Differential immunotoxic effects of ethanol on murine EL-4 lymphoma and normal lymphocytes is mediated through increased ROS production and activation of p38MAPK.

Ethanol has been used to achieve thymic depletion in myasthenia gravis patients. Ethanol (95%) has also been used widely in the therapy of many tumors including hepatocellular carcinoma. In light of these findings, we delineated the differential immunotoxic behavior and mechanism of lower concentration of ethanol towards murine EL-4 lymphoma and its normal counterpart lymphocytes. EL-4 lymphoma and normal lymphocytes were cultured with ethanol (0%-5%) for 6 h and cytotoxicity was measured by various methods. EL-4 cells treated with ethanol showed concentration-dependent loss of viability at 2%-5% ethanol concentration and exhibit proliferative arrest at preG1 stage. Acridine-orange and ethidium-bromide staining indicated that ethanol induced death in EL-4 cells, by induction of both apoptosis and necrosis which was further supported by findings of DNA-fragmentation and trypan blue dye exclusion test. However, treatment of lymphocytes with similar concentration of ethanol did not show any death-associated parameters. Furthermore, ethanol induced significantly higher ROS generation in EL-4 cells as compared to lymphocytes and caused PARP cleavage and activation of apoptotic proteins like p53 and Bax, in EL-4 cells and not in normal lymphocytes. In addition, ethanol exposure to EL-4 cells led to phosphorylation of p38MAPK, and upregulation of death receptor Fas (CD95). Taken together, these results suggest that ethanol upto a concentration of 5% caused no significant immunotoxicity towards normal lymphocytes and induced cell death in EL-4 cells via phosphorylation of p38MAPK and regulation of p53 leading to further activation of both extrinsic (Fas) and intrinsic (Bax) apoptotic markers.

L-arginine mitigates radiation-induced early changes in cardiac dysfunction: the role of inflammatory pathways.

Our earlier studies demonstrated the ability of L-arginine (L-Arg) to reverse radiation-induced immune dysfunction. The aim of the present study was to investigate cardiac dysfunction up to 24 h after 2 Gy of total-body irradiation (TBI) and its mitigation by L-Arg. The current studies also explore the association of radiation-induced inflammation and electrocardiographic (ECG) abnormalities. TBI-induced cardiac iNOS and kinin B1 R, changes in the ECG profile like bradycardia, increased RR interval, ST elevation and increased QRS duration at 4 h and 24 h after TBI. TBI with 2 Gy induced inflammatory responses in spleen and cardiac tissue. L-Arg administered 2 h after TBI (TBI+L-Arg) mitigated the entire inflammatory response and ECG profile toward normalcy. L-Arg administered just before TBI (L-Arg +TBI) could not reverse the above-mentioned changes. Radiation-induced inflammatory responses at +4 h and +24 h after TBI in spleen and cardiac tissue correlated with the changes in ECG profile at the corresponding time. The results suggest the ability of L-Arg administered at the correct therapeutic window to mitigate radiation-induced cardiac dysfunction at 4 and 24 h after TBI.

Augmentation of radiation-induced apoptosis by ellagic acid.

This study evaluates the potential of ellagic acid (EA) as an enhancer of radiation-induced apoptosis in cancer cells. HeLa cells treated with EA and gamma radiation showed increased superoxide generation, upregulated p53 protein expression, and decreased antioxidant enzymes. We also found that EA and radiation enhance capase-3 activity via oxidative stress, increased intracellular calcium levels, and phospholipase C and cause a drop in mitochondrial potential. These results might provide a basis for prominent reduction of cancer cell using EA as an adjunct to radiotherapy and an opportunity to lower the toxic radiation doses to improve the quality of life.