Frontiers in Molecular Biosciences最新文献

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.

Uveal melanoma (UM) is characterized by profound immunosuppression, resistance to immunotherapy, and significant hypoxia. This study investigates the role of hypoxia in mediating metabolic crosstalk with immune cells via CD63-enriched exosomes. Single-cell transcriptomic analysis identified a CD63-high tumor subpopulation in UM associated with lactate metabolism and vesicle transport. Under hypoxic conditions (1% O₂ vs. 21% O₂ normoxia), UMT2 cells exhibited upregulation of CD63 expression, increased exosome secretion, and elevated exosomal lactate levels. In co-culture assays, these hypoxic exosomes promoted macrophage M2 polarization, as indicated by increased CD206⁺ expression and elevated Extracellular Acidification Rate/Oxygen Consumption Rate (ECAR/OCR) ratios in macrophages and induced CD8⁺ T cell exhaustion, as evidenced by higher PD-1⁺TIM-3⁺ expression, and promoted the secretion of immunosuppressive cytokines such as TGF-β and IL-10. Importantly, these effects, which were driven by exosomal lactate transfer leading to macrophage metabolic reprogramming, were abolished upon CD63 knockdown using siRNA. Mechanistically, CD63 facilitates a hypoxia-induced exosomal lactate shuttle. We conclude that CD63-mediated transfer of hypoxic exosomal lactate establishes a critically immunosuppressive microenvironment in UM. Targeting the hypoxia/CD63/exosomal lactate axis may represent a promising novel therapeutic strategy to restore anti-tumor immunity in UM.

Introduction: Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting millions worldwide. While advances in single-cell technologies have elucidated cellular diversity and transcriptional changes in AD, the contribution of transposable elements (TEs) to disease pathogenesis remains poorly understood.

Methods: We integrated published single-nucleus RNA sequencing data from 11 AD patients and 7 controls with chromatin accessibility profiles from ATAC-seq to map the cell type-specific landscape of TE expression and regulation.

Results: We identified 508 differentially expressed TE loci, 84.3% of which were upregulated in AD, indicating widespread TE activation. TE dysregulation was most prominent in excitatory neurons (319 loci) and oligodendrocytes (165 loci), dominated by SINE (62.8%) and LINE (26.4%) elements. Several dysregulated TEs overlapped regulatory regions near key AD-associated genes including DOC2A, ABCA7, PTK2B, IL34, ABCB9, PLD3, and TARDBP.

Discussion: These findings highlight cell-type-specific TE activation in AD and provide a foundation for investigating TE-mediated regulatory disruption and its therapeutic potential.

Pharmacophore modeling has evolved from a static conceptual framework into a central computational tool in modern drug discovery. Recent advances include multi-pharmacophore strategies that better capture ligand diversity and target flexibility, as well as dynamic pharmacophore models ("dynophores") derived from molecular dynamics simulations that reflect time-dependent interaction patterns. The integration of artificial intelligence and machine learning has further improved feature extraction, virtual screening accuracy, and predictive performance across discovery pipelines. Despite these advances, pharmacophore modeling remains constrained by conformational bias, limited binding-mode representation, and computational cost. Case studies involving efflux pumps, topoisomerase IIα, and LEDGF/p75-integrase inhibitors illustrate both the strengths and limitations of current methods. Collectively, these developments underscore the value of hybrid approaches to enhance pharmacophore reliability and real-world utility.

Adeno-associated virus (AAV) vectors are widely used for in vivo gene delivery to the central nervous system (CNS), muscle, and retina, but many clinically used capsids show limited potency in human tissues, necessitating high systemic doses that increase cost and toxicity risk. Here, we summarize recent capsid-engineering strategies designed to improve on-target delivery and reduce vector dose requirements. For CNS applications, receptor-informed engineering-such as capsids targeting transferrin receptor 1 (TfR1) or alkaline phosphatase (ALPL)-has produced large gains in blood-brain barrier (BBB) penetration and cross-species translation. In the retina, intravitreal (IVT) performance improves through fine-tuning of heparan sulfate proteoglycan (HSPG) interactions to facilitate inner limiting membrane (ILM) traversal, while suprachoroidal and laterally spreading subretinal vectors expand posterior-segment coverage. For muscle, next-generation myotropic and liver-detargeted capsids enable uniform skeletal and cardiac transduction at substantially lower intravenous doses. We compare directed evolution, rational design, and machine-learning (ML) approaches, highlighting how these methods increasingly converge by integrating structural hypotheses, in vivo selections, and multi-trait computational optimization. Quantitative benchmarks across tissues demonstrate that engineered capsids routinely deliver multi-fold improvements in potency and biodistribution relative to natural serotypes. Collectively, these advances outline a translational path toward safer, lower-dose AAV gene therapies with improved precision and clinical feasibility.

In this study, we report the design and synthesis of a new series of pyrrolopyrimidine derivatives developed as dual-target nonsteroidal anti-inflammatory agents (NSAIDs). The compounds were evaluated for anti-inflammatory properties, cyclooxygenase-1/2 (COX-1/COX-2) inhibitory activity, and angiotensin-converting enzyme 2 (ACE2)-blocking activity in lipopolysaccharide (lipopolysaccharide)-stimulated RAW264.7 cells. Among the synthesized molecules, compounds 5a and 5b showed potent dual inhibitory activity, which was supported by molecular docking and molecular dynamics simulations. These findings highlight the potential of selective COX-2 inhibitors with concurrent ACE2 blockade as a promising therapeutic approach for controlling inflammation and modulating pathways relevant to viral entry and other inflammation-associated disorders. While ACE2 inhibition has received particular attention in the context of recent viral infections, the broader anti-inflammatory efficacy of these derivatives supports their potential as multi-target drug candidates.