Role of Notch-1 signaling pathway in PC12 cell apoptosis induced by amyloid beta-peptide(25–35)

Recent studies have demonstrated that Notch-1 expression is increased in the hippocampus of Alzheimer＇s disease patients. We speculate that Notch-1 signaling may be involved in PC12 cell apoptosis induced by amyloid beta-peptide （25-35） （Aβ25-35）. In the present study, PC12 cells were cultured with different doses （0, 0.1, 1.0, 10 and 100 nmol/L） of N-[N-（3,5-Difluorophenacetyl）-L-alanyl]-S-phenylglycine t-butyl ester, a Notch-1 signaling pathway inhibitor, for 30 minutes. Then cultured cells were induced with Aβ25-3s for 48 hours. Pretreatment of PC12 cells with high doses of N-[N-（3,5-Difluorophenacetyl）-L-alanyl]-S-phenylglycine t-butyl ester （〉 10 nmol/L） prolonged the survival of PC12 cells after Aβ25-35 induction, decreased the expression of apoptosis-related proteins caspase-3, -8, -9, increased the activity of oxidative stress-related superoxide dismutase and catalase, inhibited the production of active oxygen, and reduced nuclear factor kappa B expression. This study indicates that the Notch-1 signaling pathway plays a pivotal role in Aβ25-35-induced PC12 apoptosis.

Lycium barbarum polysaccharide ameliorates radiation-induced brain injury by regulating gut microbiota

Objective: To determine the extent to which Lycium barbarum polysaccharide(LBP) improves60Co γ-ray radiation-induced brain injury(RIBI) by regulating the gut microbiota.Methods: The RIBI model of mice was established with the appropriate dose of60Co γ-ray to identify the changes in the body weight, behaviors, gut microbiota, and inflammatory reactions of mice. Mice were randomly divided into healthy, RIBI model, and LBP groups. The related inflammatory cytokines were determined using an enzyme linked immunosorbent assay kit. Then, 16S rRNA sequencings of feces were carried out to evaluate the differences in intestinal flora.Results: Compared with the spontaneous activity and exploratory spirit of the healthy group, those traits in the RIBI model mice in the open field significantly decreased, the freezing time in the elevated plus maze(EPM) significantly increased, and the number of times the mice discriminated the novel object was significantly lower. Hematoxylin-eosin slides showed that the main histopathological changes of RIBI occurred in the hippocampus. In addition, the diversity and relative abundances ratio of the gut bacterial phylum, order, family, and genus in the model group varied widely. Changes in Bacteroidetes,Firmicutes, and Proteobacteria were the most obvious after head radiation exposure. In comparison, LBP could accelerate the recovery of weight loss in RIBI mice. The frequency that mice entered the center of the open field, facing the open arm in the EPM, and the number of times they discriminated the novel object were significantly increased with LBP administration. LBP could also reduce the levels of inflammatory factor caused by RIBI. LBP increased the diversity and abundance of gut microbiota in RIBI model mice. In addition, LBP increased the relative abundance of Bacteroidetes but decreased the levels of Firmicutes and Proteobacteria for irradiated mice.Conclusion: LBP can improve depression and tension by regulating the composition of gut microbiota,including lowering the relative abundance of Clostridia and Burkholderiales and raising that of Lactobacillales. Thus, LBP provides a new strategy for improving the protective effects of RIBI.

MINS, a Novel Naphthalimide-Polyamine Conjugate, Induced Apoptosis Depending on p53 Status in Human Colon Cancer Cells

Natural polyamine is an ideal antitumor drug carrier because of the great requirement difference between cancer cells and normal cells. Previous data demonstrated that many cytotoxic drugs conjugated with natural or synthetic polyamines have potent antitumor effects. Up to now, the antitumor mechanism of conjugates of naphthalimides with polyamine remains poorly understood in human colon cancer cells. The aim of this study is to evaluate the effect of MINS (a novel naph-thalimide-polyamine conjugate) and mechanism of MINS in human colon cancer cells. Mitochondrial toxicity, which was generated by ROS from mitochondria electron transport chain, might be a major factor in MINS-inducted apoptosis. Our data also demonstrated that MINS-mediated cell apoptosis depend on p53 status, for MINS induced Caco-2 cells (p53 null) only necrosis but not apoptosis. Furthermore, the apoptotic effect of MINS is stronger than that of Amonafide, the parent drug of MINS. Our data suggested that the MINS-mediated cell apoptosis depend on p53 in human colon cancer cells.

ETME,a novel β-elemene derivative,synergizes with arsenic trioxide in inducing apoptosis and cell cycle arrest in hepatocarcinoma cells via a p53-dependent pathway

Arsenic trioxide(ATO)has been identified as an effective treatment for acute promyelocytic leukemia(APL)but is much less effective against solid tumors such as hepatocellular carcinoma(HCC).In the search for ways to enhance its therapeutic efficacy against solid tumors,we have examined its use in combination with a novel derivative ofβ-elemene,N-(β-elemene-13-yl)tryptophan methyl ester(ETME).Here we report the effects of the combination on cell viability,apoptosis,the cell cycle and mitochondria membrane potential(MMP)in HCC SMMC-7721 cells.We found that the two compounds acted synergistically to enhance antiproliferative activity and apoptosis.The combination also decreased the MMP,down-regulated Bcl-2 and pro-proteins of the caspase family,and up-regulated Bax and BID,all of which were reversed by the p53 inhibitor,pifithrin-α.In addition,the combination induced cell cycle arrest at the G2/M phase and reduced tumor volume and weight in an xenograft model of nude mice.Overall,the results suggest that ETME in combination with ATO may be useful in the treatment of HCC patients particularly those unresponsive to ATO alone.