45 research outputs found

    Progesterone Metabolism by Human and Rat Hepatic and Intestinal Tissue

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    Following oral administration, the bioavailability of progesterone is low and highly variable. As a result, no clinically relevant, natural progesterone oral formulation is available. After oral delivery, first-pass metabolism initially occurs in the intestines; however, very little information on progesterone metabolism in this organ currently exists. The aim of this study is to investigate the contributions of liver and intestine to progesterone clearance. In the presence of NADPH, a rapid clearance of progesterone was observed in human and rat liver samples (t1/2 2.7 and 2.72 min, respectively). The rate of progesterone depletion in intestine was statistically similar between rat and human (t1/2 197.6 min in rat and 157.2 min in human). However, in the absence of NADPH, progesterone was depleted at a significantly lower rate in rat intestine compared to human. The roles of aldo keto reductases (AKR), xanthine oxidase (XAO) and aldehyde oxidase (AOX) in progesterone metabolism were also investigated. The rate of progesterone depletion was found to be significantly reduced by AKR1C, 1D1 and 1B1 in human liver and by AKR1B1 in human intestine. The inhibition of AOX also caused a significant reduction in progesterone degradation in human liver, whereas no change was observed in the presence of an XAO inhibitor. Understanding the kinetics of intestinal as well as liver metabolism is important for the future development of progesterone oral formulations. This novel information can inform decisions on the development of targeted formulations and help predict dosage regimens

    Epitaxial graphene immunosensor for human chorionic gonadotropin

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    Human chorionic gonadotropin (hCG), a 37 kDa glycoprotein hormone, is a key diagnostic marker of pregnancy and has been cited as an important biomarker in relation to cancerous tumors found in the prostate, ovaries and bladder.A novel chemically-modified epitaxial graphene diagnostic sensor has been developed for ultrasensitive detection of the biomarker hCG. Multi-layer epitaxial graphene (MEG), grown on silicon carbide substrates, was patterned using electron beam lithography to produce channel based devices. The MEG channels have been amine terminated using 3-Aminopropyl-triethoxysilane (APTES) in order to attach the anti-hCG antibody to the channel.Detection of binding of hCG with its graphene-bound antibody was monitored by measuring reduction of the channel current of the graphene biosensor. The sensitivity of the sensor device was investigated using varying concentrations of hCG, with changes in the channel resistance of the sensor observed upon exposure to hCG. The detection limit of the sensor was 0.62 ng/mL and the sensor showed a linear response to hCG in the range 0.62–5.62 ng/mL with a response of 142 Ω/ng/mL. At concentrations above 5.62 ng/mL the sensor begins to saturate

    Selenium nanoparticles modulate histone methylation via lysine methyltransferase activity and S-adenosylhomocysteine depletion

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    At physiological levels, the trace element selenium plays a key role in redox reactions through the incorporation of selenocysteine in antioxidant enzymes. Selenium has also been evaluated as a potential anti-cancer agent, where selenium nanoparticles have proven effective, and are well tolerated in vivo at doses that are toxic as soluble Se. The use of such nanoparticles, coated with either serum albumin or the naturally occurring alkaline polysaccharide chitosan, also serves to enhance biocompatibility and bioavailability. Here we demonstrate a novel role for selenium in regulating histone methylation in ovarian cancer cell models treated with inorganic selenium nanoparticles coated with serum albumin or chitosan. As well as inducing thioredoxin reductase expression, ROS activity and cancer cell cytotoxicity, coated nanoparticles caused significant increases in histone methylation. Specifically, selenium nanoparticles triggered an increase in the methylation of histone 3 at lysines K9 and K27, histone marks involved in both the activation and repression of gene expression, thus suggesting a fundamental role for selenium in these epigenetic processes. This direct function was confirmed using chemical inhibitors of the histone lysine methyltransferases EZH2 (H3K27) and G9a/EHMT2 (H3K9), both of which blocked the effect of selenium on histone methylation. This novel role for selenium supports a distinct function in histone methylation that occurs due to a decrease in S-adenosylhomocysteine, an endogenous inhibitor of lysine methyltransferases, the metabolic product of methyl-group transfer from S-adenosylmethionine in the one-carbon metabolism pathway. These observations provide important new insights into the action of selenium nanoparticles. It is now important to consider both the classic antioxidant and novel histone methylation effects of this key redox element in its development in cancer therapy and other applications