No abstract

Increasing evidence regarding free radical-generating agents and inflammatory processes suggests that accumulation of reactive oxygen species can cause hepatotoxicity. A short-chain analog of lipid hydroperoxide, t-butyl hydroperoxide (t-BHP), can be metabolized to free radical intermediates by cytochrome P-450 in hepatocytes, which in turn can initiate lipid peroxidation, affect cell integrity and result in cell injury. In this study, we used t-BHP to induce hepatotoxicity in vitro and in vivo and determined the antioxidative bioactivity of esculetin, a coumarin compound. Our investigations showed that pretreatment with esculetin (5-20 microg/ml) significantly decreased the leakage of lactate dehydrogenase (LDH) and alanine transaminase (ALT), and also decreased the formation of malondialdehyde (MDA) in primary cultured rat hepatocytes induced by a 30-min treatment with t-BHP. An in vivo study in rats showed that pretreatment with esculetin (i.p.) at concentrations of 0.5 and 5 mg/kg for 5 days before a single i.p. dose of t-BHP (0.1 mmol/kg) significantly lowered the serum levels of the hepatic enzyme markers (ALT and AST) and reduced oxidative stress in the liver. Histopathological evaluation of the rat livers revealed that esculetin reduced the incidence of liver lesions induced by t-BHP, including hepatocyte swelling, leukocyte infiltration, and necrosis. Based on the results described above, we speculate that esculetin may play a chemopreventive role via reducing oxidative stress in living systems.

Epidemiological evidence suggests that smoking is a major cause of human lung cancer. However, the mechanism by which cigarette smoke induces the cancer remains unestablished. To evaluate the effects of cigarette smoke on the expression of inducible nitric oxide synthase (iNOS), nuclear protooncogenes and related mitogen-activated protein kinases (MAPKs) in rat lung tissue, a histopathological study of the effects of gas-phase cigarette smoke on rat lung tissue were carried out. The terminal bronchioles were found to be infiltrated predominantly by lymphocytes in the peribronchiolar region and a mild to moderate degree of emphysema was noted in the alveolar spaces. The terminal bronchioles also showed marked lipid peroxidation, dilatation, and peribronchiolar fibrosis. Immunohistochemical evaluation showed that the expression of iNOS, NF-kappa B, MAPKs (MEK1, ERK2), phosphotyrosine protein and c-fos was increased in the terminal bronchioles but protein kinase C (PKC), MEKK-1, c-jun, p38 and c-myc showed no change. These results provide evidence to suggest that exposure to cigarette smoke results in oxidant stress which leads to the stimulation of iNOS and c-fos together with the induction of protein tyrosine phosphorylation and MEK1/ERK2 which in turn may promote lung pathogenesis.

The calcium-binding protein, parvalbumin and glutamic acid decarboxylase immunohistochemistry were used to locate candidate neurons mediating the inhibition of rat rubral neurons. A group of cells with small to medium-sized cell bodies that reacted positively to both were found in the red nucleus and its immediate vicinity. At the caudal nuclear level, these neurons gathered in the reticular formation, the pararubral area dorsolateral to the nucleus. As the nucleus expanded in size rostrally these neurons started to incorporate into the nucleus at about the anterior half of the middle nucleus and were all located within the rostral nucleus. Since these neurons were spatially segregated from the caudal nucleus we tested their connection by applying anterograde tracer to the pararubral area at the caudal red nuclear level. Labeled fibers with bouton-like swellings were found to enter the caudal nucleus and closely apposed rubrospinal neuronal cell bodies. These findings are consistent with our earlier observation that stimulating the pararubral area elicited a monosynaptic gamma-aminobutyric-acid(A) receptor-mediated inhibition on rubrospinal neurons in brainstem slices. In addition, the present study also shows that these inhibitory neurons remained unaltered in rats subjected to unilateral upper cervical rubrospinal tractotomy, suggesting that the reduction of pararubral stimulus-induced inhibition on rubrospinal neurons following spinal axonal injury resulted from causes other than the loss of these inhibitory neurons. In the rats, sensorimotor cortical fibers are known to reach the rostral red nucleus and the pararubral area but not the caudal nucleus. This prompted us to propose that neocortical inputs inhibit rubrospinal neurons through the activation of these PV-containing neurons. The proposed feedforward inhibitory circuit enables the cerebral cortex to disynaptically modulate the rubrospinal control over flexor motor execution.

GSTT1 and GSTM1 null genotypes do not associate with increased risk of HCC.