine manufacturing.

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease typically managed with broad-spectrum immunosuppressants that carry significant systemic side effects and often provide incomplete efficacy. While gut-microbiota-derived metabolites are known to influence AIH progression, the specific microbial drivers that maintain hepatic immune homeostasis remain poorly defined. Here, we show that Bacteroides acidifaciens (BA) and its metabolite 1-oleoyl-sn-glycero-3-phosphoethanolamine (O-LysoPE) are enriched in self-healing mouse models of hepatitis but markedly depleted in AIH patients. We demonstrate that O-LysoPE induces a 'hepatocyte-driven active immunosuppression' by targeting the Qa-1b (HLA-E): NKG2A immune checkpoint. Mechanistically, O-LysoPE selectively redirects the transcription factor Creb1 to the H2T23 promoter under inflammatory conditions, thereby upregulating hepatocytic Qa-1b expression. This elevation of Qa-1b engages the inhibitory receptor NKG2A on T cells, suppressing their overactivation and restoring a quiescent phenotype. Genetic disruption of H2T23 abrogates the hepatoprotective effects of O-LysoPE, confirming the central role of this metabolic-immune axis. Our findings reveal that the BA-O-LysoPE axis mobilizes the liver's intrinsic self-rescue mechanisms to restore immune quiescence. This study establishes a robust biological framework for liver-specific, targeted immunotherapy in AIH, offering a precision alternative to current systemic immunosuppression.

Mirabilite is a widely used mineral medicine with notable purgative and anti-inflammatory activities. However, medicinal mirabilite (MM) and industrial mirabilite (IM) exhibit highly similar appearances, making conventional identification methods unreliable and potentially compromising clinical safety. In this study, a multi-dimensional parallel characterization approach was established for the rapid discrimination and quality evaluation of mirabilite using electronic sensing technologies and near-infrared (NIR) spectroscopy. Each analytical modality was applied independently to characterize distinct physicochemical attributes of the samples without feature-level or decision-level data fusion. Specifically, an electronic eye (E-eye) was used to evaluate visual characteristics, an electronic nose (E-nose) was employed to characterize volatile odor profiles, and NIR spectroscopy was applied to obtain chemical information associated with crystallization water. The E-eye provided limited discriminative capability, whereas the E-nose effectively captured characteristic odor features of MM. For NIR analysis, spectra preprocessed using Savitzky-Golay smoothing with first derivative (SG + 1D) were modeled using partial least squares discriminant analysis (PLS-DA), support vector machine (SVM), and random forest (RF). Among these models, SVM achieved the best classification performance, with accuracy, precision, recall, and F1-score all reaching 100% in both the training and test sets. Furthermore, an eXtreme Gradient Boosting (XGBoost) regression model accurately predicted crystallization water content (R2 = 0.9848, RPD > 3), and SHAP analysis identified the OH combination band around 1900 nm as the most influential spectral region. The proposed approach provides accurate and interpretable discrimination of MM and IM and offers a reliable analytical tool for quality evaluation and safe clinical application.

Patients with ulcerative colitis (UC) exhibit heightened depression risk, linked to microbiota-gut-brain axis dysfunction. This study isolated a novel low-molecular-weight Schisandra chinensis polysaccharide (SCP) that ameliorated UC and comorbid depression by remodeling gut microbiota, redirecting tryptophan (Trp) metabolism toward the indole pathway, and activating aryl hydrocarbon receptor (AhR). Structurally, SCP features a →4)-α-D-Glcp backbone with O-6 branched chains. In dextran sulfate sodium-induced UC mice, SCP mitigated colonic inflammation, restored intestinal barrier integrity, and improved depression-like behaviors by repairing blood-brain barrier, reducing neuroinflammation, preserving hippocampal neurons, and modulating synaptic plasticity. Multi-omics revealed SCP enriched beneficial microbiota (e.g., Limosilactobacillus reuteri) and rebalanced Trp metabolism along the gut-brain axis. SCP suppressed the hyperactive kynurenine (Kyn) pathway (reduced Kyn/Trp ratio) while elevating indole-3-propionic acid (IPA) levels in colon, serum, and hippocampus. Functioning as a pivotal molecule, IPA exerted dual anti-inflammatory effects in both colon and hippocampus via AhR activation and NF-κB inhibition. Antibiotic depletion and fecal microbiota transplantation validated SCP's microbiota-dependent efficacy, while IPA supplementation recapitulated SCP's benefits. AhR inhibition abolished SCP's therapeutic actions, confirming AhR as the critical target. Collectively, these findings propose a novel therapeutic strategy for UC and associated depression, highlighting SCP's potential value in targeting the Trp metabolism-AhR axis.

A pivotal factor in the immune evasion of hepatocellular carcinoma (HCC) is the excessive exhaustion of CD8+ T cells; however, the molecular drivers of this phenomenon remain incompletely understood. In this study, we discovered that B7-H3 is markedly overexpressed in HCC and actively promotes CD8+ T cell exhaustion. Through high-resolution mass spectrometry and site-directed mutagenesis, we identified asparagine 215 (N215) as a critical N-linked glycosylation site of B7-H3. By employing dual orthogonal strategies-pharmacological inhibition via tunicamycin and targeted genetic ablation (N215Q mutation)-we provided strong evidence that, upon N215 glycosylation, B7-H3 maintains its cell-surface abundance through RAB11-mediated recycling of the endosomal pathway. Conversely, when glycosylation is impeded through either intervention, B7-H3 undergoes accelerated degradation via the endosome-lysosome route, thereby enhancing the cytotoxic activity of CD8+ T cells. Finally, murine experiments confirmed that both the specific genetic disruption of N215 and systemic blockade with tunicamycin enhance the antitumor effects of anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies. Collectively, our data reveal that the "B7-H3 Glycosylation-RAB11 Axis" preserves membrane expression of B7-H3, constituting an intrinsic mechanism of immune evasion in HCC, and uncover the intricate crosstalk between B7-H3 glycosylation and the immunosuppressive tumor microenvironment.

Aging is closely associated with epigenetic alterations, including changes in DNA methylation, acetylation, and shifts in histone modification patterns, which drive cellular decline and increase susceptibility to diseases. This review examines the connection between aging-related diseases and epigenetic mechanisms and explores how dietary interventions can influence this process. We discuss the Mediterranean diet (MD), caloric restriction (CR), and the ketogenic diet (KD) as key nutritional strategies. These interventions supply essential substrates and regulate enzymes central to epigenetic remodeling, thereby affecting gene expression networks involved in inflammation, metabolism, and cellular stress responses. By correcting age related epigenetic dysregulation, such dietary patterns can slow attenuate cellular senescence and reduce the risk of chronic diseases. Current evidence supports the association between diet quality and decelerated epigenetic aging. Future research is needed to establish causality and to develop personalized nutritional approaches for promoting longevity and healthspan.

Metabolic stress induced by a high-fat diet (HFD) is one of the key factors leading to ovarian dysfunction. In this study, a multi-omics approach was employed to investigate the protective effects of resveratrol (RSV) against HFD-induced ovarian dysfunction in rats. The results indicate that RSV not only significantly mitigated systemic metabolic imbalances, such as weight gain and dyslipidemia, but also restored ovarian homeostasis, as evidenced by normalized estrous cycles, improved ovarian morphology, and balanced hormone levels. Mechanistically, RSV normalized altered ovarian energy metabolism by enhancing the tricarboxylic acid (TCA) cycle and oxidative phosphorylation while inhibiting glycolysis, thereby increasing ATP production. Transcriptomic analysis further revealed significant upregulation of key pathways, including the PPAR signaling pathway and steroidogenesis, and identified Apob and Lpl as potential core regulatory genes. Notably, RSV intervention modulated the gut microbiota, increasing microbial diversity and enriching beneficial bacterial genera, suggesting a restorative effect on the gut-ovary axis. In summary, our findings demonstrate that RSV alleviates HFD-induced ovarian dysfunction partially alleviates through a multilevel network involving systemic metabolism, ovarian energy metabolism, and gut microbiota regulation. This demonstrates its potential as a functional food ingredient for protecting female reproductive health.

Uridine diphosphate glucuronosyltransferases (UGTs) are critical phase II detoxification enzymes; however, their mutational landscape and protective roles against chemical carcinogenesis in hepatocellular carcinoma (HCC) remain poorly defined. Here, targeted sequencing of ten liver-enriched UGT genes in 38 paired tissues from a Chinese HCC cohort revealed striking mutation frequencies in UGT2B15 (44.74%), UGT2B10 (36.84%), and UGT2B17 (26.32%). This genomic instability was accompanied by a profound downregulation of UGT2B15 mRNA (9.02-fold decrease, p < 0.001) and protein levels (Z-score = 2.32, p = 0.0093) in tumors, with higher UGT2B15 expression correlating with improved overall survival in TCGA cohorts (HR = 1.724, p = 0.012). Mechanistically, we identified the androgen receptor (AR) as a direct transcriptional regulator of UGT2B15 and UGT2B17, with dihydrotestosterone (DHT) inducing dose-dependent increases in their expression, thereby linking endocrine signaling to hepatic detoxification. Transcriptomic profiling following UGT2B15 knockdown in HCC cells revealed a significant enrichment in chemical carcinogenesis-related pathways. Crucially, UGT2B15 deficiency severely exacerbated carbon tetrachloride (CCl4)- and ethanol-induced hepatotoxicity both in vitro and in vivo. Our study uncovers a profound impairment of UGT-mediated detoxification in HCC and establishes the AR-UGT2B15 axis as a critical barrier against chemical-induced liver injury, highlighting its potential as a chemopreventive target in carcinogen-exposed populations.

Objectives Polypharmacy and anticholinergic burden (AB) are highly prevalent among older adults and have been linked to adverse health outcomes. However, their associations with systemic inflammation remain insufficiently characterized. Design Population-based cross-sectional study. Setting and Participants Data were obtained from the US National Health and Nutrition Examination Survey (1999-2020). A total of 11,647 adults aged 65 years or older who reported prescription medication use were included. Methods Polypharmacy was defined by prescription medication count, and AB was evaluated using multiple established AB scales. Systemic inflammation was evaluated using C-reactive protein (CRP), high-sensitivity CRP, fibrinogen, and 6 composite indices derived from blood cell counts. Correlation matrices and weighted multivariable linear regression models were used to examine associations. Results After full adjustment, hyperpolypharmacy was associated with approximately 40% higher CRP levels (P < .001), whereas polypharmacy alone was not independently associated with CRP (P = .113). Higher AB assessed using the Anticholinergic Cognitive Burden Scale, Anticholinergic Drug Scale, and Anticholinergic Risk Scale, as well as anticholinergic medication use, was associated with approximately 16% to 44% higher CRP levels (all P < .050). Associations with high-sensitivity CRP were observed primarily for the Anticholinergic Cognitive Burden Scale (P = .004), whereas associations with fibrinogen were most evident for the Anticholinergic Drug Scale (P = .030). Joint-effect analyses further showed that polypharmacy without AB was not associated with CRP, whereas the co-occurrence of polypharmacy and AB was associated with the highest CRP levels. Conclusions and Implications Among US older adults, AB was consistently associated with elevated systemic inflammation, particularly in the context of polypharmacy. These findings underscore the importance of considering anticholinergic properties in geriatric pharmacotherapy.