👤 Wei Geng

Traumatic spinal cord injury (SCI) induces neuronal apoptosis and neuroinflammation, which exacerbate secondary damage and hinder functional recovery. Efficient clearance of apoptotic cells and modulation of the inflammatory microenvironment of spinal cord are essential for promoting tissue repair. This study aimed to investigate whether Midkine (MDK), a heparin-binding growth factor, facilitates functional recovery after SCI and explores the underlying mechanisms. A rat model of moderate SCI was established using Allen's impact method. Lentiviral vectors were used to overexpress MDK in the spinal cord. Behavioral assessments, including BBB score and gait analysis, were performed to evaluate motor function recovery. Motor evoked potentials (MEPs) serve as a neurophysiological tool for evaluating the functional integrity of the corticospinal tract. In vivo and in vitro experiments were conducted to assess microglial efferocytosis and elucidate the underlying molecular mechanisms. Transcriptomic bioinformatic analysis suggests that SCI is characterized by pronounced accumulation of apoptotic cells and robust neuroinflammatory responses, whereas single-cell analysis implicates MDK as a key contributor to neurorepair after SCI. MDK expression is dynamically regulated following SCI, with an early upregulation followed by a gradual decline over time, its location predominantly observed around microglial cells. Functionally, MDK overexpression significantly enhances motor recovery after SCI, accompanied by reduced neuroinflammation, decreased neuronal apoptosis, and improved neuroprotection. Mechanistically, MDK promotes microglial efferocytosis both in vivo and in vitro, activates the AKT/mTOR signaling pathway, upregulates BDNF and LRP-1 expression, and facilitates microglial polarization toward an anti-inflammatory M2 phenotype. Notably, inhibition of LRP-1 with receptor-associated protein (RAP) abolished the efferocytic and neuroprotective effects of recombinant MDK, highlighting LRP-1 as a key mediator of MDK's actions in microglia. Our study unveils the MDK/LRP-1/efferocytosis axis as a previously unrecognized therapeutic target for SCI. By orchestrating apoptotic cell clearance, dampening neuroinflammation, and fostering neuroprotection, this axis critically shapes the post-injury microenvironment to facilitate recovery. These findings suggest that MDK-centered therapy may represent a strategy for spinal cord repair, with LRP-1 modulation offering precise control over microglial responses. Show less

Current treatments for depression have focused on improving the dysregulated monoamine neurotransmitter systems in the brain. However, the conventional antidepressants based on the monoamine hypothesis usually exert side effects and unsatisfactory responses. MicroRNAs (miRNAs) are smaller noncoding RNA which are highly expressed in the brain and play important roles in the development of neurological disorders. In this study we investigated the role of miRNAs in the occurrence of depression. A rat depression model was established by exposure to chronic mild stress (CMS) over 4 weeks. In the next week, the sucrose preference test (SPT), the forced swimming test (FST), and the open field test (OFT) were used to evaluate the depression-like behaviors. Then the rats were euthanized and total RNA was isolated from rat mPFC. We showed that the level of microRNA-129-5p (miR-129-5p) was significantly increased in the mPFC of CMS rats. Overexpression of miR-129-5p in the mPFC by bilateral microinjection of lenti-miR-129-5p virus (OE-miR-129-5p) induced the depression-like behaviors in control rats, accompanied with the impairment in neuronal structures and a decrease in synaptic plasticity. In contrast, knockdown of miR-129-5p in the mPFC by bilateral microinjection of lenti-miR-129-5p sponge virus (KD-miR-129-5p) ameliorated the depression-like behaviors in CMS rats, along with the improvement in neuronal structures and an increase in synaptic plasticity. Furthermore, we demonstrated that miR-129-5p targeted to the brain-derived neurotrophic factor (BDNF) in the mPFC to contribute to the development of depression. This study suggests that miR-129-5p in the mPFC impairs the neuronal structures and reduces the synaptic plasticity after the exposure to CMS, which underlies the development of CMS-induced depression-like behaviors in rats. Show less

Enhancing memory and alleviating amnesia are among the conditions that Ganoderma lucidum has historically been used to treat. However, there are relatively few studies on the potential therapeutic effects of active ingredients derived from Ganoderma lucidum in the treatment of memory impairment. This study investigated the ameliorative effect of Lucidenic acid A (LAA) on memory impairment via in vivo and in vitro experiments using experimental pharmacology approaches. In vivo, behavioral tests were used to evaluate memory impairment in mice. Transmission electron microscopy, Hematoxylin-Eosin (HE) staining, and Nissl staining were employed to observe pathological changes in mice. Western blotting (WB) was used for protein expression analysis. In vitro, CCK-8 assay and cell scratch test were used to evaluate changes in cell viability. Reactive oxygen species (ROS) immunofluorescence staining was used to assess intracellular oxidative stress changes. WB was also used for protein expression analysis. The results show that LAA can not only improve spatial learning and memory abilities and alleviate cholinergic system impairments in mice with memory impairment, but also mitigate oxidative stress and inflammatory responses, and reduce pathological changes in brain tissue. In addition to improving memory impairment in mice, LAA can also alleviate inflammation, oxidative stress, and neuronal apoptosis induced in cells. LAA can induce the activation of the PI3K/AKT/BDNF pathway, thereby alleviating inflammation, oxidative stress, and cholinergic system impairments caused by scopolamine (SCOP) administration, and improving memory impairment. Show less

Cereal vinegar sediment (CVS), a byproduct of traditional vinegar fermentation, has been regarded as a health-promoting product. However, its role in genetically induced hyperlipidemia remains unclear. This study systematically evaluated the effects of Dade-CVS (DD-CVS) and Hengshun-CVS (HS-CVS) on apolipoprotein-E-deficient ( Show less

Glioblastoma (GBM) remains one of the most intractable malignancies owing to the dual challenges of the blood brain barrier (BBB) and profound immunosuppression. Here, we present a nanobomb (OMV-ApoE@ALF) that integrates heterologous production of the aromatic polyketide albofungin (ALF) with programmable outer membrane vesicles (OMVs) displaying ApoE peptides for GBM immunotherapy. OMV-ApoE@ALF efficiently crossed the BBB, accumulated in tumors, and functioned as a lysosomal nanobomb to boost pyroptosis and activate cGAS-STING pathway, thereby promoting dendritic cell maturation, T-cell infiltration, and durable antitumor immunity. Mechanistically, OMV-ApoE@ALF delivered ALF into lysosomes, inducing lysosomal disruption, reactive oxygen species (ROS) production, and subsequent mitochondrial damage. Crucially, this lysosomal rupture also suppressed protective autophagy of tumor cells themselves, thereby reinforcing the cascade activation between caspase-3/GSDME-dependent pyroptosis and cGAS-STING signaling pathway. This lysosomal disruption-nanobomb represents a new strategy for advancing GBM immunotherapy. Show less

Congenital heart disease (CHD) is the most common birth defect worldwide, with over half of cases lacking a defined etiology. Maternal metabolic dysregulation has been implicated in CHD risk, but the specific metabolites and mechanisms involved in embryonic heart development remain poorly understood. Carbamoyl phosphate (CP), a key urea cycle intermediate, has not previously been linked to cardiac morphogenesis. This study aimed to identify maternal metabolites associated with offspring CHD risk and to elucidate the role of CP in regulating cardiac development. Untargeted metabolomic profiling was performed on early-pregnancy serum from 98 mothers of CHD offspring and 50 age-matched controls. Functional validation was performed using two pregnant mouse models: pharmacological inhibition of glutamine metabolism via BPTES and Cps1 heterozygous knockout (Cps1 Maternal serum CP levels were significantly reduced in CHD cases and negatively correlated with upstream nutrient levels. In mice, both BPTES treatment and maternal Cps1 knockdown increased CHD incidence in offspring. Conversely, NCG supplementation reduced CHD risk in Cps1 Maternal CP deficiency increases offspring CHD risk by disrupting TET2-mediated DNA demethylation through impaired lysine carbamylation. These findings highlight maternal CP and TET2 carbamylation as potential metabolic-epigenetic targets for CHD prevention. Show less

Hypertrophic scar (HS) represents a skin fibroproliferative disease characterized by a high incidence, frequent recurrence, and limited treatment options. Thus, identifying new targets to optimize the treatment of HS is of critical importance. Using summary statistics from the eQTLGen Consortium, Decode database, and FinnGen cohort, we conducted transcriptome-wide and proteome-wide Mendelian randomization (MR) to discover potential pharmacological targets against HS, with subsequent validation via RNA sequencing. Upstream regulators and downstream mechanisms were further investigated to better understand the roles of the pathogenic gene. Drug prediction, molecular docking, and molecular dynamics (MD) simulation were employed to estimate the value of potential drugs for HS. A high level of fibroblast growth factor receptor 1 (FGFR1) significantly increased the risk of HS according to transcriptome-wide (P = 0.011) and proteome-wide MR (P = 0.002) analyses. RNA-seq further validated the high expression of FGFR1 in HS. Gene-gene interaction network and enrichment analysis identified FGFR1 as the core gene driving the progression of HS, highlighting multiple biosynthetic processes. Pharmacological evaluation of candidate drugs predicted stable binding between Ro-4396686 and FGFR1. Our findings suggest that FGFR1 can serve as promising target for optimizing HS treatments, potentially reducing the costs of drug development. 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

In recent years, the global incidence of Non-Suicidal Self-Injury (NSSI) has risen, posing a significant challenge in public health. Adolescents are the main group affected. A cross-sectional study was conducted using a self-administered questionnaire to collect data from 6,311 adolescents in Hefei, China. This study employed the Compositional Isotemporal Substitution Model (CISM, a statistical method that estimates health effects of replacing time in one behavior with another while accounting for the interdependent, compositional nature of 24-h time-use data) to examine the impact of Screen Time (ST), Non-Screen-based Sedentary Time (NSST), Physical Activity, and Sleep Time on NSSI among adolescents. Compositional logistic regression analysis revealed that, relative to the remaining behavioral components, higher Light Physical Activity (LPA) ( The findings highlight those reasonably allocating adolescents' daily activities, reducing ST, can help lower the risk of NSSI among adolescents. Show less

To evaluate the predictive value of novel lipid parameters for coronary lesion severity in pCAD and to develop a nomogram-based prediction model. Patients newly diagnosed with pCAD at Qingdao Municipal Hospital (2021-2024) were enrolled and randomly assigned to training and validation cohorts in a 7:3 ratio. Coronary lesion severity was assessed using the Gensini score (GS), with patients stratified into mild or significant stenosis groups. Spearman correlation analysis was performed between GS and lipid parameters. Key predictors were selected using LASSO regression, and independent risk factors were identified by multivariable logistic regression to construct the nomogram model. The model's discrimination, calibration, and clinical utility were evaluated using receiver operating characteristic (ROC) curves, calibration plots, and decision curve analysis (DCA). Lp(a), non-HDL-C, RC, FFA, and BAR were positively correlated with GS (r = 0.34, 0.34, 0.18, 0.19, 0.18; all The proposed nomogram provides an effective tool for identifying pCAD patients with severe coronary artery stenosis, demonstrating robust predictive accuracy and potential clinical utility. Show less

The abuse of methamphetamine (METH) is associated with an increased risk of Parkinson's disease (PD), whereas microglial polarization and glucose metabolism disorders are closely related to the progression of PD. This study aimed to investigate the specific molecular mechanism underlying the promotion of PD progression by METH through the regulation of microglial polarization and glycolysis. METH-induced C57BL/6 mice and BV2 cells were used to construct PD-like neurotoxicity animal and cell models for experimental investigation. Behavioral tests, immunohistochemistry and Nissl staining were used to assess the behavioral ability and neuronal damage of the animals. The levels of related proteins, inflammatory cytokines and glycolysis were detected using immunofluorescence, ELISA, Western blotting, and CCK-8 assays. METH treatment significantly promoted behavioral disorders in PD mice, reduced the number of TH-positive neurons, and aggravated neuronal damage in the substantia nigra (SN). In addition, METH decreased the M2 marker proteins Arg-1 and CD206 and increased the M1 marker proteins iNOS and CD86; the proinflammatory cytokines TNF-α, IL-β, and IL-6; and glucose uptake, glucose consumption and lactic acid production, thus promoting M1 polarization and glycolytic activity in BV2 cells. In terms of the underlying molecular mechanism, METH treatment significantly increased the level of LPA. METH promotes LPA expression via upregulation of LIPH expression, and activates the PI3K/AKT pathway. Knockdown of LIPH or treatment with BrP-LPA reduces the ability of METH to promote M1 microglial polarization and glycolytic activity. Furthermore, the addition of the PI3K/AKT signaling pathway activator 740 YP weakened the inhibitory effect of BrP-LPA on the above process. METH may promote M1 polarization and glycolytic activity in microglia by activating LIPH/LPA/PI3K/AKT signaling, thus promoting the progression of PD. Show less

Accelerometer-derived physical activity is associated with reduced stroke risk. The biological pathways underpinning this relationship, however, are not yet understood. Herein, we aim to identify metabolic signatures associated with accelerometer-measured PA and investigate their relationships with reduced stroke incidence. Utilizing UK Biobank accelerometer data, we derived physical activity into total physical activity (TPA), moderate-to-vigorous physical activity (MVPA), and light physical activity (LPA) and linked them to 249 NMR-quantified plasma metabolites. The metabolomic signatures (TPA-/MVPA-/LPA-metabolomic signatures) were developed through internal validation followed by elastic-net regression modeling. Cox proportional hazards models evaluated activity-stroke associations (adjusted for sociodemographic/genetic factors), followed by mediation analysis to quantify metabolomic signature effects. Through UK Biobank study (N = 29445; 14.1-year follow-up with 513 stroke events), we identified 195 TPA, 173 MVPA, and 164 LPA metabolite associations (FDR < 0.05), with 107, 92, and 15 validated, respectively. Elastic net-derived physical activity-metabolomic signatures (TPA-/MVPA-metabolomic signatures) correlated with physical activity intensities (r = 0.20-0.30, P < 0.001) and were associated with reduced stroke risk: TPA-metabolomic signatures (HR = 0.61, 95% CI: 0.44-0.87); MVPA-metabolomic signatures (HR = 0.50, 95%CI: 0.29-0.88). Mediation analyses showed TPA-metabolomic signatures and MVPA-metabolomic signatures explained 12.2% and 8.5% of physical activity-stroke associations (P < 0.001), implicating specific lipoprotein subclasses and lipids as key mediators. TPA-metabolomic signatures and MVPA-metabolomic signatures, particularly the 11 key metabolites included, significantly mediate the association between accelerometer-derived physical activity and stroke risk. Show less

The primary renal complication of diabetes mellitus is diabetic kidney disease (DKD). The precise pathogenic mechanisms of DKD remain poorly elucidated. The aim of this study was to identify potential energy metabolism-related genes associated with DKD. The GSE30529 and GSE30528 datasets were retrieved from the Gene Expression Omnibus, and energy metabolism-related genes were obtained from the GeneCards database. Differentially expressed genes (DEGs) between DKD and control groups were analyzed. The biological functions and signaling pathways of these DEGs were evaluated using Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA). The diagnostic performance of hub genes for DKD was assessed using receiver operating characteristic (ROC) curve analysis. Expression levels of five significant energy metabolism-related genes were validated through immunohistochemistry. The Nephroseq V5 tool was used to evaluate gene expression in DKD and to determine correlations between gene expression and renal function in patients with DKD. A total of 17 energy metabolism-related DEGs were identified. Five hub genes-ALB, IGF1, CD36, LPL, and UCP2-were identified. Among these, CD36 and LPL demonstrated relatively high diagnostic accuracy for DKD. The findings suggest that CD36, IGF1, LPL, and UCP2 may serve as potential biomarkers for DKD. The genes CD36, IGF1, LPL, and UCP2 represent potential energy metabolism-related biomarkers with possible applications in the diagnosis and treatment of DKD. Show less

To explore the molecular mechanisms underlying clozapine-induced metabolic syndrome (MetS) in schizophrenia patients, providing scientific evidence for clinicians to prevent and manage metabolic syndrome during the treatment of psychiatric disorders. Ten schizophrenia patients with MetS and ten matched controls were recruited from Shanghai Mental Health Center according to the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for schizophrenia and the 2016 Chinese Adult Dyslipidemia Prevention and Treatment Guidelines for MetS. Peripheral blood RNA sequencing was performed to identify differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) network were used to pinpoint hub genes. Mendelian randomization (MR) was conducted to validate causal relationship between serum brain-derived neurotrophic factor (BDNF) levels and MetS components. A total of 1019 DEGs were identified, grouped into eight mRNA modules through WGCNA. Key hub genes included Significant differences in gene expression are observed between schizophrenia patients with and without MetS. Individual variability in clozapine-induced MetS may be linked to DEGs. Show less

Communication of gut hormones with the central nervous system is important to regulate systemic glucose homeostasis, but the precise underlying mechanism involved remain little understood. Nesfatin-1, encoded by nucleobindin-2 (NUCB2), a potent anorexigenic peptide hormone, was found to be released from the gastrointestinal tract, but its specific function in this context remains unclear. Herein, we found that gut nesfatin-1 can sense nutrients such as glucose and lipids and subsequently decreases hepatic glucose production. Nesfatin-1 infusion in the small intestine of NUCB2-knockout rats reduced hepatic glucose production via a gut - brain - liver circuit. Mechanistically, NUCB2/nesfatin-1 interacted directly with melanocortin 4 receptor (MC4R) through its H-F-R domain and increased cyclic adenosine monophosphate (cAMP) levels and glucagon-like peptide 1 (GLP-1) secretion in the intestinal epithelium, thus inhibiting hepatic glucose production. The intestinal nesfatin-1 -MC4R-cAMP-GLP-1 pathway and systemic gut-brain communication are required for nesfatin-1 - mediated regulation of liver energy metabolism. These findings reveal a novel mechanism of hepatic glucose production control by gut hormones through the central nervous system. Show less

Atrial fibrosis serves as a key pathological basis for atrial fibrillation, significantly elevating the risk of cardiovascular events. However, its molecular mechanisms remain incompletely understood. N⁶-methyladenosine (m6A) modifications have been proven to involve in the pathological processes of cardiovascular diseases, yet its role in atrial fibrosis remains unclear. m6A plays an important role in disease pathogenesis via mRNA modification. This study aimed to define the role of m6A modifications in the fibrotic atria of rats with chronic intermittent hypoxia (CIH). A CIH model was established using rats living in an intermittent hypoxia simulation chamber filled with oxygen and nitrogen. Myocardial function and atrial fibrosis were examined by echocardiography, electrophysiology, and histopathology. Methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and mRNA sequencing (mRNA-Seq) were performed on atria from control and CIH rats to identify differential m6A methylated genes and transcripts and further analyze their coexistence. Functional enrichment of the conjoint genes was analyzed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes assays. m6A distribution of the conjoint gene ANGPTL4 (angiopoietin like 4) was also observed. ANGPTL4 and m6A-related gene expression levels were determined by quantitative real-time polymerase chain reaction. CIH led to electrical conduction dysfunction and abnormal expression of fibrosis-associated proteins, indicating successful atrial fibrosis. Conjoint analysis identified 10 genes with upregulated m6A peaks and transcripts and 24 genes with downregulated m6A peaks and transcripts. These genes were functionally enriched in the calcium ion transport-related and fibrosis pathways (extracellular matrix receptor interaction). The m6A modification level of ANGPTL4 mRNA and the expression of four m6A regulatory enzymes were significantly different between control and CIH rats. Our results revealed that m6A modification plays a crucial role in atrial fibrosis and may provide new therapeutic strategies for this disease. Show less

Lipid overaccumulation in the liver predisposes ducks to metabolic disorders. The molecular mechanism of oleic acid (OA)-induced hepatic steatosis in ducks is not fully elucidated. A cellular model of steatosis was established by treating primary duck hepatocytes with OA. Transcriptome sequencing was performed to identify key signaling pathways and candidate genes. The role of Apolipoprotein A1 (APOA1) was investigated through overexpression and knockdown experiments. Intracellular triglycerides (TGs) were quantified commercially; lipid droplets were visualized by Oil Red O staining. Intracellular TG accumulation was induced by OA treatment in a dose-dependent manner. Through transcriptome analysis, 1045 differentially expressed genes (DEGs) were identified, with APOA1 being recognized as a key candidate within the peroxisome proliferator-activated receptor (PPAR) signaling pathway. The content of TGs and lipid droplets was increased by APOA1 overexpression, whereas these effects were suppressed by APOA1 knockdown. The expression of acetyl-CoA carboxylase alpha (ACACA) and fatty acid synthase (FASN) was upregulated by APOA1. Conversely, the expression of carnitine O-palmitoyltransferase 1 (CPT1), acyl-CoA oxidase 1 (ACOX1), and apolipoprotein B (APOB) was downregulated. This study demonstrates that OA upregulates APOA1, suggesting the involvement of the PPAR pathway and providing a theoretical basis for modulating hepatic fat deposition. Show less

The uptake of modified lipoproteins by macrophages to form foam cells is a crucial step in atherosclerosis (AS) development. N7-methylguanosine (m7G) is frequently methylated internally in eukaryotic RNA transcripts and plays a crucial role in various processes. This study aimed to investigate the m7G RNA methylation profile in AS. We employed high-throughput sequencing to analyze the m7G methylome in foam cells induced by ox-LDL, using an in vitro AS model. Then, m7G-seq, RNA-seq, bioinformatic analysis, cell biological analyses, followed by qRT-PCR were performed. Additionally, the roles of SCARB2 and RASSF8 were investigated in an in vivo AS mouse model, and cells with SCARB2/RASSF8 overexpression/knockdown. In vitro and in vivo oil red O staining confirmed the successful establishment of the atherosclerotic foam cell and mouse models. We identified 1197 m7G peaks and 430 differentially expressed mRNAs during foam cell formation. Bioinformatics analyses revealed different m7G peaks associated with the gonadotropin-releasing hormone (GnRH) signaling pathway, cytoskeleton-dependent intracellular transport, and mitochondrial organization, regulating the processes of macrophage foaminess. Moreover, 28 key differentially expressed methylated genes were identified. m7G methyltransferases (WDR4, METTL1, WBSCR22) were upregulated in the AS cell model, and m7G modification genes (SCARB2 and RASSF8) associated with pathological processes were confirmed. Immunofluorescence staining showed that RASSF8 and SCARB2 were both expressed in AS mice plaque tissues. Finally, RASSF8/SCARB2 overexpression could promote apoptosis and lipid accumulation of ox-LDL-induced RAW264.7 cells. An m7G transcriptome-wide map of AS in vitro was created, and the differentially m7G methylated genes SCARB2 and RASSF8 may be crucial in macrophage foaminess. Our findings offer novel insights into the underlying mechanisms and potential treatments for AS. Show less

Aβ is believed to play a significant role in synaptic degeneration observed in Alzheimer's disease and is primarily investigated as a secreted peptide. However, the contribution of intracellular Aβ or other cleavage products of its precursor protein (APP) to synaptic loss remains uncertain. In this study, we conducted a systematic examination of their cell-autonomous impact using a sparse expression system in rat hippocampal slice culture. Here, these proteins/peptides were overexpressed in a single neuron, surrounded by thousands of untransfected neurons. Surprisingly, we found that APP induced dendritic spine loss only when co-expressed with BACE1. This effect was mediated by β-CTF, a β-cleavage product of APP, through an endosome-related pathway independent of Aβ. Neuronal expression of β-CTF in mouse brains resulted in defective synaptic transmission and cognitive impairments, even in the absence of amyloid plaques. These findings unveil a β-CTF-initiated mechanism driving synaptic toxicity irrespective of amyloid plaque formation and suggest a potential intervention by inhibiting the endosomal GTPase Rab5. Show less

Radiation-induced lung injury (RILI), manifesting in its initial phase as radiation pneumonitis (RP) and progressing over time to radiation-induced pulmonary fibrosis (RIPF), represents a significant adverse consequence associated with thoracic radiation therapy. Currently, there are limited therapeutic options for RILI. Anlotinib was confirmed the efficacy of pulmonary fibrosis. Therefore, anlotinib has the potential to treat RILI. To investigate the therapeutic role of anlotinib in RILI. RILI model in mice was successfully developed for evaluating the therapeutic efficacy of anlotinib. We used network pharmacology to find six target genes and analysed the correlation between these genes and RILI-related cytokines. Molecular docking further validates the binding ability of these target genes and anlotinib. We found the importance of TGF-β in anlotinib treatment of RILI by the results of network pharmacology and correlation analysis. We then used immunohistochemistry to demonstrate that anlotinib treats RILI by lowering TGF-β. Through enrichment analysis, we obtained potential therapeutic pathways and validated them with WB. In vivo investigations demonstrated that anlotinib is able to treat RILI: Inflammation, fibrosis, and apoptosis are reduced. This result is likely to be related to the reduction of TGF-β: The therapeutic mechanism potentially involves six genes, namely, FLT1, AKT1, KDR, TGFB2, PDGFRB1, and FGFR1; these targets bind well to anlotinib; we found that the expression of most of cytokines affecting the particular processes of RILI was closely associated with the six genes, in particular TGF-β1-3; immunohistochemistry further demonstrates that anlotinib treats RILI by lowering TGF-β1-3. In addition, KEGG enrichment analysis reveals possible pathways involving in therapeutic effects, including the PI3K-Akt, MAPK, Rap1, and Ras pathway. WB showed that anlotinib treatment significantly inhibited the PI3K/Akt signalling pathway. Therefore, anlotinib has the potential for treating RILI. Our results indicated the potential targets and molecular mechanism of anlotinib against RILI. Show less

Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the global population and poses a remarkably serious threat to human health. The effect and potential molecular mechanisms of combined cold exposure and exercise intervention on NAFLD remain unclear. A high-fat diet-induced NAFLD mouse model was used. Twenty-four NAFLD mice were divided into three groups and subjected to cold exposure (5°C), regular-temperature exercise (22°C), or combined cold exposure and exercise (5°C) for 8 wk, 5 d·wk -1 , once daily for 1 h each session. Intervention effects were evaluated through bodyweight, liver mass, liver/bodyweight ratio, blood lipid profile, circulating fibroblast growth factor 21 (FGF21) levels, and liver histopathology. Immunoblotting and quantitative PCR were used to assess the protein and gene expression of liver FGF21, β-klotho, and FGFR1 to preliminarily elucidate the molecular mechanisms underlying NAFLD improvement by combined cold exposure and exercise. Compared with cold exposure or regular-temperature exercise alone, combined cold exposure and exercise significantly reduced the bodyweight, liver weight, and liver/bodyweight ratio in the NAFLD mice. The levels of blood lipids, circulating FGF21, and liver glycogen also significantly decreased. Furthermore, the combined intervention significantly reduced liver fat deposition and fibrosis and significantly increased the expression of FGFR1 and β-klotho proteins, suggesting the activation of the FGF21-β-klotho/FGFR1 signaling pathway. This preclinical study demonstrates that combined cold exposure and exercise synergistically alleviates NAFLD progression in animal models, primarily by activating the FGF21-β-klotho/FGFR1 pathway to enhance lipid metabolism and reduce liver injury. These findings highlight the translational potential of dual environmental and behavioral interventions, providing a mechanistic foundation for developing nonpharmacological therapies targeting metabolic pathways in humans, particularly for NAFLD patients resistant to conventional lifestyle modifications or pharmacotherapy. Show less

Interleukin-27 (IL-27), an Interleukin-12 (IL-12) family heterodimeric cytokine, plays a central yet complex role in immunoregulation within the intestinal mucosa, where its context-dependent actions can promote both protective and pathogenic outcomes. Although its cellular sources, receptor structure (IL-27Rα/gp130 complex), and involvement in regulating key immune cells (e.g., T-cell subsets, macrophages, neutrophils) and epithelial functions are established, the precise mechanisms underlying its paradoxical effects-balancing homeostasis with inflammation-remain incompletely resolved. This review synthesizes current understanding of IL-27 biology to clarify its multifaceted role. Crucial insights into these dual functions have emerged from preclinical models, including murine colitis (e.g., DSS-, TNBS-induced), enteric infection (e.g., Toxoplasma gondii, Citrobacter rodentium), and colorectal cancer models. These studies demonstrate that IL-27 critically orchestrates gut immunity, maintaining homeostasis through antimicrobial defense and barrier enhancement while suppressing immunopathology. Conversely, its dysregulation drives chronic inflammation and carcinogenesis. Clinically, IL-27 expression correlates with disease activity in inflammatory bowel disease (IBD), colorectal cancer (CRC), and infections, highlighting its biomarker potential. Consequently, targeting the IL-27 pathway presents promising therapeutic avenues: augmenting signaling may mitigate IBD hyperinflammation, while inhibition could bolster antitumor immunity or resolve infection-driven pathology. Future research must prioritize defining context-specific IL-27 functions, optimizing delivery strategies, and integrating IL-27 targeting with existing biologics to translate its immunomodulatory potential into novel therapies for intestinal diseases. Show less

Neurodevelopmental disorders (NDDs) exhibit complex genotype-phenotype associations that frequently result in inconclusive variant interpretations, contributing to suboptimal diagnostic yields (~ 40%). Koolen-de Vries syndrome (KdVS), an autosomal dominant NDD caused by KANSL1 haploinsufficiency, exemplifies this diagnostic challenge with its multisystem manifestations and lack of systematic genotype-phenotype associations. To address this gap, we constructed a comprehensive KdVS genotype-phenotype repository by systematically integrating all molecularly confirmed cases from global literature. Comprehensive phenotypic analysis revealed that core KdVS features include developmental delay/intellectual disability, characteristic craniofacial dysmorphism, hypotonia, and multisystem abnormalities. Phenotypic association analysis identified 249 significant correlations, demonstrating that KdVS clinical manifestations are highly interconnected rather than representing isolated features, such as the association between strabismus and hydrocephalus (OR = 14.26). Application of this repository to screen a Chinese rare disease cohort identified 53 KANSL1 variants. Among these, one de novo nonsense variant (NM₀₀₁₁₉₃₄₆₆.2: c.902T > G, p.Leu301Ter) was classified as pathogenic in a Chinese boy with classic KdVS features. The remaining 52 variants were categorized as variants of uncertain significance (VUS), approximately half of which were absent from gnomAD databases. Each VUS was comprehensively annotated with detailed clinical profiles to facilitate phenotype-driven reinterpretation. In conclusion, this study establishes KdVS as a highly interconnected multisystem disorder and demonstrates that deep phenotypic association analysis enhanced genetic diagnosis. This disease-specific repository approach provides a scalable framework for improving molecular diagnostics across rare NDDs. Show less

Hypertrophic cardiomyopathy (HCM) represents the most prevalent form of hereditary cardiomyopathy, and mutation in the cardiac myosin-binding protein C (MYBPC3) gene have been identified as a major contributor to the pathogenesis of HCM. While the desmoplakin (DSP) gene is primarily associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) and dilated cardiomyopathy (DCM), its role in HCM has been less frequently documented. This case report describes a Chinese patient with obstructive HCM harboring rare variants in both the MYBPC3 and DSP genes. These findings provide valuable insights for future investigations into the genetic underpinnings and disease associations. Show less

Colorectal cancer (CRC) is a prevalent digestive system malignancy accompanied by peritoneal metastasis occurring in 7% of cases. Methyltransferase-like 3 (METTL3) promoted the progression of CRC whereas its function in peritoneal metastasis was incompletely understood. Here, we found that METTL3 was upregulated in peritoneal metastasis tissues of CRC patients compared with CRC tissues. By sequencing the mRNA of above tissues, we discovered that METTL3-mediated N6-methyladenosine (m6A) modification regulated the downstream target Show less

Sepsis arises from a dysregulated host response to infection, leading to multiorgan inflammatory injury. Early diagnosis and treatment necessitate the identification of reliable immune biomarkers. This study investigated the relationship between aging, immunity, and sepsis by analyzing six human aging-related gene sets (656 genes). We identified 16 aging-related differentially expressed genes (DEGs) in sepsis. Among these, ATP11B, RBBP7, DOCK10, and NUP160 demonstrated the strongest connectivity with other genes and exhibited significant predictive power. Functional enrichment analysis (GO and KEGG) revealed distinct signaling pathway profiles between high-risk and low-risk sepsis groups (stratified based on risk scores). These dysregulated pathways, associated with multiple immune cells, were primarily linked to transcriptional dysregulation in cellular processes and cancer-related pathways. Experimental validation assays corroborated the roles of ATP11B and RBBP7. Collectively, our bioinformatic and experimental findings indicate that ATP11B, RBBP7, DOCK10, and NUP160 are implicated in the pathogenesis and progression of sepsis. But their potential for sepsis biomarkers still requires further verification. Show less

Spinal cord injury (SCI) is a destructive neurological trauma that induces permanent sensory and motor impairment as well as a deficit in autonomic physiological function. Melanocortin receptor 4 (MC4R) is a G protein-linked receptor that is extensively expressed in the neural system and contributes to inhibiting inflammation, regulating mitochondrial function, and inducing programmed cell death. However, the effect of MC4R in the modulation of oxidative stress and whether this mechanism is related to the role of absent in melanoma 2 (AIM2) in SCI are not confirmed yet. In the current study, we demonstrated that MC4R is significantly increased in the neurons of spinal cords after trauma and oxidative stimulation of cells. Further, activation of MC4R by RO27-3225 effectively improved functional recovery, inhibited AIM2 activation, maintained mitochondrial homeostasis, repressed oxidative stress, and prevented Drp1 translocation to the mitochondria. Meanwhile, treating Drp1 inhibitors would be beneficial in reducing AIM2 activation, and activating AIM2 could abolish the protective effect of MC4R on neuron homeostasis. In conclusion, we demonstrated that MC4R protects against neural injury through a novel process by inhibiting mitochondrial dysfunction, oxidative stress, as well as AIM2 activation, which may serve as an available candidate for SCI therapy. Show less

Rapid progression of non-target lesions (NTLs) leads to a high incidence of NTL related cardiac events post-PCI, which accounting half of the recurrent cardiac events. It is important to identify the risk factors and establish an accurate clinical prediction model for the rapid progression of NTLs post-PCI. PCSK9 inhibitors lower LDL-c levels significantly, also show the anti-inflammation effect, and may have the potential to reduce the rapid progression of NTLs post-PCI. We tried to test this hypothesis and explore the potential mechanisms. This retrospective study included 1250 patients who underwent the first PCI and underwent repeat coronary angiography for recurrence of chest pain within 24 months. General characteristics, laboratory tests and inflammatory factors(IL-10, IL-6, IL-8, IL-1β, sIL-2R, and TNF-α) were collected. Machine learning (LASSO regression) was mainly employed to select the important characteristic risk factors for the rapid progression of NTLs post-PCI and build prediction models. Finally, mediator analysis was employed to explore the potential mechanisms by which PCSK9 inhibitors reduce the rapid progression of NTLs post-PCI. There were more diabetes, less beta-blockers and PCSK9 inhibitors application, higher HbA1c, LDL-c, ApoB, TG, TC, uric acid, hs-CRP, TNF-α, IL-6, IL-8, and sIL-2R in NTL progressed group. LDL-c, hs-CRP, IL-8, and sIL-2R were characteristic risk factors for the rapid progression of NTLs post-PCI, combining LDL-c, hs-CRP, IL-8, and sIL-2R builds the optimal model for predicting the rapid progression of NTLs post-PCI (AUC = 0.632). LDL-c had a clear and incomplete mediating effect (95% CI, mediating effect: 51.56%) in the reduction of the progression of NTLs by PCSK9 inhibitors, and there was a possible mediating effect of IL-8 (90% CI), and sIL-2R (90% CI). LDL-c, hs-CRP, IL-8, and sIL-2R may be the key characteristic risk factors for the rapid progression of NTLs post-PCI, and combining these parameters might predict the rapid progression of NTLs post-PCI. The application of PCSK9 inhibitors had a negative correlation with the rapid progression of NTLs. In addition to the significant LDL-c-lowering, PCSK9 inhibitors may reduce the rapid progression of NTLs by reducing local inflammation of plaque. ChiCTR2200058529; Date of registration: 2022-04-10. Show less