June 22, 2007

Aliquots — Research highlights from VUMC laboratories

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‘Poisons’ in fruits and veggies

Bioflavonoids — components of fruits, vegetables and legumes — are associated with the prevention of a range of diseases including cancer. But the compounds have a dark side too: they can damage DNA and may trigger infant leukemias, effects attributed to their activity as “topoisomerase II poisons.” Topoisomerase II enzymes normally remove knots and tangles in the DNA, by transiently cutting it; “poisons” increase this cleavage activity and generate permanent breaks.

Biochemistry graduate student Omari Bandele and his adviser Neil Osheroff, Ph.D., characterized the activity and mechanism of action of three major classes of bioflavonoids against human topoisomerase IIa and IIb. Of the bioflavonoids tested, genistein — a component of soy beans — was most active, stimulating topoisomerase II-mediated DNA cleavage 10-fold. Certain bioflavonoids also enhanced DNA cleavage in human leukemia cells. The findings, reported May 22 in Biochemistry, support the hypothesis that bioflavonoids act as topoisomerase II poisons and provide a framework for future studies of these dietary compounds.

— Leigh MacMillan

Immune link to schizophrenia

A combination of genetic and environmental factors likely contributes to the complex etiology of schizophrenia. Previous investigations into the molecular underpinnings of schizophrenia have focused largely on brain-specific processes, including neurotransmitter systems and their receptors.

Karoly Mirnics, M.D., and colleagues now report that a novel set of genes related to immune function may contribute to the development and ongoing clinical symptoms of the illness. Using a custom 1800-gene microarray, the researchers compared gene expression patterns of postmortem prefrontal cortex samples from controls and patients with schizophrenia. Among the 67 differentially regulated transcripts identified, the researchers found a significant upregulation of immune/chaperone genes in subjects with schizophrenia.

Since there was no evidence of acute immune activity, the results, reported in the journal Biological Psychiatry, suggest that this immune transcriptome signature represents an early environmental insult during development that actively contributes to clinical features of the illness later in life.

— Melissa Marino

Progesterone’s fertile signals

Despite the fact that progesterone is known as the “hormone of pregnancy,” how it supports embryo implantation and maintains pregnancy is not entirely understood. Graduate student Susanne Tranguch, S.K. Dey, Ph.D., and colleagues are using mouse models to probe progesterone's actions. In previous studies, the investigators discovered that FKBP52, a co-chaperone molecule that optimizes progesterone receptor signaling, plays a role in female reproduction: mice lacking the Fkbp52 gene have complete implantation failure.

Now the investigators report that progesterone supplementation restores embryo implantation in Fkbp52 knockout mice on one genetic background, but not another, and that to maintain the pregnancy past implantation requires higher levels of daily progesterone. They conclude that progesterone signaling is a function of genetic makeup and pregnancy stage. The findings in the July issue of the Journal of Clinical Investigation have clinical relevance for women who are infertile and/or have endometriosis due to progesterone resistance.

— Leigh MacMillan

New target for mood disorder meds?

Appetite, sex drive and mood all rely on signaling by the neurotransmitter serotonin. One of the molecules that regulates this signaling is the serotonin transporter (SERT), which inactivates serotonin by removing it from the neuronal synapse and is an important target for antidepressants.

Randy Blakely, Ph.D., Chong-Bin Zhu, Ph.D., and colleagues have identified a new regulator of SERT. They report in the Journal of Pharmacology and Experimental Therapeutics that activation of A3 adenosine receptors increases serotonin transport in mouse brain nerve terminal preparations. The regulation of SERT was absent in preparations from mice lacking the A3 adenosine receptor, or when signaling pathways between the A3 receptor and SERT were blocked. The investigators also used serotonin-sensitive electrodes in rats to confirm that A3 adenosine receptors can enhance serotonin clearance in vivo.

The findings suggest that variants in the A3 adenosine receptor or its signaling partners may confer risk for mood disorders and represent a novel target for antidepressant development.

— Leigh MacMillan

We welcome suggestions for research to highlight in Aliquots. The items should be primary research articles (no reviews, editorials or commentaries) published within the last two months in a peer-reviewed journal. Please send the article citation (PDF if available) and any other feedback about the column to: aliquots@vanderbilt.edu.

Past Aliquots

June 22, 2012
June 8, 2012
May 11, 2012
April 27, 2012
April 13, 2012
March 30, 2012
March 16, 2012