International Journal of Medical Sciences最新文献

Cholestasis is a complex pathophysiological syndrome characterized by impaired bile secretion and excretion. Extensive research has revealed that Ubiquitin D (UBD) plays a pivotal role in numerous types of malignancies and benign diseases. However, the underlying involvement of UBD in cholestasis remains unclear. The aim of this study was to analyze the role of UBD in Cholestasis. Transcriptome data from cholestasis patients (GSE61260, GSE159676 and GSE183754) were obtained from the Gene Expression Omnibus (GEO) database. These datasets, along with cholestatic mouse models and clinical specimens, were utilized to evaluate hepatic UBD expression. Subsequently, immunohistochemistry and immunofluorescence staining were applied to validate the expression and localization of hepatic UBD. Moreover, the association of hepatic UBD levels with clinical parameters was evaluated using Pearson's correlation analysis. In addition, Gene set enrichment analysis (GSEA) and xCell were employed to investigate the immune-related signatures and immune cell infiltration link to UBD in cholestasis, with findings further validated through immunofluorescence staining. Finally, the association of the hepatic UBD with T cell-related chemokine and chemokine receptor was explored using Pearson's correlation analysis. The results showed that UBD was significantly and consistently upregulated in the livers across cholestasis patient transcriptomic data, experimental mouse models, and clinical specimens. Hepatic UBD levels positively correlate with the severity of cholestasis and hepatocytes are identified as the primary source of UBD in cholestatic livers. Functional enrichment analysis indicated that immune-related pathway was significantly activated in the cholestatic liver with high expression of UBD group. Moreover, hepatic UBD expression was positively associated with the infiltration of T cells and with the expression of T cell-related chemokines and chemokine receptors in cholestasis. In conclusion, UBD is a key gene associated with disease severity and T cells infiltration in cholestasis. These findings provide new insight into the key biomarker of cholestasis and further highlight that UBD might be a promising novel therapeutic target for patients with cholestasis.

Colorectal cancer (CRC) represents a predominant global malignancy, characterized by increasing incidence and mortality rates. Recent investigations have underscored the gut microbiota as a pivotal element in the pathogenesis and progression of CRC. This review synthesizes current evidence regarding the association between gut microbial dysbiosis and CRC, with a particular emphasis on pathogenic bacteria such as Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, pks⁺ Escherichia coli, and Enterococcus faecalis, among others. The mechanisms through which these microbes contribute to tumorigenesis include the induction of DNA damage, the promotion of chronic inflammation, and the induction of immunosuppression, and the production of oncogenic metabolites. Additionally, the review examines the clinical implications of gut microbiota, highlighting their potential as non-invasive biomarkers for early CRC detection and their impact on the efficacy and toxicity of chemotherapy, radiotherapy, and immunotherapy. Furthermore, emerging microbiota-targeted interventions, such as fecal microbiota transplantation, dietary modification, and probiotics, are evaluated for their therapeutic potential. Despite substantial progress, challenges remain in standardizing microbial markers and optimizing individualized microbiota modulation strategies. Future studies integrating multi-omics and machine learning approaches may pave the way for microbiome-based precision medicine in CRC.

Circular RNAs (circRNAs) are a subclass of noncoding RNAs characterized by their closed-loop structure without terminal 3' or 5' ends. Studies have shown that circRNAs play pivotal roles in the regulation of various cellular processes. These molecules function as microRNA (miRNA) sponges, interact with RNA-binding proteins, and modulate gene transcription. CircRNAs are vital for regulating liver homeostasis, and dysregulation of their expression is correlated with liver diseases such as hepatic fibrosis, steatosis, inflammation, and liver cancer. Elucidating the functional significance of circRNAs in liver diseases is crucial, as this knowledge may facilitate the identification of novel diagnostic biomarkers and therapeutic targets for conditions that contribute significantly to global morbidity and mortality. This review aimed to highlight current research underscoring the functional roles of circRNAs in the molecular pathogenesis and progression of liver diseases, including hepatocellular carcinoma, nonalcoholic fatty liver disease, and liver fibrosis. To provide an updated and comprehensive overview, a literature search was conducted across major scientific databases. This review reveals that circRNAs perform multifaceted functions in liver homeostasis and disease by regulating gene expression through miRNA sponging, interacting with signaling pathways, and influencing cellular processes, including vascularization, metastasis, the cell cycle, apoptosis, cellular stress, metabolic activity, inflammatory responses, and cellular senescence. Despite their pivotal involvement in liver diseases, translating circRNA-based research into clinical practice remains challenging. In conclusion, circRNAs represent an emerging frontier in liver disease research, offering considerable promise for future clinical applications.

Objective: As a dominant component within the tumor microenvironment, macrophages exert essential roles in nearly all aspects of triple-negative breast cancer (TNBC). This work explored macrophage-associated signature genes for prognostication and treatment for TNBC. Methods: Single-cell (GSE180286) and bulk transcriptome profiles (TCGA-TNBC, GSE96058 and GSE45255) were analyzed by multiple computational approaches. The expression of signature genes was verified in tumor tissues and paracancerous normal tissues from patients with TNBC (n=5), HER2⁺ breast cancer (n=5), and HR⁺ breast cancer (n=5) through immunofluorescence and Western blot. Additionally, gene expression was examined in breast cancer cells (MDA-MB-231, and MCF-7) and mammary epithelial cells (MCF10A) using RT-qPCR and Western blot. Following RNA interference or overexpression, CCK-8, wound scratch and Transwell assays were performed. To assess model robustness, 1000 iterations of Bootstrap resampling were performed to calculate optimism-corrected performance metrics; calibration curves were generated via the rms package. Decision Curve Analysis (DCA) was conducted to evaluate the clinical decision-making value. Results: A single-cell map of the microenvironment in non-TNBC and TNBC was depicted. At both the single-cell and bulk levels, macrophages exhibited a higher abundance in TNBC versus non-TNBC. A macrophage-based gene signature (CTSD, CTSL, ELK4, HSPA8, XRCC4) was developed, with a high-risk score predicting poorer outcomes. This signature demonstrated reliable performance in external validation, particularly for one-year survival (AUC > 0.9). Bootstrap analysis corrected the original AUC from 0.706 to 0.739 (optimism=-0.033, difference <5%), and AUC values from 1000 resamplings concentrated in 0.70-0.75 (standard deviation=0.018). External validation confirmed the signature's ability to reliably predict patient prognosis, especially one-year survival. High-risk patients showed greater responsiveness to immunotherapy. The aberrant expression of CTSD, CTSL, ELK4, HSPA8, and XRCC4 in TNBC and non-TNBC was validated both in vivo and in vitro. Knockdown of XRCC4 attenuated malignant behaviors of MDA-MB-231, MCF-7, and MCF10A cells, whereas overexpression of CTSD, CTSL, and HSPA8 produced the opposite effect. Conclusion: Altogether, a novel macrophage-based gene signature was proposed for estimating survival outcomes and treatment responses in TNBC. The aberrant expression of these signature genes contributes to tumor malignant progression. Our findings offer valuable insights for future clinical research involving macrophages in TNBC.

Background: Alzheimer's disease (AD) and schizophrenia (SZ) are two complex neuropsychiatric disorders characterized by significant cognitive impairment. The relationship between them is complex and multifaceted. Understanding these similarities and differences is crucial for identifying common therapeutic targets. Methods: Genetic data on plasma proteome were obtained from Icelandic datasets. Genetic variants associated with circulating inflammatory proteins, rheumatoid arthritis (RA) and AD and SZ, were sourced from large GWAS datasets. Mendelian randomization analyses were performed, and transcriptome analysis were applied to confirm the finding. Results: We observed an association between the genetic loci of the AD and SZ traits (p < 0.05) by Linkage Disequilibrium Score Regression. Furthermore, our analysis indicates that RA has a protective effect against AD (OR: 0.36, p = 0.005) while potentially increasing the risk for SZ (OR: 2.49, p = 2.06 × 10⁻⁷). Among the 1,729 proteins analyzed, 16 proteins exhibited significant inverse causal relationships with AD and positive causal relationships with SZ. Notably, DECR2 emerged as a potential therapeutic target, showing opposing effects in AD and SZ as revealed by SMR analysis and colocalization. Conclusions: This study identifies causal proteins linked to AD and SZ, enhancing the understanding of their molecular etiology and supporting targeted therapeutics development.

Inflammasomes, including NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein 3), participate in regulating immune activation and inflammation. Nonetheless, their specific roles in muscle contusion, one of the most common forms of sports injury, remain unknown. To address this, we investigated the role of NLRP3 in muscle contusion in Nlrp3-knockout (KO) mice, using a model of mass-drop injury (MDI)-induced contusion of the gastrocnemius muscle. Wild-type (WT) and Nlrp3-KO mice were assigned to four experimental groups: (1) WT-N: wild-type without MDI (control); (2) NLRP3-N: Nlrp3-KO without MDI; (3) WT-I: WT with MDI; and (4) NLRP3-I: Nlrp3-KO with MDI. Following MDI, tissue and serum samples were collected at 0, 48, 96, and 192 h. Muscle injury, recovery, and the extent of inflammation were evaluated by measuring body and muscle weight, serum biochemical markers, complete blood counts, and via histopathological immunohistochemical analysis. In the early phase following contusion, muscle weight was lower in the NLRP3-I group than in the WT-I group; however, in the later stages, it was significantly greater in the NLRP3-I group. Serum aspartate aminotransferase, lactate dehydrogenase, and creatine kinase were significantly lower in the NLRP3-I group than in the WT-I group, indicating reduced muscle damage following Nlrp3 knockout. The white blood cell and neutrophil counts were markedly higher in the WT-I group than in the NLRP3-I group. Based on histopathology, the NLRP3-I group exhibited less severe muscle injury, reduced tumor necrosis factor (TNF)-α, interleukin (IL)-6, CD68, CD206 and Caspase-3 expression, and reduced fibrosis, indicating a diminished contusion-induced inflammatory response and improved regeneration relative to the WT-I group. Nlrp3 knockout thus ameliorated contusion-induced muscle injury and inflammation. We hypothesize that NLRP3 regulates TNF-α and IL-6, with Nlrp3 downregulation reducing contusion-related muscle damage and fibrosis. NLRP3 thus represents a promising therapeutic target for treating sports injuries and for rehabilitation.

Hexavalent chromium (Cr(VI)) is a well-established environmental and occupational carcinogen, but its time-dependent molecular effects remain poorly characterized. This study aims to elucidate the transcriptional responses triggered by acute versus chronic Cr(VI) exposure through an integrated analysis of two publicly available transcriptomic datasets: GSE16349 (short-term exposure, 16 hours) and GSE24025 (long-term exposure, 4 weeks). We identified 250 differentially expressed genes across both exposure models. MetaCore pathway enrichment analysis revealed shared activation of apoptosis, survival signaling, DNA damage response and repair, and cell cycle progression. Notably, short-term exposure primarily activated acute stress responses, whereas long-term exposure induced reprograms transcription toward fibrosis, EMT, and oncogenic signaling. Protein-protein interaction (PPI) network analysis identified potential key hub genes, with potential as biomarkers for Cr(VI) exposure monitoring. Our findings highlight distinct molecular trajectories in response to Cr(VI) over time, providing valuable insights into the progression from early toxic stress to chronic carcinogenic transformation. These results advance our understanding of Cr(VI)-induced carcinogenesis and suggest these potential targets for preventive and therapeutic interventions in exposed populations.

Background: Recurrence of atrial fibrillation (AF) after catheter ablation remains a major clinical challenge in hypertensive patients with paroxysmal AF, and reliable inflammatory predictors for recurrence are lacking. Objective: To assess the predictive value of neutrophil-to-lymphocyte ratio (NLR) for AF recurrence. Methods: Cox regression models, restricted cubic splines (RCS), receiver operating characteristic (ROC) curves, interaction and joint analyses, and mediation analysis were employed to evaluate the relationship between NLR and AF recurrence. Results: AF recurrence occurred in 17.94% of patients. The NLR was independently associated with recurrence (HR: 1.30, 95% CI: 1.12-1.50; P < 0.001). RCS analysis revealed a non-linear relationship with a threshold of 2.37, above which the recurrence risk significantly increased. ROC analysis demonstrated stable predictive performance of the NLR. No significant interaction effect between the NLR and blood pressure control status was observed. Regardless of blood pressure control, an NLR ≥ 2.37 was associated with an increased recurrence risk, with the highest risk in patients with both a high NLR and uncontrolled hypertension (HR: 3.92, 95% CI: 1.82-8.42; P < 0.001). Sensitivity analysis confirmed the robustness of the findings, and mediation analysis revealed no significant mediating effect. Conclusions: The NLR is an independent predictor of post-ablation recurrence in hypertensive patients with paroxysmal AF. The combination of NLR ≥ 2.37 and uncontrolled hypertension identifies a high-risk subgroup, underscoring the need for integrated anti-inflammatory and blood pressure control strategies. Further prospective studies are needed to validate these findings and evaluate targeted anti-inflammatory strategies.

Prostate cancer (PCa) is a genetically and phenotypically heterogeneous disease, and further advancements in PCa biomarker discovery are urgently required. Hepatocyte nuclear factor 1 A (HNF1A), a transcription factor, plays a critical role in PCa progression after biochemical recurrence (BCR). However, studies investigating the impact of HNF1A genetic variants on PCa are scarce. Therefore, in this study, we explored the associations of HNF1A single-nucleotide polymorphisms (SNPs) with susceptibility to BCR in PCa and its clinicopathological development. Two nonsynonymous (missense) SNPs [rs2464196 (S487N) and rs1169288 (I27L)] and two intronic SNPs [rs1169286 and rs735396] were analyzed using a TaqMan allelic discrimination assay for genotyping in a cohort of 690 Taiwanese patients with PCa. The results demonstrated that patients with PCa carrying the HNF1A rs735396 (TC+CC), rs2464196 (GA+AA), or rs1169288 (AC+CC) had a higher risk of developing tumors with higher pathological Gleason grades (3-5). These associations were particularly evident in the BCR subpopulation. Moreover, analysis of data from The Cancer Genome Atlas revealed that HNF1A expression was higher in PCa tissues than in normal tissues. Moreover, higher HNF1A expression was correlated with higher Gleason scores, more advanced pathological T stages, and metastasis. Taken together, our findings indicated that elevated HNF1A expression promotes PCa progression and that the missense SNPs rs2464196 and rs1169288, as well as the intronic SNP rs735396, may influence HNF1A expression, thereby influencing PCa aggressiveness, particularly in patients with BCR.

Background & Aims: Pancreatic adenocarcinoma (PAAD) remains a highly lethal malignancy with limited therapeutic options, primarily due to the absence of reliable prognostic biomarkers. Immunogenic cell death (ICD) plays a pivotal role in anti-tumor immunity and has potential as both a prognostic marker and a predictor of immunotherapy response. This study aimed to identify ICD-related hub genes and establish a robust prognostic gene signature for PAAD using weighted gene co-expression network analysis (WGCNA). Methods & Results: Transcriptomic and clinical data of PAAD patients were obtained from the TCGA and GEO databases. ICD enrichment scores were calculated using single-sample gene set enrichment analysis (ssGSEA), and ICD-associated gene modules were identified through WGCNA. A prognostic ICD-related gene signature was then constructed, and patients were stratified into high- and low-score groups based on the median risk score. Functional enrichment analysis was performed using the Molecular Signatures Database (MsigDB). Correlations between the signature score, immune cell infiltration, and drug sensitivity (IC₅₀ values from the GDSC2 database) were further assessed. Among the identified genes, AJM1 emerged as a key prognostic marker, validated in an independent PAAD cohort and through in vitro functional assays. Conclusion: This study developed and validated an ICD-related gene signature capable of predicting prognosis and immunotherapy responsiveness in PAAD. The identification and validation of AJM1 highlight its potential role as a prognostic biomarker and a novel contributor to the pathogenesis of PAAD.