Résumé
Xianling Gubao is a common and effective medicine in the treatment of orthopedic diseases. In recent years, it has been reported to be associated with liver injury. However, through the analysis of the adverse drug reaction reports and key hospital cases, we found that there is considerable incomplete information in the reports of Xianling Gubao-related liver injury cases retrieved from the literature. Thus, it is difficult to accurately judge causality between the drug and liver injury. Six cases of liver injury related to Xianling Gubao were identified in key hospitals, two of which achieved the clinical diagnosis according to the assessment of the integrated evidence chain method. We further analyzed the public health data of all residents in Yinzhou. The gross incidence rate of Xianling Gubao-related liver injury was 0.034%, which corresponds to a level of rare incidence. This revealed that Xianling Gubao-related liver injury has significant divergence in individuals and an idiosyncratic nature. The gross incidence of liver injury related to Xianling Gubao was lower than that of other medicines for the treatment of orthopedic diseases. Based on the idiosyncratic drug-induced liver injury model mediated by immune stress, it was found that Epimedii Folium and Psoraleae Fructus were the major components that lead to liver injury, and the liver injury caused by a full prescription was less serious than that encountered with only Epimedii Folium and Psoraleae Fructus. This suggests that the other 4 herbs (Dipsaci Radix, Anemarrhenae Rhizoma, Rehmanniae Radix,Salviae Miltiorrhizae Radix et Rhizoma) can prevent/alleviate the liver injury. Through disassembled prescription analysis, we found that the attenuation efficacy of Salviae Miltiorrhizae Radix et Rhizoma was the most significant. In conclusion, Xianling Gubao may cause idiosyncratic liver injury in a tiny minority of susceptible individuals, but the incidence risk is lower than that of other commonly used drugs for orthopedic disease. Xianling Gubao should be discreetly applied to patients with immune stress. The major components that induced liver injury in Xianling Gubao were Epimedii Folium and Psoraleae Fructus, and Salviae Miltiorrhizae Radix et Rhizoma appears to attenuate this toxicity. This study provides a reference for the rational clinical medication with Xianling Gubao.
Résumé
Using the idiosyncratic lipopolysaccharide (LPS)-mediated hepatotoxicity model as a positive control, liver injury induced by Cortex Dictamni aqueous extract (AE) or Cortex Dictamni ethanol extracts (EE) was evaluated. Idiosyncratic hepatotoxicity model was established in rats [Institutional Animal Care and Use Committee (IACUC)-2018-008] by injecting LPS at a dosage of 2.8 mg·kg-1. Rats were randomly divided into 10 groups. The plasma levels of liver function biomarkers such as alanine transaminase (ALT), aspartate aminotransferase (AST) were measured. Histological changes (HE staining), hepatocellular apoptosis and the content of cytokines of liver were measured. Network pharmacology was used to analyze the relationship between chemical components and immunity in Cortex Dictamni. Compared with the control group, the doses (25, 50 g·kg-1) of AE or EE had no significant changes in ALT, AST and liver pathology (P>0.05). The doses of 4.2 g·kg-1 of AE or EE+LPS groups exhibited an elevation in ALT, AST and serum cytokines (P<0.01). Disorder of liver lobular arrangement and irregular island-like or massive necrosis of liver cells were observed in these groups. Network pharmacology shows that Cortex Dictamni may directly or indirectly participate in the process of immunomodulation. We found that Cortex Dictamni regulated 15 core targets and affected 19 pathways, including apoptosis, TNF-α, NF-kappa B signaling pathways. These results suggest that Cortex Dictamni can induce idiosyncratic hepatotoxicity and the water extract can induce more serious liver injury then ethanol extract of Cortex Dictamni. These findings provide a reference for elucidating the idiosyncratic hepatotoxicity induced by Cortex Dictamni.
Résumé
Objective To investigate the dynamic changes of transcription profiles of mouse thymus gene expression in different times after 6 Gy γ-irradiation.Methods High-flux cDNA microarray technique was used irradiation,the numbers and types of differentially expressed genes were gradually decreased,for instance,the induced differential expression genes were involved in cell cycle,immunity and stress,apeptosis,signal transduction,transcription regulation,DNA synthesis and recombination,cystoskeleton,ion channel and transportation,metabolism,protein translation and synthesis,development and cell differentiation,etc.correlated cell cycle(3 up-regulating:Cyclin G,Anxal,Fgf1 and 2 down-regulating:Cdc2a,Cdc25b),5 genes correlated immune stress(4 up-regulating:IL-18,Casp1,IL-15,IL-7 and 1 down-regulating:Cd28),7 genes correlated apoptosis(4 up-regulating:Caspl,Anxal,Perp,IL-7 and 3 down-regulating:Pten,Api5 and Fas).Conclusions After 6 Gy irradiation,differentially expressed genes in mouse thymus is not only involved in many targets,levels and pathways,but also displayed an obvious difference in times.This reveals the regular pattern of differential expression genes in the process of injury and reconstitution in moderate dose irradiated mouse thymus.