Metabolomics is the methodology that identifies and measures global pools of small molecules (of less than about 1,000 Da) of a biological sample, which are collectively called the metabolome. Metabolomics can therefore reveal the metabolic outcome of a genetic or environmental perturbation of a metabolic regulatory network, and thus provide insights into the structure and regulation of that network. Because of the chemical complexity of the metabolome and limitations associated with individual analytical platforms for determining the metabolome, it is currently difficult to capture the complete metabolome of an organism or tissue, which is in contrast to genomics and transcriptomics. This paper describes the analysis of Arabidopsis metabolomics data sets acquired by a consortium that includes five analytical laboratories, bioinformaticists, and biostatisticians, which aims to develop and validate metabolomics as a hypothesis-generating functional genomics tool. The consortium is determining the metabolomes of Arabidopsis T-DNA mutant stocks, grown in standardized controlled environment optimized to minimize environmental impacts on the metabolomes. Metabolomics data were generated with seven analytical platforms, and the combined data is being provided to the research community to formulate initial hypotheses about genes of unknown function (GUFs). A public database () has been developed to provide the scientific community with access to the data along with tools to allow for its interactive analysis. Exemplary datasets are discussed to validate the approach, which illustrate how initial hypotheses can be generated from the consortium-produced metabolomics data, integrated with prior knowledge to provide a testable hypothesis concerning the functionality of GUFs.

Human (h) DNA repair enzyme thymine DNA glycosylase (hTDG) is a key DNA glycosylase in the base excision repair (BER) pathway that repairs deaminated cytosines and 5-methyl-cytosines. The cell cycle checkpoint protein Rad9–Rad1–Hus1 (the 9-1-1 complex) is the surveillance machinery involved in the preservation of genome stability. In this study, we show that hTDG interacts with hRad9, hRad1 and hHus1 as individual proteins and as a complex. The hHus1 interacting domain is mapped to residues 67–110 of hTDG, and Val74 of hTDG plays an important role in the TDG–Hus1 interaction. In contrast to the core domain of hTDG (residues 110–308), hTDG(67–308) removes U and T from U/G and T/G mispairs, respectively, with similar rates as native hTDG. Human TDG activity is significantly stimulated by hHus1, hRad1, hRad9 separately, and by the 9-1-1 complex. Interestingly, the interaction between hRad9 and hTDG, as detected by co-immunoprecipitation (Co-IP), is enhanced following N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) treatment. A significant fraction of the hTDG nuclear foci co-localize with hRad9 foci in cells treated with methylating agents. Thus, the 9-1-1 complex at the lesion sites serves as both a damage sensor to activate checkpoint control and a component of the BER.

Aims: Oxidative burst is one of the earliest biochemical events in the inflammatory activation of microglia. Here, we investigated the potential role of methionine sulfoxide reductase A (MsrA), a key antioxidant enzyme, in the control of microglia-mediated neuroinflammation. Results: MsrA was detected in rat microglia and its expression was upregulated on microglial activation. Silencing of MsrA exacerbated lipopolysaccharide (LPS)-induced activation of microglia and the production of inflammatory markers, indicating that MsrA may function as an endogenous protective mechanism for limiting uncontrolled neuroinflammation. Application of exogenous MsrA by transducing Tat-rMsrA fusion protein into microglia attenuated LPS-induced neuroinflammatory events, which was indicated by an increased Iba1 (a specific microglial marker) expression and the secretion of pro-inflammatory cytokines, and this attenuation was accompanied by inhibiting multiple signaling pathways such as p38 and ERK mitogen-activated protein kinases (MAPKs) and nuclear factor kappaB (NF-jB). These effects were due to MsrA-mediated reactive oxygen species (ROS) elimination, which may be derived from a catalytic effect of MsrA on the reaction of methionine with ROS. Furthermore, the transduction of Tat-rMsrA fusion protein suppressed the activation of microglia and the expression of pro-inflammatory factors in a rat model of neuroinflammation in vivo. Innovation: This study provides the first direct evidence for the biological significance of MsrA in microglia-mediated neuroinflammation. Conclusion: Our data provide a profound insight into the role of endogenous antioxidative defense systems such as MsrA in the control of microglial function. Antioxid. Redox Signal. 22, 832-847.

These results suggest a pathological role of increased H2 S level in SLEs in vivo and in vitro. Enzymes that control H2 S biosynthesis could be interesting targets for antiepileptic strategies in poststroke epilepsy treatment.

The expression levels of estrogen receptor (ER α) are closely associated with estrogen-dependent growth, invasion and response to endocrine therapy in ERα-positive ovarian cancer. However, the underlying regulatory mechanisms remain to be fully understood. Previous studies have demonstrated that ERα is a direct target of microRNA (miR)-206. miR-206 has been found to be an important tumor suppressor in several cancer types, including ovarian, gastric and laryngeal cancer. However, the specific role of miR-206 in ovarian cancer remains unclear. The aim of the present study was to investigate the role of miR-206 in ER-a positive ovarian cancer in vitro. The present study demonstrated that miR-206 is significantly downregulated in ERα-positive but not ERα‑negative ovarian cancer tissues, compared with normal ovarian epithelium tissue. It was also found that the expression of miR-206 was decreased in ERα-positive ovarian cancer cell lines, CAOV-3 and BG-1, compared with normal ovarian epithelium tissues. This suggests that miR-206 may play a role in ERα-positive ovarian cancer cells via an estrogen-dependent mechanism. Further analysis revealed that 17β-E2 treatment significantly promoted cellular proliferation and invasion of estrogen-dependent CAOV-3 and BG-1 cells, which could be reversed by the introduction of miR-206 mimics. In conclusion, the present study suggests that miR-206 has an inhibitory role in estrogen-dependent ovarian cancer cells. Thus, miR-206 may be a promising candidate for the endocrine therapy of ERα-positive ovarian cancer.