IUBMB Life最新文献

PIWI-interacting RNAs (piRNAs) have emerged as key gene regulators in diverse biological processes. Earlier believed to be germline-specific, these endogenous small non-coding RNAs (~26–32 nucleotides) have now been identified to play an active role in non-gonadal tissues as well. piRNAs in association with PIWI proteins bind to their targets and form the piRISC complex that especially regulates transposable elements (TEs) in the germline. However, after further experiments, piRNAs have been found to target and modulate the expression of non-TEs as well. Several high-throughput technologies have identified piRNA target sites in different cells and tissues of various model organisms, but all these studies have demonstrated discrete patterns of sequence complementarity between piRNA and its target. This indicates that the principle of piRNA targeting is not uniform, unlike miRNAs, due to the lack of precise knowledge regarding their targets. Further, the co-evolution of the piRNA pathway and its targeted transposons in a species-specific manner has created distinct differences in the piRNA targeting features between different species, specifically invertebrates and mammals. In this review, we focus on the current high-throughput techniques that have been used to understand the sequence-specific features that influence structural conformations favoring piRNA-target duplex formation and target cleavage. Overall, it has been observed that modulation in the degree of sequence-based complementarity between piRNA and its target sequence choreographs piRNA target interaction, which in turn enables PIWI to leverage the vast pool of piRNAs in restricting TE escape from surveillance in a sophisticated manner.

Accumulating evidence has confirmed that snoRNAs exert a role in a variety of cancers; however, the role of SNORA33 in clear cell renal cell carcinoma (ccRCC) remains unclear. This study was aimed at elucidating the role and mechanism of SNORA33 in the tumorigenesis and progression of ccRCC. The snoRNAs expression matrices were obtained from the public TCGA and SNORic databases. Kaplan–Meier analysis was employed to investigate the survival of patients with ccRCC presenting different SNORA33 expression. The prognostic value of SNORA33 in ccRCC was examined using Cox univariate and multivariate analyses. A series of in vitro experiments were conducted to explore the functional role of SNORA33 in ccRCC. Gene set enrichment analysis (GSEA) and western blot were used to explore and validate the involved mechanisms. SNORA33 was highly expressed in patients with ccRCC and was correlated with poor prognosis. In addition, SNORA33 was intimately associated with the infiltration of diverse immune cells and positively correlated with the immune score as well as the expression levels of multiple immune checkpoint molecules, serving as a potential biomarker for immunotherapy prediction. The findings of in vitro experiments indicated that SNORA33 was capable of promoting the proliferation, invasion, migration, and resistance to sunitinib in ccRCC. SNORA33 was highly expressed in ccRCC and indicated an adverse prognosis. SNORA33 was capable of facilitating the progression, invasion, metastasis, and resistance to sunitinib of ccRCC cells through mediating the JAK/STAT pathway.

Vascular calcification (VC) is a significant pathological feature of atherosclerosis, contributing to cardiovascular morbidity and mortality, particularly in populations with diabetes and chronic kidney disease (CKD). This review examines the pivotal role of macrophages in the development and progression of VC within atherosclerotic plaques. We explore the diverse phenotypes of macrophages, particularly the pro-inflammatory M1 and anti-inflammatory M2 types, and their distinct functions in modulating vascular smooth muscle cell (VSMC) behavior. M1 macrophages promote osteogenic signaling through the secretion of pro-inflammatory cytokines and growth factors, such as oncostatin M (OSM) and bone morphogenetic proteins (BMP), which facilitate VSMC transdifferentiation and calcification. Conversely, M2 macrophages exhibit protective properties that may mitigate excessive calcification. Furthermore, we discuss the intricate balance of these macrophage populations in atherosclerotic lesions and their influence on osteoclastic differentiation, which can either enhance or inhibit the resorption of calcified deposits. Recent findings on the involvement of microRNAs (miRNAs) in regulating macrophage activation and their impact on VC highlight potential therapeutic targets for mitigating this process. By elucidating the cellular and molecular mechanisms underpinning macrophage-mediated calcification, this review aims to provide insights into the dual roles of macrophages in atherosclerosis and their significance as potential therapeutic targets. Understanding these dynamics may lead to innovative strategies for preventing VC and improving cardiovascular health outcomes, particularly in patients with diabetes and CKD.

Metabolic dysfunction-associated fatty liver disease (MAFLD), defined by fat accumulation in more than 5% of hepatocytes, is a common metabolic syndrome worldwide. However, 30%–40% of MAFLD cases progress to metabolic dysfunction-associated steatohepatitis (MASH), increasing the importance of the disease. MicroRNAs (miRNAs), non-coding RNA molecules approximately 21 nucleotides long, are used as biomarkers in many diseases and play a crucial role in regulating cellular processes by affecting gene expression. It is also known that miRNAs are effective in the progression of MASH and its profile depends on the stage of the disease. Therefore, we determined the relationship between MASH and miRNA profiles in an in vivo trial using an established model of cholesterol-induced MASH in rabbits. We also evaluated the impact of α-tocopherol, which is known to have a protective effect in MAFLD/MASH transition, on miRNA profiles. Regarding the limited information using rabbits, we first performed miRNA screening and identified miRNAs that are already described in rabbits or other organisms as well as the putative ones. Among those, two putative miRNAs (miR-230 and miR-1146) determined by sequencing may be important in the diagnosis and treatment of the disease. Furthermore, levels of five miRNAs (miR-122-5p, miR-199-5p, miR-145-5p, miR-27b-3p, miR-34a-5p) and their relevance in the pathogenesis of MASH were determined by RT-PCR and target gene prediction, respectively. In conclusion, the present study provides novel information regarding dysregulated miRNAs in high-cholesterol diet-induced MASH and the impact of α-tocopherol.

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.