👤 Lai Wei

Aging is a "multidimensional engine" of biological dysfunction that can fundamentally reshape the pathology of Alzheimer's disease (AD), This review systematically elaborates on how aging synergistically promotes the core pathologies of AD: aging upregulates the activity of β-secretase 1 (BACE1)/γ-secretase, impairs the clearance function of glial cells and meningeal lymphatic drainage, and accelerates Aβ deposition; the imbalance of kinases/phosphatases, dysfunction of molecular chaperones, and aging exosome-mediated propagation of Tau "seeds" facilitate Tau pathology; hyperreactivity of microglia and the transformation of astrocytes to the A1 phenotype form a senescence-associated secretory phenotype (SASP) → neuroinflammation vicious cycle; downregulation of synaptic proteins and disintegration of the default mode network lead to cognitive decline. Recent studies have identified that the impaired transition of aging microglia to the disease-associated microglia (DAM) phenotype, peripheral-central aging signal transmission loops (the gut-brain axis, immune-brain axis, and metabolic-brain axis), as well as circadian rhythm/vascular metabolic dysregulation, have emerged as novel intervention targets. Precision strategies targeting aging mechanisms-such as senescent cell clearance, SASP inhibition, epigenetic reprogramming, and biomarker-guided early intervention-provide a new paradigm for blocking the progression of AD. Show less

Alzheimer's disease, a progressively degenerative neurological disorder, is the most common cause of dementia in the elderly. While its precise etiology remains unclear, researchers have identified diverse pathological characteristics and molecular pathways associated with its progression. Advances in scientific research have increasingly highlighted the crucial role of non-coding RNAs in the progression of Alzheimer's disease. These non-coding RNAs regulate several biological processes critical to the advancement of the disease, offering promising potential as therapeutic targets and diagnostic biomarkers. Therefore, this review aims to investigate the underlying mechanisms of Alzheimer's disease onset, with a particular focus on microRNAs, long non-coding RNAs, and circular RNAs associated with the disease. The review elucidates the potential pathogenic processes of Alzheimer's disease and provides a detailed description of the synthesis mechanisms of the three aforementioned non-coding RNAs. It comprehensively summarizes the various non-coding RNAs that have been identified to play key regulatory roles in Alzheimer's disease, as well as how these non-coding RNAs influence the disease's progression by regulating gene expression and protein functions. For example, miR-9 targets the UBE4B gene, promoting autophagy-mediated degradation of Tau protein, thereby reducing Tau accumulation and delaying Alzheimer's disease progression. Conversely, the long non-coding RNA BACE1-AS stabilizes BACE1 mRNA, promoting the generation of amyloid-β and accelerating Alzheimer's disease development. Additionally, circular RNAs play significant roles in regulating neuroinflammatory responses. By integrating insights from these regulatory mechanisms, there is potential to discover new therapeutic targets and potential biomarkers for early detection and management of Alzheimer's disease. This review aims to enhance the understanding of the relationship between Alzheimer's disease and non-coding RNAs, potentially paving the way for early detection and novel treatment strategies. Show less

Myocardial infarction (MI) is the most severe clinical manifestation of coronary artery diseases (CVD) and serves as a critical driver of sudden cardiac death and heart failure (HF). Its pathophysiology begins with the abrupt cessation of coronary blood flow, leading to severe ischemia and subsequent cardiomyocyte necrosis. This study aimed to investigate the molecular mechanisms by which METTL14 regulates the progression of MI in mice via the OTUD1/DUSP6 signaling axis. An MI mouse model was established by ligating the left anterior descending (LAD) coronary artery. The progression of MI was evaluated through echocardiography, HE staining, Masson's trichrome staining, TUNEL assay, and assessment of inflammatory cytokines. Mechanistically, Me-RIP, PAR-CLIP Co-IP, and protein stability assays were performed to dissect the interactions within the METTL14/OTUD1/DUSP6 axis. Our results demonstrated that METTL14 was highly expressed in the MI mouse model. Silencing METTL14 significantly reduced the left Ventricular Internal Diameter at end-diastole (LVIDd) and left Ventricular Internal Diameter at end-systole (LVIDs), increased ejection fraction (EF) and fractional shortening (FS), and attenuated histopathological damage, apoptosis, and the levels of inflammatory cytokines (TNF-α and IL-β). Further analysis revealed that METTL14 promotes OTUD1 mRNA stability and expression by modulating its m Show less

Primary resistance to chimeric antigen receptor (CAR) T-cell therapies has limited their widespread application. Our prior genome-wide CRISPR/Cas9 screening revealed that the loss of CD58, a crucial intrinsic resistance factor in tumors, resulted in insufficient immune synapse formation and impaired CAR T-cell activation and cytotoxicity. However, the specific signaling pathway and transcriptional changes associated with CAR T-cell dysfunction have not been addressed. Here, we revealed that AP-1-mediated activation was attenuated in CAR T cells impaired by tumor CD58 loss, driving a decrease in mitochondrial biogenesis, metabolic kinetic impairment, mitochondrial membrane potential loss and ROS accumulation. Moreover, this AP-1 attenuation triggered death receptor-independent apoptosis through the intrinsic mitochondrial pathway. In seeking therapeutic strategies, we pharmacologically and genetically blocked three distinct inhibitory phosphatases positioned upstream of AP-1 signaling. Multifaceted validation has demonstrated that dual specificity phosphatase 6 (DUSP6) blockade is an effective approach to supplement AP-1 signaling while notably reducing CAR T-apoptosis and enhancing mitochondrial fitness, proliferation and long-term cytotoxicity. The transcriptomic profiles of DUSP6-ablated CAR T cells revealed markedly upregulated T-cell activation signatures and enriched metabolic pathways. Clinically, bulk and single-cell RNA-seq analyses revealed that DUSP6 was downregulated in patients who responded to T-cell-based immunotherapy, implying its relevance to patient outcomes. Our findings repositioned CD58 not merely as an immune synapse component but also a metabolic checkpoint in CAR T-cell biology, the loss of which triggers AP-1-dependent mitochondrial derangement and creates a permissive landscape for intrinsic apoptosis, which can be ameliorated by ablation of the inhibitory phosphatase DUSP6. Crucially, DUSP6 ablation represents a promising engineering target to potentiate CAR T-cell efficacy in broader applications. Show less

There is a close connection between aging and osteoarthritis (OA), but the specific mechanisms are still unclear. This study aims to explore the potential connections and molecular mechanisms between OA and aging through multi-omics and genetics methods. Integrating single-cell RNA sequencing (scRNA-seq), bulk RNA-seq data, Mendelian randomization (MR), colocalization analysis, and cell function analysis, this study explores the correlation between OA and aging. Furthermore, it investigates the potential causal relationship between key marker genes and OA. Integrating and analyzing scRNA-seq data from OA, aging, and control groups revealed a significant increase in the proportion of the classical monocyte core subgroup. Differential expression analysis yielded 77 marker genes, and further MR analysis identified four key marker genes (DUSP6, CSTA, CD300E, and GPX1) as causally related to OA, which was confirmed in an independent validation cohort. Reverse MR and Steiger filtering indicated no evidence of reverse causality. DUSP6- and CSTA-classical monocytes may interact with other cell subgroups through the MIF-(CD74 + CD44) signaling pathway. This study revealed the heterogeneity of monocyte subgroups in OA and aging patients, identifying key marker genes with a causal relationship to OA through an integrated multi-omics approach, providing potential molecular targets for the diagnosis and treatment of OA from an aging perspective. 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 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

Esophageal squamous cell carcinoma (ESCC) remains a major health burden, particularly in Asia, with poor patient prognosis despite advancements in radiotherapy, chemotherapy, and immunotherapy. The marked inter-patient and intra-tumor heterogeneity of ESCC underscores the need for molecularly informed diagnostic and therapeutic strategies. Recent high-throughput omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, have substantially advanced our understanding of ESCC biology. Genomic profiling has revealed recurrent alterations such as TP53 and NOTCH1 mutations, as well as actionable targets including PIK3CA, FGFR1, and SOX2 amplifications, which provide new opportunities for precision therapy. Epigenomic and transcriptomic analyses have identified methylation-based early detection markers (e.g., PAX9, SIM2) and immune-related transcriptomic subtypes associated with prognosis and immunotherapy responsiveness. Proteomic and metabolomic studies have further uncovered cell cycle and spliceosome pathway activation and altered lactate metabolism, offering additional biomarker and therapeutic insights. In this review, we synthesize these multi-omics advances and highlight how they collectively inform improved diagnostic, prognostic, and therapeutic strategies for ESCC. Despite these developments, the clinical translation of multi-omics findings remains limited due to the lack of standardized analytical pipelines, insufficient multi-center validation, and the high cost and technical complexity of integrating multi-omics data into routine clinical workflows. Future research integrating artificial intelligence with multi-omics data holds promise for enhancing diagnostic accuracy and enabling more precise therapeutic decision-making in ESCC. Show less

Autophagy is integral to the rapid proliferation of esophageal squamous cell carcinoma (ESCC), and its regulation presents a promising avenue for therapeutic intervention. Recent studies have elucidated the interplay between autophagy and glucose metabolism, while there is a paucity of anticancer drugs that concurrently target these 2 biological processes. In this study, we identified a natural compound, Show less

Hypertrophic scar (HS) is a fibroproliferative disorder characterized by fibroblast hyperactivation and aberrant extracellular matrix deposition. This study identifies macrophage-derived lactate as a key mediator of fibroblast phenotypic remodeling via monocarboxylate transporter 1 (MCT1)-mediated histone H3 lysine 23 lactylation (H3K23la) in HS. Elevated lactate levels and MCT1 expression were observed in HS tissues, with macrophages in stiff mechanical microenvironments identified as the primary lactate source. Lactate influx through MCT1 upregulated H3K23la, thereby promoting transcriptional activation of profibrotic genes HEY2 and COL11A1. Mechanistically, HEY2 activated YAP1/SMAD2 signaling, while COL11A1 stabilized MCT1 to enhance lactate transport, forming a positive loop that amplified fibrosis. Fibroblast-specific Mct1 deletion or pharmacological inhibition of Mct1 in male mice reduced collagen deposition, accelerated wound healing, and attenuated scar formation. Our findings redefine the macrophage-fibroblast crosstalk in HS and establish the MCT1-H3K23la-HEY2/COL11A1 axis, particularly its self-reinforcing loop, as a novel therapeutic target. Show less

Community-acquired pneumonia (CAP) is still a leading cause of death due to infection globally, yet precise severity assessment remains a significant clinical problem. More than any other group of cytokines, interleukins are central to the regulation of inflammation and shed light on this intricate pathology. In the present review we summarize the biological and clinical characteristics of some of the principal interleukins (ILs) in CAP, classified primarily according to their physiological activity as pro-inflammatory (IL-2, IL-6, IL-8 and IL-12), anti-inflammatory (IL-7, IL-10 and IL-37), dual-action (IL-4 and IL-17), and emerging factors (IL-3, IL-27 and IL-33). Additionally, recent multimodal approaches are discussed such as combining cytokines with organ dysfunction parameters (MR-proADM) or revealing host-response patterns to inform antibiotic and corticosteroid management. We propose that the field needs to transition to immunological endotyping, multi-omics (integrating genetics and lung microbiome), and artificial intelligence (AI) models based on dynamic patient data to achieve precision medicine in CAP management. Show less

University students exhibit high rates of mental health problems alongside a significant gap between their physical activity (PA) intentions and actual behavior. To understand the psychological heterogeneity within this intention-behavior gap (IBG) in high-pressure academic environments, a person-centered approach is essential. The present study aimed to identify distinct psychological profiles of students based on key self-regulatory constructs related to PA and to examine how these profiles longitudinally predict changes in mental health over an academic semester. A two-wave longitudinal survey was conducted with a cohort of 850 university students during the post-pandemic return to campus life, situated within a high-achieving Chinese higher education context. At baseline (T1), PA intention, action and coping planning, self-efficacy, maladaptive perfectionism, and procrastination were measured. At both T1 and the end of the semester (T2), PA behavior (IPAQ-SF) and mental health outcomes, including depression (PHQ-9), anxiety (GAD-7), and academic burnout (SBI) were assessed. Latent Profile Analysis (LPA) was employed to identify distinct profiles from the T1 psychological data. Longitudinal regression models were then used to test the predictive validity of these profiles on T2 mental health, controlling for T1 baseline mental health, demographic covariates, and critically, T1 baseline PA behavior. LPA revealed four distinct profiles: "Effective Planners" (25.0%), "Ambitious Procrastinators" (30.0%), "Cautious Doers" (24.9%), and "Indifferent & Sedentary" (20.1%). The "Ambitious Procrastinators" exhibited the largest intention-behavior gap. Even after controlling for baseline PA behavior, membership in this profile significantly predicted greater increases in depression ( The physical activity intention-behavior gap is not a monolithic phenomenon, and the "Ambitious Procrastinators" represent a particularly vulnerable subgroup. Findings suggest that university wellness programs should move beyond generic motivational campaigns and instead deliver tailored, skill-based interventions**, such as specific cognitive restructuring and behavioral activation, **targeting the specific self-regulatory deficits of these high-risk students. Show less

Older adults in nursing homes generally face psychological adaptation problems such as depression and anxiety. This study aimed to identify social relationship profiles among nursing home residents and explore their associations with depression and anxiety. A cross-sectional study was conducted between June and October 2023 among 1108 older residents from 42 nursing homes in Fujian Province, China. Social relationships were assessed using the Social Support Rating Scale (SSRS) and the Lubben Social Network Scale-6 (LSNS-6). Depressive-anxiety symptoms were measured using the Geriatric Depression Scale-Short Form and the Self-Rating Anxiety Scale (SAS), respectively. Latent Profile Analysis (LPA) was performed to identify distinct social relationship profiles, and ANOVA/ANCOVA were used to examine differences in depression and anxiety across profiles. The LPA analysis identified six distinct social relationship profiles. The "Low social support/low social network group" (24.7%) was the most prevalent, showing significantly higher levels of depression and anxiety compared to the others. The "Moderate social support/moderate friend network group" (20.9%) demonstrated an intermediate and balanced social relationship characteristic. When compared to the "Moderate-low social support/high friend network group" (8.1%) and the "Moderate-high social support/low friend network group" (18.1%), despite these two groups scoring higher or above-average in specific dimensions of social support or friend network, they still showed higher levels of depression than the "High social support/high social network group" (15.1%) and the "High social support/super high social network group" (13.1%). Social relationship profiles among nursing home residents are heterogeneous and significantly associated with depressive-anxiety symptoms. Show less

Current genetic testing for coronary artery disease (CAD) primarily targets monogenic variants in individuals with severe hypercholesterolemia. Whether supplementing monogenic testing with polygenic risk scores for CAD and Lp(a; lipoprotein[a]) levels [PRS A genetic probability for CAD (GenProb In the UK Biobank development cohort, PVs, polygenic risk scores for CAD and PRS GenProb Show less

Myopia is a critical public health issue; however, the roles of multidimensional psychological resources (i.e., resilience and emotion regulation) and potential gender differences remain underexplored. This cross-sectional study aimed to investigate the association between latent psychosocial profiles and myopia severity, and to examine the moderating role of gender in this association among adolescents. In total, 1008 Chinese seventh-grade students completed assessments of psychological resilience, emotion regulation, and depressive and anxiety symptoms. Myopia was measured as spherical equivalent refraction (SER). Latent profile analysis (LPA) was used to identify distinct psychological profiles, and moderation analysis tested gender's role in the profile-myopia association. LPA revealed three distinct psychosocial profiles: "Low-Resource", "Emotion-Driven", and "Balanced-Adaptive". The Low-Resource profile exhibited the highest levels of depression, anxiety, and myopia severity. A significant moderating effect of gender was found. Among females, both the Emotion-Driven and Balanced-Adaptive profiles were associated with significantly less myopia severity compared to the Low-Resource profile-an association not observed in males. Specific psychological resource profiles were linked to myopia severity, a relationship that was significantly moderated by gender and was prominent only in female adolescents. These findings highlight the importance of person-centered approaches and gender-specific considerations in understanding the psychosomatic pathways of myopia. Show less

PurposeThis study aims to explore the latent classes of compassion fatigue among intensive care unit (ICU) nurses and identify the factors that influence their compassion fatigue.MethodsBetween November 2024 and February 2025, 1029 ICU nurses were selected as study participants using convenience sampling. Data were gathered through general demographic questionnaires, the Chinese version of the Short Scale of Compassion Fatigue (CFSS), the Occupational Stress Scale, the Perceived Social Support Scale, as well as the Professional Identity Scale. A latent profile analysis (LPA) was conducted based on the three dimensions of the CFSS as observed indicators. Additionally, factors influencing outcomes were analyzed using both univariate and multivariate logistic regression methods.Ethical considerationsThis study was approved by the Institutional Review Board of the Affiliated Hospital of Qingdao University.ResultsA total of 1029 valid questionnaires were obtained, resulting in an effective response rate of 93.46%. The average score on the ICU Nurse Compassion Fatigue Scale was 60.00 ± 27.36 points. Three distinct profiles were identified: low compassion fatigue-low secondary trauma type (33.04%), moderate compassion fatigue-overall fluctuation type (48.30%), and high compassion fatigue-high burnout type (18.66%). Multivariate logistic regression analysis revealed that health status, sleep quality, highest education level, occupational stress, professional identity, and social support significantly influence the potential compassion fatigue profiles among critical care nurses ( Show less

This study aimed to assess the childbirth readiness of women in their third trimester of pregnancy and to identify distinct readiness profiles using latent profile analysis (LPA). Additionally, it explored the factors influencing childbirth readiness in order to guide targeted interventions for improved maternal and neonatal outcomes. A cross-sectional study was conducted among women in their third trimester of pregnancy between May and November 2024. Eligible participants completed a general information questionnaire, the Childbirth Readiness Scale (CRS), the Childbirth Attitude Questionnaire (CAQ), and the Perceived Social Support Scale (PSSS). LPA identified three groups with distinct childbirth readiness levels: "Low Readiness - Childbirth Knowledge Deficit" (37.9%), "Moderate Readiness - Good Lifestyle Habits" (47.9%), and "High Readiness - Rich Health Knowledge" (14.2%). In addition, gestational age, previous childbirth history, adverse pregnancy outcomes, childbirth attitudes, and social support had different influences on women in different latent profiles of childbirth readiness. There was significant heterogeneity in childbirth readiness among women in their third trimester. Women with lower readiness-especially in childbirth knowledge-would greatly benefit from targeted educational programs, whereas those with moderate readiness levels would find enhanced emotional and psychological support most advantageous. These findings support the implementation of profile-based, personalized prenatal care strategies to improve childbirth preparedness and optimize maternal and neonatal outcomes. Show less

Serum lipoprotein(a) [Lp(a)] is recognized as an independent risk factor for cardiovascular disease. However, whether hypertension modifies the association between Lp(a) and adverse outcomes in acute decompensated heart failure (ADHF) remains unclear. We investigated how hypertension status influences the relationship between Lp(a) and all-cause mortality in ADHF. We conducted a single-center retrospective observational study including 2610 patients hospitalized with ADHF. We normalized the distribution of Lp(a) by a logarithmic transformation and assessed the risk of all-cause mortality with Lp(a), using Cox regression with adjustment for potential confounders. Among 2610 patients (39.0% women; mean age, 68.8 years), 1606 (61.5%) had hypertension. Over 4.1 years (median), 1287 deaths occurred. In all patients, log-transformed Lp(a) was significantly associated with mortality (adjusted HR 1.21; 95% CI, 1.05-1.39; Increased admission Lp(a) levels were associated with a higher risk of all-cause mortality in ADHF patients with hypertension. Further studies are needed to explore the mechanistic links among Lp(a), hypertension and ADHF. 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

In premature infants, patent ductus arteriosus (PDA) can lead to hemodynamic instability and prematurity-related complications. The conventional left atrial-to-aortic (LA/Ao) ratio for evaluating hemodynamically significant PDA (hsPDA) has demonstrated limited accuracy. We aimed to investigate the correlation between mitral inflow E-wave velocity, left pulmonary artery (LPA) end-diastolic velocity, and hsPDA in preterm infants. Single-center, retrospective cohort study included neonates born at a gestational age (GA) between 24 and 30 weeks. The echocardiographic parameters, including mitral E-wave velocity, LPA end-diastolic velocity and LA/Ao ratio were assessed with hsPDA requiring treatment. Forty-nine infants were included, of whom 30 were diagnosed with hsPDA. The mitral E-wave (95% CI: 4.6-18.2, p = 0.0016) and LPA end-diastolic velocities (95% CI: 4.14-15.15, p = 0.0010) were significantly higher in infants with hsPDA, while the LA/Ao ratio exhibited no difference. Multivariate analysis revealed that lower GA, higher mitral E-wave, and LPA end-diastolic velocities were predictive of hsPDA. The receiver operating characteristic (ROC) analysis showed that these parameters offered better diagnostic accuracy than the LA/Ao ratio. Our findings suggest that mitral E wave and LPA end-diastolic velocities are more reliable echocardiographic markers for evaluating hsPDA in preterm infants than the conventional LA/Ao ratio. Assessment of dynamic blood flow is more reliable than the left atrium chamber size in evaluating the hemodynamic status of a PDA. Our result provides new criteria for assessing the hemodynamic significance of PDA. Utilizing this technique may yield evidence to assist clinical decision-making regarding PDA treatment. Multifactorial assessment, including birth gestational age and increased intracardiac or pulmonary blood flow velocity, provides more accurate prediction for a hsPDA. Show less

Accumulating research has demonstrated a significant association between early-life inflammation and behavioral disorders later in life. However, the effects of early-life inflammation on aggressive behavior in adulthood remain poorly understood. Here, we show that early-life inflammation induced by lipopolysaccharide (LPS) upregulated neuronal dynamin-related protein 1 (DRP1) and impaired mitochondrial function in medial prefrontal cortex (mPFC) of adult mice, thereby increasing aggressive behavior in adulthood. We further identify that CCAAT/enhancer binding protein β (C/EBPβ) is the transcription factor of Dnm1l, which was activated by an increased release of lysophosphatidic acid (LPA) induced by early-life inflammation. Moreover, the overproduction of LPA was due to a specific increase in astrocyte-secreted autotaxin (ATX). Specific knockdown of astrocytic ATX reduced early-life inflammation-induced aggression in wild-type mice, but not in Thy1-C/EBPβ transgenic mice. Remarkably, coenzyme Q10 decreased early-life inflammation-induced aggressive behavior in adult mice. Altogether, these findings provide new insights into the molecular mechanisms by which early inflammation promotes aggressive behavior in adulthood. Show less

The Hedgehog (Hh) signaling pathway is a key regulator of adipogenesis and lipid metabolism. However, the specific role of its receptor, Patched2 (Ptch2), in these processes remains unclear. Here, using a CRISPR/Cas9-mediated Show less

Obesity has become a global epidemic and a major contributor to the development of Type 2 diabetes (T2D) through the promotion of insulin resistance. Emerging evidence has shown that GPX4 expression is reduced in macrophages under hyperglycemic conditions; however, the involvement of macrophage-specific GPX4 in obesity-associated insulin resistance remains unclear. We generated macrophage-specific Gpx4 knockout (Gpx4 Show less

In this study, we used optical genome mapping (OGM), conventional karyotyping, and next-generation sequencing to analyze cytogenomic alterations in 91 cases of T-cell acute lymphoblastic leukemia/lymphoma (T-ALL). Whereas karyotyping detected abnormal karyotypes in 55% of cases, OGM identified cytogenetic abnormalities in 97.8% of the cases and provided clinically relevant information beyond karyotyping in ∼70% of cases. OGM detected gene rearrangements in 80% of cases, including 24 recurrent gene fusions and 21 previously unreported putative gene fusions in T-ALL. Copy number variants were detected in 93% of cases, with interstitial deletions the most common. Gene mutations were detected in 93% of cases, with NOTCH1 being most frequent (in 57% of cases). Combining all data, most T-ALL cases harbored 3 or more cytogenomic aberrations. Specific cytogenomic alterations differed among T-ALL subtypes as follows: rearrangements of BCL11B and PICALM::MLLT10, deletions of 7p, and mutations involving DNMT3A, WT1, TET2, IDH2, and FLT3 were common in early T-precursor and near-early T-precursor subtypes. Rearrangements of TLX1, KMT2A, STIL::TAL1, and NUP214::ABL1, deletions of 9p, and FBXW7 mutations were frequently associated with the cortical subtype. We conclude that integration of OGM and next-generation sequencing with karyotyping enables comprehensive cytogenomic profiling of T-ALL that improves detection of clinically relevant genomic alterations and may inform disease classification and future studies of risk stratification. Show less

Genetic variants near LYPLAL1 are associated with Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) in humans, but their impact on LYPLAL1 function is unknown. We identified LYPLAL1 loss-of-function variants from UK BioBank (UKBB) whole-exome sequencing data that had AlphaMissense or GPN-MSA scores in the top 20% of LYPLAL1 variants for being disruptive. We aggregated these variants and carried out burden analysis for effects on MRI Proton Density-Fat Fraction (MRI-PDFF) and ICD-based MASLD in UKBB. Rare loss-of-function LYPLAL1 variants were associated with reduced MRI-PDFF and ICD diagnosed MASLD across sexes. We used CRISPR to knockout and overexpress LYPLAL1 in human hepatoma cells (HuH-7), measuring lipid content, lipid uptake/export, and changes in de novo lipogenesis and mitochondrial β-oxidation. LYPLAL1 subcellular localization was determined by overexpressing LYPLAL1-HA tagged protein. We purified GST tagged human LYPLAL1 protein and conducted in vitro tests for esterase and depalmitoylase activity. Knocking out LYPLAL1 reduced triglycerides biochemically as well as lipid intensity after oleic (18:1, n-9) acid treatment. LYPLAL1 KO cells had increased expression of PPARα and MLXIPL, increased mitochondrial β-oxidation, and reduced capacity to both import fatty acids (FAs) and export lipoproteins. Overexpression of LYPLAL1 increased lipid droplet accumulation and decreased PPARα and MLXIPL. LYPLAL1-HA is partly localized to mitochondria when treated with oleic acid. Biochemical analyses showed that LYPLAL1 has strong esterase activity but lacks depalmitoylase activity. Reduction of LYPLAL1 esterase function likely increases β-oxidation of FAs in mitochondria through PPARα and MLXIPL and decreases FA import to protect against lipid accumulation in human liver cancer cells. Together, our results indicate that LYPLAL1 loss-of-function protects against MASLD in Europeans and in vitro, LYPLAL1 is an esterase for short-chain substrates which is involved in the regulation of mitochondrial β-oxidation and uptake of fatty acids, influencing lipid accumulation in the liver. Show less

To elucidate the molecular mechanism by which ginsenoside Rg3 (G-Rg3) protects human bronchial epithelial (HBE) cells against lipopolysaccharide (LPS)-induced injury, focusing on its regulation of autophagic flux and the TLR4/NF-κB-mediated inflammatory pathway. HBE cells were treated with LPS (1-100 ng/mL) to induce autophagy dysregulation and inflammation. G-Rg3 (2-16 μM) was administered to evaluate its protective effects. Western blotting was used to detect autophagy-related proteins (ATG4B, ATG7, PIK3C3, LC3B, p62) and TLR4/NF-κB signaling molecules; ELISA quantified proinflammatory cytokines (TNF-α, IL-1β, IL-2, IL-6, IL-8); PI staining and flow cytometry analyzed cell death and apoptosis. LPS dose-dependently upregulated the expression of autophagy-related proteins (ATG4B, ATG7, PIK3C3, p62, LC3B-II), with accumulated p62 and LC3B-II indicating impaired clearance of autophagic substrates. Additionally, G-Rg3 inhibited LPS-induced TLR4/NF-κB activation, suppressed proinflammatory cytokine secretion, and attenuated HBE cell apoptosis/necrosis. G-Rg3 mitigates LPS-induced HBE cell injury by dual mechanisms: restoring impaired autophagic flux and inhibiting the TLR4/NF-κB inflammatory cascade. These findings identify G-Rg3 as a promising therapeutic agent targeting the crosstalk between autophagy and inflammation in respiratory diseases such as COPD and acute lung injury. Show less

The global burden of heart failure is escalating, marked by persistently rising prevalence, incidence, and mortality. The emerging hypothesis that the gut microbiome, as a modifiable factor, influences HF pathogenesis through immune modulation. To examine the causal relationship, we conducted two-sample Mendelian randomization (MR) analyses using summary genetic data, which was obtained from genome-wide association studies (GWASs) of gut microbial taxa, immune cells, and HF. Single-cell RNA sequencing data and single-nucleus RNA sequencing from chronic heart failure and healthy samples were extracted for investigation. Expression quantitative trait loci (eQTL) MR analysis was used to integrate HF GWAS with eQTL from heart to confirm potential genes. We performed functional enrichment analysis to enrich their functions. The analysis revealed that genus Blautia (p = 0.0287), genus Corynebactrium (p = 0.022), genus Demequina (p = 0.0064), genus Enterococcus (p = 0.0307), genus Eubacterium (p = 0.0234), genus F0482 (p = 0.0107), genus Leclercia (p = 0.0026), genus Prevotellamassilia (p = 0.0444), and genus Ruminococcus were causally linked to a higher risk of HF, while genus CAG-125 (p = 0.0443), genus CAG-245 (p = 0.0116), genus Fournierella (p = 0.0326), genus Roseibacillus (p = 0.028) protective factors for HF. Among differential microflora, genus Leclercia was significantly related to higher level of HVEM on terminally differentiated CD4+T-cell count (p = 0.0058). Moreover, HF patients underwent obviously increased NK/T cells. We identified positive association of EIF3A, RPL5, SLC25A51, HERC5, SUSD3, ZNF292, ZNF655, and DNAJC9 with increased risk of HF, whereas the expression of RMC1, CAMK2G, RPS26, ATP5PO displayed protective effect against HF by eQTL MR analysis; they were mainly enriched in myc-Targets-V1, IFN-γ-response, IFN-α-response, PI3K/AKT/mTOR signaling, TGF-beta signaling, allograft rejection, notch signaling pathways, angiogenesis, epithelial mesenchymal transition, UV-response-DN, hedgehog signaling, myogenesis. Our multi-omics MR study uncovered the causality of gut microbiome on immune cells and HF. Genus Leclercia-related changes in T cells may present as a viable focus for HF. This offers new insights into mechanisms and therapy of gut microbiome-mediated HF. Show less

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent chronic liver disease worldwide and is closely associated with obesity, diabetes, and other metabolic disorders. Because MASLD progression poses serious health risks, elucidating the underlying mechanisms is essential to guide early intervention and therapeutic strategies. Proteomic analysis was used to identity high-fat diet (HFD)-induced proteins in mouse liver. Galectin-1 (GAL1) expression was assessed via immunohistochemistry in human liver tissues. Liver-specific GAL1-deficient mice were generated using adeno-associated virus. Mice were fed either a chow diet or an HFD. Functional studies were performed in cell lines using western blotting, RT-qPCR, immunofluorescence, co-immunoprecipitation, mass spectrometry, and molecular docking analysis. GAL1 expression was elevated in liver tissues from patients with MASLD and in mouse models. Liver-specific GAL1 knockdown alleviated hepatic steatosis and enhanced fatty acid oxidation (FAO). Mechanistically, GAL1 competitively bound to the BRCT domain of poly (ADP-ribose) polymerase 1 (PARP1), thereby interfering with its interaction with the WW domain -containing E3 ubiquitin protein ligase 2 (WWP2). Hepatic GAL1 knockdown promoted the PARP1 -WWP2 interaction and subsequently facilitated ubiquitin-dependent degradation of PARP1. This degradation led to increased NAD Hepatic deficiency of GAL1 alleviates hepatic steatosis by enhancing FAO through promotion of ubiquitin-dependent PARP1 degradation, thereby restoring NAD Show less

The adipocyte-rich tumor microenvironment (TME) is recognized as a key factor in promoting cancer progression. A distinct characteristic of peritumoral adipocytes is their reduced lipid content and the acquisition of a proinflammatory phenotype. However, the underlying mechanisms by which adipocytes rewire metabolism and boost tumor progression in triple-negative breast cancer (TNBC) remain poorly understood. We utilized transcriptomic analysis, bioinformatic analysis, metabolic flux analysis, protein-protein docking, gene and protein expression profiling, in vivo metastasis analysis and breast cancer specimens to explore how adipocytes reprogram tumor metabolism and progression in TNBC. Our findings reveal that Angiopoietin-like 4 (ANGPTL4) exhibits significantly higher expression levels in adipocyte-rich tumor circumstance compared to the symbiotic environment lacking of adipocyte. Furthermore, ANGPTL4 expression in tumor cells is essential for adipocyte-driven glycolysis and metastasis. Interleukin 6 (IL-6), enriched in cancer-associated adipocytes, and lipolysis-derived free fatty acids (FFAs) released from adipocytes, amplify ANGPTL4-mediated glycolysis and metastasis through activation of STAT3 and PPARα pathways in TNBC cells. Additionally, ANGPTL4 interacts with transcription factor KLF4 and enhances KLF4 activity, which further drives glycolysis and metastasis, whereas KLF4 knockdown attenuates migration and glycolysis in TNBC cells. Importantly, Elevated ANGPTL4 and KLF4 expression was observed in metastatic breast cancer specimens compared to non-metastatic cases and was positively correlated with poor prognosis. Collectively, our results uncover a complex metabolic interaction between adipocytes and TNBC cells that promotes tumor aggressiveness. ANGPTL4 emerges as a key mediator in this process, making it a promising therapeutic target to inhibit TNBC progression. Show less