Subcellular localization of Klf4 in non-small cell lung cancer and its clinical significance.

Kruppel-like factor 4 (Klf4) was reported to have both tumor suppressive and oncogenic roles on tumorigenesis, which is depend on its subcellular localization. In this study, the expression and subcellular localization of Klf4 in non-small cell lung cancer (NSCLC) patients as well as its clinical significance were analyzed, and the expression and subcellular localization of Klf4 in A549 cells and A549/DDP cells were detected. The results showed that the expression of Klf4 in nucleus was related to the histological grade and clinical stage of NSCLC patients. Moreover, the subcellular localization of Klf4 is the independent risk factor for NSCLC, and the high expression of Klf4 in nucleus could lead to a poor prognosis, while the high expression of Klf4 in cytoplasm could lead to a prominent prognosis for NSCLC patients. In addition, the nuclear Klf4 expression in A549/DDP cells was higher than that in A549 cells, while the cytoplasmic Klf4 expression in A549/DDP cells was lower than that in A549 cells, indicating that the subcellular localization of Klf4 might be related to the resistance of A549 cells to cisplatin. The study indicates that Klf4 could be a potential therapeutic target in NSCLC.

OP16, a novel ent-kaurene diterpenoid, potentiates the antitumor effect of rapamycin by inhibiting rapamycin-induced feedback activation of Akt signaling in esophageal squamous cell carcinoma.

Hyperactivation of mTOR signaling pathway has been viewed as a significant molecular pathogenesis of cancer. However, inhibition of mTOR by rapamycin and its analogs could induce numerous negative feedback loops to attenuate their therapeutic efficacy. As a traditional Chinese herbal medicine, Rabdosia rubescens has been used to treat esophageal squamous cell carcinoma (ESCC) for hundreds of years, and its major effective component is oridonin. Here we reported that OP16, a novel analog of oridonin, showed potent inhibition of cell proliferation and Akt phosphorylation in ESCC cells. The combination of OP16 and rapamycin possesses synergistic anti-proliferative and pro-apoptotic effects both in ESCC cells and ESCC xenografts, and no obvious adverse effect was observed in vivo. Mechanistic analysis revealed that OP16 could inhibit rapamycin-induced Akt activation through the p70S6K-mediated negative feedback loops, and the combination of OP16 and rapamycin was more effective in activating caspase-dependent apoptotic signaling cascade. This study supports the combined use of OP16 with rapamycin as a feasible and effective therapeutic approach for future treatment of ESCC.

Toxicological evaluation of the flavonoid-rich extract from Maydis stigma: Subchronic toxicity and genotoxicity studies in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Maydis stigma (corn silk) has a long history of use as a traditional herbal medicine or functional food in China and many other countries and has been listed in the Chinese Pharmacopea. However, little data about its potential toxicity is available. AIM OF THE STUDY: In this study, we evaluated the subchronic toxicity and genotoxicity of the flavonoid-rich extract from Maydis stigma (FMS) in mice. MATERIALS AND METHODS: In the subchronic toxicity study, the FMS was administered orally to mice at doses of 2.50, 5.00 and 10.00g/kg/day for 28 consecutive days. At the end of experiment, general clinical signs, mortality, haematological, biochemical and histopathological parameters were examined. The genotoxicity of FMS was also evaluated by the micronucleus assay and the sperm malformation assay. RESULTS: All animals survived until the scheduled necropsy, and no statistically significant or toxicologically relevant differences were observed in any of the FMS-treatment groups, compared with the control group. The no-observed-adverse-effect level (NOAEL) was determined as 10.00g/kg/day. Based on the results of the micronucleus assay and the sperm malformation assay, no evidence of genotoxicity was found either in somatic cells or germ cells even at an experimental upper limit dose (10.00g/kg/day). CONCLUSIONS: The results of the present studies might support the safe use of FMS as a functional food, food additive and natural remedy.

Safety Evaluation, in Vitro and in Vivo Antioxidant Activity of the Flavonoid-Rich Extract from Maydis stigma.

This study aimed to assess the acute toxicity and safety of flavonoid-rich extract from Maydis stigma (FMS) in mice. The in vitro antioxidant activity of FMS was determined by 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azinobis-(3-ethyl-benzthiazoline-6-sulphonate) (ABTS) scavenging assays. Furthermore, the in vivo antioxidant of FMS against ethanol-induced oxidative damage in mice was determined by analysis of the serum total superoxide dismutase (T-SOD) activity, malondialdehyde (MDA) content, liver tissue glutathione (GSH) content, and protein carbonyl (PC) content in liver tissue. The oral administration of FMS at doses of 30 g/kg did not cause death in mice, and there were no significant biologically adverse effects in mice. These results indicated that the median lethal dose (LD50) is higher than this dose. The IC50 values of FMS for the DPPH and ABTS scavenging activity were 50.73 and 0.23 mg/mL, respectively. Meanwhile, FMS could significantly enhance T-SOD activity, reduce MDA content in the serum, increase GSH content, and decrease PC content in the liver tissue at the tested doses (25, 50, 100, 200 mg/kg·day). These results indicate that FMS can be generally regarded as safe and used potentially as a bioactive source of natural antioxidants.