A transgenic mouse model for the in vivo bioluminescence imaging of the expression of the lysophosphatidic acid receptor 3: relevance for inflammation and uterine physiology research.

Lysophosphatidic acid (LPA) is a lipid-derived signaling molecule that plays key roles in diverse biological processes including inflammation and uterine remodeling. Although the function of LPA and its receptors has been extensively studied using knock-out mice, the temporal-spatial expression of LPA receptors is less well-characterized. To gain further insight into the dynamic regulation of LPA receptor 3 (Lpar3) expression in vivo by bioluminescence imaging, we generated and characterized mice transgenic for a putative Lpar3 promoter fragment.

A new nonestrogenic steroidal inhibitor of 17β-hydroxysteroid dehydrogenase type I blocks the estrogen-dependent breast cancer tumor growth induced by estrone.

17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) converts estrone (E1) into estradiol (E2) and is expressed in many steroidogenic tissues and breast cancer cell lines. Because the potent estrogen E2 stimulates the growth and development of hormone-dependent diseases, inhibition of the final step of E2 synthesis is considered a promising strategy for the treatment of breast cancer. On the basis of our previous study identifying 16β-(m-carbamoylbenzyl)-E2 (CC-156) as a lead compound for the inhibition of 17β-HSD1, we conducted a number of structural modifications to reduce its undesired residual estrogenic activity.

Solid-phase chemical synthesis and in vitro biological evaluation of novel 2β-piperazino-(20R)-5α-pregnane-3α,20-diol N-derivatives as anti-leukemic agents.

The steroid nucleus is an interesting scaffold for the development of new therapeutic agents. Within the goal of identifying anticancer agents, new pregnane derivatives were prepared by using a sequence of liquid and solid-phase reactions. After we dehydrated epi-allopregnanolone in one step with diethylaminosulfur trifluoride and generated a 2,3α-epoxide, the regio- and stereo-selective aminolysis of this epoxide enabled us to obtain a 2β-piperazino-pregnane, whose secondary amine was protected as N-Fmoc-derivative.

Effects of mild chronic cerebral hypoperfusion and early amyloid pathology on spatial learning and the cellular innate immune response in mice.

Understanding the contribution of cerebrovascular factors in the progression of cognitive decline in Alzheimer's disease (AD) is a key step for the development of preventive therapies. Among these factors, chronic cerebral hypoperfusion is an early component of AD pathogenesis that can predict the progression from mild cognitive impairment to AD. Here, we investigated the effects of a protocol of mild chronic cerebral hypoperfusion in the APPswe/PS1 transgenic mouse model of AD.

Two androsterone derivatives as inhibitors of androgen biosynthesis.

The title compounds, (3R,5S,5'R,8R,9S,10S,13S,14S)-10,13-dimethyl-5'-(2-methylpropyl)tetradecahydro-6'H-spiro[cyclopenta[a]phenanthrene-3,2'-[1,4]oxazinane]-6',17(2H)-dione, C(26)H(41)NO(3), (I), and methyl (2R)-2-[(3R,5S,8R,9S,10S,13S,14S)-10,13-dimethyl-2',17-dioxohexadecahydro-3'H-spiro[cyclopenta[a]phenanthrene-3,5'-[1,3]oxazolidin-3'-yl]]-4-methylpentanoate, C(28)H(43)NO(5), (II), possess the typical steroid shape (A-D rings), but they differ in their extra E ring. The azalactone E ring in (I) shows a half-chair conformation, while the carbamate E ring of (II) is planar. The orientation of the E-ring substituent is clearly established and allows a rationalization of the biological results obtained with such androsterone derivatives.

New diethylsilylacetylenic linker for parallel solid-phase synthesis of libraries of hydroxy acetylenic steroid derivatives with improved metabolic stability.

Acetylenic tertiary alcohols are well-known to be compounds that are biologically more stable than their corresponding secondary alcohols. The linkage of an acetylenic compound to a polymer support and further introduction of molecular diversity was found to be an interesting way to generate libraries of hydroxy acetylenic derivatives and thus potentially improve their biological properties. For the first time, we describe the loading of an ethynyl steroid to a polystyrene-diethylsilane resin and its uses for the solid-phase synthesis of a model library of 21 steroid derivatives.

Hematopoietic MyD88-adaptor protein acts as a natural defense mechanism for cognitive deficits in Alzheimer's disease.

Accumulating evidence supports a critical role of Toll-like receptors in the clearance of Amyloid beta (Aβ) by microglial cells. Myeloid differentiation factor 88 (MyD88) is an adaptor protein that bridges the intracellular signal to nucleus for most of these innate immune receptors. We investigated here the role of competent MyD88 hematopoietic stem cells on the cognitive decline of a mouse model of Alzheimer's disease (AD).

Crucial Role of 3-Bromoethyl in Removing the Estrogenic Activity of 17β-HSD1 Inhibitor 16β-(m-Carbamoylbenzyl)estradiol.

17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) represents a promising therapeutic target for breast cancer treatment. To reduce the undesirable estrogenic activity of potent 17β-HSD1 inhibitor 16β-(m-carbamoylbenzyl)estradiol (1) (IC(50) = 27 nM), a series of analogues with a small functionalized side chain at position 3 were synthesized and tested. The 3-(2-bromoethyl)-16β-(m-carbamoylbenzyl)-estra-1,3,5(10)-trien-17β-ol (5) was found to be a potent inhibitor (IC(50) = 68 nM) for the transformation of estrone (E1) into estradiol (E2) and, most importantly, did not stimulate the proliferation of estrogen-sensitive MCF-7 cells, suggesting no estrogenic activity.

Reduced airborne transmission of oseltamivir-resistant pandemic A/H1N1 virus in ferrets.

Background: The H275Y neuraminidase mutation conferring oseltamivir resistance has been reported in several pandemic A/H1N1 (pH1N1) isolates. We sought to evaluate transmission of this mutant virus through the direct contact and the airborne (aerosol and droplet) routes in the ferret model.

Methods: Groups of four ferrets were infected with either wild-type (WT) or oseltamivir-resistant pH1N1 (H275Y) strains.

Chemical synthesis and evaluation of 17α-alkylated derivatives of estradiol as inhibitors of steroid sulfatase.

Steroid sulfatase (STS) controls the levels of 3-hydroxysteroids available from circulating steroid sulfates in several normal and malignant tissues. This and the known involvement of active estrogens and androgens in diseases such as breast and prostate cancers thus make STS an interesting therapeutic target. Here we describe the chemical synthesis and characterization of an extended series of 17α-derivatives of estradiol (E2) using different strategies.

Development of 3-substituted-androsterone derivatives as potent inhibitors of 17β-hydroxysteroid dehydrogenase type 3.

17Beta-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is a steroidogenic enzyme that catalyzes the transformation of 4-androstene-3,17-dione (Δ⁴-dione) into androgen testosterone (T). To provide effective inhibitors of androgen biosynthesis, we synthesized two different series (amines and carbamates) of 3β-substituted-androsterone derivatives and we tested their inhibitory activity on 17β-HSD3. From the results of our structure-activity relationship study, we identified a series of compounds producing a strong inhibition of 17β-HSD3 overexpressed in HEK-293 cells (homogenized cells).

TNF-alpha promotes LPA1- and LPA3-mediated recruitment of leukocytes in vivo through CXCR2 ligand chemokines.

Lysophosphatidic acid (LPA) is a bioactive lysophospholipid present in low concentrations in serum and biological fluids but in high concentrations at sites of inflammation. LPA evokes a variety of cellular responses via binding to and activation of its specific G protein-coupled receptors (GPCR), namely LPA(1-6). Even though LPA is a chemoattractant for inflammatory cells in vitro, such a role for LPA in vivo remains largely unexplored.

Steroid sulfatase inhibitors: a review covering the promising 2000-2010 decade.

The steroid sulfatase (STS) plays a major role in the regulation of steroid hormone concentrations in several human tissues and target organs and therefore, represents an interesting target to regulate estrogen and androgen levels implicated in different diseases. In this review article, the emphasis is put on STS inhibitors reported in the fruitful 2000-2010 decade, which consolidated the first ones that were previously developed (1990-1999). The inhibitors reviewed are divided into four categories according to the fact that they are sulfamoylated or not or that they have a steroid nucleus or not.

Chemical synthesis, characterisation and biological evaluation of furanic-estradiol derivatives as inhibitors of 17β-hydroxysteroid dehydrogenase type 1.

Local biosynthesis of estrogens, especially estradiol (E2), is thought to be important for the maintenance and growth of estrogen-sensitive diseases. To control E2 formation, we have investigated a series of epoxide and furanic E2 derivatives as inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), the enzyme responsible for the conversion of estrone (E1) into E2. We report here a strategy to synthesize a series of E2-furanic derivatives from E1.

Contribution to the development of inhibitors of 17β-hydroxysteroid dehydrogenase types 1 and 7: key tools for studying and treating estrogen-dependent diseases.

17β-Hydroxysteroid dehydrogenases (17β-HSDs) belong to a group of key enzymes involved in the biosynthesis of steroidal hormones by catalyzing the reduction of 17-ketosteroids or the oxidation of 17β-hydroxysteroids. From three members known in the early nineties, the 17β-HSD functional family has grown to 15 members over the last 20 years. This growing number of 17β-HSD isoforms questioned the importance of each member, especially in their implication in estrogen- and androgen-dependent diseases, such as breast and prostate cancers.

Genetics of digital osteoarthritis.

Genetic factors contribute to the development of digital osteoarthritis, whose heritability has been estimated at 48 to 65%. Among the manifestations of digital osteoarthritis, only Heberden's nodes are transmitted by Mendelian inheritance, as a dominant trait in women and a recessive trait in men. The other forms of digital osteoarthritis are multifactorial, with a major gene and a residual multifactorial component that probably interacts with environmental factors.

Libraries of 2β-(N-substituted piperazino)-5α-androstane-3α, 17β-diols: chemical synthesis and cytotoxic effects on human leukemia HL-60 cells and on normal lymphocytes.

Libraries of steroid derivatives with two levels of molecular diversity were prepared to optimize the antiproliferative activity on leukemia HL-60 cells by first varying the amino acid (AA) at R(1) (libraries A, B, C, and D: with 45, 45, 20, and 20 members, respectively) and, subsequently, the capping group at R(2) (library E: 168 members). The screening of these aminosteroids revealed interesting structure-activity relationships. In library A, the compounds bearing a tetrahydroisoquinolone residue as the first element of diversity showed potent cytotoxicity, principally when isovaleric or cyclohexyl acetic acid was used as a capping group (>40% of cell growth inhibition at 1 μM).

Oseltamivir-resistant pandemic A/H1N1 virus is as virulent as its wild-type counterpart in mice and ferrets.

The neuraminidase inhibitor oseltamivir is currently used for treatment of patients infected with the pandemic A/H1N1 (pH1N1) influenza virus, although drug-resistant mutants can emerge rapidly and possibly be transmitted. We describe the characteristics of a pair of oseltamivir-resistant and oseltamivir-susceptible pH1N1 clinical isolates that differed by a single change (H274Y) in the neuraminidase protein. Viral fitness of pH1N1 isolates was assessed in vitro by determining replication kinetics in MDCK alpha2,6 cells and in vivo by performing experimental infections of BALB/c mice and ferrets.

17beta-Hydroxysteroid dehydrogenase inhibitors: a patent review.

Importance Of The Field: 17beta-Hydroxysteroid dehydrogenases (17beta-HSDs) mainly catalyze the reduction of C17-ketosteroids to their corresponding hydroxylated forms as well as the reverse reaction (oxidation). Able to convert inactive or less active steroid hormones into more potent ones and vice versa, certain 17beta-HSDs play a key role, especially in the regulation of estrogen and androgen levels. The therapeutic potential of this enzyme family, especially for the treatment of breast cancer, prostate cancer, acne and osteoporosis, then stimulated the development of inhibitors of 17beta-HSDs and important progress was achieved over the last years.

Plasma interleukin-18 (IL-18) levels are correlated with antioxidant vitamin coenzyme Q(10) in preeclampsia.

Objective: Alteration of cytokines level and oxidative stress are both associated with preeclampsia (PE). We have investigated if IL-6 and IL-18 levels were related to coenzyme Q(10) (CoQ(10)), an antioxidant and a marker of oxidative stress in the plasma from normotensive and preeclamptic pregnancies.

Design: IL-6 and IL-18 levels were determined by enzyme-linked immunosorbent assays in plasmas from preeclamptic (n = 29) and normotensive pregnancies (n = 30).

Photoactivated multivitamin preparation induces poly(ADP-ribosyl)ation, a DNA damage response in mammalian cells.

Multivitamin preparation (MVP) is part of total parenteral nutrition given to premature infants. Photoactivated MVP carries an important load in peroxides, but their cellular effects have not yet been determined. We hypothesized that these peroxides may elicit a DNA-damage response.

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).

Advances in development of inhibitors of 17beta hydroxysteroid dehydrogenases.

The 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) are involved in the regulation of estrogens and androgens by catalyzing the reduction of 17-ketosteroids or the oxidation of 17beta hydroxysteroids. The enzyme activities associated with the different 17beta-HSD isoforms are widespread in human tissues, not only in classic steroidogenic tissues but also in a large series of peripheral intracrine tissues. Being involved at the end of steroidogenesis, the numerous members of 17beta-HSD family constitute interesting therapeutic targets for controlling the concentration of estrogens and androgens.