Background: Drug-induced liver injury (DILI) is gradually becoming a common global problem that causes acute liver failure, especially in acute hepatic damage caused by acetaminophen (APAP). Paeoniflorin (PF) has a wide range of therapeutic effects to alleviate a variety of hepatic diseases. However, the relationship between them is still poorly investigated in current studies. Purpose: This work aimed to explore the protective effects of PF on APAP-induced hepatic damage and researched the potential molecular mechanisms. Methods: C57BL/6J male mice were injected with APAP to establish DILI model and were given PF for five consecutive days for treatment. Aiming to clarify the pharmacological effects, the molecular mechanisms of PF in APAP-induced DILI was elucidated by high-throughput and other techniques. Results: The results demonstrated that serum levels of ALP, γ-GT, AST, TBIL, and ALT were decreased in APAP mice by the preventive effects of PF. Moreover, PF notably alleviated hepatic tissue inflammation and edema. Meanwhile, the results of TUNEL staining and related apoptotic factors coincided with the results of transcriptomics, suggesting that PF inhibited hepatocyte apoptosis by regulated MAPK signaling. Besides, PF also acted on reactive oxygen species (ROS) to regulate the oxidative stress for recovery the damaged mitochondria. More importantly, transmission electron microscopy showed the generation of autophagosomes after PF treatment, and PF was also downregulated mTOR and upregulated the expression of autophagy markers such as ATG5, ATG7, and BECN1 at the mRNA level and LC3, p62, ATG5, and ATG7 at the protein level, implying that the process by which PF exerted its effects was accompanied by the occurrence of autophagy. In addition, combinined with molecular dynamics simulations and western blotting of MAPK, the results suggested p38 as a direct target for PF on APAP. Specifically, PF-activated autophagy through the downregulation of MAPK/mTOR signaling, which in turn reduced APAP injury. Conclusions: Paeoniflorin mitigated liver injury by activating autophagy to suppress oxidative stress and apoptosis via the MAPK/mTOR signaling pathway. Taken together, our findings elucidate the role and mechanism of paeoniflorin in DILI, which is expected to provide a new therapeutic strategy for the development of paeoniflorin. Graphical

The popular beverage green tea possesses chemopreventive activity against various types of tumors. However, the effects of its chemopreventive effect on hematological malignancies have not been defined. In the present study, we evaluated antitumor efficacies of a specific green tea, sencha tea, on sensitive and multidrug-resistant leukemia and a panel of nine multiple myelomas (MM) cell lines. We found that sencha extracts induced cytotoxicity in leukemic cells and MM cells to different extents, yet its effect on normal cells was limited. Furthermore, sencha extracts caused G2/M and G0/G1 phase arrest during cell cycle progression in CCRF/CEM and KMS-12-BM cells, respectively. Specifically, sencha-MeOH/H₂O extracts induced apoptosis, ROS, and MMP collapse on both CCRF/CEM and KMS-12-BM cells. The analysis with microarray and COMPARE in 53 cell lines of the NCI panel revealed diverse functional groups, including cell morphology, cellular growth and proliferation, cell cycle, cell death, and survival, which were closely associated with anti-tumor effects of sencha tea. It is important to note that PI3K/Akt and NF-κB pathways were the top two dominant networks by ingenuity pathway analysis. We demonstrate here the multifactorial modes of action of sencha tea leading to chemopreventive effects of sencha tea against cancer.

Purpose: Artemisinin regulates the immune system and is applied in RA treatment. Nevertheless, the effectiveness and potential mechanisms of artemisinin in the treatment of RA remain unclear, especially in fibroblast-like synoviocytes (FLSs). This study aimed to investigate the mechanism of artemisinin in the treatment of rheumatoid arthritis (RA) through an integrated network pharmacology and bioinformatics approach, supported by experimental validation both in MH7A cells and collagen-induced arthritis (CIA) mice. Methods: SwissTargetPrediction database, TCMSP, TargetNet, SuperPred, and PharmMapper were used to identify the targets of artemisinin. RA-related differentially expressed genes (DEGs) were collected by integrating three GEO datasets. DEGs related to artemisinin were utilized to create protein-protein interaction networks and visualize them with STRING and Cytoscape. GO and KEGG functional enrichment analyses were executed. Molecular docking and molecular dynamics (MD) simulations were carried out to analyze core targets using the AutoDock Vina and Desmond software. Furthermore, CIA mouse and MH7A cells were used to validate the results obtained from network pharmacology. Results: There were 73 target genes intersecting between the artemisinin targets and the DEGs. PPI network analysis and its topology indicated that AR, EGFR, JAK2, and PTGS2 had the greatest centrality. GO and KEGG enrichment analyses suggested that the candidate targets were significantly associated with the PI3K/AKT signaling pathway. Molecular docking and an in vivo study were used for further investigation. Artemisinin interacted with the cavities of AR, JAK2, EGFR, and PTGS2 with binding energies of –8.65, –8.61, –7.48, and –8.48 kcal/mol, respectively. MD simulations showed that the AR–artemisinin complex maintained persistent interactions and stable energy profiles over 20 ns. The CIA model and MH7A cell studies confirmed that artemisinin exposure inhibited the proliferation and production of IL-1β, IL-6, and IL-8 triggered by IL-17. Furthermore, artemisinin attenuated IL-17-induced AKT phosphorylation levels. Conclusion: These findings suggest that artemisinin may ameliorate RA partly by suppressing IL-17-induced inflammatory activation and PI3K/AKT signaling. AR, EGFR, JAK2, and PTGS2 were prioritized as candidate hub targets.