👤 Ruyue Ma

To identify distinct latent frailty profiles using latent profile analysis (LPA) in patients undergoing radiotherapy for head and neck cancer (HNC) and to examine the factors associated with profile membership. A cross-sectional study. This research used data acquired from a major tertiary referral hospital in China. This study recruited 391 HNC patients receiving radiotherapy. Validated instruments included a demographic questionnaire, Charlson Comorbidity Index (CCI), Pittsburgh Sleep Quality Index, FRAIL Scale, Hospital Anxiety and Depression Scale and Perceived Social Support Scale. Profile membership associations were assessed using χ The frailty status of patients can be divided into three different categories: (1) robust group (23.0%), (2) prefrail group (49.6%) and (3) frail group (27.4%). Frailty demonstrated independent associations with nine clinical parameters in adjusted regression models: radiotherapy session frequency, social support, age, CCI score, educational attainment, metastasis, nutritional risk, radiation-induced injuries and serum albumin levels (p<0.05). The distinct frailty profiles identified by LPA can inform the future development of targeted care protocols for specific subgroups (eg, the frail group), with a focus on key predictors such as age and nutritional risk. Show less

Pulmonary artery sling (PAS) is a rare congenital vascular anomaly, in which the left pulmonary artery arises aberrantly from the right pulmonary artery and courses between the trachea and esophagus, often causing tracheobronchial compression. It is frequently considered within the spectrum of vascular rings. Prenatal diagnosis remains challenging yet crucial for optimizing perinatal management and neonatal outcomes. This case report illustrates the enhanced diagnostic capability achieved by integrating conventional two-dimensional (2D) ultrasound with spatiotemporal image correlation (STIC) technology for the accurate prenatal identification of PAS. A 33-year-old gravida 2 para 0 woman was referred for routine fetal assessment at 31 weeks of gestation. Initial 2D ultrasonography in the three-vessel tracheal view revealed an anomalous vascular configuration, suggesting the left pulmonary artery (LPA) originating from the right pulmonary artery (RPA). To confirm the diagnosis and delineate the vascular course, STIC technology was employed. The STIC volumetric acquisition and subsequent multi-planar reconstruction unequivocally demonstrated the LPA arising from the RPA and coursing posteriorly behind the trachea, thereby confirming the diagnosis of PAS. A comprehensive fetal echocardiogram excluded associated intracardiac anomalies. Following extensive parental counseling, the pregnancy continued uneventfully. The infant was delivered via elective cesarean section at 38 The synergistic use of routine 2D ultrasound and STIC technology provides a robust, clinically accessible method for the precise prenatal diagnosis of fetal PAS. This integrated imaging approach facilitates definitive diagnosis, enhances parental counseling, enables coordinated multidisciplinary perinatal planning, and ensures timely surgical intervention, all of which are pivotal for achieving favorable long-term outcomes in affected infants. Show less

This study aimed to identify latent classes of adherence for serum phosphorus control and their influencing factors among patients receiving Peritoneal Dialysis with hyperphosphatemia. This cross-sectional study using convenience sampling was conducted among patients receiving peritoneal dialysis with hyperphosphatemia between December 2024 and May 2025. Participants were assessed using the Phosphate Control Adherence Scale, Self-Efficacy Scale, and Family Care and Social Support Scale. Demographic and clinical data were also collected. Latent profile analysis (LPA) was used to identify adherence subgroups. Univariate analysis and multicollinearity diagnostics were performed, followed by binary logistic regression to determine predictors of adherence. Blood phosphorus control adherence can be classified into two categories: the low-level medical adherence group, characterized by poor dietary self-control (19.93%), and the high-level medical adherence group, marked by effective medication adherence (80.07%). The results indicated that residence conditions, types of medication, and self-efficacy significantly influenced blood phosphorus control adherence among patients with various forms of PD hyperphosphatemia (all p < 0.05). Patients with hyperphosphatemia undergoing peritoneal dialysis exhibit heterogeneity in adherence to serum phosphorus control. This indicates that healthcare providers should identify the adherence characteristics of different patient groups at an early stage and implement targeted intervention strategies to enhance patients' adherence to serum phosphorus management. Show less

Corneal transparency maintenance relies on the water-pumping function of the corneal endothelium. Currently, corneal transplantation remains the only available treatment for corneal endothelial dysfunction, therefore, the development of alternative therapies is critical due to the global shortage of donor corneas. In our previous study, we confirmed that corneal stromal cells (CSCs) secretion can promote corneal endothelial cells (CEnCs) proliferation. This effect can be enhanced by treatment with lysophosphatidic acid (LPA), a bioactive phospholipid. Nevertheless, the components involved in CSC secretion remain to be elucidated. In this study, we investigated the therapeutic potential of CSC-derived exosomes and exosomal microRNAs (miRNAs) for enhancing CEnCs proliferation and corneal endothelial healing. CSC exosomes were characterized via nanoparticle tracking (NTA), transmission electron microscopy (TEM), and immunoassays. The miRNA expression profiles of CSC exosomes were identified via RNA sequencing, revealing a total of 767 distinct miRNAs. The proliferative effects of CSC exosomes and exosomal miR-221-3p were increased by LPA. Ectopic expression of miR-221-3p further increased CEnC proliferation and suppressed the expression of the CDK inhibitor p27 Show less

Background Although substantial evidence has demonstrated the impact of obesity on brain structure and cognition, the heterogeneity of adiposity-particularly in terms of fat distribution patterns-and its differential neurologic effects remain poorly understood. Purpose To identify body fat distribution patterns with MRI and latent profile analysis (LPA) and their associations with brain structure measurements, cognition, and neurologic diseases. Materials and Methods This secondary analysis used prospective data from the UK Biobank, including health records and MRI scans of the brain, heart, and abdomen. Fat distribution profiles were classified using LPA based on eight body mass index (BMI)-adjusted MRI-derived fat quantification metrics. Differences in brain volume, white matter properties, cognition, and the risk of neurologic disorders were analyzed across profiles and relative to a benchmark lean profile; analyses were stratified by sex. Group differences were examined using analysis of covariance (ANCOVA) or rank-based ANCOVA. Results Among 25 997 participants (mean age, 55 years ± 7.4 [SD]; 13 536 female participants), LPA identified six profiles of body fat distribution in both sexes. Four high-adiposity patterns were identified, including the pancreatic-predominant profile (profile 1), with elevated proton density fat fraction (mean BMI-adjusted Show less

Postoperative symptoms in lung cancer patients are complex and dynamic, yet recovery is highly heterogeneous. Traditional analyses often fail to capture individual recovery trajectories, limiting the ability to provide personalized care. This study aimed to identify distinct postoperative symptom trajectories and their clinical predictors using a person-centered approach. We conducted a prospective longitudinal study with 394 patients undergoing uniportal video-assisted thoracoscopic surgery (uniportal VATS) for early-stage non-small cell lung cancer. Patient-reported symptoms were collected at 1, 7, 14, and 30 days postoperatively. Latent Profile Analysis (LPA) was used to identify distinct symptom profiles, and Latent Transition Analysis (LTA) modeled the transitions between these profiles over time. Multinomial logistic regression was used to identify predictors of these transitions. LPA identified two distinct recovery profiles: a "Rapid Recovery" group (C1) and a "High-Symptom, Slow Recovery" group (C2). The first postoperative week was a critical window, with 73.0% of patients in the High-Symptom, Slow Recovery group transitioning to the Rapid Recovery group. This transition rate slowed significantly in subsequent weeks. A higher ASA classification, use of a thicker chest tube, and extensive lymph node dissection predicted a slower recovery. Conversely, better pulmonary function (FEV1%, MVV%) facilitated a faster transition, while postoperative complications were associated with a negative trajectory shift. Postoperative recovery in lung cancer patients follows predictable, heterogeneous trajectories. This person-centered approach enables the early identification of high-risk patients based on preoperative and surgical factors. Understanding these distinct pathways allows for a shift from a one-size-fits-all model to staged, personalized interventions designed to optimize symptom management and enhance patient recovery. Show less

Parents of children with congenital heart disease (CHD) face chronic stress impairing family functioning and well-being. As a key protective factor, family resilience aids their adaptation. However, existing research predominantly measures general family resilience, neglecting heterogeneous resilience patterns and subgroup profiles. Our study uses person-centered Latent Profile Analysis (LPA) to identify latent family resilience classes in Chinese culture to provide tailored support. This study adopted a cross-sectional survey design. From October 2024 to July 2025, convenience sampling was used to recruit 426 eligible parents of children with CHD from two tertiary hospitals in Yunnan Province, China. Data were collected using the General Information Questionnaire, Family Hardiness Index (FHI), Simplified Coping Style Questionnaire (SCSQ), and Social Support Rating Scale (SSRS). LPA was applied to classify the family resilience levels of these parents. Subsequently, univariate and multivariate ordinal logistic regression analyses were conducted to explore the factors associated with different latent classes of family resilience. A total of 400 valid questionnaires were collected, with an effective response rate of 93.9%. The mean total score for family resilience in parents of children with CHD was 58.13 ± 5.79, suggesting a moderate overall level of family resilience in this group. The family resilience of parents of children with CHD was classified into three latent profiles: “High family resilience responsibility-anchored type” ( Parents of children with CHD demonstrate heterogeneity in family resilience. Healthcare professionals should pay attention to the family resilience differences among parents of children with CHD and implement targeted intervention measures based on the characteristics of different subgroups, thereby enhancing parents’ family resilience and further promoting family well-being. The online version contains supplementary material available at 10.1186/s12889-025-26143-0. Show less

High-density lipoprotein(a) (Lp(a)) is a well-established independent risk factor for atherosclerotic cardiovascular diseases (ASCVD). However, the interaction between Lp(a), low-density lipoprotein cholesterol (LDL-C), and polygenic risk score (PRS) in cardiovascular diseases has been the subject of relatively limited research. The present study included a total of 346,751 participants from the UK Biobank. According to the guideline of Lp(a), the study subjects were divided into 3 groups: the first group was <75 mmol/L (n = 272,643), the second group was 75 to 125 mmol/L (n = 35,792), and the third group was >125 mmol/L (n = 38,316). Elevated Lp(a) levels were associated with a progressively increased risk of overall cardiovascular events (CVEs), including ischemic stroke (IS), coronary heart disease (CHD), angina pectoris, and myocardial infarction (MI). In contrast, the risks of atrial fibrillation (AF) and heart failure (HF) decreased with higher Lp(a) levels. Additive interaction analyses revealed significant synergistic effects between Lp(a) and LDL-C for CHD (relative excess risk interaction [RERI] = 0.081, attributable proportion of interaction [AP] = 0.046, synergy index [SI] = 1.117), angina pectoris (RERI = 0.112, AP = 0.055, SI = 1.121), and MI (RERI = 0.183, AP = 0.079, SI = 1.161), with MI showing the strongest synergy. Incorporating PRS further amplified these effects, and the RERI (CHD: RERI = 0.721; angina pectoris: RERI = 0.781; MI: RERI = 1.318) and SI (CHD: SI = 2.218; angina pectoris: SI = 1.97; MI: SI = 2.326) were significantly higher than those of the interaction model containing only Lp(a) and LDL-C. In conclusion, Lp(a) and LDL-C show a significant synergistic effect in ASCVD, and this effect is more prominent in individuals with a higher PRS, suggesting that dual lipid management should be strengthened for such populations. While AF and HF may require alternative risk factor management. Show less

This article presents a case of a rare lymphoplasmacytic lymphoma (LPL) complicated by spherocytosis in a 74-year-old male. The patient reported progressive fatigue and anemia and had a medical history of type 2 diabetes, hypertension, and cerebral infarction. Laboratory tests indicated moderate anemia (hemoglobin 80 g/L) and a monoclonal increase in serum IgG. A bone marrow biopsy combined with immunohistochemistry confirmed the diagnosis of lymphoplasmacytic lymphoma (IgG-κ type, MYD88 L265P negative). A peripheral blood smear revealed an increase in spherocytes, a positive acidified glycerolysis test (AGLT50), abnormal erythrocyte osmotic fragility, and a negative direct antiglobulin test. Genetic screening for hereditary erythrocyte diseases showed no pathogenic variations. The patient's condition stabilized following targeted therapy with zanubrutinib and rituximab (ZR regimen). This case underscores the complexity of diagnosing dual hematological anomalies, highlights the importance of multidisciplinary collaboration, and seeks to explore the potential pathophysiological link between LPL and spherocytosis, offering a reference for diagnosis and treatment in similar clinical scenarios. Show less

Norethindrone (NET) and levonorgestrel (LNG) are synthetic progestins frequently detected in aquatic environments, have unclear effects on lipid metabolic homeostasis during the early life stages of aquatic organisms. Although progestins commonly occur as mixtures, their combined impacts remain unclear. In this study, we investigated the individual and combined impacts of NET and LNG at environmentally relevant concentrations (2-200 ng/L) on lipid metabolism in zebrafish larvae. NET and LNG significantly disrupted early development in zebrafish. It also altered lipid profiles, as indicated by elevated triglyceride (TG) levels, reduced total cholesterol (TC), as well as alterations in key metabolic enzymes (FASN, LPL) and lipid-regulatory genes (pparγ, fasn, lpl, pparα). Co-exposure with LNG resulted in non-additive responses across multiple endpoints. Antagonistic interactions were predominant at medium and high concentrations, while occasional synergism was observed at low doses. These complex patterns were further supported by Bliss independence model analysis. Notably, combined exposure suppressed both lipid synthesis and degradation pathways more strongly than individual treatments, leading to lipid accumulation and altered energy regulation. This study advanced understanding of the ecological risks caused by progestins in aquatic environments and highlighted the necessity of mixture-based risk assessment of endocrine-disrupting compounds. Show less

Organic and organic-inorganic hybrid materials exhibiting room-temperature phosphorescence (RTP) and long persistent luminescence (LPL) materials have attracted growing attention for various time-resolved optoelectronic applications. To date, realizing intrinsically distinct RTP and LPL emissions within a single material system remains elusive, yet it is crucial for unlocking multifunctional applications such as multilevel optical encryption. Here, a Mn Show less

We aimed to investigate whether maternal and fetal genetic predispositions to insulin deficiency and resistance affect offspring fetal growth through distinct pathways in multi-ethnic populations. In 5065 multi-ethnic mother-infant pairs, we examined the conditional associations of maternal and fetal partitioned polygenic risk scores (pPRSs) for type 2 diabetes-related pathways with fetal growth outcomes, including birthweight, sum of skinfold thicknesses (SSF), large-for-gestational-age (LGA) births and small-for-gestational-age (SGA) births. Two-sample Mendelian randomisation (2SMR) in Europeans was performed for triangulation. Exposures were eight type 2 diabetes-related pathways (n=1,812,017), eight beta cell function indices (n=26,356) and two insulin sensitivity indices (n=53,657). Outcomes were maternal and fetal genetically determined birthweight (n=406,063). Mediation analysis was used to assess the mediation effects of maternal glucose levels and BMI on maternal genetic effects and of cord blood C-peptide on fetal genetic effects. Co-localisation analyses were performed to test for shared causal variants. Fetal type 2 diabetes polygenic risk score (PRS) and pPRSs for lipodystrophy-related insulin resistance and impaired fasting glucose (IFG)-related insulin deficiency were associated with lower birthweight and SSF, while maternal type 2 diabetes PRS and pPRSs for IFG-related insulin deficiency and obesity-related insulin resistance were associated with higher offspring birthweight, SSF and LGA. These associations were consistent across five ethnic groups. Maternal post-load hyperglycaemia mediated 44.2% and 34.2% of the effects of type 2 diabetes PRS and IFG pPRS, respectively, while maternal BMI mediated 43.4% of the effect of Obesity pPRS. 2SMR found consistent results in Europeans and further revealed that fetal insulin sensitivity index and corrected insulin response were associated with higher birthweight. Some loci with shared causal variants acted through multiple pathways, including CDKAL1, TCF7L2, ADCY5 and MACF1. Reduced fetal growth may be driven by lipodystrophy-related insulin resistance and IFG-related insulin deficiency pathways. Targeting pregnant women with high type 2 diabetes PRS/pPRS and prescribing interventions to reduce their post-load hyperglycaemia and BMI may help reduce offspring risk of LGA. Show less

The increasing prevalence of age-related osteoporosis has emerged as a critical public health issue in the context of the globally aging population. Chronic oxidative stress, induced by excessive reactive oxygen species (ROS) associated with aging, is a critical factor underlying the development of osteoporosis in elderly individuals and a diminished capacity for bone formation and osteogenic differentiation. However, the mechanism underlying age-related osteoporosis remains unclear. MACF1 (microtubule actin crosslinking factor 1) is an essential factor that regulates bone formation and development, and exhibits reduced expression as humans age. In this study, we used MACF1 conditional knockout (MACF1-cKO) mice as a premature aging model and found that MACF1-cKO mice exhibited chronic oxidative stress. Moreover, the expression level, nuclear translocation, and transcriptional activity of FoxO1 were promoted in MACF1 deficient osteoblastic cells. In addition, the binding of FoxO1 to β-catenin was enhanced, increasing the transcriptional activity of the FoxO1/β-catenin pathway in MACF1 deficient osteoblastic cells. The enhanced FoxO1/β-catenin pathway competitively weakens the binding of β-catenin to TCF7 and decreases the activity of the TCF7/β-catenin pathway. Our study showed that FoxO1 responded to chronic oxidative stress induced by MACF1 deficiency to determine β-catenin fate and regulate osteoblast differentiation during senile osteoporosis. Show less

This study aimed to elucidate the spectrum of clinical manifestations, cytomorphology, immunophenotype, and the molecular genetic features of lymphoblastic lymphoma/acute lymphoblastic leukemia (LBL/ALL) in the context of serous effusions (SE). A retrospective analysis evaluated the cytomorphological features, immunophenotype, and the cyto-histological correlations of twenty-one LBL/ALL associated with SE. Concurrently, bone marrow (BM) aspiration samples were analyzed using an integrated approach, including flow cytometry, reverse transcription PCR (RT-PCR), next-generation sequencing (NGS), or whole transcriptome sequencing (WTS). Of the 21 cases of SE LBL/ALL, 16 cases were T-LBL/ALL and 5 cases were B-LBL/ALL. The cases included 17 pleural, 2 peritoneal, and 2 pericardial fluid samples. Both T-LBL/ALL and B-LBL/ALL in SE exhibit a blast-like morphology, characterized by small to medium size, irregular nuclear membranes, and inconspicuous nucleoli, alongside frequent nuclear fragmentation and apoptotic bodies. LBL/ALL express immaturity markers such as terminal deoxynucleotidyl transferase (7/17, 41.2%), CD10 (6/12, 50%), CD43 (8/8, 100%), and CD99 (6/6, 100%). T-LBL/ALL and B-LBL/ALL specifically express T-cell markers (CD2 [3/6, 50%], CD3 [10/12, 83.3%], CD5 [2/11, 18.2%], CD7 [10/10, 100%]) or B-cell markers (CD20 [3/5, 60%], CD79a [4/4, 100%], PAX5 [5/5, 100%]), respectively. A high proportion of primitive and immature lymphocytes exceeding 25% in BM was observed in T-LBL/ALL (5/7) and in one case of B-LBL/ALL. No BCR/ABL gene rearrangements were detected in any cases. Furthermore, fusion gene MLL::ENL and PLCALM::MLLT10, as well as mutations in genes including WT1, NOTCH1, PAX5, IKZF, ARID1A, BCOR, SETD2, ARID2, TET2, JAK3, NF1, and CEBPA, were identified in LBL/ALL through RT-PCR, NGS, or WTS analyses. The integration of clinical manifestations, cytological evaluation, and gene expression profiles is instrumental in achieving accurate diagnosis, subclassification, and prognosis of LBL/ALL within the context of SE. Show less

BRCA1-deficient epithelial ovarian cancer (EOC) is reported to respond to poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPis); however, acquired resistance frequently emerges, limiting the long-term clinical efficacy of PARPis. The mechanisms driving acquired PARPi resistance in these patients remain poorly understood. In this study, we performed a systemic screen of epigenetic inhibitors in patient-derived organoids (PDOs) and identified enhancer of zeste homolog 2 (EZH2) as the key driver of PARPi resistance in BRCA1-deficient EOC. We found that in PARPi-resistant cells, intracellular EZH2 translocated from the nucleus to the mitochondria, where it promoted mitochondrial fusion and subsequently prevented PARPi-mediated apoptosis. Mechanistically, we determined that PARPi treatment activated YES1 to phosphorylate EZH2 at the Y728 residue, which promoted the mitochondrial translocation of EZH2 in a TOM20-dependent manner. Using mass spectrometry, we identified MYO19 as a main substrate of EZH2 in mitochondria and found that EZH2 trimethylated MYO19 at the K928 residue to trigger mitochondrial fusion. Moreover, Y728 phosphorylation also increased EZH2 protein stability by hindering TRIM4 binding, thus blocking TRIM4-mediated ubiquitination and subsequent proteasomal degradation. Notably, the efficacy of targeting YES1 or EZH2 to resensitize tumors to PARPis was validated in PDOs, xenograft models and EOC cell lines. Here, our findings reveal a YES1-EZH2-MYO19 post-translational modification cascade, whereby PARPi-induced phosphorylation of EZH2 triggered mitochondrial fusion, and targeting phosphorylated EZH2 rebalanced mitochondrial dynamics and resensitized BRCA1-deficient EOC to PARPis, suggesting a promising therapeutic strategy. Show less

Although large-scale studies and potential pathways of genes on intramuscular fat (IMF) in livestock have been reported, research on circRNAs in yaks-a unique, low-IMF-content animal species that is native to the Qinghai-Tibetan Plateau-is still lacking. Based on previous high-throughput sequencing results on Show less

Osteoarthritis (OA) represents a prevalent degenerative joint condition, in which chondrocyte dysfunction plays a key role in disease progression. Although accumulating evidence underscores the importance of cellular stemness regulation in OA development, systematic screening of related biomarkers has been insufficient. The current study sought to discover and validate potential biomarkers through bioinformatics and machine learning (ML), offering novel perspectives for early detection and therapeutic intervention in OA. The present study examined six OA-related transcriptomic profiles from the Gene Expression Omnibus (GEO) to discover and validate stemness-associated biomarkers. Differentially expressed genes (DEGs) were selected and analyzed for enriched biological functions. OA-related modules were determined via weighted gene coexpression network analysis (WGCNA). Key stemness-related genes were selected using ML algorithms, including support vector machine (SVM), random forest (RF), extreme gradient boosting (XGBoost), and the least absolute shrinkage and selection operator (LASSO) regression. Receiver operating characteristic (ROC) analysis was implemented to determine diagnostic accuracy. Utilizing single-sample gene set enrichment analysis (ssGSEA), the link with immune cell infiltration was examined. Ultimately, immunohistochemistry was employed for experimental validation. Intersection analysis identified 56 stemness-related DEGs in OA cartilage. WGCNA analysis yielded 7 modules significantly associated with stemness genes, and a combined screening approach identified 60 candidate genes. Using four machine learning algorithms-SVM, LASSO, XGBoost, and RF-four feature genes were ultimately determined (WWP2, CDKN1A, IL11, and CRTAC1), among which WWP2, CDKN1A, and CRTAC1 showed significant differential expression between OA and normal samples and demonstrated good diagnostic performance in both the training and validation cohorts (AUC > 0.7). ssGSEA analysis revealed that the expression of these three genes was significantly correlated with specific immune cell subpopulations. Immunohistochemistry further confirmed that WWP2 and CDKN1A were downregulated in OA tissues, whereas CRTAC1 was upregulated. Through bioinformatics analysis and IHC validation, we identified three stemness-associated biomarker genes (WWP2, CDKN1A, CRTAC1) in OA. These findings may provide meaningful implications for future clinical assessment, treatment, and research on OA. Show less

Cisplatin resistance remains a major challenge in bladder cancer. Although the tumor suppressor ASPP2 is a critical co-factor for TP53-mediated apoptosis, its role in metabolic reprogramming and cisplatin response remains unclear. This study aimed to delineate the mechanism by which ASPP2 regulates cisplatin sensitivity through metabolic reprogramming. We first assessed the clinical significance of ASPP2 using patient tissues and public databases, finding that its downregulation in bladder cancer is associated with poor patient survival. Through gain- and loss-of-function studies in vitro and in vivo, we further demonstrated that ASPP2 inhibits the mevalonate (MVA) pathway independently of TP53 status, thereby sensitizing cells to cisplatin-induced DNA damage and apoptosis. This chemosensitizing effect was specifically reversed by the addition of MVA pathway metabolites. Moreover, WWP2 was identified as the E3 ubiquitin ligase responsible for ASPP2 degradation via K48-linked ubiquitination. Finally, WWP2 silencing was shown to stabilize ASPP2, suppress the MVA pathway, and synergize with cisplatin to impede tumor growth in mouse models. Overall, the WWP2-ASPP2-MVA pathway axis is identified as a novel driver of cisplatin resistance in bladder cancer. These results establish a mechanistic basis for targeting this axis to restore chemosensitivity, offering a promising therapeutic strategy for recalcitrant disease. Show less

The stimulator of interferon genes (STING) is a central mediator of innate immune sensing and represents a critical regulator of chronic inflammation. Upon persistent infection, excessive neutrophil activation leads to the formation of neutrophil extracellular traps (NETs) that damage the tissues. However, the mechanism by which STING signaling regulates NETs formation under chronic inflammatory conditions remains poorly understood. In this study, using LPS-induced murine endometritis models in wild-type and STING-deficient mice, we demonstrated that STING deficiency significantly suppressed myeloperoxidase activity, and diminished NETs formation. We identified neutrophil surface molecular CD11b as a key downstream target of STING, whose expression was transcriptionally regulated via IRF7. Furthermore, the STING-IRF7 axis was found to drive lipocalin-2 (LCN2) expression, which acted through its receptor MC4R to upregulate intracellular adhesion molecule-1 (ICAM-1), thereby facilitating neutrophil recruitment and NETosis during LPS stimulation. The role of this pathway was validated both Our findings revealed a novel mechanism in which the STING-IRF7 pathway exacerbated endometrial inflammation and tissue damage by coordinately upregulating CD11b and activating the LCN2-ICAM-1 axis. Consequently, targeting the STING signaling pathway may offer a promising therapeutic strategy for chronic endometritis. Show less

Systemic delivery of adeno-associated virus serotype 9 (AAV9) to the central nervous system (CNS) is insufficient due to hindrance from the tight junctions of the blood-brain barrier (BBB). While peptide-display-based AAV engineering has advanced CNS-targeting capsid development, traditional strategies inserting or substituting a 7-mer peptide remain limited by low success rates and scarcity of efficient variants. To address these issues, we developed the Multiple Capsid Mutation Strategies (MCMS) library, which enhanced sequence diversity by incorporating random peptide insertions flanked by AAV9 or variant-derived residues and peptide substitutions within the VR-VIII of the AAV9 capsid protein. Following capsid selection in mice, the leading AAV variant BRC06 was identified and validated across different mouse strains. BRC06 exhibited approximately 1.9-fold higher brain transgene expression than AAV.PHP.eB in C57BL/6J mice. In BALB/c mice, BRC06 achieved a 1,482-fold brain enhancement with a 92-fold liver reduction relative to AAV9. Sequence analysis revealed that BRC06 was derived from the MCMS library's substitution strategies. Additionally, host factor screening revealed AAVR-dependent entry with accessory factors like Show less

Primordial follicle formation and activation are key for the reproductive ability of females. In mice, primordial follicles are formed and begin to activate during the perinatal period, when the levels of estrogen are fluctuating. Whether estrogen plays a role in primordial follicle formation and activation, and its mechanism are still not fully elucidated. In this study, estrogen remained at high levels before birth and declined after birth. When fetal mouse ovaries (E16.5) were cultured in vitro, higher levels (10 nM) of estrogen maintained the germ cell cysts, prevented primordial follicles from forming prematurely, and promoted the full differentiation of oocytes. Furthermore, it was found that estrogen-regulated JNK-signal pathway through both nuclear and membrane receptors, thereby inhibited the degradation of E-cadherin and maintained the germ cell cysts. After birth, ovarian estrogen concentration decreases and is accompanied by the activation of primordial follicles. Hence, the ovaries of newborn mice (P3) were treated with lower concentrations (0.1 nM) of estrogen to investigate the effect of estrogen on primordial follicle activation. The results demonstrated that estrogen regulated the protein expression of cAMP synthase adenylyl cyclase 3 (ADCY3) through the membrane receptor G-protein-coupled estrogen receptor (GPER), increased the level of cAMP in the ovary, and activated the cAMP-PKA signaling pathway to promote the activation of primordial follicles. This study revealed the regulatory role of perinatal estrogen levels on primordial follicle formation and activation before and after birth, which would help to better understand the potential physiological effect of estrogen in vivo. Show less

Cadmium (Cd) contamination in plants and soil poses significant risks to livestock, particularly sheep. Cd exposure often leads to severe gastrointestinal diseases in sheep that are difficult to treat. Milk-derived exosomes, particularly those from sheep milk (SM-Exo), have shown potential in treating gastrointestinal disorders, though their efficacy in Cd-induced colitis remains unclear. In this study, we investigated the therapeutic potential of SM-Exo in a Cd-induced colitis model. Hu sheep were exposed to Cd, and their fecal microbiota were collected to prepare bacterial solutions for fecal microbiota transplantation (FMT) in mice. The changes in gut microbiota and gene expression were analyzed through microbiome and transcriptomics. Our results showed that prior to treatment, harmful bacteria (e.g., Show less

Inflammatory bowel disease (IBD) is a chronic, immune-mediated intestinal disorder driven by dysregulated immune responses in genetically susceptible individuals. Despite recent advances in treatment, more than 30% of patients either fail to respond initially or lose response over time, underscoring the need for a deeper mechanistic understanding of immunogenetic pathways and the development of individualized therapeutic strategies. We first discuss how newly identified susceptibility genes (e.g., IL23R, NOD2, BDNF, SLC) and their polymorphisms influence immune cell function and epithelial barrier integrity. Single-cell technologies have further revealed novel cell subsets and interactions underlying disease heterogeneity. We then explore the clinical efficacy of classical and emerging targeted therapies, including cytokine-specific biologics, JAK inhibitors, and novel strategies aimed at restoring regulatory T-cell function or blocking integrin-mediated lymphocyte trafficking. Additionally, we highlight promising therapeutic approaches such as fecal microbiota transplantation, microbial metabolite-based interventions, and nanotherapeutics. We further discuss how genetic insights and immune biomarkers can facilitate treatment personalization and improve prognostic stratification. Ultimately, this review emphasizes the transition from broad immunosuppression to precision medicine and proposes integrated approaches-combining multiomics profiling, immune monitoring, and novel therapeutics-to achieve sustained remission and improve long-term outcomes in IBD patients. Show less

To investigate the protective effects of secoisolarciresinol digucoside (SDG) on trans fatty acid (TFA)-induced brain inflammatory response and oxidative stress in offspring mice, and to explore the roles of brain-derived neurotrophic factor (BDNF) 28 and tropomyosin receptor kinase B (TrkB) in this process. Female C57BL/6 mice were used in the study. First, pregnant C57BL/6 mice were divided into 5 groups, receiving a normal diet, TFA, low-dose SDG, medium-dose SDG, and high-dose SDG, respectively. After birth, the offspring of the normal diet and TFA groups were subdivided into 2 groups, the normal diet during pregnancy group and the TFA during pregnancy group. The offspring of the low, medium, and high-dose SDG during pregnancy groups were subdivided into 3 groups of low, medium, and high-dose SDG. As a result, the offspring were divided into 13 groups during the lactation period. Only the mother mice were exposed to TFA or SDG intervention. The growth status of the offspring was monitored. After 21 days of lactation, the offspring were sacrificed and the relevant indicators, including pathological changes in the hippocampal region of the brain, levels of tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ), antioxidant levels, and BDNF and TrkB mRNA and protein expression levels, were measured. Maternal TFA exposure and SDG intervention did not result in significant differences in the weight, brain weight, and brain weight coefficient of offspring ( Maternal exposure to a TFA-enriched environment during pregnancy and lactation can induce varying degrees of structural and functional impairment in the brains of offspring and alter the expression levels of BDNF and TrkB proteins in the offspring brain. SDG intervention during TFA exposure exerts protective effects against brain injury in offspring mice, potentially by regulating BDNF and TrkB protein expression to appropriate levels, reactivating BDNF-TrkB downstream signaling pathways, and alleviating inflammatory and oxidative damage. Show less

Diabetes-associated cognitive dysfunction (DACD) is a prevalent and debilitating complication of diabetes, yet effective therapies remain limited. The traditional Chinese medicine compound Naofucong (NFC) has shown neuroprotective potential, but its underlying mechanisms are not fully understood. This study investigated the therapeutic efficacy and molecular mechanisms of NFC against DACD using an integrated multi-omics approach combined with experimental validation. Streptozotocin-induced DACD rats received NFC (22.5 g/kg/day) for 12 weeks. Cognitive performance was assessed by the Morris water maze. Transcriptomics and untargeted metabolomics were integrated to identify key regulatory pathways, which were further validated using immunofluorescence, Golgi staining, cytokine profiling, qPCR, and western blotting. NFC significantly improved spatial learning and memory, attenuated neuronal damage in the hippocampus and cortex, and reduced pathological protein accumulation (APP, phosphorylated Tau). By integrating transcriptomics and metabolomics, we elucidated that NFC primarily acts via activation of the cAMP/PKA/CREB signaling pathway, leading to synaptic repair and neuroinflammatory modulation. Mechanistically, NFC restored synaptic ultrastructure, enhanced dendritic complexity and spine maturation, and upregulated neurotrophic factors (BDNF, NGF) and synaptic proteins (PSD-95, SYN). Furthermore, NFC inhibited glial overactivation, decreased pro-inflammatory cytokines (IL-1β, TNF-α, IFN-γ, IL-6, KC/GRO), and increased anti-inflammatory cytokines (IL-10, IL-13, IL-4), thereby re-establishing neuroimmune balance. NFC exerts multi-target neuroprotective effects by activating the cAMP/PKA/CREB pathway and coordinately regulating synaptic plasticity and neuroinflammation. These findings highlight NFC as a promising candidate for DACD treatment. Show less

The prevalence of depression, a common mental disorder in clinical practice, has been continuously increasing in recent years, with its intricate etiology and pathogenesis incompletely understood. MicroRNA (miRNA), a highly conserved and widely distributed genetic regulatory factor in eukaryotic organisms, plays a crucial role in the pathophysiology of depression. miR-132, a miRNA molecule specifically enriched in the central nervous system, has emerged as a significant focus in the study of depression. miR-132 is involved in the pathogenesis by modulating critical processes such as dendritic spine remodeling and synaptic efficacy. Current research confirms that the expression profile of miR-132 in peripheral blood and brain tissue samples from animal models of depression shows significant abnormal fluctuations, and its expression level is dose-dependently associated with disease severity, progression, and treatment response. Therefore, this article focuses on a few key elements, including brain-derived neurotrophic factor, neuroinflammatory cascade reactions, neurogenesis, and plasticity, to comprehensively examine the potential role of miR-132 expression in the onset and progression of depression. This review also aims to provide a theoretical foundation for future in-depth research and clinical applications in the field of depression therapy. Show less

Cognitive impairment is acknowledged as an early stage between normal aging and Alzheimer's disease, emphasizing the need for prompt intervention. There is growing evidence that the gut-brain axis plays a role in regulating cognitive function, indicating that probiotics and their derivatives may impact cognitive functions through the brain-gut axis. In this study, we isolated and identified a novel bacterial strain Show less

We aimed to discover the biomarkers associated with UI and their correlation with immune cell infiltration. The GSE165004 data set was extracted from the Gene Expression Omnibus and IRGs were obtained from Immport and InnateDB databases. Differential expression analysis, WGCNA, and three machine learning algorithms (LASSO, SVM, and random forest) were used to determine the immune-related hub biomarkers for UI. The diagnostic performance of these markers was evaluated in GSE165004 and validation set (GSE16532). Furthermore, single-sample GSEA was employed to analyze the infiltration level of immune cells and Spearman analysis was conducted to assess the correlation between biomarker and immune cells. The functional enrichment and potential drugs for each biomarker were explored. The biomarker genes were validated in clinical samples by real time PCR assay. Six shared genes (ANXA2, CD300E, IL27RA, SEMA3F, GIPR, and WFDC2) were identified as diagnostic biomarkers by integration analysis. ROC analysis revealed that these markers had diagnostic value for UI both in training and validation sets. Moreover, these biomarkers are closely associated with immune cells, such as natural killer T cells and effector memory CD8 T cells. GSEA analysis showed that these genes were mainly involved in chromosome and mitochondria-related biological functions. Drug prediction indicated that all genes targeted Benzo(a)pyrene. All the biomarker genes, expect for GIPR were differentially expressed in endometrium tissues of UI patients, compared with controls. This study identified immune-related diagnostic biomarkers in UI, providing new insights into understanding the molecular mechanisms and therapeutic targets of UI. Show less

Astrocytes are key regulators of neuroinflammation in multiple sclerosis (MS). Electroacupuncture (EA), a safe and cost-effective adjuvant therapy, has shown benefits in neurodegenerative diseases, but its astrocyte-related mechanisms remain unclear. Here, we demonstrated that EA at ST36 alleviated blood-brain barrier (BBB) disruption and neuroinflammation during the peak period of experimental autoimmune encephalomyelitis (EAE). Additionally, EA at ST36 upregulated the expression of α-melanocyte-stimulating hormone (α-MSH) and its receptor melanocortin-4 receptor (MC4R) in spinal astrocytes. Pharmacological studies showed that MC4R agonist RO27-3225 mimicked the therapeutic effects of EA, whereas MC4R antagonist TCMCB07 weakened EA-mediated BBB protection and neuroinflammation suppression. Moreover, astrocyte-specific silencing of MC4R via adeno-associated virus (AAV) weakened EA-mediated BBB protection and neuroinflammation suppression. RNA-sequencing (RNA-seq) and western blot (WB) revealed that EA exerts neuroprotective effects by activating MC4R to inhibit MAPK and NF-κB signaling pathways. Moreover, in MC4R-overexpressing astrocytes, α-MSH and RO27-3225 reduced inflammation responses, while TCMCB07 reversed the effects by MAPK/NF-κB signaling pathways. Collectively, our findings identify astrocytic MC4R as a critical mediator of EA-driven neuroprotection by suppressing MAPK/NF-κB signaling, providing mechanistic insight and a promising therapeutic target for EAE and other neuroinflammatory disorders. Show less