Frontiers in bioscience (Landmark edition)最新文献

Ischemic stroke ranks among the leading global causes of death and disability, driven by intricate mechanisms such as neuronal injury, inflammation, and oxidative stress. Emerging as a pivotal player in ischemic stroke progression is ferroptosis-an iron-dependent form of regulated cell death. Its hallmarks-iron metabolic dysregulation and lipid peroxidation-trigger cell membrane disruption and irreversible neuronal damage. Beyond that, ferroptosis intensifies inflammation and compromises the blood-brain barrier (BBB), substantially increasing the impact of ischemic injury. Research indicates that modulating ferroptosis-related molecular pathways could significantly mitigate the pathological progression of ischemic stroke. Based on a systematic search of PubMed, Web of Science, Embase, and Cochrane Library databases (as of April 30, 2025), this review focuses on the progress of research on the mechanisms and treatments of ferroptosis in ischemic stroke over the past five years, aiming to investigate the underlying mechanisms, pathological roles, cross-disease associations, and targeted therapeutic strategies, to lay a theoretical foundation for the development of advanced therapies, and to outline the challenges and future directions of the field.

Lung cancer, the leading cause of cancer-related mortality worldwide, poses considerable therapeutic challenges due to the varied responses to programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors. Emerging highlight the pivotal role of host-microbiome interactions in modulating antitumor immunity and influencing clinical outcomes. This review examines how the respiratory and gut microbiota contribute to the immunosuppressive tumor microenvironment through dysbiosis-induced T-cell exhaustion and regulatory cell activation, while certain commensals facilitate dendritic cell-mediated recruitment of cytotoxic T lymphocytes. Additionally, this review explores the molecular mechanisms by which microbial metabolites, such as short-chain fatty acids, influence myeloid-derived suppressor cells. Therapeutically, microbiota-modulation strategies-such as tailored probiotic formulations and precision fecal microbiota transplantation-offer potential to enhance immunotherapy efficacy. This review provides a foundation for microbiome-guided immunotherapy, advocating for biomarker-driven patient stratification and the use of engineered microbial consortia to counteract therapeutic resistance. These findings pave the way for the integration of microbiome science into next-generation precision oncology.

Background: Programmed death-ligand 1 (PD-L1) partners with specificity Protein 1 (SP1) or signal transducer and activator of transcription 3 (STAT3) to modulate the transcription of growth arrest-specific 6 (GAS6) and early growth response protein 1 (EGR1), necessitating mediators to avoid feedback. Based on binding and stemness data, high mobility group A1 (HMGA1) and Small Mother Against Decapentaplegic3 (SMAD3) were identified as potential mediators in this context. While the SMAD3-P300-STAT3 complex facilitates SMAD3-STAT3 crosstalk, it remains unclear whether the PD-L1-HMGA1-SP1 or PD-L1-SMAD3-SP1 complexes bind to GAS6 and EGR1 promoters to regulate their transcription.

Methods: MG63 osteosarcoma cells and SW620 colon cancer cells with unidentified nuclear PD-L1 function were chosen for our study. Chromatin immunoprecipitation and co-immunoprecipitation assays were performed to evaluate SP1, HMGA1, SMAD3, STAT3, P300 and PD-L1 (also denoted CD274) enrichment at the GAS6 and EGR1 promoters; the existence of the PD-L1-(HMGA1 or SMAD3)-SP1 complexes; whether P300 binds to STAT3; and whether HMGA1 and SMAD3 bind to P300. The alterations in GAS6, EGR1 and PD-L1 mRNA levels after their combined over-expression and/or knockdown were assessed via qPCR. Two representative target genes identified via PD-L1 chromatin immunoprecipitation (ChIP)-seq were examined to determine whether HMGA1 and SMAD3 were enriched at their promoters.

Results: PD-L1, HMGA1, SMAD3, SP1, P300 and STAT3 were enriched at GAS6 and EGR1 promoters in two cell lines. HMGA1 or SMAD3 antibody pulled down PD-L1 and SP1; PD-L1 antibody pulled down HMGA1, SMAD3 and SP1; P300 antibody pulled down STAT3; and, surprisingly, HMGA1 and SMAD3 antibodies pulled down P300. Combined over-expression or knockdown significantly altered GAS6, EGR1 and PD-L1 mRNA levels. PD-L1 ChIP-seq indicated 114 target genes, among which PD-L1 and beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC) were chosen to verify the promoter enrichment of HMGA1 and SMAD3.

Conclusion: Our study provides initial evidence that PD-L1 might form HMGA1- and SMAD3-dependent complexes to bind the GAS6, EGR1 and CD274 promoters, thus modulating the transcription of GAS6, EGR1 and PD-L1 mRNA in cancer and sarcoma cells.

Histone post-translational modifications (HPTMs) have emerged as crucial epigenetic regulators in urological malignancies, including prostate, bladder, and renal cell carcinomas. This review systematically examines four key modifications-lactylation, acetylation, methylation, and phosphorylation-and their roles in carcinogenesis. These dynamic modifications, mediated by "writers", "erasers", and "readers", influence chromatin structure and gene expression, thereby driving oncogenic processes such as metabolic reprogramming, immune evasion, and treatment resistance. The newly discovered lactylation modification links cellular metabolism to epigenetic regulation through lactate-derived histone marks, particularly in clear cell renal cell carcinoma, where it activates oncogenic pathways. Acetylation modifications, regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), modulate chromatin accessibility and are implicated in silencing cancer suppressors. Methylation patterns, controlled by histone lysine methyltransferases (KMTs) and histone lysine demethylases (KDMs), demonstrate dual roles in gene regulation, with specific marks either promoting or suppressing carcinogenesis. Finally, phosphorylation dynamics affect critical cellular processes such as cell cycle progression and DNA repair. This review underscores the therapeutic potential of targeting these modifications, as evidenced by promising results with HDAC and Enhancer of zeste homolog 2 (EZH2) inhibitors. However, challenges persist in clinical translation, including off-target effects and the complexity of the cancer microenvironment. Future research should utilize multi-omics approaches to elucidate modification crosstalk and develop precision therapies. Overall, this comprehensive analysis provides valuable insights into the epigenetic mechanisms underlying urological cancers and highlights remaining knowledge gaps and therapeutic opportunities in this rapidly evolving field.

Background: Plant-derived treatments for skin inflammation are gaining increasing interest, driven by the growing demand for safer alternatives to conventional synthetic drugs. Curcuma longa L. (turmeric) is traditionally utilized in many Asian countries for various pharmacological applications. Although the inflammation-suppressing properties of turmeric rhizomes are well established, the bioactive potential of its leaves and pseudostems remains largely unexplored. This study investigates the effects of turmeric leaf and pseudostem extract (CLE) on tumor necrosis factor (TNF)-α/interferon (IFN)-γ-stimulated HaCaT keratinocytes (HK) and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ear edema in a mouse model.

Methods: Cell viability and intracellular ROS levels in response to CLE were assessed. The potential of CLE to suppress inflammation was evaluated by monitoring the inhibition of signaling pathways and changes in cytokine/chemokine expression through Western blotting and real-time quantitative polymerase chain reaction (RT-qPCR) analyses. CLE was also examined for its impact on skin hydration and tight junction integrity. For in vivo analysis, an ear edema model was established using female BALB/c mice (7 weeks old).

Results: CLE treatment led to a dose-dependent decline in intracellular ROS and enhanced cell viability of TNF-α/IFN-γ-stimulated HK. Treatment with CLE resulted in decreased transcription of epithelial-derived cytokines (thymic stromal lymphopoietin (TSLP), IL-25, IL-33), pro-inflammatory mediators (IL-6, IL-8, IL-13, TNF-α, IFN-γ, IL-1β), and chemokines (macrophage-derived chemokine (MDC), regulated on activation, normal T cells expressed and secreted (RANTES), thymus and activation-regulated chemokine (TARC)), along with inhibition of mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signaling proteins in stimulated HK. CLE improved expression of proteins associated with skin hydration and tight junctions, helping to preserve moisture balance and structural integrity. Moreover, CLE markedly reduced ear redness, swelling, and thickness in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mice, while alleviating histopathological changes, including inflammatory cell infiltration and dermal thickening. Additionally, CLE effectively diminished inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and pro-inflammatory cytokine expression in the ear tissues of edema-induced mice.

Conclusions: Collectively, CLE exhibited potential as a natural anti-inflammatory agent by attenuating oxidative stress, downregulating inflammatory mediators, enhancing skin barrier function in vitro, and reducing ear edema in vivo.

Fibrotic diseases encompass a range of pathological conditions characterized by the abnormal growth of connective tissue, involving various cell types and intricate signaling pathways. Central to the onset and development of fibrosis are macrophages and fibroblasts, whose interactions are a pivotal area of investigation. Macrophages facilitate the activation, growth, and collagen production of fibroblasts, doing so either directly or indirectly through the release of cytokines, chemokines, and growth factors. Conversely, fibroblasts boost macrophage activity and intensify local inflammatory responses by secreting cytokines and matrix proteins associated with fibrosis. Throughout the different phases of fibrosis, these two cell types communicate via cytokines and signaling pathways, thereby sustaining the pathological condition. This review emphasizes the interplay between macrophages and fibroblasts and their contributions to fibrosis in the lungs, liver, kidneys, and other organs. Furthermore, it delves into potential therapeutic targets within these interactions, with the aim of shedding light on future clinical research and treatment approaches for fibrotic diseases.

The role of macrophages has transcended the traditional binary framework of M1/M2 polarization, emerging as "tissue microenvironment engineers" that dynamically govern organismal homeostasis and disease progression. Under physiological conditions, they maintain balance through phagocytic clearance, metabolic regulation (e.g., lipid and iron metabolism), and tissue-specific functions (such as hepatic detoxification by Kupffer cells and intestinal microbiota sensing), all meticulously orchestrated by epigenetic mechanisms and neuro-immune crosstalk. In pathological states, their functional aberrations precipitate chronic inflammation, fibrosis, metabolic disorders, and neurodegenerative diseases. Notably, this plasticity is most pronounced within the tumor microenvironment (TME): tumor-associated macrophages (TAMs) polarize toward a protumoral phenotype under conditions of low pH and high reactive oxygen species (ROS). They promote angiogenesis via vascular endothelial growth factor (VEGF), suppress immunity through interleukin-10 (IL-10)/programmed death-ligand 1 (PD-L1), and facilitate tumor invasion by degrading the extracellular matrix, ultimately fostering an immune-evasive niche. Novel intervention strategies targeting TAMs in the TME have shown remarkable efficacy: CRISPR-Cas9 spatiotemporal editing corrects aberrant gene expression; pH/ROS-responsive nanoparticles reprogram TAMs to an antitumoral phenotype; chimeric antigen receptor-macrophage (CAR-M) 2.0 enhances antitumor immunity through programmed death-1 (PD-1) blockade and IL-12 secretion; and microbial metabolites like butyrate induce polarization toward an antitumor phenotype. Despite persisting challenges-including the functional compensation mechanisms between tissue-resident and monocyte-derived macrophages, and obstacles to clinical translation-the macrophage-centered strategy of "microenvironmental regulation via cellular engineering" still holds revolutionary promise for the treatment of tumors and other diseases.

The intestinal microbiota, present in vast numbers within the human body, plays a pivotal role, with its composition and abundance varying significantly across individuals. This gut microbiota not only contributes to normal physiological development but also impacts the initiation, progression, resolution, and prognosis of various diseases. Recent studies have increasingly illuminated the connection between intestinal microbiota and pain, with a particular focus on the relationship between gut microbiota and neuropathic pain (NP). NP, an acute and chronic pain disorder arising from sensory nervous system injury, encompasses both peripheral and central neuropathic pain. Evidence suggests that intestinal microbiota influences NP occurrence and may modulate its severity. This review synthesizes current research findings on the microbiota-NP relationship, aiming to establish a theoretical foundation for future clinical investigations.

The Akt/PKB (protein kinase B) is a major transducer of the phosphoinositide 3-kinase (PI3K) signaling axis, regulating key cellular processes such as growth, proliferation, apoptosis, survival, and migration in both normal and cancer cells. In normal cells, oncoproteins and tumor suppressor proteins within the Akt pathway exist in equilibrium. However, this equilibrium is disrupted in cancer cells due to activating mutations in oncoproteins and inactivating mutations in tumor suppressor proteins. This dysregulation drives tumor growth and progression, making the Akt pathway an attractive target for cancer therapies. A deeper understanding of the molecular mechanisms of the Akt signaling pathway is crucial for developing novel therapeutic agents targeting Akt and its downstream effectors for cancer treatment. This review discusses the role of Akt in cancer, current Akt-targeted agents, their limitations, and future trends.