PurposeNatural triterpenoid saponins isolated from Anemone flaccida Fr. Schmidt have exhibited anti-cancer properties and exerted remarkable inhibitory effects on tumor growth. Herein, we investigated the potential mechanism involved in the suppression of hepatocellular carcinoma (HCC) development by triterpenoid saponins in a mouse model.MethodsAn HCC model was established in H22 tumor-bearing mice and triterpenoid saponins were administered at various doses. Immunofluorescence, flow cytometry, and western blot were performed to analyze the effect of triterpenoid saponins on immune response in tumor tissues. Metabolomic analysis was carried out to assess the metabolites involved in mediating the effect of triterpenoid saponins on tumor tissues.ResultsTriterpenoid saponins induced anti-tumor immune response by decreasing the number of Treg cells, increasing that of B cells, natural killer cells, and CD3+/CD28+ T cells, and reducing the secretion of inflammatory factors including nuclear factor-κB, cyclooxygenase-2, and microsomal prostaglandin E synthase-1. In addition, triterpenoid saponins inhibited tumor growth and induced the apoptosis of HCC cells by blocking the activation of PD1/PD-L1, ERK1/2, p38 MAPK, JNK, and STAT3 signaling pathways. Furthermore, triterpenoid saponins regulated tumor immune response by upregulating a number of metabolites (including 1,3-diaminopropane, lauric acid, 2,4-diaminobutyric acid 2, and ribitol) and modulating the metabolism of histidine, arginine, proline, beta-alanine, glycine, serine, and threonine.ConclusionThe findings suggested that triterpenoid saponins interfered with multiple signaling cascades involved in tumorigenesis and tumor metabolism and have potential applications in HCC therapy.
Asarum is frequently applied in combination with other agents for prescriptions in practices of Traditional Chinese Medicine. A number of studies have previously indicated that asarum treatment induces lung toxicity by triggering inflammation. However, the potential effects of asarum in the liver and the underlying mechanisms have remained largely elusive. Therefore, transcriptomics and metabolomics approaches were used in the present study to examine the mechanisms of the hepatotoxicity of asarum. Specifically, mRNA and metabolites were obtained from rat liver samples following intragastric administration of asarum powder. RNA sequencing analysis was subsequently performed to screen for differentially expressed genes (DEGs), and a total of 434 DEGs were identified in liver tissue samples, 214 of which were upregulated and 220 were downregulated. Pathway enrichment analysis found that these genes were particularly enriched in processes including the regulation of p53 signaling, metabolic pathways and bile secretion. To investigate potential changes to the metabolic profile as a result of asarum treatment, a metabolomics analysis was performed, which detected 14 significantly altered metabolites in rat liver samples by gas chromatography-mass spectrometry. These metabolites were predominantly members of the taurine, hypotaurine and amino acid metabolic pathways. Metscape network analyses were subsequently performed to integrate the transcriptomics and metabolomics data. Integrative analyis revealed that the DEGs and metabolites were primarily associated with bile acid biosynthesis, amino acid metabolism and the p53 signaling pathway. Taken together, these results provide novel insight into the mechanism of asarum-mediated hepatotoxicity, which may potentially aid the clinical diagnosis and future therapeutic intervention of asarum poisoning.
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