Complement component C3 as a new target to lower albuminuria in hypertensive kidney disease.

Background And Purpose: Complement activation may drive hypertension through its effects on immunity and tissue integrity.

Experimental Approach: We examined expression of C3, the central protein of the complement cascade, in hypertension.

Key Results: Increased C3 expression was found in kidney biopsies and micro-dissected glomeruli of patients with hypertensive nephropathy.

Regulation of bone homeostasis by MERTK and TYRO3.

The fine equilibrium of bone homeostasis is maintained by bone-forming osteoblasts and bone-resorbing osteoclasts. Here, we show that TAM receptors MERTK and TYRO3 exert reciprocal effects in osteoblast biology: Osteoblast-targeted deletion of MERTK promotes increased bone mass in healthy mice and mice with cancer-induced bone loss, whereas knockout of TYRO3 in osteoblasts shows the opposite phenotype. Functionally, the interaction of MERTK with its ligand PROS1 negatively regulates osteoblast differentiation via inducing the VAV2-RHOA-ROCK axis leading to increased cell contractility and motility while TYRO3 antagonizes this effect.

Oxidative activity of 17β-hydroxysteroid dehydrogenase on testosterone in male abdominal adipose tissues and cellular localization of 17β-HSD type 2.

Testosterone can be converted into androstenedione (4-dione) by 17β-hydroxysteroid dehydrogenase (HSD) activity likely performed by 17β-HSD type 2. Our objective was to evaluate the rate of testosterone conversion to 4-dione as well as expression and localization of 17β-HSD type 2 in omental (OM) vs. subcutaneous (SC) adipose tissues of men.

Updated survey of the steroid-converting enzymes in human adipose tissues.

Over the past decade, adipose tissues have been increasingly known for their endocrine properties, that is, their ability to secrete a number of adipocytokines that may exert local and/or systemic effects. In addition, adipose tissues have long been recognized as significant sites for steroid hormone transformation and action. We hereby provide an updated survey of the many steroid-converting enzymes that may be detected in human adipose tissues, their activities and potential roles.

Assessment of steroidogenesis and steroidogenic enzyme functions.

There is some confusion in the literature about steroidogenesis in endocrine glands and steroidogenesis in peripheral intracrine tissues. The objective of the present review is to bring some clarifications and better understanding about steroidogenesis in these two types of tissues. Concerns about substrate specificity, kinetic constants and place of enzymes in the pathway have been discussed.

Androgens in the maternal and fetal circulation: association with insulin resistance.

Objective: To examine maternal insulin resistance in relationship with maternal and fetal androgen levels as well as with term placenta mRNA and protein abundance of steroidogenic enzymes implicated in androgen dynamics.

Methods: The study included 20 women with gestational diabetes mellitus and 27 controls tested using a 120 min., 75 g oral glucose tolerance test.

Specific transcriptional response of four blockers of estrogen receptors on estradiol-modulated genes in the mouse mammary gland.

Novel agents for the endocrine therapy of breast cancer are needed, especially in order to take advantage of the multiple consecutive responses observed in metastatic progressing breast cancer following previous hormone therapy, thus delaying the use of cytotoxic chemotherapy with its frequent poor tolerance and serious side effects. Acolbifene (ACOL) is a novel and unique antiestrogen which represents a unique opportunity to achieve the most potent and specific blockade of estrogen action in the mammary gland and uterus while exerting estrogen-like beneficial effects in other tissues, especially the bones. To better understand the specificity of action of ACOL, we have used Affymetrix GeneChips containing 45,000 probe sets to analyze 34,000 genes to determine the specificity of this compound compared to the pure antiestrogen fulvestrant, as well as to the mixed antagonists/agonists tamoxifen and raloxifene to block the effect of estradiol (E(2)) and to induce effects of their own on the genomic profile in the mouse mammary gland.

Regulation of neurosteroid biosynthesis by neurotransmitters and neuropeptides.

The enzymatic pathways leading to the synthesis of bioactive steroids in the brain are now almost completely elucidated in various groups of vertebrates and, during the last decade, the neuronal mechanisms involved in the regulation of neurosteroid production have received increasing attention. This report reviews the current knowledge concerning the effects of neurotransmitters, peptide hormones, and neuropeptides on the biosynthesis of neurosteroids. Anatomical studies have been carried out to visualize the neurotransmitter- or neuropeptide-containing fibers contacting steroid-synthesizing neurons as well as the neurotransmitter, peptide hormones, or neuropeptide receptors expressed in these neurons.

Glucocorticoid-induced androgen inactivation by aldo-keto reductase 1C2 promotes adipogenesis in human preadipocytes.

Adipogenesis and lipid storage in human adipose tissue are inhibited by androgens such as DHT. Inactivation of DHT to 3α-diol is stimulated by glucocorticoids in human preadipocytes. We sought to characterize glucocorticoid-induced androgen inactivation in human preadipocytes and to establish its role in the antiadipogenic action of DHT.

Assessment of steroidogenic pathways that do not require testosterone as intermediate.

Traditional literature and textbooks generally describe that estradiol (E2) and dihydrotestosterone (DHT) are synthesized from the aromatization and 5α-reduction of testosterone (T), respectively, following a pathway in which T is an essential intermediate (Tpath). This pathway implies that the steps of aromatization and 5α-reduction follow the reaction of the androgenic 17β-hydroxysteroid dehydrogenase (17β-HSD) that catalyzes the conversion of 4-androstenedione (4-dione) into T, and that estrogenic 17β-HSDs are not required. Contrary to this belief, the cloning of many estrogen-specific 17β-HSDs and the observation of higher affinity of aromatase and 5α-reductase for 4-dione than T are strongly in favor of biosynthetic pathways in which the steps catalyzed by aromatase and 5α-reductase precede that catalyzed by 17β-HSDs.

Expression of 11β-hydroxysteroid dehydrogenase type 1 in breast cancer and adjacent non-malignant tissue. An immunocytochemical study.

Intratumoral biosynthesis of hormone steroids is thought to play a role in the pathogenesis and development of human breast cancer. There is evidence that glucocorticoids may inhibit the development and progression of breast cancer. 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 is the enzyme which converts inactive cortisone to active cortisol.

Neurosteroid biosynthesis in the brain of amphibians.

Amphibians have been widely used to investigate the synthesis of biologically active steroids in the brain and the regulation of neurosteroid production by neurotransmitters and neuropeptides. The aim of the present review is to summarize the current knowledge regarding the neuroanatomical distribution and biochemical activity of steroidogenic enzymes in the brain of anurans and urodeles. The data accumulated over the past two decades demonstrate that discrete populations of neurons and/or glial cells in the frog and newt brains express the major steroidogenic enzymes and are able to synthesize de novo a number of neurosteroids from cholesterol/pregnenolone.

Expression of 5α-reductase type 1 in breast cancer and adjacent non-malignant tissue: an immunohistochemical study.

Intratumoral biosynthesis of sex steroids is thought to play a role in the pathogenesis and development of human breast cancer. There is evidence that androgens can inhibit the development and progression of breast cancer. Among the enzymes involved in the biosynthesis of androgens, 5α-reductase plays a key role by reducing testosterone to dihydrotestosterone, the most potent androgen.

Human type 3 5α-reductase is expressed in peripheral tissues at higher levels than types 1 and 2 and its activity is potently inhibited by finasteride and dutasteride.

5α-Reductases are crucial enzymes involved in the biosynthesis of dihydrotestosterone, the most potent natural androgen. To date, three types of 5α-reductases, chronologically named types 1, 2 and 3 5α-reductases (SRD5a-1, 2 and 3) have been described. In the present paper, we characterized the activity and compared the mRNA expression levels of SRD5a-3 with those of SRD5a-1 and 2 in various human tissues, and determined its sensitivity to finasteride and dutasteride.

The intracrine sex steroid biosynthesis pathways.

There is an increasing number of differences reported between the steroidogenesis pathways described in the traditional literature related to gonadal steroidogenesis and the more recent observations achieved using new technologies, especially molecular cloning, pangenomic expression studies, precise quantification of mRNA expression using real-time PCR, use of steroidogenic enzymes stably transfected in cells, detailed enzymatic activity analysis in cultured cell lines and mass spectrometry analysis of steroids. The objective of this chapter is to present steroidogenesis in the light of new findings that demonstrate pathways of biosynthesis of estradiol (E(2)) and dihydrotestosterone (DHT) from adrenal dehydroepiandrosterone (DHEA) in peripheral intracrine tissues which do not involve testosterone as intermediate as classically found in the testis and ovary. Steroidogenic enzymes different from those of the ovary and testis act in a tissue-specific manner to catalyze the transformation of DHEA into active sex steroids.

Expression of genes related to glucocorticoid action in human subcutaneous and omental adipose tissue.

Adipose tissue glucocorticoid action relies on local enzymatic interconversion and glucocorticoid receptor (GR) availability. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1), 2 (11β-HSD2) and hexose-6-phosphate dehydrogenase (H6PDH) are likely involved in glucocorticoid activation/inactivation within adipose tissue. We examined adipose tissue mRNA expression of genes related to glucocorticoid action and their association with total and visceral adiposity.

Sequential transformation of 4-androstenedione into dihydrotestosterone in prostate carcinoma (DU-145) cells indicates that 4-androstenedione and not testosterone is the substrate of 5α-reductase.

Background: Although it is well recognized that 5α-reductases possess higher affinity for 4-androstenedione than testosterone, and the affinity of 4-androstenedione is higher for 5α-reductases than 17β-hydroxysteroid dehydrogenases, it is generally believed that dihydrotestosterone is necessarily produced by the transformation of testosterone into dihydrotestosterone, suggesting that the step catalyzed by 17β-hydroxysteroid dehydrogenase precedes the step catalyzed by 5α-reductase. This interpretation is in contradiction with the enzymatic kinetic law that suggests that the 5α-reduction step that catalyzes the transformation of 4-dione into 5α-androstane-3,17-dione precedes the 17keto-reduction step.

Materials And Methods: To verify which of these two pathways is operative, we quantified mRNA expression levels of steroidogenic enzymes in prostate carcinoma DU-145 cells by real-time PCR and determined the metabolites produced after incubation with [14C]4-dione in the presence and absence of a 5α-reductase inhibitor and analyzed the metabolites produced by thin layer chromatography and HPLC.

Potent and selective steroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 7, an enzyme that catalyzes the reduction of the key hormones estrone and dihydrotestosterone.

17beta-Hydroxysteroid dehydrogenase type 7 (17beta-HSD7) catalyzes the reduction of estrone (E(1)) into estradiol (E(2)) and of dihydrotestosterone (DHT) into 5alpha-androstane-3beta,17beta-diol (3beta-diol), therefore modulating the level of mitogenic estrogens and androgens in humans. By classical and parallel chemistry, we generated several 4-methyl-4-aza-5alpha-androstane derivatives differing in their C-17 substituent: 17beta-formamide, 17beta-benzamide, and 17beta-tertiary amine. Best candidates in each category had demonstrated good inhibitory potency toward the conversion of E(1) into E(2) (IC(50) = 189-451 nM) and also toward the conversion of DHT into 3beta-diol (69-91% at 3 microM).

Immunohistochemical localization and biological activity of 3beta-hydroxysteroid dehydrogenase and 5alpha-reductase in the brain of the frog, Rana esculenta, during development.

The occurrence of several enzymes responsible for the biosynthesis of neurosteroids in the brain of adult frogs is now firmly established but the expression of these enzymes during ontogenesis has not yet been investigated. In the present report, we describe the immunohistochemical distribution and biological activity of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and 5alpha-reductase (5alpha-R) in the brain of the European green frog, Rana esculenta, during larval development. The spatio-temporal distribution of 3beta-HSD and 5alpha-R immunoreactivities in the tadpole brain was generally different, although these two enzymes were occasionally detected in the same areas such as the olfactory bulbs and cerebellum.

Omental adipose tissue type 1 11 beta-hydroxysteroid dehydrogenase oxoreductase activity, body fat distribution, and metabolic alterations in women.

Context: Modulation of adipose tissue exposure to active glucocorticoids by type 1 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD1) is involved in abdominal obesity of rodent models, but only a few studies have related 11 beta-HSD1 oxoreductase activity to fat distribution in humans.

Objective: The objective of the study was to examine the link between 11 beta-HSD1 oxoreductase activity, fat distribution patterns, and the metabolic profile in women.

Methods: Omental (OM) and sc adipose tissue samples were obtained from 36 lean to obese women (aged 47.

Neurosteroid biosynthesis: enzymatic pathways and neuroendocrine regulation by neurotransmitters and neuropeptides.

Neuroactive steroids synthesized in neuronal tissue, referred to as neurosteroids, are implicated in proliferation, differentiation, activity and survival of nerve cells. Neurosteroids are also involved in the control of a number of behavioral, neuroendocrine and metabolic processes such as regulation of food intake, locomotor activity, sexual activity, aggressiveness, anxiety, depression, body temperature and blood pressure. In this article, we summarize the current knowledge regarding the existence, neuroanatomical distribution and biological activity of the enzymes responsible for the biosynthesis of neurosteroids in the brain of vertebrates, and we review the neuronal mechanisms that control the activity of these enzymes.