The androgen derivative 5α-androstane-3β,17β-diol inhibits tumor necrosis factor α and lipopolysaccharide induced inflammatory response in human endothelial cells and in mice aorta

Department of Pharmacological Sciences, Università degli Studi di Milano, Italy.
Atherosclerosis (Impact Factor: 3.99). 09/2010; 212(1):100-6. DOI: 10.1016/j.atherosclerosis.2010.05.015
Source: PubMed


An increasing body of evidence suggests that testosterone may exert beneficial effects against the development of atherosclerosis. These effects are thought to be the consequence of its conversion into estradiol and the activation of the estrogen receptors; however a direct role of androgens, such as dihydrotestosterone, has also been proposed. More recently, it has been shown that the transformation of the dihydrotestosterone to 5alpha-androstane-3alpha,17beta-diol (3alpha-diol) and 5alpha-androstane-3beta,17beta-diol (3beta-Adiol), generates two molecules unable to bind the androgen receptor, but with a high affinity for the estrogen receptors (ERs) in particular the beta isoform. As the actions of testosterone may result from the balance between androgenic and estrogenic molecules originating from its catabolism, we investigated the effects of the 3beta-Adiol on inflammatory responses in vitro in human endothelial cells and ex vivo in mice aortas.
3beta-Adiol reverts the pro-inflammatory gene expression pattern induced by TNF-alpha in HUVECs as determined by a cDNA microrray approach. Q-real-time PCR and protein array approaches confirmed that TNF-alpha-induced ICAM-1, VCAM-1 and ELAM-1 as well as MCP-1 and IL-6 induction was affected upon 3beta-Adiol pre-incubation. ICI 182780, an estrogen receptor antagonist and R,R-THC, an estrogen receptor beta antagonist, counteracted the effect of 3beta-Adiol while bicalutamide, an androgen receptor antagonist, had minor effects. 3beta-Adiol exerted a similar action on macrophages. Finally in castrated male mice, 3beta-Adiol significantly counteracted the LPS mediated mRNA induction of IL-6, ELAM-1and PECAM-1 in the aortas.
3beta-Adiol reverts in vitro the TNF-alpha and LPS induced pro-inflammatory activation of endothelial cells and macrophages. 3beta-Adiol in vivo modulates the inflammatory response induced by LPS in the arterial vascular wall.

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    • "The compound 2 has been earlier derived from DHEA (dehydroepiandrosterone) by the action of 17β-hydroxysteroid dehydrogenase type 7 enzyme [12]. 5α-Androstan-3β,17β-diol (2) has been reported to inhibit lipopolysaccharide induced inflammatory response and tumor necrosis factor in human endothelial cells [13]. "
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    ABSTRACT: Biotransformation is an effective technique for the synthesis of libraries of bioactive compounds. Current study on microbial transformation of dihydrotestosterone (DHT) (1) was carried out to produce various functionalized metabolites. Microbial transformation of DHT (1) by using two fungal cultures resulted in potent butyrylcholinesterase (BChE) inhibitors. Biotransformation with Macrophomina phaseolina led to the formation of two known products, 5alpha-androstan-3beta,17beta-diol (2), and 5beta-androstan-3alpha,17beta-diol (3), while biotransformation with Gibberella fujikuroi yielded six known metabolites, 11alpha,17beta-dihydroxyandrost-4-en-3-one (4), androst-1,4-dien-3,17-dione (5), 11alpha-hydroxyandrost-4-en-3,17-dione (6), 11alpha-hydroxyandrost-1,4-dien-3,17-dione (7), 12beta-hydroxyandrost-1,4-dien-3,17-dione (8), and 16alpha-hydroxyandrost-1,4-dien-3,17-dione (9). Metabolites 2 and 3 were found to be inactive, while metabolite 4 only weakly inhibited the enzyme. Metabolites 5--7 were identified as significant inhibitors of BChE. Furthermore, predicted results from docking simulation studies were in complete agreement with experimental data. Theoretical results were found to be helpful in explaining the possible mode of action of these newly discovered potent BChE inhibitors. Compounds 8 and 9 were not evaluated for enzyme inhibition activity both in vitro and in silico, due to lack of sufficient quantities. Biotransformation of DHT (1) with two fungal cultures produced eight known metabolites. Metabolites 5--7 effectively inhibited the BChE activity. Cholinesterase inhibition is among the key strategies in the management of Alzheimer's disease (AD). The experimental findings were further validated by in silico inhibition studies and possible modes of action were deduced.
    Full-text · Article · Oct 2013 · Chemistry Central Journal
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    • "However, androgen receptors are not located only within the prostrate. Androgen receptors are known to be expressed in endothelial cells and have been shown to regulate a number of endothelial responses [2]. ADT has been shown to lead to an increase in cardiovascular disease that correlates with an increase in myocardial infarction and even sudden cardiac death in some studies. "
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    ABSTRACT: Quality of life has become increasingly more important for men diagnosed with prostate cancer. In light of this and the recognized risks of androgen deprivation therapy (ADT), the guidelines and use of ADT have changed significantly over the last few years. This paper reviews the current recommendations and the future perspectives regarding ADT. The benefits of ADT are evident neoadjuvantly and adjuvantly in patients treated with external beam radiation therapy for intermediate- and high-risk disease, in patients who have undergone prostatectomy with lymph node involvement, in high-risk patients after definitive therapy, and in patients who have developed progression or metastasis. Finally, this paper reviews the risks and benefits of each of these scenarios and the risks of androgen deprivation in general, and it delineates the areas where ADT was previously recommended, but where evidence is lacking for its additional benefit.
    Full-text · Article · Feb 2011
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    ABSTRACT: Matrix metalloproteinases (MMPs) play a key role in the pathogenesis of chronic inflammatory disease, such as atherosclerosis. Among MMPs, MMP-2 is regarded as a major proteinase in atherosclerotic plaque lesions. Peroxisome proliferator activated receptor-gamma (PPARγ) ameliorates oxidative stress and the inflammatory response. The aim of the present study was to evaluate the effect of Rosiglitazone on lipopolysaccharide (LPS)-induced MMP-2 activation as well as its possible mechanism. Primary culture of rat aortic endothelial cells (RAEC) was derived from male Sprague-Dawley rat. MMP-2 activity was assayed by gelatin zymography. Protein expressions were determined by Western Blotting. DNA binding activity of NF-κB was studied with electrophoretic mobility shift assay. LPS-induced MMP-2 activity was inhibited by Rosiglitazone (PPARγ agonist) in the rat aortic endothelial cells (RAEC). LPS-induced MMP-2 activation was diminished due to exposure to NF-κB Activation Inhibitor II (JSH-23) or Ras inhibitor, farnesylthiosalicylic acid (FTS). Further study shows that LPS-induced activation of Phospho-Ras homologue gene family, member A (Rho A) and Phospho-mitogen-activated protein kinase kinase 1/2 (MEK1/2) were significantly inhibited by Rosiglitazone. The activation of NF-κB p65 in the nuclear extract of cells was also significantly suppressed by Rosiglitazone, moreover, the expression of NF-κB p65 was partly activated by GW9662 (PPARγ antagonist). NF-κB DNA binding activity was also demolished by Rosiglitazone. Our data shows that PPARγ agonist, Rosiglitazone suppresses LPS-activated MMP-2 secretion via Ras-MEK1/2 signaling pathways and NF-κB activation. PPARγ agonist and Ras-MEK1/2 pathway may be another potential therapeutic target for the disease induced by chronic inflammation.
    No preview · Article · Nov 2011 · International journal of cardiology
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