ß-Glucan Combined With PD-1/PD-L1 Checkpoint Blockade for Immunotherapy in Patients With Advanced Cancer.

Programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) checkpoint blocking antibodies have been shown to be a powerful immune checkpoint blockade (ICB) therapy for patients with cancer. However, patients quickly develop resistance to immunotherapy. ß-glucan, an immune adjuvant, has been found to stimulate innate and adaptive immune responses. In this study, we assessed the use of whole glucan particle (WGP) ß-glucan in combination with PD-1/PD-L1-blocking antibodies to slow down the resistance to immunotherapy. Results from a tumor mouse model demonstrated that administration of WGP ß-glucan plus PD-1/PD-L1-blocking antibodies led to increased recruitment of immune-associated cells, improved regulation of the balance between T-cell activation and immune tolerance, and delayed tumor progression. This combination therapy was also found to improve progression-free survival in patients with advanced cancer who had previously discontinued anti-PD-1/PD-L1 because of disease progression. These findings suggest that ß-glucan could be used as an immune adjuvant to reverse anti-PD-1/PD-L1 resistance by regulating the immune system.

MicroRNA­1929­3p participates in murine cytomegalovirus­induced hypertensive vascular remodeling through Ednra/NLRP3 inflammasome activation.

MicroRNAs (miRNAs) play an important role in the development of vascular remodeling in essential hypertension (EH) by mediating the effects of human cytomegalovirus (HCMV) on the vascular system. Therefore, the aim of the present study was to investigate the effects of murine cytomegalovirus (MCMV) infection on blood pressure and vascular function in mice, in order to elucidate the role of miR­1929­3p in this process. For model development, 7­month­old C57BL/6J mice were infected with the Smith strain of MCMV, and MCMV DNA, IgG and IgM were detected. Subsequently, blood pressure was measured via the carotid artery, and the morphological changes of the aorta were evaluated by hematoxylin and eosin and Masson's trichrome staining. miR­1929­3p transfection was performed using an adeno­associated virus packaged vector and the changes in vascular structure were then observed. The levels of nitric oxide (NO) and endothelial NO synthase were also assessed with colorimetry. Vascular remodeling and expression of NLRP3 inflammasome pathway­related proteins were detected by immunohistochemistry and western blotting. Endothelin­1 (ET­1), interleukin (IL)­1ß and IL­18 were assayed by ELISA. The results revealed that MCMV infection increased the blood pressure, promoted vascular remodeling, caused endothelial cell injury, and downregulated miR­1929­3p. However, these effects were alleviated by miR­1929­3p overexpression, which downregulated endothelin A receptor (Ednra) and NLRP3 inflammasome, as well as endothelial injury­ and vascular remodeling­related genes. Taken together, the findings of the present study indicated that overexpression of miR­1929­3p may improve MCMV­induced vascular remodeling, possibly via the deactivation of the NLRP3 inflammasome by ET­1/Ednra.

Promotion of SIRT1 protein degradation and lower SIRT1 gene expression via reactive oxygen species is involved in Sb-induced apoptosis in BEAS-2b cells.

Antimony (Sb) has been reported to lead to pulmonary damage, but the underlying mechanism remains unclear. Accumulating evidence indicates that silent mating type information regulation 2 homolog 1 (SIRT1), an NAD+-dependent deacetylase, mediates stimuli-induced cellular apoptosis. Here, we investigated whether SIRT1 plays a role in Sb-triggered apoptosis in human bronchial epithelial cells (BEAS-2b). First, we showed that Sb initiated apoptosis. Furthermore, the expression of SIRT1 was markedly downregulated by Sb treatment, while overexpression of SIRT1 through resveratrol treatment or transfection with SIRT1-Flag plasmid attenuated the Sb-induced apoptosis. Accelerated degradation of SIRT1 protein and lower SIRT1 gene expression contributed to low expression of SIRT1. In addition, Sb activated the ERK and JNK pathways; however, inhibition of ERK rather than JNK rescued SIRT1 suppression. Subsequent analyses demonstrated that antioxidant N-acetylcysteine (NAC) attenuated SIRT1 repression, increased SIRT1 mRNA levels and decreased SIRT1 protein degradation in Sb-treated cells. In addition, NAC also inhibited JNK and ERK activation by Sb exposure. These data suggest that reactive oxygen species-dependent SIRT1 suppression mediates Sb-stimulated cell apoptosis in BEAS-2b cells via lower SIRT1 gene expression and protein stability.