Sepsis is a syndrome caused by the host's inflammatory response to an infection with an unknown mechanism. This study aimed to identify differentially expressed genes (DEGs) potentially involved in th Show more
Sepsis is a syndrome caused by the host's inflammatory response to an infection with an unknown mechanism. This study aimed to identify differentially expressed genes (DEGs) potentially involved in the development and recovery of tracheal injury from septic shock. Nine New Zealand white rabbits were randomized to control (CON), septic shock model (SS), and septic shock norepinephrine treatment (SSNE) groups (each group n = 3). The SS and SSNE groups were injected with lipopolysaccharide to induce septic shock. The SSNE group was administered Ringer lactate with norepinephrine to maintain normal blood pressure. All animals underwent cuffed endotracheal intubation for 2 h. The injured tracheal segment was harvested. RNA sequencing was performed to identify the DEGs, followed by bioinformatics analysis, and pathological staining (both HE and Masson) was performed for pathological evaluation. Bioinformatics analysis included principal component analysis (PCA), gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) network construction. Key findings were validated by qRT-PCR and immunohistochemistry. We obtained 124 upregulated and 28 downregulated DEGs in SS vs. CON groups, along with 60 upregulated and 178 downregulated DEGs in SSNE vs. SS groups. The pathological score showed that trachea tissue in the SS group had the highest score. The protein-protein interaction (PPI) prediction identified APOB and CD36 as the hub genes. The molecular experiments further confirmed that at mRNA and protein levels, APOB was significantly upregulated, while CD36 was significantly downregulated. Subsequent qRT-PCR and immunohistochemical analyses confirmed that APOB expression was significantly upregulated while CD36 was downregulated in the septic shock group, a trend partially reversed by norepinephrine treatment. Our study results suggest that APOB and CD36 may be involved in the pathogenesis of tracheal injury recovery in septic shock patients treated with NE. Not applicable. Show less
Huangqi Guizhi Wuwu Decoction (HGWD) is a classic formula recorded in the Jin Gui Yao Lue. It is primarily used to treat symptoms of "blood stasis", such as numbness in the limbs and poor circulation, Show more
Huangqi Guizhi Wuwu Decoction (HGWD) is a classic formula recorded in the Jin Gui Yao Lue. It is primarily used to treat symptoms of "blood stasis", such as numbness in the limbs and poor circulation, and has been widely applied clinically in the treatment of stroke. Its traditional efficacy suggests potential for promoting neurological function recovery and regulating the microenvironment. However, its mechanism in neuroprotection and functional recovery after ischemic stroke (IS) remains unclear. This study aims to elucidate the molecular mechanism by which HGWD exerts neuroprotective effects and promotes neurological recovery following IS by inducing M2 polarization of microglia through activation of the PI3K/Akt/mTOR signaling pathway. The chemical constituents of HGWD were identified using Ultra Performance Liquid Chromatography-Mass Spectrometry (UHPLC-MS). Network pharmacology was employed to predict the active components of HGWD and targets, along with potential signaling pathways. A middle cerebral artery occlusion (MCAO) in vivo model was established using Sprague-Dawley (SD) rats, whilst primary microglia were isolated to construct an oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro model. TTC staining was used to assess the volume of cerebral infarction, and neurological function was evaluated using mNSS and the rotarod test. RT-qPCR, Western blot, immunofluorescence, or flow cytometry were used to detect axonal remodeling, the PI3K/Akt/mTOR signaling pathway, and microglial polarization markers, while ELISA was used to detect inflammatory cytokines. The in vivo dosage of HGWD was 2.5 g/kg i.g. and 5 g/kg i.g., and the in vitro concentrations were 50 μg/mL and 100 μg/mL. Using LY294002 and Rapamycin as PI3K and mTOR inhibitors, we verified that HGWD promotes the recovery of neurological function after IS by activating the PI3K/Akt/mTOR signaling pathway. Network pharmacology revealed that the core components of HGWD overlap with the PI3K/Akt/mTOR signaling pathway and microglial polarization targets. HGWD significantly improved neurological function in MCAO rats, reduced cerebral infarction area, and increased neuronal survival. This formula increased the expression of GAP-43, PSD95, and BDNF, while promoting axonal remodeling and synaptic repair. HGWD inhibited the expression of M1-type markers (CD86, iNOS) and increased the expression of M2-type markers (CD206, ARG1), while ELISA showed a shift of inflammatory cytokines towards anti-inflammatory effects. In microglia, HGWD restored OGD/R-induced cell viability and promoted M2 polarization via the PI3K/Akt/mTOR signaling pathway. Both in vivo and in vitro experiments showed that HGWD significantly increased the phosphorylation levels of PI3K, Akt, and mTOR. LY294002 and rapamycin partially blocked these results, while rescue experiments using the Akt activator SC79 combined with analysis of downstream STAT3 and P65 further illustrate that this process is Akt pathway dependent. The results suggest that HGWD can exert a neuroprotective effect by activating the PI3K/Akt/mTOR signaling pathway, thereby promoting neurological function recovery. HGWD may activate the PI3K/Akt/mTOR signaling pathway, drive microglia to M2 polarization, regulate neuroinflammation, and promote neuroplasticity, thereby achieving neuroprotection and functional recovery after IS. Show less
While active ingredients from compound Chinese herbal medicines (CCHMs) have demonstrated potential in alleviating symptoms of polycystic ovary syndrome (PCOS), their mechanisms of action remain insuf Show more
While active ingredients from compound Chinese herbal medicines (CCHMs) have demonstrated potential in alleviating symptoms of polycystic ovary syndrome (PCOS), their mechanisms of action remain insufficiently understood. This study aimed to identify key active ingredients and gene targets in Xiaochaihu Decoction, Sijunzi Decoction, and Shensiwei that contribute to their efficacy against PCOS. Transcriptomic data of PCOS were obtained from public databases. Information on gut microbiota metabolite-related targets and active ingredients of CCHMs was retrieved from relevant databases. Key gene targets and active ingredients were identified using Graph-based Bioactive Network Analysis (GraphBAN) and toxicological assessments. Molecular docking and dynamic simulations were conducted to validate interactions. Functional enrichment and regulatory network analysis were performed. LCT, FADS1, and CYP11A1 were identified as key genes associated with α-β T cell activation, immune receptor signaling, and adaptive immune responses. LCT and FADS1 were targeted by linolenic acid, while CYP11A1 was regulated by mandenol, EIC, and linolenic acid. Three microRNAs (hsa-miR-320a-3p, hsa-miR-4487, hsa-miR-6090) co-regulated these genes. Molecular docking and dynamics simulations confirmed stable binding between key genes and active ingredients, with binding energies < -5.0 kcal/mol. The findings indicate that CCHMs exert therapeutic effects on PCOS by multi-target regulation of key genes involved in androgen synthesis, metabolic regulation, and immune-inflammatory activation. The observed strong binding affinities provide a structural basis for these interactions. This study identified three key genes and three core active ingredients in CCHMs for PCOS treatment, laying a theoretical foundation for developing multi-target therapeutics. Show less
DUSP6, a dual-specificity phosphatase, has become a focal point in understanding the pathogenesis of various liver disorders. This study aims to investigate the role of DUSP6 in liver fibrosis and exp Show more
DUSP6, a dual-specificity phosphatase, has become a focal point in understanding the pathogenesis of various liver disorders. This study aims to investigate the role of DUSP6 in liver fibrosis and explore the underlying mechanism. Using a CCL4-induced mouse model, the consistent upregulation of DUSP6 expression was observed. Notably, when Dusp6 was knocked down, liver fibrosis showed significant improvement, revealing a protective effect intricately linked to the ERK pathway. This was accompanied by an increase in ferroptosis-related proteins SLC7A11 and GPX4, underscoring the role of ferroptosis, an iron-dependent form of regulated cell death, in this process. Transcriptomic analysis further revealed a crucial downregulation of Cyp2e1 following Dusp6 knockdown. In vitro, DUSP6 knockdown not only promoted ERK phosphorylation but also suppressed CYP2E1 expression, enhancing cell proliferation, bolstering hepatocyte resistance to ferroptosis, and alleviating hepatocyte injury. Importantly, inhibiting CYP2E1 in mouse models of liver fibrosis effectively slowed the progression. These findings illuminate a critical regulatory mechanism that DUSP6 regulates liver fibrosis via targeting ferroptosis, offering new a direction for therapeutic strategies in liver disease. Show less
Hypothyroidism, the most prevalent endocrine disorder globally, is associated with increased cardiovascular risk. This study aims to evaluate cardiovascular risk factors-including serum oxidized low-d Show more
Hypothyroidism, the most prevalent endocrine disorder globally, is associated with increased cardiovascular risk. This study aims to evaluate cardiovascular risk factors-including serum oxidized low-density lipoprotein (ox-LDL), serum homocysteine (Hcy), and lipid profiles-and their correlations with thyroid-stimulating hormone (TSH) levels. Early identification of these risk predictors may reduce the incidence and mortality of cardiovascular disease in hypothyroid patients. This cross-sectional study included 676 participants. Subjects were stratified into four groups: three corresponding to TSH quartiles within the reference range and a fourth comprising subclinical hypothyroidism (SCH) patients with TSH levels above this range. All participants underwent physical examinations and provided fasting blood samples for measurement of TSH, free thyroxine (FT4), free triiodothyronine (FT3), blood glucose, triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), lipoprotein(a) [Lp(a)], ox-LDL, and Hcy. Across the four subgroups, LDL-C, ApoB, ox-LDL, and Hcy levels exhibited significant increasing trends (all The observed correlations between ox-LDL, Hcy, and dyslipidemia in subclinical hypothyroidism may indicate a proatherogenic state. Elevated ox-LDL and Hcy emerge as independent factors associated with accelerated atherosclerosis in this condition. Show less
BackgroundPrevious whole exome and whole genome sequencing (WES/WGS) studies identified genome-wide significant associations for late-onset Alzheimer's disease (AD) with rare variants but highlighted Show more
BackgroundPrevious whole exome and whole genome sequencing (WES/WGS) studies identified genome-wide significant associations for late-onset Alzheimer's disease (AD) with rare variants but highlighted the need for larger samples.ObjectiveIdentify associations of rare coding variants with AD risk in a large-scale, multi-ancestry exome-wide.MethodsWe combined non-overlapping portions of the Alzheimer's Disease Sequencing Project (ADSP) WES (n = 18 717) and WGS (n = 35 014) datasets obtaining a sample (n = 34 202) including participants ages ≥ 60 from four genomic similarity clusters consistent with European ancestry (EA, 9 744 AD cases and 9 095 controls), African American (AA, 1 944 AD cases and 4 215 controls), Caribbean Hispanic (CH 2 344 AD cases and 3 465 controls), and Native American Hispanic (NAH 743 AD cases and 2 652 AD controls) populations. Association of AD with 253,421 bi-allelic variants with minor allele count ≥ 20 in the total sample and each population group was evaluated using GENESIS. Gene-based tests comprising predicted moderate and high-impact variants were performed using SAIGE.ResultsNovel study-wide significant associations (p < 1.97 × 10 Show less
Human embryonic stem cell (hESC)-derived hepatocytes (hEHs) display functional deficits, particularly impaired albumin secretion and ammonia metabolism, compared to primary human hepatocytes (PHHs). H Show more
Human embryonic stem cell (hESC)-derived hepatocytes (hEHs) display functional deficits, particularly impaired albumin secretion and ammonia metabolism, compared to primary human hepatocytes (PHHs). Here, we investigated the regulatory role of CCAAT/enhancer-binding protein beta (C/EBPβ) in hepatocyte maturation. Forced C/EBPβ expression enhanced hepatocyte functionality and upregulated hepatocyte-specific genes, while suppressing epithelial-mesenchymal transition (EMT) via downregulating canonical EMT markers. Mechanistically, CUT&Tag and luciferase reporter assays confirmed C/EBPβ directly binds to the promoter regions of CDH1 (E-cadherin) and CPS1 (carbamoyl phosphate synthetase 1). Co-immunoprecipitation identified an interaction between C/EBPβ and the MAPK pathway. RNA interference combined with Western blot analysis revealed that MAPK1-mediated phosphorylation of C/EBPβ at Thr-235 augmented its transactivation activity, accelerating hepatocyte maturation. Our findings establish C/EBPβ as a master regulator that coordinates transcriptional networks and post-translational modifications during hEHs maturation, providing novel insights for generating mature hepatocytes for disease modeling and regenerative medicine applications. The transcriptional activity of C/EBPβ is regulated by MAPK1 protein within the ERK/MAPK signaling pathway. MAPK1 moves from the cytoplasm into the nucleus and transfers phosphate groups to C/EBPβ. This process reverses the "self-inhibition" state of C/EBPβ and enhances its transcriptional activity on downstream target genes. Show less
Clinical application of mesenchymal stem cells for endometrial repair has been hampered by variability in cell quality, large-scale production, and uncertainty regarding the optimal delivery route. In Show more
Clinical application of mesenchymal stem cells for endometrial repair has been hampered by variability in cell quality, large-scale production, and uncertainty regarding the optimal delivery route. In this study, we investigated the therapeutic potential of clinical-grade human embryonic stem cell-derived immunity-and-matrix-regulatory cells (IMRCs) for treating refractory moderate-to-severe intrauterine adhesion (IUA). In a rabbit IUA model, sub-endometrial injection of IMRCs significantly reduced fibrosis and enhanced endometrial angiogenesis, outperforming uterine perfusion. Transcriptomic analysis revealed distinct pro-angiogenic gene expression profiles between the two delivery routes. In vitro, IMRCs co-cultured with endometrial stromal cells (ESCs) markedly enhanced angiogenic potential compared to either cell type alone. Protein array analysis of the co-culture supernatant showed elevated levels of angiogenic factors, with functional assays confirming that inhibition of ANGPTL4, a non-canonical pro-angiogenic mediator, impaired angiogenesis. In a first-in-human, single-center, phase 1 dose-escalation trial involving 18 patients with refractory IUA, high-dose sub-endometrial IMRC injection promoted angiogenesis, reduced uterine scarring, and improved pregnancy outcomes, with no safety concerns observed over 3 years of follow-up. These findings highlight the translational promise of IMRCs as a novel therapeutic strategy for endometrial regeneration in severe IUA. Show less
Aortic valve calcification increases leaflet stiffness and contributes to the development of calcific aortic valve disease. The molecular and cellular mechanisms underlying calcification remain unclea Show more
Aortic valve calcification increases leaflet stiffness and contributes to the development of calcific aortic valve disease. The molecular and cellular mechanisms underlying calcification remain unclear. Here, we aimed to investigate the role of PRMT3 (protein arginine methyltransferase 3) in valvular calcification and calcific aortic valve disease progression. Both aortic valve leaflets and valvular interstitial cells from patients were used to evaluate the expression pattern and investigate the underlying mechanism of PRMT3 in calcific aortic valve disease pathogenesis. High-cholesterol diet-fed Apoe (apolipoprotein E)-deficient ( We found that PRMT3 expression was significantly upregulated during aortic valve calcification. RUNX2 (runt-related transcription factor 2) recruited P300 to promote PRMT3 expression through histone H3 lysine 27 acetylation. Moreover, We identify a previously unrecognized posttranslational mechanism regulating PCSK9 stability in valve interstitial cells during calcific aortic valve disease and establish a link between PRMT3-mediated arginine methylation and valve-specific lipid-osteogenic coupling. Show less
This study aimed to analyze the clinical features, genetic basis, and management of late-onset carbamoyl phosphate synthetase 1 deficiency (CPS1D) through a pediatric case report and literature review Show more
This study aimed to analyze the clinical features, genetic basis, and management of late-onset carbamoyl phosphate synthetase 1 deficiency (CPS1D) through a pediatric case report and literature review, highlighting diagnostic challenges and therapeutic strategies. We present a 19-year-old female with recurrent neurological symptoms since age 8. She underwent comprehensive metabolic screening, neuroimaging, and whole-exome sequencing of theCPS1gene. Identified variants were assessed for pathogenicity using multiple orthogonalin silicoprediction tools. The patient's initial hyperammonemic crisis at age 8 was misdiagnosed as encephalitis. Workup at age 13 confirmed hyperammonemia (peak 168 µmol/L), hypocitrullinemia, and elevated glutamine. Genetic analysis identified compound heterozygousCPS1variants: a novel c.1058 T > C (p.F353S) and known pathogenic c.1145C > T (p.P382L). A self-selected low-protein diet controlled acute crises but led to severe growth failure (height 145 cm, weight 30 kg). Late-onset CPS1D's nonspecific neurological symptoms often lead to misdiagnosis. Diagnosis requires a high index of suspicion, integrating metabolic profiling with genetic confirmation. This case expands the pathogenic genotypic spectrum of CPS1D. It crucially highlights that while dietary management is life-saving, it requires expert multidisciplinary oversight to prevent devastating consequences like growth failure, especially in resource-limited settings. Routine ammonia testing in unexplained encephalopathy is paramount. Show less
Increasing evidence indicates that modulating pyroptosis in endothelial cells (ECs) can alleviate atherosclerosis (AS) progression; however, despite reports that nucleolin (NCL) regulates vascular smo Show more
Increasing evidence indicates that modulating pyroptosis in endothelial cells (ECs) can alleviate atherosclerosis (AS) progression; however, despite reports that nucleolin (NCL) regulates vascular smooth muscle cell proliferation in AS, the potential mechanism by which cell surface NCL mediates pyroptosis in ECs during AS remains poorly understood. AS was induced in ApoE AS model mice developed severe aortic lesions accompanied by pronounced EC pyroptosis and inflammation, together with elevated NCL expression in ECs of the aortic root. Both inhibition of NLRP3 and NCL knockdown alleviated atherosclerotic lesion severity in ApoE This study demonstrates that, in AS, NCL exacerbates EC pyroptosis and promotes disease progression by facilitating nuclear transport of RASSF2. This study defines the mechanistic roles of NCL in AS, thereby identifying a new molecular pathway and suggesting potential therapeutic targets. Show less
Chronic pain, marked by nociceptive sensitization and maladaptive neuroplasticity, affects 30% of the global population with escalating socioeconomic burdens. Epidemiological data show a 2-3-fold incr Show more
Chronic pain, marked by nociceptive sensitization and maladaptive neuroplasticity, affects 30% of the global population with escalating socioeconomic burdens. Epidemiological data show a 2-3-fold increase in neuropsychiatric co-morbidities among individuals with chronic pain, where epigenetic dysregulation serves as a key mechanism linking ongoing pain to emotional disorders. This review systematically explores epigenetic signatures in supraspinal integration hubs, notably the limbic-paralimbic networks and prefrontal regulatory circuits. The identified epigenetic signatures encompass dysregulation of DNA methyltransferases (DNMTs), RNA modifications, histone post-translational modifications and locus-specific alterations, including aberrant methylation at the brain-derived neurotrophic factor (BDNF), opioid μ receptor and transient receptor potential ankyrin 1 (TRPA1) gene loci. Additionally, they involve dysfunction of the glucocorticoid receptor (GR)/corticotropin-releasing factor (CRF) axis via epigenetic modulation. Building on these findings, we evaluate therapeutic strategies addressing epigenetic dysregulation. While preclinical data demonstrate the efficacy of histone deacetylase (HDAC) and DNMT inhibitors, clinical translation faces significant barriers, including limited blood-brain barrier permeability. Notably, our analysis highlights the benefits of combining pharmacological interventions with non-invasive neuromodulation for enhanced co-morbidity management. Looking forward, this review proposes innovative approaches that leverage CRISPR-based chromatin editing platforms, biomimetic nanocarriers for neuron-specific delivery and closed-loop neuromodulation integrating real-time biomarker feedback, collectively establishing a precision medicine framework for pain or neuropsychiatric co-morbidities. Show less
Atherosclerotic lesions commonly develop in curved or bifurcated arteries, where blood flow exhibits characteristics of low shear stress (LSS). Subjected to LSS continually, endothelial cells (ECs) ad Show more
Atherosclerotic lesions commonly develop in curved or bifurcated arteries, where blood flow exhibits characteristics of low shear stress (LSS). Subjected to LSS continually, endothelial cells (ECs) adopt a pro-atherosclerotic phenotype. Ferroptosis is a recently identified form of controlled cell demise prompted by iron-dependent buildup of cellular reactive oxygen species (ROS), which has been associated with diverse cardiovascular diseases, particularly atherosclerosis (AS). P53 is a broadly acting tumor suppressor that can be activated by diverse stimuli and mediates multiple biological outcomes, including cell cycle arrest, DNA repair, apoptosis, and ferroptosis. However, it remains unknown whether LSS promotes the development of AS by inducing P53-dependent ferroptosis in endothelial cells. In our experiments, we induced LSS by partial ligation of the right common carotid artery in high-fat diet-fed (HFD) male ApoE Our findings demonstrated that LSS induced endothelial ferroptosis, which in turn accelerated AS development both in vivo and in vitro. This effect was partially counteracted by both the ferroptosis inhibitor Fer-1 and endothelium-specific glutathione peroxidase 4 (GPX4) overexpression in ApoE Our experiments suggested that LSS promotes atherosclerosis by inducing endothelial ferroptosis through the P53/xCT signaling pathway. Show less
With the widespread use of smartphones among adolescents, smartphone addiction has become a growing mental health concern. Adolescents' limited self-regulation makes them particularly vulnerable to us Show more
With the widespread use of smartphones among adolescents, smartphone addiction has become a growing mental health concern. Adolescents' limited self-regulation makes them particularly vulnerable to using smartphones to escape real-life stress, heightening addiction risk. However, the heterogeneity of addictive behaviors and the dynamic role of experiential avoidance have been underexplored. This 6-month longitudinal study surveyed 547 Chinese primary and secondary students using the Smartphone Addiction Scale (SAS) and the Acceptance and Action Questionnaire-II (AAQ-II). Latent profile analysis (LPA) and latent transition analysis (LTA) were applied to identify subgroups and examine transitions between these subgroups. Cross-lagged panel network analysis (CLPN) revealed key symptom interactions between experiential avoidance and addiction. The study identified two addiction subgroups: a stable "low-risk group" (84.9 percent) and a "high-risk group," 51.4 percent of whom transitioned to low risk over time. Logistic regression showed that experiential avoidance significantly predicted high-risk membership (odds ratios [OR] = 1.083-1.102) and deterioration within the low-risk group (OR = 1.036). The CLPN identified "online intimacy" (SPA-3) and "hesitation and overcautious" (EA-7) as driver nodes, with "withdrawal symptoms" (SPA-2) serving as a central node. These findings emphasize the crucial role of experiential avoidance in adolescent smartphone addiction and suggest symptom-level targets for early intervention. The results support acceptance and commitment therapy (ACT) as a promising approach for reducing smartphone addiction among youth. Show less
Hepatocellular carcinoma (HCC) is a major malignancy with rising global incidence and mortality. Clinical treatment is limited by molecular heterogeneity and drug resistance. In recent years, endocrin Show more
Hepatocellular carcinoma (HCC) is a major malignancy with rising global incidence and mortality. Clinical treatment is limited by molecular heterogeneity and drug resistance. In recent years, endocrine-disrupting chemicals (EDCs) have attracted attention as emerging risk factors, but systematic pathogenic evidence for their roles in HCC initiation and progression remains insufficient. First, we predicted potential targets of EDCs using SwissTargetPrediction, STITCH, and ChEMBL, and intersected them with differentially expressed genes and key module genes from WGCNA in the GEO database to screen candidate key genes. Second, based on these candidates, we constructed diagnostic models using 14 machine-learning algorithms and evaluated feature importance via the SHAP framework to identify key biomarkers and their functional contributions. Molecular docking and molecular dynamics simulations were used to validate interaction mechanisms between EDCs and key target proteins. We then built a multivariable Cox proportional hazards model in the TCGA-LIHC cohort and performed stratified survival analysis, somatic mutation profiling, and immune evasion characterization. Subsequently, we evaluated the tumor immune microenvironment using CIBERSORT and ssGSEA, and integrated single-cell transcriptomic data to resolve cell-subtype heterogeneity, target expression distributions, and cell-cell communication. Meanwhile, we integrated the GDSC drug-sensitivity database to evaluate associations between risk scores and drug response, and conducted pan-cancer analyses to examine cross-cancer applicability. We identified 18 genes jointly associated with EDCs and HCC, significantly enriched in AMPK, p53, and FoxO signaling pathways and cell cycle-related pathways. Among models built with 14 machine-learning algorithms, CatBoost showed the best discriminative performance and identified CCNB2 and AKR1C3 as core driver genes. Docking and dynamics simulations indicated strong binding affinities and stable binding conformations between EDCs and target proteins including CCNB1 (-8.9 kcal/mol), AKR1C3 (-8.4 kcal/mol), and FADS1 (-8.5 kcal/mol). A multivariable Cox risk model based on nine key genes served as an independent prognostic predictor for HCC (HR = 1.746, 95% CI: 1.477-2.064, P < 0.001). The nomogram achieved AUCs of 0.836, 0.810, and 0.788 at 1, 3, and 5 years, respectively, indicating good predictive performance. The high-risk group was significantly associated with high tumor mutational burden (TMB), TP53 mutations, and low immune evasion scores. Regarding the tumor immune microenvironment, CIBERSORT and ssGSEA analyses showed marked enrichment of Tregs and M0 macrophages, while most effector immune cells and functions were suppressed. Single-cell transcriptomics further showed enrichment of endothelial cells, fibroblasts, hepatocytes, and macrophages in HCC tissues, with notable reductions in T cells, B cells, NK cells, and neutrophils, indicating an immunosuppressive microenvironment with stromal remodeling. Cell-cell communication analysis indicated that the MIF-CD74 receptor axis is central in immune-cell interactions. Drug-sensitivity analysis suggested that the high-risk group was more sensitive to GDC0810, BPD-00008900, and Fulvestrant, indicating potential beneficiary populations. Pan-cancer analysis showed that the risk model also had diagnostic and prognostic value in LUAD, KIRP, KIRC, and KICH, suggesting cross-cancer generalizability. This study systematically reveals that EDCs promote HCC initiation and progression by perturbing cell cycle, metabolic, and immune homeostasis through multi-target, multi-pathway mechanisms. The nine-gene risk model demonstrates superior performance in HCC diagnosis and prognosis and shows potential clinical translational value in drug-sensitivity prediction and pan-cancer analyses. This work provides a new perspective at the intersection of environmental toxicology and precision oncology and informs individualized therapeutic strategies. Show less
The abuse of methamphetamine (METH) is associated with an increased risk of Parkinson's disease (PD), whereas microglial polarization and glucose metabolism disorders are closely related to the progre Show more
The abuse of methamphetamine (METH) is associated with an increased risk of Parkinson's disease (PD), whereas microglial polarization and glucose metabolism disorders are closely related to the progression of PD. This study aimed to investigate the specific molecular mechanism underlying the promotion of PD progression by METH through the regulation of microglial polarization and glycolysis. METH-induced C57BL/6 mice and BV2 cells were used to construct PD-like neurotoxicity animal and cell models for experimental investigation. Behavioral tests, immunohistochemistry and Nissl staining were used to assess the behavioral ability and neuronal damage of the animals. The levels of related proteins, inflammatory cytokines and glycolysis were detected using immunofluorescence, ELISA, Western blotting, and CCK-8 assays. METH treatment significantly promoted behavioral disorders in PD mice, reduced the number of TH-positive neurons, and aggravated neuronal damage in the substantia nigra (SN). In addition, METH decreased the M2 marker proteins Arg-1 and CD206 and increased the M1 marker proteins iNOS and CD86; the proinflammatory cytokines TNF-α, IL-β, and IL-6; and glucose uptake, glucose consumption and lactic acid production, thus promoting M1 polarization and glycolytic activity in BV2 cells. In terms of the underlying molecular mechanism, METH treatment significantly increased the level of LPA. METH promotes LPA expression via upregulation of LIPH expression, and activates the PI3K/AKT pathway. Knockdown of LIPH or treatment with BrP-LPA reduces the ability of METH to promote M1 microglial polarization and glycolytic activity. Furthermore, the addition of the PI3K/AKT signaling pathway activator 740 YP weakened the inhibitory effect of BrP-LPA on the above process. METH may promote M1 polarization and glycolytic activity in microglia by activating LIPH/LPA/PI3K/AKT signaling, thus promoting the progression of PD. Show less
Severe peripheral nerve injury (PNI) remains a major clinical challenge, and functional recovery after conventional neurorrhaphy is often unsatisfactory due to fascicular mismatch, suture tension, and Show more
Severe peripheral nerve injury (PNI) remains a major clinical challenge, and functional recovery after conventional neurorrhaphy is often unsatisfactory due to fascicular mismatch, suture tension, and limited Schwann cell viability. To address these limitations, we previously developed a small-gap chitosan-based conduit that provides a controlled microenvironment for regenerative interventions. This study aimed to investigate whether SOX5 overexpression enhances Schwann cell regenerative potential and, when combined with this conduit, synergistically promotes peripheral nerve regeneration. Schwann cells were transduced with SOX5 lentivirus and assessed for proliferation, migration, and neurotrophic factor secretion in vitro. In a rat sciatic nerve transection model (2-mm gap), animals received a chitosan conduit with intraluminal injection of SOX5 lentivirus. Histological, electrophysiological, and behavioral assessments were conducted at 12 weeks post-surgery. SOX5 overexpression significantly enhanced Schwann cell proliferation, migration, and secretion of BDNF, NGF, CNTF, and VEGF, while maintaining the dedifferentiated repair phenotype. In vivo, the combination of SOX5 lentivirus and chitosan conduit improved axonal regeneration, reduced muscle atrophy, and increased conduction velocity and locomotor recovery relative to the empty conduit group. Lentivirus-mediated SOX5 overexpression drives Schwann cells toward a repair phenotype and, when integrated with a small-gap chitosan-based conduit, effectively promotes structural and functional nerve regeneration. Show less
Fear of progression (FoP) is a prevalent psychological issue among stroke patients. Previous studies failing to distinguish characteristics of patient groups with varying FoP levels. Latent profile an Show more
Fear of progression (FoP) is a prevalent psychological issue among stroke patients. Previous studies failing to distinguish characteristics of patient groups with varying FoP levels. Latent profile analysis (LPA) classifies individuals into distinct subgroups via continuous FoP indicators, boosting classification accuracy by accounting for variable uncertainty. Given FoP's heterogeneity, investigating FoP profiles and their influencing factors in stroke patients is clinically significant for personalized psychological care and improved patient quality of life. A total of 366 stroke patients were selected as study subjects through convenience sampling, and a cross-sectional survey was conducted. FoP was assessed using the Fear of Progression Questionnaire-Short Form (FoP-Q-SF, 2 dimensions, 12 items). Independent variables included demographic characteristics, clinical indicators, the Recurrence Risk Perception Scale for Stroke patients (RRPSS), and the Medical Coping Modes Questionnaire (MCMQ). LPA was performed on the FoP-Q-SF items to identify subgroups. The R3STEP method was used to analyze influencing factors of subgroup membership, and the BCH method was applied to compare differences in distal outcomes across subgroups. Statistical significance was set at The study sample had a mean age of 63.93 ± 10.58 years, with 70.5% males and 65.0% first-ever stroke patients. Two latent profiles were identified: Low-FoP Adaptive Type (C1, 48.6%) and High-FoP Sustained Type (C2, 51.4%). The R3STEP showed that age 18-59 years (OR = 0.476, 95%CI = 0.245-0.924, This study revealed significant heterogeneity in FoP among stroke patients. Age, hypertension comorbidity, excessive recurrence risk perception, MCMQ-confrontation, and MCMQ-avoidance were associated with high FoP. Healthcare providers should prioritize identifying high-risk individuals and develop tailored interventions to reduce FoP and improve rehabilitation outcomes. Show less
Non-suicidal self-injury (NSSI) is highly prevalent among adolescents with depression, yet the heterogeneity of underlying temperamental risk factors remains poorly understood. Traditional variable-ce Show more
Non-suicidal self-injury (NSSI) is highly prevalent among adolescents with depression, yet the heterogeneity of underlying temperamental risk factors remains poorly understood. Traditional variable-centered approaches fail to capture how distinct affective temperaments co-occur within individuals. This study aimed to identify latent profiles of affective temperaments and examine their association with NSSI, exploring the statistical mediating role of cognitive emotion regulation (CER). A cross-sectional study was conducted from February 2025 to September 2025 at the First Hospital of Hebei Medical University. A total of 290 adolescents (aged 10–19) diagnosed with Major Depressive Disorder were recruited, with 282 valid responses included in the final analysis. Participants completed the TEMPS-A, CERQ, and ASHS. Latent Profile Analysis (LPA) was utilized to identify temperament subgroups. Mediation analysis with bootstrapping was performed to test the indirect effects of CER strategies. LPA identified three distinct profiles: Resilient/Low-risk (Class 1, 32.6%), Anxious-Depressive (Class 2, 46.1%), and Mixed-Dysregulated (Class 3, 21.3%). The Mixed-Dysregulated group, characterized by simultaneous elevations in depressive, anxious, irritable, and cyclothymic temperaments, exhibited the highest frequency (45.2 ± 21.3 times/year) and prevalence (98.8%) of NSSI compared to other groups ( The findings delineate a specific “Mixed-Dysregulated” risk phenotype within adolescent depression that is associated with severe NSSI. Interventions should move beyond standard depression care to target cognitive flexibility and emotional regulation skills. Statistical mediation analysis suggests that this risk is mediated by maladaptive cognitive emotion regulation strategies. Not applicable. Show less
Atherosclerosis (AS) is a prevalent typical chronic inflammation disease characterised by lipid deposition, immune cell infiltration and inflammatory response in the arterial intima. The long-term tre Show more
Atherosclerosis (AS) is a prevalent typical chronic inflammation disease characterised by lipid deposition, immune cell infiltration and inflammatory response in the arterial intima. The long-term treatments of the existing drugs suffered safety concerns. Show less
High-dose methotrexate for pediatric cancer treatment is frequently associated with mucositis, which can lead to delayed or discontinued treatment and impact survival. While individual genetic variant Show more
High-dose methotrexate for pediatric cancer treatment is frequently associated with mucositis, which can lead to delayed or discontinued treatment and impact survival. While individual genetic variants have been implicated, the cumulative impact of genetic variation within relevant biological pathways remains unexplored. We evaluated single nucleotide polymorphisms across 18 pathways previously identified as relevant to mucositis in 278 pediatric patients with acute lymphoblastic leukemia from six academic health centers across Canada. Pathway enrichment was assessed using the Joint Association of Genetic variants tool, and a predictive model was developed using XGBoost, a supervised machine learning algorithm based on gradient-boosted decision trees. Pathway enrichment identified significant associations in IL6 (P = 0.04) and WNT/β-catenin (P = 0.048) signaling pathways. The predictive model (area under the curve [AUC] = 0.76) highlighted single nucleotide polymorphisms associated with inflammation- and mucosa-related genes, including PRKCD, IL17B, MAST3, and CAPN9, with both risk and protective effects. Model performance dropped by 0.15 in AUC (from 0.76 to 0.61) after removing single nucleotide polymorphism features, underscoring their predictive value. This pathway-informed approach identifies genetic contributors to methotrexate-induced mucositis and supports polygenic risk prediction. Our findings provide a foundation for individualized toxicity risk profiling and suggest potential therapeutic targets to mitigate treatment-limiting mucositis in pediatric oncology. Show less
Given the potential of polyphenols to mitigate neurodegenerative diseases (NDDs), this meta-analysis investigated whether clinical evidence supports the use of polyphenols for neuroprotection and as n Show more
Given the potential of polyphenols to mitigate neurodegenerative diseases (NDDs), this meta-analysis investigated whether clinical evidence supports the use of polyphenols for neuroprotection and as nutritional strategies in NDDs. We analyzed different polyphenol types across seven NDDs, 13 studies involving 849 participants were included. Prespecified outcomes comprised global cognition (Mini-Mental State Examination, MMSE), domain-specific cognition (Alzheimer's Disease Cooperative Study-Cognitive Subscale, ADCS-Cog), activities of daily living (Alzheimer's Disease Cooperative Study-Activities of Daily Living, ADCS-ADL), neuropsychiatric symptoms (Neuropsychiatric Inventory, NPI), and selected biomarkers (plasma amyloid-β40 and brain-derived neurotrophic factor, BDNF). Reporting followed PRISMA 2020 guidelines, methods conformed to the Cochrane Handbook, and certainty of evidence was assessed using GRADE. Overall, polyphenol supplementation was associated with improved global cognition (pooled MD in MMSE = 2.06; 95% CI 0.62-3.49). In subgroup analyses, flavonoids were associated with a modest but significant improvement in MMSE scores, whereas stilbenes produced a significant benefit in daily functioning (ADCS-ADL) without clear gains in MMSE or ADCS-Cog and no consistent effects on NPI. Anthocyanidins, phenolic acids, and lignans did not significantly affect cognitive outcomes (MMSE or ADCS-Cog), and polyphenol subclasses did not yield robust or consistent changes in NPI or biomarker endpoints (Aβ40 and BDNF). Specific polyphenol subclasses therefore appear to confer selective cognitive and functional benefits, with stilbenes primarily supporting functional outcomes and flavonoids potentially enhancing global cognition. Show less
We recently showed that METRNL (Meteorin-like) protects against atherosclerosis. However, the mechanism for METRNL in atherosclerosis is largely unclear. This study aimed to demonstrate the relative i Show more
We recently showed that METRNL (Meteorin-like) protects against atherosclerosis. However, the mechanism for METRNL in atherosclerosis is largely unclear. This study aimed to demonstrate the relative importance of endothelial METRNL in atherosclerosis by comparing the effects of whole-body METRNL deficiency to endothelial-specific deficiency, and to show the subcellular distribution of endothelial METRNL and its role in mitochondrial homeostasis against atherosclerosis. Our study demonstrated that a deficiency in either endothelial or global METRNL exacerbated atherosclerosis to a similar degree in both spontaneous (age-related) and high fat diet-induced atherosclerosis, suggesting that endothelial METRNL is pivotal in the progression of atherosclerosis due to METRNL deficiency. Endothelial METRNL was diffusely distributed in the cytoplasm with subcellular localization to mitochondria, nucleus, endoplasmic reticulum, and Golgi apparatus (especially enriched in mitochondria and nucleus). In both an in vivo apolipoprotein E-deficient (ApoE Show less
To evaluate the effectiveness of personalized moderate-intensity aerobic brisk walking intervention based on real-time feedback from wrist-worn photoplethysmography (PPG) in improving mild-to-moderate Show more
To evaluate the effectiveness of personalized moderate-intensity aerobic brisk walking intervention based on real-time feedback from wrist-worn photoplethysmography (PPG) in improving mild-to-moderate depressive symptoms. Using an N-of-1 randomized crossover trial design, 33 patients with mild-to-moderate depression (PHQ-9 scores 10-19) completed a 6-week trial consisting of three personalized PPG feedback periods (Period A) and three standardized exercise prescription periods (Period B), each lasting 7 days with 2-day washout periods between phases. The personalized group dynamically adjusted exercise intensity based on real-time heart rate variability (HRV) monitoring (40-59% heart rate reserve), while the standardized group adopted fixed intensity parameters (walking speed 5-6 km/h). The primary outcome was change in PHQ-9 depression scale score, with secondary outcomes including heart rate variability, 6-minute walking distance, serum BDNF, and inflammatory cytokine levels. Compared to standardized prescription, personalized intervention additionally reduced PHQ-9 scores by 2.8 points (95% CI: 1.9-3.7, P < 0.001) with an effect size of 0.73; HRV RMSSD increased by 8.7 ms versus 4.3 ms (P < 0.001), and HRV improvement predicted subsequent symptom relief (β = -0.42); exercise adherence rate in the personalized group was 87.3% compared to 82.1% in the standardized group (P = 0.029); BDNF increased by 28.4% versus 18.7% (P = 0.018); participants with baseline HRV < 25 ms derived greater benefit from personalized intervention (additional improvement of 3.8 points versus 2.1 points, P = 0.008). Both intervention conditions produced clinically meaningful within-group PHQ-9 improvements, though the between-group difference of 2.8 points did not reach the minimal clinically important difference (MCID) threshold of 5 points. Both personalized and standardized moderate-intensity walking interventions substantially improved mild-to-moderate depressive symptoms. Personalized exercise intervention based on real-time PPG monitoring provided statistically significant additional benefits over standardized prescriptions, with advantages in physiological adaptation, exercise adherence, and biomarker improvement. The incremental benefit of personalized monitoring was most pronounced among individuals with impaired autonomic function, providing evidence for precision exercise medicine approaches in depression management. Show less
Coronary heart disease (CHD) remains a leading cause of morbidity and mortality worldwide. Mitochondria-associated endoplasmic reticulum membranes (MAMs) have recently emerged as critical mediators in Show more
Coronary heart disease (CHD) remains a leading cause of morbidity and mortality worldwide. Mitochondria-associated endoplasmic reticulum membranes (MAMs) have recently emerged as critical mediators in cardiovascular pathophysiology; however, their specific contributions to CHD pathogenesis remain largely unexplored. This study aimed to identify and validate MAM-related biomarkers in CHD through integrated analysis of transcriptomic sequencing data and Mendelian randomization, and to elucidate their underlying mechanisms. We analyzed two gene expression microarray datasets (GSE113079 and GSE42148) and one genome-wide association study (GWAS) dataset (ukb-d-I9_CHD) to identify differentially expressed genes (DEGs) associated with CHD. MAM-related DEGs were filtered using weighted gene co-expression network analysis (WGCNA). Functional enrichment analysis, Mendelian randomization, and machine learning algorithms were employed to identify biomarkers with direct causal relationships to CHD. A diagnostic model was constructed to evaluate the clinical utility of the identified biomarkers. Additionally, we validated the two hub genes in peripheral blood samples from CHD patients and normal controls, as well as in aortic tissue samples from a low-density lipoprotein receptor-deficient (LDLR-/-) atherosclerosis mouse model. We identified 4174 DEGs, from which 3326 MAM-related DEGs (DE-MRGs) were further filtered. Mendelian randomization analysis coupled with machine learning identified two biomarkers, DHX36 and GPR68, demonstrating direct causal relationships with CHD. These biomarkers exhibited excellent diagnostic performance with areas under the receiver operating characteristic (ROC) curve exceeding 0.9. A molecular interaction network was constructed to reveal the biological pathways and molecular mechanisms involving these biomarkers. Furthermore, validation using peripheral blood from CHD patients and aortic tissues from the Ldlr-/- atherosclerosis mouse model corroborated these findings. This study provides evidence supporting a mechanistic link between MAM dysfunction and CHD pathogenesis, identifying candidate biomarkers that have the potential to serve as diagnostic tools and therapeutic targets for CHD. While the validated biomarkers offer valuable insights into the molecular pathways underlying disease development, additional studies are needed to confirm their clinical relevance and therapeutic potential in larger, independent cohorts. Show less
To investigate the association between combined vitamin D and N-acetylcysteine (NAC) supplementation and clinical outcomes in patients with generalized anxiety disorder (GAD). This retrospective cohor Show more
To investigate the association between combined vitamin D and N-acetylcysteine (NAC) supplementation and clinical outcomes in patients with generalized anxiety disorder (GAD). This retrospective cohort study included 88 propensity-score-matched patients with GAD from Beidahuang Group Neuropsychiatric Hospital. Based on clinical records, patients were classified into an observation group (vitamin D3 + NAC + usual care) and a control group (usual care only). Anxiety symptoms and cognitive function were assessed using the Beck Anxiety Inventory (BAI), Automatic Thought Questionnaire (ATQ), and Dysfunctional Attitudes Scale (DAS). Serum levels of 25-hydroxyvitamin D [25(OH)D], inflammatory markers [high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6)], oxidative stress parameters [glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD)], and neurochemical markers [brain-derived neurotrophic factor (BDNF), dopamine (DA), Serotonin (5-HT), norepinephrine (NE)] were measured at baseline and week 8. After 8 weeks, both groups showed significant improvements in BAI, ATQ, and DAS scores, with greater reductions in the observation group (all In this retrospective cohort, combined vitamin D and NAC supplementation was associated with significantly greater improvements in anxiety symptoms, cognitive patterns, and relevant metabolic biomarkers in patients with GAD compared to usual care alone, supporting its potential as an adjunctive therapy. Show less
Ischemic heart failure (IHF) is one of the leading causes of death in the world. Plasma apolipoprotein C3 (ApoC3) levels are significantly elevated in patients with heart failure and positively associ Show more
Ischemic heart failure (IHF) is one of the leading causes of death in the world. Plasma apolipoprotein C3 (ApoC3) levels are significantly elevated in patients with heart failure and positively associated with the incidence of ischemic heart disease (IHD). However, the causal association between ApoC3 and IHD development is unclear. ApoC3 expression changes were assessed in plasma from IHF patients/healthy donors and cardiac tissue from rodent models. 10-week-old male human ApoC3 transgenic (ApoC3 Overexpression of human ApoC3 in ApoC3 ApoC3 overexpression could activate cardiac TLR2/NF-κB to trigger the inflammation, oxidation, and apoptosis pathways, finally aggravating IHF in mice. Inactivation of ApoC3 could significantly alleviate IHF in hamsters. Show less
Fusion genes are pivotal drivers of tumorigenesis, often generating oncogenic chimeric RNAs and fusion circular RNAs. However, the mechanisms by which these transcripts synergistically contribute to c Show more
Fusion genes are pivotal drivers of tumorigenesis, often generating oncogenic chimeric RNAs and fusion circular RNAs. However, the mechanisms by which these transcripts synergistically contribute to cancer progression remain poorly understood. Here, we identified a lung cancer-specific chimeric RNA KANSL1-ARL17A (chKANSARL) and its circular variant fusion circular RNA KANSL1-ARL17 A (F-circKA), both derived from the fusion gene KANSARL. Functional assays revealed that overexpression of either chKANSARL or F-circKA significantly enhanced lung cancer cell proliferation, migration, and invasion, while their knockdown suppressed these malignant phenotypes. In vivo experiments demonstrated that chKANSARL overexpression accelerated tumor growth in immunodeficient mice. Notably, coexpression experiments uncovered a synergistic regulatory interaction between F-circKA and chKANSARL, amplifying oncogenic effects. Mechanistically, miRNA sequencing and dual-luciferase assays revealed that F-circKA acts as a molecular sponge for miR-6860, thereby derepressing chKANSARL expression. Rescue experiments further validated this regulatory axis, wherein miR-6860 inhibition reversed the tumor-suppressive effects of F-circKA knockdown. Collectively, our study identifies and characterizes a novel F-circKA/miR-6860/chKANSARL regulatory axis, revealing how dual transcriptional outputs from the KANSARL fusion gene can synergistically drive lung cancer progression. These findings highlight a previously unrecognized layer of cooperative regulation between linear and circular fusion RNAs in oncogenesis and provide a new framework for understanding fusion gene-mediated tumorigenesis. Show less