Background: Notch signaling is critical for regulating the function of vascular endothelial cells (ECs). However, the effect of the intracellular domain of Notch1 (NICD) on EC injury in sepsis remains unclear.Methods: We established a cell model of vascular endothelial dysfunction and induced sepsis in a mouse model via lipopolysaccharide (LPS) injection and cecal ligation and puncture (CLP). Endothelial barrier function and expression of endothelial-related proteins were determined using CCK-8, permeability, flow cytometry, immunoblot, and immunoprecipitation assays. The effect of NICD inhibition or activation on endothelial barrier function was evaluated in vitro. Melatonin was used for NICD activation in sepsis mice. The survival rate, Evans blue dye of organs, vessel relaxation assay, immunohistochemistry, ELISA, immunoblot were used to explore the specific role of melatonin for sepsis induced vascular dysfunction in vivo.Results: We found that LPS, interleukin 6, and serum collected from septic children could inhibit the expression of NICD and its downstream regulator Hes1, which impaired endothelial barrier function and led to EC apoptosis through the AKT pathway. Mechanistically, LPS decreased the stability of NICD by inhibiting the expression of a deubiquitylating enzyme, ubiquitin-specific proteases 8 (USP8). Melatonin, however, upregulated USP8 expression, thus maintaining the stability of NICD and Notch signaling, which ultimately reduced EC injury in our sepsis model and elevated the survival rate of septic mice.Conclusions: We found a previously uncharacterized role of Notch1 in mediating vascular permeability during sepsis, and we showed that inhibition of NICD resulted in vascular EC dysfunction in sepsis, which was reversed by melatonin. Thus, the Notch1 signaling pathway is a potential target for the treatment of sepsis.

Background: Upregulation of lncRNA BBOX1 antisense RNA 1 (BBOX1-AS1) has been examined in various tumors. However, its role in nasopharyngeal carcinoma (NPC) remains poorly understood. Methods: RT-qPCR was performed to measure the expression of BBOX1-AS1, KPNA2, and miR-3940-3p. In vitro assays were performed to determine the alteration of cell phenotypes in NPC cells upon transfection or co-transfection with sh-BBOX1-AS1, sh-KPNA2, or miR-3940-3p inhibitor. The BBOX1-AS1–miR-3940-3p and miR-3940-3p-KPNA2 interplay was verified via luciferase reporter and RNA pull-down assays. Results: High BBOX1-AS1 levels were detected in the nasopharyngeal carcinoma tissues. BBOX1-AS1 silencing considerably suppressed the proliferative, migratory, and invasive abilities of NPC cells in vitro. Interestingly, BBOX1-AS1 could specifically bind to miR-3940-3 and abrogate the inhibition of KPNA2 induced by miR-3940-3. Additionally, analysis of tissue samples showed that miR-3940-3 was inversely correlated with BBOX1-AS1 and KPNA2. Conclusion: Our findings revealed that the BBOX1-AS1/miR-3940-3/KPNA2 axis is pro-oncogenic in NPC progression, uncovering novel insights into targeted therapy for this disorder.