Figure S3 from JQ1 Induces DNA Damage and Apoptosis, and Inhibits Tumor Growth in a Patient-Derived Xenograft Model of Cholangiocarcinoma
Patrick L. GarciaAubrey L. MillerTracy L. GamblinLeona N. CouncilJohn D. ChristeinJ. Pablo ArnolettiMarty J. HeslinSushanth ReddyJoseph H. RichardsonXiangqin CuiRobert C.A.M. van WaardenburgJames E. BradnerEddy S. YangKarina J. Yoon
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<p>Immunohistochemistry analysis and nuclear expression indices of BRD4 in first generation (F1) CCA3, CCA4 and CCA5.</p>Objective To explore the effects of selenium on DNA damage and apoptosis of L-02 cell induced by fluoride.Method The DNA damage and apoptosis were measured after L-02 cell incubated with 80μg/ml sodium fluoride and/or 1.73μg/ml selenium.Results The rates of DNA damage and apoptosis of L-02 cell in the fluoride group were significantly higher than those of the control group,the selenium group and the F-Se group(P0.01).However,the DNA damage and cell apoptosis rates in the control group,the selenium group,and the F-se group showed no significant difference each other(P0.05).Conclusion Fluoride exposure induces DNA damage and apoptosis of L-02 cell,and the proper level of selenium can inhibit the DNA damage and cell apoptosis induced by fluoride.
Sodium fluoride
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Purpose: While the effects of high doses of ionizing radiation (IR) are relatively well characterized, the molecular mechanisms underlying cellular responses to prolonged exposure to low doses of radiation remain largely under-investigated.Materials and methods: Here, we addressed the DNA damage and apoptotic response in the spleen tissue of C57BL/6 male mice after fractionated exposure to X-rays within the 0.1–0.5 Gy dose range.Results: The response to initial exposure to 0.1 Gy of IR was characterized by increased DNA damage and elevated levels of apoptosis. Subsequent exposures (cumulative doses of 0.2 and 0.3 Gy) resulted in adaptive response-like changes, represented as increased proliferation and apoptotic response. Cumulative doses of 0.4 and 0.5 Gy were characterized by accumulation of DNA damage and reactivation of apoptosis and apoptosis-related proteins. Additionally, spleen cells with irreversible damage caused by radiation can undergo apoptosis via activation of p38, which does not necessarily involve the Atm/p53 pathway.Conclusions: Fractionated exposure to low doses of X-rays resulted in accumulation of DNA damage in the murine spleen and induction of apoptotic response in p53/Atm-independent manner. Further studies are needed to understand the outcomes and molecular mechanisms underlying cellular responses and early induction of p38 in response to prolonged exposure to IR.
Radiobiology
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Abstract DNA damage and DNA damage response (DDR) pathways in β-cells have received little attention especially in the context of type-2 diabetes. We postulate that p21 plays a key role in DDR by preventing apoptosis, associated through its overexpression triggered by DNA stand breaks (DSBs). Our results show that β-cells from chronic diabetic mice had a greater extent of DSBs as compared to their non-diabetic counterparts. Comet assays and nuclear presence of γH2AX and 53bp1 revealed increased DNA DSBs in 16 weeks old (wo) db/db β-cells as compared to age matched non-diabetic β-cells. Our study of gene expression changes in MIN6 cell line with doxorubicin (Dox) induced DNA damage, showed that the DDR was similar to primary β-cells from diabetic mice. There was significant overexpression of DDR genes, gadd45a and p21 after a 24-hr treatment. Western blot analysis revealed increased cleaved caspase3 over time, suggesting higher frequency of apoptosis due to Dox-induced DNA strand breaks. Inhibition of p21 by pharmacological inhibitor UC2288 under DNA damage conditions (both in Dox-induced MIN6 cells and older db/db islets) significantly increased the incidence of β-cell apoptosis. Our studies confirmed that while DNA damage, specifically DSBs, induced p21 overexpression in β-cells and triggered the p53/p21 cellular response, p21 inhibition exacerbated the frequency of apoptosis.
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To study DNA damage and apoptosis induced by chlorination by-product MX of drinking water.Single cell gel electrophoresis (SCGE) and flow cytometry were used to detect DNA damage and apoptosis in human fetal hepatocytes (L-02) treated with MX.DNA strand breaks were found to increase in L-02 cells treated with MX in a dose-response manner. On treatment levels of 100 and 300 micromol/L, MX led to significant increase of DNA damage in comparison to the solvent controls (DMSO) (P < 0.05, and P < 0.01 respectively). Statistically significant increase of L-02 cell apoptosis were observed in all MX treated groups in comparison to the solvent controls (DMSO) (P < 0.001).Chlorination by-product MX of drinking water could induce obviously DNA damage and apoptosis in L-02 cells.
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Purpose: To critically review the data supporting membrane damage-induced increases in ceramide levels as the primary initiator of ionizing radiation-induced apotosis and to point out that there is compelling evidence supporting the involvement of DNA damage in this process. Conclusions: There is now a significant literature suggesting that irradiation of cells can quickly lead to a modest, transitory increase in the level of the putative second messenger ceramide. These results have been used to support the views that membrane damage is the primary trigger for radiation-induced apoptosis and that DNA damage is irrelevant to this process. It is argued, however, that the data are inadequate to support such conclusions because it is questionable whether the induced levels of ceramide are toxic and because the ceramide hypothesis cannot convincingly explain the delayed apoptosis, dependent on events such as mitosis, that is shown by many cell lines. In contrast, it is suggested that the sensitivity of some cell types to the induction of apoptosis by DNA-targeted radiation damage, the relationship between p53 status and radiation response, and the influence of enzymatic DNA repair capability on susceptibility to apoptosis, argue strongly that DNA damage is relevant to the triggering of apoptosis.
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