Effects of diammonium glycyrrhizinate on hepatic and intestinal UDP-Glucuronosyltransferases in rats: Implication in herb-drug interactions

Glycyrrhizin is a major bioactive component of liquorice, which exerts multiple biochemical and pharmacological activities and is frequently used in combination with other drugs in the clinic. Mycophenolate mofetil(MMF), an immunosuppressant widely used in transplant patients, is metabolized by UDP-glucuronyltransferases(UGTs). Although significant evidence supports that glycyrrhizin could interact with the cytochrome P450s(CYPs), few studies have addressed its effects on UGTs. The present study aimed at investigating the regulatory effects of diammonium glycyrrhizinate(GLN) on UGTs in vitro and in vivo. We found that long-term administration of GLN in rats induced overall metabolism of MMF, which might be due to the induction of UGT1A protein expression. Hepatic UGT1A activity and UGT1A mRNA and protein expression were significantly increased in GLN-treated rats. UGT1A expression levels were also increased in the intestine, contradicting with the observed decrease in intestinal UGT1A activities. This phenomenon may be attributed to different concentrations of glycyrrhetinic acid(GA) in liver and intestine and the inhibitory effects of GA on UGT1A activity. In conclusion, our study revealed that GLN had multiple effects on the expression and activities of UGT1A isoforms, providing a basis for a better understanding of interactions between GLN and other drugs.

Traditional Chinese medicine targets on hepatic stellate cells for the treatment of hepatic fibrosis: A mechanistic review

Liver cirrhosis is a leading cause of death from liver‐related diseases accompanied by a variety of complications;however,hepatic fibrosis,an inevitable stage of cirrhosis,is possible to be reversed and cured.Hepatic stellate cells(HSCs)are the primary cells that secrete extracellular matrix in the liver and play a dominant role in the pathogenesis of hepatic fibrosis.Effective therapeutic approaches for reversing hepatic fibrosis aim at inhibiting the activation of HSCs and inducing their inactivation or death.This review highlights the mechanism by which traditional Chinese medicine(TCM)regulates the activity of HSCs and exerts antifibrotic effects,providing insights and prospects for the treatment of hepatic fibrosis with TCM.

Delayed treatment effect predicting(DTEP)model for guiding immuno-oncology trial designs

Background:The presence of delayed treatment effects(DTE)is common in immuno-oncology trials.However,conventional trial designs often overlook the potential presence of DTE,which can result in an underestimation of the required sample size and loss of statistical power.Conversely,when there is actually no apparent delay in treatment effects,alternative trial designs for addressing DTE may lead to an over-estimation of sample size and unnecessary prolongation of the trial duration.To mitigate this challenge,we propose the use of a DTE predicting(DTEP)model to better guide immuno-oncology trial designs.Methods:The DTEP model was developed and validated using data from 147 pub-lished randomized immuno-oncology trials.The eligible trials were divided into a training set(approximately 75%of the trials)and a test set(approximately 25%).We employed linear discriminant analysis(LDA)to develop the DTEP model for pre-dicting the DTE status using baseline characteristics available at the trial design stage.The receiver operating characteristic(ROC)curve was utilized to assess the ability of the model to distinguish between trials with and without DTE.We further re-conducted the JUPITER-02 trial in a simulation setting,employing three design approaches to assess the potential benefits of utilizing the DTEP model.Results:Baseline characteristics available during the trial design stage,including cancer type,line of treatment,and experimental and control arm regimens were incorporated,and high accuracy in predicting the DTE status in both the training set(area under the operating characteristic curve(AUC),0.79;95%confidence interval(CI),0.71-0.88)and test set(AUC,0.78;95%CI,0.66-0.90)was achieved.Notably,the model successfully predicted the DTE status in two randomized trials among the test sets that were conducted by our team(ESCORT-1st(absence of DTE)and JUPITER-02(presence of DTE)).In silico re-conduct of the JUPITER-02 trial further showed that the statistical power would be markedly improved when trial designs were guided by the DTEP model.Conclusions:The DTEP model can significantly enhance the precision and effectiveness of immuno-oncology trial designs,thereby facilitating the discovery of effective im-munotherapeutics in a more streamlined and expedited manner.

Angiogenesis and Hepatic Fibrosis： Western and Chinese Medicine Therapies on the Road

Hepatic fibrosis is a common feature of almost all chronic liver diseases. Formation of new vessels （angiogenesis） is a process strictly related to the progressive fibrogenesis which leads to cirrhosis and liver cancer. This review mainly concerns the relationship between angiogenesis and hepatic fibrosis, by considering the mechanism of angiogenesis, cells in angiogenesis, anti-angiogenic and Chinese medicine therapies.