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Sebastian, B.

Publications and source records attributed to Sebastian, B..

2 recordsLinked to original sources

Discovery and Visualization of Age-dependent Patterns in the Diurnal Transcriptome of Drosophila

Many critical life processes are regulated by input from 24-hour external light/dark cycles, such as metabolism, cellular homeostasis, and detoxification. The circadian clock, which helps coordinate the response to these diurnal light/dark cycles, remains rhythmic across lifespan; however, rhythmic transcript expression is altered during normal aging. To better understand how aging impacts diurnal expression, we present an improved Fourier-based method for detecting and visualizing rhythmicity that is based on the relative power of the 24-hour period compared to other periods (RP24). We apply RP24 to transcript-level expression profiles from the heads of young (5-day) and old (55-day) Drosophila melanogaster, and reveal novel age-dependent rhythmicity changes that may be masked at the gene level. We show that core clock transcripts phase advance during aging, while most rhythmic transcripts phase delay. Transcripts rhythmic only in young flies tend to peak before lights on, while transcripts only rhythmic in old peak after lights on. We show that several pathways including glutathione metabolism, gain or lose coordinated rhythmic expression with age providing insight into possible mechanisms of age-onset neurodegeneration. Remarkably, we find that many pathways show very robust coordinated rhythms across lifespan, highlighting their putative roles in promoting neural health. We investigate statistically enriched transcription factor binding site motifs that may be involved in these rhythmicity changes.

systems biology↗

ω-imidazolyl-alkyl derivatives as new preclinical drug candidates for NASH therapy

Cytochrome P450 2E1 (CYP2E1) and its production of ROS play an essential role in the development and progression of inflammatory liver diseases such as alcoholic steatohepatitis. For this isoenzyme we have developed two new inhibitors - 12-imidazolyl-1-dodecanol (I-ol) and 1-imidazolyldodecane (I-an) - and wanted to test their effect on the related disease of non-alcoholic steatohepatitis (NASH). The fat-rich Lieber-DeCarli diet, which was administered over the entire experimental period of 16 weeks, was used for disease induction in the rat model, while the experimental substances were administered in parallel over the last four weeks. This high-calorie diet pathologically altered the ROS balance, the amount of adipocytokines, TNF- and lipids as well as the activities of liver enzymes. Together with the histological examinations, the conclusion could be drawn that the diet led to the formation of NASH. I-ol and to a lesser extent I-an were able to shift the pathological values towards the normal range - despite continued administration of the noxious agent. I-ol, in particular, showed an extremely good tolerability in the acute toxicity study in rats. Thus, CYP2E1 appears to be a suitable drug target as well as I-ol and I-an promising drug candidates for the treatment of NASH.

pharmacology and toxicology↗