Controlled dual release of dihydrotestosterone and flutamide from polycaprolactone electrospun scaffolds accelerate burn wound healing.

Wound healing is a complex process involving multiple independent and overlapping sequential physiological mechanisms. In addition to cutaneous injury, a severe burn stimulates physiological derangements that induce a systemic hypermetabolic response resulting in impaired wound healing. Topical application of the anti-androgen drug, flutamide accelerates cutaneous wound healing, whereas paradoxically systemic dihydrotestosterone (DHT) improves burn wound healing.

The contradictory role of androgens in cutaneous and major burn wound healing.

Wound healing is a complex process involving four overlapping phases: haemostasis, inflammation, cell recruitment and matrix remodeling. In mouse models, surgical, pharmacological and genetic approaches targeting androgen actions in skin have shown that androgens increase interleukin-6 and tumor necrosis factor-α production and reduce wound re-epithelization and matrix deposition, retarding cutaneous wound healing. Similarly, clinical studies have shown that cutaneous wound healing is slower in men compared to women.

Dihydrotestosterone (DHT) Enhances Wound Healing of Major Burn Injury by Accelerating Resolution of Inflammation in Mice.

Androgens have been known to inhibit cutaneous wound healing in men and male mice. However, in children with major burn injuries, a synthetic androgen was reported clinically to improve wound healing. The aim of this study is to investigate the role of dihydrotestosterone (DHT) as a new therapeutic approach in treating major burn injury.

Glandular epithelial AR inactivation enhances PTEN deletion-induced uterine pathology.

Phosphatase and tensin homolog (PTEN) deletion induces uterine pathology, whereas androgen actions via androgen receptor (AR) support uterine growth and therefore may modify uterine cancer risk. We hypothesized that the androgen actions mediated via uterine glandular epithelial AR could modify PTEN deletion-induced uterine pathology. To test our hypothesis, we developed uterine glandular epithelium-specific PTEN and/or AR knockout mouse models comparing the uterine pathology among wild-type (WT), glandular epithelium-specific AR inactivation (ugeARKO), PTEN deletion (ugePTENKO), and the combined PTEN and AR knockout (ugePTENARKO) female mice.

A simple, accurate and universal method for quantification of PCR.

Background: Research into gene expression enables scientists to decipher the complex regulatory networks that control fundamental biological processes. Quantitative real-time PCR (qPCR) is a powerful and ubiquitous method for interrogation of gene expression. Accurate quantification is essential for correct interpretation of qPCR data.

Androgen actions in mouse wound healing: Minimal in vivo effects of local antiandrogen delivery.

The aims of this work were to define the role of androgens in female wound healing and to develop and characterize a novel wound dressing with antiandrogens. Androgens retard wound healing in males, but their role in female wound healing has not been established. To understand androgen receptor (AR)-mediated androgen actions in male and female wound healing, we utilized the global AR knockout (ARKO) mouse model, with a mutated AR deleting the second zinc finger to disrupt DNA binding and transcriptional activation.

Androgen action in female reproductive physiology.

Purpose Of Review: In the last decade, it has been proven that androgens acting via the androgen receptor (AR) play an important role in the regulation of female reproductive function. However, the specific site of action and the precise pathways involved remain to be fully elucidated. This review aims to combine findings from emerging basic research to provide new insights into the roles of AR-mediated actions, and the mechanisms involved, in normal ovarian, uterine, and mammary gland function.

Development and Characterization of Uterine Glandular Epithelium Specific Androgen Receptor Knockout Mouse Model.

While estrogen action is the major driver of uterine development, androgens acting via the androgen receptor (AR) may also promote uterine growth as suggested by uterine phenotypes in global AR knockout (ARKO) female mice. Because AR is expressed in uterine endometrial glands, we generated (Cre/loxP) uterine gland epithelium-specific ARKO (ugeARKO) to determine the role of endometrial gland-specific androgen actions. However, AR in uterine gland epithelium may not be required for normal uterine development and function because ugeARKO females had normal uterine development and fertility.

In utero/lactational and adult exposures to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) show differential effects on craniofacial development and growth in rats.

In a previous study of female Han/Wistar (H/W) and Long-Evans (L-E) rats, we found that adult exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was associated with size decreases in the cranium and especially the face. In this study we compared these crania to those from male and female Sprague-Dawley (S-D) rats with in utero/lactational exposure to TCDD, using morphometric variables of size, shape, and fluctuating asymmetry to quantify the effects of dose on craniofacial development and growth. At the highest levels of exposure, in utero/lactational and adult TCDD exposures both resulted in small but significant reductions in facial size parameters (i.

Androgen actions via androgen receptor promote PTEN inactivation induced uterine cancer.

Haploinsufficient inactivating phosphatase and tensin homolog (Pten) mutations cause Cowden syndrome, an autosomal dominant risk genotype for hormone dependent reproductive cancers. As androgen actions mediated via the androgen receptor (AR) supports uterine growth and may modify uterine cancer risk, we hypothesized that a functional AR may increase PTEN inactivation induced uterine cancer. To test the hypothesis, we compared the PTEN knockout (PTENKO) induced uterine pathology in heterozygous PTENKO and combined heterozygous PTEN and complete AR knockout (PTENARKO) female mice.

Macronutrient balance, reproductive function, and lifespan in aging mice.

In invertebrates, reproductive output and lifespan are profoundly impacted by dietary macronutrient balance, with these traits achieving their maxima on different diet compositions, giving the appearance of a resource-based tradeoff between reproduction and longevity. For the first time in a mammal, to our knowledge, we evaluate the effects of dietary protein (P), carbohydrate (C), fat (F), and energy (E) on lifespan and reproductive function in aging male and female mice. We show that, as in invertebrates, the balance of macronutrients has marked and largely opposing effects on reproductive and longevity outcomes.

Androgen receptor inactivation resulted in acceleration in pubertal mammary gland growth, upregulation of ERα expression, and Wnt/β-catenin signaling in female mice.

The androgen receptor (AR) is widely expressed in mammary cells of female mammals including humans and mice, indicating a possible role for AR-mediated androgen actions in breast development, function, and pathology, although the specific mechanisms remain unclear. To elucidate the mechanisms of androgen action in mammary gland physiology and development, we used AR-knockout (AR(Δex3)KO) female mice with a universally expressed, transcriptionally inactive AR protein harboring an in-frame deletion of its second zinc finger. Although in sexually mature wild-type (WT) and AR(ex3Δ)KO females, the mammary epithelial growth was fully extended to the edge of the fat pad, during puberty, AR(ex3Δ)KO females exhibit significantly accelerated mammary ductal growth and an increased number of terminal end buds compared with WT females.

Loss of PTEN stabilizes the lipid modifying enzyme cytosolic phospholipase A₂α via AKT in prostate cancer cells.

Aberrant increase in pAKT, due to a gain-of-function mutation of PI3K or loss-of-function mutation or deletion of PTEN, occurs in prostate cancer and is associated with poor patient prognosis. Cytosolic phospholipase A₂α (cPLA₂α) is a lipid modifying enzyme by catalyzing the hydrolysis of membrane arachidonic acid. Arachidonic acid and its metabolites contribute to survival and proliferation of prostate cancer cells.

Glucocorticoid receptor in prostate epithelia is not required for corticosteroid-induced epithelial hyperproliferation in the mouse prostate.

Background: Glucocorticoids are used as a last resort treatment for prostate cancer but the cell-specific glucocorticoid receptor (GR) mediated actions and the role of endogenous glucocorticoids in prostate are not understood.

Methods: We evaluated the influence of prostate epithelial GR mediated actions of glucocorticoids in prostate structural development by comparing the intact wild-type (WT) and prostate epithelia selective GR knockout (peGRKO) males at 8, 20, and 35 weeks of age. We also determined the cell-specific role of GR on corticosterone treatment induced prostate abnormalities by treating peGRKO and WT male mice with corticosterone depot pellets or placebo for 4 weeks.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) increases bilirubin formation but hampers quantitative hepatic conversion of biliverdin to bilirubin in rats with wild-type AH receptor.

In haem degradation, haem oxygenase-1 (HO-1) first cleaves haem to biliverdin, which is reduced to bilirubin by biliverdin IXα reductase (BVR-A). The environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes hepatic accumulation of biliverdin in moderately TCDD-resistant line B (Kuopio) rats. Using line B and two TCDD-sensitive rat strains, the present study set out to probe the dose-response and biochemical mechanisms of this accumulation.

Evidence for increased tissue androgen sensitivity in neurturin knockout mice.

Neurturin (NTN) is a member of the glial cell line-derived neurotrophic factor (GDNF) family and signals through GDNF family receptor alpha 2 (GFRα2). We hypothesised that epithelial atrophy reported in the reproductive organs of Ntn (Nrtn)- and Gfrα2 (Gfra2)-deficient mice could be due to NTN affecting the hormonal environment. To investigate this, we compared the reproductive organs of Ntn- and Gfrα2-deficient male mice in parallel with an analysis of their circulating reproductive hormone levels.

An electrospun scaffold loaded with anti-androgen receptor compound for accelerating wound healing.

Current dermal regenerative scafolds provide wound coverage, and structural support and guidance for tissue repair, but usually lack enough bio-signals needed for speeding up skin cell growth, migration, wound closure, and skin regeneration. In this study, an androgen receptor (AR) inhibitor called ASC-J9 is used to demonstrate the concept and feasibility of fabricating drug-loaded scafolds via electrospinning. Inhibition of androgen is known to promote skin wound healing.

Targeted loss of androgen receptor signaling in murine granulosa cells of preantral and antral follicles causes female subfertility.

Ovarian granulosa cells display strong androgen receptor (AR) expression, suggesting a functional role for direct AR-mediated actions within developing mammalian follicles. By crossing AR-floxed and anti-Müllerian hormone (AMH)-Cre recombinase mice, we generated granulosa cell-specific androgen receptor knockout mice (GCARKO). Cre expression, assessed by lacZ activity, localized to 70%-100% of granulosa cells in most preantral to antral follicles, allowing for selected evaluation of granulosa cell AR-dependent actions during follicle development.

Prostate epithelial AR inactivation leads to increased intraprostatic androgen synthesis.

Background: Regulation of steroid synthesis within the prostate is not well understood. In this study, we examined androgen synthesis and metabolism in the mouse prostate.

Methods: Using LC-MSMS steroid assays, immunohistochemistry and real-time PCR we examined the role of prostate epithelial AR in regulating 5αR expression and subsequent androgen metabolism by analyzing natural differences in epithelial AR expression between lobes as well as in the prostate epithelial AR knockout (PEARKO) mouse model.

Androgen resistance in female mice increases susceptibility to DMBA-induced mammary tumors.

Hormones, notably estrogens, are pivotal in the origins of breast cancer but androgenic effects, while supported by persistence of AR expression in breast cancers, remain controversial. This study determined the role of the androgen actions via androgen receptor (AR) in experimental mammary cancer. Androgen-resistant female and male mice (ARKO) were generated using Cre/loxP technique and featured a global AR inactivation.

The mouse as a model to investigate sex steroid metabolism in the normal and pathological prostate.

Metabolism of sex steroids within the prostate is an important factor affecting its growth and pathology. Mouse models with genetic gain- and especially loss-of-function have characterised different steroid metabolic pathways and their contribution to prostate pathology. With reference to the human prostate, this review aims to summarize the steroidogenic pathways in the mouse prostate as the basis for using the mouse as a model for intraprostatic steroid signalling.

Anterior prostate epithelial AR inactivation modifies estrogen receptor expression and increases estrogen sensitivity.

Androgens influence prostate growth and development, so androgen withdrawal can control progression of prostate diseases. Although estrogen treatment was originally used to induce androgen withdrawal, more recently direct estrogen effects on the prostate have been recognized, but the nature of androgen-estrogen interactions within the prostate remain poorly understood. To characterize androgen effects on estrogen sensitivity in the mouse prostate, we contrasted models of castration-induced androgen withdrawal in the prostate stromal and epithelial compartments with a prostate epithelial androgen receptor (AR) knockout (PEARKO) mouse model of selective epithelial AR inactivation.