ABSTRACT
Acetaminophen (APAP) hepatotoxicity is the leading cause of acute liver failure in the western world. Oridonin (OD), which is the major active ingredient of the traditional Chinese medicine Rabdosia rubescens, reportedly exerts anti-inflammatory and antioxidative effects. Here, we first find that OD protects against APAP-induced hepatotoxicity. The results of hepatic tissue-associated RNA-seq and metabolomics showed that the protective effects of OD were dependent upon urea cycle regulation. And such regulation of OD is gut microbiota partly dependent, as demonstrated by fecal microbiota transplantation (FMT). Furthermore, using 16S rRNA sequencing, we determined that OD significantly enriched intestinal Bacteroides vulgatus, which activated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway to regulate redox homeostasis against APAP by urea cycle. In conclusion, our study suggests that the Bacteroides vulgatus-urea cycle-Nrf2 axis may be a potential target for reducing APAP-induced liver injury, which is altered by OD.
Subject(s)
Bacteroides/drug effects , Chemical and Drug Induced Liver Injury/prevention & control , Diterpenes, Kaurane/pharmacology , Gastrointestinal Microbiome/drug effects , Liver/drug effects , Urea/metabolism , Acetaminophen , Animals , Bacteroides/genetics , Bacteroides/metabolism , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/microbiology , Chemical and Drug Induced Liver Injury/pathology , Disease Models, Animal , Dysbiosis , Fecal Microbiota Transplantation , Liver/metabolism , Male , Metabolome , Mice, Inbred C57BL , Mice, Knockout , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolismABSTRACT
OBJECTIVE: To clarify the mechanism by which interleukin?22 (IL?22) promotes the proliferation of fibroblast?like synoviocytes (FLS) from patients with rheumatoid arthritis (RA). METHODS: FLS were isolated from the synovial tissues of patients with RA and identified by immunohistochemistry for vimentin/CD68. The cells were subcultured and incubated with different concentrations of IL?22 for 24, 48, or 72 h, and their proliferation was examined using MTT assay. After treatment of the cells with IL?22 and AG490, alone or in combination, the expressions of the total and phosphorylated proteins of STAT3, ERK1/2 and P38 were detected with Western blotting. RESULTS: IL?22 significantly increased the proliferation of FLS in a dose?dependent manner (P<0.05). The total protein of STAT3 in the cells showed no significant changes with extended time of IL?22 treatment (P=0.68), but the expression of phosphorylated STAT3 protein increased significantly (P<0.001). The total and phosphorylated proteins of ERK1/2 and P38 underwent no significant changes after IL?22 treatment (P>0.05). A combined treatment with 50 ng/mL IL?22 and 100 µmol/L AG490 resulted in a significant decrease in the proliferation of FLS as compared with IL?22 treatment alone (P<0.01). CONCLUSION: IL?22 can dose?dependently promote the proliferation of FLS from patients with RA by inducing phosphorylation of STAT3 protein but not through ERK1/2 or P38 signal pathway.
