An Integrative Pan-Cancer Analysis Revealing MLN4924 (Pevonedistat) as a Potential Therapeutic Agent Targeting Skp2 in YAP-Driven Cancers.

Background: YAP, coded by YAP1 gene, is critical in the Hippo pathway. It has been reported to be involved in the tumorigenesis and progression of several cancers. However, its roles on tumor cell proliferation in diverse cancers remain to be elucidated. And there is currently no clinically feasible drug that can directly target YAP in cancers. This research aimed to explore the regulatory mechanism of YAP in promoting tumor proliferation of multiple cancers, in order to find new strategies for inhibiting the overgrowth of YAP-driven cancers. Methods: We investigated the expression pattern of YAP1 in pan-cancer across numerous databases and our cohorts. First, univariate Cox regression analysis and survival analysis were used to evaluate the effect of YAP1 on the prognosis of cancer patients. Second, TIMER was used to explore the relationship between YAP1 expression and tumor cell proliferation. Third, functional and pathway enrichment was performed to search for targets of YAP involved in cell cycle in cancers. At last, GDSC and CCLE datasets were used to assess the correlation between SKP2 expression and MLN4924 IC50 values. Results: Differential expression analysis of multiple databases and qPCR validation showed that YAP1 was generally overexpressed in pan-cancers. Survival analysis revealed that YAP1 over-expression was significantly related to poor prognosis of patients with PAAD. The expression level of YAP1 was positively correlated with the proliferation in varieties of tumors. Further, SKP2 was confirmed as a target of YAP in promoting tumor cell proliferation. In addition, SKP2 expression was negatively correlated with MLN4924 IC50 values in almost all cancer types. Conclusion: YAP1 is frequently overexpressed in human cancers. YAP promoted tumor cell proliferation by up-regulating SKP2 expression in multiple cancers. The comprehensive pan-cancer analysis suggested that inhibition of Skp2 with MLN4924 might be an effective therapeutic strategy for attenuating tumor cell proliferation in YAP-driven cancers.

Shenlian (SL) Decoction, a Traditional Chinese Medicine Compound, May Ameliorate Blood Glucose via Mediating the Gut Microbiota in db/db Mice.

Shenlian (SL) decoction is a herbal formula composed of Coptis and ginseng, of which berberine and ginsenoside are the main constituents. Even though SL decoction is widely used in treating diabetes in China, the mechanism of its antidiabetes function still needs further study. Gut microbiota disorder is one of the important factors that cause diabetes. To explore the effect of SL decoction on intestinal microbiota, gut microbiota of mice was analyzed by sequencing the gut bacterial 16S rRNA V3+V4 region and metagenomics. In this study, results demonstrated that SL decoction had a better hypoglycemic effect and ß cell protection effect than either ginseng or Coptis chinensis. Alpha diversity analysis showed that all interventions with ginseng, Coptis, and SL decoction could reverse the increased diversity and richness of gut microbiota in db/db mice. PCoA analysis showed oral SL decoction significantly alters gut microbiota composition in db/db mice. 395 OTUs showed significant differences after SL treatment, of which 37 OTUs enriched by SL decoction showed a significant negative correlation with FBG, and 204 OTUs decreased by SL decoction showed a significant positive correlation with FBG. Results of KEGG analysis and metagenomic sequencing showed that SL decoction could reduce the Prevotellaceae, Rikenellaceae, and Helicobacteraceae, which were related to lipopolysaccharide biosynthesis, riboflavin metabolism, and peroxisome, respectively. It could also upregulate the abundance of Bacteroidaceae, which contributed to the metabolism of starch and sucrose as well as pentose-glucuronate interconversions. In the species level, SL decoction significantly upregulates the relative abundance of Bacteroides_acidifaciens which showed a significant negative correlation with FBG and was reported to be a potential agent for modulating metabolic disorders such as diabetes and obesity. In conclusion, SL decoction was effective in hypoglycemia and its mechanism may be related to regulating gut microbiota via upregulating Bacteroides_acidifaciens.

Antiviral Activity of Plantago asiatica Polysaccharide against Pseudorabies Virus In Vitro.

Pseudorabies (PR) is an acute infectious disease of various domestic animals and wild animals caused by pseudorabies virus (PRV). It is mainly characterized by fever, itching, encephalomyelitis, and respiratory and neurological disorders. Plantago asiatica polysaccharide (PLP), extracted from the whole plant of Plantago asiatica L., showed immunomodulatory and antioxidation effects, but the antiviral activity had not been reported. In this study, the inhibitory effect of PLP on PRV infection was studied. Our study first revealed that PLP could inhibit PRV infection in a dose-dependent manner. By adding PLP at different stages of the virus's life cycle, we revealed that PLP could reduce the attachment and penetration of PRV into PK15 cells. The inhibition of PRV attachment was better than inhibition of PRV penetration. However, PLP did not affect PRV replication and inactivation. In addition, PLP decreased the intracellular ROS levels in infected cells significantly, and ROS scavenger NAC decreased PRV infection. Therefore, our study provided preliminary data of anti-PRV activity of PLP, which was established to be a novel anti-PRV infection agent.