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Major depressive disorder (MDD) is associated with various biochemical changes that contribute to chronic inflammation and the buildup of reactive oxygen species (ROS) in the body. One of the key alterations observed in MDD is the depletion of glutathione (GSH). This decrease in GSH results from impaired cysteine uptake, reduced glutathione peroxidase (GPx) activity, and mitochondrial dysfunction. In the human body, GSH is a vital intracellular antioxidant responsible for metabolizing ROS and modulating immune responses. This paper summarizes current literature on how GSH depletion associated with MDD disrupts key immunoregulatory functions, specifically as it applies to the immune response to Mycobacterium tuberculosis (M. tb). Research has shown that this disruption leads to increased oxidative stress and a weakened host immune response. Effective control of M. tb depends on balanced ROS activity and GSH-dependent macrophage function. Reduced GSH compromises these processes by limiting the ability of immune cells to function normally. Therefore, individuals with MDD-associated GSH depletion are at risk of developing severe tuberculosis (TB). Understanding this connection has important clinical and public health implications, particularly in regions where TB is endemic and depression is underdiagnosed. Integrating mental health assessment and considering antioxidant supportive strategies may improve TB management, especially in high-burden settings. Emerging evidence suggests that increasing levels of GSH through adjunct treatment with N-acetylcysteine or liposomal GSH may improve both depressive symptoms and the antimicrobial immune response. Despite this supporting research, further exploration is needed to clarify their therapeutic potential in individuals with comorbid MDD and TB.
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Since ferroptosis was first described in 2012, it has attracted considerable attention in the medical community as an emerging mode of cell death driven by iron-dependent lipid peroxidation, distinct from apoptosis, necrosis, and autophagy. This unique cell death mode is regulated by multiple pathways, including the classical System Xc–glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1)-CoQ10 systems, as well as lipid metabolism, mitochondrial metabolism, cholesterol metabolism, sex hormone metabolism, and other auxiliary pathways. Notably, the cholesterol biosynthesis pathway exhibits bidirectional regulation—7-dehydrocholesterol (7-DHC) acts as a “sacrificial antioxidant” to inhibit ferroptosis, whereas elevated cholesterol levels promote it. Sex hormones regulate MBOAT1/2 to remodel membrane phospholipids and reduce ferroptosis susceptibility. Key signaling pathways, such as P53/SLC7A11, Nrf2-Keap1, and Hippo-YAP/TAZ, further fine-tune ferroptosis through iron homeostasis and redox balance regulation. Crosstalk exists between ferroptosis and other cell death modalities: copper chelators sensitize cells to ferroptosis, while lipid peroxidation products activate pyroptosis via the NLRP3 inflammasome. Novel inhibitors, including JKE-1674 (FSP1-targeted) and SRS11-92 (lipid radical scavenger), show improved pharmacokinetics and tissue specificity, while nanoparticle-based delivery systems enhance targeting efficacy. Multiple cancer cells are highly susceptible to ferroptosis, and ferroptosis is implicated in neurodegenerative diseases, ischemia-reperfusion injury, and metabolic disorders. This review systematically summarizes the molecular mechanisms, regulatory networks, novel modulators, and clinical translation progress of ferroptosis, highlighting its potential as a therapeutic target for various diseases and providing insights for future research and clinical application.
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During the interaction between a virus and its host, a complex interplay arises between the host's defence mechanisms and the viral survival strategies. This interaction impacts not only viral replication and the viral lifecycle but also affects the host's homeostasis, including cellular genetics and immune responses. The outcomes of host-virus interactions can vary widely, ranging from successful pathogen clearance to severe disease or even death, influenced by factors such as host genetics, age, comorbidities, and environmental conditions. Viruses adeptly manipulate cellular machinery and metabolism, reprogram signalling pathways, and undermine immune responses to enhance their survival. A key strategy employed by viruses is immune evasion, utilising various techniques to bypass the host's immunovigilance. These strategies not only encourage persistent infections but also raise concerns about oncogenic potential, particularly in hematologic malignancies like acute lymphoblastic leukaemia (ALL). Such mechanisms may play a pivotal role in the alterations induced by viral contributions that disrupt immune surveillance and foster malignancy. This review seeks to elucidate the potential role of human cytomegalovirus (HCMV) as a risk factor and etiological contributor to the development of ALL in children. Although HCMV has not been officially recognized as an oncogenic virus, emerging evidence suggests that early-life infection may predispose to malignant transformation by promoting oncogenic pathways and immune dysregulation.
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Sleep deprivation (SD) has been recognized as a pivotal factor exacerbating the risk of psychiatric disorders; however, the neurobiological mechanisms underlying SD-induced alterations in brain network structure cannot be fully explained by monoaminergic neurotransmitter imbalances alone. This review systematically elucidates the “sleep-microglia-synaptic remodeling” axis as a core pathological mechanism, proposing that SD disrupts central nervous system homeostasis and induces a phenotypic transition of microglia from physiological synaptic sentinels to pathological agents of excessive phagocytosis. At the molecular level, SD promotes the “over-pruning” of functional synapses by aberrantly reactivating developmental signaling pathways in the adult brain—specifically the complement component 3–complement receptor 3 (C3–CR3), adenosine triphosphate–P2Y12 receptor signaling (ATP–P2Y12), and astrocyte-microglia crosstalk. This process results in a reduced synaptic density and impaired structural plasticity. Such neuroimmune-mediated synaptic pathology constitutes a shared anatomical substrate for the cognitive and emotional deficits observed in major psychiatric conditions, including major depressive disorder, schizophrenia, and anxiety disorders. In summary, dissecting this mechanism not only offers a novel perspective on the comorbidity of sleep disturbances and psychiatric disorders but also highlights that targeting the blockade of pathological microglial phagocytic pathways serves as a promising therapeutic strategy for restoring synaptic homeostasis and treating psychiatric diseases.
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Pediatric obstructive sleep apnea (OSA) is a multifactorial condition with serious neurocognitive, cardiovascular, and metabolic consequences. While adenotonsillectomy (AT) remains the first-line therapy for many cases, complex presentations involving obesity, craniofacial anomalies, or neuromuscular disorders require coordinated multidisciplinary management. This review provides a comprehensive synthesis of current strategies across diagnosis, treatment, and long-term follow-up. Diagnostic approaches include clinical screening with a combination of physical examination, polysomnography, imaging, and drug-induced sleep endoscopy. Treatment options range from surgical interventions to positive airway pressure therapy, pharmacologic treatments, dental and orthodontic approaches, behavioral modification, and psychological therapy. Special considerations are given to high-risk populations such as children with Down syndrome, Prader-Willi syndrome, neuromuscular disease, and extreme obesity. The emphasis is on residual or refractory OSA and the importance of individualized treatment pathways, shared decision-making, and multidisciplinary clinics. Longitudinal care—neurocognitive monitoring, cardiometabolic surveillance, and digital health tool use—is critical for optimizing long-term outcomes. By synthesizing evidence across specialties, this review provides practical guidance for comprehensive, patient-centered care in pediatric OSA.
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Background: Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system, characterized by inflammation, demyelination, and neurodegeneration. Experimental autoimmune encephalomyelitis (EAE) is a well-established preclinical model for examining MS pathophysiology. Peptide inhibitor of transendothelial migration (PEPITEM) is an immunomodulatory peptide; however, its effects on gene expression in EAE remain insufficiently characterized. In this study, we aimed to evaluate the immunomodulatory effects of PEPITEM in EAE by comparing therapeutic (postinduction) and prophylactic (preinduction) administration using RT2 Profiler™ PCR Array–based gene expression analysis.
Methods: Ten female C57BL/6 mice aged 9–13 weeks (body weight, 21 ± 3 g) were induced with EAE and assigned to four experimental groups: G1 (EAE + scramble peptide), G2 (EAE + PEPITEM), G3 (EAE + scramble peptide administered preinduction), and G4 (EAE + PEPITEM administered preinduction). Gene expression was assessed using RT2 Profiler™ PCR Arrays, with fold regulation calculated for each gene.
Results: PEPITEM exerted distinct, time-dependent effects on immune gene expression. Therapeutic administration (G2 vs. G1) resulted in broad upregulation of immune-related genes, with notable increases in motif chemokine ligand 11 (Cxcl11) (30.14-fold), Cd28 (3.83-fold), and Cd40 (3.81-fold), consistent with enhanced expression of genes associated with T-cell costimulation, cytokine signaling, and chemokine signaling. Conversely, prophylactic administration (G4 vs. G3) produced marked suppression of inflammatory gene expression, with 33 of 34 genes downregulated. The most strongly suppressed genes were motif chemokine ligand 10 (Cxcl10) (–17.11-fold), interferon-gamma (Ifng) (–13.12-fold), and tumor necrosis factor-alpha (Tnf) (–12.43-fold), indicating reduced expression of genes involved in chemokine signaling and T-cell migration.
Conclusion: PEPITEM modulates immune-related gene expression in EAE in a timing-dependent manner. Its opposing effects—gene expression activation postinduction and suppression preinduction—suggest context-specific immunomodulatory properties that may be relevant to therapeutic strategies for MS.
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Background: Although cervical lymphatic metastasis (LM) of thyroid carcinoma (TC) occurs most frequently in children, adolescents, and young adults (CAYA), this population exhibits the most favorable prognosis. This study aimed to clarify the characteristics of LM in CAYA TC patients from immunobiological and epidemiological perspectives.
Methods: The collected preoperative clinical data included serum levels of inflammatory and immunobiological markers. The two-tailed t-test or the Mann–Whitney U test was used to compare variables. To control the false discovery rate (FDR), the Benjamini-Hochberg procedure was applied. Categorical variables were analyzed with the chi-squared test. Correlations between continuous variables were identified by Spearman analysis. Receiver operating characteristic (ROC) curve analysis and binary logistic regression were performed to evaluate the association of these factors with LM. Bootstrap resampling (1000 replicates) was used to correct for optimism and assess model stability.
Results: This study was ultimately limited to 487 CAYA participants, including 317 (65.1%) with cervical LM. The LM rate was higher in CAYA males (71.9%) than in CAYA females (62.4%) (p = 0.045). Patients with LM exhibited elevated levels of monocyte ratio (MOR) (q = 0.038), thyroglobulin (Tg) (q = 0.008), and tumor necrosis factor-alpha (TNF-α) (q = 0.04) (q-values representing FDR-adjusted p-values). Young age (OR = 0.79, 95% CI: 0.70–0.91, p = 0.001) and larger tumor size (OR = 1.43, 95% CI: 1.05–1.96, p = 0.02) were independent risk factors for LM. The ROC curve revealed that age (area under the curve (AUC) = 0.63, 95% CI: 0.56–0.70), tumor size (AUC = 0.66, 95% CI: 0.59–0.74), Tg (AUC = 0.58, 95% CI: 0.51–0.66), and TNF-α (AUC = 0.61, 95% CI: 0.53–0.68) were predictive of LM. The combination of four indicators (age, tumor size, Tg, and TNF-α) enhanced predictive performance, achieving an AUC of 0.70 (95% CI: 0.63–0.76). In the N1 subgroup, significant sex differences were observed in markers, including Tg, interleukin (IL)-6, IL-4, MOR, natural killer cells, lymphocyte ratio, antithyroglobulin antibody, neutrophil ratio, platelet and Th/Ts (all q < 0.05).
Conclusion: This study identified younger age and larger tumor size as independent risk factors for LM in CAYA TC patients, and preoperative immune-inflammatory markers were associated with LM. Additionally, patients with LM displayed distinct sex-specific immune-inflammatory features.
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Background: N-Butylphthalide (NBP) can effectively improve cerebral vascular microcirculation and cellular energy metabolism in patients with ischemic stroke. This study aims to explore the underlying mechanism by which NBP exerts protective effects in ischemic stroke.
Methods: After exposure of primary neuronal cells to different concentrations of NBP (0, 0.1, 1, 10 μM), the optimal concentration for promoting cell survival was determined using a cell counting kit 8 (CCK8) assay. The primary neuronal cell damage model was established with oxygen-glucose deprivation/re-oxygenation (OGD/R), after which treatment with NBP alone or in combination with glycogen synthase kinase 3 beta (GSK-3β) inhibitors was performed. Cell viability and levels of oxidative stress (lactate dehydrogenase (LDH) and reactive oxygen species (ROS)) were detected. The changes of 4-Hydroxynonenal (4-HNE) and malondialdehyde (MDA) were examined by enzyme-linked immunosorbent assay (ELISA). Fe2+ levels, proteins associated with ferroptosis, and the GSK-3β/nuclear factor erythroid 2-related factor 2 (NRF2) signaling were tested.
Results: Both 1 μM and 10 μM NBP effectively alleviated OGD/R-induced cell damage. NBP increased cell viability, inhibited oxidative stress, and down-regulated LDH, ROS, 4-HNE and MDA levels. The cellular Fe2+ content was also significantly decreased after NBP treatment. NBP up-regulated ferroptosis-related proteins (glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11)) and activated the GSK-3β/NRF2 signaling. GSK-3β/NRF2 inhibitors reversed the effects of NBP on OGD/R-induced cells.
Conclusion: NBP effectively ameliorates neuronal ferroptosis in ischemic stroke by activating the GSK-3β/NRF2 signaling pathway, which provides a promising therapeutic strategy and a novel mechanistic basis for clinical management of stroke.
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Background: Methotrexate (MTX) is the main rheumatoid arthritis (RA) therapy. However, the molecular pathways directly modulated by MTX and transcriptomic features that distinguish clinical responders from non-responders remain unclear. This study aimed to define MTX‑associated transcriptional programs and baseline synovial gene expression pathways associated with a clinical response to MTX-treated RA through cross‑tissue transcriptomic integration.
Methods: Peripheral blood gene expression profiles collected before and after MTX treatment were obtained from the Gene Expression Omnibus (GSE35455) database. Differential gene expression analysis was used to identify upregulated and downregulated genes, and functional enrichment analyses were conducted for each gene set. Clinical response–associated transcriptional signatures were independently evaluated on a dataset of baseline synovial tissue from MTX‑treated patients with RA (GSE45867). Gene set enrichment analysis was used to identify pathways associated with the MTX response.
Results: In the GSE35455 dataset, MTX treatment was associated with significant differential expression of 730 genes, which were predominantly downregulated. MTX-downregulated genes showed limited enrichment in classical Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways but demonstrated significant suppression of inflammatory signaling modules, including TNF-α signaling via NF-κB. In contrast, MTX-upregulated genes were enriched for metabolic stress responses, including Hypoxia and Glycolysis pathways, and innate immune response modules. Disease and phenotype enrichment analyses of the upregulated genes highlighted immune-related disease annotations and lymphoid tissue abnormalities. In synovial tissue (GSE45867), MTX responders exhibited strong baseline enrichment of interferon-stimulated gene programs, cytokine-regulated JAK-STAT signaling pathways, and immune activation signatures.
Conclusions: MTX induces broad immunomodulatory transcriptional effects characterized by the suppression of inflammatory signaling networks, and baseline activation of interferon- and cytokine-responsive programs in the synovial tissue. This cross-tissue integration provides mechanistic insights into MTX response heterogeneity in RA.
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Background: Colorectal cancer (CRC) is a leading cause of cancer-related mortality, and the occurrence of lymph node metastasis (LNM) and postoperative gastrointestinal dysfunction (POGD) significantly dictates long-term survival and quality of life. Accurate preoperative risk assessment is crucial for optimizing surgical planning and perioperative management. This study aimed to evaluate the predictive value of preoperative inflammation-nutrition indicators for LNM and POGD in CRC, and to construct nomogram prediction models.
Methods: A retrospective analysis was conducted on the data from 200 CRC patients who underwent radical surgery. Multiple preoperative inflammation-nutrition indicators were collected. Logistic regression was used to screen for independent predictors of LNM and POGD, and nomogram models were constructed accordingly. Multicollinearity was assessed using variance inflation factors (VIFs), and the linearity-in-the-logit assumption for continuous predictors was evaluated using the Box-Tidwell test. Discrimination was evaluated using receiver operating characteristic (ROC) curves and the area under the curve (AUC). Model calibration, internal validation via Bootstrap resampling (1000 iterations), and clinical net benefit were assessed using calibration curves and decision curve analysis (DCA).
Results: The incidence rates of LNM and POGD were 39.0% and 32.0%, respectively. The independent predictors for LNM were neutrophil percentage-to-albumin ratio (NPAR) (per 1-unit increase; OR = 1.24, 95% CI 1.08–1.42), cT3–4 stage (OR = 3.20, 95% CI 1.62–6.33), history of smoking (OR = 3.11, 95% CI 1.50–6.46), and fibrinogen-to-albumin ratio (FAR) (per 1-unit increase; OR = 1.22, 95% CI 1.03–1.45). The independent predictors for POGD were NPAR (per 1-unit increase; OR = 1.21, 95% CI 1.08–1.35), open surgery (OR = 2.60, 95% CI 1.14–5.93), advanced age (per 1-year increase; OR = 1.09, 95% CI 1.04–1.13), and prolonged operative time (per 1-min increase; OR = 1.04, 95% CI 1.02–1.06). The AUC of the LNM predictive model was 0.80 (95% CI 0.74–0.87), and the adjusted AUC after internal validation using Bootstrap was 0.78 (95% CI 0.69–0.87); The AUC of the POGD prediction model was 0.80 (95% CI 0.73–0.87), and the adjusted AUC was 0.77 (95% CI 0.66–0.87). DCA indicated that it has a certain clinical net benefit.
Conclusion: The NPAR-based nomogram model shows promising predictive performance, and preoperative NPAR may serve as a key indicator for predicting LNM and POGD in CRC patients.
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Background: Atopic dermatitis (AD), a persistent inflammatory condition of the skin, presents features of pruritus, skin barrier dysfunction, and immune dysregulation, affecting millions globally with increasing prevalence. Acetate (Ace), a short-chain fatty acid with immunomodulatory and barrier-protective properties, has been reported to enhance skin barrier integrity in AD, but its precise molecular mechanisms remain unclear. This study aims to investigate the therapeutic potential of Ace and its underlying mechanism in an AD mouse model.
Methods: An AD mouse model was established via repeated topical application of 2,4-dinitrochlorobenzene (DNCB) and treated with Ace sodium. Macroscopic situation, AD severity, and dorsal tissue pathology were evaluated. Skin mRNA expression levels of inflammatory factors, histone deacetylase 2 (HDAC2), and signal transducer and activator of transcription 1 (STAT1), as well as HDAC2-STAT1 promoter correlation, were examined using chromatin immunoprecipitation. CD4+ T cells from healthy mouse splenocytes were transfected with HDAC2/STAT1 overexpression plasmids, and treated under Th17-inducing conditions with Ace. Th17/regulatory T (Treg) in splenocytes was assessed by flow cytometry.
Results: Ace mitigated DNCB-induced dryness, erosion of dorsal skin, and ear redness. Furthermore, Ace downregulated the expression levels of pro-inflammatory factors and HDAC2 in the dorsal skin tissue, reduced the proportion of Th17 cells in the splenocytes, and promoted the expression of STAT1. Chromatin immunoprecipitation confirmed the binding of HDAC2 to the STAT1 promoter. Ace also suppressed the Th17 differentiation of CD4+ T cells, which was counteracted by HDAC2 overexpression, while STAT1 overexpression offset the regulatory effect of HDAC2 overexpression.
Conclusions: Ace mitigates DNCB-induced AD by inhibiting HDAC2 to activate STAT1 and block Th17 differentiation, uncovering a novel HDAC2-STAT1-Th17 regulatory axis and providing a promising metabolite-based therapeutic strategy for AD.
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Background: Ovarian cancer (OV) is a heterogeneous gynecologic malignancy with limited and patient-specific responses to immunotherapy. This study aimed to develop and validate a CD40LG-centered 6-gene signature based on immune-modulatory genes (IMGs) for prognostic stratification and prediction of immunotherapy response in OV patients.
Methods: Transcriptomic data and corresponding clinical annotations for normal and malignant ovarian tissues were retrieved from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) database, respectively. The IMG-based prognostic signature (IMPS) was generated by identifying and integrating differentially expressed IMGs using univariate Cox regression and least absolute shrinkage and selection operator (LASSO)-Cox analysis. Tumor microenvironment (TME) characteristics, survival outcomes, and immunotherapy responses were analyzed with CIBERSORT, ESTIMATE, and Tumor Immune Dysfunction and Exclusion (TIDE) algorithms, and major IMGs were verified by quantitative real-time PCR (qRT-PCR).
Results: The IMPS, including CD40LG, HMGB3, IL27RA, TNFRSF8, BTLA, and HLA-DOB, exhibited significant prognostic ability. Kaplan-Meier curves demonstrated a survival advantage in the low-risk group (p < 0.0001), which was successfully cross-validated using the International Cancer Genome Consortium (ICGC) dataset. The low-risk group exhibited an anti-tumor immune phenotype (increased M1 macrophage infiltration, enriched antigen-processing pathways, activated T-cell signaling), whereas the high-risk group had higher immune-evasion potential (TIDE: r = 0.206, p < 0.0001). Analysis of the IMvigor210 trial indicated that individuals within the low-risk category exhibited a more favorable response to PD-1/PD-L1 blockade therapy. CD40LG expression was downregulated in OV tissues and associated with sensitivity to immunotherapy.
Conclusions: The CD40LG-centered 6-gene IMPS enables precise stratification of OV patients according to clinical outcomes and immunotherapy responsiveness, serving as a promising tool for guiding personalized immunotherapy strategies.
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Background: Specific biomarkers for the diagnosis, treatment, and prognostication of thyroid cancer (THCA), the most common tumor in the endocrine system, are still lacking. CYP26A1 is overexpressed in some cancers and exerts pro-tumor effects. However, its role in THCA development has not been established. Therefore, this study aims to comprehensively investigate the potential role of CYP26A1 in THCA tumorigenesis and immune infiltration, as well as its clinical prognostic value.
Methods: Data from 510 THCA patients with complete progression-free interval (PFI) and tumor staging information were obtained from the Cancer Genome Atlas. Differentially expressed genes associated with high/low CYP26A1 expression were identified and evaluated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, gene set enrichment analysis (GSEA), protein–protein interaction network construction, and miRNA-mRNA interaction network construction. Single-sample GSEA (ssGSEA) was performed to evaluate correlations between CYP26A1 expression and immune cell infiltration. Associations between clinical pathological characteristics and the expression of CYP26A1 were analyzed. Finally, the correlations between CYP26A1 and the hub gene expression were evaluated, along with their relationships with sensitivity to chemotherapeutic drugs and small-molecule compounds.
Results: CYP26A1 expression was higher in THCA than in paired para-cancerous tissues (p < 0.001). Genes associated with high CYP26A1 expression in THCA were enriched in pathways related to the endoplasmic reticulum lumen, P53 signaling, cytokine receptor binding, and apoptosis signaling. CYP26A1 expression was positively correlated with the abundance of various immune cells (T cells, B cells, CD8 T cells, cytotoxic cells, neutrophils, and Th1 cells). High CYP26A1 expression was related to the PFI, T stage, cervical lymph node metastasis, and extra-glandular invasion (p < 0.05).
Conclusion: High CYP26A1 expression is associated with THCA development and has prognostic value, suggesting its potential as a therapeutic target.
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Background: Endothelial dysfunction is a pivotal contributor to coronary heart disease (CHD). The study aimed to elucidate the involvement of YT521-B homology domain 1 (YTHDF1) in mediating endothelial dysfunction triggered by oxidized low-density lipoprotein (ox-LDL) in human coronary artery endothelial cells (HCAECs).
Methods: Cell viability was evaluated using the Cell Counting Kit-8 (CCK-8) assay, while apoptotic status was determined by flow cytometric analysis. Cell migratory capacity was examined through a Transwell assay. The concentrations of pro-inflammatory cytokines (Tumor necrosis factor (TNF)-α, Interleukin (IL)-1β, and IL-18) together with the adhesion molecule VCAM-1 were measured using Enzyme-linked immunosorbent assay (ELISA). Intracellular Reactive oxygen species (ROS) production was assessed via DCFH-DA fluorescent staining. The N6-methyladenosine (m6A) modification level of BTB and CNC homology 1 (BACH1) was analyzed using Methylated RNA binding protein immunoprecipitation (MeRIP), and molecular interactions were further explored using RNA binding protein immunoprecipitation (RIP) assay.
Results: YTHDF1 expression was significantly increased in peripheral blood mononuclear cells (PBMCs) from CHD patients compared with healthy controls and in ox-LDL-treated HCAECs compared with untreated cells (p < 0.05). YTHDF1 silencing significantly attenuated ox-LDL-induced endothelial injury, as evidenced by increased cell viability and migration and decreased apoptosis, inflammatory cytokine secretion, and ROS production (all p < 0.05). Mechanistically, YTHDF1 promoted BACH1 mRNA translation in HCAECs in an m6A-dependent manner (p < 0.05). Furthermore, BACH1 overexpression significantly reversed the protective effects of YTHDF1 knockdown on HCAEC survival and migration and restored ox-LDL-induced oxidative stress and inflammatory responses (p < 0.05).
Conclusion: YTHDF1 promoted ox-LDL-induced HCAEC dysregulation by enhancing BACH1 mRNA translation in an m6A-dependent manner.
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Background: Serine/arginine-rich splicing factor 1 (SRSF1) is a critical RNA splicing regulator implicated in various cancer types. However, its cell-type-specific expression patterns and functions within the tumor microenvironment remain poorly understood, particularly its interaction with immune cell populations. This study aimed to investigate SRSF1 expression patterns across different cell types in the endometrial carcinoma microenvironment using single-cell RNA sequencing and explore its potential association with macrophage efferocytosis.
Methods: We analyzed single-cell RNA sequencing data from five endometrial carcinoma samples (GSE173682, n = 33,178 cells) to characterize SRSF1 expression patterns. Efferocytosis activity was assessed using gene signature scoring with the AUCell algorithm. Cell-cell communication networks were analyzed using CellChat to identify interaction patterns. SRSF1 expression was validated in bulk tissue datasets from The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC). Functional validation studies were performed in the Ishikawa endometrial cancer cell line using lentiviral-mediated SRSF1 knockdown.
Results: Single-cell analysis revealed significantly elevated SRSF1 expression in tumor-associated macrophages compared to other cell types (p < 0.05), with moderate expression also detected in tumor epithelial cells. Spatial analysis demonstrated a strong overlap between regions of high SRSF1 expression and areas exhibiting elevated efferocytosis activity. Functional enrichment analysis showed that efferocytosis-related genes participate in immune responses, extracellular activities, and antigen processing pathways. Pseudotime trajectory analysis identified seven functionally distinct macrophage subpopulations, including pro-inflammatory (M1-like) and immunosuppressive (M2-like) phenotypes, with varying SRSF1 expression levels. Cell-cell communication analysis revealed extensive interactions between macrophages and other cell types through specific ligand-receptor pairs, including SPP1-CD44. Bulk tissue analysis confirmed SRSF1 upregulation in endometrial carcinoma at both mRNA (TCGA, p < 0.05) and protein (CPTAC, p < 0.05) levels. In vitro functional validation in the Ishikawa cell line demonstrated that SRSF1 knockdown significantly inhibited cell proliferation (30–40% reduction at 96 hours), migration, invasion, and modulated epithelial-mesenchymal transition markers.
Conclusion: This study reveals cell-type-specific SRSF1 expression patterns in the endometrial carcinoma microenvironment and demonstrates strong associations between SRSF1 and macrophage efferocytosis activity. Correlation analysis showed significant associations between SRSF1 and key efferocytosis receptors (Mer tyrosine kinase (MERTK)), growth arrest-specific protein 6 (GAS6), providing molecular evidence for SRSF1's involvement in macrophage function.
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Background: Endothelial progenitor cells (EPCs) can alleviate atherosclerosis (AS) through their roles in endothelial repair and angiogenesis, but their function is often impaired under pathological conditions. Notoginsenoside R1 (NGR1), an extract from traditional Chinese medicine, has demonstrated therapeutic efficacy in alleviating AS. This study aims to investigate whether NGR1 ameliorates AS progression by restoring EPCs' dysfunction.
Methods: Apolipoprotein E-deficient (ApoE-/-) mice were treated with angiotensin II for 4 weeks to establish an AS model, and treated with long-term infusion of NGR1 using an Alzet osmotic micropump. Metabolic characteristics and pathological changes in aortic tissues were measured using kits, Hematoxylin and Eosin (H&E) staining, Masson staining and Oil red O staining. EPCs extracted from mice were verified by immunofluorescence staining and then were treated with NGR1, Signal transducer and activator of transcription 3 (STAT3) overexpression plasmid (oe-STAT3) and / or Heparanase short hairpin RNA (shHPSE). The biological behaviors of EPCs were determined using cell counting kit 8, colony formation, scratch assay and tube formation assay. The relationship between STAT3 and HPSE was determined by Dual-luciferase reporter assay and Chromatin immunoprecipitation. The expression levels of STAT3, HPSE and syndecan-1 (SDC-1) were analyzed using Western blot and quantitative reverse transcription polymerase chain reaction (qRT-PCR) analyses.
Results: In vivo, NGR1 ameliorated disturbances of lipid metabolism and reduced aortic plaque formation in AS mice. In vitro, NGR1 facilitated the viability, proliferation, migration and tube formation of EPCs, while downregulating the expression levels of STAT3 and Heparanase and upregulating the SDC-1 expression level. However, these effects were reversed by oe-STAT3. STAT3 activated HPSE transcription, and the effects of oe-STAT3 on EPCs were reversed by shHPSE.
Conclusion: NGR1 restores EPCs' function by regulating the STAT3/HPSE axis, thereby alleviating the development of AS.
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Background: Outcomes of transarterial chemoembolization (TACE) combined with programmed cell death-1 (PD-1) inhibitors for unresectable hepatocellular carcinoma (HCC) remain heterogeneous. This study evaluated the prognostic value of the dynamic Systemic Immune-Inflammation Index (Delta SII) and Albumin-Bilirubin (ALBI) grade to construct a predictive nomogram.
Methods: We retrospectively analyzed 168 patients with unresectable HCC treated with TACE plus PD-1 inhibitors. Delta SII was defined as the relative change from baseline to the first follow-up. Independent prognostic factors for Overall Survival (OS) were identified via Cox regression to build a nomogram. Delta SII was categorized into High and Low groups using an optimal cut-off of 32.7%, determined by maximally selected rank statistics. Post-treatment SII (SII_T1) was measured within a prespecified window of 28–42 days post-treatment. The nomogram was internally validated using 500-bootstrap resampling, and performance was assessed by time-dependent Area Under the Curve (AUC) with 95% confidence intervals, calibration plots, and Decision Curve Analysis (DCA). All patients received toripalimab (240 mg every 3 weeks) as the PD-1 inhibitor.
Results: Patients with a High Delta-SII or ALBI Grade 2/3 exhibited significantly inferior OS and Progression-Free Survival (PFS) (p < 0.001). Multivariate analysis identified Tumor Size (Hazard Ratio (HR): 1.10, 95% CI: 1.04–1.16), Tumor Number (HR: 1.34, 95% CI: 1.10–1.63), macrovascular invasion (MVI) (HR: 1.64, 95% CI: 1.08–2.48), ALBI Grade 2/3 (HR: 2.76, 95% CI: 1.62–4.70), and High Delta-SII group (HR: 2.84, 95% CI: 1.86–4.33) as independent risk factors for mortality. The constructed nomogram demonstrated robust discrimination, with AUCs of 0.804 (95% CI: 0.737–0.872) for 1-year and 0.823 (95% CI: 0.756–0.890) for 2-year OS. Calibration curves showed excellent agreement between predicted and observed survival, and DCA confirmed the model's clinical utility.
Conclusion: The dynamic evolution of systemic inflammation (Delta SII) and baseline hepatic reserve (ALBI grade) are powerful synergistic predictors of survival in unresectable HCC patients receiving TACE plus PD-1 inhibitors. The proposed nomogram, which prioritizes host biological resilience over tumor burden alone, offers a precise and visual tool to guide clinical decision-making and identify patients most likely to benefit from this combination therapy.
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Background: Mycoplasma pneumoniae pneumonia (MPP) is a common cause of community-acquired pneumonia in children. Immune dysregulation, particularly involving T-cell subsets, plays a key role in its pathogenesis, but the dose-response relationship between the peripheral blood CD4+/CD8+ T cell ratio and MPP severity remains unclear. This study aimed to investigate this correlation and dose-response relationship in pediatric MPP patients.
Methods: A cohort of 237 pediatric patients diagnosed with MPP was enrolled from Zhongshan Hospital, Xiamen University between June 2022 and June 2025. Based on disease severity assessed using clinical criteria, the participants were stratified into a mild group (n = 181) and a severe group (n = 56). General information, laboratory indicators, and immune cell levels of the children were collected. Stratified regression analysis was used to analyze the relationship between the CD4+/CD8+ T cell ratio and the clinical characteristics of the children. A generalized linear model (GLM) was used to assess the association between the CD4+/CD8+ T cell ratio and the severity of the children's condition. The dose-response relationship between the two was analyzed using restricted cubic splines (RCS).
Results: The CD4+/CD8+ T cell ratio in the severe group was significantly lower than that in the mild group (0.83 ± 0.29 vs 1.36 ± 0.41, p < 0.001). Stratified regression analysis revealed that duration of fever, Pediatric Early Warning Score (PEWS), interleukin-10 (IL-10), lactate dehydrogenase (LDH), and ferritin all had independent negative effects on the CD4+/CD8+ T cell ratio (all p < 0.05). GLM analysis indicated that a lower CD4+/CD8+ T cell ratio was associated with a higher risk of disease exacerbation. After adjusting for confounding factors, children with a ratio <0.80 exhibited a 6.195-fold higher risk of disease exacerbation compared to the control group (>1.65) (95% CI: 2.380–16.125). RCS analysis further revealed a significant nonlinear negative dose-response relationship between the CD4+/CD8+ T cell ratio and disease severity (nonlinear p = 0.008).
Conclusions: The peripheral blood CD4+/CD8+ T cell ratio in children with MPP was negatively correlated with the severity of the disease, and a significant dose-response relationship was observed. This ratio can be used as a potential immunological indicator for assessing the severity of the disease in children.
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Background: Post-surgical pain is a common clinical complication following surgical procedures, significantly impacting patient comfort, functional recovery, and long-term prognosis. Its pathological mechanisms, particularly those involving vascular and inflammatory pathways, remain incompletely understood, which limits therapy options and necessitates the exploration of novel therapeutic targets. Angiopoietin-1 (Ang-1), a crucial growth factor, is essential for vascular homeostasis and inflammatory regulation, processes implicated in pain pathogenesis, while playing an unknown role in post-surgical pain. Herein, we aimed to elucidate the role of Ang-1 in post-surgical pain and its potential molecular mechanisms for pain relief.
Methods: Post-surgical pain rat models were established using skin/muscle incision and retraction (SMIR), followed by assessment of pain hypersensitivity (paw withdrawal threshold (PWT) and paw withdrawal latency (PWL)). After Ang-1 treatment, examinations were performed on oxidative stress and inflammation in dorsal root ganglion (DRG) neurons, as well as whether NADPH oxidase 4 (NOX4)–reactive oxygen species (ROS)–nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway was implicated.
Results: SMIR induced pronounced pain hypersensitivity, reflected by downregulated PWT and PWL, accompanied by reduced Ang-1 expression in DRG neurons (p < 0.001). Elevation of Ang-1 alleviated post-surgical pain behaviors and attenuated the upregulation of ROS, NOX4, Tumor Necrosis Factor-alpha (TNF-α), and Interleukin-6 (IL-6) in SMIR-exposed DRG neurons (p < 0.001). Moreover, NF-κB level was enhanced by SMIR, yet later suppressed by Bay (p < 0.001). Ang-1 also reduced DRG neuronal apoptosis and inflammation, suggesting the inhibitory role of NF-κB (p < 0.001).
Conclusion: Ang-1 alleviates post-surgical pain by modulating oxidative stress and inflammatory responses via NOX4/ROS/NF-κB signaling pathway in DRG neurons. These findings identify Ang-1 as a promising candidate for effective post-surgical pain management and the development of novel analgesic strategies.
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Background: In the past decade, it has been established that dynamic communication exists among nerves, macrophages, and podocytes (PODO) within the kidney, which plays a crucial role in renal homeostasis and the response to acute and chronic renal injury. However, the exact molecular mechanisms of the interplay among these three elements in the progression of diabetic nephropathy (DN) remain to be elucidated. The aim of this study is to explore the intercellular communication via signaling molecules among neurons, macrophages, and PODO, and to determine their mechanism of action in renal inflammation in DN.
Methods: Multiple DN-related single-cell transcriptome sequencing datasets were merged. Using the Seurat pipeline, cells were standardized, underwent principal component analysis (PCA), dimensionality reduction, clustering, and annotation. Cells transmitting neural signals, macrophages, and PODO were identified using biomarkers from CellMarker 2.0 and SingleR method. The interactions of ligand-receptor pairs between these cells were analyzed using Celltalker and CellphoneDB. Additionally, differentially expressed genes (DEGs) in macrophages, and PODO in DN were obtained and annotated for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functions.
Results: A total of 2394 cells from kidneys exhibiting transcriptome characteristics highly similar to neurons were identified. These neuron-like cells were clustered into 11 cell clusters. Among these, cluster 7 (GABBR1hiCHRM3hi) showed a significant decrease in relative proportion in DN tissue (p < 0.05). A total of 202 macrophages were identified, clustered into 4 cell clusters. Notably, cluster C3 (RYR1+ESRRG+BICC1+) was significantly reduced in DN. Functional analysis indicated that RYR1+ESRRG+BICC1+ macrophages were associated with negative regulation of inflammatory responses. Cell communication analysis further revealed weakened interactions between GABBR1hiCHRM3hi neuron-like cells and RYR1+ESRRG+BICC1+ macrophages involving Amyloid β precursor protein (APP)-CD74. Additionally, interactions of PODO with RYR1+ESRRG+BICC1+ macrophages involving SLIT1-ROBO2, EFNA5-EPHA4, and PDGFB-PDGFRB were weakened, as was the interaction of GABBR1hiCHRM3hi neuron-like cells involving VEGFA-FLT1.
Conclusion: In DN, there is signal crosstalk between GABBR1hiCHRM3hi cells, anti-inflammatory phenotype macrophages, and PODO. The communication between these cells is primarily mediated through signaling pathways such as APP-CD74, PDGFB-PDGFRB, and VEGFA-FLT1.
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Background: The Duffy Antigen Receptor for Chemokines (DARC/ACKR1) regulates inflammatory chemokine levels. The functional ACKR1 rs12075 G>A (p.Gly42Asp) polymorphism influences this activity and varies across populations, but studies on its association with human diseases such as coronary artery disease (CAD) are limited. The purpose of this study was to investigate the potential genetic link between this specific variation in the Duffy blood group gene ACKR1 and the risk of developing CAD within a Saudi Arabian population cohort.
Methods: A case-control study of 100 confirmed CAD patients and 100 matched healthy controls was conducted. Genomic DNA was extracted from peripheral blood and genotyped for the ACKR1 rs12075 variant using the Amplification Refractory Mutation System PCR (ARMS-PCR). Allelic and genotypic frequencies were compared using Chi-square tests, and associations with CAD risk were estimated via logistic regression, calculating odds ratios (ORs) with 95% confidence intervals (CI).
Results: The genotype distribution differed significantly between cases and controls (p = 0.0004). The AA genotype frequency was markedly higher in CAD patients (15%) versus controls (2%). In a recessive inheritance model, the AA genotype conferred a significantly increased risk of CAD (OR = 8.64, 95% CI: 1.92–38.90, p = 0.004). The GA genotype was also associated with elevated risk (OR = 2.06, 95% CI: 1.04–4.11, p = 0.037). Furthermore, the AA and GA genotypes showed significant associations with key CAD comorbidities, including hypertension, hyperlipidemia, diabetes mellitus, and a history of myocardial infarction (p < 0.05).
Conclusion: The ACKR1 rs12075 A allele, particularly in the homozygous state, is strongly associated with an increased risk of CAD in a Saudi Arabian cohort and is linked to a more severe clinical phenotype. These findings suggest that this genetic variant may serve as a potential biomarker for CAD susceptibility and severity in this population.
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Background: Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder characterized by ovarian dysfunction. High mobility group box 1 (HMGB1) is elevated in PCOS and implicated in its pathogenesis, while nuclear factor E2-related factor 2 (Nrf2) is a key regulator of antioxidative defense. However, the role and mechanism of HMGB1 in PCOS, particularly its relationship with Nrf2 signaling in ovarian granulosa cell injury, remain unclear. This study aimed to investigate whether HMGB1 deficiency protects human ovarian granulosa cells from Dehydroepiandrosterone (DHEA)-induced impairments and to explore whether this protective effect is mediated through activation of the Nrf2 pathway.
Methods: In this work, a PCOS cellular model was established by treating KGN cells with 20 nM DHEA for 48 h. Then, si-HMGB1 or si-NC was transfected into KGN cells for loss-of-function experiments. To further elucidate the role of Nrf2 signaling in the HMGB1-mediated protective effect on ovarian cells, rescue experiments were performed wherein KGN cells underwent pretreatment with 10 μM Nrf2 inhibitor ML385 for 24 h before subsequent interventions.
Results: HMGB1 knockdown enhanced DHEA-treated KGN cells' impaired viability, as well as inhibited DHEA-induced ferroptosis and mitochondrial dysfunction of KGN cells (p < 0.05). ML385 treatment partially reversed the relieving impact of HMGB1 deficiency regarding impaired viability of ovarian granulosa cells (GCs) treated by DHEA, as well as inhibitory effects of HMGB1 deficiency on ferroptosis and mitochondrial dysfunction of ovarian GCs caused by DHEA induction (p < 0.05).
Conclusion: Deficiency of HMGB1 improves impaired viability of DHEA-treated GCs and suppresses ferroptosis and mitochondrial dysfunction in PCOS through Nrf2 activation.
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Background: The malignant progression of lung adenocarcinoma (LUAD) is not only a hallmark of this prevalent cancer but is also closely linked to epigenetic regulation, particularly N6-methyladenosine (m6A) methylation. Disruption of the m6A regulatory machinery results in the uncontrolled upregulation of multiple oncogenic drivers, thereby fueling tumor development. Our study investigated the mechanism by which G Protein Subunit Gamma 4 (GNG4), a gene upregulated via m6A modification, promoted LUAD by enhancing its mRNA stability and subsequently inhibiting the cGAS-STING pathway. This provides novel mechanistic insight for clinical LUAD research.
Methods: Based on transcriptomic and m6A sequencing data from The Cancer Genome Atlas Program (TCGA) database, the candidate gene GNG4, associated with m6A regulation, was identified. Correlations of GNG4 expression with two m6A regulators—the writer Vir Like M6A Methyltransferase Associated (VIRMA) and reader Insulin Like Growth Factor 2 MRNA Binding Protein 3 (IGF2BP3)—were statistically evaluated. Prediction of the biological functions pertaining to GNG4 was performed using Single-gene Gene Set Enrichment Analysis (Single-gene GSEA). Cellular experiments, including gene knockdown/overexpression, Western blot, flow cytometry, m6A-related assays, and cellular senescence detection, as well as animal models were employed to investigate the regulatory effects of m6A-modified GNG4 on the cGAS–STING pathway and its impact on cell cycle progression and cellular senescence.
Results: TCGA data combined with functional experiments demonstrated that GNG4 was highly expressed in LUAD (p < 0.05). Knockdown of GNG4 activated the cGAS-STING pathway, upregulated p21, induced G1/S cell cycle arrest (p < 0.05) and cellular senescence (p < 0.05), thereby inhibiting LUAD cell proliferation (p < 0.05) and tumor growth (p < 0.05). Mechanistically, increased GNG4 mRNA expression was associated with elevated m6A modification in LUAD. GNG4 expression was positively correlated with the m6A writer VIRMA and the m6A reader IGF2BP3. Knockdown of VIRMA or IGF2BP3 significantly reduced both m6A modification and mRNA expression of GNG4 (p < 0.05), thereby alleviating its suppressive effect on the cGAS-STING pathway, promoting cellular senescence (p < 0.05), and inhibiting proliferation in LUAD cells (p < 0.05).
Conclusion: The upregulation of m6A modification of GNG4 in LUAD enhances its mRNA stability, which in turn suppresses the cGAS–STING signaling pathway, ultimately inhibiting cellular senescence and promoting LUAD cell proliferation, thereby driving disease progression.
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Background: Targeted therapy with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for lung adenocarcinoma still inevitably leads to drug resistance. The estrogen pathway interacts with the epidermal growth factor receptor (EGFR) signaling pathway, which is a potential combined therapeutic approach. However, findings from some previous preclinical studies evaluating the combination of EGFR-TKI with estrogen receptor antagonists have been inconsistent. The failure to stratify tumors based on the expression status of estrogen receptors may partly explain the inconsistency in the reported results. This study aims to explore the correlation between the expression status of G protein-coupled estrogen receptor (GPER), estrogen receptor α (ERα), and estrogen receptor β (ERβ) in lung adenocarcinoma with malignant pleural effusion (MPE) and the treatment outcomes of patients receiving EGFR-TKI.
Methods: The clinical data of 106 lung cancer patients with MPE at the initial diagnosis were retrospectively analyzed. The expression of GPER, ERα and ERβ in the malignant pleural effusion cell blocks of the patients was detected using immunohistochemistry, and the expression correlation among GPER, ERα and ERβ was analyzed using Spearman method. The Kaplan-Meier method and log-rank test were used to compare the effects of different expression levels of GPER, ERα, and ERβ on the progression-free survival (PFS) of patients. The Cox proportional hazards model was used to analyze the independent risk factors influencing the PFS rate of patients.
Results: Among these 106 cases, a total of 68 cases (64.2%) tested positive for GPER, 56 cases (52.8%) tested positive for ERα, and 60 cases (56.6%) tested positive for ERβ. The expression levels of GPER, ERα and ERβ were significantly correlated. Specifically, for ERα and GPER, rs = 0.515, p < 0.001; ERβ and GPER, rs = 0.497, p < 0.001; ERα and ERβ, rs = 0.469, p < 0.001. The objective response rate (ORR) of GPER-positive patients was lower than that of GPER-negative patients (48.5% vs 73.7%, p = 0.012). The 12-month PFS rates of the GPER positive group and the GPER negative group were 41.0% and 57.9%, respectively, and the median PFS of the GPER positive group and the GPER negative group were 10.6 months and 13.2 months, respectively (p = 0.035). Cox multivariate analysis confirmed that positive GPER was significantly and independently associated with a shorter PFS (hazard ratio [HR] 2.003, 95% CI 1.231–3.259, p = 0.005).
Conclusion: High expression of GPER in advanced lung adenocarcinoma with malignant pleural effusion is a negative predictor of the efficacy of EGFR-TKI in these patients. Further prospective studies based on the stratification of GPER expression are warranted to understand the differences in the therapeutic effects of anti-estrogen treatment among patients with different levels of GPER expression.
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Background: This study aims to investigate the correlation between the low-density lipoprotein cholesterol (LDL-C)/high-density lipoprotein cholesterol (HDL-C) ratio, in combination with complete blood count and coagulation panel parameters, and both the severity of coronary artery lesions and prognosis in patients with early-onset coronary heart disease, and to provide novel, comprehensive clinical indicators for risk assessment and prognosis evaluation in this patient population.
Methods: A retrospective study was conducted on the clinical data of 159 patients diagnosed with early-onset coronary heart disease through initial coronary angiography between January 2023 and August 2025. Patients were categorized into three groups based on coronary lesion severity: a mild lesion group (n = 78), a moderate disease group (n = 59), and a severe disease group (n = 22). Lipid profiles [total cholesterol (TC), triglycerides (TG), LDL-C, HDL-C, LDL-C/HDL-C ratio], fasting blood glucose, uric acid, and coagulation parameters [prothrombin time (PT), prothrombin time ratio (PTR), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (FIB)], complete blood count [hemoglobin (HGB), red cell distribution width-coefficient of variation (RDW-CV), red cell distribution width-standard deviation (RDW-SD), mean platelet volume (MPV), platelet distribution width (PDW)] were detected, and the correlation between statistically significant indicators and the severity of coronary artery lesions was analyzed. Participants were divided into the MACE group and the non-MACE group based on the occurrence of major adverse cardiac events (MACE) within 100 days, and binary logistic regression analysis was applied to identify MACE risk factors.
Results: The severe group showed higher TC, LDL-C, LDL-C/HDL-C, fasting blood glucose, and uric acid levels than the moderate group, which in turn had higher levels than the mild group; TG was higher than in the moderate/mild groups; HDL-C was lower than in the moderate group but higher than in the mild group (p < 0.05). The severe group had higher PT, PTR, APTT, TT, and FIB than the moderate group, which in turn was higher than the mild group (p < 0.05). There were no statistically significant differences in HGB levels among the groups (p > 0.05); however, the severe group had higher RDW-CV, RDW-SD, MPV, and PDW than the moderate group, and the mild group had the lowest (p < 0.05). Kendall's correlation coefficients indicated that TC, TG, LDL-C, LDL-C/HDL-C, fasting blood glucose, uric acid, PT, PTR, APTT, TT, FIB, RDW-CV, RDW-SD, MPV, and PDW were positively correlated with the severity of coronary artery lesions (τ = 0.375, 0.372, 0.346, 0.448, 0.305, 0.239, 0.388, 0.310, 0.299, 0.447, 0.364, 0.476, 0.226, 0.401, 0.466, p < 0.001), HDL-C was negatively correlated with the severity of coronary artery lesions (τ = –0.410, p < 0.001). The incidence of MACE was highest in patients with severe early-onset coronary heart disease, followed by moderate and mild severity (χ2 = 23.283, p < 0.001). Binary logistic regression analysis revealed that severity of coronary artery disease (severe), LDL-C/HDL-C ratio, fasting blood glucose, uric acid, PT, APTT, TT, FIB, RDW-SD, and PDW were all independent predictors of MACE in patients with early-onset coronary heart disease (p < 0.05).
Conclusion: In patients with early-onset coronary heart disease, LDL-C/HDL-C ratio, coagulation function indicators (PT, APTT, TT, FIB), and blood routine parameters (RDW-SD, PDW) show significant positive correlations with the anatomical severity of coronary artery lesions and are closely associated with increased short-term adverse prognosis risk.
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Background: Cardiac fibrosis, characterized by aberrant cardiac fibroblast (CFs) activity and extracellular matrix deposition, is a fundamental pathological process underlying multiple heart diseases. Tripartite motif 34 (TRIM34), a K63-linked ubiquitin ligase, is upregulated in failing human hearts, yet its function in cardiac fibrosis remains unclear. This study aims to investigate the role of TRIM34 in cardiac fibrosis.
Methods: In vivo, fibrosis was induced by myocardial infarction (MI) via left anterior descending coronary artery ligation in mice, while TRIM34 knockdown was achieved using recombinant adenovirus-mediated shRNA. Fibrosis area and related markers were evaluated. In vitro, cardiac fibroblasts were treated with transforming growth factor beta 1 (TGF-β1) and transfected with shTRIM34; proliferation, migration, invasion, and fibroblast activation markers were assessed. Protein interaction, ubiquitination, and promoter activity were examined. Rescue experiments were performed using SMAD family member 7 (SMAD7) or heterogeneous nuclear ribonucleoprotein L (HNRNPL) knockdown.
Results: Upregulation of TRIM34 was found in fibrotic tissue of mice and TGF-β1-exposed CFs. Knockdown of TRIM34 reduced the cardiac fibrosis area and the expression of fibrosis markers in MI mice. Also, TRIM34 knockdown decreased the cell viability, numbers of migrated and invaded cells, and the level of myofibroblast marker, with the increased level of fibroblast markers in TGF-β1-induced CFs. Moreover, TRIM34 directly interacted and promoted ubiquitination degradation of HNRNPL. Furthermore, TRIM34 suppressed the transcription of the SMAD7 promoter by inhibiting the expression of HNRNPL. Rescue experiments showed that knockdown of HNRNPL or SMAD7 counteracted the antifibrotic role of shTRIM34 in MI mice and TGF-β1-exposed CFs.
Conclusion: TRIM34 exacerbated cardiac fibrosis by ubiquitinating HNRNPL and regulating SMAD7 expression, highlighting TRIM34 as a potential therapeutic target for fibrotic heart disease.
