Abstract
Saikosaponin d (SSd) is a major hepatoprotective component of saikosaponins derived from Radix Bupleuri, which was also linked to hepatotoxicity. Previous studies have demonstrated that caspases play a key role in SSd-induced liver cell death. Our in vitro and in vivo studies also showed that treatment with caspase inhibitor z-VAD-fmk could significantly reduce the L02 hepatocyte cells death and lessen the degree of liver damage in mice caused by SSd. In order to further reveal the underlying mechanisms of caspase inhibition in SSd-induced hepatotoxicity, mass spectrometry based untargeted metabolomics was conducted. Significant alterations in metabolic profiling were observed in SSd-treated group, which could be restored by caspase inhibition. Bile acids and phospholipids were screened out to be most significant by spearman correlation analysis, heatmap analysis and S-Plot analysis. These findings were further confirmed by absolute quantitation of bile acids via targeted metabolomics approach. Furthermore, cytokine profiles were analyzed to identify potential associations between inflammation and metabolites. The study could provide deeper insight into the hepatotoxicity of SSd and the efficacy of caspase inhibition.
Highlights
Radix Bupleuri, one of the famous crude drugs in the prescriptions of traditional Chinese medicines, has been used in China for over 2000 years (Yu et al, 2017)
Our preliminary studies have showed that caspase-1 contributed to the hepatocyte cells death induced by SSd, which could be effectively alleviated by the caspase inhibitor z-VAD-fmk
hematoxylin and eosin (HE) stained liver sections revealed that several pathological damages were observed after SSd-treatment, including hepatocellular necrosis, inflammatory cell infiltration compared with normal liver of control group (Supplementary Figure S2)
Summary
Radix Bupleuri, one of the famous crude drugs in the prescriptions of traditional Chinese medicines, has been used in China for over 2000 years (Yu et al, 2017). It has been increasingly reported liver injury in clinical context along with wide usage of R. Bupleuri that could cause liver injury (Chen et al, 2013; Zhang F. et al, 2016; Yuan et al, 2017). Zhang et al and Li et al found that SSd could cause liver injury and hepatocyte death in animal experiments
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