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1 Cellular injury, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States; Armed Froces Radiobiology Research Institute, Bethesda, Maryland, United States; Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States; Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States
2 Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States
3 Center for Surgical Research, University of Alabama at Birmingham, Birmingham, Alabama, United States
4 Center for Surgical Research, U Alabama at Birmingham, Birmingham, Alabama, United States; , Alabama, United States
5 Cellular Injury, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States; Medicine, Uniformed Services University of The Health Sciences, Bethesda, Maryland, United States
* To whom correspondence should be addressed. E-mail: kiangj{at}comcast.net.
Soft tissue trauma and hemorrhage (T-H) diminishes various aspects of liver function, while it increases hepatic nitrate/nitrite, iNOS and endothelin-1 levels. Treatment with androstenediol (AED) inhibits the T-H-induced alterations of the above parameters. We sought to identify the molecular events underlying the beneficial effect of AED. Exposure of rats to T-H significantly increased the caspase-3 activity and protein while treatment with AED significantly limited these increases. AED treatment also suppressed the T-H-induced increase in iNOS by effectively altering the levels of key transcription factors involved in the regulation of iNOS expression. Immunoprecipitation and immunobloting analysis indicates that T-H increased apoptosome formation and AED treatment significantly decreased it. Modulating the iNOS protein by transfecting cells with iNOS gene or siRNA further confirmed the correlation between iNOS and caspase-3. Our data indicate that AED limits caspase-3 expression by suppressing the expression of transcription factors involved in the production of iNOS resulting in decreased apoptosome. AED can potentially be a useful adjuvant for limiting liver apoptosis following trauma-hemorrhagic shock.
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