Structure–activity relationship of 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone)

Abstract

This paper describes the discovery of a novel free radical scavenger, 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone, 1), as a potent antioxidant agent against lipid peroxidation. The structure-activity relationship of edaravone indicated that lipophilic substituents were essential to show its lipid peroxidation-inhibitory activity. In vivo studies revealed that edaravone showed brain-protective activity in a transient ischemia model.     

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Abstract

Arsenic-induced tissue damage is a major concern to the human population. An impaired antioxidant defense mechanism followed by oxidative stress is the major cause of arsenic-induced toxicity, which can lead to reproductive failure. The present study was carried out to investigate the preventive role of arjunolic acid, a triterpenoid saponin isolated from the bark of Terminalia arjuna, against arsenic-induced testicular damage in mice. Administration of arsenic (in the form of sodium arsenite, NaAsO₂, at a dose of 10 mg/kg body weight) for 2 days significantly decreased the intracellular antioxidant power, the activities of the antioxidant enzymes, as well as the levels of cellular metabolites. In addition, arsenic intoxication enhanced testicular arsenic content, lipid peroxidation, protein carbonylation and the level of glutathione disulfide (GSSG). Exposure to arsenic also caused significant degeneration of the seminiferous tubules with necrosis and defoliation of spermatocytes. Pretreatment with arjunolic acid at a dose of 20 mg/kg body weight for 4 days could prevent the arsenic-induced testicular oxidative stress and injury to the histological structures of the testes. Arjunolic acid had free radical scavenging activity in a cell-free system and antioxidant power in vivo. In summary, the results suggest that the chemopreventive role of arjunolic acid against arsenic-induced testicular toxicity may be due to its intrinsic antioxidant property.     

Energy metabolism,thyroid calorigenesis,and oxidative stress: functional and cytotoxic consequences

Abstract

Recent findings indicate that nitric oxide (NO^?) over-production might be an important factor in the pathogenesis of sporadic amyotrophic lateral sclerosis (SALS). We measured significantly higher concentrations of uric acid and thiol group-containing molecules (R–SH groups) in the cerebrospinal fluid (CSF) from SALS patients compared to controls. The above factors, together with a slightly increased free iron concentration found in the CSF, favour conditions necessary for the formation of the dinitrosyl iron complex, capable of NO^? bio-transformation. Thus, we performed ex vivo saturation of CSF (from both SALS patients and controls) with NO^?. A decrease in the level of R–SH was found. This was more pronounced in the CSF from SALS patients. In the CSF from SALS patients the production of nitrite and hydroxylamine was greater than that observed in the CSF from controls. Moreover, we also found increased Cu,Zn-SOD activity in the CSF from SALS patients (when compared to control subjects) but no activity corresponding to Mn-SOD in any CSF samples. As Cu,Zn-SOD can react with nitroxyl forming NO^?, the conditions for a closed, but continuous, loop of NO^? biotransformation are present in the CSF of ALS patients.     

Arachidonic acid induces an increase of β-1,4-galactosyltransferase I expression in MDA-MB-231 breast cancer cells

Arachidonic acid (AA) is a common dietary n‐6 cis polyunsaturated fatty acid that under physiological conditions is present in an esterified form in cell membrane phospholipids, and it might be present in the extracellular microenvironment. AA and its metabolites are implicated in FAK activation and cell migration in MDA‐MB‐231 breast cancer cells, and an epithelial‐to‐mesenchymal‐like transition process in mammary non‐tumorigenic epithelial cells MCF10A. During malignant transformation is present an altered expression of glycosiltransferases, which promote changes on the glycosilation of cell‐surface proteins. The β‐1,4‐galactosyltransferase I (GalT I) is an enzyme that participates in a variety of biological functions including cell growth, migration, and spreading. However, the participation of AA in the regulation of GalT I expression and the role of this enzyme in the cell adhesion process in breast cancer cells remains to be investigated. In the present study, we demonstrate that AA induces an increase of GalT I expression through a PLA2α, Src, ERK1/2, and LOXs activities‐dependent pathway in MDA‐MB‐231 breast cancer cells. Moreover, MDA‐MB‐231 cells adhere to laminin via GalT I expression and pretreatment of cells with AA induces an increase of cell adhesion to laminin. In conclusion, our findings demonstrate, for the first time, that AA promotes an increase of GalT I expression through an AA metabolism, Src and ERK1/2 activities‐dependent pathway, and that GalT I plays a pivotal role in cell adhesion to laminin in MDA‐MB‐231 breast cancer cells. J. Cell. Biochem. 113: 3330–3341, 2012. © 2012 Wiley Periodicals, Inc.