Combination of molecular docking and liver transcription sequencing analysis for the evaluation of salt-processed psoraleae fructus-induced hepatotoxicity in ovariectomized mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Salt-processed Psoraleae fructus (SPF) is widely used as a phytoestrogen-like agent in the treatment of osteoporosis. However, SPF-associated hepatotoxicity is a known health hazard. Cholestasis is often associated with SPF-induced hepatotoxicity. Notably, clinical liver injury is a common side effect of SPF in the treatment of osteoporosis; however, the exact mechanism underlying this phenomenon is unclear. AIM OF THE STUDY: To evaluate SPF-induced hepatotoxicity in an ovariectomized murine model of estrogen deficiency and examine the mechanisms underlying this process. MATERIALS AND METHODS: To explore the molecular mechanism of SPF-induced cholestatic liver injury, different concentrations of SPF (5 and 10 g/kg) were intragastrically administered to ovariectomized and non-ovariectomized female ICR mice for 30 days. RESULTS: SPF-treated mice showed noticeably swollen hepatocytes, dilated bile ducts, and elevated levels of serum biochemical markers. Compared to ovariectomized mice, these changes were more prominent in non-ovariectomized mice. According to the sequence data, a total of 6689 mRNAs were identified. Compared with the control group, 1814 differentially expressed mRNAs were identified in the group treated with high SPF doses (SPHD), including 939 upregulated and 875 downregulated mRNAs. Molecular docking and Western blot experiments showed that liver injury was closely related to the estrogen levels. Compared with the negative control group, the expression levels of FXR, Mrp2, CYP7a1, BSEP, SULT1E1, HNF4a, and Nrf2 decreased in the estradiol-treated (E2), low-dose SPF-treated (SPLD), and SPHD groups. Interestingly, the expression levels of FXR, CYP7a1, SULT1E1, and HNF4α were significantly higher in the ovariectomized groups than in the non-ovariectomized groups (#P < 0.05; ###P < 0.001). CONCLUSIONS: Overall, this study demonstrates that SPF downregulates key enzymes involved in cholesterol and bile acid biosyntheses, posing a risk for cholestatic liver injury. SPF also regulates the FXR-SULT1E signaling pathway via HNF4α, which is an important causative factor of cholestasis. Moreover, the severity of liver damage was significantly lower in the ovariectomized groups than in the non-ovariectomized group. These results suggest that the estrogen level is the most critical factor determining liver injury.

Effect and Mechanism of Qingfei Paidu Decoction in the Management of Pulmonary Fibrosis and COVID-19.

Qingfei Paidu decoction (QFPD) has been repeatedly recommended for the clinical treatment of novel coronavirus disease 2019 (COVID-19) in multiple provinces throughout China. A possible complication of COVID-19 lung involvement is pulmonary fibrosis, which causes chronic breathing difficulties and affects the patient's quality of life. Therefore, there is an important question regarding whether QFPD can alleviate the process of pulmonary fibrosis and its potential mechanisms. To explore this issue, this study demonstrated the anti-pulmonary fibrosis activity and mode of action of QFPD in vivo and in vitro pulmonary fibrosis models and network pharmacology. The results showed that QFPD effectively ameliorated the bleomycin-induced inflammation and collagen deposition in mice and significantly improved the epithelial-mesenchymal transition in pulmonary fibrosis in mice. In addition, QFPD inhibited bleomycin-induced M2 polarization of macrophages in pulmonary tissues. An in-depth study of the mechanism of QFPD in the treatment of pulmonary fibrosis based on network pharmacology and molecular simulation revealed that SRC was the main target of QFPD and sitosterol (a key compound in QFPD). QFPD and sitosterol regulate the EMT process and M2 polarization of macrophages by inhibiting the activation of SRC, thereby alleviating pulmonary fibrosis in mice. COVID-19 infection might produce severe fibrosis, and antifibrotic therapy with QFPD may be valuable in preventing severe neocoronavirus disease in patients with IPF, which could be a key factor explaining the role of QFPD in the treatment of COVID-19.

A network pharmacology strategy to investigate the anti-osteoarthritis mechanism of main lignans components of Schisandrae Fructus.

Osteoarthritis (OA) is a chronic age-related progressive joint disorder. Degradation of the cartilage extracellular matrix (ECM) is considered a hallmark of OA and may be a target for new therapeutic methods. Schisandrae Fructus (SF) has been shown to be effective in treating OA. The major active components of SF are lignans. However, the targets of SF and the pharmacological mechanisms underlying the effects of SF lignans in the treatment of OA have not been elucidated. Therefore, based on network pharmacology, this research predicted the treatment targets of six lignans in SF, constructed a protein-protein interaction network and identified 15 hub genes in the OA-target protein-protein interaction network. Through Gene Ontology function and pathway analyses, the gene functions of lignans in the treatment of OA were determined. Finally, the anti-OA effects of lignans and underlying mechanisms identified in the network pharmacology analysis were verified by molecular docking, real-time PCR and western blotting in vitro. The biological processes of the genes and proteins targeted by lignans in the treatment of OA included the immune response, inflammatory response, cell signal transduction and phospholipid metabolism. Moreover, 20 metabolic pathways were enriched. Network pharmacology, molecular docking and in vitro and in vivo experimental results revealed that SF, schisanhenol and gamma-schisandrin inhibited EGFR and MAPK14 gene expression by inhibiting SRC gene expression and activity and then decreased MMP 13 and collagen II protein and gene expression. This research provides a basis for further study of the anti-OA effects and mechanisms of SF, schisanhenol and gamma-schisandrin.

Comparative in vivo pharmacokinetics study of affeic acid, isoferulic acid and ferulic acid in crude and three different prepared Cimicifuga foetida L.

Our study investigated the differences in pharmacokinetics of three major components of crude Cimicifuga foetida L. and its fried product and honey- and liquor-prepared products. A rapid and sensitive ultra-high performance liquid chromatography with tandem mass spectrometry approach was established for determing caffeic acid, isoferulic acid and ferulic acid in rat plasma. The approach has good linearity, precision, accuracy, recovery and stability. Phenolic acid was rapidly absorbed. The times to peak concentration were shorter in the processed group than those for the crude product, with their values of <30 min. The peak concentration values of caffeic acid and isoferulic acid were higher in the crude group than in the processed groups (p < 0.05). Area under the curve values of the three phenolics in the crude group were significantly higher than those of the processed groups (p < 0.05).