Dihydroartemisinin increased the abundance of Akkermansia muciniphila by YAP1 depression that sensitizes hepatocellular carcinoma to anti-PD-1 immunotherapy / 医学前沿

The effect of anti-programmed cell death 1 (anti-PD-1) immunotherapy is limited in patients with hepatocellular carcinoma (HCC). Yes-associated protein 1 (YAP1) expression increased in liver tumor cells in early HCC, and Akkermansia muciniphila abundance decreased in the colon. The response to anti-PD-1 treatment is associated with A. muciniphila abundance in many tumors. However, the interaction between A. muciniphila abundance and YAP1 expression remains unclear in HCC. Here, anti-PD-1 treatment decreased A. muciniphila abundance in the colon, but increased YAP1 expression in the tumor cells by mice with liver tumors in situ. Mechanistically, hepatocyte-specific Yap1 knockout (Yap1LKO) maintained bile acid homeostasis in the liver, resulting in an increased abundance of A. muciniphila in the colon. Yap1 knockout enhanced anti-PD-1 efficacy. Therefore, YAP1 inhibition is a potential target for increasing A. muciniphila abundance to promote anti-PD-1 efficacy in liver tumors. Dihydroartemisinin (DHA), acting as YAP1 inhibitor, increased A. muciniphila abundance to sensitize anti-PD-1 therapy. A. muciniphila by gavage increased the number and activation of CD8+ T cells in liver tumor niches during DHA treatment or combination with anti-PD-1. Our findings suggested that the combination anti-PD-1 with DHA is an effective strategy for liver tumor treatment.

Effect of revolvin D1 on TLR4 in skeletal muscle of type 2 diabetic mice / 中国医师杂志

Objective To observe the effect of supplemental Revolvin D1 (RvD1) on Toll-like receptor 4 (TLR4) in skeletal muscle of type 2 diabetic mice.Methods 35 male C57BL/6 mice were randomly divided into control group (NC group) and high glucose and high fat diet group.After 8 weeks,mice in high glucose and high fat diet group were given intraperitoneal injection of streptozotocin (STZ) 100 mg/ kg.Then they were randomly divided into two groups:Type 2 diabetes group (T2DM group) and type 2 diabetes + RvD1 intervention group (T2DM + RvD1 group).Mice in T2DM group mice were injected with phosphate buffer saline 0.2 ml and T2DM + RvD1 group mice were injected with Revolvin D1 100 ng/day respectively.The levels of fasting blood glucose,serum insulin and inflammatory factors were detected.The mRNA expression level of TLR4 was detected by real-time quantitative polymerase chain reaction (RT-qPCR) method,and the expression of TLR4 protein was detected by Western blot.Results The levels of insulin resistance index,interleukin(IL)-6 and tumor necrosis factor-α (TNF-α) in T2DM group and T2DM + RvD1 group increased (P ＜ 0.05).Compared with the T2DM group,the levels of insulin resistance index,IL-6 and TNF-α in T2DM + RvD1 group decreased (P ＜0.05).The expression of TLR4 protein in T2DM group and T2DM + RvD1 group was higher than that in NC group (P ＜ 0.05).The expression of TLR4 protein in T2DM + RvD1 group,was lower than that in T2DM group (P ＜0.05).The mRNA level of TLR4 in mice was consistent with the above results by RT-qPCR.Conclusions Moderate supplementation of RvD1 can not only decrease the level of inflammatory factors in type 2 diabetic mice,but also reduce the expression of TLR4 and insulin resistance in skeletal muscle of type 2 diabetic mice.