International Journal of Medical Sciences最新文献

Non-coding regions of eukaryotic genomes, once considered transcriptionally inert, are increasingly recognized as potential sources of bioactive peptides. Here, we mined the intergenic "genomic dark matter" of Saccharomyces cerevisiae to identify peptide ligands targeting the angiotensin-(1-7)/Mas receptor axis. Intergenic sequences were computationally translated in all reading frames and screened for short peptides with sequence and structural similarity to angiotensin-(1-7), a key modulator of the renin-angiotensin system. Two candidates showing 72-86% similarity were identified and structurally modeled. A homology-independent model of the human Mas receptor was generated, followed by molecular docking and 100-ns membrane-embedded molecular dynamics simulations to assess binding modes and complex stability. Both peptides adopted angiotensin-(1-7)-like conformations and engaged conserved receptor residues involved in ligand recognition. Docking and dynamics analyses indicated stable binding and sustained receptor engagement, with one peptide exhibiting enhanced interaction density and conformational stability relative to the native ligand. Overall, our results support the concept that non-coding genomic regions can encode functional peptide ligands and provide a scalable in silico framework for discovering peptide modulators of clinically relevant G protein-coupled receptors (GPCRs).

This study provides a comprehensive analysis of the application of artificial intelligence (AI) in diagnosing acute traumatic wrist joint injuries (WJIs), including fractures and ligament damage. AI has demonstrated significant potential in identifying fractures and ligament damage. The study highlights the use of various AI technologies and algorithms, including Convolutional Neural Networks (CNNs), Gradient Class Activation Mapping (Grad-CAM), deep learning models, object detection models, automated assessment algorithms, traditional machine learning techniques, data augmentation and preprocessing, Natural Language Processing (NLP), and integration with other imaging modalities. Compared with traditional diagnostic methods, AI offers substantial benefits, such as efficient processing of large datasets, minimizing diagnostic errors and missed cases, aiding in interpreting complex fracture patterns, optimizing workflow, enhancing diagnostic efficiency, and providing comprehensive diagnoses through multimodal integration. AI has significantly improved the precision and efficiency of fracture detection, reduced unnecessary imaging procedures, expedited the diagnostic and reporting process, optimized resource allocation, and improved patient outcomes. However, clinical application of AI faces challenges, including ethical considerations, regulatory hurdles, data privacy and security issues, algorithm transparency and interpretability problems, and unclear liability definitions. The future of AI in diagnosing WJIs is promising, with potential advancements in fracture detection, treatment planning, and rehabilitation strategies. However, challenges such as model validation and training of healthcare professionals must be addressed to fully integrate AI into orthopedic practice and advance the management of WJIs.

Objectives: Lupus nephritis (LN) is a major complication of systemic lupus erythematosus (SLE). This study evaluated the association of C1q-circulating immune complexes (C1q CIC) with LN and their potential adjunctive rule-out value compared with conventional biomarkers.

Methods: We conducted a retrospective analysis of 883 SLE patients from the Asia Pacific Lupus Collaboration (APLC) cohort in Taiwan. C1q CIC was assessed for its association with disease activity and compared to anti-dsDNA, C3, and C4. Logistic regression and ROC analysis were performed.

Results: C1q CIC levels were significantly elevated in active SLE and in non-renal manifestations, including cutaneous involvement, serositis, and hematologic abnormalities. In patients with LN, C1q CIC levels were significantly higher than in those without LN, whereas anti-dsDNA, C3, and C4 showed no significant differences. Overall discriminative performance was modest, and C1q CIC is not suitable as a diagnostic or screening tool for LN. At a cutoff of 5.31 μg Eq/mL, C1q CIC showed a high negative predictive value (NPV = 86.04%) but low positive predictive value (PPV = 29.51%). In stratified analysis, discriminative ability was limited in patients with low disease activity (SLEDAI-2K < 4; AUC = 0.55), whereas NPV remained high (97.15%).

Conclusion: C1q CIC may serve as an adjunctive rule-out biomarker for LN, particularly when levels are low or in patients with low disease activity. Although not suitable for diagnosis or screening, its relatively high NPV may help identify patients at lower risk of LN. Results should be interpreted in conjunction with clinical and laboratory assessment.

Aims: Atrial fibrillation or flutter (AFl) frequently coexists with chronic heart failure (CHF), yet its impact on in-hospital outcomes in large, unselected populations remains insufficiently defined.

Methods: We analyzed all hospitalizations for CHF (ICD-10-GM I50*) in Germany from 2014 to 2022 using nationwide administrative data. Patients were stratified by rhythm status (AFl vs. non-AFl). Outcomes included in-hospital mortality, complications, length of stay, and health care costs. Multivariable logistic regression was used to identify independent predictors of mortality.

Results: Among 4,057,291 hospitalizations, 56.9% had AFl. These patients were older (median 82 vs. 79 years), more often female, and showed a higher comorbidity burden, particularly CKD, hypertension, and stroke. AFl was associated with higher rates of complications such as AKI (11.9% vs. 9.7%; p < 0.001) and cardiogenic shock (1.15% vs. 1.03%; p < 0.001), but lower use of mechanical ventilation and assist devices. Despite this, in-hospital mortality was slightly lower in AFl (8.30% vs. 8.66%). AFl patients had longer median hospital stays (8 vs. 7 days), while costs were comparable. Ventilated AFl patients had longer ventilation times (28 vs. 21 hours). In multivariable analysis, AFl was independently associated with higher mortality in most age groups, except for patients aged 40-49, 80-89, and > 90 years.

Conclusions: In this nationwide cohort, AFl was common among CHF patients and linked to more advanced disease. Its impact on in-hospital mortality was age-dependent and complex, highlighting the need for tailored clinical management.

Breast cancer is the second most common cancer worldwide and remains the leading cause of cancer-related deaths among women. Triple-negative breast cancer (TNBC) represents approximately 15-20% of all breast cancer cases and is characterized by an aggressive clinical course and a high risk of metastasis. Extracellular signal-regulated kinase 5 (ERK5) is a critical biomarker that promotes tumor progression through mechanisms involving cell proliferation, invasion, and metastasis; however, its precise role in epithelial-mesenchymal transition (EMT) in TNBC remains unclear. In this study, we analyzed data from 117 patients with TNBC and found that high ERK5 expression was significantly associated with tumor progression, shorter progression-free survival, and shorter overall survival. RNA sequencing of a highly metastatic TNBC cell line revealed that ERK5 knockdown modulated the expression of various gene clusters, particularly those associated with DNA repair, G2/M checkpoint regulation, and angiogenesis. In addition, ERK5 knockdown in a mouse xenograft model significantly suppressed tumor proliferation and lung metastasis, inhibited tumor cell migration, and reduced the expression of EMT-related proteins. Mechanistically, our data further demonstrated that ERK5 regulates the interaction between cellular JUN (c-JUN) and the vimentin promoter, thereby modulating vimentin expression and downstream signaling pathways. A significant positive correlation between ERK5 and vimentin expression in human TNBC tissue specimens further supported this regulatory association. These findings suggest that ERK5 mediates the recruitment of c-JUN to regulate vimentin expression, thereby promoting EMT and metastasis. Thus, the ERK5/c-JUN/vimentin axis may be a potential therapeutic target to improve clinical outcomes in patients with TNBC.

Background: Hypertension (HTN) is a common and complex disorder influenced by multiple genetic and environmental factor, where the underlying mechanisms of its etiology remain incompletely understood although the identification of several contributing elements. This research sought to evaluate the possible relationship between genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and With-No-Lysine Kinase 1 (WNK1) genes and susceptibility to hypertension.

Method: Genomic DNA was extracted from blood samples collected from 220 individuals with hypertension and 220 normotensive controls. Genotyping of MTHFR (rs1801133 and rs1801131) and WNK1 (AluYb8) polymorphisms was performed using direct PCR and PCR-RFLP techniques. The resulting data were subjected to appropriate statistical analyses.

Results: A statistically significant association was identified between the rs1801131 polymorphism of the MTHFR gene and susceptibility to hypertension (p = 0.0006). This association remained significant under the codominant, dominant, and recessive genetic models, with all p-values < 0.016. Furthermore, the CC haplotype of the MTHFR gene showed a significant association with hypertension (OR = 2.02, p = 1e-04).

Conclusion: These findings indicate that the MTHFR rs1801131 polymorphism is significantly associated with hypertension susceptibility and may represent a potential genetic marker. This highlights its relevance for future studies exploring genotype-driven risk assessment and personalized approaches to hypertension management.

Introduction: Cholangiocarcinoma (CCA) is high prevalent in Asia. Emerging evidence indicates gut and tissue microbiota are involved in CCA carcinogenesis and progression. This study investigated the potential role of gut and tissue microbiota as prognostic biomarkers associated with treatment outcomes in advanced intrahepatic CCA (ICCA) patients.

Methods: This prospective study comprised two cohorts: hepatocellular carcinoma (HCC) or ICCA patients undergoing surgery or biopsy, and unresectable ICCA patients treated with cisplatin and gemcitabine. Gut bacterial profiles were characterized from pre-treatment fecal samples using 16S rRNA and analyzed with clinical outcomes. Tissue bacterial profiles were determined by real-time qPCR.

Results: In 30 ICCA patients receiving chemotherapy, gut microbiota differed based on chemotherapy response, PFS, overall survival, and Opisthorchis viverrini infection. An increase in Acidaminococcus and Sutterella, along with a decrease in NK4A214_group, Lachnospiraceae_FCS020_group, and UCG-010, were associated with poor clinical outcomes. Notably, Intestinimonas levels were significantly associated with less progression of disease within six months (aOR 0.92). Of total 70 patients, bacterial profiles of ICCA and HCC tissues did not significantly differ.

Conclusion: Advanced ICCA patients with poor outcomes following chemotherapy exhibited the distinct pattern of gut microbiota, which might be used as potential prognostic biomarkers.

Melatonin is a pleiotropic hormone with well-documented antioxidant, anti-inflammatory, neuroprotective, and immunomodulatory properties, making it a promising candidate for the treatment of diverse diseases including neurodegenerative disorders, cardiovascular diseases, cancer, and sleep disturbances. However, its clinical translation has been hampered by several biopharmaceutical limitations, including poor aqueous solubility, extensive hepatic first-pass metabolism, rapid systemic clearance, and low oral bioavailability. Additionally, physiological barriers such as the blood-brain barrier, stratum corneum, and mucosal epithelia restrict its accumulation at target sites. In recent years, nanotechnology-based drug delivery systems have emerged as powerful tools to overcome these challenges. This review provides a comprehensive overview of advanced melatonin nanocarriers with a focus on their design principles, formulation strategies, and therapeutic applications. A central theme of this review is the integration of carrier design with biological barrier circumvention and administration routes-elucidating how specific nanocarrier platforms address the shortcomings of conventional immediate- and prolonged-release melatonin formulations through spatial and temporal control over drug distribution. We summarize recent preclinical progress in melatonin nanocarriers for a wide range of disease models, including Alzheimer's disease, Parkinson's disease, myocardial infarction, retinal degeneration and glaucoma, depression, and various cancers, with emphasis on the relationship between administration routes and therapeutic outcomes. Finally, critical challenges in clinical translation are addressed, including large-scale manufacturing, long-term toxicity evaluation, regulatory considerations, and the development of chronotherapy-compatible delivery systems. By integrating insights from materials science, pharmaceutics, and nanomedicine, this review aims to provide a rational framework for the future design and clinical application of melatonin-based nanotherapeutics.

Lutein is a bioactive carotenoid best known for its role in retinal protection, but emerging evidence suggests that it may also exert anti-inflammatory activity in chronic inflammatory disorders. In this study, we investigated the anti-inflammatory and joint-protective effects of lutein in rheumatoid arthritis (RA)-related experimental models. Transcriptomic profiling was performed in MH7A fibroblast-like synovial cells treated with lutein, followed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA). The results showed that lutein regulated inflammation-related transcriptional programs, particularly pathways associated with cytokine signaling and inflammatory responses. In TNF-α-activated MH7A cells, lutein suppressed inflammatory cytokine production and inhibited cell proliferation. The in vivo effects of lutein were further evaluated in a collagen antibody-induced arthritis (CAIA) mouse model. Mice were assigned to control, CAIA, and lutein-treated CAIA groups, and disease progression was assessed by monitoring body weight, paw thickness, and arthritis scores. Lutein treatment significantly attenuated arthritis severity and joint inflammation without affecting body weight. Micro-computed tomography demonstrated reduced bone erosion and osteophyte formation in lutein-treated CAIA mice. Histological analyses using hematoxylin and eosin and Safranin O staining further showed that lutein alleviated synovial hyperplasia and cartilage destruction. These findings indicate that lutein exerts anti-inflammatory and joint-protective effects in experimental models relevant to RA and support further mechanistic and preclinical investigation of lutein as a bioactive natural compound in inflammatory joint disease.