Comparative antioxidant, prooxidant and cytotoxic activity of sigmoidin A and eriodictyol

Sigmoidin A (SGN) is a prenylated flavanone derivative of eriodictyol (ERD) with reported moderate antioxidant, antimicrobial and anti-inflammatory activity. Since ERD and other structurally similar antioxidant phenolic compounds have been shown to induce prooxidative macromolecular damage and cytotoxicity in cancer cells, the comparative in vitro effects of these structural analogues on cancer cell viability and Cu(II)-dependent DNA damage were studied. In the presence of Cu(II) ions, both SGN and ERD (7.4-236 µM) caused comparable concentration-dependent pBR322 plasmid DNA strand scission. The DNA damage induced by SGN and ERD could be abolished by ROS scavengers, glutathione (GSH) and catalase as well as EDTA and a specific Cu(I) chelator neocuproine. Both ERD and SGN readily reduce Cu(II) to Cu(I) suggesting a prooxidative mechanism of DNA damage. In a cell free system, ERD and SGN did also show comparable radical scavenging activity. SGN was, however, by an order of magnitude more cytotoxic to cancer cells than ERD and this effect was significantly attenuated by GSH suggesting a prooxidative mechanism of cell death. A depletion of intracellular GSH level by SGN in cancer cells is also demonstrated.

Polyunsaturated fatty acids in the pathogenesis and treatment of multiple sclerosis

Epidemiological, biochemical, animal model and clinical trial data described in this overview strongly suggest that polyunsaturated fatty acids, particularly n-6 fatty acids, have a role in the pathogenesis and treatment of multiple sclerosis (MS). Data presented provides further evidence for a disturbance in n-6 fatty acid metabolism in MS. Disturbance of n-6 fatty acid metabolism and dysregulation of cytokines are shown to be linked and a "proof of concept clinical trial" further supports such a hypothesis. In a randomised double-blind, placebo controlled trial of a high dose and low dose selected GLA (18:3n-6)-rich oil and placebo control, the high dose had a marked clinical effect in relapsing-remitting MS, significantly decreasing the relapse rate and the progression of disease. Laboratory findings paralleled clinical changes in the placebo group in that production of mononuclear cell pro-inflammatory cytokines (TNF-alpha, IL-1 beta) was increased and anti-inflammatory TGF-beta markedly decreased with loss of membrane n-6 fatty acids linoleic (18:2n-6) and arachidonic acids (20:4n-6). In contrast there were no such changes in the high dose group. The improvement in disability (Expanded Disability Status Scale) in the high dose suggests there maybe a beneficial effect on neuronal lipids and neural function in MS. Thus disturbed n-6 fatty acid metabolism in MS gives rise to loss of membrane long chain n-6 fatty acids and loss of the anti-inflammatory regulatory cytokine TGF-beta, particularly during the relapse phase, as well as loss of these important neural fatty acids for CNS structure and function and consequent long term neurological deficit in MS.

Probabilistic modeling of structural deterioration of reinforced concrete beams under saline environment corrosion

For existing reinforced concrete structures exposed to saline or marine conditions, there is an increasing engineering interest in their remaining safety and serviceability. A significant factor is the corrosion of steel reinforcement. At present there is little field experience and other data available. This limits the possibility for developing purely empirical models for strength and performance deterioration for use in structural safety and serviceability assessment. An alternative approach using theoretical concepts and probabilistic modeling is proposed herein. It is based on the evidence that the rate of diffusion of chlorides is influenced by internal damage to the concrete surrounding the reinforcement. This may be due to localized stresses resulting from external loading or through concrete shrinkage. Usually, the net effect is that the time to initiation of active corrosion is shortened, leading to greater localized corrosion and earlier reduction of ultimate capacity and structural stiffness. The proposed procedure is applied to an example beam and compared to experimental observations,including estimates of uncertainty in the remaining ultimate moment capacity and beam stiffness. Reasonably good agreement between the results of the proposed procedure and the experiment was found