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Target identification of hepatic fibrosis using Pien Tze Huang based on mRNA and lncRNA.

ABSTRACT: Hepatic fibrosis is a spontaneous wound-healing response triggered by chronic liver injury. Pien Tze Huang (PZH), a traditional Chinese herbal medicine, has been widely used to treat various hepatic diseases in Asia. We used a CCl₄-induced mouse model to establish a PZH group of hepatic fibrosis mice treated with PZH and a control group of hepatic fibrosis mice without any treatment. We performed RNA-seq and mass spectrometry sequencing to investigate the mechanism of the PZH response in hepatic fibrosis and identified multiple differentially expressed transcripts (DETs) and proteins (DEPs) that may be drug targets of PZH. Liver functional indices, including serum albumin (ALB), alanine aminotransferase (ALT) and aspartate aminotransferase (AST), were significantly decreased in the PZH treatment group (P < 0.05) in the eighth week. Hematoxylin-eosin (HE), Masson and Sirius red staining demonstrated that PZH significantly inhibited infiltration of inflammatory cells and collagen deposition. A total of 928 transcripts and 138 proteins were differentially expressed in PZH-treated mice compared to the control group. Gene Ontology (GO) enrichment analysis suggested that PZH may alleviate liver injury and fibrosis by enhancing the immune process. Taken together, our results revealed that multiple DETs and DEPs may serve as drug targets of PZH in hepatic fibrosis patient in future clinical practice.

SUBMITTER: Zhu J

PROVIDER: S-EPMC8379174 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Pien Tze Huang (PZH), a common hepatoprotective Traditional Chinese Medicine that has been found to be an effective treatment for carbon tetrachloride‑induced hepatic damage, including liver fibrosis. Circular RNAs (circRNAs) serve a crucial role in regulating gene expression levels via circRNA/micro (mi)RNA/mRNA networks in several human diseases and biological processes. However, whether circRNAs are involved in the underlying mechanism of the therapeutic effects of PZH on liver fibrosis remains unclear. Therefore, the aim of the present study was to investigate these effects using circRNA expression profiles from PZH‑treated fibrotic livers in model mice. A case‑control study on >59,476 circRNAs from CCl4‑induced (control group, n=6) and PZH‑treated (case group, n=6) mice was performed using circRNA sequencing in liver tissues. PZH treatment resulted in the differential expression of 91 circRNAs, including 58 upregulated and 33 downregulated circRNAs. Furthermore, the construction of competing endogenous networks also indicated that differentially expressed circRNAs acted as miRNA sponges. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of miRNA targets demonstrated that PZH‑affected circRNAs were mainly involved in biological processes such as 'positive regulation of fibroblast proliferation', 'cellular response to interleukin‑1' and 'regulation of DNA‑templated transcription in response to stress' and in a number of important pathways, such as 'TNF signaling pathway', 'PI3K‑Akt signaling pathway', 'IL‑17 signaling pathway' and 'MAPK signaling pathway'. To further validate the bioinformatics data, reverse transcription‑-quantitative PCR was performed on seven miRNA targets in a human hepatic stellate LX‑2 cell model. The results suggested that seven of the miRNAs exhibited regulatory patterns that were consistent with those of the transcriptome sequencing results. Kaplan‑Meier survival analysis demonstrated that the expression levels of dihydrodiol dehydrogenase and solute carrier family 7, member 11 gene were significantly associated with patient survival, 269 patients with liver hepatocellular carcinoma from The Cancer Genome Atlas database. To the best of our knowledge, this was the first study to provide evidence that PZH affects circRNA expression levels, which may serve important roles in PZH‑treated fibrotic liver through the regulation of functional gene expression. In conclusion, the present study provided new insights into the mechanism underlying the pathogenesis of liver fibrosis and identified potential novel, efficient, therapeutic targets against liver injury.

Project description:The Chinese medicine formula Pien Tze Huang (PZH) has been applied to the treatment of various diseases, the reported anti-tumor mechanisms included regulation of inflammation-associated cytokine secretion and cancer growth pathways. However, the potential influence of PZH on tumor metabolism remains unclear. This study aimed to investigate the global effect of PZH on hepatocellular carcinoma (HCC) compared with the anti-tumor agent sorafenib based on tandem mass tag (TMT) label proteomic and phosphoproteomic analysis in addition to parallel reaction monitoring (PRM) verification. It was observed that PZH could inhibit tumor weight by 59-69% in different concentrations. TMT proteomic studies indicated that fructose/mannose metabolism and glucagon signaling pathway in PZH group, and arachidonic acid metabolism and PPAR signaling pathway in sorafenib group, were significantly enriched, while glycolysis/gluconeogenesis pathway was found to be enriched remarkably both in PZH and sorafenib groups in TMT phosphoproteomic study. PRM verification further indicated that both PZH and sorafenib could down-regulate phosphorylations of the glycolytic enzymes phosphofructokinases 1, fructose-bisphosphate Aldolase A, phosphoglycerate mutase 2 and lactate dehydrogenase A chain, while phosphorylations of long chain fatty acid CoA ligase in fatty acid activation and acetyl-coenzyme A synthetase in glycolysis were significantly inhibited by PZH and sorafenib, respectively. This study proposed that PZH shared a similar anti-tumor mechanism of metabolic regulation to sorafenib, but differed in the regulation of some metabolic nodes. This is the first time to uncover the relationship between the anti-tumor effect of PZH and metabolic related enzymes, which distinguished from the known mechanisms of PZH. These data provided the potential molecular basis for PZH acting as a therapeutic drug for HCC, and offered cues of manipulation on Warburg effect under the treatment of PZH.

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Target identification of hepatic fibrosis using Pien Tze Huang based on mRNA and lncRNA.

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