International Journal of Medical Sciences最新文献

Background: Glycosylphosphatidylinositol transamidase (GPI-T) catalyzes the attachment of glycosylphosphatidylinositol (GPI) anchors to membrane proteins implicated in oncogenic signaling. However, the specific contribution of individual GPI-T subunits to head and neck cancer (HNC) remains unclear.

Methods: We first compare the expression profiles of GPI-T subunits in HNC and then integrate multi-omics analyses to assess phosphatidylinositol glycan class K (PIGK) expression, genomic alterations, function and pathway enrichment, molecular interactions, and immune associations. Clinical relevance is validated by immunohistochemistry on tissue microarray, and in vitro assays were conducted to assess PIGK-mediated phenotypes, regulation of Family with sequence similarity 20-member C (FAM20C), taxane response, and cancer-associated fibroblast (CAF) formation.

Results: Among the five subunits, PIGK was uniquely and consistently upregulated at both mRNA and protein levels in tumors. High PIGK expression correlates with aggressive clinicopathological features and poor survival across independent cohorts. Genomic analysis shows that PIGK overexpression is associated with copy number gains and inversely correlated with mutations in FAT1, CDKN2A, NOTCH1, and CASP8. Functionally, PIGK knockdown significantly suppressed cell migration, invasion, proliferation, and colony formation, reduced FAM20C expression, decreased sensitivity to paclitaxel and docetaxel, and attenuated fibroblast activation. Enrichment analysis of co-expressed genes showed involvement in cancer-related biological processes, while protein-level interactors of PIGK were enriched in GPI-anchor biosynthesis and membrane-associated pathways. Clinically, patients with PIGK ^high/FAM20C ^high profile exhibited the worst survival outcomes.

Conclusion: PIGK functions as a potential oncogenic driver in HNC with prognostic and therapeutic relevance. Its association with FAM20C, taxane response, and modulation of fibroblast activation provides insights into PIGK-mediated oncogenesis and may inform patient stratification strategies.

Introduction: Bladder cancer (BLCA) is the second most common malignancy of the male urinary tract, with frequent metastasis to pelvic lymph nodes and, in advanced stages, to distant organs such as the lungs, liver, and bones. Thrombospondin-4 (TSP4), an extracellular matrix protein, has been implicated in cell adhesion, migration, proliferation, and cytoskeletal regulation. However, its role in lymphatic metastasis remains poorly understood. Methods: TSP4 mRNA and protein levels were assessed by RT-qPCR and Western blot analyses. Lymphangiogenesis and lymphatic endothelial cell (LEC) migration were respectively evaluated using tube-formation and transwell assays. The Cancer Genome Atlas (TCGA)-BLCA datasets were analyzed to compare expressions of TSP family members across lymph node metastasis stages. A popliteal lymph node metastasis model was employed to isolate lymph node-tropic BLCA cell lines. Results: TSP4 expression was positively associated with lymph node metastasis stages in BLCA tissues. In vitro, conditioned medium (CM) from 5637 and T24 cells promoted LEC recruitment and tube formation, while a TSP4-neutralizing antibody impaired LEC migration without affecting tube formation. Mechanistically, TSP4 enhanced LEC migration by upregulating intercellular cell adhesion molecule (ICAM)-1 and activating the integrin αvβ3/focal adhesion kinase (FAK)/extracellular signal-regulated kinase (ERK) pathway. Notably, TSP4 also induced vascular endothelial growth factor C (VEGF-C) expression in BLCA cells. Both TSP4 and VEGF-C were upregulated in lymph node-tropic BLCA cell lines, with a positive correlation observed in TCGA-BLCA datasets. VEGF-C neutralization abolished CM-induced LEC tube formation, highlighting the role of the TSP4/VEGF-C axis in lymphangiogenesis. Conclusions: This is the first study to demonstrate that BLCA-derived TSP4 cooperates with VEGF-C to promote lymphangiogenesis within the tumor microenvironment. These findings suggest that TSP4 could serve as a potential therapeutic target for preventing lymphatic metastasis in human BLCA.

Chronic systemic inflammation and autoimmunity are hallmarks of rheumatoid arthritis (RA), an inflammatory illness that progressively deteriorates joints, resulting in permanent disability. Monocyte adhesion and infiltration into synovial tissue are critical steps in RA progression. WISP-3 (referred to as CCN6) is a member of the CCN family and plays a role in regulating various developmental processes. However, the role of WISP-3 in monocyte adhesion and macrophage polarization in RA remains unknown. Our high-throughput cytokine array data indicate that WISP-3 induces CCL4 synthesis in RA synovial fibroblasts (RASFs), subsequently enhancing monocyte adhesion to the synovium. Result from the GEO database confirm that levels of WISP-3 and CCL4 are markedly higher in RA patients compared to healthy controls. We also elucidated a detailed mechanism by which WISP-3 increases CCL4 synthesis in RASFs and promotes monocyte adhesion to the synovium by reducing miR-6894-5p expression via the MEK and ERK pathways. Furthermore, WISP-3 augments M1 macrophage polarization in the RA microenvironment. Thus, the WISP-3/CCL4 axis may serve as a novel therapeutic goal for RA treatment.

Osteoarthritis (OA) is a common inflammatory degenerative disease that causes joint pain and irreversible bone damage, affecting many middle-aged and elderly people. Currently, there is no effective treatment available. Okara, a byproduct of soybean processing, contains bioactive compounds with antioxidant and anti-inflammatory properties similar to those found in soybeans, making it a promising candidate for reuse as a food supplement to provide health benefits. In this study, we explored the therapeutic potential of soybean okara extract (SOE) in OA using a rat surgical anterior cruciate ligament transection (ACLT) OA model. Oral administration of SOE significantly alleviated bone pain associated with ACLT, as demonstrated by a weight-bearing behavioral assay. Histopathological analysis revealed that oral SOE ameliorated ACLT-induced bone destruction, improved cartilage and synovium integrity, and reduced the levels of proinflammatory cytokines IL-1β, TNF-α, and the chondrolytic enzyme MMP-3. This, in turn, led to a decrease in the degradation of aggrecan and collagen type II, thereby preserving cartilage. These findings suggest that oral administration of SOE could be a promising approach for the prevention and treatment of OA.

Objective: To examine how maternal thyroid-stimulating hormone (TSH), free thyroxine (FT4) and thyroid peroxidase antibody (TPOAb) status in early pregnancy relate to low birth weight (LBW) or small for gestational age (SGA) outcomes. Methods: This prospective cohort analysis utilized data from 125,365 singleton pregnancies in the China Birth Cohort Study (2018-2022), with participants enrolled at 6-13⁺⁶weeks gestation from 9 tertiary hospitals. The potential associations among maternal thyroid functional indices, spectrum of thyroid dysfunction, and adverse neonatal outcomes (LBW/SGA) were statistically evaluated employing generalized linear mixed modeling techniques. Besides, to verify the consistency of these findings, we conducted comprehensive subgroup analyses across multiple demographic and clinical strata. Results: Among the final 86,015 eligible participants, LBW and SGA occurred in 3.18% (n=2,731) and 3.56% (n=3,060), respectively. After adjusting for maternal and neonatal characteristics, analyses revealed significant negative associations between circulating maternal thyroid hormone levels and offspring birth weight measurements (per 1 mIU/L increase in TSH: β = -5.62, 95% CI: -7.29 to -3.95, P < 0.001; per 1 pmol/L increase in FT4: β = -1.43, 95% CI: -2.21 to -0.65, P < 0.001). First-trimester subclinical hypothyroidism (SCH) was associated with increased risks of both LBW (aOR = 1.29, 95% CI: 1.04-1.59; P = 0.021) and SGA (aOR = 1.18, 95% CI:1.01-1.38; P = 0.037). Women in the highest TSH quintile had 20% higher LBW risk (aOR = 1.20, 95% CI: 1.02-1.41; P = 0.028) and 16% higher SGA risk compared to the lowest quintile (aOR = 1.16, 95% CI: 1.03-1.30; P = 0.012). The associations of TSH and FT4 with LBW and SGA were consistent across all subgroups. Conclusions: Elevated maternal TSH, elevated FT4 (even within high-normal ranges), and SCH in early pregnancy serve as significant risk indicators for LBW and SGA.

Background: Dysfunction of fatty acid metabolism plays a critical role in the pathogenesis of Rheumatoid Arthritis (RA). This study aimed to screen for Hub genes involved in fatty acid metabolism that contribute to the inflammatory state of RA synovium. Methods: Four mRNA microarray datasets for RA were integrated into an expression matrix as a test dataset. One RNA-seq and five microarray datasets were preprocessed as validation datasets. Immune cell infiltration combined with Weighted Gene Co-expression Network Analysis (WGCNA) were used to feature infiltrated cells and their correlation with candidate genes in RA. Five machine learning algorithms were applied to Hub genes screening. Temporal, immuno-efficacy, drug target prediction, molecular docking, ceRNA, and transcription factors networks analyses were conducted to elucidate the association of the Hub genes with RA. Immunofluorescence assay was performed in Collagen-Induced Arthritis (CIA) mouse, and qPCR and Western blot were applied to TNFα or IL-6 treated MH7A cells to reveal the potential roles of the proinflammatory cytokines on Hub genes expression in RA synovium. Results: Three Hub genes with better diagnostic efficiency were screened, with PDK1 and XBP1 up-regulated and ACACB down-regulated in RA. These genes were associated with immune cells infiltration and immuno-efficacy in RA, and their expression patterns showed time-dependent characteristics during disease progression. Mechanistically, MALAT1, NEAT1 and FOXC1 were involved in the regulation of PDK1, XBP1 and ACACB expression, and TNFα or IL-6 treatment mimicked their expression phenotypes in RA. Conclusion: Our study identified PDK1, XBP1 and ACACB as the Hub genes from the fatty acid metabolic pathway and indicated that PDK1, XBP1 and ACACB might play key roles in the pathogenesis of RA synovium.

Atherosclerosis is the leading cause of heart attack and stroke worldwide. The key characteristic of atherosclerosis is accumulation of LDL cholesterol in artery walls, the subsequent infiltration by monocytes/macrophages, and the development of inflammation. Recently, we reported that plasma protein complement factor H-related 1 (FHR1) binds to the necrotic surfaces of cardiovascular plaques and induces inflammation. Moreover, the concentration of FHR1 is higher, whereas CFHR1 gene deletion frequency is significantly lower in patients with atherosclerosis in comparison to healthy controls. Here we generated muFHR1-/- (the murine homolog of FHR1) knockout mice and then crossed them with ApoE-/- knockout mice (a model of human hyperlipidemia). Notably, deletion of muFHR1 enhanced lipid conversion in the liver as evidenced by RNAseq analysis. This resulted in normalized cholesterol levels, reduced inflammation and plaque formation in muFHR1-/-ApoE-/- mice. These data suggest that muFHR1 directs uptake of oxLDL by macrophages, and supports foam cell formation, plaque development, and inflammation in dyslipidemic mice. As human FHR1 correlates with non-HDL cholesterol concentrations and inflammation markers in patients with atherosclerosis-associated cardiovascular disease (ACVD) we assume that FHR1 plays a key role in the development of atherosclerosis and subsequent events such as stroke and myocardial infarction.

Ferroptosis is an iron-dependent nonapoptotic form of cell death that links iron, lipid, and glutathione levels to a variety of disease-related activities. However, the characteristics of ferroptosis in cervical carcinoma (CC) are poorly understood. We acquired raw data on CC cohorts from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. Key genes were identified using differential gene expression analysis and intersected for further immune infiltration, transcription regulation, gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), and drug sensitivity analysis. We also used immunohistochemical (IHC) staining to confirm the expression of important genes in cervical cancer tissue and their prognostic relevance. Finally, gene silencing and cell coculture experiments were used to verify the biological functional mechanism and its role in the tumor microenvironment (TME). Through bioinformatics analysis, we discovered that GCH1 and H1.2 are key ferroptosis-related molecules in cervical cancer. GCH1 and H1.2 could act as useful prognostic markers in cervical cancer, and in addition to their connection with the tumor microenvironment, the possible transcriptional regulatory network, hallmark pathways and chemotherapy sensitivity were also clarified. IHC of the tissue microarray (TMA) and immunofluorescence spatial distance evaluation revealed that GCH1 was more highly expressed in cervical cancer tissue than in paracarcinoma tissue. For patients with cervical cancer, higher GCH1 expression corresponded to a lower M2 cell proportion and a higher M1/M2 ratio as well as a greater GCH1-M2 distance. Silencing GCH1 in SiHa cells blocked the cell cycle, promoted apoptosis, and inhibited the migration and invasion abilities of the cells, possibly through the inhibition of the phosphorylated PI3K/AKT/mTOR pathway. Coculture of the cells with macrophages revealed that the silencing of GCH1 led to decreased expression of tumor necrosis factor (TNF), a biomarker of M1 macrophages. In this study, we performed a thorough investigation of ferroptosis-related genes and identified the functional complexity of GCH1 during tumorigenesis in cervical cancer.

Background and Aim: The patterns of medication use among elderly patients with inflammatory bowel disease vary owing to several factors. This study aimed to present the outcomes of immunomodulator therapy in both geriatric and non-geriatric patient groups, highlighting the differences in treatment effectiveness, reasons for discontinuation, and incidence of side effects between the two groups. Materials and Methods: A retrospective database was established by reviewing the records of patients with inflammatory bowel disease aged 18 years and older who received immunomodulatory therapy at our clinic over a seven-year period. Patients aged 65 years or older were included in the geriatric cohort. In addition to demographic and clinical variables, disease activity in ulcerative colitis patients was assessed using the Mayo Disease Activity Index and the Rachmilewitz Endoscopic Activity Index, whereas the Harvey-Bradshaw Index was used for Crohn's disease patients. Results: This study included 120 patients, comprising 52 with ulcerative colitis and 68 with Crohn's disease. The median age was 66.5 years (range: 23-87), with 64 patients (53.3%) classified as geriatric (≥65 years). Immunomodulator therapy was discontinued owing to side effects in 37 patients (30.8%) and remission in 13 patients (10.8%). In addition, 29 patients (24.2%) did not respond to the treatment. During follow-up, 3 patients (2.5%) developed malignancy and 1 patient (0.8%) died. No significant differences were observed between the geriatric and non-geriatric groups regarding the type of inflammatory bowel disease, duration of therapy, concomitant treatments, reasons for discontinuation, side effects, occurrence of malignancy, malignancy type, or mortality. Conclusion: With careful patient selection and close monitoring, immunomodulator therapy in elderly patients with inflammatory bowel disease can achieve similar effectiveness and risk of side effects as those observed in younger patient groups.

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.