The early contribution of cerebrovascular factors to the pathogenesis of Alzheimer's disease.

Alzheimer's disease (AD) and cerebrovascular disorders are the leading causes of dementia in our ageing population. Given that the progression of neuropathological changes in the brains of AD patients initiates several years, and even decades, before the diagnosis of dementia, a great effort has been made to identify potentially modifiable factors that contribute to the pathogenesis of sporadic late-onset AD. Among these factors, cerebrovascular disease and microvascular alterations seem to bilaterally interact with the underlying AD pathology, affecting the progression of cognitive deficits.

MyD88 deficiency results in both cognitive and motor impairments in mice.

The myeloid differentiation primary response gene 88 (MyD88) product is the most common adaptor protein implicated in Toll-like and interleukin receptor (TIR) domain signaling and thus plays an important role in the innate immune system. Despite the fact that the MyD88-dependent pathway has emerged as an important player in cell death processes described in several animal models of neurodegenerative disorders, the contribution of this pathway to specific behavioral phenotypes has been largely ignored. To understand the full implication of this pathway, we tested MyD88(-/-) mice for both motor and cognitive functions in normal conditions.

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.

Impact of estradiol structural modifications (18-methyl and/or 17-hydroxy inversion of configuration) on the in vitro and in vivo estrogenic activity.

It is well recognized that the majority of breast cancers are initially hormone-dependent and that 17β-estradiol (17β-E2) plays a crucial role in their development and progression. For this reason, using a compound able to block a specific enzyme involved in the last steps of the biosynthesis of 17β-E2 remains a rational way to treat estrogen-dependent diseases such as breast cancer. The present study describes the biological in vitro and in vivo evaluation of a structural modification (inversion of C18-methyl group at position 13 from β to α face) of 17β-E2 (1) and 17α-estradiol (17α-E2; 2).

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).

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.

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.

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).

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.

Expression of the alpha 5 integrin subunit gene promoter is positively regulated by the extracellular matrix component fibronectin through the transcription factor Sp1 in corneal epithelial cells in vitro.

The accumulation of fibronectin (FN) in response to corneal epithelium injury has been postulated to turn on expression of the FN-binding integrin alpha(5)beta(1). In this work, we determined whether the activity directed by the alpha(5) gene promoter can be modulated by FN in rabbit corneal epithelial cells (RCEC). The activity driven by chloramphenicol acetyltransferase/alpha(5) promoter-bearing plasmids was drastically increased when transfected into RCEC grown on FN-coated culture dishes.