Pharmacology Commons^™

Molecular Mechanisms Underlying The Early Life Programming Of The Liver, Gurjeev Sohi

Electronic Thesis and Dissertation Repository

Clinical studies have demonstrated that intrauterine growth restriction (IUGR) offspring, faced with a nutritional mismatch postpartum, have an increased risk of developing the metabolic syndrome. The maternal protein restriction (MPR) rat model has been extensively studied to investigate the adverse effects of a nutritional mismatch in postnatal life of IUGR offspring. Previous studies have demonstrated that MPR leads to impaired function of the liver, an important metabolic organ. However the underlying mechanisms which predispose these offspring to the metabolic syndrome remain elusive. In the following studies, low protein diet during pregnancy and lactation led to IUGR offspring with decreased liver …

N-Acetylcysteine As A Chemoprotectant Against Ifosfamide Nephrotoxicity; From Mechanism To Prevention, Lauren Hanly

Electronic Thesis and Dissertation Repository

The chemotherapy drug ifosfamide is used in the treatment of several childhood cancers. While effective, its use in children results in a 30% incidence of nephrotoxicity, and 5% incidence of Fanconi syndrome. This late effect is caused by oxidative damage, generated by chloroacetaldehyde, a toxic metabolite of ifosfamide cytochrome P450-mediated bioactivation in the kidney tubules. N-acetylcysteine has been identified as a promising strategy to mitigate nephrotoxicity through its antioxidant and glutathione stimulating properties. Furthermore, with current use in children for acetaminophen poisoning, its clinical utility is evident. Both cell and animal models have demonstrated n-acetylcysteine’s effectiveness in mitigating ifosfamide kidney …

Mechanism Of Ascorbate Protection Against Sepsis-Induced Capillary Blood Flow Impairment, Dan Secor

Electronic Thesis and Dissertation Repository

Sepsis is a systemic inflammatory response to an infection. The overwhelming inflammation has many deleterious effects, including cessation of capillary blood flow. This cessation may lead to organ failure and subsequent death, but the cause of cessation during sepsis is not fully understood. Ascorbate (reduced vitamin C) has been shown to restore capillary blood flow by an unknown mechanism. I hypothesized that activation of both platelets and the coagulation pathway in sepsis contributes to the cessation of capillary blood flow and that ascorbate protects against cessation by reducing platelet activation.

Using intravital microscopy in the mouse hindlimb skeletal muscle in …