This article is available online at http://dmd.aspetjournals.org ABSTRACT:Even though the degradation of ginsenosides has been thoroughly studied in animals and in vitro using acids, enzymes, and intestinal bacteria, knowledge concerning the systemic availability of ginsenosides and their degradation products in humans is generally lacking. Therefore, the attention in this article is focused on the identification of ginsenosides and their hydrolysis products reaching the systemic circulation in man. This is of great importance in understanding clinical effects, preventing herb-drug interactions, and optimizing the biopharmaceutical properties of ginseng preparations. Using a sensitive mass spectrometric method, which is specific for the identification of ginsenosides in complex biological matrices, the degradation pathway of ginsenosides in the gastrointestinal tract of humans could be elucidated following the oral administration of ginseng. Within the frame of a pilot study, human plasma and urine samples of two subjects were screened for ginsenosides and their possible degradation products. In general, the urine data coincided well with the plasma data. In both volunteers the same hydrolysis products, which are not originally present in the Ginsana extract (Pharmaton S.A., Lugano, Switzerland) ingested, were identified in plasma and urine. It was shown that two hydrolysis products of the protopanaxatriol ginsenosides, namely G-Rh 1 and G-F 1 may reach the systemic circulation. In addition, compound-K, the main intestinal bacterial metabolite of the protopanaxadiol ginsenosides, was detected in plasma and urine. These products are probably responsible for the action of ginseng in humans. In opposition to previous reports, G-Rb 1 was identified in plasma and urine of one subject.

The cyclic derivative of 13(S)-hydroperoxolinolenic acid, 12-oxophytodienoic acid, serves as a signal transducer in higher plants, mediating mechanotransductory processes and plant defenses against a variety of pathogens, and also serves as a precursor for the biosynthesis of jasmonic acid, a mediator of plant herbivore defense. Biosynthesis of 12-oxophytodienoic acid from ␣-linolenic acid occurs in plastids, mainly in chloroplasts, and is thought to start with free linolenic acid liberated from membrane lipids by lipase action. In Arabidopsis thaliana, the glycerolipid fraction contains esterified 12-oxophytodienoic acid, which can be released enzymatically by sn1-specific, but not by sn2-specific, lipases. The 12-oxophytodienoyl glycerolipid fraction was isolated, purified, and characterized. Enzymatic, mass spectrometric, and NMR spectroscopic data allowed us to establish the structure of the novel oxylipin as sn1-O-(12-oxophytodienoyl)-sn2-O-(hexadecatrienoyl)-monogalactosyl diglyceride. The novel class of lipids is localized in plastids. Purified monogalactosyl diglyceride was not converted to the sn1-(12-oxophytodienoyl) derivative by the combined action of (soybean) lipoxygenase and (A. thaliana) allene oxide synthase, an enzyme ensemble that converts free ␣-linolenic acid to free 12-oxophytodienoic acid. When leaves were wounded, a significant and transient increase in the level of (12-oxophytodienoyl)-monogalactosyl diglyceride was observed. In A. thaliana, the major fraction of 12-oxophytodienoic acid occurs esterified at the sn1 position of the plastid-specific glycerolipid, monogalactosyl diglyceride.

Statins have been reported to lower the risk of developing Alzheimer's disease; however, the mechanism of this potentially important neuroprotective action is not understood. Lowering cholesterol levels does not appear to be the primary mechanism. Statins have pleiotropic effects in addition to lowering cholesterol, and statins may act on several different pathways involving distinct gene expression patterns that would be difficult to determine by focusing on a few genes or their products in a single study. In addition, gene expression patterns may be specific to a particular statin. To understand the molecular targets of statins in brain, DNA microarrays were used to identify gene expression patterns in the cerebral cortex of mice chronically treated with lovastatin, pravastatin, and simvastatin. Furthermore, brain statin levels were determined using liquid chromatography/tandem mass spectrometry. These studies revealed 15 genes involved in cell growth and signaling and trafficking that were similarly changed by all three statins. Overall, simvastatin had the greatest influence on expression as demonstrated by its ability to modify the expression of 23 genes in addition to those changed by all three drugs. Of particular interest was the expression of genes associated with apoptotic pathways that were altered by simvastatin. Reverse transcription-polymerase chain reaction experiments confirmed the microarray findings. All three drugs were detected in the cerebral cortex, and acute experiments revealed that statins are relatively rapidly removed from the brain. These results provide new insight into possible mechanisms for the potential efficacy of statins in reducing the risk of Alzheimer's disease and lay the foundation for future studies.