Frontiers in Cellular and Infection Microbiology最新文献

Bladder cancer remains a significant global health concern, with environmental carcinogen exposure-particularly from tobacco-derived compounds such as aromatic amines, polycyclic aromatic hydrocarbons (PAHs), and nitrosamines-recognized as a primary etiological factor. These carcinogens undergo complex metabolic activation in the liver, bladder epithelium, and gut microbiota, generating reactive intermediates that initiate DNA damage, oxidative stress, and pro-tumorigenic signaling. This review synthesizes emerging evidence on how carcinogen-induced metabolic reprogramming contributes to bladder cancer initiation and progression, emphasizing the roles of key genetic pathways and metabolic enzymes involved in xenobiotic detoxification, DNA repair, and redox regulation. In parallel, we examine the influence of gut microbiota on carcinogen bioactivation and biotransformation, highlighting its dual role as both a metabolic modulator and a potential preventive target. We critically evaluate human observational data linking microbiome dysbiosis to bladder cancer risk, while addressing limitations such as small cohort sizes and confounders like diet and age. Finally, we discuss promising strategies for risk mitigation, including microbiome-directed interventions, dietary modulation, and chemopreventive agents that counteract carcinogenic effects. By integrating molecular oncology, toxicogenomics, and host-microbiome interactions, this review provides a mechanistic framework for understanding bladder cancer etiology and identifies novel opportunities for preventive and precision interventions.

Introduction: Porphyromonas gingivalis (Pg), a keystone periodontal pathogen, is a known risk factor for atherosclerosis and cardiovascular disease. Lysine lactylation (Kla) is an emerging post-translational modification (PTM) that bridges cellular metabolism and epigenetic regulation. However, the involvement of Kla in bacteria-induced endothelial dysfunction remains unexplored. This study aims to characterize the global lactylation landscape in human umbilical vein endothelial cells (HUVECs) following Pg infection.

Methods: HUVECs were infected with Pg, and their lactylome was analyzed using LC-MS/MS-based quantitative proteomics. Differentially lactylated sites were identified based on a fold change (FC) of ≥ 1.5 or ≤ 0.67 with a significance level of p < 0.05. Bioinformatics tools, including pathway enrichment and protein-protein interaction (PPI) network analyses, were employed to determine the biological significance of the modified proteins.

Results: A total of 5,788 Kla sites were identified across 1,881 proteins. Following Pg infection, 487 sites were significantly upregulated and 598 sites were downregulated. Functional enrichment analysis revealed that differentially lactylated proteins are primarily involved in nucleocytoplasmic transport, bacterial invasion, ribosome biogenesis, and DNA repair mechanisms. Network analysis highlighted five highly interconnected clusters regulating translation, RNA processing, and metabolism. Notably, key endothelial structural and regulatory proteins, including AHNAK (160 sites), MYH9 (56 sites), and FLNA (34 sites), exhibited extensive lactylation.

Discussion: This study provides the first comprehensive lactylome profile of Pg-infected HUVECs, identifying lysine lactylation as a novel mechanism linking periodontal infection to endothelial dysfunction. These findings offer a new molecular framework for understanding the pathogenesis of periodontitis-associated cardiovascular diseases and suggest potential biomarkers and therapeutic targets.

Zika virus (ZIKV) infection has emerged as a global public health emergency due to its expansion capacity and ability to cause neurological and congenital diseases. Muscle cells are targets for ZIKV, and myalgia and muscle disorders are frequently related symptoms during infection. We have previously demonstrated that myoblasts, the proliferating muscle stem cells essential for muscle repair, are permissive to ZIKV infection, generating infectious viral particles. In contrast, differentiated myotubes, derived from myoblast differentiation and fusion, control ZIKV replication. Nevertheless, little is known about the impact of ZIKV infection on muscle myogenesis. Using an in vitro model of skeletal muscle regeneration, human myoblasts were infected with the ZIKV-Rio-U1 strain, and their proliferation, adhesion, migration, and differentiation/fusion properties were analyzed 72 hours post-infection. We found that ZIKV replicates within myoblasts, promoting biological alterations such as the inhibition of cell cycle progression, preventing cell proliferation. Infected myoblasts exhibit poor adhesion, lack of membrane elongation, a reduced cell area, and decreased migratory capacity. Moreover, infection impaired the fusion of human myoblasts. Although differentiated and fused myotubes control ZIKV infection, proliferating infected myoblasts present an altered myogenic program. These results strongly suggest that ZIKV infection can affect myogenesis, modulating key biological processes crucial for skeletal muscle differentiation and regeneration. Accordingly, it is conceivable that ZIKV infection may impact myogenesis during embryogenesis, growth, and subsequent regenerative episodes during the adult period.

Introduction: Zika virus (ZIKV) infection is associated with severe neurological complications, but no clinically approved antiviral therapies exist, leaving management reliant on symptomatic support. The essential NS2B/NS3 protease represents a promising drug target for ZIKV.

Methods: We performed structure-based virtual screening of 5,980 FDA-approved compounds from the ZINC database against the ZIKV NS2B/NS3 protease. Molecular docking identified 10 high-affinity candidates (LibDock score >150), which were subsequently evaluated for cytotoxicity and antiviral activity in Vero cells. The most promising compounds were further validated using immunofluorescence and Western blot assays. Their in vivo efficacy was assessed in a lethal AG6 mouse model.

Results: Chlorhexidine and indinavir exhibited potent anti-ZIKV activity in vitro, with EC50 values of 16.41 µM and 12.8 µM, respectively, and favorable selectivity indices (CC50: 57.56 µM and 38.96 µM). Both compounds demonstrated a dose-dependent inhibition of ZIKV replication (5-40 µM) at the protein level. In the AG6 mouse model, treatment with either compound (50 mg/kg/day) significantly prolonged survival (p<0.001), delayed disease-associated weight loss, and reduced viral loads in key tissues compared to untreated controls.

Discussion: Our integrated computational and experimental approach identifies chlorhexidine and indinavir as promising repurposed anti-ZIKV agents. While toxicity concerns require further investigation, these findings provide a validated foundation for the development of therapeutics against ZIKV infection.

Introduction: The emergence of new SARS-CoV-2 variants with immune evasion capabilities underscores the importance of developing a broad-spectrum and effective vaccine. The receptor binding domain (RBD) of the Spike protein has been widely utilized in vaccine due to its high immunogenicity. However, the Spike protein, particularly the RBD region, exhibits significant variability in the evolution of SARS-CoV-2, leading to viral immune evasion and reduced vaccine effectiveness.

Methods: A broad-spectrum antigen (M5-RBD) was developed via mutation patching, incorporating key high-impact mutation sites (K417T, L452R, T478K, E484K, N501Y). Additionally, extra mutations (N440K or G446S) were introduced into M5-RBD to evaluate their impact on immune response. M5-RBD was further combined with a novel CpG adjuvant HP007 for immunization.

Results: M5-RBD elicited high titers of broad-spectrum neutralizing antibodies against SARS-CoV-2 wild-type and various variants (Delta, Omicron BA.1, BA.2, BA.2.75, BA.5, BF.7, BQ.1.1, XBB, EG.5, JN.1, KP.3 strains). Introduction of N440K or G446S significantly diminished the immune response to viral strains. When combined with HP007 adjuvant, M5-RBD induced efficient and durable T cell responses, providing protection to K18-hACE2 KI mice against lethal infections with both wild-type and Omicron BA.2 strains.

Discussion: Rationally designed with key high-impact mutation sites, M5-RBD effectively overcomes SARS-CoV-2 variant immune evasion and elicits broad-spectrum neutralizing antibodies. The combination with HP007 adjuvant enhances immune protection, providing a promising strategy for the development of next-generation COVID-19 vaccines.

Endometriosis (EMs), a common and frequently occurring gynecological disease, is a major cause of chronic pelvic pain and infertility in women. Its pathogenesis remains unclear to date, and it is characterized by high invasiveness and recurrence tendency. Although the specific pathogenesis of EMs has not been clarified, existing studies have confirmed that gut microbiota dysbiosis plays an important role in its pathogenic process. Studies suggest that gut microbiota may affect the occurrence and progression of EMs through immunoinflammatory pathways and metabolic pathways (such as enhanced estrogen metabolism and abnormal lipid metabolism). Meanwhile, approaches including dietary intervention, supplementation of probiotics or prebiotics, and microbiota transplantation can help prevent and alleviate EMs symptoms, providing potential therapeutic methods. This article will review the research progress on the correlation between gut microbiota dysbiosis and EMs, with the aim of offering more references for the diagnosis and treatment of EMs.

[This corrects the article DOI: 10.3389/fcimb.2022.814413.].

The rapid escalation of antimicrobial resistance (AMR) has rendered many conventional antibiotics ineffective, emphasizing the need for alternative therapeutic approaches. Probiotics have emerged as promising biotherapeutic agents capable of inhibiting multidrug-resistant (MDR) pathogens through diverse mechanisms, including secretion of antimicrobial metabolites (bacteriocins, organic acids, short-chain fatty acids, and hydrogen peroxide), competitive exclusion, quorum-sensing interference, and immune modulation. However, their clinical application is limited by poor stability under environmental and gastrointestinal stressors. Encapsulation technologies, particularly those employing natural biopolymers such as alginate, chitosan, pectin, carrageenan, and gelatin, have substantially improved probiotic viability, storage stability, and site-specific release. Recent advances in semi-synthetic and synthetic carriers, including PLGA, PVA, Eudragit^®, and hybrid nanofiber systems, have further enabled controlled delivery and synergistic protection in intestinal, topical, and food-based applications. Collectively, encapsulated probiotics represent a potent strategy for combating AMR by enhancing antimicrobial efficacy and therapeutic consistency. Future research should focus on optimizing encapsulation parameters, integrating multi-strain and synbiotic formulations, and employing multi-omics tools to translate laboratory findings into standardized clinical interventions.

Background: Ulcerative colitis (UC) is subtype of inflammatory bowel disease that is frequently comorbid with anxiety disorders. However, effective dual-targeting therapies are still lacking. Hyperoside (HYP), a natural flavonoid, exhibits anti-inflammatory and neuroprotective properties, yet its potential therapeutic effects on UC and associated anxiety, as well as the underlying mechanisms, remain largely unexplored.

Methods: A murine model of DSS-induced colitis was established and treated with HYP. Disease activity was assessed through body weight, colon length, and histopathology. Anxiety-like behaviors were evaluated using open field and elevated plus maze tests. Neuroinflammation was examined through immunohistochemistry of BDNF expression and microglial activation. Gut microbiota composition was profiled by metagenomic sequencing, and metabolomic profiling was conducted using the Q300 Kit. Network pharmacology and molecular docking were employed to predict signaling pathways, which were further validated by Western blotting. Additionally, antibiotic depletion experiments were conducted to determine microbiota dependency.

Results: HYP administration significantly ameliorated DSS-induced colitis, as evidenced by attenuated weight loss, restored colon length, and improved histopathology. It suppressed pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and restored intestinal barrier integrity by upregulating Mucin-2 and ZO-1. Furthermore, HYP also alleviated anxiety-like behaviors and mitigated neuroinflammation by increasing BDNF levels and suppressing microglial activation. HYP treatment also restored gut microbial homeostasis, enriching beneficial bacteria such as Enterobacter ludwigii while reducing the abundance of Enterobacter hormaechei, Escherichia coli, and Acinetobacter baumannii. Metabolomic analysis revealed that HYP significantly promoted arginine biosynthesis. Network pharmacology and molecular docking identified the MAPK, PI3K-Akt, and NF-κB pathways as potential targets, with HYP showing strong binding affinity to MAPK3, AKT1, and NFκB1. Importantly, the therapeutic effects of HYP were abolished in microbiota-depleted mice.

Conclusion: Our findings demonstrate that HYP effectively alleviates DSS-induced colitis and comorbid anxiety-like behaviors. Its efficacy is dependent on the gut microbiota and is associated with the restoration of microbial homeostasis, enhancement of arginine metabolism, and modulation of the MAPK/PI3K-Akt/NF-κB signaling pathways. HYP represents a promising microbiota-targeting therapeutic candidate for UC and its neuropsychiatric comorbidities.

AMPylation, as a crucial post-translational modification, is widely present in both prokaryotes and eukaryotes, playing a key role in regulating biological functions. The regulation of biological functions by AMPylation is a complex and diverse process. In prokaryotes, AMPylation plays a role in processes such as self-metabolic regulation, gene expression control, and maintenance of cellular redox homeostasis. Eukaryotes utilize AMPylation to regulate endoplasmic reticulum stress, participate in disease progression, and modulate immune responses. During interactions between prokaryotes and eukaryotes, bacteria can influence host cytoskeletal function, anti-apoptotic processes, and vesicular transport through AMPylation, thereby enhancing their survival within the host. Currently, AMPylation has been applied in numerous directions, such as detecting modifications, constructing disease models, and studying protein functions. This article highlights the diverse roles of AMPylation in regulating biological functions and reviewed the application progress in various fields, aiming to provide theoretical foundations for understanding their mechanisms in pathogen control and eukaryotic disease prevention.