Metabolism and action of glucocorticoids and interference with the antioxidant redox pathway
Denise Kratschmar, Alex Odermatt, Hubert Hug
2011
unpublished
Disturbance of endocrine systems and signaling pathways can lead to severe disorders. Such disorders can have endogenous as well exogenous origin. The awareness of environmentally occurring xenobiotics that are able to directly interfere with and modulate the action of endogenous hormones has driven the need for mechanistic studies. Although there is a vast literature on potentially endocrine disrupting chemicals, there are only few studies investigating disturbance of glucocorticoid action by
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... enobiotics, despite of the importance of these hormones. In this work, the organotin dibutyltin (DBT) was identified as an endocrine disruptor of the glucocorticoid pathway. Its extensive use in plastic industry, as well as an antifouling agent explains its occurrence in water and seafood. In the present study, we were able to show that DBT disturbs GR mediated anti-inflammatory effects. Furthermore, DBT was found to potentiate NFκB mediated production of the proinflammatory cytokines IL-6 and TNFα in macrophages. The presented work therefore contributes to the mechanistic understanding of DBT-induced immunotoxicity. There are several therapeutic purposes accompanied by the modulation of the endogenous hormone system. In traditional medicines natural compounds, and plant extracts are applied since centuries for different purposes, including the treatment of diseases such as diabetes and hypertension. The benefits of evidence based medicines, even if their mechanisms of action are unknown, are widely accepted. In conventional medicine the re-awareness of naturally derived compounds and their huge potential promoted the investigation of the underlying specific mechanisms of action of such compounds over the last decades. In this context, the present work investigated effects of eriobotrya japonica, a plant used for anti-diabetic treatment in Chinese medicine. The project aimed to identify potential constituents that are active on 11β-HSD1. Several pentacyclic triterpenes were isolated and further characterized. These compounds included potent and, compared with 11β-HSD2, selective 11β-HSD1 inhibitors such as corosolic acid and urosolic acid, as well as urosolic acid derivatives with only low inhibitory potential but considerable synergistic effects. Inhibitors for research and/or therapeutic purposes ideally display high selectivity to avoid miss-leading interpretations of their action. Furthermore,
doi:10.5451/unibas-005640208
fatcat:5x7rhuxupzghdpuwqpagatlf7q