Hypoglycemic and lipid lowering effects of theaflavins in high-fat diet-induced obese mice.

Theaflavins (TFs) are the characteristic components of black tea and have been widely acknowledged for their health benefits. The current study aimed to investigate the effects and mechanism of TFs, TF1, TF2a and TF3 on glycolipid metabolism in obese mice induced by a high-fat diet (HFD). Mice were randomly divided into seven groups (n = 8 per group) as follows: low-fat diet (LFD), HFD, HFD + metformin (Met, 100 mg kg-1 d-1), HFD + TFs (TFs, 200 mg kg-1 d-1), HFD + TF1 (TF1, 100 mg kg-1 d-1), HFD + TF2a (TF2a, 100 mg kg-1 d-1), and HFD + TF3 (TF3, 100 mg kg-1 d-1). All groups were studied for 9 weeks continuously. The levels of serum glucose, insulin, TC, TG, LDL and HLD in the plasma, lipid accumulation in the liver, and injury of the liver were investigated. In addition, the effects of TFs and their monomers on the SIRT6/AMPK/SREBP-1/FASN pathway were also evaluated. The results showed that oral administration of TFs, TF1, TF2a and TF3 not only dramatically suppressed weight gain, reduced blood glucose level, and ameliorated insulin resistance but also obviously lowered the levels of serum TC, TG and LDL, suppressed the activities of ALT and AST, and ameliorated hepatic damage in mice fed a HFD when compared to the HFD group. Western blot analysis showed that TFs, TF1, TF2a and TF3 treatments increased the expression of SIRT6 and suppressed the expression levels of SREBP-1 and FASN significantly in mice fed a HFD as compared to the HFD group. The phosphorylation of AMPK in mice fed a HFD was obviously elevated by TF2a and TF3 when compared to the HFD group. These results proved for the first time that TF1, TF2a and TF3 improved the glucolipid metabolism of mice fed a HFD, and activated the SIRT6/AMPK/SREBP-1/FASN signaling pathway to inhibit the synthesis and accumulation of lipids in the liver to ameliorate obesity in mice fed a HFD. These findings indicate that TFs, TF1, TF2a and TF3 as the main functional components of black tea might potentially be used as a food additive for improving glycolipid metabolism and ameliorating obesity, and TF3 may be the best choice.

Shikonin inhibits cancer cell cycling by targeting Cdc25s.

BACKGROUND: Shikonin, a natural naphthoquinone, is abundant in Chinese herb medicine Zicao (purple gromwell) and has a wide range of biological activities, especially for cancer. Shikonin and its analogues have been reported to induce cell-cycle arrest, but target information is still unclear. We hypothesized that shikonin, with a structure similar to that of quinone-type compounds, which are inhibitors of cell division cycle 25 (Cdc25) phosphatases, will have similar effects on Cdc25s. To test this hypothesis, the effects of shikonin on Cdc25s and cell-cycle progression were determined in this paper. METHODS: The in vitro effects of shikonin and its analogues on Cdc25s were detected by fluorometric assay kit. The binding mode between shikonin and Cdc25B was modelled by molecular docking. The dephosphorylating level of cyclin-dependent kinase 1 (CDK1), a natural substrate of Cdc25B, was tested by Western blotting. The effect of shikonin on cell cycle progression was investigated by flow cytometry analysis. We also tested the anti-proliferation activity of shikonin on cancer cell lines by MTT assay. Moreover, in vivo anti-proliferation activity was tested in a mouse xenograft tumour model. RESULTS: Shikonin and its analogues inhibited recombinant human Cdc25 A, B, and C phosphatase with IC50 values ranging from 2.14 ± 0.21 to 13.45 ± 1.45 µM irreversibly. The molecular modelling results showed that shikonin bound to the inhibitor binding pocket of Cdc25B with a favourable binding mode through hydrophobic interactions and hydrogen bonds. In addition, an accumulation of the tyrosine 15-phosphorylated form of CDK1 was induced by shikonin in a concentration-dependent manner in vitro and in vivo. We also confirmed that shikonin showed an anti-proliferation effect on three cancer cell lines with IC50 values ranging from 6.15 ± 0.46 to 9.56 ± 1.03 µM. Furthermore, shikonin showed a promising anti-proliferation effect on a K562 mouse xenograph tumour model. CONCLUSION: In this study, we provide evidence for how shikonin induces cell cycle arrest and functions as a Cdc25s inhibitor. It shows an anti-proliferation effect both in vitro and in vivo by mediating Cdc25s.