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https://www.readbyqxmd.com/read/28648378/steroidogenic-metabolism-of-galeterone-reveals-a-diversity-of-biochemical-activities
#1
Mohammad Alyamani, Zhenfei Li, Michael Berk, Jianneng Li, Jingjie Tang, Sunil Upadhyay, Richard J Auchus, Nima Sharifi
Galeterone is a steroidal CYP17A1 inhibitor, androgen receptor (AR) antagonist, and AR degrader, under evaluation in a phase III clinical trial for castration-resistant prostate cancer (CRPC). The A/B steroid ring (Δ(5),3β-hydroxyl) structure of galeterone is identical to that of cholesterol, which makes endogenous steroids with the same structure (e.g., dehydroepiandrosterone and pregnenolone) substrates for the enzyme 3β-hydroxysteroid dehydrogenase (3βHSD). We found that galeterone is metabolized by 3βHSD to Δ(4)-galeterone (D4G), which is further converted by steroid-5α-reductase (SRD5A) to 3-keto-5α-galeterone (5αG), 3α-OH-5α-galeterone, and 3β-OH-5α-galeterone; in vivo it is also converted to the three corresponding 5β-reduced metabolites...
June 19, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28645657/gross-pathology-physiological-and-toxicological-responses-in-relation-to-metals-and-persistent-organic-pollutants-pops-burden-in-tilapia-species-from-ogun-river-nigeria
#2
Oju R Ibor, Aina O Adeogun, Azubuike V Chukwuka, Augustine Arukwe
We have investigated gross pathology, physiological (steroid precursors) and toxicological responses (oxidative stress and phase II biotransformation) in relation to tissue contaminant burden in Tilapia species along the entire length (320 km) of Ogun River, Nigeria. The Ogun River is the longest and largest river in Southwestern Nigeria located along heavily industrialized cities and receives complex mixtures of effluents. A total of 1074 tilapias were collected from three sampling points (Abeokuta, Isheri and Ikorodu) and from an upstream control point (Igboho) and evaluated for gross pathological changes, hepatic transcript levels for oxidative stress and phase II biotransformation responses...
June 8, 2017: Marine Environmental Research
https://www.readbyqxmd.com/read/28641386/the-neurosteroid-pregnenolone-reverts-microtubule-derangement-induced-by-the-loss-of-a-functional-cdkl5-iqgap1-complex
#3
Isabella Barbiero, Diana Peroni, Marco Tramarin, Chetan Chandola, Laura Rusconi, Nicoletta Landsberger, Charlotte Kilstrup-Nielsen
CDKL5 is a protein kinase that plays a key role for neuronal functions as testified by the onset of complex neuronal dysfunctions in patients with genetic lesions in CDKL5. Here we identify a novel interactor of CDKL5, IQGAP1, a fundamental regulator of cell migration and polarity. In accordance with a functional role of this interaction, depletion of CDKL5 impairs cell migration and impedes the localization of IQGAP1 at the leading edge. Moreover, we demonstrate that CDKL5 is required for IQGAP1 to form a functional complex with its effectors, Rac1 and the microtubule plus end tracking protein CLIP170...
June 21, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28638078/the-stress-response-factor-daf-16-foxo-is-required-for-multiple-compound-families-to-prolong-the-function-of-neurons-with-huntington-s-disease
#4
Francesca Farina, Emmanuel Lambert, Lucie Commeau, François-Xavier Lejeune, Nathalie Roudier, Cosima Fonte, J Alex Parker, Jacques Boddaert, Marc Verny, Etienne-Emile Baulieu, Christian Neri
Helping neurons to compensate for proteotoxic stress and maintain function over time (neuronal compensation) has therapeutic potential in aging and neurodegenerative disease. The stress response factor FOXO3 is neuroprotective in models of Huntington's disease (HD), Parkinson's disease and motor-neuron diseases. Neuroprotective compounds acting in a FOXO-dependent manner could thus constitute bona fide drugs for promoting neuronal compensation. However, whether FOXO-dependent neuroprotection is a common feature of several compound families remains unknown...
June 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28637490/lipoid-congenital-adrenal-hyperplasia-by-steroidogenic-acute-regulatory-protein-star-gene-mutation-in-an-italian-infant-an-uncommon-cause-of-adrenal-insufficiency
#5
Carla Bizzarri, Elisa Pisaneschi, Mafalda Mucciolo, Stefania Pedicelli, Daniela Galeazzi, Antonio Novelli, Marco Cappa
BACKGROUND: Lipoid congenital adrenal hyperplasia (CAH) (OMIM n. 201710) is the most severe form of congenital adrenal hyperplasia. It is characterized by severe adrenal and gonadal steroidogenesis impairment due to a defect in the conversion of cholesterol to pregnenolone. Affected infants experience salt loss, but glucocorticoid and mineralocorticoid replacement therapy enables long-term survival. Classic lipoid congenital adrenal hyperplasia is relatively common in Japan and Korea but extremely rare in Caucasian populations...
June 20, 2017: Italian Journal of Pediatrics
https://www.readbyqxmd.com/read/28637041/the-effects-of-fungicides-on-human-3%C3%AE-hydroxysteroid-dehydrogenase-1-and-aromatase-in-human-placental-cell-line-jeg-3
#6
Shuyan Cao, Leping Ye, Ying Wu, Baiping Mao, Lanlan Chen, Xiudi Wang, Ping Huang, Ying Su, Ren-Shan Ge
Placenta secretes a large amount of progesterone and estradiol, which are critical for maintaining pregnancy. In human placenta, 3β-hydroxysteroid dehydrogenase 1 (HSD3B1) catalyzes pregnenolone to form progesterone, and aromatase (CYP19A1) catalyzes testosterone into estradiol. Fungicides display antifungal activities and are widely used to prevent fungal infections in agricultural plants. These chemicals include azoles, such as tebuconazole (TEB), triadimefon (TRI), and vinclozolin (VCZ) or organotins, such as tributyltin (TBT) and tetrabutyltin (TTBT)...
June 22, 2017: Pharmacology
https://www.readbyqxmd.com/read/28636871/pregnane-glycosides-from-cynanchum-menarandrense
#7
Michail Tsoukalas, Arianna Psichas, Frank Reimann, Fiona M Gribble, Annelise Lobstein, Aurélie Urbain
Five new pregnane-type steroidal glycosides, named menarandrosides A-E (1-2, 5-7) were isolated from the aerial parts of Cynanchum menarandrense, together with three known compounds, carumbelloside I (3), carumbelloside II (4), and pregnenolone-3-O-gentiobioside (8). Their structures were determined on the basis of spectroscopic analyses including NMR and mass spectrometry, reporting C-21 steroids glycosylated only by one or two glucose moieties. Compounds were then investigated for their potential to stimulate glucagon-like peptide-1 (GLP-1) secretion in intestinal cells; although none of the pure compounds had any influence, the fraction enriched in pregnanes exhibited a significant activity, suggesting a possible synergistic effect...
June 18, 2017: Steroids
https://www.readbyqxmd.com/read/28629239/cortisol-precursors-in-neonates-with-vasopressor-resistant-hypotension-in-relationship-to-demographic-characteristics
#8
Abdelmoneim Khashana, Hoda Ahmed, Amal Ahmed, Amina Abdelwahab, Timo Saarela, Mika Rämet, Mikko Hallman
OBJECTIVE: To correlate between cortisol precursors in neonates with vasopressor resistant hypotension and demographic characteristics. METHODS: We investigated 48 neonates with vasopressor-resistant hypotension. Gestation at birth ranged from 34 to 42 weeks and postnatal age from 4 to 14 days. Cortisol and precursor steroids were measured soon after the onset of volume expansion and inotropes for treatment of shock. Their concentrations were determined using liquid chromatography-mass spectrometry...
June 19, 2017: Journal of Maternal-fetal & Neonatal Medicine
https://www.readbyqxmd.com/read/28624525/regulation-of-hepatic-abcb4-and-cyp3a65-gene-expression-and-multidrug-multixenobiotic-resistance-mdr-mxr-functional-activity-in-the-model-teleost-danio-rerio-zebrafish
#9
Jeremy S Jackson, Christopher J Kennedy
Multidrug/multixenobiotic resistance (MDR/MXR) confers resistance to a diverse range of potentially toxic pharmaceuticals and environmental contaminants through a cellular response that involves the coordinated induction and activity of the ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp) and the Phase I metabolizing enzyme cytochrome P450 3A (CYP3A). In mammals, ligand-mediated pregnane X receptor (PXR) transcriptional activity regulates the induction of P-gp and CYP3A; however, this mechanism has not been well-characterized in fish...
June 14, 2017: Comparative Biochemistry and Physiology. Toxicology & Pharmacology: CBP
https://www.readbyqxmd.com/read/28609670/differential-effects-of-the-18-kda-translocator-protein-tspo-ligand-etifoxine-on-steroidogenesis-in-rat-brain-plasma-and-steroidogenic-glands-pharmacodynamic-studies
#10
Philippe Liere, Antoine Pianos, Jean-Paul Oudinet, Michael Schumacher, Yvette Akwa
Etifoxine is indicated in humans for treating anxiety. In rodents, besides its anxiolytic-like properties, it has recently shown neuroprotective and neuroregenerative activities. It acts by enhancing GABAA receptor function and by stimulating acute steroid biosynthesis via the activation of the 18-kDa translocator protein. However, the regulatory action of etifoxine on steroid production is not well characterized. In this work, we performed dose-response, acute and chronic time-course experiments on the effects of intraperitoneal injections of etifoxine on steroid levels in adult male rat brain and plasma analyzed by gas chromatography-mass spectrometry...
June 3, 2017: Psychoneuroendocrinology
https://www.readbyqxmd.com/read/28598779/preclinical-biomarker-associations-with-both-incident-rheumatoid-arthritis-and-its-subsequent-mortality-sex-effects-in-a-41-year-community-based-case-control-cohort-study
#11
Alfonse T Masi, Azeem A Rehman, Laura C Jorgenson, Jean C Aldag
OBJECTIVES: To identify sex effects and preclinical serum biomarker associations with both incident rheumatoid arthritis (RA) and its subsequent mortality, using a 41-year, community-based, case-control cohort. METHODS: After cohort entry in 1974, incident RA cases (n=54) had clinical onsets between 1977 and 1994. Cohort control (CN) subjects were individually matched on entry to cases (4 CN:1 RA, n=216). All subjects were followed for survival from 1995 through 2015...
June 5, 2017: Clinical and Experimental Rheumatology
https://www.readbyqxmd.com/read/28589573/in-vitro-and-in-vivo-effect-of-flutamide-on-steroid-hormone-secretion-in-canine-and-human-inflammatory-breast-cancer-cell-lines
#12
S Caceres, B Monsalve, L Peña, P J de Andres, A Alonso-Diez, M J Illera, W A Woodward, J M Reuben, G Silvan, J C Illera
The aim was to study the effects of flutamide on cell proliferation, in vivo tumour growth and steroid production in canine and human IBC cell lines. IPC-366 and SUM149 cell cultures were exposed to flutamide concentrations for 72 hours. Additionally, IPC-366 and SUM149 xenotransplanted mice were treated subcutaneously with flutamide 3 times a week for 2 weeks. Steroid hormones determination in culture media, serum and tumour homogenates (pregnenolone, progesterone, androstenedione, testosterone, dihydrotestosterone, 17β-oestradiol and oestrone sulphate) were assayed by EIA...
June 6, 2017: Veterinary and Comparative Oncology
https://www.readbyqxmd.com/read/28538409/a-case-report-of-pedigree-of-a-homozygous-mutation-of-the-steroidogenic-acute-regulatory-protein-causing-lipoid-congenital-adrenal-hyperplasia
#13
Rong Fu, Lin Lu, Jun Jiang, Min Nie, Xiaojing Wang, Zhaolin Lu
RATIONALE: Lipoid congenital adrenal hyperplasia (LCAH) is extremely rare, but is the most fatal form of congenital adrenal hyperplasia resulting from mutations in the steroidogenic acute regulatory protein (STAR) gene. LCAH arises from severe defects in the conversion of cholesterol to pregnenolone, the precursor of all steroids. PATIENT CONCERNS: A case was reported that an 11-month-old Chinese girl who presented with a sex development disorder and hyponatremia...
May 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28530704/upregulation-of-cyp17a1-by-sp1-mediated-dna-demethylation-confers-temozolomide-resistance-through-dhea-mediated-protection-in-glioma
#14
J-Y Chuang, W-L Lo, C-Y Ko, S-Y Chou, R-M Chen, K-Y Chang, J-J Hung, W-C Su, W-C Chang, T-I Hsu
Steroidogenesis-mediated production of neurosteroids is important for brain homeostasis. Cytochrome P450 17A1 (CYP17A1), which converts pregnenolone to dehydroepiandrosterone (DHEA) in endocrine organs and the brain, is required for prostate cancer progression and acquired chemotherapeutic resistance. However, whether CYP17A1-mediated DHEA synthesis is involved in brain tumor malignancy, especially in glioma, the most prevalent brain tumor, is unknown. To investigate the role of CYP17A1 in glioma, we determined that CYP17A1 expression is significantly increased in gliomas, which secrete more DHEA than normal astrocytes...
May 22, 2017: Oncogenesis
https://www.readbyqxmd.com/read/28520937/atypical-endocannabinoid-signaling-initiates-a-new-form-of-memory-related-plasticity-at-a-cortical-input-to-hippocampus
#15
Weisheng Wang, Yousheng Jia, Danielle T Pham, Linda C Palmer, Kwang-Mook Jung, Conor D Cox, Gavin Rumbaugh, Daniele Piomelli, Christine M Gall, Gary Lynch
Endocannabinoids (ECBs) depress transmitter release at sites throughout the brain. Here, we describe another form of ECB signaling that triggers a novel form of long-term potentiation (LTP) localized to the lateral perforant path (LPP) which conveys semantic information from cortex to hippocampus. Two cannabinoid CB1 receptor (CB1R) signaling cascades were identified in hippocampus. The first is pregnenolone sensitive, targets vesicular protein Munc18-1 and depresses transmitter release; this cascade is engaged by CB1Rs in Schaffer-Commissural afferents to CA1 but not in the LPP, and it does not contribute to LTP...
May 17, 2017: Cerebral Cortex
https://www.readbyqxmd.com/read/28507119/regulation-of-the-sperm-calcium-channel-catsper-by-endogenous-steroids-and-plant-triterpenoids
#16
Nadja Mannowetz, Melissa R Miller, Polina V Lishko
The calcium channel of sperm (CatSper) is essential for sperm hyperactivated motility and fertility. The steroid hormone progesterone activates CatSper of human sperm via binding to the serine hydrolase ABHD2. However, steroid specificity of ABHD2 has not been evaluated. Here, we explored whether steroid hormones to which human spermatozoa are exposed in the male and female genital tract influence CatSper activation via modulation of ABHD2. The results show that testosterone, estrogen, and hydrocortisone did not alter basal CatSper currents, whereas the neurosteroid pregnenolone sulfate exerted similar effects as progesterone, likely binding to the same site...
May 30, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28502863/synthesis-of-16%C3%AE-amino-pregnenolone-derivatives-via-ionic-liquid-catalyzed-aza-michael-addition-and-their-evaluation-as-c17-20-lyase-inhibitors
#17
Eszter Szánti-Pintér, Lilla Maksó, Ágnes Gömöry, Johan Wouters, Bianka Edina Herman, Mihály Szécsi, Gábor Mikle, László Kollár, Rita Skoda-Földes
Aza-Michael addition of 16-dehydropregnenolone was studied in the presence of a basic ionic liquid, [DBU][OAc] as catalyst and solvent. The reaction was carried out using different primary and secondary amines as N-nucleophiles. The products were obtained in moderate to good yields and were characterized by (1)H and (13)C NMR, MS and IR. The ionic liquid was found to be an efficient and recyclable catalyst that was reused five times. The products were investigated for the inhibition of in vitro C17,20-lyase activity and displayed moderate inhibitory effect...
May 11, 2017: Steroids
https://www.readbyqxmd.com/read/28479316/reference-intervals-for-plasma-concentrations-of-adrenal-steroids-measured-by-lc-ms-ms-impact-of-gender-age-oral-contraceptives-body-mass-index-and-blood-pressure-status
#18
Graeme Eisenhofer, Mirko Peitzsch, Denise Kaden, Katharina Langton, Christina Pamporaki, Jimmy Masjkur, George Tsatsaronis, Anastasios Mangelis, Tracy A Williams, Martin Reincke, Jacques W M Lenders, Stefan R Bornstein
BACKGROUND: Mass spectrometric-based measurements of the steroid metabolome have been introduced to diagnose disorders featuring abnormal steroidogenesis. Defined reference intervals are important for interpreting such data. METHODS: Liquid chromatography-tandem mass spectrometry was used to establish reference intervals for 16 steroids (pregnenolone, progesterone, 11-deoxycorticosterone, corticosterone, aldosterone, 18-oxocortisol, 18-hydroxycortisol, 17-hydroxyprogesterone, 21-deoxycortisol, 11-deoxycortisol, cortisol, cortisone, dehydroepiandrosterone, dehydroepiandrosterone-sulfate, androstenedione, testosterone) measured in plasma from 525 volunteers with (n=227) and without (n=298) hypertension, including 68 women on oral contraceptives...
July 2017: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/28472487/11-oxygenated-androgens-are-biomarkers-of-adrenal-volume-and-testicular-adrenal-rest-tumors-in-21-hydroxylase-deficiency
#19
Adina F Turcu, Ashwini Mallappa, Meredith Elman, Nilo A Avila, Jamie Marko, Hamsini Rao, Alexander Tsodikov, Richard J Auchus, Deborah P Merke
Context: Patients with 21-hydroxylase deficiency (21OHD) suffer from long-term complications, which might result from poor disease control and/or glucocorticoid overtreatment. Lack of optimal biomarkers has made it challenging to tailor therapy and to predict long-term outcomes. Objective: To identify biomarkers of disease control and long-term complications in 21OHD. Setting and participants: Cross-sectional study of 114 patients (70 males), ages 2 to 67 (median, 15) years, seen in a tertiary referral center...
May 1, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28471529/reduced-steroidogenesis-in-patients-with-pcdh19-female-limited-epilepsy
#20
Marina Trivisano, Chiara Lucchi, Cecilia Rustichelli, Alessandra Terracciano, Raffaella Cusmai, Grazia Maria Ubertini, Germana Giannone, Enrico Silvio Bertini, Federico Vigevano, Jozef Gecz, Giuseppe Biagini, Nicola Specchio
Patients affected by protocadherin 19 (PCDH19)-female limited epilepsy (PCDH19-FE) present a remarkable reduction in allopregnanolone blood levels. However, no information is available on other neuroactive steroids and the steroidogenic response to hormonal stimulation. For this reason, we evaluated allopregnanolone, pregnanolone, and pregnenolone sulfate by liquid chromatographic procedures coupled with electrospray tandem mass spectrometry in 12 unrelated patients and 15 age-matched controls. We also tested cortisol, estradiol, progesterone, and 17OH-progesterone using standard immunoassays...
June 2017: Epilepsia
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