Protective Role of Vitamin K3 on SARS-CoV-2 Structural Protein-Induced Inflammation and Cell Death.

The structure proteins of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), such as nucleocapsid protein (N protein) and envelop protein (E protein), are considered to be the critical pro-inflammatory factors in coronavirus disease 2019 (COVID-19). Vitamin K3 has been reported to exert an anti-inflammatory effect. In this study, we investigated the protective effects of vitamin K3 on SARS-CoV-2 N protein induced-endothelial activation and SARS-CoV-2 E protein induced-cell death in THP-1 cells. The results showed that vitamin K3 reduced N protein-induced monocyte adhesion, suppressed the expression of adhesion molecules, and decreased the mRNA levels of pro-inflammatory cytokines in HLMECs. We confirmed that the effects of vitamin K3 on endothelial activation may be related to the inhibition of the NF-κB signal pathway. In addition, vitamin K3 reversed E protein-induced pyroptosis, inhibited NLRP3/GSDMD signal pathway and reduced the mRNA expression of pro-inflammatory cytokines in THP-1 cells. Our results also showed the protective effects of vitamin K3 on the SARS-CoV-2 structural protein-induced THP-1 cells pyroptosis and endothelial activation via NF-κB signaling pathway. These findings suggested that vitamin K3 potently suppressed the inflammatory response to prevent endothelial activation and monocyte pyroptosis induced by SARS-CoV-2 proteins. This may provide a new strategy for the treatment of COVID-19.

The Protein Kinase R Inhibitor C16 Alleviates Sepsis-Induced Acute Kidney Injury Through Modulation of the NF-κB and NLR Family Pyrin Domain-Containing 3 (NLPR3) Pyroptosis Signal Pathways.

BACKGROUND Protein kinase R (PKR) is implicated in the inflammatory response to bacterial infection while the role of PKR in sepsis-induced acute kidney injury (AKI) is largely unknown. This study aimed to investigate the effects of the specific PKR inhibitor C16 (C13H8N4OS) on lipopolysaccharide (LPS)-induced AKI, and its mechanisms of action. MATERIAL AND METHODS C57BL/6J mice were injected intraperitoneally with C16 or vehicle 1 h before the LPS challenge and then injected intraperitoneally with LPS or 0.9% saline. After the LPS challenge, histopathological damage, renal function, and levels of proinflammatory cytokines were assessed. All the related signaling pathways were analyzed. RESULTS C16 effectively inhibited LPS-induced renal elevation of proinflammatory cytokines and chemokines. C16 prevented NF-kappaB activation and suppressed the PKR/eIF2alpha signaling pathway in AKI after the LPS challenge. Furthermore, C16 significantly inhibited pyroptosis during AKI, as evidenced by decreased renal levels of apoptosis-associated speck-like protein; NACHT, LRR, NLR Family Pyrin Domain-Containing 3; caspase-1; interleukin (IL)-1ß; and IL-18. CONCLUSIONS Our findings suggest that inhibition by C16 ameliorated LPS-induced renal inflammation and injury, at least partly through modulation of the pyroptosis signal pathway in the kidney.

Irinotecan combined with co-stimulatory molecule blockade prolongs survival of cardiac allografts in alloantigen-primed mice.

Memory T cells play an important role in graft rejection. In this study, we investigated the potential effect of Irinotecan (CPT-11), a topoisomerase I inhibitor used in the treatment of a variety of solid tumor malignancies, on memory T cells. CPT-11 treatment alone or combined with blocking monoclonal antibodies (mAb) against co-stimulatory molecules (LFA-1 and CD154) was evaluated in the prevention of heart transplant rejection in alloantigen-primed mice. Our data suggest that CPT-11 reduced the expression of IL-2/IFN-γ and increased IL-10/TGF-ß expression in both peripheral blood and within the grafts. CPT-11 could also inhibit alloresponses of memory T cells, while decreasing the proportion of CD4(+) memory T cells in the spleen of the recipients and significantly reducing serum alloantibody levels. Our study highlights obvious synergistic effects of CPT-11 when combined with co-stimulatory molecule blockade in prolonging the survival of cardiac allografts in alloantigen-primed mice.