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Distinct Roles of the Sister Nuclear Receptors PXR and CAR in Liver Cancer Development.

Pregnane X receptor (PXR) and constitutively active receptor/constitutive androstane receptor (CAR) are xenobiotic-responsible transcription factors belonging to the same nuclear receptor gene subfamily and highly expressed in the liver. These receptors are activated by a variety of chemicals and play pivotal roles in many liver functions, including xenobiotic metabolism and disposition. Phenobarbital, an enzyme inducer and liver tumor promoter, activates both rodent and human CAR but causes liver tumors only in rodents. Although the precise mechanism for phenobarbital/CAR-mediated liver tumor

Steroids in the establishment and maintenance of pregnancy and at parturition in the mare.

Historically, studies on the endocrinology of pregnancy and parturition in horses have made major contributions of relevance to mammals in g … sed ratio of equine PR-B:PR-A in myometrium, suggesting that progestin withdrawal is both systemic (pregnanes) and local (receptor-dependent) in mares. In addition, some steroids detected during equine pregnancy by immuno-assay are not detected by mass spectrometry, further illustrating the immense value of this technology.

Biological analysis of endocrine-disrupting compounds in Tunisian sewage treatment plants.

Endocrin-disrupting compounds (EDCs) are frequently found in wastewater treatment plants (WWTPs). So far, research has been mainly focused on the detection of estrogenic compounds and very little work has been carried out on other receptors activators. In this study, we used reporter cell lines, which allow detecting the activity of estrogen (ERalpha), androgen (AR), pregnane X (PXR), glucocorticoid (GR), progesterone (PR), mineralocorticoid (MR), and aryl hydrocarbon (AhR) receptors, to characterise the endocrine-disrupting profile of the aqueous, suspended particulate matter, and sludge frac

Clinical and biochemical variability of congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency. A study of 25 patients.

Twenty five patients (10 males and 15 females) aged 0-23 yr with congenital adrenal hyperplasis due to 11 beta-hydroxylase deficiency were studied. They were divided into 13 classic (group A), and 12 mild (group B) patients. The patients of group A were diagnosed at a younger age and had more severe clinical symptoms (ambiguous genitalia in girls, pseudoprecocious puberty in boys). Two had neonatal salt wasting before treatment, and one gynecomastia. Seven had moderate to severe hypertension. Their mean 3 alpha,17,21-trihydroxy-5 beta-pregnan-20-one (THS) and 3 alpha, 21-dihydroxy-5 beta-pregn

Review of the reproductive endocrinology of the pregnant and parturient mare.

Analytical advancements, especially methods using gas or liquid chromatography tandem mass spectrometry, have allowed more specific and reli … egnanolone) dominate in late gestation, some exceeding DHP by 10-fold near term. However, all major pregnanes decrease from 3 days before foaling, when fetal cortisol is reportedly rising. Though unique, equine pregnancy and parturition share many features in common with those seen in human pregnancy and birth.

Advances in congenital adrenal hyperplasia newborn screening: 11-ketotestosterone and 21-deoxycortisone as additional discriminatory biomarkers.

BACKGROUND: A major limitation of newborn screening (NBS) for congenital adrenal hyperplasia (CAH) is the lack of specificity of the fluoroi … tly, the class of 11-oxygenate-androgens-such as 11-ketotestosterone-and more recently 11-oxygenate pregnanes-such as 21-deoxycortisone-has attracted growing interest in the diagnosis of 21-hydroxylase deficiency. These derivatives result from the combined action of 11-beta hydroxysteroid dehydrogenase and 11-beta hydroxylase. METHODS: We propose a revisit …

Neuroactive steroids in pregnancy: key regulatory and protective roles in the foetal brain.

Neuroactive steroid concentrations are remarkably high in the foetal brain during late gestation. These concentrations are maintained by placental progesterone synthesis and the interaction of enzymes in the placenta and foetal brain. 5α-Pregnane-3α-ol-20-one (allopregnanolone) is a key neuroactive steroid during foetal life, although other 3α-hydroxy-pregnanes may make an additional contribution to neuroactive steroid action. Allopregnanolone modulates GABAergic inhibition to maintain a suppressive action on the foetal brain during late gestation. This action suppresses foetal behaviour and m…

[Role of medical treatment for symptomatic leiomyoma management in premenopausal women].

The most frequent symptom with leiomyoma is menometrorrhagia. However, it can be responsible of pelvic pain, dysmenorrhea or urinary and digestive compression when it is particularly voluminous. These recommandations were made in order to review medical management of fibroids. If no therapy is able to have them disappear, various drugs may reduce their related symptoms. Tranexamic acid, non-steroidal anti-inflammatory drugs and high dose of oestrogen may be useful in the management of acute hemorrhagic disorders. Progestin, such as lynestrenol induces small reduction in leiomyoma volume and mo

GABA(B) receptor-mediated increase of neurosteroids by gamma-hydroxybutyric acid.

Among the pharmacological actions of gamma-hydroxybutyric acid (GHB), some may involve GABA(A) receptor-mediated mechanisms. GHB, however, fails to directly interact with sites for agonists and modulators on the GABA(A) receptor complex. We hypothesized that, in vivo, GHB may interfere with GABA(A) receptor function by altering the brain concentrations of the neurosteroids 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone, AP) and 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (allotetrahydrodeoxycorticosterone, THDOC), positive allosteric modulators of GABA-gated chloride currents. In mal

Modulation of the GABAA receptor complex by steroids in slices of rat cuneate nucleus.

1. Several derivatives of pregnane and androstane that have hypnotic properties have been investigated for their ability to potentiate responses to the GABAA receptor agonist muscimol and to reduce the effect of the non-competitive GABAA antagonist picrotoxin. 2. Depolarizing responses to muscimol in slices of rat cuneate nucleus were potentiated most potently by 3 alpha-hydroxy,5 alpha-pregnane-11,20-dione (alphaxalone), which gave half-maximal potentiation at 0.15 microM. The 5 beta isomer of alphaxalone had little effect up to 3 microM but in analogues lacking an 11-keto substituent (pregna

Aldosterone antagonists. 2. Synthesis and biological activities of 11,12-dehydropregnane derivatives.

Several steroid derivatives having the delta 11-pregnane skeleton with a 17-gamma-spirolactone function were synthesized to evaluate their antialdosterone activity and to elucidate the relation between their binding affinity to mineralocorticoid receptor (MR) and their mineralo- and/or antimineralocorticoid activity. Although many of the synthesized compounds showed strong binding affinity for the MR and aldosterone agonist activity, 3-(17 beta-hydroxy-3-oxoandrosta-1,4,6,11-tetraen-17 alpha-yl)propionic acid gamma-lactone exhibited good aldosterone antagonist activity in an in vivo assay. Its

Optimization of Benzoxazinorifamycins to Minimize hPXR Activation for the Treatment of Tuberculosis and HIV Coinfection.

Tuberculosis (TB) is one of the most significant world health problems, responsible for 1.5 M deaths in 2020, and yet, current treatments rely largely on 40 year old paradigms. Although the rifamycins (RIFs), best exemplified by the drug rifampin (RMP), represent a well-studied and therapeutically effective chemotype that targets the bacterial RNA polymerase (RNAP), these agents still suffer from serious drawbacks including the following: 3-9 month treatment times; cytochrome P450 (Cyp450) induction [particularly problematic for human immunodeficiency virus-Mycobacterium tuberculosis (MTB) co-

Differential effect of chronic ethanol treatment on barbiturate and steroid modulation of muscimol-binding to rat brain cortex.

We report the differential alterations produced by chronic ethanol treatment on the modulation, by the barbiturate thiopental and the steroid 5 beta-pregnan-3 alpha-ol-20-one, of the binding of [3H]muscimol to membrane preparations from rat brain cortex. We found a clear barbiturate- and steroid-promoted enhancement of muscimol-binding to membranes in both control and ethanol-treated animals. However, the enhancements were higher in control animals, using the barbiturate, and in ethanol-treated rats, using the steroid, Bmax and Kd values were also differentially affected in control and ethanol

Воздействие лечения на стероидом у женщин с множественным склерозом.

Множественный склероз (MS) — хроническое воспалительное нейродегенеративное заболевание центральной нервной системы. Происхождение MS связано с стероидными изменениями во время менструального цикла и беременности. Поскольку данных о воздействии лечения противомоскитных препаратов на стероидом недостаточно, мы провели оценку стерейдомичных изменений (79 стероидов) у 61 женщины-психолога репродуктивного возраста 39 лет (29, 47 лет) после лечения с помощью антимиосных препаратов на платформе GC-MS/MS и иммуномассы (кортизол и эстрадиол). Эти изменения были оценены с использованием уровней стероид

Совпадение в аннотации оригинала
Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system. The manifestation of MS is relate … itors of the sphingosine-1-phosphate receptor (S1PRI); and IFNβ-1a decreased circulating 17-hydroxy-pregnanes and shifted the CYP17A1 functioning from the hydroxylase- toward the lyase step. Decreased conjugated/unconjugated steroid ratios were found after treatment with anti-MS drugs, especially for glatiramer acetate and anti-CD20 mAb. In the luteal phase …

Increased PXR and Suppressed T-Cell Signaling Are Associated With Malignant Degeneration of Barrett's Esophagus.

BACKGROUND AND AIMS: Barrett's esophagus (BE) is the precursor lesion for esophageal adenocarcinoma (EAC). To detect EAC in early stage, patients with BE undergo endoscopic surveillance. Surveillance cohorts largely consist of nondysplastic BE (NDBE) patients with a low annual progression risk (<0.5%). Predictive biomarkers for malignant progression of NDBE could improve efficacy of surveillance. Biomarker research has mostly focused on aberrant protein expression on BE epithelial cells. Moreover, insight in cell signaling driving malignant transformation is unknown. This study uses a data-dri

Reduced expression of UGT1A1 in intestines of humanized UGT1 mice via inactivation of NF-κB leads to hyperbilirubinemia.

BACKGROUND & AIMS: Bilirubin is a natural and potent antioxidant that accumulates in the blood of newborn children and leads to physiological jaundice. Breastfed infants have higher serum levels of bilirubin than formula-fed infants and are at risk for bilirubin-induced neurological dysfunction (BIND). Clearance of bilirubin requires the expression of uridine diphosphate glucuronosyltransferase (UGT) 1A1; we investigated its role in the association between breast feeding with jaundice in mice. METHODS: We studied mice in which the original Ugt1 locus was disrupted and replaced with the human

Steroid inhibition of [3H]SR 95531 binding to the GABAA recognition site.

The interaction of three types of steroids with the GABAA recognition site labeled by the antagonist ligand [3H]SR 95531 was evaluated in rat brain cortical membranes. The first type is the GABA site antagonist RU 5135, which potently (IC50 7 nM) but also incompletely (Imax 82%) displaced [3H]SR 95531. RU 5135 probably binds only to high affinity [3H]SR 9553] sites recognized by GABA and unlabelled SR 95531. The second type are the neuroactive steroids which act as positive allosteric modulators, including 3 alpha-hydroxy-5 beta-pregnan-20-one (3 alpha, 5 beta-P) and 5 beta-tetrahydrodeoxycort

A change in the steroid metabolic pathway in human testes showing deteriorated spermatogenesis.

During androgen biosynthesis, the human testes normally produce only small quantities of Δ4-C21 steroids as these are products of the Δ4-pathway and healthy human testes preferentially use the Δ5-pathway. However, the Δ4-C21 steroid progesterone accumulates in the thickened lamina propria of the seminiferous tubules in testes with deteriorated spermatogenesis. The objectives of this study were to analyse the pregnenolone metabolites in testes with deteriorated spermatogenesis and to establish whether the androgen biosynthesis pathway changes in this condition. Biopsied or orchiectomised testic

Role of progesterone receptor isoforms in female sexual behavior induced by progestins in rats.

Progesterone and its ring A reduced metabolites regulate female sexual behavior through the direct or indirect activation of progesterone receptor (PR) which has two isoforms with different function and regulation: PR-A and PR-B. The contribution of each PR isoform to the regulation of lordosis in rats is unknown. We explored the role of PR isoforms in lordosis display induced by progesterone and two of its ring A reduced metabolites: 5alpha-pregnan-3,20-dione (5alpha-DHP), and 5beta,3beta-pregnan-20-one (5beta,3beta-Pgl) in adult ovariectomized rats. Two weeks after ovariectomy, the animals w

Characterization of the discriminative stimulus effects of the neuroactive steroid pregnanolone in DBA/2J and C57BL/6J inbred mice.

Neurosteroids represent a class of endogenous compounds that exert rapid, nongenomic effects through neurotransmitter receptor systems such as GABA(A). Two neurosteroids, allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) and pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one), possess anxiolytic and sedative properties and show substitution for ethanol, benzodiazepines, and barbiturates in drug discrimination assays. This study aimed to examine the effects of strain and sex on the discriminative stimulus effects of pregnanolone. Twelve male and female DBA/2J mice and 12 male and female C5