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.
Highlights
Acetaminophen (APAP) is a common analgesic and antipyretic drug
Urea cycle inhibition with H3B-120 increased ALT and AST levels and eliminated the protective effects of B. vulgatus (Figures 6(m) and 6(n)). These results indicated that B. vulgatus enrichment by OD attenuated Acetaminophen acute liver failure (ALF) (APAP) hepatotoxicity through the urea cycle-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway
OD exerts anti-inflammatory and antiapoptotic effects on liver injury, there is no direct evidence supporting the notion that OD protects against APAP hepatotoxicity, and any underlying mechanism that might enable such protective activity has yet to be proposed, all of which limits its clinical application [15]
Summary
An APAP overdose can lead to severe hepatotoxicity, acute liver failure (ALF), and death [1]. APAP is predominantly metabolized via sulfation and glucuronidation in the liver. A small amount of the drug is metabolized by cytochrome P450 enzymes into N-acetyl-p-benzoquinoneimine (NAPQI), which is mainly detoxified by glutathione (GSH) [2, 3]. An overdose of APAP results in excess NAPQI, which exhausts hepatic GSH, leading to mitochondrial dysfunction and damage, and thereby hepatocyte necrosis and ALF [4, 5]. Urea cycle-related amino acids arginineornithine homeostasis plays a crucial role for liver injury by adaptive immune response regulation [9]. It was necessary to assess the influence of the urea cycle on APAP-induced liver injury
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
