Doctoral Degrees (Biochemistry)

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Browsing Doctoral Degrees (Biochemistry) by Subject "Adrenal steroid hormones -- Effect of Sutherlandia frutescens"

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    The influence of sutherlandia frutescens on adrenal steroid hormones and downstream receptor interactions
    (Stellenbosch : Stellenbosch University, 2017-12) Sergeant, Catherine Anne; Swart, Amanda C.; Africander, Donita; Stellenbosch University. Faculty of Science. Dept. of Biochemistry.
    ENGLISH ABSTRACT: The study was aimed at: 1. linking anti-stress properties of Sutherlandia frutescens to its influence on adrenal steroid biosynthesis in terms of extracts, sutherlandioside (SU) compounds and gammaaminobutyric acid (GABA). 2. linking anti-inflammatory and anti-hypertension properties to steroid receptor interaction, the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). The influence of S. frutescens extracts, and SUs, on key steroidogenic enzymes was assayed in COS-1 cells and binding to adrenal P450-dependent enzymes was assayed in ovine adrenal mitochondrial and microsomal suspensions. The effects of the methanol extract and sutherlandioside B (SUB) were assayed on basal, forskolin and angiotensin II (Ang II) stimulated hormone levels in the adrenal H295R cell model. The effect of GABA on basal steroid production was investigated in H295R cells. Agonist activity of the methanolic extract and SUB, for both transactivation and transrepression of GR and MR mediated gene transcription, was subsequently investigated. S. frutescens extracts affected all the steroidogenic enzymes with inhibition being substrate specific. SUB had a greater effect on substrate binding to mitochondrial and microsomal P450 enzymes than sutherlandioside A (SUA). SUB inhibited the catalytic activity of CYP17A1, CYP11B2 and 3β-HSD2 while not affecting CYP21A2. In H295R cells, while the extract decreased total steroid production under basal and forskolin stimulated conditions, only cortisol and its precursor, deoxycortisol, and mineralocorticoid metabolites were decreased significantly in the presence of forskolin. A SU mixture did not influence steroid production, with only cortisol levels decreasing significantly with SUB decreasing cortisol, deoxycortisol, androstendione and 11-hydroxyandrostenedione significantly. The data show that the SU mixture was not able to elicit the same effects as SUB, suggesting that the compounds do not act synergistically. GABA significantly decreased adrenal steroid production in H295R cells with the greatest inhibitory effect observed in the production of adrenal androgens. S. frutescens extracts and SUB repressed NF-κB-driven gene expression without activating GREdriven gene expression while neither activated MR mediated gene transcription while both antagonized the effects of aldosterone via the MR. The results of this study provide evidence linking anti-stress, anti-inflammatory and antihypertensive properties of S. frutescens to the inhibition of steroidogenic enzymes and modulation of adrenal hormone biosynthesis. The findings suggesting that S. frutescens and SUB exhibit dissociated glucocorticoid characteristics underline potential therapeutic applications in the treatment of inflammation and hypertension.