Xanthohumol improved cognitive flexibility in young mice.

The protein palmitoylation cycle has been shown to be important for protein signaling and synaptic plasticity. Data from our lab showed a change in the palmitoylation status of certain proteins with age. A greater percentage of the NMDA receptor subunits GluN2A and GluN2B, along with Fyn and PSD95 proteins, were palmitoylated in the old mice. The higher level of protein palmitoylation was also associated with poorer learning scores. Xanthohumol is a prenylated flavonoid that has been shown to increase beta-oxidation in the livers of rodents, decreasing circulating free fatty acids in the serum. What is not known is whether the application of xanthohumol could influence the palmitoylation status of proteins. In this study, young and old mice were fed a diet supplemented with xanthohumol for 8 weeks. Spatial memory was assessed with the Morris water maze and protein palmitoylation quantified. The young xanthohumol-treated mice showed a significant improvement in cognitive flexibility. However, this appeared to be associated with the young control mice, on a defined, phytoestrogen-deficient diet, performing as poorly as the old mice and xanthohumol reversing this effect. The old mice receiving xanthohumol did not significantly improve their learning scores. Xanthohumol treatment was unable to affect the palmitoylation of NMDA receptor subunits and associated proteins assessed in this study. This evidence suggests that xanthohumol may play a role in improving cognitive flexability in young animals, but it appears to be ineffective in adjusting the palmitoylation status of neuronal proteins in aged individuals.

Flavin-containing monooxygenase S-oxygenation of a series of thioureas and thiones.

Mammalian flavin-containing monooxygenase (FMO) is active towards many drugs with a heteroatom having the properties of a soft nucleophile. Thiocarbamides and thiones are S-oxygenated to the sulfenic acid which can either react with glutathione and initiate a redox-cycle or be oxygenated a second time to the unstable sulfinic acid. In this study, we utilized LC-MS/MS to demonstrate that the oxygenation by hFMO of the thioureas under test terminated at the sulfenic acid. With thiones, hFMO catalyzed the second reaction and the sulfinic acid rapidly lost sulfite to form the corresponding imidazole. Thioureas are often pulmonary toxicants in mammals and, as previously reported by our laboratory, are excellent substrates for hFMO2. This isoform is expressed at high levels in the lung of most mammals, including non-human primates. Genotyping to date indicates that individuals of African (up to 49%) or Hispanic (2-7%) ancestry have at least one allele for functional hFMO2 in lung, but not Caucasians nor Asians. In this study the major metabolite formed by hFMO2 with thioureas from Allergan, Inc. was the sulfenic acid that reacted with glutathione. The majority of thiones were poor substrates for hFMO3, the major form in adult human liver. However, hFMO1, the major isoform expressed in infant and neonatal liver and adult kidney and intestine, readily S-oxygenated thiones under test, with Kms ranging from 7 to 160 µM and turnover numbers of 30-40 min(-1). The product formed was identified by LC-MS/MS as the imidazole. The activities of the mouse and human FMO1 and FMO3 orthologs were in good agreement with the exception of some thiones for which activity was much greater with hFMO1 than mFMO1.

Identifying Rates of Meadowfoam (Limnanthes alba) Seed Meal Needed for Suppression of Meloidogyne hapla and Pythium irregulare in Soil.

Meadowfoam (Limnanthes alba) is a commercial oilseed annual crop grown in Oregon. After extracting oil from seed, the remaining seed meal is rich in the secondary plant metabolite glucolimnanthin, which can be converted into pesticidal compounds such as 3-methoxybenzyl isothiocyanate (ITC) and 3-methoxyphenylacetonitrile (nitrile) in the presence of the enzyme myrosinase. In previous studies, we demonstrated that ITC and nitrile, produced by mixing freshly ground meadowfoam seed with meadowfoam seed meal, are toxic to the plant-parasitic nematode Meloidogyne hapla and the plant pathogen Pythium irregulare. In this study, we evaluated factors that might influence the implementation of meadowfoam seed meal into agricultural production systems for soilborne pathogen and nematode control. Rate-finding experiments demonstrated that a minimum 1.0% seed/seed meal formulation (wt/wt) was necessary to achieve nematode and pathogen suppression; seed meal alone was insufficient for complete control of M. hapla and stimulated the growth of P. irregulare. When this 1.0% seed/seed meal formulation was used, a greater soil amendment rate was required to cause 100% mortality of P. irregulare (1.0% wt/wt) than for M. hapla (0.5% wt/wt). In phytotoxicity experiments, soil amended with the 1.0% seed/seed meal formulation was consistently phytotoxic to wheat, cucumber, and tomato. However, phytotoxic effects were mitigated by a delayed planting into the amended soil. A final assay to monitor concentrations of ITC and nitrile in conjunction with assessing M. hapla and P. irregulare mortality was conducted over a 6-day period in soils amended at 0.5 and 1.0% (wt/wt) with the 1.0% seed/seed meal formulation. The response was rapid, with 100% mortality of both organisms within 2 h after exposure to amended soil. Concentrations of nitrile remained relatively constant over the 6-day period (approximately 0.017 and 0.032 mg/ml at 0.5 and 1.0% amendment rates, respectively), whereas ITC production increased rapidly and peaked 12 to 24 h after amendment (0.083 and 0.171 mg/ml at 0.5 and 1.0% amendment rates, respectively) before returning to near undetectable levels.