This study aimed to investigate the effects of oral curcumin on the pharmacokinetics of intravenous and oral etoposide in rats. Intravenous (6 mg/kg) or oral (2 mg/kg) etoposide was administered to rats in the absence and the presence of oral curcumin (0.4, 2 or 8 mg/kg). The effects of curcumin on the P-glycoprotein (P-gp) and CYP3A4 activity was also evaluated. Curcumin inhibited CYP3A4 enzyme activity with a 50% inhibition concentration (IC(50) ) of 2.7 µM. In addition, curcumin (10 µm) significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. Compared with the control group (given etoposide alone), curcumin (2 or 8 mg/kg) increased significantly the oral bioavailability (AUC and C(max) ) of etoposide. Consequently, the extent of absolute oral bioavailability (F) of etoposide with curcumin was significantly enhanced compared with that in the control group. In contrast, curcumin did not affect the pharmacokinetics of etoposide after intravenous administration. Therefore, the enhanced oral bioavailability of etoposide in the presence of curcumin might be due mainly to inhibition of the P-gp efflux pump in the small intestine and possibly by reduced first-pass metabolism of etoposide in the small intestine by inhibition of CYP3A activity in rats. The combined use of curcumin may be helpful to improve the F of etoposide in chemotherapeutic applications.

This study is the first report on the XO inhibitory and antihyperuricemic effects of C. coreana Uyeki flos extract, which can be therapeutically applied in treating hyperuricemia and gout.

Ferroptosis is a type of programmed necrosis triggered by iron-dependent lipid peroxidation. We investigated the role of B-cell translocation gene 1 (BTG1) in cystine and methionine deficiency (CST/Met (–))-mediated cell death. CST/Met (–) depleted reduced and oxidized glutathione in hepatocyte-derived cells, increased prostaglandin-endoperoxide synthase 2 expression, and promoted reactive oxygen species accumulation and lipid peroxidation, as well as necrotic cell death. CST/Met (–)-mediated cell death and lipid peroxidation was specifically inhibited by pretreatment with ferroptosis inhibitors. In parallel with cell death, CST/Met (–) blocked global protein translation and increased the expression of genes associated with the integrated stress response. Moreover, CST/Met (–) significantly induced BTG1 expression. Using a BTG1 promoter-harboring reporter gene and siRNA, activating transcription factor 4 (ATF4) was identified as an essential transcription factor for CST/Met (–)-mediated BTG1 induction. Although knockout of BTG1 in human HAP1 cells did not affect the accumulation of reactive oxygen species induced by CST/Met (–), BTG1 knockout significantly decreased the induction of genes associated with the integrated stress response, and reduced lipid peroxidation and cell death in response to CST/Met (–). The results demonstrate that CST/Met (–) induces ferroptosis by activating ATF4-dependent BTG1 induction.

Nonalcoholic fatty liver disease is the most common chronic disease affecting a wide range of the world’s population and associated with obesity-induced metabolic syndrome. It is possibly emerging as a leading cause of life-threatening liver diseases for which a drug with a specific therapeutic target has not been developed yet. Previously, there have been reports on the benefits of Cudrania tricuspidata (CT) for treating obesity and diabetes via regulation of metabolic processes, such as lipogenesis, lipolysis, and inflammation. In this study, we investigated the ameliorative effect of orally administered 0.25% and 0.5% (w/w) CT mixed with high-fat diet (HFD) to C57BL/6J mice for 7 weeks. It was found that body weight, fat mass, hepatic mass, serum glucose level, and liver cholesterol levels were significantly reduced after CT treatment. In CT-treated HFD-fed mice, the mRNA expression levels of hepatic lipogenic and inflammatory cytokine-related genes were markedly reduced, whereas the expression level of epididymal lipogenic genes was increased. The mRNA expression level of beta-oxidation and Nrf-2/HO-1 genes significantly increased in CT-treated obese mice livers. We propose that CT alleviates hepatic steatosis by reducing oxidative stress and inflammation.

Interleukin 22 (IL-22), which acts as either a pro-inflammatory or anti-inflammatory cytokine in various disease models, is markedly upregulated in chronic liver diseases, including viral hepatitis B and C infection. In this report, we demonstrate a strong correlation between IL-22 expression in the liver with active, inflammatory human liver disease. To clarify the role of IL-22 upregulation in the pathogenesis of liver diseases, liver specific IL-22 transgenic (IL-22TG) mice, under the control of albumin promoter, were developed. Despite elevated IL-22 serum levels ranging from 4000 to 7000 pg/ml, IL-22TG mice developed normally without obvious adverse phenotypes or evidence of chronic inflammation. Most interestingly, IL-22 TG mice were completely resistant to Concanavalin A-induced T cell hepatitis with minimal effect on liver inflammation and had accelerated liver regeneration after partial hepatectomy. Although they did not spontaneously develop liver tumors, IL-22 TG mice were more susceptible to diethylnitrosamine-induced liver cancer. Microarray analyses revealed that a variety of anti-oxidant, mitogenic, acute phase genes were upregulated in the livers from IL-22TG mice compared with those from wild-type mice. These findings indicate that localized production of IL-22 in the liver promotes hepatocyte survival and proliferation but primes the liver to be more susceptible to tumor development without significantly affecting liver inflammation.