Browsing by Author "Visser, Koch"
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- ItemAbrogation of glucocorticoid receptor dimerization correlates with dissociated glucocorticoid behavior of compound A(HighWire Press, 2010-03) Robertson, Steven; Allie-Reid, Fatima; Vanden Berghe, Wim; Visser, Koch; Binder, Anke; Africander, Donita; Vismer, Michael; De Bosscher, Karolien; Hapgood, Janet; Haegeman, Guy; Louw, Ann; A-7620-2012Compound A (CpdA), a dissociated glucocorticoid receptor modulator, decreases corticosteroid-binding globulin (CBG), adrenocorticotropic hormone (ACTH), and luteneinizing hormone levels in rats. Whether this is due to transcriptional regulation by CpdA is not known. Using promoter reporter assays we show that CpdA, like dexamethasone (Dex), directly transrepresses these genes. Results using a rat Cbg proximal-promoter reporter construct in BWTG3 and HepG2 cell lines support a glucocorticoid receptor (GR)-dependent transrepression mechanism for CpdA. However, CpdA, unlike Dex, does not result in transactivation via glucocorticoid-responsive elements within a promoter reporter construct even when GR is co-transfected. The inability of CpdA to result in transactivation via glucocorticoid- responsive elements is confirmed on the endogenous tyrosine aminotransferase gene, whereas transrepression ability is confirmed on the endogenous CBG gene. Consistent with a role for CpdA in modulating GR activity, whole cell binding assays revealed that CpdA binds reversibly to the GR, but with lower affinity than Dex, and influences association of [3H]Dex, but has no effect on dissociation. In addition, like Dex, CpdA causes nuclear translocation of the GR, albeit to a lesser degree. Several lines of evidence, including fluorescence resonance energy transfer, co-immunoprecipitation, and nuclear immunofluorescence studies of nuclear localization- deficient GR show that CpdA, unlike Dex, does not elicit ligand-induced GR dimerization. Comparison of the behavior of CpdA in the presence of wild type GR to that of Dex with a dimerization-deficient GR mutant (GRdim) strongly supports the conclusion that loss of dimerization is responsible for the dissociated behavior of CpdA.
- ItemCyclopia extracts act as ERα antagonists and ERβ agonists, in vitro and in vivo(Public Library of Science (PLOS), 2013-11) Visser, Koch; Mortimer, Morne; Louw, AnnHormone replacement therapy associated risks, and the concomitant reluctance of usage, has instigated the search for new generations of estrogen analogues that would maintain estrogen benefits without associated risks. Furthermore, if these analogues display chemo-preventative properties in breast and endometrial tissues it would be of great value. Both the selective estrogen receptor modulators as well as the selective estrogen receptor subtype modulators have been proposed as estrogen analogues with improved risk profiles. Phytoestrogen containing extracts of Cyclopia, an indigenous South African fynbos plant used to prepare Honeybush tea may serve as a source of new estrogen analogues. In this study three extracts, P104, SM6Met, and cup-of-tea, from two species of Cyclopia, C. genistoides and C. subternata, were evaluated for ER subtype specific agonism and antagonism both in transactivation and transrepression. For transactivation, the Cyclopia extracts displayed ERα antagonism and ERβ agonism when ER subtypes were expressed separately, however, when co-expressed only agonism was uniformly observed. In contrast, for transrepression, this uniform behavior was lost, with some extracts (P104) displaying uniform agonism, while others (SM6Met) displayed antagonism when subtypes were expressed separately and agonism when co-expressed. In addition, breast cancer cell proliferation assays indicate that extracts antagonize cell proliferation in the presence of estrogen at lower concentrations than that required for proliferation. Furthermore, lack of uterine growth and delayed vaginal opening in an immature rat uterotrophic model validates the ERα antagonism of extracts observed in vitro and supports the potential of the Cyclopia extracts as a source of estrogen analogues with a reduced risk profile.
- ItemInterplay of the inflammatory and stress systems in a hepatic cell line : interactions between glucocorticoid receptor agonists and interleukin-6(HighWire Press, 2010-11) Visser, Koch; Smith, Carine; Louw, AnnThe liver plays an important role in inflammation and stress by producing the acute phase proteins (APPs) required for resolution of inflammation as well as by delivering systemic glucose, through gluconeogenesis, required to fuel the stress response. Disruption of the interplay between interleukin 6 (IL-6) and glucocorticoids (GCs), the peripheral mediators of inflammation and stress, respectively, maylead to side-effects associated with the pharmacological use of GCs.Thecurrent study investigated the interplay between IL-6 and GCs in a hepatoma cell line (BWTG3) at protein (protein activity assays, Western blotting, and ELISA) andmRNA(qPCR) levels. Specifically, the action of dexamethasone (Dex), a known antiinflammatory drug and glucocorticoid receptor (GR) agonist, is compared to that of Compound A (CpdA), a selective glucocorticoid receptor agonist (SEGRA). CpdA, like IL-6, but unlike Dex, increases GR binding and decreases the metabolic enzymes, tyrosine aminotransferase, phosphoenolpyruvate carboxykinase, andgammaglutamyltransferase, at protein ormRNAlevel. Like Dex, both CpdA and IL-6 increase the positive APPs, serum amyloid A and C-reactive protein, and decrease the negative APP, corticosteroid binding globulin. The study shows that the GC, Dex, and IL-6 generally have divergent effects on the GR and metabolic enzymes, while their functions are convergent on the APPs. In contrast to Dex,CpdAhas effects convergent to that of IL-6onthe GR, metabolic enzymes,and APPs. Thus these findings suggest that CpdA, like Dex, modulates APPs, leading to effective control of inflammation, while, in contrast to Dex, it is less likely to lead to GC-induced side-effects.
- ItemPhytoestrogenic potential of Cyclopia extracts and polyphenols(Georg Thieme Verlag, 2013-05) Louw, Ann; Joubert, Elizabeth; Visser, KochCyclopia Vent. species, commonly known as honeybush, are endemic to Southern Africa. The plant is traditionally used as an herbal tea but several health benefits have recently been recorded. This minireview presents an overview of polyphenols found in Cyclopia and focusses on the phytoestrogenic potential of selected polyphenols and of extracts prepared from the plant.