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Total parenteral nutrition (TPN) dependence leads to development of intestinal failure-associated liver disease (IFALD). The spectrum of diseases ranges from cholestasis, steatosis, fibrosis, and cirrhosis that causes significant morbidity. Understanding the disease at molecular level helps us to develop therapeutic targets. We performed transcriptomic analysis on liver from rats with TPN administration, and we assessed the role of selected differentially expressed genes (DEGs), functional pathways, transcriptional factors, and their associations with pathological parameters of IFALD. Sprague-Dawley rats were subjected to TPN or standard chow with 0.9% saline for 7 days as controls. RNA-seq analysis was performed on liver samples. Correlations between transcriptional factor hairy and enhancer of split 6 (Hes6) and pathological parameters of IFALD were investigated. We provided a comprehensive transcriptomic analysis to identify DEGs and functional pathways in liver from TPN-fed rats. We identified solute carrier family 7 member 11 (Slc7a11) as the most up-regulated mRNA, and ferroptosis-associated pathways were enriched in TPN group. Transcriptional factor (TF) analysis revealed that Hes6 interacted with Nr1d1, Tfdp2, Zbtb20, and Hmgb2l1. TF target gene prediction analysis suggested that Hes6 may regulate genes associated with bile acid secretion and fatty acid metabolism. Last, hepatic Hes6 expression was significantly decreased in TPN-fed rats, and was positively correlated with several taurine-conjugated bile acids and negatively correlated with hepatic triglyceride level. RNA-seq analysis revealed unique transcriptomic signatures in the liver following TPN administration. Hes6 may be a critical regulator for IFALD pathogenesis. [ABSTRACT FROM AUTHOR]

Weifuchun capsule (WFC) is a traditional Chinese patent medicine for chronic atrophic gastritis (CAG) in clinic. However, the mechanism of action of WFC for CAG still remains unclear due to its complex composition. The study was projected to uncover the mechanism of action of WFC and the corresponding pharmacodynamic substance of WFC against CAG as well as providing a standard example for the research of traditional Chinese medicine (TCM) from the perspective of the network and the system. We identified the compounds of WFC through LC-MS/MS analysis and performed a systematic network targets analysis for WFC in the treatment of CAG which thoroughly described the mechanism of action of WFC for CAG. Based on analysis integrating omics data and algorithms, we focused on the specific immune regulatory role of WFC in the treatment of CAG, especially on a hub pathway, Toll-like receptor signaling pathway and thus deciphered the role of WFC in immune regulation, anti-inflammation and mediation of HES6. In experiments part, MNNG-GES-1-cell line and rat models were used to validate our findings. In this study, compounds of WFC are identified through LC‒MS/MS and network target analysis is performed to dissect the specific immunoregulatory effect as well as mediation of HES6, a newly discovered biomolecule related to gastritis carcinoma progression, of WFC on CAG through the Toll-like receptor signaling pathway. Based on cell line and rat models, we verify the mechanism of action of WFC for CAG in inhibiting inflammatory cytokines, regulating immune cells like T cells and macrophages, related genes including TLR2 and CD14. It is also validated that WFC inhibits the expression of HES6 (P < 0.05). Based on the combination of computational strategy and experiments, our study offers a comprehensive analysis to reveal the role of WFC in regulating immune response, inhibiting inflammation in the treatment of CAG, and provides a standard example for the research of TCM from the perspective of the network and the system. [Display omitted] • Weifuchun capsule regulated immune response and inhibited inflammation in the treatment of chronic atrophic gastritis. • Network target analysis explored the potential effect of Weifuchun capsule, especially on Toll-like receptor pathway. • Experiments were conducted to validate the effect of Weifuchun capsule on immune cells and inflammatory cytokines. [ABSTRACT FROM AUTHOR]

Abstract: Hes6 is a member of hairy/enhancer of split (Hes) family that plays a role in the cell proliferation and differentiation. Recently, we found that Hes6 is involved in the regulation of cell proliferation via p53-dependent pathway. In addition to the proliferating regions, brain regions where early post-mitotic neurons are enriched also exhibited Hes6 and p53 mRNA expression. Because p53 is involved in the post-mitotic neuronal apoptosis, here we investigated whether Hes6 can influence the neuronal survival/death. Overexpression of wild-type Hes6 and its mutants induced the apoptosis of primary cultured cortical neurons. In addition, neuronal apoptosis by Hes6 overexpression was markedly blunted in p53−/− or Bax−/− cortical neurons, suggesting that these pro-apoptotic effects are mediated by p53- and Bax-dependent pathway. However, transactivation-defective mutants of Hes6 also enhanced neuronal apoptosis, suggesting that apoptogenic activity of Hes6 is not directly related to its role in the transcriptional regulation. We propose that Hes6 may play a significant role in the neuronal cell death and/or pathological neurodegeneration via activation of p53 signaling. [Copyright &y& Elsevier]