Frontiers in Molecular Biosciences最新文献

Endophytic fungi are an uncharted source of bioactive metabolites with varied therapeutic characteristics. In this research, an endophytic Aspergillus sp. (HAG1) was collected from Phragmites australis and identified using morphological and molecular methods. The large-scale fermentation, chromatographic purification, and spectroscopic approaches (FT-IR, UV-Vis, ¹H NMR, and ESI-MS) resulted in the identification of three metabolites: vaccenic acid (C1), pipericine (C2), and guaiacylglycerol (C3). Of these, C3 is reported here for the first time as an endophyte-derived metabolite from P. australis. All the metabolites exhibited significant antioxidant, antibacterial, antibiofilm, and anti-inflammatory activity. The activities of C3 were the most effective in DPPH and ABTS scavenging, COX-1/COX-2 inhibition, and suppression of biofilm for bacteria, although C3 was inactive against acetylcholinesterase activity. Molecular docking and molecular dynamics (MD) simulations underscored a favorable binding with a high binding conformation stability of C3 for antioxidant (1DGF), anti-inflammatory (3NLO), and antibiofilm (5TZ1) targets. In addition, density function theory (DFT) calculations delivered insights regarding electronic structure, explaining observed reactivity and hydrogen bonding ability. Moreover, ADMET predictions indicated that C3 has favorable solubility, metabolic stability, and low toxicity when compared to C1 and C2.

Caenorhabditis elegans encode two synaptic proteins linked to the Rim/Piccolo/Fife-family, through conserved motifs: 1) Clarinet (CLA-1), has 3 isoforms (short(S), medium(M) and long(L)) that are anchored at the active zone through a common C-terminal domain and 2) UNC-10/Rim that is also highly enriched at the presynaptic density. Both the cla-1 and unc-10 mutants have demonstrable effects on synaptic transmission and in combination produce a synergistic impact that virtually eliminates synaptic transmission and that has yet to be fully understood. Recently, CLA-1L and UNC-10 were shown to differentially regulate key active zone components, culminating in reduced Ca²⁺ channels and UNC-13 levels, but these changes cannot account for the severity of the release defects in the double mutants. CLA-1L extends far beyond the synaptic active zone and has been implicated in recycling of the key autophagy protein ATG-9. In this study, we show that cla-1L and unc-10 mutants negatively impact proteins involved in endocytic processing (ITSN-1 and AP-2) and endolysosomal maturation (RAB-5 and RAB-7). These abnormalities correlate with an accumulation of synaptic pleiomorphic vesicles by EM, in both cla-1L and unc-10 mutants. In addition, unc-10 mutants accumulate dense core vesicles, due to a dramatic reduction in neuropeptide release. These observations are accompanied by significant decreases in lifespan in both cla-1L and unc-10 mutants, which are exacerbated in the double mutants. Together these data suggest that the cumulative effects on synaptic transmission that result from distinct roles of CLA-1L and UNC-10 have an impact on survival.

Sepsis poses a significant threat to preterm infants and is a leading cause of white matter injury (WMI); however, effective therapeutic strategies remain limited. Recent studies suggest that gut microbiota dysbiosis contributes to sepsis-induced systemic inflammation and neurological damage. After treating mice with LPS-induced sepsis with glycine, we evaluated pathological changes in the brain and ileum by HE staining and analyzed gut microbiota composition by 16S rRNA gene sequencing. Inflammatory cytokine levels in brain and ileal tissues were quantified by ELISA. Transcriptomic profiling was performed to identify differentially expressed genes and enriched pathways in the brains of septic mice with WMI. Additionally, protein expression levels of occludin, Iba-1, BMP, and C5aR1 were assessed by IHC and Western blotting. The study demonstrates that sepsis induces WMI. Glycine alleviated intestinal dysbiosis, restored the expression and function of intestinal tight junction proteins, and reduced pro-inflammatory cytokine levels in both ileal and brain tissues. Moreover, glycine attenuated microglial activation, as evidenced by decreased Iba-1 expression, and preserved myelin integrity by preventing the loss of MBP in the brain. Transcriptomic analysis revealed significant upregulation of C5aR1 in brain tissue associated with sepsis-induced WMI. Collectively, these findings indicate that glycine represents a promising therapeutic strategy for the prevention and treatment of sepsis-associated WMI, and that targeting the C5aR1-mediated complement pathway may offer a novel approach to mitigate neuroinflammation and white matter damage.

Background: Bladder cancer (BLCA) is a highly heterogeneous malignancy with an unpredictable prognosis. Tumour progression is closely linked to the complex tumour microenvironment (TME), particularly the role of epithelial cells. This study aims to identify key epithelial cell-derived signature genes driving tumour progression, construct a reliable prognostic model, and further explore the biological functions of a pivotal gene, OAS1, in BLCA.

Methods: Single-cell RNA sequencing (scRNA-seq) data from public cohorts were analyzed to identify epithelial cell subpopulations and delineate their malignant progression trajectory. Genes significantly associated with this progression were identified through pseudotime analysis. Bulk RNA-seq and clinical data from The Cancer Genome Atlas (TCGA) BLCA cohort were utilized for least absolute shrinkage and selection operator (LASSO) Cox regression to build a prognostic risk model. The model's predictive efficacy was validated in an independent Gene Expression Omnibus (GEO) cohort. Furthermore, in vitro experiments including CCK-8, transwell, and wound healing assays were conducted to investigate the impact of OAS1 on the proliferation, migration, and invasion capabilities of BLCA cells.

Results: scRNA-seq analysis revealed a distinct epithelial cell subpopulation with high tumor-suppressive activity. A four-gene signature associated with tumor progression was successfully constructed into a prognostic model. Patients in the high-risk group exhibited significantly poorer overall survival in both the TCGA and validation cohorts. Multivariate Cox analysis confirmed the model as an independent prognostic factor. The risk score was significantly correlated with immune infiltration patterns and response to immunotherapy. Among the signature genes, OAS1 was identified as a critical factor. In vitro functional experiments demonstrated that knockdown of OAS1 markedly promoted the proliferation, migration, and invasion of BLCA cells.

Conclusion: We established a novel prognostic model for BLCA based on epithelial cell tumor progression-associated genes, which serves as a robust predictor for patient outcomes and immunotherapeutic responsiveness. Our findings further highlight OAS1 as a key gene that suppresses the aggressive phenotypes of BLCA cells, suggesting it is a potential therapeutic target. This study provides valuable insights for precise prognosis and treatment stratification of BLCA patients.

Background: The Golden Mussel, Limnoperna fortunei, represents one of the most successful aquatic invaders in South America, causing significant ecological and economic impacts. Repetitive DNA sequences, particularly satellite DNAs (satDNAs), play crucial roles in genome architecture and evolution, yet the satDNA landscape of this invasive species remains largely uncharacterized. This study aimed to comprehensively analyze the satellitome of L. fortunei using integrated computational and cytogenetic approaches.

Methods: We employed a read-clustering approach (RepeatExplorer2) to identify satDNA families from short-read genomic data. The identified families were then mapped onto the chromosome-level reference genome in silico to determine their chromosomal distribution. The physical localization of two representative satDNA families with contrasting distribution patterns was validated through fluorescence in situ hybridization (FISH) on meiotic chromosomes.

Results: Our analysis identified 129 distinct satDNA families, which were estimated to comprise approximately 9.1% of the genome based on read clustering. Subsequent in silico mapping successfully localized 126 of these families to the reference genome, where they collectively represented approximately 5.3% of the assembled chromosomes. Most families showed low divergence levels (0%-5% Kimura substitutions), suggesting recent amplification events. While most satDNAs were distributed across all 15 chromosomes, FISH analysis of two distinct families revealed contrasting distribution patterns: LfoSat025 showed preferential localization to pericentromeric regions, while LfoSat004 exhibited localized enrichment in specific chromosomal regions, demonstrating diverse organizational strategies within the satellitome. Meiotic analysis revealed normal chromosome pairing (15 bivalents), with no evidence of differentiated sex chromosomes, consistent with the species' predominantly gonochoristic reproductive mode.

Conclusion: This study provides the first comprehensive characterization of the L. fortunei satellitome, revealing a diverse and recently amplified repetitive landscape. The discrepancy between the genome-wide abundance (9.1%) and the mapped abundance (5.3%) highlights the challenges of assembling repetitive regions and underscores the value of using complementary methodologies. The identification of chromosome-specific satDNA markers establishes a foundation for developing molecular tools for invasion monitoring, including population genetic analyses to trace invasion routes and identify source populations. These findings contribute to understanding the role of repetitive DNA in genome evolution and the adaptive success of invasive species.

Background: Given the lack of effective treatment for chronic nonbacterial prostatitis (CNP) and the anti-inflammatory property of natural bioactive compound forsythiaside A (FTA), the therapeutic potential of FTA on CNP is worthy of investigation.

Methods: CNP rat models were established using complete Freund's adjuvant, followed by a 4-week administration of FTA at different concentrations (40 and 80 mg/kg/d). The body and prostate of rats were weighed to calculate the prostatic index. Prostate damage and inflammatory infiltration were assessed using histological analysis and immunohistochemistry staining. Levels of inflammation-related cytokines, autophagic markers as well as the protein kinase C alpha (PKCα)/NF-κB pathway in prostate tissues were detected using enzyme-linked immunosorbent assay and western blot.

Results: No significant change was observed in the body weight of CNP rat models administered with or without FTA. FTA treatment reduced the prostatic index and mitigated prostate damage and inflammatory infiltration of CNP rat models. FTA treatment decreased the number of CD3-positive cells and CD45-positive cells, while downregulating interleukin 1 beta (IL-1β), IL-2, IL-6, IL-17A, monocyte chemoattractant protein-1, and tumor necrosis factor alpha in prostate tissues of CNP rat models. FTA treatment promoted Beclin-1 and LC3B II/LC3B I expressions, and inhibited PKCα and p-p65/p65 expressions in prostate tissues of CNP rat models.

Conclusion: FTA alleviates inflammation and facilitates autophagy in CNP rat models by blocking the PKCα/NF-κB pathway.

Objective: In view of the high incidence of type 2 diabetes mellitus (T2DM) and the high prevalence of multi-organ complications, as well as the issues that traditional hypoglycemic drugs are prone to causing weight gain and the molecular targets and signaling pathways of classic drugs such as metformin have not been systematically clarified, this study aims to systematically analyze the mechanism of action and clinical value of glucagon-like peptide-1 receptor agonists (GLP-1RAs), and It further clarifies key signaling pathways including adenosine monophosphate-activated protein kinase (AMPK), phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt), cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA), and interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) cytokine pathways, prkviding theoretical support for precision interventions in T2DM.

Methods: The latest domestic and international multi-omics research data, cell/animal functional experiment results, and clinical evidence were systematically integrated to analyze the structural modification strategies and glucose concentration-dependent mechanism of action of GLP-1RAs. Emphasis was placed on dissecting their regulatory pathways for insulin/glucagon secretion, as well as key receptor-related networks.

Result: Glucagon-like peptide-1 receptor agonist (GIP-1RA), when modified at specific amino acid positions, becomes resistant to dipeptidyl peptidase 4 (DPP-4) degradation. It activates the Gs/cAMP/PKA/exchange protein activated by cAMP (EPAC) signaling axis to promote insulin release in a glucose concentration-dependent manner, while suppressing glucagon secretion through Gi/cAMP downregulation and insulin synergistic effects. Additionally, it induces transient IL-6 release in monocytes, enhancing adipose tissue brownification and thermogenesis via the IL-6/STAT3 pathway. This mechanism protects pancreatic β-cells by preventing apoptosis and promoting proliferation, while improving insulin resistance in adipose, hepatic, and skeletal muscle tissues. The compound also exhibits dual effects of weight loss and hepatoprotective (miRNA-regulated lipid metabolism) and nephroprotective (sodium excretion and anti-inflammatory) actions. Key regulatory targets include AMPK, PI3K-Akt, cAMP-PKA, and IL-6/STAT3.

Conclusion: GLP-1RAs overcome the limitations of endogenous GLP-1 and traditional hypoglycemic drugs, providing a new strategy for the comprehensive treatment of T2DM featuring "hypoglycemia-organ protection-weight loss". The mechanisms and pathway networks analyzed in this study lay a foundation for the precise intervention of T2DM and rational clinical drug use.

Myocardial infarction (MI) is a leading cause of morbidity and mortality globally, often resulting in heart failure due to adverse cardiac remodeling triggered by inflammation and fibrosis. Traditional Chinese Medicine (TCM), particularly compounds like Quercetin from Licorice and Peony, has shown promise in modulating inflammation and oxidative stress in cardiovascular diseases. This study integrates bioinformatics and experimental validation to explore the therapeutic potential of Quercetin in MI. Using Mendelian Randomization (MR) and colocalization analysis, we identified key MI-related genes, such as VEGFA, PTK2, and GGT1, whose expression is influenced by Quercetin. Bioinformatics tools predicted these genes as targets of Quercetin, with molecular docking revealing stable interactions between the compound and these genes. Single-cell RNA-sequencing of MI samples confirmed the expression of these genes in cardiac muscle cells (CMs) and macrophages, highlighting their role in tissue repair and inflammation. In experimental models, Quercetin treatment significantly altered the expression of these genes, enhancing myocardial cell recovery and reducing infarct size. This study provides molecular insights into how Quercetin and other TCM compounds could modulate critical pathways involved in MI recovery, supporting their potential as adjunct therapies. The findings bridge traditional medicine with modern bioinformatics, opening new avenues for therapeutic strategies to improve cardiac function and patient outcomes in MI.

Background: Some antidiabetic drugs have been shown to have tumor suppressor or activator properties. The associations between the treatment durations of three relatively new classes of antidiabetic medications, namely glucagon-like peptide-1 receptor agonists (GLP-1RA), dipeptidyl peptidase 4 inhibitors (DPP-4I), and sodium-glucose cotransporter 2 inhibitors (SGLT-2I), and lung cancer prognosis remain unclear.

Methods: A retrospective analysis was conducted on 11,357 newly diagnosed lung cancer patients with type 2 diabetes; these patients were recruited from the National Healthcare Big Data (East) Center and were divided into three groups based on their use of DPP-4I, GLP-1RA, or SGLT-2I, along with categorization of their treatment durations. Cox proportional hazards models were employed to assess the associations between drug duration and survival outcomes, including progression-free survival (PFS) and overall survival (OS). The multivariable models were adjusted for covariates like age, sex, smoking status, biomarkers, and cancer treatments. Sensitivity analyses and Kaplan-Meier estimates were used to validate the findings.

Results: In terms of the PFS, the highest quartile of GLP-1RA treatment (≥560 days) showed a lower incidence of cancer progression (hazard ratio (HR): 0.43; 95% confidence interval (CI): 0.18, 1.03), although the results were not statistically significant. DPP-4I and SGLT-2I showed less consistent trends. In terms of OS, GLP-1RA demonstrated a linear dose-response characteristic with reduced mortality risk over longer treatment durations, whereas DPP-4I and SGLT-2I showed non-linear associations. The sensitivity analyses confirmed these findings.

Conclusion: Longer treatment durations of GLP-1RA, SGLT-2I, and DPP-4I reduced the risks of disease progression and mortality in lung cancer patients with type 2 diabetes. Among these drug classes, GLP-1RA showed consistent benefits while DPP-4I and SGLT-2I had non-linear associations, with shorter treatment durations being linked to higher risk.