Glutathione peroxidase (GSHPx) is a critical intracellular enzyme involved in detoxification of hydrogen peroxide (H(2)O(2)) to water. In the present study we examined the susceptibility of mice with a disruption of the glutathione peroxidase gene to the neurotoxic effects of malonate, 3-nitropropionic acid (3-NP), and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). Glutathione peroxidase knock-out mice showed no evidence of neuropathological or behavioral abnormalities at 2-3 months of age. Intrastriatal injections of malonate resulted in a significant twofold increase in lesion volume in homozygote GSHPx knock-out mice as compared to both heterozygote GSHPx knock-out and wild-type control mice. Malonate-induced increases in conversion of salicylate to 2,3- and 2, 5-dihydroxybenzoic acid, an index of hydroxyl radical generation, were greater in homozygote GSHPx knock-out mice as compared with both heterozygote GSHPx knock-out and wild-type control mice. Administration of MPTP resulted in significantly greater depletions of dopamine, 3,4-dihydroxybenzoic acid, and homovanillic acid in GSHPx knock-out mice than those seen in wild-type control mice. Striatal 3-nitrotyrosine (3-NT) concentrations after MPTP were significantly increased in GSHPx knock-out mice as compared with wild-type control mice. Systemic 3-NP administration resulted in significantly greater striatal damage and increases in 3-NT in GSHPx knock-out mice as compared to wild-type control mice. The present results indicate that a knock-out of GSHPx may be adequately compensated under nonstressed conditions, but that after administration of mitochondrial toxins GSHPx plays an important role in detoxifying increases in oxygen radicals.

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Summary.To elucidate the neuroprotective effects of the iron chelator desferrioxamine (DFO) and the antioxidant vitamin E on excessive ironinduced free radical damage, a chronic iron-loaded mice model was established. The relationship between striatal iron content, oxidized to reduced glutathione ratio, hydroxyl radical ('OH) levels and dopamine concentrations were observed in DFO or vitamin E pretreated iron-loaded/1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP)-treated C57BL/6 mice. The results demonstrated that both DFO and vitamin E inhibit the iron accumulation and thus reverses the increase in oxidized glutathione (GSSG), oxidized to reduced glutathione ratios, "OH and lipid peroxidation levels. The striatal dopamine concentration was elevated to normal value. Our data suggested that: (1) iron may induce neuronal damage and thus excessive iron in the brain may contribute to the neuronal loss in PD; (2) iron chelators and antioxidants may serve as potential therapeutic agents in retarding the progression of neurodegeneration.

In this study a chronic cerebral iron-loaded model was established by feeding mice with high iron diet. Data indicated that brain iron concentrations were significantly increased in iron-fed mice compared with those of controls. A significant increase in oxidized glutathione (GSSG), decrease in total glutathione (oxidized and reduced glutathione, GSSG + GSH), and therefore increase in the GSSG/(GSSG + GSH) ratios were observed in iron-loaded mice. Hydroxyl radical (.OH) levels in striatum and brainstem were also significantly increased. Excessive iron alone did not change either dopamine (DA) or lipid peroxidation (LPO) concentrations in striatum. However, a single injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg, i.p.) into the iron-loaded mice caused a great enhancement in all these biochemical abnormalities. These findings suggest that iron does induce oxidative stress, but not severely injury neurons per sc. Excessive iron accumulation in the brain, however, is a potential risk for neuronal damage, which may promote by triggering factor(s). This supports the hypothesis that excessive cerebral iron may contribute to the aetiology of Parkinson's disease (PD).

Dysfunctional umbilical cord blood (UCB) is a key factor for the development of intrauterine growth restriction (IUGR) in utero. Poor degrees of angiogenesis were observed during IUGR development. Here, it was demonstrated that NV-EXO (normal piglet's Umbilical Veins derived exosomes) promoted angiogenesis within the subdued pro-angiogenesis context of IV-EXO (IUGR piglet's Umbilical Veins derived exosomes). Investigation of the miRNA transcriptome of umbilical cord vein and artery exosomes between IUGR and normal littermates showed significant differences between umbilical veins from normal (NV) and IUGR (IV) piglets. Similar patterns were observed in normal (NA) and IUGR (IA) umbilical arteries as well. Moreover, the miRNAs expession level was more stable in NV. Further analysis revealed that miRNAs related to angiogenesis exhibited aberrant expression in IUGR pigs. The miRNA expression patterns between IUGR and normal piglets showed great difference. Expression of miR-150 in the tissues and UCB exosomes of IUGR pigs was significantly decreased. Up-regulation of miR-150 was able to increase proliferation, migration and tube formation of Human umbilical vein endothelial cells (HUVECs), suggesting a pro-angiogenic role. Furthermore, the data demonstrated that UCB derived miRNAs participate in fetal epigenetic regulation during pregnancy, suggesting a novel possible explanation for abnormal embryologic vascular development and several congenital cardiovascular diseases.