Ann Louw

Stellenbosch University | SUN · Department of Biochemistry

Central to the pharmacological use of glucocorticoids (GCs) is the availability of the glucocorticoid receptor alpha (GRα). However, chronic GC therapy often results in the ligand-mediated downregulation of the GRα, and the subsequent development of an acquired GC resistance. While studies have demonstrated the dimerization-dependent downregulation...

The glucocorticoid (GC) receptor (GR) is essential for normal development and in the initiation of inflammation. Healthy GRdim/dim mice with reduced dimerization propensity due to a point mutation (A465T) at the dimer interface of the GR DNA binding domain (DBD) (here GRD/D) have previously helped to define the functions of GR monomers and dimers....

For over 70 years, the unique anti-inflammatory properties of glucocorticoids (GCs), which mediate their effects via the ligand-activated transcription factor, the glucocorticoid receptor alpha (GRα), have allowed for the use of these steroid hormones in the treatment of various autoimmune and inflammatory-linked diseases. However, aside from the o...

The formal honeybush tea industry has reached a 20-year milestone on 24 February 2019, giving an opportunity to reflect on the research targeting phenolic composition, quality and bioactivity, since a previous review published in 2008. This research underpins ongoing endeavours to unlock the potential of this indigenous agricultural commodity. The...

Pharmacologically, glucocorticoids, which mediate their effects via the glucocorticoid receptor (GR), are a most effective therapy for inflammatory diseases despite the fact that chronic use causes side-effects and acquired GC resistance. The design of drugs with fewer side-effects and less potential for the development of resistance is therefore c...

The development of resistance to glucocorticoids (GCs) in therapeutic regimes poses a major threat. Generally, GC resistance is congenital or acquired over time as a result of disease progression, prolonged GC treatment or, in some cases, both. Essentially, disruptions in the function and/or pool of the glucocorticoid receptor α (GRα) underlie this...

Abstract Glucocorticoids (GCs), acting via the glucocorticoid receptor (GRα), remain the mainstay therapeutic choice for the treatment of inflammation. However, chronic GC use, aside from generating undesirable side-effects, results in GRα down-regulation, often coupled to a decrease in GC-responsiveness, which may culminate in acquired GC resistan...

Time-course of mammary tumor progression in rats treated with water (TW) or vehicle (TV). Points are indicative of mean tumor volume ± SEM. Number of rats in TW (n = 8) and TV (n = 10). Statistical analysis was performed using a paired two-tailed t-test and no significant difference was observed.

Time-course of percentage tumor inhibition (%TI). (A) SM6Met, (B) SOC endocrine therapies (TAM, FUL, and LET), (C) E2, and (D) a comparison of S500 with SOCs. Points are indicative of mean %TI. Statistical analysis for (D) was performed using repeated measures ANOVA plus Dunnett’s post hoc test comparing mean %TI time-course of all SOC treatments t...

Breast cancer (BC) is the leading cause of cancer-related deaths in women. Chemoprevention of BC by using plant extracts is gaining attention. SM6Met, a well-characterized extract of Cyclopia subternata with reported selective estrogen receptor subtype activity, has shown tumor suppressive effects in a chemically induced BC model in rats, which is...

SM6Met, a phytoestrogenic extract of Cyclopia subternata indigenous to the Western Cape province of South Africa, displays estrogenic attributes with potential for breast cancer chemoprevention. In this study, we report that SM6Met, in the presence of estradiol, induces a significant cell cycle G0/G1 phase arrest similar to the selective estrogen r...

The genus Cyclopia, an indigenous South African fynbos plant used to prepare honeybush tea, contains phytoestrogenic compounds. An extract from C. subternata, SM6Met, displays three desirable estrogenic attributes for future development of a phytoestrogenic nutraceuti-cal, namely, ERα antagonism, ERβ agonism, and also antagonism of E 2-induced brea...

Corticosteroid-binding globulin (CBG), a negative acute phase protein produced primarily in the liver, is responsible for the transport of glucocorticoids (GCs). It also modulates the bioavailability of GCs, as only free or unbound steroids are biologically active. Fluctuations in CBG levels therefore can directly affect GC bioavailability. This st...

Hormone 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....

Glucocorticoid receptor (GR) levels vary between tissues and individuals and are altered by physiological and pharmacological effectors. However, the effects and implications of differences in GR concentration have not been fully elucidated. Using three statistically different GR concentrations in transiently transfected COS-1 cells, we demonstrate...

Figure S1. Whole-cell saturation binding, immunoblotting and fluorescent intensity used to monitor and determine GR levels. (A) COS-1 cells were transfected with GRwt or GRdim (low, medium or high levels) during assays. Immunoblotting was performed (see Material and Methods) on cell lysates and pixels from densitometric analysis of the immunoblots...

Cyclopia 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 pre...

A central question in glucocorticoid mechanism of action via the glucocorticoid receptor (GR) is what determines ligand-selective transcriptional responses. Using a panel of 12 GR ligands, we show that the extent of GR phosphorylation at S226 and S211, GR half-life and transcriptional response, occur in a ligand-selective manner. While GR phosphory...

The 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...

Compound 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), directl...

Genetic defects in the heme synthesis enzymes lead to a group of heterogeneous disorders termed the porphyrias. Numerous factors influence the clinical expression of porphyrias, primarily by altering the rate of heme synthesis. To date, no genotype-phenotype correlation has been made to explain the variable penetrance observed in variegate porphyri...

The mechanisms that determine ligand-selective transcriptional responses by the glucocorticoid receptor (GR) are not fully understood. Using a wide panel of GR ligands, we investigated the relationships between the potency and maximal response for transactivation via a glucocorticoid response element (GRE) and transrepression via both nuclear facto...

Rooibos (Aspalathus linearis (Brum.f) Dahlg.) and honeybush (Cyclopia Vent. species) are popular indigenous South African herbal teas enjoyed for their taste and aroma. Traditional medicinal uses of rooibos in South Africa include alleviation of infantile colic, allergies, asthma and dermatological problems, while a decoction of honeybush was used...

Previous work established the phytoestrogenicity of "unfermented"Cyclopia (honeybush) extracts. The current study investigated the phytoestrogenicity of four Cyclopia harvestings (M6-9) for preparation of extracts with enhanced phytoestrogenicity for benchmarking against commercial preparations. Two extracts, from M6 (C. subternata) and M7 (C. geni...

Unfermented C. genistoides methanol extracts of different harvestings and selected polyphenols were evaluated for phytoestrogenic activity by comparing binding to both ER subtypes, transactivation of an ERE-containing promoter reporter, proliferation of MCF-7-BUS and MDA-MB-231 breast cancer cells, and binding to SHBG. The extracts from one harvest...

Intermittent psychological stress was induced in adult rats by 2 h/day of immobilization stress for 4 days, with or without blocking the function of IL-6 by using an anti-IL-6 antibody. Basal concentrations of serum corticosterone, IL-1beta, IL-6, and TNF-alpha were assessed 24 h after the last intervention, as were levels of glucocorticoid recepto...

Phyto-oestrogens mediate an oestrogenic effect through binding to the oestrogen receptor (ER) subtypes, ERα and ERβ. Four commercially available Cyclopia (honeybush) species—C. intermedia, C. subternata, C. genistoides and C. sessiliflora—together with nine commercially obtainable polyphenols present in some or all of the species, were screened for...

The identification of selective glucocorticoid receptor (GR) modifiers, which separate transactivation and transrepression properties, represents an important research goal for steroid pharmacology. Although the gene-activating properties of GR are mainly associated with undesirable side effects, its negative interference with the activity of trans...

The synthetic progestins, medroxyprogesterone acetate (MPA) and norethisterone acetate (NET-EN or NET-A), are widely used as female contraceptive agents and in hormone replacement therapy (HRT). Competitive binding revealed that MPA displays a higher relative binding affinity than NET-A and progesterone (prog) for the human GR (Kd of 4.2 nM for dex...

Recent clinical evidence showing unexpected side-effects of progestins used in contraception and hormone replacement therapy has highlighted the importance of choice of synthetic progestin. The molecular mechanisms of action of the relatively nonspecific and most widely used synthetic progestins, medroxyprogesterone acetate and norethisterone, are...

Plants belonging to the genus Salsola (Family: Chenopodiaceae) are common in the arid and semiarid regions of our planet with no less than 69 different Salsola species found in Namibia and the Republic of South Africa. This genus is used as a traditional medicine and aqueous extracts of Salsola have been used by Bushmen women as an oral contracepti...

We investigated the interactions between Compound A (CpdA), an analog of a hydroxyphenyl aziridine precursor found in an African shrub, and the androgen receptor (AR). CpdA represses androgen-induced activation of both specific and non-specific androgen DNA response elements. While a similar effect was obtained for the progesterone receptor (PR) vi...

The interaction of several biogenic amines and Compound A (2-(4-acetoxyphenyl)-2-chloro- N-methyl-ethylammonium chloride), an analogue of the active substance in a HPLC fraction isolated from the shrub, Salsola tuberculatiformis Botsch., with cytochrome P450c11 was investigated. Noradrenaline, octopamine and Compound A inhibited the type I DOC indu...

Our objective was to identify the primary site of the reduced adrenal function in South African Angora goats (Capra aegagrus) that causes a decrease in cortisol production and leads to severe losses of Angora goats during cold spells. Angora goats, Boer goats (Capra hircus), and Merino sheep (Ovis aries) were assigned to three intravenous treatment...

Aziridines are highly reactive alkylating compounds used in cancer treatment. Salsola tuberculatiformis Botsch., which causes prolonged gestation in sheep and contraception in rats, contains a very labile hydroxy-phenylaziridine or its precursor. A less labile analogue, 2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethylammonium chloride (Compound I), was...

Salsola tuberculatiformis Botschantzev causes prolonged gestation in sheep and contraception in rats. An active fraction isolated from the shrub, containing a highly labile hydoxyphenyl aziridine or precursor, and a more stable analog, compound A, inhibits sheep adrenal cytochrome P450c11. In addition, compound A has been shown to bind to and be st...

Oral and intraperitoneal administration of 2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethylammonium chloride (Compound A), an analogue of phenyl aziridine precursors that occur in the shrub Salsola tuberculatiformis Botsch, had a contraceptive effect on female Wistar rats with a concomitant decrease in total body, uterus, and every mass and an increase...

V. tuberciilatiformis is contraceptive in rats. Aziridines, or their precursors, may be the active components in the biologically active but labile HPLC fraction (S2) isolated from the shrub. An aziridine precursor (Compound A:2-(4-acetoxy-phenyl)-2-chloro-N-methyl-ethyl-ammonium chloride), which cyclises to the corresponding aziridine, was synthes...