International Journal of Medical Sciences最新文献

Hericium erinaceus, renowned for its pharmaceutical potential, is particularly notable for its isolated diterpenoid derivative, erinacine S. Colorectal cancer (CRC) is one of the most prevalent cancers, characterized by CSC that contribute to chemoresistance and sustained tumor growth. While various drugs have been explored, the precise mechanism underlying multifaceted functions of erinacine S in inhibiting chemoresistant human CRC cells remains elusive. By using annexin-V/propidium iodide staining and a Fluo-3 fluorescence staining assay, the cell death and viability in cancer cells and an in vivo xenograft mouse model were measured by western blots and an immunohistochemical assay. This study unequivocally demonstrates that erinacine S treatment significantly induces apoptosis and suppresses the aggressiveness of chemoresistant human CRC cells. Erinacine S also exhibits remarkable inhibitory effects on tumor growth in an in vivo xenograft mouse model. Immunohistochemical analyses unveiled that erinacine S treatment significantly upregulates the expression of TRAIL, TNFR1, and DR5 proteins while downregulating p-AKT, p-ERK, HIF1α, PCNA, and NFκB levels in the xenograft mouse model of chemoresistant human CRC cells. Erinacine S treatment of HCT-116/FUR cells triggered the activation of extrinsic apoptosis pathways (TRAIL, TNFR1, DR5, and caspase-3) and exerted a time-dependent suppression on the expression of anti-apoptotic molecules like Bcl-2 in intrinsic pathway. The activation of the p-PAK/FAK/p300 pathways was intricately involved in erinacine S-induced transcriptional activation; this was evidenced by histone H3K9K14ac (Acetyl Lys9/Lys14) modifications in the promoters of TRAIL, TNFR1, and DR5. The inactivation of the CXCR4/PI3K/Akt/HIF-1 pathway played a pivotal role in mediating the capacity of erinacine S to inhibit chemoresistant CRC growth while enhancing tumor apoptosis. Thus, erinacine S demonstrates notable inhibitive effects, both in vitro and in vivo, through the inhibition of invasion, migration, and proliferation in human chemoresistant cell lines, and holds promise as a natural agent for clinical therapy of patients with CRC.

Background & Aims: The heterogeneity among patients with locally advanced rectal cancer (LARC) necessitates identifying predictive markers of response to neoadjuvant chemoradiotherapy (nCRT) to enable personalized treatment strategies. Adipose tissue, which reflects nutritional status and chronic inflammation, has been implicated in tumorigenesis and disease progression. This study investigated the potential of adipose tissue as a predictive marker of nCRT response and prognosis in patients with LARC. Methods: We analyzed pre- and post-nCRT non-contrast computed tomography images at the third lumbar vertebral level to quantify adipose tissue in patients with LARC. We examined the relationship between changes in the subcutaneous adipose tissue index (SATI) and treatment outcomes, including disease-free survival (DFS), tumor regression grade (TRG), and tumor downstaging, using Cox proportional hazards and logistic regression analyses. Results: This study included 290 patients who underwent radical surgery after nCRT. Patients with significant increases in SATI had improved DFS (P = 0.002) and better short-term treatment responses, including superior TRG (P = 0.019) and more favorable tumor downstaging (P = 0.005). Multivariate analyses revealed that SATI gain was an independent prognostic factor for both long-term outcomes (DFS, P = 0.018) and short-term treatment responses (TRG, P = 0.020; tumor downstaging, P = 0.008). Additionally, calibration and decision curve analyses demonstrated the strong predictive ability of the nomogram incorporating SATI gain for DFS. Conclusions: An increase in SATI during nCRT was an independent protective factor for DFS and an independent predictor of treatment response in patients with LARC.

Wound healing is a complex and dynamic process that requires the coordination of cellular, molecular, and physiological events to restore tissue integrity. Despite notable advances in treatment strategies, optimizing healing outcomes, particularly in chronic wounds, remains a major challenge. Emerging evidence highlights the therapeutic promise of peptides, especially tripeptides, in accelerating tissue repair through diverse mechanisms. These short peptides regulate key processes such as cell migration, proliferation, and differentiation, while also modulating inflammation, promoting angiogenesis, and facilitating extracellular matrix (ECM) remodeling. This review, covering studies published between 2016 and 2025, explores the role of tripeptides in enhancing wound repair, emphasizing their biological functions, mechanisms of action, and therapeutic applications. Recent findings demonstrate that tripeptides can stimulate fibroblast migration, enhance collagen deposition, and support angiogenesis. In addition, they exhibit antimicrobial and anti-inflammatory properties, making them valuable candidates for both acute and chronic wound management. GHK-based formulations, including nanoparticle conjugates, hydrogels, and clinical derivatives such as TriHex and TriHex 2.0, enhance fibroblast migration, ECM remodeling, collagen and elastin synthesis, and wound closure while providing antimicrobial activity. KdPT mitigates hyperglycemia-induced oxidative stress and restores keratinocyte function, whereas KPV-loaded hydrogels reduce inflammation, promote tissue regeneration, and combat MRSA infections. Additionally, lipotripeptides (DICAMs) inhibit and disrupt bacterial biofilms, and GPE supports neuroprotection and regeneration through ERK and PI3K/Akt signaling activation. Beyond wound repair, this review also discusses comparative physicochemical properties and wound healing applications of tripeptides versus larger peptides, factors influencing their performance, strategies for combination with biomaterial scaffolds, and emerging applications in fields such as cancer and cosmetics. Collectively, tripeptides represent a promising class of multifunctional bioactive molecules in wound care, offering novel avenues for targeted tissue regeneration. Future research should focus on improving their stability, bioavailability, and delivery systems to fully harness their clinical potential in regenerative medicine.

Developmental dysplasia of the hip (DDH) is a common pediatric orthopedic disorder that can lead to lifelong disability if undetected. Ultrasound is the primary diagnostic modality but is subject to operator dependence and inter-observer variability. To address this challenge, we propose an attention-enhanced YOLOv11 framework for automated DDH classification. A dataset of 6,075 hip ultrasound images was preprocessed with augmentation and dimensionality reduction via UMAP. The model integrates Cross-Stage Partial (CSP) modules and C2PSA spatial attention to improve feature extraction, and was trained using Focal Loss and IoU Loss. It achieved 95.05% accuracy with an inference speed of 11.5 ms per image, substantially outperforming MobileNetV3 and ShuffleNetV2. Grad-CAM visualizations confirmed that the model consistently attends to the acetabular roof and femoral head, landmarks central to Graf classification, thereby enhancing clinical interpretability. These findings demonstrate that the proposed framework combines technical robustness with clinical relevance. Future work will emphasize multi-center validation and multimodal integration to ensure generalizability and support widespread clinical adoption.

Cholangiocarcinoma (CCA) is a highly aggressive malignancy and represents the most common form of adenocarcinoma in the hepatobiliary system. Placental alkaline phosphatase (ALPP), a member of the alkaline phosphatase (ALP) isoenzyme family, catalyzes phosphate ester hydrolysis under alkaline conditions. While ALPP overexpression has been observed in various germ cell tumors and specific cancers, its functional relevance and regulatory mechanisms in CCA remain poorly understood. In this study, we evaluated ALPP expression in CCA patient cohorts and explored its correlation with clinicopathological features and patient prognosis. We further assessed the relationship between ALPP expression and tumor-infiltrating immune cells, focusing on B cells and dendritic cells (DCs). To elucidate ALPP-associated molecular networks, weighted gene co-expression network analysis (WGCNA) was performed, followed by functional enrichment analyses using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The methylation landscape of the ALPP gene was also examined. Our findings demonstrated that elevated ALPP expression is significantly associated with increased serum CA19-9 levels and reduced overall survival in CCA patients. Immune infiltration analyses revealed a positive correlation between ALPP expression and the abundance of infiltrating B cells and DCs. WGCNA identified a gene module associated with ALPP that was highly enriched in the PI3K-Akt signaling pathway. Additionally, hypomethylation of a specific CpG site (cg19654061) within the ALPP gene was significantly associated with its upregulation. Collectively, these results suggest that ALPP functions as a potential prognostic biomarker in CCA and may contribute to disease progression through modulation of the immune microenvironment and activation of oncogenic signaling pathways.

The application of bispecific antibody (BsAbs)-based therapeutic strategies for glioblastoma (GBM) has shown considerable promise. By concurrently targeting tumor-associated antigens and immune effector cells, BsAbs can traverse the blood-brain barrier, modulate the immunosuppressive tumor microenvironment, and surmount challenges such as intratumoral heterogeneity and immune evasion. Accumulating evidence indicates that BsAbs surpass conventional monoclonal antibodies and chimeric antigen receptor T cell therapies in the context of GBM through mechanisms that include the redirection of immune cells, blockade of immune checkpoints, and synergistic inhibition of oncogenic signaling pathways. Although constrained by limitations in intracerebral delivery efficiency and the potential for immune-related adverse events, BsAbs represent a promising new frontier in GBM immunotherapy. They particularly enhance therapeutic precision and durability, underscoring their potential as a transformative approach for managing this aggressive malignancy.

Heart failure (HF) is a complex clinical syndrome characterized by impaired exercise capacity and reduced quality of life. While musculoskeletal conditions such as degenerative lumbar spine disease (DLSD) are common in older adults, their contribution to exercise intolerance in HF patients remains under-investigated. This retrospective cohort study evaluated the relationship between DLSD and functional capacity in HF patients using cardiopulmonary exercise testing (CPET) and the six-minute walk test (6MWT). We included 286 HF patients who underwent CPET following hospitalization for acute decompensated HF. Based on imaging findings, patients were divided into DLSD (n = 143) and non-DLSD (n = 143) groups after propensity score matching for age, sex, and BMI. The DLSD group exhibited significantly poorer exercise tolerance, with lower oxygen uptake efficiency slope (OUES) (1.05 ± 0.44 vs. 1.17 ± 0.45; p = 0.017) and shorter 6MWT distances (244.9 ± 130.36 vs. 283.36 ± 132.22 m; p = 0.014). Multivariate logistic regression adjusting for age, sex, BMI, and comorbidities revealed that higher OUES and longer 6MWT distances were independently associated with reduced odds of DLSD (OUES: OR = 0.477; 95% CI: 0.259-0.879; p = 0.018; 6MWT: OR = 0.997; 95% CI: 0.995-0.999; p = 0.01). These findings suggest that DLSD may exacerbate exercise intolerance in HF and highlight the value of CPET and 6MWT in identifying high-risk subgroups. Early recognition of DLSD may facilitate tailored rehabilitation strategies to improve clinical outcomes in patients with HF.

Hepatocellular carcinoma (HCC), the most prevalent form of primary liver cancer, continues to pose significant clinical challenges globally. Enhancer of Zeste Homolog 2 (EZH2), a central component of the Polycomb Repressive Complex 2 (PRC2), possesses histone methyltransferase activity through its SET domain and is frequently overexpressed in various cancers. Nevertheless, the precise role and regulatory mechanisms of EZH2 in HCC remain inadequately defined. In this research, we evaluated the expression levels of EZH2 at the mRNA and protein stages in HCC samples and examined their correlation with clinical features and patient survival outcomes. Patients were categorized into early- and late-stage groups based on tumor grade. Our methylation analyses pinpointed two specific CpG sites within the EZH2 gene, cg08558971 and cg18416251, which exhibited inverse methylation patterns between tumor stages. One patient subgroup displayed high methylation at cg08558971 during early-stage disease and reduced methylation at cg18416251 during late-stage disease, while another subgroup demonstrated the reverse pattern. Further pathway enrichment analysis suggested these methylation variations might influence enhanced T-cell differentiation and suppress metabolic pathways. Additionally, correlation analyses consistently linked EZH2 expression to genes involved in these immune and metabolic pathways. Collectively, our data propose that EZH2 could serve as a meaningful independent prognostic biomarker for HCC, regulated by stage-dependent epigenetic changes that may drive tumor progression by modulating immune response and cellular metabolism.

Endothelin-1 (ET-1), a potent vasoconstrictor, plays multifaceted roles in cellular growth, differentiation, and metabolic regulation. Elevated plasma levels of ET-1 have been observed in obesity, in which ET-1 regulates adipogenesis and the endocrine activity of fat cells. Human white adipocytes are central to energy storage and endocrine regulation. However, relatively little is known about the involvement of the ET-1 signaling pathway in the growth of human white preadipocytes (HWPs). Dysfunction or dysregulation of HWPs may contribute to the development of obesity and associated diseases. Therefore, we investigated the cellular signaling mechanisms in HWPs, focusing on the cellular and functional basis of the actions of ET-1. In this study, signaling protein levels, cell proliferation, and the numbers of visceral and subcutaneous HWPs were measured by immunoblotting and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and trypan blue exclusion assays. Both ET type A receptor (ETAR) and ET type B receptor (ETBR) antagonists inhibited the ET-1-induced growth of visceral HWPs and the phosphorylation of AMPK, PKC, and STAT3 in these cells. The ETBR antagonist alone blocked the ET-1-induced phosphorylation of ERK and c-JUN. Pretreatment with specific inhibitors of AMPK, ERK, JNK, STAT3, and PKC prevented ET-1-induced cell proliferation and attenuated the phosphorylation of AMPK, ERK, c-JUN, STAT3, and PKC induced by ET-1. Similar ETAR- and ETBR-dependent and AMPK- and ERK-dependent effects of ET-1 on the growth of primary subcutaneous HWPs were observed. In summary, the transduction of growth-related ET-1 signals in HWPs could occur through similar (e.g., AMPK, PKC, and JAK2/STAT3) or different (e.g., ERK and JNK/c-JUN) pathways. These distinct signaling pathways, along with the optimization of pathway-specific inhibitors, have potential implications for the future management of obesity and metabolic disorders.

Background: Ventricular septal defect (VSD) is the most common congenital heart defect in children. While previously considered benign, recent studies suggest long-term impacts on cardiopulmonary fitness (CPF). Overweight and obesity, increasingly prevalent among children, may further impair CPF in this population. This study aimed to evaluate the relationship between adiposity and CPF in children with VSD using cardiopulmonary exercise testing (CPET). Methods: This retrospective study included 349 children and adolescents with VSD and 349 age-, sex-, and body mass index (BMI)-matched healthy controls. Participants underwent symptom-limited treadmill CPET. Children with VSD were stratified into BMI categories (underweight, normal, overweight, obesity) based on national standards. Multiple CPET parameters were analyzed, including anaerobic threshold metabolic equivalents (AT MET) and peak metabolic equivalents (peak MET). Results: Children with VSD had significantly higher rates of both underweight (15.5% vs. 4.3%) and obesity (14.6% vs. 9.7%) compared to controls (p < 0.001). Within the VSD group, AT MET and peak MET declined progressively with increasing BMI. [AT MET: 7.41 ± 1.57 (underweight), 6.86 ± 1.38 (normal), 6.01 ± 1.23 (overweight), 5.62 ± 1.23 (obese), p < 0.001; Peak MET: 10.37 ± 2.22 (underweight), 9.58 ± 1.94 (normal), 8.56 ± 1.70 (overweight), 7.81 ± 1.60 (obese), p < 0.001]. Compared to controls, children with VSD showed lower AT MET (6.56 ± 1.51 vs. 6.97 ± 1.47, p < 0.001) and peak MET (9.32 ± 2.03 vs. 10.17 ± 1.95, p < 0.001), along with reduced peak heart rate and heart rate at AT. Conclusion: Children with VSD, regardless of surgical status, exhibit diminished CPF compared to healthy peers. Moreover, both undernutrition and excessive adiposity are more prevalent in the VSD group. Obesity was associated with significantly impaired cardiopulmonary fitness, highlighting the need for early identification and lifestyle interventions. Routine CPET and weight management strategies should be incorporated into long-term care for pediatric VSD patients.