[Intensive care nurse in 2021, from expertise to recognition].

The profession of intensive care nurse has been in constant evolution since the 1960s. The technical nature of medical equipment and the care of increasingly complex patients require a high level of qualification. The current health crisis has highlighted the difficulties of this profession and the lack of recognition of these carers.

Chemical and biochemical approaches to the production of 7-hydroxylated C19-steroids.

Abstract Interest has developed into 7-hydroxylated derivatives of 3β-hydroxylated C19-steroids, such as dehydroepiandrosterone (DHEA) and epiandrosterone because of their effects on inflammation, immune response, and cell repair. These steroids are not currently available from commercial sources, and it is necessary to produce them for relevant studies. We report here the chemical and biochemical approaches that were used for their production.

Cytochrome P450-7B1 and 11β-hydroxysteroid dehydrogenase type 1 distribution in human tissues.

Abstract Successive action of cytochrome P450-7B1 (CYP7B1) and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) on 3β-hydroxysteroids such as DHEA and epiandrosterone leads to the production of cytoprotective 7β-hydroxylated derivatives. Investigation of the presence of these enzymes in human tissues could be carried out on commercially available human tissue arrays with use of antibodies specific to CYP7B1 and 11β-HSD1 for immunohistochemistry. Both enzymes were detected mainly in tissues of endodermic and ectodermic origin which are prone to undergo inflammation.

Synthesis of a 19-(O-carboxymethyl)oxime hapten of 7β-hydroxy-epiandrosterone.

In order to develop an immunoassay of 7β-hydroxy-epiandrosterone, a stereoselective synthesis of a specific hapten, 7β-hydroxy-19-oxo-androstan 19-(O-carboxymethyl)oxime (17), was performed. This synthesis was achieved in 16% overall yield starting from the well-known 3β-acetoxy-19-hydroxy-5-androsten-17-one (1). After coupling of the alkyl oxime moiety, an allylic oxidation of the C-7 carbon under mild conditions followed by two selective reductions established all the functionalities of the final compound 17.

New insights into the protective effects of DHEA1).

Numerous studies investigated the effects of pharmacological doses of DHEA in animals. Among protective effects, antiglucocorticoid potencies, triggering and modulation of immunity and anticancerous effects were reported. Because DHEA levels decrease in aging humans, this steroid has been assayed as replacement therapy in elderly volunteers without striking evidence for beneficial effects.

Synthesis of 7β-hydroxy-epiandrosterone.

The synthesis of 7β-hydroxy-epiandrosterone (6) possessing strong anti-inflammatory properties was achieved starting from 3β-acetoxy-17,17-(ethylenedioxy)-5-androsten (1). This approach involved as a main step an allylic oxidation of the C-7 followed by two reduction reactions of the double bond and of the carbonyl group. This stereoselective synthesis in 5 steps gave 7β-hydroxy-epiandrosterone in 63% overall yield.

A native steroid hormone derivative triggers the resolution of inflammation.

Inflamed tissues produce both prostaglandins (PGs) and 7α-hydroxylated derivatives of native circulating 3β-hydroxysteroids. These 7α-hydroxysteroids are in turn transformed into 7β-hydroxylated epimers by 11β-hydroxysteroid dehydrogenase type 1 in the tissue. 7β-Hydroxy-epiandrosterone (7β-hydroxy-EpiA) affects PG production in two models of inflammation, dextran sodium sulfate-induced colitis in the rat and TNF-α-induced activation of PG production and PG synthase expression in cultured human peripheral blood monocytes (hPBMC).

7-Hydroxylated derivatives of dehydroepiandrosterone in the human ventricular cerebrospinal fluid.

Objective: Dehydroepiandrosterone is a long established neuroactive steroid. Some authors documented that 7-oxygenated derivatives of this steroid may be responsive at least by part for its physiological activity.

Methods: In the ventricular cerebrospinal fluid obtained from 15 patients with hydrocephalus (8 postmenopausal women and 7 men) potentially neuroactive steroid 7-oxygenated derivatives of dehydroepiandrosterone were quantified using gas chromatography/mass spectrometry.

Epimerase activity of the human 11beta-hydroxysteroid dehydrogenase type 1 on 7-hydroxylated C19-steroids.

Cytochrome P4507B1 7alpha-hydroxylates dehydroepiandrosterone (DHEA), epiandrosterone (EpiA) and 5alpha-androstane-3beta,17beta-diol (Adiol). 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) interconverts 7alpha- and 7beta-forms. Whether the interconversion proceeds through oxido-reductive steps or epimerase activity was investigated.

7beta-Hydroxy-epiandrosterone-mediated regulation of the prostaglandin synthesis pathway in human peripheral blood monocytes.

7alpha-Hydroxy-DHEA, 7beta-hydroxy-DHEA and 7beta-hydroxy-EpiA are native metabolites of dehydroepiandrosterone (DHEA) and epiandrosterone (EpiA). Since numerous steroids are reported to interfere with inflammatory and immune processes, our objective was to test the effects of these hydroxysteroids on prostaglandin (PG) production and related enzyme gene expression. Human peripheral blood monocytes were cultured for 4 and 24 h in the presence of each of the steroids (1-100 nM), with and without addition of TNF-alpha (10 ng/mL).

Anti-inflammatory effects and changes in prostaglandin patterns induced by 7beta-hydroxy-epiandrosterone in rats with colitis.

High dose levels of dehydroepiandrosterone and its 7-hydroxylated derivatives have been shown to reduce oxidative stress and inflammatory responses in dextran sodium sulfate (DSS)-induced colitis in rats. Another endogenous steroid, 7beta-hydroxy-epiandrosterone (7beta-hydroxy-EpiA) has been shown to exert neuroprotective effects at much smaller doses. Our aims were to evaluate whether 7beta-hydroxy-EpiA pre-treatment prevents DSS-induced colitis and to determine whether the effects involve changes in anti-inflammatory prostaglandin (PG) D(2) and 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) levels.

5Alpha-androstane-3beta,7alpha,17beta-triol and 5alpha-androstane-3beta,7beta,17beta-triol as substrates for the human 11beta-hydroxysteroid dehydrogenase type 1.

Several studies have shown that the native 7alpha-hydroxy-dehydroepiandrosterone (7alpha-hydroxy-DHEA) is a substrate for the human 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) which converts the 7alpha- into the 7beta-epimer through an oxido-reduction process. Research on the 11beta-HSD1 has investigated its function and structure through using native glucocorticoid substrates and known inhibitors. Other steroid substrates are also of interest.

Regulation and expression of human CYP7B1 in prostate: overexpression of CYP7B1 during progression of prostatic adenocarcinoma.

Background: Cytochrome P450 (CYP) 7B1 is involved in many metabolic processes including androgen metabolism. Cytochrome P450 (CYP) 7B1 is expressed within the prostate and may determine the levels of the natural estrogen receptor beta (ERbeta) ligand 5alpha-androstane-3beta,17beta-diol (3betaAdiol) available and hence affect the regulation of prostate proliferation. We hypothesized that CYP7B1 expression is increased in prostate tumors and that promoter methylation contributes to the regulation of CYP7B1 expression in human prostate tissue.

7alpha- and 7beta-hydroxy-epiandrosterone as substrates and inhibitors for the human 11beta-hydroxysteroid dehydrogenase type 1.

The human 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes both the NADP(H)-dependent oxido-reduction of cortisol and cortisone and the inter-conversion of 7alpha- and 7beta-hydroxy-dehydroepiandrosterone (DHEA) through a 7-oxo-DHEA intermediate. As shown with human liver and intestine fractions, 7alpha-hydroxy-epiandrosterone (7alpha-hydroxy-EpiA) and 7beta-hydroxy-EpiA were readily inter-converted with no evidence for a 7-oxo-EpiA intermediate. Whether this inter-conversion resulted from action of the 11beta-HSD1 or from an unknown epimerase is unresolved.

Dehydroepiandrosterone 7alpha-hydroxylation in human tissues: possible interference with type 1 11beta-hydroxysteroid dehydrogenase-mediated processes.

Dehydroepiandrosterone (DHEA) is 7alpha-hydroxylated by the cytochome P450 7B1 (CYP7B1) in the human brain and liver. This produces 7alpha-hydroxy-DHEA that is a substrate for 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) which exists in the same tissues and carries out the inter-conversion of 7alpha- and 7beta-hydroxy-DHEA through a 7-oxo-intermediary. Since the role of 11beta-HSD1 is to transform the inactive cortisone into active cortisol, its competitive inhibition by 7alpha-hydroxy-DHEA may support the paradigm of native anti-glucocorticoid arising from DHEA.

Dehydroepiandrosterone metabolites and their interactions in humans.

Dehydroepiandrosterone (DHEA) is 7alpha-hydroxylated by the cytochrome P4507B1 in the liver, skin and brain, which are targets for glucocorticoids. 7alpha-Hydroxy-DHEA produced anti-glucocorticoid effects in vivo but the interference between the glucocorticoid hormone binding with its receptor could not be determined. In the organs mentioned above, circulating inactive cortisone is reduced to active cortisol by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1).

The native anti-glucocorticoid paradigm.

Circulating 3beta-hydroxysteroids including dehydroepiandrosterone (DHEA) are 7alpha-hydroxylated by the cytochrome P450-7B1 in the liver, skin and brain, which are the target organs of glucocorticoids. Anti-glucocorticoid effects with 7alpha-hydroxy-DHEA were observed in vivo without an interference with glucocorticoid binding to its receptor. In the organs mentioned above, the circulating inactive cortisone was reduced into active cortisol by the 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1).

Inter-conversion of 7alpha- and 7beta-hydroxy-dehydroepiandrosterone by the human 11beta-hydroxysteroid dehydrogenase type 1.

The dehydroepiandrosterone (DHEA) 7alpha-hydroxylation in humans takes place in the liver, skin, and brain. These organs are targets for the glucocorticoid hormones where 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activates cortisone through its reduction into cortisol. The putative interference of 7alpha-hydroxy-DHEA with the 11beta-HSD1-catalyzed reduction of cortisone into cortisol has been confirmed in preliminary works with human liver tissue preparations of the enzyme demonstrating the transformation of 7alpha-hydroxy-DHEA into 7-oxo-DHEA and 7beta-hydroxy-DHEA.

Protection against dextran sodium sulfate-induced colitis by dehydroepiandrosterone and 7alpha-hydroxy-dehydroepiandrosterone in the rat.

In this study the anti-oxidant effect of DHEA and 7alpha-hydroxy-DHEA against oxidative stress induced by colitis was investigated in vivo in rats. The two steroids were intraperitoneally injected once daily (50 mg/kg body weight) for 7 days before the induction of colitis that was effected by a daily treatment of 5% (w/v) dextran sodium sulfate (DSS) in drinking water for 7 days. This was quantified by the evidence of weight loss, rectal bleeding, increased wall thickness, and colon length.

Neurosteroids: metabolism in human intestine microsomes.

Both dehydroepiandrosterone (DHEA) and epiandrosterone (EpiA) are substrate for cytochrome P450 species and enzymes that produce 7alpha- and 7beta-hydroxylated metabolites in the brain and other organs. In contrast to DHEA and EpiA, the 7-hydroxylated derivatives were shown to mediate neuroprotection, and 7beta-hydroxy-EpiA was the most potent. The suggested use of any of these steroids as drugs administered per os for neuroprotection requires the assessment of their metabolism in the human intestine and liver.

Dehydroepiandrosterone and its 7-hydroxylated metabolites do not interfere with the transactivation and cellular trafficking of the glucocorticoid receptor.

The human brain is a target tissue for glucocorticoids (GC). Dehydroepiandrosterone (DHEA) is a neurosteroid produced in the brain where it is transformed into 7alpha-hydroxy-DHEA and 7beta-hydroxy-DHEA. The antiglucocorticoid effects of both 7-hydroxylated metabolites have been investigated with evidence in mice that neither form of DHEA interfered with the binding of GC to its glucocorticoid receptor (GR), but contributed to a decreased nuclear uptake of the activated GR.

The human cytochrome P4507B1: catalytic activity studies.

The cytochrome P4507B1 (P4507B1) in the human hippocampus is responsible for the production of 7alpha-hydroxylated derivatives of dehydroepiandrosterone (DHEA) and other 3beta-hydroxylated neurosteroids. Minor quantities of the 7beta-hydroxylated derivatives are also produced. Neuroprotective action of these 7-hydroxysteroids was reported.

Immunohistochemical detection of the human cytochrome P4507B1: production of a monoclonal antibody after cDNA immunization.

The cytochrome P4507B1 (P4507B1) is responsible for the 7alpha-hydroxylation of dehydroepiandrosterone (DHEA) and other 3beta-hydroxysteroids in the brain and other organs. The cDNA of human P4507B1 was used for DNA immunization of mice. The best responding mouse led to the production of monoclonal antibodies (mAbs).

Human liver S9 fractions: metabolism of dehydroepiandrosterone, epiandrosterone, and related 7-hydroxylated derivatives.

Dehydroepiandrosterone (DHEA) and 3beta-hydroxy-5alpha-androstan-17-one (epiandrosterone, EpiA) are both precursors for 7alpha- and 7beta-hydroxylated metabolites in the human brain. These 7-hydroxylated derivatives were shown to exert anti-glucocorticoid and neuroprotective effects. When these steroids are administered per os to humans, the first organ encountered is the liver, where extensive metabolism takes place.