F. Hafez

Protective effect of Withania somnifera against radiation-induced hepatotoxicity in rats

The aim of this study was to investigate the protective effect of root extract of Withania somnifera (WS) against gamma-irradiation-induced oxidative stress and DNA damage in hepatic tissue after whole body gamma-irradiation. Fourty male albino rats were divided into four groups. In the control group, rats were administered vehicle by tube for 7 consecutive days. The second group were administered WS (100mg/kg, by gavage) for 7 consecutive days. Animals in the third group were administered vehicle by tube for 7 consecutive days, then exposed to single dose gamma-irradiation (6 Gy). The fourth group received WS for 7 consecutive days, one hour later rats were exposed to gamma-irradiation. Irradiation hepatotoxicity was manifested biochemically by an increase in hepatic serum enzymes, significant elevation in levels of malondialdehyde (MDA) and total nitrate/nitrite NO(x), significant increase in heme oxygenase activity (HO-1), as well as a significant decrease in reduced glutathione (GSH) content and the activities of antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GSHPx) in hepatic tissues. Marked DNA damage was observed. WS pretreatment showed significant decrease in serum hepatic enzymes, hepatic NO(x) and MDA levels and DNA damage, significant HO-1 induction and significant increase in SOD, GSHPx activities and GSH content compared to irradiated group. These observations suggest that WS could be developed as a potential preventive drug for ionizing irradiation induced hepatotoxicity disorders via enhancing the antioxidant activity and induction of HO-1.

The Combination of α-Tocopheryl Succinate and Sodium Selenite on Breast Cancer: A Merit or a Demerit?

α-Tocopheryl succinate (α-TOS), a mitochondria-targeting agent, induces apoptosis in malignant cells in vitro and in vivo. Selenite is a nutritional supplement that has been shown to stimulate apoptosis in cancer cells. This study was designed to investigate the cytotoxic effect of combined treatment of α-TOS and sodium selenite (SSe) in vitro and in vivo and to explore their effect on apoptosis and autophagy in breast cancer. The type of interaction between α-TOS and SSe was evaluated and levels of oxidative stress and apoptotic and autophagic markers were determined. SSe alone showed varying degrees of cytotoxicity on all the tested cell lines. Its combination with α-TOS was antagonistic in vitro in MCF7 and in vivo in mice bearing Ehrlich tumor compared to α-TOS-treated one. Combination of TOS with 2 μM of SSe increased the level of glutathione without changes in antiapoptotic markers Bcl-2 and Mcl-1 at 16 and 48 hrs. SSe decreased caspase 3 activity and protein level of caspases 7 and 9, while it increased autophagic markers beclin-1 and LC3B protein levels of MCF7 cells treated with α-TOS. In conclusion, SSe antagonizes α-TOS-induced apoptosis via inhibition of oxidative stress and promoting prosurvival machinery of autophagy.

Impact of Global DNA Methylation in Treatment Outcome of Colorectal Cancer Patients

Background: Global DNA methylation has an impact in cancer pathogenesis and progression. This study aimed at investigating the impact of global DNA methylation in treatment outcome of Colorectal Cancer (CRC). Patients and Methods: Global DNA methylation was measured by LC/MS/MS in peripheral blood leucocytes of 102, 48, and 32 Egyptian CRC patients at baseline and after 3 and 6 months of Fluoropyrimidine (FP) therapy respectively, in addition to 32 normal healthy matched in age and sex. The genetic expressions of DNA methyl transferases (DNMTs) were determined and correlated with patients‘ survival using univariate and multivariate methods of analyses. Results: Egyptian CRC patients had significant global hypomethylation of 5mC level and 5mC % with overexpression of DNMT3A and DNMT3B. Significant higher 5mC levels were shown in patients > 45 years, male gender, T2 tumors, stage II, negative lymph nodes, and absence of metastasis. FP therapy significantly reduced DNA methylation particularly in the subgroups of patients with high DNA methylation level at baseline and good prognostic features. After 3 years of follow up, patients with 5mC % > 8.02% had significant poor overall survival (OS) while, significant better event-free survival (EFS) was found in patients with 5mC level > 0.55. High initial CEA level and presence of metastasis were significantly associated with hazards of disease progression and death. Conclusion: Global DNA methylation has a significant impact on the treatment outcome and survival of Egyptian CRC patients treated with FP- based therapy.