Inflammation Journal

Background: Data on the expression and regulation of immune checkpoint inhibitors in prostate tissue and cells remain limited. This study aims to characterize the expression and regulatory mechanisms of B7-H3 (CD276) in prostate tissues and cell models. Methods: In silico analyses were performed to evaluate the expression of B7-H3 and other checkpoint inhibitors in prostate tissues and cell lines. In vitro experiments assessed the impact of tumor microenvironmental factors on B7-H3 expression. Results: B7-H3 was identified as the most abundant checkpoint inhibitor in prostate tissues and cell lines. Its expression was highest in androgen-responsive LNCaP cells compared to other commonly used prostate cancer models. Hypoxic conditions and charcoal dextran-treated serum (CDS) significantly reduced B7-H3 mRNA and protein levels in LNCaP cells but not in androgen-independent DU145 or PC3 cells. Conversely, dihydrotestosterone (DHT) did not influence B7-H3 expression. Conclusion: B7-H3, rather than other checkpoint inhibitors, may play a critical role in prostate cancer tumorigenesis. Hypoxia, rather than androgen signaling, appears to regulate B7-H3 expression, and this regulatory response may be lost in more aggressive androgen-independent prostate cancer cells.

This review examines how structural injury to the endothelial glycocalyx is known to initiate the collapse of caveolin-1-dependent caveolae, and how this may influence the dysregulation of endothelin type B receptors. The glycocalyx, caveolae, and endothelin type B receptors are proposed to form an integrated mechanosensory axis that coordinates shear-dependent signaling, redox control, and endothelin peptide clearance. Under physiological flow conditions, heparan sulfate-mediated mechanotransduction is known to sustain caveolin-1 expression, which preserves caveolar organization, endothelial nitric oxide synthase coupling, and localization of endothelin type B receptors. Under disturbed flow or inflammatory stress, enzymatic shedding of the glycocalyx is associated with reduced caveolin-1 stability and subsequent disruption of caveolar microdomains. These structural alterations coincide with the uncoupling of endothelial nitric oxide synthase, increased reactive oxygen species generation, enhanced endothelin-1 transcription, and possibly the impaired localization of the endothelin type B receptors meant to clear endothelin-1 peptides. The combination of these processes suggests a potentially self-amplifying interaction between mechanotransductive failure, increased oxidative stress, and endothelin imbalance. The objective here is to reframe the current understanding of glycocalyx degradation and caveolar collapse as direct upstream contributors to endothelin type B receptor dysfunction, while simultaneously highlighting the preservation of this pathway as a potential therapeutic focus in vascular diseases such as hypertension and atherosclerosis. A stronger mechanistic definition of the relationship between glycocalyx degradation, caveolae destabilization, and altered endothelin type B receptor function is necessary to clarify how vascular injury may lead to persistent endothelial dysfunction. Future research in this area may present opportunities for therapeutic interventions focused on preservation or restoration of glycocalyx integrity and function and may allow interruption of the proposed pathological feedback loop responsible for these diseases, improving patient outcomes.

Background: Rheumatoid arthritis (RA) is linked to increased risks of major adverse cardiovascular events (MACE), venous thromboembolism (VTE), malignancy, and mortality. However, differences in these risks by treatment class—particularly among older adults with cardiovascular (CVD) risk factors—remain unclear. Methods: We conducted a population-based cohort study using Ontario administrative data. Patients aged ≥67 years with incident RA (2008–2013) were followed through 2023. Outcomes included healthcare utilization for MACE and VTE, all-cause mortality, and cancer-related encounters. Time-varying treatment groups were: no csDMARD/advanced therapy (AT), glucocorticoids (GC) only, csDMARDs (reference), and biologic/targeted synthetic DMARDs (b/tsDMARDs). Weighted Fine–Gray models within a marginal structural framework were used, stratified by baseline CVD risk. Results: Among 10,058 patients, 80% had high CVD risk. Compared with csDMARDs, untreated patients (SHR 15.0; 95% CI 13.8–16.2) and GC users (SHR 1.29; 95% CI 1.13–1.47) had higher MACE risk, while AT use was associated with lower risk (SHR 0.53; 95% CI 0.37–0.77). Similar patterns were observed in low-risk patients. AT use was not associated with VTE. Untreated and GC users had increased mortality, whereas AT use reduced mortality. Increased cancer-related utilization was observed only in untreated patients. Conclusion: Treatment type strongly influences major outcomes in older adults with RA, underscoring the importance of integrating CVD and thrombotic risk into therapeutic decisions.