Frontiers in bioscience (Landmark edition)最新文献

Background: Cervical cancer (CC) is one of the most prevalent gynecological malignancies. The expression and functional role of the long non-coding RNA (lncRNA) Ras-related protein Rab-11B antisense RNA 1 (RAB11B-AS1) in CC remain poorly understood.

Methods: The expression profile of lncRNA RAB11B-AS1 across multiple cancer types was initially assessed using data from The Cancer Genome Atlas. Its expression in CC tissues and lesions of varying pathological grades was subsequently validated via RNA in situ hybridization. To investigate its functional role in CC, a combination of transcriptomic, proteomic, and functional assays was employed to delineate the molecular role of RAB11B-AS1. The effects of alterations in RAB11B-AS1 expression on cervical cancer growth were ultimately validated in vivo.

Results: LncRNA RAB11B-AS1 was downregulated in CC and associated with a favorable patient prognosis. Functionally, RAB11B-AS1 promoted apoptosis while suppressing proliferation, migration, and invasion of CC cells in vitro, and inhibited tumor growth in vivo. Mechanistically, RAB11B-AS1 upregulated ribosomal protein L26 (RPL26) expression. Notably, RAB11B-AS1 suppressed cervical cancer progression by activating the p53 pathway via RPL26. Critically, in vitro and in vivo experiments confirmed that RPL26 knockdown abrogates the tumor-suppressive functions of RAB11B-AS1, establishing RPL26 as a pivotal downstream effector of RAB11B-AS1 in CC.

Conclusions: Our findings demonstrate that lncRNA RAB11B-AS1 suppresses cervical cancer progression primarily through upregulation of RPL26 and suggest that RAB11B-AS1 may serve as a potential biomarker and therapeutic target in cervical cancer.

Endocrine-disrupting chemicals (EDCs), including bisphenol A (BPA), phthalates, organochlorine pesticides, and heavy metal ions, pose serious threats to reproductive health by interfering with hormonal balance and molecular signaling pathways. Recent research had expanded our understanding of these compounds has beyond their traditional role in hormone receptor interference. EDCs can trigger lasting epigenetic changes, including abnormal DNA methylation, histone modifications, RNA methylation, and altered regulation of non-coding RNA, which can impair reproductive functions such as gametogenesis, folliculogenesis, steroidogenesis, and embryo implantation. Importantly, EDC-mediated epigenetic alterations have been linked to various reproductive disorders, including polycystic ovary syndrome (PCOS), endometriosis, reduced ovarian reserve, and impaired spermatogenesis. For example, BPA exposure alters DNA methylation in estrogen signaling and aromatase gene expression, whereas phthalates disrupt histone acetylation and methylation in hormone synthesis pathways. Similarly, pesticides and heavy metal ions may influence microRNA expression and histone structure, further disrupting endocrine-regulated gene networks. These alterations may occur during sensitive developmental windows and can lead to long-term or transgenerational effects on reproductive health. Understanding how EDCs exert their toxicity through epigenetic mechanisms is essential for early detection of exposure, identification of molecular biomarkers, and development of targeted therapies to reduce reproductive risks. Here, we discuss the emerging molecular evidence that provides a comprehensive overview of how EDCs impair reproductive health through epigenetic pathways, thereby offering a framework for future research and translational applications.

The wingless-int1/β-catenin (Wnt/β-catenin) signaling pathway plays a key role in left ventricular hypertrophy (LVH) and arrhythmias, which significantly contribute to global morbidity and mortality. Activation of Wnt/β-catenin signaling induces oxidative stress in cardiomyocytes by regulating mitochondrial function, reactive oxygen species (ROS) production, fibrosis, metabolic reprogramming, and cell death in LVH and arrhythmias. Additionally, Wnt/β-catenin signaling promotes cardiomyocyte hypertrophy and cardiac fibrosis by interacting with transforming growth factor beta (TGF-β), mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-κB), extracellular signal-related kinase (ERK), and other signaling pathways. In addition, activation of Wnt/β-catenin signaling can induce cardiomyocyte apoptosis by interfering with normal glucose or lipid metabolism. However, this opposing effect is evident in epicardial preadipocytes, where pathway activation may instead alleviate adipogenesis. This reflects the complexity of Wnt/β-catenin signaling in the metabolic reprogramming of cardiac cells. In this review, we discuss potential therapeutic strategies targeting the Wnt/β-catenin signaling pathway to mitigate LVH and arrhythmias.

Background: Dysregulation of the transforming growth factor (TGF)-β/Ras homolog family member A (RhoA)/Rho-associated protein kinase (ROCK) pathway can lead to fibrotic changes in ocular diseases. The present study investigated its role in epithelial-mesenchymal transition (EMT) and fibrosis in the ciliary body in lens-induced myopia (LIM) guinea pigs.

Methods: A lens-induced myopia model was established in guinea pigs. Refraction, axial length, and ciliary body alterations were assessed via quantitative polymerase chain reaction (qPCR), western blot, PCR array, histological, and biomechanical analyses. Upstream mechanisms were explored using Ingenuity Pathway Analysis. Functional experiments were performed using the ROCK inhibitor Y-27632.

Results: Refraction and axial length were increased in the myopic ciliary body in a time-dependent manner. Protein levels of TGF-β1, RhoA, ROCK1, ROCK2, α-smooth muscle actin (α-SMA), and matrix metalloproteinase (MMP)1 were significantly elevated in the myopic ciliary body, peaking at 6 weeks. In the ultra-early stage of lens myopia, functional changes such as refractive errors and increased biological parameters like axial length occur earlier than changes in EMT transcription factor levels. The differentially expressed genes were involved in cell movement, development, growth, proliferation, and transport in early myopia. Compared with those of normal animals, the Ca²⁺ inflow and Young's modulus of the ciliary body were greater, the ciliary body elasticity was lower, and the degree of tissue fibrosis was aggravated in animals with deepening myopia. Furthermore, ROCK inhibition can alleviate the pathological levels of EMT and fibrosis in the cilia of myopic guinea pigs.

Conclusion: Collectively, our findings indicate that activation of the TGF-β/RhoA/ROCK pathway induces EMT in the ciliary body, promotes Ca²⁺ inflow, and reduces ciliary body elasticity in myopic animals, resulting in tissue fibrosis and dysfunction. It provides a new perspective on the pathological mechanisms of ciliary body fibrosis in the development of myopia.

Background: Alveolar echinococcosis (AE) is a serious zoonotic parasitic disease. This study aimed to investigate the mechanisms underlying the formation of the dense fibrotic band surrounding hepatic alveolar echinococcosis (HAE) lesions, which impedes chemotherapeutic drug penetration. Additionally, the roles of Interleukin-33 (IL-33) and eosinophils in the progression of fibrosis within this band were examined.

Methods: IL-33/suppression of tumorigenicity 2 (ST-2) expression levels were compared between patients with HAE and healthy controls, as well as between close to lesion tissues (CLT) and distant from the lesion tissues (DLT) using enzyme-linked immunosorbent assay (ELISA), western blot, and immunohistochemistry. Immunofluorescence co-localization analysis was performed to examine IL-33/ST-2 and eosinophil distribution. Masson's trichrome staining was used to evaluate fibrosis in AE lesions. Cellular assays were carried out to assess the effects of IL-33 on eosinophil phagocytosis and migration, as well as its impact on α-smooth muscle actin (α-SMA) expression in hepatic stellate cells (HSCs).

Results: ELISA findings indicated significantly elevated serum IL-33/ST-2 levels in patients with AE compared with healthy controls (p < 0.05). Immunohistochemistry and western blot analyses demonstrated higher IL-33/ST-2 expression in CLT than in DLT (p < 0.05), with IL-33/ST-2 and eosinophils exhibiting a highly consistent distribution within CLT. Masson's trichrome staining confirmed increased fibrosis in CLT. Cellular assays showed that IL-33 enhanced eosinophil phagocytosis and migration, while IL-33 stimulation upregulated α-SMA expression on the HSC surface, with this effect being more pronounced in the presence of eosinophils.

Conclusion: IL-33 contributed to microenvironmental fibrosis within AE lesions via eosinophil-mediated mechanisms, highlighting a potential therapeutic target to improve chemotherapy efficacy in patients with AE.

Acute lung injury (ALI) is a severe condition characterized by an inflammatory response and increased vascular permeability, with its pathological mechanisms closely associated with the dysfunction of vascular smooth muscle cells (VSMCs). The present study investigates the molecular mechanisms through which lactate dehydrogenase A (LDHA) influences the inflammatory response in ALI by modulating VSMC metabolic reprogramming. It was observed that under pathological conditions, hypoxia and the inflammatory microenvironment significantly upregulate LDHA expression in lung VSMCs via the activation of the hypoxia-inducible factor (HIF) signaling pathway. The LDHA-mediated Warburg effect not only provides energetic support to VSMCs but also exacerbates inflammatory responses through both direct and indirect mechanisms. This review highlights the critical role of LDHA as a metabolic-inflammatory nexus in ALI and offers a theoretical foundation for targeting LDHA to regulate metabolic reprogramming as a means to mitigate the progression of ALI. Future research will further investigate the specific mechanisms by which LDHA regulates VSMC metabolic reprogramming and will seek to identify effective intervention strategies.

Chronic skin diseases like psoriasis, atopic dermatitis, and vitiligo, characterized by long-term courses, frequent relapses, and complex management, severely affect patients' lives. This review summarizes their epidemiology, pathogenesis, and therapeutic strategies, focusing on elucidating the core synergistic roles of cytokines including interleukin (IL)-17, tumor necrosis factor-α (TNF-α), and interferon-gamma (IFN-γ). Comparative analysis reveals overlapping genetic, immune, and environmental factors. Current therapeutic approaches have limitations, whereas targeted biologics, especially novel biologics developed using gene editing and cell therapy technologies to achieve precise immune modulation, demonstrate tremendous potential. Cross-disease immune investigations hold substantial value: (1) The identification of common targets to uncover shared immunoregulatory features, cross-regulatory patterns of key signaling pathways, and common disease targets amenable to drug repurposing. (2) The advancement of precision medicine through mechanism-based treatment approaches, such as broad-spectrum inhibitors and optimized combination therapies. (3) To guide drug development of individualized treatments using novel therapeutics by providing crucial insights into skin immunology. This research facilitates the shift from "disease-classification-based management" to "immune phenotype-directed therapeutics," supporting the development of novel biologics and individualized strategies.

Background: Odontogenesis-associated phosphoprotein (Odaph) is essential for tooth development. However, its role in osteoblast function and bone remodeling remains unclear. Recent studies suggest that Odaph may influence bone integrity, particularly in the maxillofacial region, thereby implicating it in craniofacial skeletal disorders. The study is designed to clarify the regulatory roles of Odaph in the proliferation, differentiation, and autophagy of osteoblasts, with particular emphasis on its participation in the AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) signaling pathway.

Methods: The MC3T3-E1 osteoblast cell line was employed as an in vitro model, and the effects of Odaph overexpression on cell proliferation, differentiation, and migration were assessed via qPCR, Western blotting, CCK-8 assay, EdU staining, alkaline phosphatase (ALP) staining, and Alizarin Red S (ARS) staining. RNA sequencing (RNA-seq) was carried out to screen for differentially expressed genes, and subsequent Kyoto Encyclopedia of Genes and Genomes (KEGG)/GO enrichment analyses were conducted to verify the participation of the AMPK/mTOR signaling pathway. Autophagy was assessed via Western blotting, fluorescence double staining, transmission electron microscopy, and autophagy tandem lentiviral detection. For exploring the function of autophagy in osteogenic differentiation, the autophagy inhibitor 3-MA was used to treat the cells. Furthermore, a mouse model was utilized to confirm the impacts of Odaph overexpression on osteogenesis and autophagy in vivo.

Results: Overexpression of Odaph markedly enhanced the proliferation, migration, and osteogenic differentiation of MC3T3-E1 cells, which was supported by the increased expression of osteogenic markers runt-related transcription factor 2 (RUNX2), Collagen I (COL1), and ALP. RNA-seq analysis demonstrated that genes regulated by Odaph were notably enriched in the AMPK/mTOR signaling pathway. Further validation demonstrated that Odaph increased AMPK phosphorylation while suppressing mTOR activity. Odaph overexpression also enhanced the expression of autophagy-related proteins LC3B-II and BECLIN1 while reducing p62 levels, whereas 3-MA treatment markedly attenuated these pro-osteogenic effects. Consistently, animal experiments confirmed that Odaph overexpression enhanced osteogenesis in vivo, accompanied by increased AMPK activation and autophagy induction.

Conclusions: Odaph enhances osteoblast function through autophagy induction mediated by the AMPK/mTOR axis. These results reveal a new regulatory mechanism in bone biology and indicate that Odaph could serve as a potential therapeutic target for maxillofacial bone conditions, including jaw osteopenia and periodontal bone loss.

Background: Glaucoma is a major cause of irreversible blindness, characterized by the progressive degeneration of retinal ganglion cells (RGCs), with oxidative stress and apoptosis playing central roles in its pathogenesis. Sirtuin 3 (SIRT3) has demonstrated antioxidant and anti-apoptotic effects in various neurodegenerative diseases; however, its precise role in glaucoma remains unclear. This study aimed to elucidate the neuroprotective function and mechanistic basis of the SIRT3/AMP-activated protein kinase (AMPK) axis in glaucoma.

Methods: A rat model of chronic ocular hypertension (COH) was generated using cross-linked hydrogel injection, while an N-methyl-D-aspartate (NMDA)-induced RGC injury model was developed in vitro. SIRT3 overexpression was achieved using adeno-associated virus (AAV) transfection, either alone or combined with the AMPK inhibitor Compound C. Functional and molecular analyses were performed, including intraocular pressure (IOP) measurement, hematoxylin-eosin (H&E) staining, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunofluorescence, Cell Counting Kit-8 (CCK-8) cell viability assay, flow cytometry, Quantitative real-time PCR (qRT-PCR), and western blotting.

Results: In the COH model, both SIRT3 expression and the p-AMPK/AMPK ratio were significantly reduced at weeks 2, 4, and 6 (p < 0.05). Overexpression of SIRT3 lowered IOP, preserved retinal thickness, and decreased the number of TUNEL-positive cells (p < 0.001), while Compound C partially reversed these effects (p < 0.05). In addition, SIRT3 overexpression markedly educed reactive oxygen species (ROS) accumulation (p < 0.001) and restored the p-AMPK/AMPK ratio (p < 0.001), both of which were partially inhibited by Compound C. In NMDA-induced RGCs, SIRT3 overexpression significantly increased SIRT3 mRNA levels (p < 0.01), enhanced cell viability (p < 0.001), and suppressed apoptosis (p < 0.001), with these effects attenuated by Compound C (p < 0.01). The reduction of ROS and activation of AMPK by SIRT3 in this model were also partly reversed by AMPK inhibition (p < 0.01).

Conclusion: This study provides the first comprehensive in vivo and in vitro evidence in glaucoma models that SIRT3 confers neuroprotection in experimental glaucoma, primarily through activation of the AMPK signaling pathway. These findings identify the SIRT3/AMPK axis as a novel mechanistic target and suggest a promising therapeutic strategy for IOP-independent neuroprotection in glaucoma.

Background: Turmeric-derived exosome-like nanoparticles (TELNs) are nanoscale vesicles of plant origin with therapeutic potential. However, the specific efficacy and mechanisms of TELNs in inhibiting non-small cell lung cancer (NSCLC) remain unclear. This study investigated the effects of TELNs on NSCLC by epigenetically regulatiing histone acetyltransferase human males absent on the first (hMOF) and histone H4K16 acetylation (H4K16ac).

Methods: TELNs were isolated from turmeric using differential centrifugation and characterized by nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), and zeta potential measurements. Cellular uptake was assessed via PKH26 labeling. In vitro assays evaluated the effects of TELNs on apoptosis (annexin V/PI staining, JC-1 mitochondrial depolarization, caspase-3 cleavage) and proliferation (CCK-8). The in vivo efficacy of TELNs was examined in A549 xenografts. Bioinformatics and molecular docking analyses revealed the interaction of curcumin in TELNs with hMOF, while RNA interference validated the role of hMOF in TELN-mediated apoptosis and migration suppression.

Results: TELNs exhibited exosome-shaped morphology and efficient uptake by A549 cells. Treatment with TELNs induced apoptosis and reduced tumor volume by 58.1%. Mechanistically, TELNs upregulated hMOF expression and H4K16ac levels. RNA interference confirmed that knockdown of hMOF weakened the effect of the TELNs. Molecular docking suggested curcumin in TELNs may interact with hMOF.

Conclusion: This study reveals a novel epigenetic mechanism wherein TELNs suppress NSCLC by activating hMOF/H4K16ac. Curcumin within TELNs increases hMOF levels, thus positioning TELNs as a potential nanotherapeutics with the capacity for epigenetic modulation. Our findings underscore the potential of TELNs in NSCLC treatment and highlight hMOF as a therapeutic target.