IUBMB Life最新文献

Lung injury and fibrosis involve a complex interplay between inflammation and coagulation, with tissue factor (TF/CF-III/Thromboplastin/CD142) acting as a crucial mediator. Despite its known role in initiating the extrinsic coagulation cascade, TF's contribution to fibrin deposition in lung injury remains underexplored. This study examines the dysregulation of the extrinsic coagulation cascade and its pathological implications in lung injury, contributing to the progression of pulmonary fibrosis (PF). Utilizing bleomycin (BLM), transforming growth factor-β (TGF-β), and TF models, we systematically investigate coagulation-driven inflammatory responses in lung pathology. By integrating in vitro (A549 and Beas2b epithelial cell models) and in vivo (C57BL/6 murine models) approaches, this study elucidates TF-mediated molecular mechanisms driving inflammation, fibrin deposition, endothelial dysfunction, and fibrotic remodeling. Protein-protein interaction (PPI) network analysis highlights functional associations between coagulation factors (CFs) and inflammatory mediators, reinforcing their involvement in lung homeostasis. Also, gene enrichment analysis identifies key biological processes, including coagulation, fibrinolysis, and immune activation, emphasizing their role in disease progression. In A549 and Beas2b epithelial cells, CF-III, CF-VII, and CF-X expression increased significantly, with A549 cells exhibiting a heightened pro-coagulant response. Elevated IL-6, TNF-α, and IL-1β levels suggest an inflammatory amplification tied to TF activation. Immunofluorescence analysis demonstrates marked TF upregulation and TNF-α activation, reinforcing the interplay between coagulation pathways and inflammatory cytokine signaling. Histological assessments (H&E, and Masson Trichrome [MT] staining) in murine lung tissues confirm fibrotic and inflammatory changes, reinforcing TF's pathogenic role. Our findings establish TF as a key molecular driver of thrombo-inflammatory lung injury, providing potential therapeutic targets to mitigate fibrosis and improve patient outcomes.

Phagocytic engulfment of apoptotic cells, particularly neutrophils by macrophages, known as efferocytosis, is crucial in preventing secondary necrosis and promoting tissue repair. 17-Oxo-DHA, an electrophilic metabolite of docosahexaenoic acid (DHA), is generated in macrophages and has been reported to contribute to inflammation resolution by enhancing efferocytosis. However, many gaps remain in our understanding of the pro-resolving effects of 17-oxo-DHA. Our results reveal that 17-oxo-DHA augments the efferocytic activity of bone marrow-derived macrophages (BMDMs) by stimulating the biosynthesis of resolvin D2 (RvD2), one of the prototypic pro-resolving mediators (SPMs), while reducing the expressions of IL-6 and TNF-α. Mechanistically, either gene silencing of Nrf2 or pharmacological inhibition of its target protein HO-1 suppresses 17-oxo-DHA-induced efferocytosis, decreasing the levels of 15-LOX, COX-2, and various SPMs. Notably, treatment of macrophages with SPMs was able to restore 17-oxo-DHA-induced efferocytosis even when HO-1 activity was suppressed. Thus, our study suggests critical roles of SPMs and the Nrf2/HO-1 axis in mediating 17-oxo-DHA-induced efferocytosis, which are novel candidate therapeutic targets in non-resolving inflammatory diseases.

Muscle wasting, characterized by loss of muscle mass and strength, severely impacts patient quality of life and is associated with numerous chronic diseases and aging. The molecular mechanisms are complex, involving protein synthesis/degradation imbalance. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) and ubiquitin-specific peptidase 7 (USP7) have diverse cellular roles, but their coordinated function in skeletal muscle homeostasis remains poorly understood. DYRK1A overexpression in vivo induced muscle atrophy phenotypes, including reduced muscle mass, grip strength, fiber cross-sectional area (CSA), altered fiber type composition, and neuromuscular junction integrity, accompanied by elevated atrophy markers: muscle atrophy F-box protein (Atrogin-1), muscle ring finger 1 (MuRF-1), myostatin and suppressed myogenic markers: myoblast determination protein 1 (MyoD), myogenin (MyoG), myocyte enhancer factor 2C (Mef2c), myogenic factor 5 (Myf5). Conversely, pharmacological inhibition of DYRK1A with Harmine ameliorated these atrophy phenotypes in transgenic DYRK1A overexpressing (TgD) mice. In vivo, USP7 deficiency resulted in similar muscle wasting phenotypes. In vitro, DYRK1A overexpression or USP7 overexpression inhibited C2C12 myoblast proliferation and differentiation, effects rescued by Wnt3a treatment or USP7 knockdown, respectively. Mechanistically, DYRK1A activity suppressed active β-catenin levels. USP7 was found to interact with and deubiquitinate axis inhibition protein 1 (Axin1), leading to its stabilization. Knockdown of USP7 increased Axin1 ubiquitination and degradation, thereby promoting β-catenin signaling and myogenesis, counteracting the effects of DYRK1A. Our findings reveal a novel signaling axis where DYRK1A and USP7 cooperatively suppress Wnt/β-catenin signaling to promote muscle wasting. DYRK1A likely acts upstream, potentially phosphorylating pathway components, whereas USP7 stabilizes the β-catenin destruction complex scaffold protein Axin1 through deubiquitination. This coordinated action inhibits myogenesis and activates atrophy pathways. Targeting DYRK1A or USP7 could represent promising therapeutic strategies for muscle wasting disorders.

Disco interacting protein 2 homolog B (DIP2B) is a protein-coding gene implicated in various biological processes, including embryonic development, cell cycle regulation, DNA repair, and transcriptional regulation. While its precise role in cancer remains largely unknown, emerging evidence suggests its potential involvement in tumorigenesis. In this study, we provide a comprehensive analysis of DIP2B in cancer, exploring its expression patterns, molecular functions, and potential clinical implications across different cancer types. We examined the expression, dysregulation, and prognostic significance of DIP2B. The mRNA and protein expression status of DIP2B was determined using data from TCGA, GTEx, and UALCAN. Using TCGA database data, we investigated associations between DIP2B expression and gene mutations, survival outcomes, DNA methylation, immune cell infiltration, tumor mutation burden (TMB), and drug sensitivity. High DIP2B expression was associated with poor overall survival (OS) in BRCA, KICH, LUAD, MESO, SARC, and THCA, but with improved OS in KIRC. For disease-specific survival (DSS), elevated DIP2B levels correlated with adverse outcomes in ACC, MESO, and UVM. GO and KEGG analyses implicated DIP2B in cytoskeleton organization, MAPK signaling, and ubiquitin-dependent protein catabolism. Experimental validation in KIRC cells showed that DIP2B knockdown significantly reduced cell proliferation and migration. Conversely, DIP2B exhibited oncogenic functions in LUAD cells. These findings suggest DIP2B may serve as a potential prognostic and diagnostic biomarker, displaying a unique tumor-suppressive role in KIRC progression.

Cervical cancer remains a significant challenge to global health, necessitating the development of reliable clinical prognostic models to predict patient survival outcomes with accuracy. This study aims to develop an mRNA signature model based on tumor immune infiltration characteristics of cervical cancer. By employing RNA sequencing technologies at both tissue and single-cell resolutions, a survival predictive gene signature was constructed for cervical cancer through the application of machine learning methods. To further validate the key prognostic genes identified in the prognostic signature, we performed additional experiments, including tissue microarray (TMA) analysis and in vitro assays. Our developed signature model comprised nine genes, which ranks at the top tier when compared to previously published mRNA signature models. Gamma-interferon-inducible lysosomal thiol reductase (IFI30) emerged as a critical prognostic marker, validated externally through immunohistochemistry (IHC) and multiplex immunohistochemistry staining (mIHC) on cervical cancer TMAs. Notably, IFI30 exhibited pronounced expression in macrophages compared to other cell types within the tumor microenvironment (TME). We further investigated the potential role of IFI30 in regulating macrophage polarization. Specifically, a reduced expression of IFI30 in macrophages co-cultured with HeLa cells induced a polarization transition from the M2 to the M1 phenotype. In conclusion, we have successfully established a prognostic model on the basis of tumor immune infiltration characteristic of cervical cancer, highlighting IFI30 as a pivotal prognostic marker potentially involved in macrophage polarization. Future investigation is required to explore the underlying mechanisms for the advancement of therapeutic strategies in cervical cancer.

Osteosarcoma (OS) is an uncommon malignancy with stagnant survival rates over the past four decades and early-stage metastasis, predominantly affecting children and adolescents. This study identified significant metabolic differences between metastatic and non-metastatic OS samples through bioinformatics analysis, highlighting key processes such as cell proliferation, mitochondrial assembly, and changes in mitochondrial membrane permeability. Among differentially expressed genes, Pleckstrin Homology And FYVE Domain Containing 1 (PLEKHF1) was the most significantly downregulated in metastatic OS samples. Functional experiments demonstrated that PLEKHF1 overexpression in Saos-2 and U2OS cells induced mitochondrial dysfunction, evidenced by increased mtROS levels, decreased mitochondrial membrane potential, and altered cytochrome C distribution. Additionally, PLEKHF1 overexpression inhibited OS cell viability, colony formation, migration, invasion, and epithelial-mesenchymal transition (EMT), while promoting apoptosis. Conversely, knockdown of PLEKHF1 had the opposite effects on Saos-2 and U2OS cells. In vivo, PLEKHF1 overexpression reduced tumor growth and lung metastasis in a mouse model. Conversely, PLEKHF1 knockdown ameliorated Rotenone-induced mitochondrial dysfunction and mitophagy, partially reversing the suppressive effects of Rotenone on OS cell aggressiveness. These findings suggest that PLEKHF1 could serve as an anti-tumor factor by inducing mitochondrial dysfunction, thereby inhibiting OS growth and metastasis. The study highlights the potential of PLEKHF1 as a therapeutic target for managing osteosarcoma, providing valuable insights into the role of mitochondrial dysfunction in OS pathogenesis.

Bone cancer remains a life-threatening malignancy predominantly affecting pediatric and adolescent populations, with tyrosine kinase inhibitors (TKIs) emerging as promising therapeutic agents; however, their clinical utility is limited by poor bioavailability, systemic toxicity, and inadequate tumor targeting. Recent advancements in nanocarrier-based delivery systems have significantly mitigated these limitations by enhancing targeted accumulation of TKIs at tumor sites, reducing off-target effects, and enabling controlled drug release. Various nanocarrier platforms, including liposomes, polymeric nanoparticles, micelles, dendrimers, metal- and metal oxide-based nanoparticles, carbon-based carriers, polymeric implants, and hydroxyapatite-based systems, have been systematically evaluated for their efficacy in delivering TKIs for bone cancer therapy. This review further examines the impact of nanoparticle size on cellular uptake and tumor penetration, with emphasis on liposomal and proteinaceous carriers (albumin-bound and transferrin-conjugated nanoparticles) that optimize tumor selectivity while minimizing systemic toxicity. Inorganic nanocarriers such as gold, silver, and metal oxides also demonstrate potential for multimodal therapeutic and diagnostic applications. Notwithstanding these advances, challenges including drug resistance, toxicity, and regulatory barriers remain, necessitating ongoing efforts to optimize nanocarrier formulations. This comprehensive review provides critical insights into the evolving landscape of nanotechnology-driven TKI delivery strategies aimed at enhancing therapeutic outcomes in bone cancer management.

Lung cancer is a severe malignant disease and causes plenty of deaths each year. The survival and prognosis are disappointing for patients with recurrence or metastasis. This is partially due to the lack of mechanisms underlying lung cancer. The ZEB1 gene was reported to promote progression in lung cancer. However, the mechanism of ZEB1 in lung cancer is a puzzle. ZEB1 and WNT7B were expressed more strongly in lung cancer cells. In clinical lung cancer tissues, ZEB1 was also overexpressed compared to the adjacent normal tissues. ZEB1 knockdown (ZEB1-KD) inhibited the activation of Wnt/β-catenin signaling. However, overexpression of WNT7B alleviated this inhibition. Furthermore, ZEB1 was shown to regulate the expression of WNT7B, and WNT7B was the bridge between ZEB1 and Wnt signaling. Cell proliferation and invasion ability were inhibited by ZEB1-KD, which was reversed by WNT7B overexpression. This regulation was supported by the expression patterns of PCNA, E-cadherin, and N-cadherin. In addition, much more cell apoptosis was induced in ZEB1-KD cells treated with Docetaxel compared to that without ZEB1-KD. This induction was reversed when WNT7B was overexpressed. Consistently, the IC50 value in the ZEB1-KD/Docetaxel group was much lower than that in the ZEB1-KD or Docetaxel alone group. In contrast, WNT7B overexpression increased the IC50 value of Docetaxel. In conclusion, ZEB1 positively regulates Wnt/β-catenin signaling in lung cancer and contributes to cancer progression. ZEB1 knockdown increases the efficacy of Docetaxel in lung cancer.

The development of acquired drug resistance in breast cancer (BC) significantly compromises treatment efficacy and patient survival, yet the underlying molecular mechanisms remain completely understood. In this study, we investigated the role of the Hippo signaling pathway and its regulatory factor, LIM Domain Only 4 (LMO4), in the acquired Adriamycin (ADR)-resistant MCF-7 (AdrR) cells. Using a combination of bioinformatics and experimental approaches, we demonstrated that AdrR cells exhibit defective apoptosis upon ADR treatment, characterized by abnormal expression of apoptotic proteins such as BAX and BCL2. RNA sequencing (RNA-seq) and ATAC sequencing (ATAC-seq) revealed significant dysregulation of the Hippo pathway in AdrR cells compared to parental MCF-7 cells, suggesting its involvement in mediating drug resistance. Further experiments showed that small interfering RNA (siRNA)-mediated knockdown of LMO4 (siLMO4) altered the expression of apoptotic proteins and partially restored ADR sensitivity in AdrR cells. Mechanistically, LMO4 was found to modulate the Hippo pathway, as evidenced by changes in the nuclear translocation of YAP and the phosphorylation levels of key Hippo pathway components (MST1/2 and YAP). Inhibition of the Hippo pathway using a Lats kinase inhibitor further confirmed its role in regulating drug resistance. Our findings highlight the critical involvement of the LMO4-Hippo signaling axis in ADR resistance and propose LMO4 as a potential therapeutic target for reversing chemoresistance in BC. This study provides novel insights into the molecular mechanisms of drug resistance and offers a foundation for future research aimed at improving treatment strategies for ADR-resistant breast cancer.