No abstract

Acute kidney injury (AKI) is a common complication of sepsis characterized by a rapid degradation of renal function. The effect of vitamin D on AKI remains poorly understood. Here, we showed that vitamin D receptor (VDR) activation protects against lipopolysaccharide (LPS)-induced AKI by blocking renal tubular epithelial cell apoptosis. Mice lacking VDR developed more severe AKI than wild-type (WT) control mice after LPS treatment, which was manifested by marked increases in body weight loss and accumulation of serum blood urea nitrogen and creatinine as well as the magnitude of apoptosis of tubular epithelial cells. In the renal cortex, LPS treatment led to more dramatic downregulation of Bcl-2, more robust induction of p53-upregulated modulator of apoptosis (PUMA) and miR-155, and more severe caspase-3 activation in VDR knockout mice compared with WT control mice. Conversely, paricalcitol pretreatment markedly prevented LPS-induced AKI. Paricalcitol ameliorated body weight loss, attenuated serum blood urea nitrogen and creatinine accumulation, blocked tubular cell apoptosis, prevented the suppression of Bcl-2, and reversed PUMA and miR-155 induction and caspase-3 activation in LPS-treated WT mice. In HK2 cells, LPS induced PUMA and miR-155 by activating NF-κB, whereas 1,25(OH)2D3 blocked PUMA and miR-155 induction by repressing NF-κB activation. Both PUMA and miR-155 target Bcl-2 to promote apoptosis; namely, PUMA inhibits Bcl-2 activity, whereas miR-155 promotes Bcl-2 mRNA degradation and inhibits Bcl-2 protein translation. Collectively, these data provide strong evidence that LPS induces tubular cell apoptosis via upregulating PUMA and miR-155, whereas vitamin D/VDR signaling protects against AKI by blocking NF-κB-mediated PUMA and miR-155 upregulation.

Head and neck cancer has high heterogeneity with poor prognosis, and emerging researches have been focusing on the prognostic markers of head and neck cancer. PD-L1 expression is an important basis for strategies of immunosuppressive treatment, but whether it has prognostic value is still controversial. Although meta-analysis on PD-L1 expression versus head and neck cancer prognosis has been performed, the conclusions are controversial. Since PD-L1 and PD-L2 are two receptors for PD-1, here we summarize and analyze the different prognostic values of PD-1, PD-L1, and PD-L2 in head and neck cancer in the context of different cell types, tissue localization and protein forms. We propose that for head and neck cancer, the risk warning value of PD-1/PD-L1 expression in precancerous lesions is worthy of attention, and the prognostic value of PD-L1 expression at different subcellular levels as well as the judgment convenience of prognostic value of PD-1, PD-L1, PD-L2 should be fully considered. The PD-L1 evaluation systems established based on immune checkpoint inhibitors (ICIs) are not fully suitable for the evaluation of PD-L1 prognosis in head and neck cancer. It is necessary to establish a new PD-L1 evaluation system based on the prognosis for further explorations. The prognostic value of PD-L1, PD-L2 expression in head and neck cancer may be different for early-stage and late-stage samples, and further stratification is required.