[Pseudo-targeted metabolomics study of immune stress-mediated idiosyncratic liver injury induced by synergistic effects of bavachin and epimedin B].

Chinese patent medicine preparations containing Epimedii Folium and Psoraleae Fructus have been associated with the occurrence of idiosyncratic drug-induced liver injury(IDILI). However, the specific toxic biomarkers and mechanisms underlying these effects remain unclear. This study aimed to comprehensively assess the impact of bavachin and epimedin B, two principal consti-tuents found in Psoraleae Fructus and Epimedii Folium, on an IDILI model induced by tumor necrosis factor-α(TNF-α) treatment, both in vitro and in vivo. To evaluate the extent of liver injury, various parameters were assessed. Lactate dehydrogenase(LDH) release in the cell culture supernatant, as well as the levels of alanine aminotransferase(ALT) and aspartate transaminase(AST) in mouse plasma were measured. Additionally, histological analysis employing hematoxylin-eosin staining was performed to observe liver tissue changes indicative of the severity of liver injury. Furthermore, a pseudo-targeted metabolomics approach was employed, followed by multivariate analysis, to identify differential metabolites. These identified metabolites were subsequently subjected to Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis. The results showed that at the cellular level, after 2 hours of TNF-α stimulation, bavachin significantly increased the release of LDH in HepG2 cells compared to the normal group and the group treated alone; after the combination of bavachin and epimedin B, the release of LDH further significantly increased on the original basis. Similarly, although the individual or combination treatments of bavachin and epimedin B did not induce liver injury in normal mice, the combination of both drugs induced marked liver injury in TNF-α treated mice, leading to a significant elevation in plasma AST and ALT levels and substantial infiltration of inflammatory immune cells in the liver tissue. Pseudo-targeted metabolomics analysis identified seven common differential metabolites. Among these, D-glucosamine-6-phosphate, N1-methyl-2-pyridone-5-carboxamide, 17beta-nitro-5a-androstane, irisolidone-7-O-glucuronide, and N-(1-deoxy-1-fructosyl) valine emerged as potential biomarkers, with an area under the curve(AUC) exceeding 0.9. Furthermore, our results suggest that the metabolism of nicotinic acid and nicotinamide, as well as the linoleic acid metabolic pathway, may play pivotal roles in bavachin and epimedin B-induced IDILI. In conclusion, within an immune-stressed environment mediated by TNF-α, bavachin and epimedin B appear to induce IDILI through disruptions in metabolic processes.

Receptor-Meditated Endocytosis by Hyaluronic Acid@Superparamagnetic Nanovetor for Targeting of CD44-Overexpressing Tumor Cells.

The present report proposes a more rational hyaluronic acid (HA) conjugation protocol that can be used to modify the surface of the superparamagnetic iron oxide nanoparticles (SPIONs) by covalently binding the targeting molecules (HA) with glutamic acid as a molecular linker on peripheral surface of SPIONs. The synthesis of HA-Glutamic Acid (GA)@SPIONs was included oxidization of nanoparticle's surface with H2O2 followed by activation of hydroxyl group and reacting glutamic acid as an intermediate molecule demonstrating transfection of lung cancer cells. Fourier transform infrared (FTIR) and zeta-potential studies confirmed the chemical bonding between amino acid linker and polysaccharides. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assay showed that HA-SPIONs-treated cells remained 82.9% ± 2.7% alive at high particle dosage (200 µg/mL iron concentration), whereas GA-SPIONs and bare SPIONs (B-SPIONs) treated cells had only 59.3% ± 13.4% and 26.5% ± 3.1% survival rate at the same conditions, respectively. Confocal microscopy analysis showed increased cellular internalization of HA-SPIONs compared to non-interacting agarose coated SPIONs (AgA-SPIONs).