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The chemoprotective effects of caffeic (CA), chlorogenic (CHA) and rosmarinic (RA) acids were tested against the toxicity of doxorubicin (DOX) in neonatal rat cardiomyocytes and the iron-dependent DOX induced lipid peroxidation of heart membranes, mitochondria and microsomes. The protectivity of these acids was compared with dexrazoxan, used as an adjuvant during DOX chemotherapy. The cytoprotective effects were assessed by enzyme (LDH and ASAT) and troponin I leakage, secondly by intracellular ATP content. All hydroxycinnamic acids proved non-cytotoxic, and they stabilized both membranes and the energetic status of cardiomyocytes. After preincubation of cardiomyocytes with the test compounds (100, 200 microm; 1 h) the cardiomyocytes were treated with the toxic agent, DOX (100 microm; 8 h). The test compounds protected cardiomyocytes against DOX induced oxidative stress (RA > CHA > or = CA) on all monitored parameters. Substantial preservation of monolayer integrity of the cardiomyocytes by test compounds was also found microscopically. All the acids were more effective in the assays used than dexrazoxan. RA showed the most effective cytoprotectivity. All the acids significantly reduced the iron-dependent DOX induced lipid peroxidation of heart membranes, although of the test compounds, CHA was found to be the most effective (IC(50) = 8.04 +/- 0.74/6.87 +/- 0.52 micro m for microsomes/mitochondria).

ABSTRACT:The subchronic safety of sanguiritrin, a mixture of sanguinarine (SA) and chelerythrine (CHE) quaternary benzo[c]phenanthridine alkaloids (QBA), obtained from Macleaya cordata was assessed. Rats were fed a diet containing 120 ppm sanguiritrin (100 ppm QBA) for 109 days. The feed consumption and the animal weight were monitored. The content of QBA in selected tissues and plasma was determined using HPLC. It was evidenced that 2% of QBA were absorbed through the GIT while 98% were excreted in the feces. In plasma, bilirubin, urea, creatinine, glomerular filtration, AST, ALT, GMT, ALP and total antioxidant capacity were determined. In liver, GSH level, lipoperoxidation products, SOD and GPx activities and total amount of cytochrome P450 were evaluated. Damage to nuclear DNA was assessed; a 32 P-postlabeling assay proved that no DNA-adducts were detected in nuclear and mitochrondrial DNA in liver. No adverse effects were observed on rat organism. QBA had no influence on the gut mucosal epithelium, liver tissue and any biochemical parameters tested. Oxidative stress was not manifested during the experiment.

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Aims-To study the patterns of p53 and Bcl-2 expression in relation to cell proliferation during human embryogenesis in order to help elucidate their potential roles in the regulation of cell proliferation and apoptosis during morphogenesis. Methods-Immunohistochemistry for p53, Bcl-2, and proliferating cell nuclear cell antigen (PCNA) proteins was performed, using a variety of monoclonal antibodies, on paraYn wax embedded sections of tissues from 68 human embryos and fetuses of between 4 and 30 weeks gestation. Results-Positive relations between sites of proliferative activity (as detected by PCNA expression) and p53 expression were found in the kidney, early developmental stages of intestine and lungs, liver, pancreas, heart, and in embryonic osteoblasts. On the other hand, positive relations between proliferative activity and Bcl-2 expression were found in the gonads, adrenal glands, in the cells of the dental lamina, hair follicles, syncytiotrophoblast, chondrocytes, and more advanced stages of intestinal development. In tissues of the central nervous system, p53 and Bcl-2 were co-expressed at the same sites but there was an inverse relation between p53/ Bcl-2 expression and proliferative activity. Conclusions-These data suggest that p53 and Bcl-2 have tissue specific and stage specific functions during embryogenesis. (J Clin Pathol: Mol Pathol 1998;51:131-137)