Biomedical subjects

Lei Xu

Publications and source records attributed to Lei Xu.

8 recordsLinked to original sources

PubMed2026

Antibacterial activity and mechanistic insights of Lucilia illustris antimicrobial peptide Cecropin A2 against Pseudomonas aeruginosa.

Pseudomonas aeruginosa (P. aeruginosa) poses a serious public health threat due to multidrug resistance and biofilm formation. This study investigated the antibacterial mechanisms of the antimicrobial peptide, Cecropin A2 (CA2), against P. aeruginosa. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of CA2 against P. aeruginosa ATCC 9027 (PA ATCC 9027) were determined by broth microdilution. Antibacterial activity was evaluated using growth curves and time-kill assays. The mechanism was explored by assessing membrane integrity (outer/inner membrane permeability, SEM, and fluorescence microscopy), and intracellular responses (ATP, SDH activity, and ROS). Biofilm effects were assessed by crystal violet staining (biomass) and viable cell counting (biofilm-embedded bacteria). The MIC and MBC of CA2 against PA ATCC 9027 were 37.34 μM and 74.68 μM, respectively. CA2 exhibited moderate antibacterial activity against PA ATCC 9027. Scanning electron microscopy (SEM) revealed marked morphological damage after treatment. CA2 affected intracellular metabolism, potentially interacted with genomic DNA, and reduced biofilm biomass. Cecropin A2 exhibits concentration-dependent in vitro antibacterial activity against P. aeruginosa ATCC 9027, providing mechanistic insights and a theoretical basis for the development of alternative antimicrobial strategies.

Antimicrobial activity↗

PubMed2026

Potential Involvement of the IL-6/STAT3/MMP12 Signaling Axis in DMSO-Mediated Anti-Fibrotic Effects in Experimental Silicosis.

This study aims to investigate the anti-inflammatory and anti-fibrotic effects of dimethyl sulfoxide (DMSO) in a mouse model of silicosis, thereby exploring its potential therapeutic value. A mouse model of silicosis was established by intranasal instillation, and DMSO treatment was administered via intraperitoneal injection. The experiment was conducted over a period of 1 month. Lung tissues were collected from all mice; a subset was subjected to transcriptomic analysis, and differentially expressed genes were identified using the limma package. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses were conducted using ClusterProfiler to investigate gene functions and associated pathways. The remaining samples were subjected to histopathological assessment by hematoxylin and eosin staining (HE) and Masson's trichrome staining, while Western blot analysis was performed to validate transcriptomic results. This study suggests that DMSO may alleviate the fibrotic process in silicosis by modulating the IL-6/STAT3-MMP12 signaling axis. In the silica-induced silicosis mouse model, DMSO attenuated disease-associated weight loss and reduced collagen deposition. Transcriptomic analysis indicated that DMSO suppressed the activity of multiple fibrosis-related pathways and identified 51 key genes, including MMP12, which was significantly downregulated. Western blot analysis further confirmed reduced MMP12 expression, accompanied by markedly decreased levels of IL-6 and p-STAT3, suggesting the IL-6/STAT3 pathway may play a crucial role in regulating MMP12 expression. DMSO may attenuate inflammatory responses and pulmonary fibrosis in silicosis by inhibiting activation of the IL-6/STAT3 signaling pathway, thereby reducing MMP12 expression.

Animals↗

PubMed2025

Serum N-glycomics for non-invasive detection of significant liver pathology across clinical phases of treatment-naïve chronic hepatitis B.

BACKGROUND: Early identification of significant liver pathology is crucial for timely antiviral intervention in individuals with chronic hepatitis B (CHB) infection. Current non-invasive methods show limited accuracy in detecting occult liver damage, particularly in those with normal ALT. This study evaluated serum N-glycan profiles for diagnosing significant liver pathology in treatment-naïve CHB patients across clinical phases. METHODS: This cross-sectional study analyzed 626 treatment-naïve CHB patients confirmed by liver biopsy, classified according to 2025 EASL guidelines. Serum N-glycan profiles were determined using DNA sequencer-assisted fluorophore-assisted carbohydrate electrophoresis. Significant liver pathology was defined as inflammation grade ≥ G2 and/or fibrosis stage ≥ S2 (per Scheuer scoring system). Multivariate logistic regression models were developed and compared with traditional non-invasive markers. RESULTS: Among 626 CHB patients, 66.0% had significant inflammation and 58.9% had significant fibrosis. Patients with significant pathology showed characteristic alterations, with elevated P1, P3, P6, P7, P11 peaks and decreased P0, P5, P8, P10 peaks (all p < 0.0001). Compared to respective infection phases, hepatitis phases showed P1 increases of 19.6% and 36% in HBeAg(+) and HBeAg(-) patients, with P11 increases of 82.4% and 73.4%, while P0 decreased by 20.3% and 27.6%, and P10 by 21.6% and 20.3%. Relative to mild pathology (G and S < 2), P1 increased by 27% in significant pathology (G and/or S ≥ 2), reaching 58.7%/48.7% in G4/S4 stages (vs. G0/S0). In ALT-normal HBeAg(+) infection phase, P1 increased by 80.2%/65.8% in G4/S4 stages (vs. G0/S0), with P2 also increasing by 54.1%/45.2%. Multivariate analysis identified P11 as strongest risk factor (OR = 3.84, 95%CI: 1.74-8.45, p = 0.0008), followed by P1 (OR = 2.04, 95%CI: 1.57-2.64, p < 0.0001) and P7 (OR = 1.75, 95%CI: 1.31-2.34, p = 0.0002), while P2 (OR = 0.07, 95%CI: 0.02-0.26, p < 0.0001) and P0 (OR = 0.30, 95%CI: 0.12-0.79, p = 0.0140) served as protective factors. The glycomics combined model (AUC = 0.876 (0.844-0.908)) achieved superior performance and outperformed the clinical model (AUC = 0.818 (0.779-0.857)), LSM (AUC = 0.817 (0.775-0.858)), APRI (AUC = 0.830 (0.792-0.867)), and FIB-4 (AUC = 0.672 (0.621-0.723)) (all p < 0.001), with 78.7% sensitivity and 83.2% specificity. The optimized model reached AUC = 0.917 (0.891-0.942) with accuracy 84.2%, with 78.7% sensitivity and 94.6% specificity. Both glycomics-based models maintained diagnostic capability in ALT-normal patients particularly in HBeAg(+) infection. CONCLUSIONS: Serum N-glycomics demonstrates promising potential for non-invasive identification of significant liver pathology in treatment-naïve CHB patients, providing an alternative approach for early treatment decisions, especially in ALT-normal patients with occult liver damage.

Humans↗

PubMed2025

A genome-wide CRISPRi screen identifies homologous recombination pathway as potential target for broad-spectrum antibiotic adjuvants.

INTRODUCTION: The widespread misuse and overuse of antibiotics have driven the emergence of multidrug-resistant and pan drug-resistant bacteria, constituting a formidable global health threat. Antibiotic adjuvants that potentiate the efficacy of existing antibiotics represent a particularly promising avenue to address this challenge. METHODS: We performed a genome-wide CRISPR interference (CRISPRi) screening to identify potential targets for broad-spectrum antibiotic adjuvants, which highlighted the homologous recombination pathway as a promising candidate. To functionally validate this pathway, we employed three strategies to suppress the expression and function of recA, a key component of homologous recombination, including a CRISPRi system delivered via transconjugation, a RecX-derived peptide (RecX-20) fused to a cell-penetrating motif, and a small-molecule inhibitor cisplatin validated by surface plasmon resonance. RESULTS: Disruption of the homologous recombination pathway not only significantly increased bacterial susceptibility to multiple classes of antibiotics, including quinolones, β-lactams, aminoglycosides, and nitrofurantoin, but also reduced horizontal gene transfer of antibiotic resistance. In addition, recA deficiency resulted in a cascade of physiological disruptions, including membrane damage, efflux pump dysfunction, oxidative stress imbalance and metabolic disruption. All three recA-targeting strategies enhanced the antibacterial activity, with cisplatin exhibiting the most pronounced potentiating effect both in vitro and in vivo. CONCLUSIONS: This study reveals that the homologous recombination pathway, particularly RecA, is a viable target for the development of broad-spectrum antibiotic adjuvant. Our findings provide mechanistic insights and practical strategies to restore the effectiveness of existing antibiotics and address the growing threat of antimicrobial resistance.

Anti-Bacterial Agents↗

PubMed2025

An image-based protein-ligand binding representation learning framework via multi-level flexible dynamics trajectory pre-training.

MOTIVATION: Accurate prediction of protein-ligand binding (PLB) relationships plays a crucial role in drug discovery, which helps identify drugs that modulate the activity of specific targets. Traditional biological assays for measuring PLB relationships are time consuming and costly. In addition, models for predicting PLB relationships have been developed and widely used in drug discovery tasks. However, learning more accurate PLB representations is essential to meet the stringent standards required for drug discovery. RESULTS: We propose an image-based PLB representation learning framework, called ImagePLB, which equips ligand representation learner (LRL) and protein representation learner (PRL) to accept 3D multi-view ligand images and protein graphs as input, respectively, and learns rich interaction information between ligand and protein through a binding representation learner (BRL). Considering the scarcity of protein-ligand pairs, we further propose a multi-level next trajectory prediction (MLNTP) task to pre-train ImagePLB on the 4D flexible dynamics trajectory of 16 972 complexes, including ligand level, protein level, and complex level, to learn information related to trajectories. Besides, by introducing trajectory regularization (TR), we effectively alleviate the problem of high (even almost identical) feature similarity caused by adjacent trajectories. Compared with the current state-of-the-art methods, ImagePLB has achieved competitive improvements on PLB-related prediction tasks, including protein-ligand affinity and efficacy prediction tasks. This study opens the door to the image-based PLB learning paradigm. AVAILABILITY AND IMPLEMENTATION: All data and implementation details of code can be obtained from https://github.com/HongxinXiang/ImagePLB.

Ligands↗

PubMed2025

AAV gene therapy for autosomal recessive deafness 9: a single-arm trial.

Gene therapy for congenital deafness has shown promising results in children but lacks data in older populations. We conducted a single-arm trial of adeno-associated virus (AAV)-OTOF gene therapy using the Anc80L65 capsid in ten participants with autosomal recessive deafness 9 aged 1.5 to 23.9 years at five sites in China. The primary endpoints were safety and tolerability within 5 years, and secondary endpoints assessed auditory function. Initial findings from the ten patients with 6-12 months of follow-up, including one patient who received two injections, revealed that the therapy was well tolerated, with 162 grade I/II adverse events. Decreased neutrophil percentage was the most common event (16 of 162). All ten participants had at least 6 months of follow-up and improved their pure-tone-average hearing level from baseline 106 ± 9 (mean ± s.d.) to 52 ± 30 decibels (dB). Other secondary endpoints showed similar improvements, including the average click auditory brainstem response (ABR) threshold, the tone-burst ABR threshold and the auditory steady-state response (101 ± 1 to 48 ± 26 dB, 91 ± 4 to 57 ± 19 dB and 80 ± 14 to 64 ± 21 dB, respectively). Post hoc analyses were conducted to evaluate the timecourse and factors contributing to the hearing improvement. Therapeutic effect was rapid, taking 1 month to achieve most of the overall hearing improvement. On an individual level, click and tone-burst ABR thresholds, but not the auditory steady-state response, reliably predicted the behavioral pure-tone-average thresholds after 4 months (R2 = 0.68, 0.73 and 0.17, respectively). An age-dependent therapeutic effect was observed, with optimal outcomes in 5- to 8-year-olds. These preliminary results show that AAV-OTOF was safe and well tolerated in patients ranging from toddlerhood to adulthood. The trial remains ongoing and requires extended follow-up to confirm the long-term safety and efficacy. ClinicalTrials.gov registration: NCT05901480 .

Humans↗

PubMed2025

Rv2741 Promotes Mycobacterium Survival by Modulating Macrophage Function via the IL-1α-MAPK Axis.

One of the primary healthcare problems in the world today is tuberculosis (TB), a chronic infectious illness brought on by Mycobacterium tuberculosis (M. tuberculosis). A distinct family of PE_PGRS proteins, encoded by the M. tuberculosis genome, has attracted more attention because of their involvement in immune evasion and bacterial pathogenicity. Nevertheless, the specific functions and mechanisms of action for the majority of PE_PGRS proteins remain largely unexplored. This study focuses on the Rv2741 (PE_PGRS47) gene, which is exclusively present in pathogenic mycobacteria. To examine the function of Rv2741 in host-pathogen interactions, we created recombinant strains of Mycobacterium smegmatis (M. smegmatis) that expressed the M. tuberculosis Rv2741 gene. IL-1α was found to be a key mediator of host response modulation by Rv2741. Rv2741 downregulates the secretion of IL-1α and inhibits the MAPK signaling pathway, particularly the p38 and ERK1/2 pathways, thereby cooperatively inhibiting macrophage autophagy and apoptosis. Meanwhile, the decrease in IL-1α secretion directly leads to changes in the cytokine secretion pattern and a reduction in nitric oxide (NO) production. This multifaceted regulatory mechanism ultimately favors the survival of M. smegmatis in macrophages. This research significantly expands our understanding of Rv2741 function, revealing its crucial role as a multifunctional virulence factor in the immune evasion of M. tuberculosis.

Interleukin-1alpha↗

PubMed2024

Transcriptome analysis reveals that PRV XJ delgE/gI/TK protects against intestinal damage in nose-dropping-infected mice by regulating ECM-ITGA/ITGB-P-FAK.

Pseudorabies virus (PRV) is an ideal model for mechanistic investigations into α-herpesvirus. The neurotropism and latent infection of PRV have been extensively studied. Apart from neurological symptoms, diarrhea caused by PRV infection is also an essential cause of mortality in newborn and weaned piglets. However, little research has been done on PRV invasion of the gut. To fill this gap, a nasal drip PRV-infection mouse model was developed, consisting of three groups: the challenged group (Group A), the immunization-challenged group (Group B), and a mock group (Group C). The results showed that immunization with PRV XJ delgE/gI/TK successfully prevented intestinal damage caused by PRV drop-nose infection. Subsequently, intestines were collected for transcriptional analysis. Differentially expressed genes analysis revealed that PRV XJ delgE/gI/TK was effective in reducing the organismal intestinal transcriptional activity caused by PRV. The Group A vs Group C and Group A vs Group B had similar Kyoto Encyclopedia of Genes and Genomes (KEGG)-enriched signaling pathways and the differentially expressed genes were primarily enriched in pathways, such as cell adhesion molecules, focal adhesion kinase, and actin cytoskeleton regulation. Notably, transcriptome analysis indicated that genes associated with the focal adhesion kinase (FAK) signaling pathway (ECM-ITGA/ITGB-p-FAK) were significantly more highly expressed in Group A than in Group B and Group C. The results of quantitative real-time PCR (RT-qPCR) and western blotting were consistent with KEGG analysis. Therefore, we hypothesized that PRV promotes self-infection through activation of the ECM-ITGA/ITGB-p-FAK signaling pathway and that PRV XJ delgE/gI/TK immunization could attenuate the intestinal damage caused by PRV by inhibiting the activation of this pathway.IMPORTANCEPseudorabies virus (PRV) poses a significant threat to the swine industry and public health due to its ability to infect multiple species, including humans, leading to substantial economic losses and potential health risks. This study addresses a critical gap in understanding the impact of PRV infection on the gut, which has been less explored compared to its neurological effects. By developing a drip-nose PRV-infection mouse model, the research indicated that PRV might promote self-infection through activation of the ECM-ITGA/ITGB-p-FAK signaling pathway, and PRV XJ delgE/gI/TK immunization effectively prevents intestinal damage by significantly reducing the expression of genes in the ECM-ITGA/ITGB-p-FAK signaling pathway. The research has important implications for the swine industry and public health by contributing to the development of better vaccines and treatments, ultimately helping to control PRV and prevent its cross-species transmission.

Animals↗