👤 Wanmeng Mu

The global prevalence and incidence of metabolic dysfunction-associated fatty liver disease (MAFLD), including its progressive form metabolic dysfunction-associated steatohepatitis (MASH), are steadily rising, making them the most common chronic liver diseases worldwide. However, therapeutic options for MAFLD are currently limited. Glucolipid dysregulation drives MAFLD pathogenesis through intertwined glucose metabolic imbalance and lipid accumulation. Patients with type 2 diabetes mellitus (T2DM) are particularly prone to developing MASH and are at a higher risk of progressing to cirrhosis and hepatocellular carcinoma. The coexistence of MAFLD and T2DM correlates with clinical prognosis and elevates the risk of extrahepatic complications. Given the close association between MAFLD and T2DM, glucagon-like peptide-1 receptor agonists (GLP-1RAs), which have been approved for the treatment of T2DM and obesity, were the first to be investigated in patients with MAFLD/MASH. Recently, beyond GLP-1RAs, novel combination agents integrating glucose-dependent insulinotropic peptide receptor (GIPR) and/or glucagon receptor (GCR) agonists have also been explored. A large number of phase II randomized clinical trials have demonstrated significant improvements in body weight, insulin resistance, and liver parameters. Thus, GLP-1RAs and dual/triple agonists are promising for MAFLD/MASH, especially in those with obesity or T2DM. This study explores mechanisms and clinical evidence of incretin-based therapies for MAFLD by targeting its core pathogenesis-glucolipid disorders. With growing evidence, it also forecasts the broad clinical prospects on MAFLD treatment. Show less

Silica exposure precipitates irreversible lung injury; however, its long-term neurological sequelae—and the microglial mechanisms underlying these effects—remain poorly understood. Here, we demonstrate that inhaled crystalline silica induces persistent hippocampal inflammation, anxiety- and depression-like behaviors, and neuronal loss in mice. Bulk RNA sequencing, immunophenotyping, and pharmacological depletion studies revealed that microglia are the primary source of complement C1q in silica-exposed brains. Mechanistically, silica-induced lipocalin-2 (LCN2) engages the melanocortin-4 receptor (MC4R) on microglia, activating a cAMP/PKA/NF-κB cascade that transcriptionally upregulates C1q. Pharmacological blockade of MC4R (using PF) abolished C1q overproduction, normalized brain-derived neurotrophic factor levels, and restored both synaptic integrity and behavioral performance. Our findings establish the LCN2–MC4R–C1q axis as a critical microglial pathway in silica-related neurotoxicity and identify MC4R antagonism as a promising, readily translatable intervention for occupational neuroinflammation. The online version contains supplementary material available at 10.1186/s12974-026-03695-5. Show less

Osteoarthritis (OA) often coexists with metabolic traits (MTs), causing significant disability. Our study aims to uncover the shared genetic mechanisms between OA and MTs, revealing novel OA-MT related genes, proteins and pathways. We first explored the clinical associations between OA and MTs based on UK Biobank data. Using GWAS statistics for 9 OA subtypes and 51 MTs, we identified both global and regional genetic correlations. Multi-trait GWAS helped revealed credible genes and relevant pathways through various methods. Protein-level analyses were also conducted to identify key proteins. We developed polygenic scores (PGS), machine learning models and drug repurposing strategies were explored to translate these findings into clinical applications. We identified 152 trait pairs with significant associations and 709 local regions linked to OA-MT. Key SNVs like rs13135092 (SLC39A8) and rs34811474 (ANAPC4) were associated with multiple OA-MT pairs. Lipid and glucose metabolism emerged as central pathways, with tissue-specific enrichment analyses revealing key gene clusters in hepatocytes, arteries, and brain regions. Protein-level analyses identified 205 protein subgroups. PGS integrating MTs outperformed model based solely on OA, improving AUC by 17.5%. Causal gene-based models showed strong diagnostic accuracy (average AUC = 0.875 in external cohorts). Drug prediction highlighted fenofibrate as a promising treatment among 71 candidates. This study provides new insights into the genetic links between OA and MTs. We identified genes, proteins, and pathways related to comorbidities, revealing shared mechanisms, highlighting the potential of integrating metabolic factors to improve OA prediction, diagnosis, and treatment. Show less

Diabetic retinopathy (DR) is a leading cause of vision loss in working-age adults and often progresses to proliferative diabetic retinopathy (PDR) with irreversible complications. Anti-vascular endothelial growth factor (VEGF) therapy remains the first-line treatment; however, resistance poses a significant challenge, necessitating alternative therapeutic targets. This study explores the role of angiopoietin-like protein 4 (ANGPTL4) in PDR pathogenesis, emphasizing vascular-immune-lymphatic interactions. We found significantly elevated ANGPTL4 and VEGF-C levels in the vitreous humor of patients with PDR, which were not affected by anti-VEGF therapy. In vivo, full-length ANGPTL4 and its C-terminal fragment promoted pathological angiogenesis and lymphatic-like remodeling in diabetic murine retinas, characterized by increased lymphatic vessel endothelial hyaluronan receptor 1, prospero homeobox 1, and VEGF receptor 3 (VEGFR3) expression. Single-cell sequencing further revealed ANGPTL4-driven immune dysregulation, with abnormal infiltration of CD4+ T cells and dendritic cells. Knockdown of ANGPTL4 in mice with oxygen-induced retinopathy alleviated retinal hypoxia, neovascularization, and vascular leakage. Mechanistically, retinal hypoxia markedly increased ANGPTL4 expression levels in the retina, which activated the activator protein-1 (AP-1) transcription factor complex and promoted Cd83 transcription in mouse heart microvascular endothelial cells. Additionally, ANGPTL4 bound to neuropilin-1 (NRP1)/VEGFR3, driving human lymphatic endothelial cell proliferation and lymphatic vessel ingrowth from the optic nerve sheath into the retina, a finding that suggests a novel pathway independent of angiopoietin-Tie signaling. These findings establish ANGPTL4 as a key mediator of immune-vascular interactions in PDR and a potential therapeutic target to address both pathological angiogenesis and lymphatic dysfunction. Some patients with proliferative diabetic retinopathy (PDR) have poor responses to anti-vascular endothelial growth factor (anti-VEGF) therapy. This situation highlights the need for additional therapeutic approaches. In proliferative diabetic retinopathy, what is the role of ANGPTL4 that differs from VEGF? We found that ANGPTL4 is elevated in the vitreous humor of patients with PDR who are poorly responsive to anti-VEGF therapy. ANGPTL4, particularly its C-terminal fragment, causes retinal lymphatic-like remodeling in diabetic mice. This study provides novel insights into the complex interplay between immune activation, neovascularization, and lymphatic-like remodeling in PDR. Our findings deepen our understanding of PDR pathophysiology and propose a promising therapeutic target. Show less

Hypertriglyceridemia (HTG) and mixed dyslipidemia are significant risk factors for cardiovascular diseases. Despite the widespread use of traditional therapies, many patients continue to experience elevated triglycerides and residual cardiovascular risk. Small interfering RNA (siRNA) therapies represent a novel approach to lipid-lowering treatment. A systematic review and meta-analysis were conducted on randomized controlled trials comparing siRNA versus placebo for hypertriglyceridemia or mixed dyslipidemia. The search included PubMed, Cochrane Library, Web of Science, and Embase databases from inception to 1 October 2025, limited to English-language publications. Data extraction was performed independently by two authors. Eight RCTs involving 2,671 participants met the inclusion criteria. siRNA therapies significantly reduced triglycerides (TG) (MD, -52%; 95%, -57.9 to -46.2), non-high-density lipoprotein cholesterol (non-HDL-C) (MD, -21.9%; 95%, -26 to -17.7), very low-density lipoprotein cholesterol (VLDL-C) (MD, -49.5%; 95%, -60.1 to -38.9), apolipoprotein B (apoB) (MD, -12.6%; 95%, -16.4 to -8.8), and remnant cholesterol (MD, -64.8%; 95%, -81.7 to -47.9)compared with placebo. The reduction in TG was particularly notable. Subgroup analysis revealed that ANGPTL3-targeted therapies resulted in more substantial reductions in low-density lipoprotein cholesterol (MD, -13.2%; 95% CI, -20.1 to -6.2), while APOC3-targeted therapies had a neutral effect on LDL-C levels (MD, 0.6%; 95% CI, -5.7-6.9) ( siRNA therapies demonstrate significant efficacy in reducing triglycerides and improving lipid profiles in patients with HTG and mixed dyslipidemia. APOC3-targeted treatments primarily reduce triglycerides while increasing HDL-C, whereas ANGPTL3-targeted therapies offer broader lipid modulation, including substantial reductions in LDL-C. Both therapies demonstrate favorable safety profiles. Show less

Scavenger receptor B3/differentiation cluster 36 (SCARB3/CD36) has been established as a fatty acid transporter and genetic deficiency of CD36 in mice models shows decreased uptake of oxidized low-density lipoprotein (oxLDL) and reduced atherosclerosis. The present study proposes CD36 as a drug target inhibited by leonurine to alleviate inflammation and prohibit unstable atherosclerotic plaques. We showed that the anti-atherosclerotic effects of leonurine were dependent on CD36 in a mice model of arterial atherosclerosis induced by tandem stenosis surgery fed with Western diet (TS + WD) established in both wild type (WT) and Cd36 Show less

It is known that insulin stimulates skeletal muscle glucose uptake via the InsR-IRS-PI3K pathway. The signaling downstream of PI3K is divided into the Akt-AS160-Rabs branch and the Rac1-actin cytoskeleton branches. These two signaling branches jointly mediate the effect of insulin to promote GLUT4 transporters to transport glucose into the cell. The scaffolding protein Axin1 plays a crucial role in maintaining glucose homeostasis and TNKS, a member of the PARP family, is involved in insulin-stimulated GLUT4 translocation. However, the specific roles of Axin1 and TNKS and their relationship are elusive in insulin-stimulated skeletal muscle cell glucose uptake. Here, we showed that insulin up-regulated the protein levels of Axin1 and TNKS in an Akt-dependent manner in C2C12 skeletal muscle cells. Knockdown of Axin1 inhibited insulin-stimulated GLUT4myc translocation in C2C12-GLUT4myc myotubes. Both over-expression Axin1 and TNKS activity inhibitor XAV939 enhanced insulin-stimulated GLUT4myc translocation. XAV939 up-regulated Axin1 and TNKS protein levels. Knockdown or over-expression of Axin1 down- or up-regulated the protein level of TNKS, respectively. Axin1 interacted with TNKS which was enhanced by insulin. Knockdown of Axin1 inhibited insulin-induced the phosphorylation of the Rac1 target protein PAK. Over-expression of Axin1 and XAV939 increased insulin-phosphorylated PAK. Up- and down-regulation of Axin1 and XAV939 had no effects on the phosphorylation of Akt and AS160. Insulin increased the Rac1-GEF Tiam1 protein levels. Knockdown of Tiam1 diminished insulin-stimulated PAK phosphorylation and GLUT4myc translocation. Knockdown of Axin1 inhibited insulin-induced Tiam1 expression, while over-expression of Axin1 and XAV939 had the opposite effect. In summary, our results suggest that an Akt-Axin1/TNKS-Tiam1-Rac1 signaling pathway mediates insulin-stimulated GLUT4 translocation in skeletal muscle cells. Show less

Pharmacological preconditioning of mesenchymal stem cells (MSCs) is a promising strategy to enhance their therapeutic efficacy for end-stage liver disease; however, maximizing this benefit remains a major clinical challenge. Senkyunolide H (SNH), a small-molecule compound derived from Angelica sinensis, exhibits anti-inflammatory, antioxidant, and anti-apoptotic properties. Nevertheless, its capacity to optimize MSCs-based therapy for liver disease has not been fully elucidated. Here, we demonstrate that SNH preconditioning significantly enhances the therapeutic efficacy of bone marrow mesenchymal stem cells (BMSCs) in a murine model of liver cirrhosis. Specifically, SNH-pretreated BMSCs markedly alleviated hepatocellular injury, promoted hepatocyte proliferation, and attenuated collagen deposition. Mechanistically, SNH augments the therapeutic potency of BMSCs by partly binding to macrophage erythroblast attacher (MAEA), a subunit of the E3 ubiquitin ligase complex. This interaction stabilizes MAEA, which in turn facilitates the ubiquitination and proteasomal degradation of dual specificity phosphatase 6 (DUSP6), thereby activating ERK/STAT3 signaling and upregulating the secretion of hepatocyte growth factor (HGF). Collectively, our findings highlight SNH preconditioning as a robust approach to enhance the paracrine function and therapeutic potential of BMSCs, and identify MAEA as a novel therapeutic target for BMSCs-based interventions in liver cirrhosis. 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, 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

This study aims to elucidate the role of FGFR1 in activating the Wnt/β-catenin signaling pathway and the underlying mechanisms by which it promotes malignant progression in lung squamous cell carcinoma (LUSC). By integrating multi-omics analysis with functional experiments, the clinical heterogeneity of FGFR1 amplification, signaling crosstalk, and their regulatory networks governing tumor phenotypes were revealed. Using TCGA data (n = 490), we analyzed the relationship between FGFR1 copy number variation (CNV) and mRNA expression in LUSC, and validated the correlation with protein expression in a clinical cohort (n = 38). GSEA and single-gene GSEA were performed to identify signaling pathways associated with high FGFR1 expression. The interaction between FGFR1 and the Wnt/β-catenin pathway was investigated by immunohistochemistry, immunofluorescence, stable cell lines, Western blot, qPCR, and functional assays. FGFR1 amplification correlated with increased mRNA and protein expression. The top 25% FGFR1 high-expression group enriched Wnt/β-catenin, PI3K-Akt, and cAMP pathways. Mechanistically, FGFR1 promoted β-catenin nuclear accumulation and enhanced β-catenin signaling through PKA-associated phosphorylation and Akt/GSK3β-related regulation of β-catenin stability, and these effects were attenuated by AKT inhibition. CTNNB1 knockdown significantly inhibited proliferation, migration, invasion, and tumor growth of LUSC cells. Our findings indicate that FGFR1 activates Wnt/β-catenin signaling through coordinated regulation of β-catenin phosphorylation, stability, and subcellular localization, thereby promoting malignant progression in LUSC. These results provide a rationale for targeting the FGFR1-Wnt/β-catenin axis as a potential therapeutic strategy. 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

This study aims to elucidate the regulatory mechanisms of host genetics on the porcine gut microbiota and their subsequent impact on the feed conversion ratio (FCR). While initial genome-wide association studies (GWAS) did not identify significant SNPs directly associated with FCR, we investigated the gut microbiota as a potential intermediate phenotype influencing feed efficiency. Nonmetric multidimensional scaling (NMDS) based on Bray–Curtis distances demonstrated a distinct separation in microbial community structure between the high-feed conversion ratio (HFCR) and low-feed conversion ratio (LFCR) groups (stress = 0.19), suggesting a link between FCR and gut microbial composition. Furthermore, a significant, albeit weak, negative correlation was observed between the genomic relatedness matrices and microbial Bray‒Curtis dissimilarity ( The online version contains supplementary material available at 10.1186/s42523-026-00527-y. Show less

To analyze the potential therapeutic value and mechanism of luteolin in age-related macular degeneration (AMD) using network pharmacology and cellular experiments. SHD-compound targets were retrieved from the TCMSP database, while AMD-related targets were extracted from OMIM and DisGeNET databases. Overlapping targets were identified via Venny 2.1. A PPI network was constructed using the STRING database, followed by functional enrichment analysis of overlapping targets via Metascape. Pharmacological networks were mapped using Cytoscape. For cellular experiments, the optimal concentration of luteolin was determined by CCK-8 assay. Human umbilical vein endothelial cells (HUVECs) were divided into: Control group (Without any intervention), Model group (VEGF165-induced model), and Treatment group (VEGF165-induced + luteolin). Angiogenesis was evaluated via scratch, transwell migration, invasion, and tube formation assays. VEGFA protein expression was assessed by Western blot. We identified 157 SHD-compound targets and 87 AMD-related targets, yielding 6 overlapping targets (ESR1, PON1, SOD1, APOB, VEGFA, IL6). PPI networks and enrichment analysis revealed that luteolin in SHD may inhibit AMD neovascularization via VEGFA signaling pathways. The concentration of luteolin (25 µmol/L) used in the experiments was selected based on the dose-response results. In vitro assays showed the Treatment group exhibited: significantly reduced horizontal migration (scratch assay, p < 0.05), decreased vertical migration (transwell assay, p < 0.05), suppressed invasion (p < 0.05), and inhibited tube formation (p < 0.05). Western blot confirmed reduced VEGFA expression in the treatment group (p < 0.05). Luteolin alleviates angiogenesis in HUVECs by inhibiting VEGFA expression, highlighting its potential as a therapeutic candidate for neovascular AMD. Show less

To investigate the mechanisms underlying sevoflurane-induced POCD, C57BL/6 J mice and SH-SY5Y cells were treated with sevoflurane for model establishment. After the treatment with sevoflurane, CCK-8, EdU and flow cytometry were employed to detect cell damage. The levels of N6-methyladenosine (m6A), METTL14 and DUSP6 were determined by qPCR and Western blot. The interaction between METTL14 and DUSP6 was analyzed using RIP-qPCR and Me-RIP methodologies. The cognitive function in mice were assessed by water maze test. After sevoflurane treatment, the cell viability, cell proliferation and METTL14 expression were markedly suppressed, while apoptosis was significantly enhanced. METTL14 overexpression elevated the levels of m6A and DUSP6, increased the binding level of METTL14 to DUSP6 mRNA, reducing damage to cells and cognitive dysfunction of mice. Knockdown of DUSP6 negated the beneficial effects observed with METTL14 overexpression. Sevoflurane induced POCD by regulating METTL14/DUSP6 through m6A methylation. Show less

Cervical cancer remains one of the leading causes of cancer-related deaths among women globally, and there is still a need to research molecular targets that can be used for prognosis assessment and personalized molecular therapies. Here, we investigate the role of potential molecular target ribosomal L22-like 1 (RPL22L1) on cervical cancer, identify its potential mechanisms, and explore its related applications in prognosis and molecular therapies. Multiple cervical cancer cohorts online, tissue microarrays and clinical tissue specimens were analyzed for the association between RPL22L1 expression and patient outcomes. Functional and molecular biology studies of cell and mice models were used to clarify the effects and potential mechanisms of RPL22L1 on cervical cancer. RPL22L1 is highly expressed in both cervical adenocarcinoma and squamous cell carcinoma, and its expression is significantly associated with histology grade, clinical stage, recurrence, vascular space involvement, tumor sizes and poor prognosis. In vitro and in vivo experiment revealed that RPL22L1 overexpression significantly promoted cervical cancer cell proliferation, migration, invasion, tumorigenicity and Sorafenib resistance, which were attenuated by RPL22L1 knockdown. Mechanistically, RPL22L1 competitively binds to ERK phosphatase DUSP6, leading to excessive activation of ERK. The combined application of ERK inhibitors can effectively inhibit RPL22L1 overexpressing cervical cancer cells both in vivo and in vitro. RPL22L1 promotes malignant biological behavior of cervical cancer cells by competitively binding with DUSP6, thereby activating the ERK pathway. The combined use of Sorafenib and an ERK inhibitor is a potentially effective molecular targeted therapy for RPL22L1-high cervical cancer. Show less

Microplastics intrigue kidney toxicity such as mitochondrial dysfunction and inflammation promotion. However, as an organ relying heavily on fatty acid oxidation, how microplastics influence kidney lipidomes remain unclear. Hence, we performed Raman spectra and multidimensional mass spectrometry-based shotgun lipidomics to decode kidney lipidomics landscape under polypropylene microplastics exposure. Kidney functions and cellular redox homeostasis were remarkably disturbed as revealed by levels of biochemical renal function markers, malonaldehyde, hydrogen peroxide and antioxidants. Ultrastructure alterations including the foot process fusion implied the kidney injury associated with lipidomic changes. Raman spectra successfully further confirmed the cellular change of reactive oxygen species and lipid disorders. Lipidomics showed that polypropylene microplastics caused abnormal lipidome and irregular exchange by remodeling triglycerides and phospholipids. Genes involved in lipid metabolism such as Fads1 and Elovl5 exhibited highly diversified expression profiles responding to polypropylene microplastics stress and possessed significant correlations with ROS indicators. These results explained ultrastructure alterations and aggravation of kidney injuries. Our work revealed polypropylene microplastics inducing lipidomic detriment in mouse kidney by Raman spectra and lipidomics firstly, elucidating the significances of lipidomic remodeling coupled with ROS stress in the kidney damages. The findings provided reliable evidence on the health risks of polypropylene microplastics in kidney. Show less

Bats are natural reservoirs for diverse viruses, yet they rarely develop disease, suggesting unique antiviral adaptations. In this study, we performed a comprehensive genome-wide analysis in the common vampire bat ( Show less

Notch2 activation promotes kidney cyst growth. Silencing Notch2 ameliorated cyst growth in mice with autosomal dominant polycystic kidney disease. Notch signaling, a conserved mechanism of cell-to-cell communication, plays a crucial role in regulating cellular processes, such as proliferation and differentiation, in a context-dependent manner. However, the specific contribution of Notch signaling to the progression of polycystic kidney disease (PKD) remains unclear. We investigated the changes in Notch signaling activity (Notch1–4) in the kidneys of patients with autosomal dominant PKD (ADPKD) and two ADPKD mouse models (early and late onset). Multiple genetic and pharmacologic approaches were used to explore Notch2 signaling during kidney cyst formation in PKD. Notch2 expression was significantly increased in the kidney tissues of patients with ADPKD and ADPKD mice. Targeted expression of Notch2 intracellular domain in renal epithelial cells resulted in cyst formation and kidney failure in neonatal and adult mice. Mechanistically, Notch2/Hey2 signaling promoted renal epithelial cell proliferation by driving the expression of the E26 transformation–specific homologous factor (Ehf). Depletion of Ehf delayed Notch2 intracellular domain overexpression–induced cyst formation and kidney failure in mice. A gain-of-function mutation in exon 34 of Notch2 signaling promoted kidney cyst growth, partially by upregulating Ehf expression. Show less

Adipogenic differentiation of adipose-derived stem cells (ADSCs) is fundamental to both adipose tissue homeostasis and clinical applications, particularly fat grafting. However, the global and stage-specific transcriptional regulatory networks underlying ADSC adipogenesis remain incompletely elucidated. In this study, we integrated bulk and single-cell RNA-seq datasets across multiple time points of ADSC adipogenesis to identify core regulators of differentiation and maturation. A total of 41 genes were consistently upregulated during early differentiation, among which eight hub genes (FABP4, FASN, FABP5, ADIPOQ, PLIN1, LPL, CIDEC, and ACSL1) formed a tightly connected protein-protein interaction (PPI) module associated with lipid metabolism, lipid droplet formation, and adipocyte maturation. Further integration of differentially expressed lncRNAs and miRNAs led to the construction of a ceRNA network involving 7 mRNAs, 9 miRNAs, and 4 lncRNAs, comprising 34 predicted lncRNA-miRNA-mRNA regulatory axes. To identify temporal transcriptional regulators, we defined five genes (TTC14, MBNL2, UBR3, ABCD2, and SORT1) as early-stage inducers of adipogenesis, and four genes (UQCR11, NDUFB4, S100A10, and PRDX3) as late-stage regulators involved in maintaining the mature phenotype. These stage-specific regulators showed distinct temporal expression patterns and were validated by qPCR. GeneMANIA network analysis further revealed that early-stage regulators were enriched in lipid transport and lipase activity regulation, while late-stage regulators were associated with mitochondrial electron transport and energy metabolism. These findings highlight the stage-dependent transcriptional landscape of ADSC adipogenesis and provide candidate regulatory targets for modulating adipocyte differentiation and stability. Show less

This study was conducted to investigate the effects of replacing fish meal with either whole-fat or defatted krill powder on the growth, body color, immunity, and related gene expression of red-white koi carp. A total of 630 red-white koi carp with an initial body mass of 13.5 ± 0.05 g were randomly divided into seven groups with three replicates per group and 30 fish per replicate. The control group was fed a basic diet (C0). The other six diets were supplemented with different levels of whole krill meal or defatted krill meal as replacements (10% whole fat, 20% whole fat, 30% whole fat, 10% defatted, 20% defatted, and 30% defatted) in the experimental groups, named W10, W20, W30, D10, D20, and D30, respectively, for a total duration of 60 days. The growth, body color, immunity and gene expression indexes were measured in the koi after completion. The results indicate the following. (1) Compared with C0, the experimental groups of koi showed a significant increase in the specific growth rate (SGR) ( Show less

In vitro cell culturing witnessed its applications in scientific research and industrial activities. Attempts to shorten the doubling time of cultured cells have never ceased. In plants, auxin is applied to promote plant growth, the synthetic derivative 1-Naphthaleneacetic acid (NAA) is a good example. Despite the auxin's naturally occurring receptors are not present in mammalian cells, studies suggested they may affect cell culturing. Yet the effects and mechanisms are still unclear. Here, an up to 2-fold increase in the yield of in vitro cultured human cells is observed. Different types of human cell lines and primary cells are tested and found that NAA is effective in all the cells tested. The PI staining followed by FACS suggested that NAA do not affect the cell cycling. Apoptosis-specific dye staining analysis implicated that NAA rescued cell death. Further bulk RNA sequencing is done and it is identified that the lipid metabolism-engaging and anti-apoptosis gene, ANGPTL4, is enhanced in expression upon NAA treatment. Studies on ANGPTL4 knockout cells indicated that ANGPTL4 is required for NAA-mediated response. Thus, the data identified a beneficial role of NAA in human cell culturing and highlighted its potency in in vitro cell culturing. Show less

Apoprotein A-I (ApoA-I) and Apoprotein B (ApoB) have emerged as novel cardiovascular risk biomarkers influenced by feeding behavior. Hypothalamic appetite peptides regulate feeding behavior and impact lipoprotein levels, which effects vary in different weight states. This study explores the intricate relationship between body mass index (BMI), hypothalamic appetite peptides, and apolipoproteins with emphasis on the moderating role of body weight in the association between neuropeptide Y (NPY), ghrelin, orexin A (OXA), oxytocin in cerebrospinal fluid (CSF) and peripheral ApoA-I and ApoB. In this cross-sectional study, we included participants with a mean age of 31.77 ± 10.25 years, categorized into a normal weight (NW) (n = 73) and an overweight/obese (OW/OB) (n = 117) group based on BMI. NPY, ghrelin, OXA, and oxytocin levels in CSF were measured. In the NW group, peripheral ApoA-I levels were higher, while ApoB levels were lower than in the OW/OB group (all p < 0.05). CSF NPY exhibited a positive correlation with peripheral ApoA-I in the NW group (r = 0.39, p = 0.001). Notably, participants with higher CSF NPY levels had higher peripheral ApoA-I levels in the NW group and lower peripheral ApoA-I levels in the OW/OB group, showing the significant moderating effect of BMI on this association (R This study provides hitherto undocumented evidence that BMI moderates the relationship between CSF NPY and peripheral ApoA-I levels. It also reveals the protective role of NPY in the NW population, contrasting with its risk factor role in the OW/OB population, which was associated with the at-risk for cardiovascular disease. Show less

The formation of well-designed synthetic compartments or membraneless organelles for applications in synthetic biology and cellular engineering has aroused enormous interest. However, establishing stable and robust intracellular compartments in bacteria remains a challenge. Here, we use the structured DIX domains derived from Wnt signaling pathway components, more specifically, Dvl2 and Axin1, as building blocks to generate intracellular synthetic compartments in Show less

Infigratinib, an FGFR1-3 selective oral tyrosine kinase inhibitor, has shown clinical activity in cancers with FGFR alterations. The pharmacokinetics (PK) of infigratinib and its major metabolites have been characterized in global populations. This study examined the PK profile of infigratinib and its metabolites in Chinese patients. In this phase II, open-label, single-arm study in China, patients with advanced gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJ) harboring FGFR2 gene amplification received 125 mg infigratinib orally once daily in a "3 weeks on, 1 week off" schedule for 28-day cycles. Plasma PK parameters were calculated with a non-compartmental model. Data were available from 21 patients (19 GC and two GEJ). After a single dose, peak infigratinib plasma concentration was reached at a median time of 3.1 h, with geometric mean C Show less

Neurexin-3 (Nrxn3) has been genetically associated with obesity, but the underlying neural mechanisms remain poorly understood. This study aimed to investigate the role of Nrxn3 in the paraventricular nucleus of the hypothalamus (PVN) in regulating energy balance and glucose homeostasis. We found that Nrxn3 expression in the PVN was upregulated in response to metabolic stressors, including cold exposure and fasting. Using Cre-loxP technology, we selectively ablated Nrxn3 in CaMKIIα-expressing neurons of the PVN in male mice. This genetic manipulation resulted in marked weight gain attributable to increased adiposity and impaired glucose tolerance, without affecting food intake. Our findings identify PVN CaMKIIα-expressing neurons as a critical locus where Nrxn3 modulates energy balance by regulating adipogenesis and glucose metabolism, independently of appetite. These results reveal a novel neural mechanism potentially linking Nrxn3 dysfunction to obesity pathogenesis, suggesting that targeting PVN Nrxn3-dependent neural pathways may inform new therapeutic approaches for obesity prevention and treatment. Show less