miR-194-5p down-regulates tumor cell PD-L1 expression and promotes anti-tumor immunity in pancreatic cancer.

Pancreatic cancer is a highly malignant cancer of the digestive tract. Studies have shown that in some types of cancer, a high level of microRNA-194-5p (miR-194-5p) is beneficial for controlling tumor progression, while in other cancers it plays a completely opposite role. However, how miR-194-5p affects anti-tumor immunity of pancreatic cancer remains unclear. In this study, we found that high expression of miR-194-5p in human pancreatic cancer patients is associated with a better survival rate, while increased expression of programmed cell death ligand 1 (PD-L1) in human pancreatic cancer patients is associated with a worse survival rate. In pancreatic cancer, the expression level of PD-L1 is negatively correlated with the expression level of miR-194-5p, and we identified that PD-L1 was target gene of miR-194-5p. In addition, we found that overexpression of miR-194-5p inhibited the migration, invasion and proliferation of pancreatic cancer cells in vitro. The orthotopic mouse model of pancreatic cancer shown that miR-194-5p suppressed the progression of pancreatic cancer, promoted the infiltration of CD8+ T cells in tumor immune microenvironments, and enhanced the IFN-γ production of CD8+ T cells. Consistently, the co-culture experiments showed that overexpression of miR-194-5p in tumor cell enhanced IFN-γ production by CD8+ T cells. In conclusion, miR-194-5p may serve as a novel immunotherapeutic target for pancreatic ductal adenocarcinoma (PDAC) by inhibiting the expression of PD-L1, and play important roles in inhibiting the progression of pancreatic cancer and boosting the anti-tumor effect of CD8+ T cells.

Pin1 Promotes NLRP3 Inflammasome Activation by Phosphorylation of p38 MAPK Pathway in Septic Shock.

Pin1 is the only known peptidyl-prolyl cis-trans isomerase (PPIase) that can specifically recognize and isomerize the phosphorylated Serine/Threonine-Proline (pSer/Thr-Pro) motif, change the conformation of proteins through protein phosphorylation, thus regulate various cellular processes in the body. Pin1 plays an important role in cancer, Alzheimer's disease, and autoimmune diseases. However, the specific mechanism of Pin1 regulation in LPS-induced septic shock is unclear. Here, we found that lack of Pin1 reduced shock mortality and organ damage in mice, and NLRP3 inflammasome activation also was reduced in this process. We further confirmed that Pin1 can affect the expression of NLRP3, ASC, Caspase1, and this process can be regulated through the p38 MAPK pathway. We analyzed that p38 MAPK signaling pathway was highly expressed in septic shock and showed a positive correlation with Pin1 in the Gene Expression Omnibus database. We found that Pin1 could affect the phosphorylation of p38 MAPK, have no obvious difference in extracellular signal-regulated kinases (ERK) and Jun-amino-terminal kinase (JNK) signaling. We further found that Pin1 and p-p38 MAPK interacted, but not directly. In addition, Pin1 deficiency inhibited the cleavage of gasdermin D (GSDMD) and promoted the death of macrophages with LPS treatment, and reduced secretion of inflammatory cytokines including IL-1ß and IL-18. In general, our results suggest that Pin1 regulates the NLRP3 inflammasome activation by p38 MAPK signaling pathway in macrophages. Thus, Pin1 may be a potential target for the treatment of inflammatory diseases such as septic shock.

Arctigenin protects mice from thioglycollate-induced acute peritonitis.

Acute peritonitis is an acute inflammatory response of the peritoneal cavity to physical injury and chemical stimulation. Timely resolution of this response is critical to prevent further damage to the body, which can eventually lead to more severe chronic inflammation. Arctigenin (ATG) is the main active ingredient of the Chinese medicine Arctium lappa. In recent years, there have been an increasing number of studies on the anti-inflammatory effect of ATG, but there have been few studies on the effect of ATG on acute inflammation, especially in acute peritonitis, which has not been reported. In this study, a mouse model of experimental acute peritonitis induced by thioglycolate (TG) solution was used to study the protective anti-inflammatory effect of ATG against acute peritonitis and the relevant mechanism. Our results showed that, after 12 hours of TG treatment, ATG significantly reduced inflammatory cell infiltration in mouse tissues and inhibited the secretion and expression of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in mice. ATG significantly reduced the percentage of CD11b+ Ly6G+ neutrophils and F4/80+ macrophages in the spleen and peritoneal exudate. In addition, ATG significantly inhibited the expression of the chemokines CCL3 and CCL4 and the adhesion molecule CD62L on the surface of CD11b-positive monocytes. ATG was observed to inhibit the phosphorylation of p65 and p38 in LPS-stimulated RAW264.7 cells. In conclusion, ATG can improve the symptoms of TG-induced acute peritonitis through immune regulation. ATG can reduce the inflammatory response in TG-induced acute peritonitis in mice.