To dissect the transcriptional changes induced by protective MTM and SDK treatment and to prioritize candidates for additional study, we performed an unbiased network analysis of the microarray expression profiles, which allows groups of tightly coexpressed genes to be identified across many experimental conditions.Because genes expressed by the same cells or involved in similar functions are often closely coexpressed in modules, large datasets enable such gene groups to be identified. MTM and its ana logs SK and SDK protect pr imary neurons from ox idat ive stress when adm in istered up to severalhours after HCA sign if icant ly protects neurons from ox idat ive stress when adm in istered up to hafter HCA treatment, whereas the SK ana logs cont inue tosign if icant ly protect up to hafter HCA treatment. We reasoned that the optimal time to analyze gene changes induced by MTM, SDK, and SK that are relevant to their respective biological effects would require an understanding of the latest time the drugs can be added and still protect of neurons.To determine the commitment point, we exposed cells to HCA and then added MTM, SK, or SDK at different time points.This is interesting considering that DNA repair is among the top categories affected by MTM and SDK treatment.Of note, p wafcip expression is increased by MTM and SDK treatment.We applied this analysis on the subset of probes affected by both MTM and SDK, SDK. B, DE genes are highly overlapping after treatment with protective doses of MTM and SDK.We also chose these two factors because their DNA binding domains are virtually identical. Based on the accepted mode of action of MTM, it should inhibit both of these proteins to a similar extent.Expression of genes involved in carcinogenesis covaries with protective doses of MTM, SK, and SDK in immature cortical neurons. PreB did not have any effect on any of the constructs.Untreated controls are calculated at luciferase activity.F, MTM significantly induce the expression of a bp p cipwaf promoter driving luciferase.PreB did not have any effect on any of the constructs.Myc is generated by a nonAUG translational start site.Cysteine and histidine residues that coordinate zinc ions are XY1 highlighted in light gray, and protein regions that contact the DNA are highlighted in dark gray.Additionally, our analysis also provides unexpected insights that may require a complete refinement in our understanding of the mode of action of MTM.MTM was identified in a screen for compounds effective in inhibiting tumor cell growth without affecting normal cells. It is also one of the most effective agents tested to date in a worm model and mouse model of HD.Moreover, MTM protects against dopaminergic neurotoxicity in the mouse brain after administration of methamphetamine, suggesting that it may be effective in treating methamphetamine users. Together, these studies highlight its potential therapeutic potential for many cancers as well as CNS diseases characterized by neurodegeneration or acute insults.Translation of MTM to the bedside will be facilitated by the development of analogs that are less toxic and more efficacious.

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