The plant natural product 2-methoxy-1,4-naphthoquinone stimulates therapeutic neural repair properties of olfactory ensheathing cells.

Olfactory ensheathing cells (OECs) are crucial for promoting the regeneration of the primary olfactory nervous system that occurs throughout life. Transplantation of OECs has emerged as a promising therapy for nervous system injuries, in particular for spinal cord injury repair. Functional outcomes in both animals and humans are, however, highly variable, primarily because it is difficult to rapidly obtain enough OECs for transplantation. Compounds which can stimulate OEC proliferation without changing the phenotype of the cells are therefore highly sought after. Additionally, compounds which can stimulate favourable cell behaviours such as migration and phagocytic activity are desirable. We conducted a medium-throughput screen testing the Davis open access natural product-based library (472 compounds) and subsequently identified the known plant natural product 2-methoxy-1,4-naphthoquinone as a stimulant of OEC viability. We showed that 2-methoxy-1,4-naphthoquinone: (i) strongly stimulates proliferation over several weeks in culture whilst maintaining the OEC phenotype; (ii) stimulates the phagocytic activity of OECs, and (iii) modulates the cell cycle. We also identified the transcription factor Nrf2 as the compound's potential molecular target. From these extensive investigations we conclude that 2-methoxy-1,4-naphthoquinone may enhance the therapeutic potential of OECs by stimulating proliferation prior to transplantation.

Acute selenium selenite exposure effects on oxidative stress biomarkers and essential metals and trace-elements in the model organism zebrafish (Danio rerio).

Selenium (Se) is an essential trace-element that becomes toxic when present at high concentrations. Little is known regarding Se effects on parameters such as oxidative stress biomarkers. The aim of the present study was to investigate the effects of acute selenium exposure on oxidative stress biomarkers in a model organism, zebrafish (Danio rerio). Fish were exposed to selenium selenite at 1mgL(-1). Reduced glutathione (GSH), and metallothionein (MT) concentrations were determined in liver, kidney and brain, with MT also being determined in bile. Essential metals and trace-elements were also determined by inductively coupled mass spectrometry (ICP-MS) in order to verify possible metal homeostasis alterations. GSH concentrations in liver, kidney and brain increased significantly (1.05±0.03µmolg(-1) ww, 1.42±0.03µmolg(-1) ww and 1.64±0.03µmolg(-1) ww, respectively) in the Se-exposed group when compared to the controls (0.88±0.05µmolg(-1) ww, 0.80±0.04µmolg(-1) ww and 0.89±0.03µmolg(-1) ww for liver, kidney and brain, respectively). MT levels in Se-exposed liver (0.52±0.03µmolg(-1) ww) decreased significantly in comparison to the control group (0.64±0.02µmolg(-1) ww), while levels in bile increased, albeit non-significantly. This is in accordance with previous studies that indicate efficient biliary MT action, leading to a rapid metabolism and elimination of contaminants from the body. Levels in the brain increased significantly after Se-exposure (0.57±0.01µmolg(-1) ww) when compared to the control group (0.35±0.03µmolg(-1) ww) since this organ does not present a detoxification route as quick as the liver-gallbladder route. Several metal and trace-elements were altered with Se-exposure, indicating that excess of selenium results in metal dyshomeostasis. This is the first report on metal dyshomeostasis due to Se-exposure, which may be the first step in the mechanism of action of selenium toxicity, as is postulated to occur in certain major human pathophysiologies.

A benzylisoquinoline alkaloid from Doryphora sassafras.

Chemical investigation of the Australian rainforest plant Doryphora sassafras has resulted in the isolation of a new natural product, 2-methyl-1-(p-methoxybenzyl)-6,7-methylenedioxyisoquinolinium chloride (1). The iodide salt of compound 1 has previously been synthesized but only partially characterized. This paper reports the full spectroscopic characterization of 1 by MS, IR, UV, and NMR data.

Cholesterol 7alpha-hydroxylase influences the expression of hepatic apoA-I in two inbred mouse strains displaying different susceptibilities to atherosclerosis and in hepatoma cells.

C57BL/6 mice are susceptible to diet-induced atherosclerosis, whereas BALB/c mice are resistant. The susceptibility of C57BL/6 mice has been linked to decreased plasma HDL cholesterol in response to a diet containing fat, cholesterol, and cholic acid. Feeding C57BL/6 mice a diet consisting of fat and cholesterol, but no cholic acid, increased plasma high density lipoprotein (HDL) cholesterol. The increase in HDL was associated with increases in both plasma apolipoprotein (apo)A-I and hepatic apoA-I mRNA. Supplementation of the cholesterol-rich diet with cholic acid inhibited the stimulatory effect of cholesterol on hepatic apoA-I mRNA expression, resulting in similar hepatic apoA-I mRNA levels compared to chow-fed mice. Atherosclerosis-resistant BALB/c mice were also resistant to diet-induced changes in plasma HDL, apoA-I, and hepatic apoA-I mRNA levels. Previous studies showed that the diets changed both the activity and mRNA encoding the liver specific enzyme 7alpha-hydroxylase (1993.J. Lipid Res. 34: 923-931). In both strains of mice, hepatic expression of apoA-I and 7alpha-hydroxylase mRNA varied in parallel. Whereas susceptible C57BL/6 mice also showed a significant correlation between HDL cholesterol and expression of 7alpha-hydroxylase, no such correlation was observed in BALB/c mice, suggesting that genetic differences in HDL metabolism, not hepatic apoA-I synthesis, are responsible for the strain specific differences in plasma HDL levels. The finding that lecithin: cholesterol acyltransferase (LCAT) activity was significantly decreased in C57BL/6 mice, but not in BALB/ c mice fed the atherogenic diet, further supports this conclusion. Additional studies show that McArdle hepatoma cells stably expressing plasmid-derived rat 7alpha-hydroxylase recapitulated the parallel linear relationship between 7alpha-hydroxylase and apoA-I mRNA expression observed in both strains of mice. These data link hepatic apoA-I mRNA expression to hepatic cholesterol/bile acid metabolism.

Dietary nicotine: a source of urinary cotinine.

Foods, principally from plants in the family Solanaceae, and a number of teas were examined for the presence of nicotine. Dietary nicotine would give rise to cotinine in urine and compromise estimates of exposure to tobacco smoke that depend on urinary cotinine. All foods were homogenized, extracted and analysed for nicotine and cotinine by gas chromatography with nitrogen-sensitive detection (GC) and/or GC/MS (mass spectrometry). Weak acid and aqueous extracts of the teas were analysed in a similar manner. Nicotine was not detected (less than 1 ng/ml of extract) in egg plant or green pepper. The average values for nicotine in tomato and potato were 7.3 ng/g wet weight and 15 ng/g wet weight, respectively. Black teas, including regular and decaffeinated brands, had nicotine contents ranging from non-detectable to greater than 100 ng/g wet weight. Instant teas yielded the highest nicotine contents observed (up to 285 ng/g wet weight). The possible sources of nicotine in these foods are discussed. A range of potential values for urinary cotinine concentrations (0.6 to 6.2 ng/ml) was calculated based upon estimated average and maximal consumptions of these foods and beverages. Because of the potential for exposure to nicotine by way of these routes, the use of urinary cotinine as a biomarker of exposure to environmental tobacco smoke may be compromised.

Teenage pregnancy: a theoretical analysis of a social problem.

This paper begins by contrasting the two basic ways of defining a social problem (i.e., as a "problem" in society or of society). The implications of these two definitions are discussed within the context of the various approaches which have emerged from each. A typology is then developed which allows these divergent approaches to be synthesized into three broad categories (Social Disorganizational, Social Definitional, and Social Organizational). This typology helps to further clarify the implications of isolating certain noxious conditions (whether personal or social) and conceptualizing them as social problems. These implications for the emergence, scope, and possible solution to the problem of teenage pregnancy are discussed. The paper concludes with a theoretical critique that leaves little room for optimism about the piecemeal solutions to teenage pregnancy offered by either the social disorganizational or the social definitional approaches, yet it recognizes the unlikely prospects that the holistic solution is likely to be adopted soon. The paper thus concludes that this problem is likely to be with us for some time to come, and the best that we can hope to do is to treat the symptoms.