Journal of Translational Medicine最新文献

Background: Accurate differentiation between malignant and benign pulmonary nodules, especially those measuring 5-10 mm in diameter, continues to pose a significant diagnostic challenge. This study introduces a novel, precise approach by integrating circulating cell-free DNA (cfDNA) methylation patterns, protein profiling, and computed tomography (CT) imaging features to enhance the classification of pulmonary nodules.

Methods: Blood samples were collected from 419 participants diagnosed with pulmonary nodules ranging from 5 to 30 mm in size, before any disease-altering procedures such as treatment or surgical intervention. High-throughput bisulfite sequencing was used to conduct DNA methylation profiling, while protein profiling was performed utilizing the Olink proximity extension assay. The dataset was divided into a training set and an independent test set. The training set included 162 matched cases of benign and malignant nodules, balanced for sex and age. In contrast, the test set consisted of 46 benign and 49 malignant nodules. By effectively integrating both molecular (DNA methylation and protein profiling) and CT imaging parameters, a sophisticated deep learning-based classifier was developed to accurately distinguish between benign and malignant pulmonary nodules.

Results: Our results demonstrate that the integrated model is both accurate and robust in distinguishing between benign and malignant pulmonary nodules. It achieved an AUC score 0.925 (sensitivity = 83.7%, specificity = 82.6%) in classifying test set. The performance of the integrated model was significantly higher than that of individual methylation (AUC = 0.799, P = 0.004), protein (AUC = 0.846, P = 0.009), and imaging models (AUC = 0.866, P = 0.01). Importantly, the integrated model achieved a higher AUC of 0.951 (sensitivity = 83.9%, specificity = 89.7%) in 5-10 mm small nodules. These results collectively confirm the accuracy and robustness of our model in detecting malignant nodules from benign ones.

Conclusions: Our study presents a promising noninvasive approach to distinguish the malignancy of pulmonary nodules using multiple molecular and imaging features, which has the potential to assist in clinical decision-making.

Trial registration: This study was registered on ClinicalTrials.gov on 01/01/2020 (NCT05432128). https://classic.

Clinicaltrials: gov/ct2/show/NCT05432128 .

Background: Obesity has emerged as a growing global public health concern over recent decades. Obesity prevalence exhibits substantial global variation, ranging from less than 5% in regions like China, Japan, and Africa to rates exceeding 75% in urban areas of Samoa.

Aim: To examine the involvement of metabolism-related genes.

Methods: Gene expression datasets GSE110729 and GSE205668 were accessed from the GEO database. DEGs between obese and lean groups were identified through DESeq2. Metabolism-related genes and pathways were detected using enrichment analysis, WGCNA, Random Forest, and XGBoost. The identified signature genes were validated by real-time quantitative PCR (qRT-PCR) in mouse models.

Results: A total of 389 genes exhibiting differential expression were discovered, showing significant enrichment in metabolic pathways, particularly in the propanoate metabolism pathway. The orangered4 module, which exhibited the highest correlation with propanoate metabolism, was identified using Weighted Correlation Network Analysis (WGCNA). By integrating the DEGs, WGCNA results, and machine learning methods, the identification of two metabolism-related genes, Storkhead Box 1 (STOX1), NACHT and WD repeat domain-containing protein 2(NWD2) was achieved. These signature genes successfully distinguished between obese and lean individuals. qRT-PCR analysis confirmed the downregulation of STOX1 and NWD2 in mouse models of obesity.

Conclusion: This study has analyzed the available GEO dataset in order to identify novel factors associated with obesity metabolism and found that STOX1 and NWD2 may serve as diagnostic biomarkers.

Autophagy is an important lysosomal degradation process that digests and recycles bio-molecules, protein or lipid aggregates, organelles, and invaded pathogens. Autophagy plays crucial roles in regulation of metabolic and oxidative stress and multiple pathological processes. In cancer, the role of autophagy is dual and paradoxical. Ubiquitination has been identified as a key regulator of autophagy that can influence various steps in the autophagic process, with autophagy-related proteins being targeted for ubiquitination, thus impacting cancer progression and the effectiveness of therapeutic interventions. This review will concentrate on mechanisms underlying autophagy, ubiquitination, and their interactions in cancer, as well as explore the use of drugs that target the ubiquitin-proteasome system (UPS) and ubiquitination process in autophagy as part of cancer therapy.

Background: Osteonecrosis of the femoral head (ONFH) significantly impacts young and middle-aged adults, with steroid use implicated in many cases. Traditional treatments have limited efficacy, prompting a shift towards innovative approaches, such as stem cell therapy, offering less invasive regenerative solutions.

Methods: Using bibliometric analysis from 1997 to 2023, we identified 392 articles on stem cell therapy for ONFH from the Web of Science Core Collection and analysed them using VOSviewer and CiteSpace to identify key trends and research directions.

Results: From 1997 to 2023, stem cell therapy for ONFH research expanded significantly, with 392 articles evidencing global collaboration, particularly from China, the United States and South Korea. The field is characterised by 158 core authors across 26 clusters and contributions from 417 institutions in 104 research clusters, with Shanghai Jiao Tong University as a notable leader. This research is disseminated through 23 journal clusters, emphasising interdisciplinary work, with Clinical Orthopaedics and Related Research among the most influential journals. Key findings include the identification of the most influential papers, highlighting advances, such as use of autologous mesenchymal stem cells (MSCs) and innovative delivery mechanisms. High-frequency keyword analysis further mapped the evolution of the field, from basic mechanisms to advanced therapies, underscoring a trend towards more targeted stem cell treatments for ONFH.

Conclusion: Stem cell therapy for ONFH has advanced significantly, showcasing a successful transition from basic research to clinical practice, particularly highlighted by developments in use of autologous MSCs and delivery methods. Future research will focus on refining therapies through exosome technology, targeted modulation of stress and inflammation and integration with surgical techniques, with the aim of tailored patient care and improved ONFH outcomes.

Background: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a prevalent genetic disorder characterized by the formation of renal cysts leading to kidney failure. Despite known genetic underpinnings, the variability in disease progression suggests additional regulatory layers, including epigenetic modifications.

Methods: We utilized various ADPKD models, including Pkd1 and Ezh2 conditional knockout (Pkd1^delta/delta:Ezh2^delta/delta) mice, to explore the role of Enhancer of Zeste Homolog 2 (EZH2) in cystogenesis. Pharmacological inhibition of EZH2 was performed using GSK126 or EPZ-6438 across multiple models.

Results: EZH2 expression was significantly upregulated in Pkd1^-/- cells, Pkd1^delta/delta mice, and human ADPKD kidneys. EZH2 inhibition attenuates cyst development in MDCK cells and a mouse embryonic kidney cyst model. Both Ezh2 conditional knockout and GSK126 treatment suppressed renal cyst growth and protected renal function in Pkd1^delta/delta mice. Mechanistically, cAMP/PKA/CREB pathway increased EZH2 expression. EZH2 mediated cystogenesis by enhancing methylation and activation of STAT3, promoting cell cycle through p21 suppression, and stimulating non-phosphorylated β-catenin in Wnt signaling pathway. Additionally, EZH2 enhanced ferroptosis by inhibiting SLC7A11 and GPX4 in ADPKD.

Conclusion: Our findings elucidate the pivotal role of EZH2 in promoting renal cyst growth through epigenetic mechanisms and suggest that EZH2 inhibition or ablation may serve as a novel therapeutic approach for managing ADPKD.

Background: Although the representative treatment for colorectal cancer (CRC) is radiotherapy, cancer cells survive due to inherent radioresistance or resistance acquired after radiation treatment, accelerating tumor malignancy and causing local recurrence and metastasis. However, the detailed mechanisms of malignancy induced after radiotherapy are not well understood. To develop more effective and improved radiotherapy and diagnostic methods, it is necessary to clearly identify the mechanisms of radioresistance and discover related biomarkers.

Methods: To analyze the expression pattern of miRNAs in radioresistant CRC, sequence analysis was performed in radioresistant HCT116 cells using Gene Expression Omnibus, and then miR-1226-5p, which had the highest expression in resistant cells compared to parental cells, was selected. To confirm the effect of miR-1226-5 on tumorigenicity, Western blot, qRT-PCR, transwell migration, and invasion assays were performed to confirm the expression of EMT factors, cell mobility and invasiveness. Additionally, the tumorigenic ability of miR-1226-5p was confirmed in organoids derived from colorectal cancer patients. In CRC cells, IRF1, a target gene of miR-1226-5p, and circSLC43A1, which acts as a sponge for miR-1226-5p, were discovered and the mechanism was analyzed by confirming the tumorigenic phenotype. To analyze the effect of tumor-derived miR-1226-5p on macrophages, the expression of M2 marker in co-cultured cells and CRC patient tissues were confirmed by qRT-PCR and immunohistochemical (IHC) staining analyses.

Results: This study found that overexpressed miR-1226-5p in radioresistant CRC dramatically promoted epithelial-mesenchymal transition (EMT), migration, invasion, and tumor growth by suppressing the expression of its target gene, IRF1. Additionally, we discovered circSLC43A1, a factor that acts as a sponge for miR-1226-5p and suppresses its expression, and verified that EMT, migration, invasion, and tumor growth are suppressed by circSLC43A1 in radioresistant CRC cells. Resistant CRC cells-derived miR-1226-5p was transferred to macrophages and contributed to tumorigenicity by inducing M2 polarization and secretion of TGF-β.

Conclusions: This study showed that the circSLC43A1/miR-1226-5p/IRF1 axis is involved in radioresistance and cancer aggressiveness in CRC. It was suggested that the discovered signaling factors could be used as potential biomarkers for diagnosis and treatment of radioresistant CRC.

Background: Asthma poses a significant global health challenge, characterized by high rates of morbidity and mortality. Despite available treatments, many severe asthma patients remain poorly managed, highlighting the need for novel therapeutic strategies. This study aims to identify potential drug targets for asthma by examining the influence of circulating plasma proteins on asthma risk.

Methods: This study employs summary-data-based Mendelian randomization (MR) and two-sample MR methods to investigate the association between 2940 plasma proteins from the UK Biobank study and asthma. The analysis includes discovery (FinnGen cohort) and replication (GERA cohort) phases, with Bayesian colocalization used to validate the relationships between proteins and asthma. Furthermore, protein-protein interaction and druggability assessments were conducted on high-evidence strength protein biomarkers, and candidate drug prediction and molecular docking were performed for proteins without targeted drugs. Given the complexity of asthma pathogenesis, the study also explores the relationships between plasma proteins and asthma-related endpoints (e.g., obesity-related asthma, infection-related asthma, childhood asthma) to identify potential therapeutic targets for different subtypes.

Results: In the discovery cohort, 75 plasma proteins were associated with asthma, including IL1RAP, IL1RL1, IL6, CXCL5, and CXCL8. Additionally, 6 proteins (IL4R, LTB, CASP8, MAX, PCDH12, and SCLY) were validated through co-localization analysis and validation cohort. The assessment of drug targetability revealed potential drug targets for IL4R, CASP8, and SCLY, while candidate drugs were predicted for LTB and MAX proteins. MAX exhibited strong binding affinity with multiple small molecules indicating a highly stable interaction and significant druggability potential. Analysis of the 75 proteins with 9 asthma-related endpoints highlighted promising targets such as DOK2, ITGAM, CA1, BTN2A1, and GZMB.

Conclusion: These findings elucidate the link between asthma, its related endpoints, and plasma proteins, advancing our understanding of molecular pathogenesis and treatment strategies. The discovery of potential therapeutic targets offers new insights into asthma drug target research.

Background: Non-alcoholic fatty liver disease (NAFLD) is one of the most universal liver diseases with complicated pathogenesis throughout the world. Insulin resistance is a leading risk factor that contributes to the development of NAFLD. Vascular endothelial growth factor B (VEGFB) was described by researchers as contributing to regulating lipid metabolic disorders. Here, we investigated VEGFB as a main target to regulate insulin resistance and metabolic syndrome.

Methods: In this study, bioinformatics, transcriptomics, morphological experiments, and molecular biology were used to explore the role of VEGFB in regulating insulin resistance in NAFLD and its molecular mechanism based on human samples, animal models, and cell models. RNA-seq was performed to analyze the signal pathways associated with VEGFB and NAFLD; Palmitic acid and High-fat diet were used to induce insulin-resistant HepG2 cells model and NAFLD animal model. Intracellular glucolipid contents, glucose uptake, hepatic and serum glucose and lipid levels were examined by Microassay and Elisa. Hematoxylin-eosin staining, Oil Red O staining, and Periodic acid-schiff staining were used to analyze the hepatic steatosis, lipid droplet, and glycogen content in the liver. Western blot and quantitative real-time fluorescent PCR were used to verify the expression levels of the VEGFB and insulin resistance-related signals PI3K/AKT pathway.

Results: We observed that VEGFB is genetically associated with NAFLD and the PI3K/AKT signal pathway. After VEGFB knockout, glucolipids levels were increased, and glucose uptake ability was decreased in insulin-resistant HepG2 cells. Meanwhile, body weight, blood glucose, blood lipids, and hepatic glucose of NAFLD mice were increased, and hepatic glycogen, glucose tolerance, and insulin sensitivity were decreased. Moreover, VEGFB overexpression reduced glucolipids and insulin resistance levels in HepG2 cells. Specifically, VEGFB/VEGFR1 activates the PI3K/AKT signals by activating p-IRS1^Ser307 expression, inhibiting p-FOXO1^pS256 and p-GSK3^Ser9 expressions to reduce gluconeogenesis and glycogen synthesis in the liver. Moreover, VEGFB could also enhance the expression level of GLUT2 to accelerate glucose transport and reduce blood glucose levels, maintaining glucose homeostasis.

Conclusions: Our studies suggest that VEGFB could present a novel strategy for treating NAFLD as a positive factor.