Frontiers in bioscience (Landmark edition)最新文献

Background: Knee osteoarthritis (KOA), a chronic degenerative joint disease, is primarily driven by inflammation-induced cartilage degradation, which represents its core pathological feature. Eupatorin, with its distinct anti-inflammatory properties, has emerged as a promising candidate for KOA research. This study aimed to explore the therapeutic potential of Eupatorin and elucidate its underlying mechanisms in KOA through an integration of network pharmacology analysis and experimental validation.

Methods: Potential targets of Eupatorin and KOA-related genes were retrieved from multiple databases, and the overlapping targets were utilized to build a protein‒protein interaction (PPI) network to identify core targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to characterize the associated biological processes (BP), molecular functions (MF), and cellular components (CC). Additionally, molecular docking was performed to assess the binding affinities of Eupatorin with the core targets. Direct target engagement was confirmed using a cellular thermal shift assay (CETSA). Finally, biological experiments using interleukin-1β (IL-1β)-stimulated primary rat chondrocytes were carried out to validate the protective effects of Eupatorin through its anti-inflammatory activity.

Results: Network pharmacology analysis revealed 46 overlapping targets, with Matrix Metallopeptidase 9 (MMP9), Epidermal Growth Factor Receptor (EGFR), and Prostaglandin G/H synthase 2 (PTGS2) as key nodes within the PPI network. GO and KEGG enrichment analyses revealed significant associations with inflammatory responses and extracellular matrix (ECM) metabolism, particularly the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and estrogen signalling pathways. Molecular docking further confirmed strong binding affinities between Eupatorin and key targets, including MMP9, EGFR, and PTGS2. CETSA validated the direct binding of Eupatorin to PTGS2. Eupatorin significantly inhibited IL-1β-induced cytokine expression and ECM degradation while promoting ECM synthesis and restoring impaired autophagy in inflamed chondrocytes, as indicated; however, no significant effect on cellular senescence was observed. Mechanistically, Eupatorin exerted its protective effects on chondrocytes by attenuating the upregulation of the PI3K/AKT and estrogen signalling pathways.

Conclusion: Eupatorin has demonstrated potential for use in KOA therapy by targeting inflammation and ECM, and by regulating the PI3K/AKT and estrogen-associated signaling pathways.

Background: Disruption of the blood labyrinth barrier (BLB) is considered a pathological cause of diverse hearing impairments. Perivascular-resident macrophage-like melanocytes (PVM/Ms) play a critical role in maintaining inner ear homeostasis and BLB integrity. Activation of PVM/Ms leads to decreased production of pigment epithelium-derived factor (PEDF), contributing to BLB breakdown. This study investigated the role of the adenosine A2A receptor (A2AR) pathway in lipopolysaccharide (LPS)-induced inflammation in PVM/Ms and elucidated the underlying mechanisms.

Methods: The anti-inflammatory effects of adenosine and its specific receptor A2AR were evaluated in LPS-induced PVM/Ms. The levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and tissue inhibitor of matrix metalloproteinase 1 (TIMP-1) were measured by quantitative real-time PCR (qRT-PCR) and enzyme linked immunosorbent assay (ELISA). Additionally, matrix metalloproteinase-9 (MMP-9) and PEDF were quantified using western blot and ELISA, respectively. An endothelial cell (EC)-PVM/M co-culture model exposed to LPS was established and treated with adenosine and SCH58261 to assess effects on BLB permeability.

Results: LPS treatment significantly changed the production of inflammatory factors, including IL-6 and TNF-α, as well as MMP-9, TIMP-1, and PEDF. These changes were abrogated by adenosine, which also reduced the production of reactive oxygen species (ROS) and inhibited the activation of PVM/Ms. SCH58261 partially reversed the effects of adenosine following LPS treatment. The p38 MAPK pathway was found to be involved in adenosine regulation of LPS-induced PVM/Ms.

Conclusions: Adenosine attenuates the inflammatory activation of PVM/Ms and enhances their ability to maintain endothelial barrier integrity by binding to A2AR. The findings support adenosine and A2AR as potential therapeutic targets for treating hearing impairments.

Collagen, the primary structural protein of the extracellular matrix, shows marked structure-function duality in the tumor immune microenvironment (TIME). Biomechanical and biophysical alterations-matrix stiffening, viscoelastic energy dissipation, fiber alignment and tumor-associated collagen signatures, reduced pore size, and solid stress-create migration tracks, sequester signaling cues that regulate proliferation and metabolism, and from dense barriers that impede immune infiltration. These changes are sensed and transduced via mechanosensing and mechanotransduction pathways, thereby reinforcing malignant behavior and immune exclusion. Given its dynamic, spatiotemporally regulated roles, collagen is a promising therapeutic target to overcome immunotherapy resistance. This review examines the structural features, biological functions, and regulatory pathways of collagen within the TIME. Based on these insights, several clinical strategies were highlighted: targeting cancerassociated fibroblasts and profibrotic signaling to reduce fibrosis; remodeling the matrix enzymatically or physically; and inhibiting collagen receptor signaling. These approaches are often combined with immune checkpoint inhibition. Future directions will emphasize biomarker-guided stratification of collagen status; combining therapies informed by mechanobiology; and using scalable, noninvasive monitoring to optimize immunotherapy outcomes.

Phosphodiesterases (PDEs) are a huge superfamily of enzymes that fine-tune the intracellular levels of cyclic nucleotides -cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP)-thus playing a pivotal role in the control of many cellular processes. While traditionally studied in the context of cardiovascular and neurological systems, mounting evidences highlight a crucial involvement of PDEs in metabolic homeostasis. This review explores the expanding landscape of PDEs function beyond classical cyclic nucleotide degradation, focusing on their roles in glucose and lipid metabolism and their implications in metabolic disorders, including obesity, type 2 diabetes (T2DM), and metabolic syndrome (MetS). Starting from an overview of the PDE superfamily, this work deeply examines the compartmentalized actions of cAMP-dependent protein kinase A (PKA) and cGMP-dependent protein kinase G (PKG) signaling pathways in key metabolically active tissues integrating PDE activities across different organs and disease states to offer a holistic view of their metabolic relevance. Special attention is given to the therapeutic relevance of PDE inhibitors (PDEi), distinguishing between established applications and emerging strategies targeting specific PDE isoforms in metabolic disease contexts to underscore the evolving concept that PDEs act as dynamic regulators of metabolic signaling networks. Understanding their isoform-specific and tissue-specific actions could thus open new avenues for therapeutic intervention in complex metabolic disorders.

Bone remains one of the most hospitable-and devastating-destinations for metastatic cancer cells. At the center of this unwelcome alliance is transforming growth factor‑β (TGF‑β), a cytokine stored in the mineralized matrix and unleashed during osteoclastic bone resorption. Once activated, TGF‑β fuels a self‑reinforcing "vicious cycle": it co‑opts tumor cells to undergo epithelial‑to‑mesenchymal transition, recruits and primes osteoclasts, suppresses osteoblast function, and shapes an immunosuppressive niche that shields malignant clones. The result is a micro‑environment exquisitely tuned for tumor survival, skeletal destruction, and therapy resistance. This review traces the molecular choreography of TGF‑β signaling within the bone tumor microenvironment (TME), detailing its crosstalk with osteogenic, immune, and stromal compartments across breast, prostate, and lung cancer metastases. We synthesize pre‑clinical and clinical efforts to interrupt this pathway, ranging from ligand-neutralizing antibodies and activin receptor-like kinase 5 (ALK5) kinase inhibitors to antisense oligonucleotides and tumor-selective ligand traps-and examine why benefits observed in early trials are tempered by dose‑limiting toxicities and adaptive resistance. Beyond TGF‑β itself, we highlight parallel targets in the TME, including receptor activator of nuclear factor kappa-B ligand (RANKL)‑driven osteoclastogenesis, vascular endothelial growth factor/fibroblast growth factor (VEGF/FGF)‑mediated angiogenesis, and immune checkpoints such as PD‑1, TIM‑3, and LAG‑3, arguing that multi‑pronged combinations guided by real‑time TME profiling offer the most promising path forward. We outline pressing research priorities: mapping the spatiotemporal dynamics of TGF‑β activation, identifying predictive biomarkers for patient stratification, and engineering bone‑targeted delivery systems that preserve normal tissue repair. By decoding and disrupting the TGF‑β‑centered circuitry of bone metastasis, we can move closer to therapies that not only palliate skeletal complications but also prolong life for patients with advanced cancer.

The utilization of cell-free therapies derived from extracellular vesicles (EVs) has garnered mounting interest as a promising approach to address the myriad challenges associated with ischemic stroke. These Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) possess considerable therapeutic potential due to their inherent properties, including low immunogenicity, efficient cargo transportation, and the ability to cross the blood-brain barrier. This review examines the mechanisms underlying mesenchymal stem cell-derived EVs in the treatment of ischemic stroke. Future research should aim to identify optimal strategies for EV-based interventions, including combination therapy and preconditioning strategies.

Background: TP53 gene mutations are common in breast cancer and are linked to chemoresistance. p63, a p53 family member, can induce apoptosis independently of p53, representing a potential therapeutic target in TP53-mutant tumors. This study evaluated the synergistic effects of SB431542, a TGF-β type I receptor inhibitor, and doxorubicin in TP53-mutant breast cancer cells.

Methods: Isoform-specific RT-PCR was used to assess TAp63 and ΔNp63 expression following SB431542 treatment in T47D, MDA-MB-231, and MDA-MB-468 cells. Cell viability was assessed using the CCK8 assay. Synergistic interaction was quantified using the Coefficient of Drug Interaction (CDI). Caspase-3/7 activity assays and immunocytochemistry analyses were performed to evaluate apoptotic signaling and p63 expression. Inhibition studies using PETα, a p53-family inhibitor, and a pan-caspase inhibitor were conducted to determine the pathway dependency of the observed effects.

Results: SB431542 selectively increased TAp63 but not ΔNp63 expression in all three TP53-mutant breast cancer cells. GAS6, a TAp63 target, was also upregulated by SB431542. Treatment with SB431542 and doxorubicin used in combination significantly reduced cell viability (CDI 0.54-0.63), increased caspase activity, and enhanced p63 expression. The anticancer effect was significantly reduced by co-treatment with either the p53-family inhibitor or the pan-caspase inhibitor, confirming that the cytotoxic response was mediated through TAp63 and caspase activation.

Conclusions: SB431542 potentiates doxorubicin-induced apoptosis in TP53-mutant breast cancer cells by upregulating TAp63 and activating caspase-dependent pathways. These findings suggest that targeting the TGF-β/TAp63 signaling axis may offer a novel therapeutic approach to overcome chemoresistance in aggressive, TP53-mutant breast cancers.

Background: Exosomes are specialized secreted vesicles for intercellular communication and signaling pathways as specialized secreted vesicles. Multiple studies have suggested the potential roles of hepatocyte-derived exosomes as biomarkers of liver injury and facilitators of hepatocyte proliferation and liver regeneration.

Methods: By utilizing murine models of hepatic ischemia-reperfusion injury (IRI), we examined the impact of hepatocyte-derived exosomes on mitigating hepatic IRI.

Results: Our experiments have demonstrated that significantly lower levels of alanine transaminase, aspartate transaminase, and lactate dehydrogenase in mice treated with hepatocyte-derived exosomes compared with mice treated with phosphate-buffered saline (PBS). Furthermore, hepatocyte-derived exosomes inhibited hepatocyte apoptosis, reduced levels of inflammatory cytokines, and suppressed the entry of inflammatory cells into the liver following hepatic IRI. Complement 3d (C3d) expression showed a notable decrease in exosome-treated mice compared with PBS-treated mice, suggesting that hepatocyte-derived exosomes effectively inhibited complement activation during hepatic IRI. Blocking the fusion of exosomes with cells using Annexin V weakened the protective effects of the exosomes against hepatic IRI.

Conclusions: Our findings highlight the ability of hepatocyte-derived exosomes to mitigate hepatic IRI by inhibiting complement activation. These results reveal a novel role for exosomes in blocking complement activation, suggesting a potential new therapeutic avenue for preventing hepatic IRI.

Objective: This integrated study aimed to characterize fibroblast heterogeneity in diabetic ulcers and evaluate the efficacy of platelet-rich plasma (PRP) using multi-omics approaches.

Methods: We analyzed single-cell RNA sequencing (scRNA-seq) data (GSE165816) from healed (n = 9) and non-healed (n = 5) patients with diabetic foot ulcers (DFU) to characterize fibroblast dynamics, utilizing cell-cell communication analysis, transcription factor profiling, and pseudotime trajectory reconstruction. A streptozotocin-induced diabetic ulcer rat model was established to validate the therapeutic effects of PRP.

Results: scRNA-seq identified 13 cell types, with fibroblasts showing the most significant proportional increase in healed DFU (32% versus 25% in non-healed tissue). Fibroblast-centric communication networks revealed synergistic interactions with endothelial and keratinocyte lineages. Three key transcription factors (PLAGL1, RUNX2, and ZKSCAN7) were upregulated in healed fibroblasts, regulating pathways related to extracellular matrix (ECM) synthesis, angiogenesis, and cell migration. Pseudotemporal analysis confirmed the differentiation of fibroblasts toward ECM-producing states, with enrichment of platelet-derived growth factor (PDGF) signaling pathways. In the rat model, PRP treatment resulted in epidermal/dermal thickening, reduced inflammatory infiltration, and transcriptomic reprogramming that converged with non-diabetic profiles. Venn analysis identified a 26-core gene signature (e.g., COL1A1, FN1) associated with fibroblast-mediated ECM reorganization.

Conclusion: Fibroblasts drive diabetic ulcer healing via transcription factor-regulated functional networks. PRP accelerates tissue repair by modulating fibroblast ECM-related gene expression, with the 26-gene signature providing a promising foundation for novel diagnostic and therapeutic targets.