Frontiers in bioscience (Landmark edition)最新文献

Background: Liver fibrosis, the end-stage pathological state of many liver diseases, is primarily driven by the activation of hepatic stellate cells (HSCs) and collagen deposition resulting from various pathogenic causes. Thrombospondin-2 (THBS2), a secreted extracellular matrix glycoprotein encoded by the TSP gene family, has been found to activate the TLR4-transforming growth factor-β (TGF-β)/FAK signaling axis and HSCs through autocrine signalling, thereby contributing to the development of liver fibrosis. Latexin (LXN), the only known zinc-dependent metallocarboxypeptidase inhibitor in humans, has not yet been studied for its role in liver fibrosis is yet to be studied.

Methods: In this study, we used adeno-associated virus 9 (AAV9) to generate a mouse model of liver fibrosis with LXN knockdown and used siLXN to knock down the LXN gene in the human hepatic stellate cell line LX-2. The mechanisms underlying the association between LXN and hepatic fibrosis progression were investigated using quantitative polymerase chain reaction, western blot, immunohistochemistry, and immunofluorescence staining.

Results: LXN knockdown reduced carbon tetrachloride (CCl₄)-induced liver injury and suppressed activation of hepatic stellate cells, while also inhibiting the expression of α-SMA and collagen I. Furthermore, LXN demonstrates a substantial positive correlation with THBS2, and LXN knockdown was capable of downregulating THBS2.

Conclusion: The LXN-THBS2 signaling axis may promote liver fibrosis progression by inducing the activation of HSCs.

This review examines the applications of natural coumarins in the context of bone and joint disorders. It provides comprehensive coverage of their fundamental pharmacology, the epidemiology and pathological mechanisms of osteoarticular diseases, as well as the pharmacological actions, clinical applications, future prospects, and ongoing challenges associated with these compounds. Through systematic analysis of relevant studies, we summarize the basic characteristics of natural coumarins, including their chemical structures, metabolic pathways, and pharmacological activities. We also examine their mechanisms of action in conditions such as osteoarthritis, rheumatoid arthritis, and osteoporosis, with a particular emphasis on their anti-inflammatory and cartilage-repairing properties. Furthermore, we summarize current clinical trials, formulation development, delivery strategies, and safety evaluations. We also explore potential new indications, combination therapies, and personalized treatment approaches. Several controversies and ongoing challenges are discussed, including variability in dose-dependent efficacy, divergent therapeutic outcomes across diseases, and concerns regarding long-term safety. This review aims to provide a foundational reference for further research and clinical application of natural coumarins in the treatment of bone and joint disorders.

Background: Rotator cuff injuries are common musculoskeletal disorders and are frequently complicated by impaired tendon-bone healing and high re-tear rates after surgical repair. Exosomes derived from adipose-derived stem cells (ADSCs) have shown regenerative potential through paracrine mechanisms; however, the role of exosomal insulin-like growth factor 1 (IGF1) in tendon-bone healing remains unclear.

Methods: Exosomes were isolated from rat ADSCs with or without lentiviral knockdown of IGF1. A rat supraspinatus tendon tear and repair model was established, and 200 μg of exosomes was administered systemically post-surgery. Tendon-bone healing was evaluated at 8 weeks post-operation using histological, immunohistochemical, and micro-computed tomography analyses. Early molecular responses were assessed at 1-week post-surgery by Western blot and RT-qPCR. Angiogenic markers (vascular endothelial growth factor (VEGF), CD31, α-SMA), inflammatory cytokines (interleukin (IL)-1β, IL-18), pyroptosis-related proteins (gasdermin D N-terminal fragment (GSDMD-N)), and NLRP3 inflammasome components were examined.

Results: ADSC-derived exosomes significantly enhanced bone mineral density, fibrocartilage formation, vascularization, and biomechanical strength at the tendon-bone interface. These effects were accompanied by reduced inflammatory cytokine expression, inhibition of pyroptosis, and suppression of NLRP3 inflammasome activation. In contrast, exosomes derived from IGF1-deficient ADSCs exhibited markedly reduced therapeutic efficacy, with attenuated angiogenic, anti-inflammatory, and anti-pyroptotic effects.

Conclusions: Exosomal IGF1 plays a critical role in promoting angiogenesis, suppressing inflammation and pyroptosis, and improving structural and biomechanical outcomes during tendon-bone healing. IGF1-enriched ADSC-derived exosomes represent a promising therapeutic strategy for enhancing rotator cuff repair.

Objective: Arsenic trioxide (ATO) is a cornerstone of acute promyelocytic leukemia (APL) therapy but induces severe gut microbiota dysbiosis, limiting its efficacy and safety. This study investigated whether adjunctive Bifidobacterium pseudolongum (BP) could mitigate these adverse effects and enhance therapeutic outcomes.

Methods: 16S rRNA gene sequencing data of gut microbiota were obtained from a cohort of 22 APL patients treated with ATO-based regimens (20 of 22 data were obtained and analysis further), accessible under BioProject ID PRJNA935705. To evaluate the within-sample microbial community richness and evenness, alpha and beta diversity indices were calculated. Using a murine APL model, we compared ATO monotherapy with ATO+BP co-treatment. Analyses included fecal metagenomic sequencing, single-cell RNA sequencing (sc-RNA-seq), flow cytometric immune profiling, and assessment of intestinal tight junction proteins (claudin-1, occludin, and ZO-1) via immunofluorescence.

Results: ATO treatment significantly reduced gut microbial diversity and depleted beneficial taxa. Sc-RNA-seq data showed that ATO could orchestrate the APL immune microenvironment mainly through functional activation of CD8+ T cells and monocytes. BP supplementation restored microbial homeostasis and synergistically enhanced ATO's antileukemic effect, reducing the leukemic burden in peripheral blood by 72% and in bone marrow by 64% compared to ATO alone. Mechanistically, BP preserved intestinal barrier integrity by upregulating tight junction protein expression and modulated anti-tumor immunity, notably increasing bone marrow CD8+ T cells by 2.21-fold.

Conclusions: BP is an effective adjunct to ATO therapy, counteracting gut dysbiosis, intestinal damage, and the immune microenvironment while synergistically improving antileukemic efficacy. Targeting the gut-leukemia axis with BP represents a promising strategy for improving the precision and safety of APL treatment.

Background: High-grade ovarian cancer (HGOC) is a heterogeneous and aggressive malignancy with a tumor microenvironment (TME) that suppresses immune responses, limiting immunotherapy efficacy. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a potential therapeutic target.

Methods: We investigated the immunomodulatory effects of the ferroptosis inducer RAS-Selective Lethal 3 (RSL3) in four HGOC cell lines (ES-2, OVCAR-5, HEY, PEO-1) using flow cytometry and lactate dehydrogenase (LDH) release assays.

Results: RSL3 modulated Natural Killer (NK) ligand expression in a cell line-dependent manner, resulting in differential susceptibility to NK cell-mediated cytotoxicity. OVCAR-5 cells became more susceptible to NK cell killing after treatment, whereas HEY cells showed reduced susceptibility, and ES-2 and PEO-1 cells exhibited minimal changes.

Conclusions: Ferroptosis induction alone does not consistently enhance NK cell-mediated cytotoxicity in HGOC cells. These findings underscore the heterogeneity of tumor responses and highlight the need for further studies, particularly in in vivo models, to elucidate mechanisms linking ferroptosis to immune recognition and thereby inform therapeutic development.

Background: Achondroplasia (ACH), the predominant inherited form of disproportionate short stature, results from specific genetic alterations in fibroblast growth factor receptor 3 (FGFR3). N6-methyladenosine (m⁶A) modification is reported to modulate mRNA stability and translation. The present investigation systematically explored the epigenetic regulatory function of METTL16, an m⁶A RNA methyltransferase, within the pathophysiological framework of ACH.

Methods: We generated an ACH mouse model via Fgfr3380R (Fgfr3^ach) gene mutation. Primary chondrocytes were isolated from newborn mice and stimulated with IL-1β to induce cell death. Proximal tibia tissues were collected and analyzed with HE staining, toluidine blue staining, safranin O staining, and immunohistochemical (IHC) analysis. Bone structure was analyzed by measuring bone mineral density (BMD), ratio of bone volume to total tissue volume (BV/TV), trabecular number (TbN), and trabecular thickness (TbTh). Cell viability and proliferation were assessed using the Cell Counting Kit-8 (CCK-8) and colony formation assays. The levels of iron (Fe²⁺), malondialdehyde (MDA), and glutathione (GSH) were measured to assess ferroptosis. Protein and RNA levels were measured by western blotting and quantitative real-time PCR (qPCR) assay, respectively, while the m⁶A modification level was assessed by m⁶A mRNA immunoprecipitation (IP).

Results: METTL16 improved bone chondrogenesis in the ACH mouse model, with METTL16 overexpression promoting the proliferation of primary chondrocytes. METTL16 decreased ferroptosis both in vitro and in vivo and increased glutathione peroxidase 4 (GPX4) expression. METTL16 enhanced m⁶A modification of GPX4 mRNA and suppressed its degradation. Depletion of GPX4 abolished the effects of METTL16 on ACH mice and chondrocytes.

Conclusion: Overexpression of METTL16 improved bone growth and alleviated ferroptosis of chondrocytes by increasing m⁶A modification of GPX4 mRNA and thus GPX4 expression in chondrocytes. The METTL16/GPX4 axis may be a promising therapeutic approach for ACH treatment.

Hepatobiliary malignancies remain a major clinical challenge because they are highly aggressive and resistant to therapy. In eukaryotes, N6-methyladenosine (m6A), the most prevalent internal RNA modification, regulates post-transcriptional gene expression. Insulin-like growth factor 2 mRNA-binding proteins (IGF2BP1/2/3) act as pivotal m6A readers, stabilizing coding and non-coding RNAs to modulate cancer-related signaling networks. In hepatobiliary cancers, dysregulated IGF2BP expression is associated with proliferation, metastasis, metabolic adaptation, and immune evasion, underscoring its potential as a biomarker and therapeutic targets. This review provides a comprehensive overview of IGF2BP-mediated regulatory mechanisms and explores their translational potential in precision diagnostics and targeted interventions.

Activation of autoreactive lymphocytes leads to cellular and tissue damage, which results in the development of autoimmune diseases. External environmental changes, such as chronic microbial infections, can alter the immune homeostasis and disrupt the balance of autoreactive T and B cells. In this review, we first summarize immune tolerance mechanisms of T and B cells, and then describe the breakthroughs of immune tolerance in T and B cells, followed by related autoimmune diseases. Furthermore, we explore how microbial infections can induce the production of autoreactive antibodies via carrier effects when the balance of autoreactive T and B cells is disrupted. These kinds of antibodies can lead to autoimmune diseases through molecular mimicry mechanisms. Our perspective provides a theoretical framework and novel insights into the mechanism of autoreactive antibodies in the pathogenesis of autoimmune diseases associated with microbial infections. This analysis may offer novel directions for drug discovery of autoimmune diseases.

Ion channels are fundamental to neuronal excitability, synaptic transmission, and the coordinated development of brain circuits. Disruptions in their function-collectively termed ion channelopathies-have emerged as central mechanisms underlying a broad spectrum of neurodevelopmental disorders (NDDs), including epilepsy, autism spectrum disorder, and intellectual disability. This review synthesizes current knowledge on the physiological roles of voltage-gated and ligand-gated ion channels during brain development and elucidates how their genetic and functional dysregulation contributes to disease pathogenesis. We examine key channel families, such as sodium, potassium, calcium, and glutamate/(gamma-aminobutyric acid) GABA receptors, as well as mechanosensitive and polymodal channels including transient receptor potential and Piezo channels, highlighting the molecular mechanisms, pathogenic variants, and circuit-level consequences of their dysfunction. Emerging therapeutic strategies are discussed, spanning subtype-specific small molecule modulators, antisense oligonucleotides, CRISPR-based genome editing, and patient-derived organoid models for precision medicine and drug screening. We also address significant challenges in the field, including cellular heterogeneity, developmental timing, and translational model fidelity. Together, these advances underscore a rapidly evolving landscape in which precision neurogenetics and integrative platforms hold promise for transforming the diagnosis and treatment of ion channel-related neurodevelopmental disorders.

Background: Purple sweet potato anthocyanins (PSPAs), a class of dietary flavonoids, have shown anticancer potential. However, their ability to induce ferroptosis in T-cell acute lymphoblastic leukemia (T-ALL) remains unexplored. This study aimed to investigate whether PSPAs can trigger ferroptosis in T-ALL cells and to elucidate the underlying mechanisms.

Methods: Jurkat T-ALL cells were treated with PSPAs, and cell viability, reactive oxygen species (ROS), lipid peroxidation, intracellular Fe²⁺, and expression of ferroptosis-related proteins (glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), nuclear factor erythroid 2-related factor 2 (Nrf2)) were assessed. Ferrostatin-1 was used to verify ferroptosis involvement. Ultrastructural changes were examined by electron microscopy. Molecular docking was performed to evaluate PSPA binding to SLC7A11, and in vivo efficacy was tested in T-ALL xenograft mice.

Results: PSPAs exhibited significant cytotoxicity in Jurkat cells, which was reversed by ferrostatin-1, indicating ferroptosis involvement. Treatment elevated ROS and lipid peroxidation, increased intracellular Fe²⁺, and downregulated GPX4 and SLC7A11 without altering Nrf2, suggesting that SLC7A11 may be directly targeted. Electron microscopy revealed hallmark ferroptotic changes, including increased mitochondrial membrane density, loss of cristae, and rupture of the outer membrane. Molecular docking demonstrated strong binding of four PSPA components to multiple residues of SLC7A11, including Cys158, a key functional site. In vivo, PSPAs markedly inhibited tumor growth in T-ALL xenograft mice, achieving up to 75% suppression, as evidenced by histological analysis showing disrupted tumor architecture and cell membrane rupture.

Conclusions: This study provides the first evidence that PSPAs induce ferroptosis in T-ALL through modulation of the SLC7A11/GPX4 pathway. These findings reveal new mechanistic insights into ferroptosis in T-ALL and highlight PSPAs as safe, naturally derived therapeutic agents with promising therapeutic potential for leukemia.