HMDB: a knowledgebase for the human metabolome.

The Human Metabolome Database (HMDB, http://www.hmdb.ca) is a richly annotated resource that is designed to address the broad needs of biochemists, clinical chemists, physicians, medical geneticists, nutritionists and members of the metabolomics community. Since its first release in 2007, the HMDB has been used to facilitate the research for nearly 100 published studies in metabolomics, clinical biochemistry and systems biology. The most recent release of HMDB (version 2.0) has been significantly expanded and enhanced over the previous release (version 1.0). In particular, the number of fully annotated metabolite entries has grown from 2180 to more than 6800 (a 300% increase), while the number of metabolites with biofluid or tissue concentration data has grown by a factor of five (from 883 to 4413). Similarly, the number of purified compounds with reference to NMR, LC-MS and GC-MS spectra has more than doubled (from 380 to more than 790 compounds). In addition to this significant expansion in database size, many new database searching tools and new data content has been added or enhanced. These include better algorithms for spectral searching and matching, more powerful chemical substructure searches, faster text searching software, as well as dedicated pathway searching tools and customized, clickable metabolic maps. Changes to the user-interface have also been implemented to accommodate future expansion and to make database navigation much easier. These improvements should make the HMDB much more useful to a much wider community of users.

Homocysteine induces 3-hydroxy-3-methylglutaryl coenzyme a reductase in vascular endothelial cells: a mechanism for development of atherosclerosis?

BACKGROUND: It has been established that hyperhomocyst(e)inemia (HHCy) is an independent and graded risk factor for atherosclerosis, although the molecular link to the atherosclerotic process remains obscure. METHODS AND RESULTS: Screening human umbilical vein endothelial cells (HUVECs) with complementary DNA microarray for the gene expression modified by homocysteine (Hcy) revealed that 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) was upregulated. This effect was confirmed using quantitative reverse transcriptase-polymerase chain reaction. Actinomycin D studies revealed that Hcy stabilized HMGCR mRNA (tau(1/2), 9.5 +/- 1.0 versus 5.0 +/- 0.2 hours). Expression of immunodetectable HMGCR in both HUVECs and renal microvascular endothelial cells was increased in Hcy-treated cells in association with the increased abundance of caveolin. Application of a cell-permeable superoxide dismutase mimetic, Mn-TBAP, reversed the Hcy-induced expression of HMGCR. Additional biochemical analysis of the abundance of total cellular cholesterol showed that 0, 20, 50, and 100 micromol/L Hcy resulted in 22.2 +/- 7.3%, 39.5 +/- 1.2%, and 50.4 +/- 6.8% increase, respectively. Gas chromatography mass spectrometry analysis of extracted cholesterol from Hcy-treated HUVECs and from the culture medium showed 17.8 +/- 5.2% and 24.0 +/- 14.5% increases, respectively. Application of simvastatin to Hcy-treated cells reduced cellular cholesterol and prevented Hcy-induced suppression of NO production by HUVECs in a dose-dependent manner. CONCLUSIONS: Using a cDNA microarray, the data disclosed an unexpected link between Hcy and cholesterol dysregulation based on the finding of increased abundance of HMGCR mRNA and protein in endothelial cells, demonstrated the possible role of Hcy-induced oxidative stress in this response, and revealed the improvement of endothelial NO production in Hcy-treated HUVECs by statins. Collectively, these findings may provide a solid explanation for the observed proatherogenic effect of HHcy.