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Pregnenolone

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https://www.readbyqxmd.com/read/28428138/pregnane-x-receptor-regulates-the-ahr-cyp1a1-pathway-and-protects-liver-cells-from-benzo-%C3%AE-pyrene-induced-dna-damage
#1
Hongmei Cui, Xinsheng Gu, Jingshu Chen, Ying Xie, Sui Ke, Jing Wu, Andrei Golovko, Benjamin Morpurgo, Chunhong Yan, Timothy D Phillips, Wen Xie, Jianyuan Luo, Zhijun Zhou, Yanan Tian
Pregnane X receptor (PXR) plays an important role in protecting cells from mutagenic DNA damages induced by endogenous and exogenous toxicants. This protective function is often attributed to the PXR-regulated metabolic detoxification. Here we report a novel potential mechanism that PXR reduces benzo-[α]-pyrene(BaP)-induced DNA damage through inhibiting the transcriptional activity of aryl hydrocarbon receptor (AhR) which plays a pivotal role in the bioactivation of BaP. We have utilized three well-characterized cell lines, i...
April 17, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28411812/quantifying-endogenous-androgens-estrogens-pregnenolone-and-progesterone-metabolites-in-human-urine-by-gas-chromatography-tandem-mass-spectrometry
#2
Juan Robles, Josep Marcos, Nuria Renau, Lorena Garrostas, Jordi Segura, Rosa Ventura, Bernardí Barceló, Antonia Barceló, Oscar J Pozo
A method for the quantitation of 22 urinary steroids (androgens, estrogens and the main pregnenolone and progesterone metabolites) by means of gas chromatography tandem mass spectrometry using a triple quadrupole analyzer has been developed. Two different enzymatic hydrolysis protocols were investigated; one capable of releasing steroids present as both sulfates and glucuronides (total fraction), and another with β-glucuronidase activity only. After selecting adequate internal standards and choosing the optimal instrumental parameters, i...
July 1, 2017: Talanta
https://www.readbyqxmd.com/read/28410883/aminoglutethimide-induced-lysosomal-changes-in-adrenal-gland-in-mice
#3
Mayu Mutsuga, Yoshiji Asaoka, Naoko Imura, Tomoya Miyoshi, Yuko Togashi
Aminoglutethimide is a steroidogenesis inhibitor and inhibits a cholesterol side-chain cleavage enzyme (CYP11A1) that converts cholesterol to pregnenolone in mitochondria. We investigated histopathological changes induced by 5-day administration of AG in mice. Cytoplasmic vacuoles of various sizes and single cell necrosis were found in zona fasciculata cells in AG-treated mice. Some vacuoles were positive for adipophilin, whereas others were positive for lysosome-associated membrane protein-2 on immunohistochemical staining, indicating they were enlarged lipid droplets and lysosomes, respectively...
April 11, 2017: Experimental and Toxicologic Pathology: Official Journal of the Gesellschaft Für Toxikologische Pathologie
https://www.readbyqxmd.com/read/28408350/neuroactive-steroid-levels-and-psychiatric-and-andrological-features-in-post-finasteride-patients
#4
Roberto Cosimo Melcangi, Daniele Santi, Roberto Spezzano, Maria Grimoldi, Tommaso Tabacchi, Maria Letizia Fusco, Silvia Diviccaro, Silvia Giatti, Giuseppe Carrà, Donatella Caruso, Manuela Simoni, Guido Cavaletti
Recent reports show that, in patients treated with finasteride for male pattern hair loss, persistent side effects including sexual side effects, depression, anxiety and cognitive complaints may occur. We here explored the psychiatric and andrological features of patients affected by post-finasteride syndrome (PFS) and verified whether the cerebrospinal fluid (CSF) and plasma levels of neuroactive steroids (i.e., important regulators of nervous function) are modified. We found that eight out of sixteen PFS male patients considered suffered from a DSM-IV major depressive disorder (MDD)...
April 10, 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28396219/novel-synthesis-of-steroidal-oximes-and-lactams-and-their-biological-evaluation-as-antiproliferative-agents
#5
Roxana Martínez-Pascual, Socorro Meza-Reyes, José Luis Vega-Baez, Penélope Merino-Montiel, José M Padrón, Ángel Mendoza, Sara Montiel-Smith
A novel three-step methodology to obtain 6a-aza-B-homo steroidal lactams has been developed starting from the easily available cholesterol and pregnenolone. In addition, a new procedure for the synthesis of a 6a-aza-B-homo steroidal lactam analog of vespertilin, starting from diosgenin has been established. In both synthetic pathways, the key intermediate is a hydroxyimino derivative obtained in a one- or two-step sequence from the starting materials. These methods avoid the use of hazardous oxidant agents in the process...
April 7, 2017: Steroids
https://www.readbyqxmd.com/read/28389510/association-of-tissue-abiraterone-levels-and-slco-genotype-with-intraprostatic-steroids-and-pathologic-response-in-men-with-high-risk-localized-prostate-cancer
#6
Elahe A Mostaghel, Eunpi Cho, Ailin Zhang, Mohammad Alyamani, Arja Kaipainen, Sean Green, Brett Marck, Nima Sharifi, Jonathan L Wright, Roman Gulati, Lawrence D True, Massimo Loda, Alvin M Matsumoto, Daniel Tamae, Trevor N Penning, Steven P Balk, Philip W Kantoff, Peter S Nelson, Mary-Ellen Taplin, Bruce Montgomery
Germline variation in solute carrier organic anion (SLCO) genes influences cellular steroid uptake and is associated with prostate cancer (PCa) outcomes. We hypothesized that, due to its steroidal structure, the CYP17A inhibitor abiraterone may undergo SLCO-mediated transport and that SLCO gene variation may influence intracellular abiraterone levels and outcomes.<br /><br />Experimental Design: Steroid and abiraterone levels were measured by mass spectrometry in serum and tissue from 58 men with localized PCa in a clinical trial of LHRH agonist plus abiraterone acetate plus prednisone for 24 weeks prior to prostatectomy...
April 7, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28387522/mechanism-of-cytochrome-p450-17a1-catalyzed-hydroxylase-and-lyase-reactions
#7
Silvia Bonomo, Flemming Steen Jørgensen, Lars Olsen
Cytochrome P450 17A1 (CYP17A1) catalyzes C17 hydroxylation of pregnenolone and progesterone and the subsequent C17-C20 bond cleavage (lyase reaction) to form androgen precursors. Compound I (Cpd I) and peroxo anion (POA) are the heme-reactive species underlying the two reactions. We have characterized the reaction path for both the hydroxylase and lyase reactions using density functional theory (DFT) calculations and the enzyme-substrate interactions by molecular dynamics (MD) simulations. Activation barriers for positions subject to hydroxylase reaction have values close to each other and span from 54 to 60 kJ·mol(-1) with a small preference for 17α hydroxylation, in agreement with experimental observations...
April 19, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28347660/effect-of-genetic-polymorphism-on-the-inhibition-of-dopamine-formation-from-p-tyramine-catalyzed-by-brain-cytochrome-p450-2d6
#8
Toshiro Niwa, Marina Shizuku, Kaori Yamano
The inhibitory effects of steroid hormones, including glucocorticoids such as cortisol, and related compounds on dopamine formation from p-tyramine, catalyzed by cytochrome P450 (CYP) 2D6.2 (Arg296Cys, Ser486Thr) and CYP2D6.10 (Pro34Ser, Ser486Thr) were compared with the effects of those catalyzed by CYP2D6.1 (wild type), to investigate the effect of a CYP2D6 polymorphism on neuroactive amine metabolism in the brain. Inhibition constants (Ki) or 50% inhibitory concentrations of six steroid hormones (cortisol, cortisone, corticosterone, dehydroepiandrosterone, progesterone, and pregnenolone) and quinidine and quinine-typical potent inhibitors of the human CYP2D6 and rat CYP2D subfamily, respectively-toward dopamine formation catalyzed by CYP2D6...
April 15, 2017: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28341595/systems-characterization-of-differential-plasma-metabolome-perturbations-following-thrombotic-and-non-thrombotic-myocardial-infarction
#9
Patrick J Trainor, Bradford G Hill, Samantha M Carlisle, Eric C Rouchka, Shesh N Rai, Aruni Bhatnagar, Andrew P DeFilippis
Myocardial infarction (MI) is an acute event characterized by myocardial necrosis. Thrombotic MI is caused by spontaneous atherosclerotic plaque disruption that results in a coronary thrombus; non-thrombotic MI occurs secondary to oxygen supply-demand mismatch. We sought to characterize the differential metabolic perturbations associated with these subtypes utilizing a systems approach. Subjects presenting with thrombotic MI, non-thrombotic MI and stable coronary artery disease (CAD) were included. Whole blood was collected at two acute time-points and at a time-point representing the quiescent stable disease state...
March 22, 2017: Journal of Proteomics
https://www.readbyqxmd.com/read/28302174/feedback-inhibition-of-creb-signaling-by-p38-mapk-contributes-to-the-negative-regulation-of-steroidogenesis
#10
Jiaxin Li, Qian Zhou, Zhuang Ma, Meina Wang, Wen-Jun Shen, Salman Azhar, Zhigang Guo, Zhigang Hu
BACKGROUND: Steroidogenesis is a complex, multi-steps biological process in which, cholesterol precursor is converted to steroids in a tissue specific and tropic hormone dependent manner. Given that steroidogenesis is achieved by coordinated functioning of multiple tissue specific enzymes, many steroids intermediates/metabolites are generated during this process. Both the steroid products as well as major lipoprotein cholesterol donor, high-density lipoprotein 3 (hHDL3) have the potential to negatively regulate steroidogenesis via increased oxidative stress/reactive oxygen species (ROS) generation...
March 16, 2017: Reproductive Biology and Endocrinology: RB&E
https://www.readbyqxmd.com/read/28300583/synthesis-of-new-c-25-and-c-26-steroidal-acids-as-potential-ligands-of-the-nuclear-receptors-daf-12-lxr-and-gr
#11
María V Dansey, María C Del Fueyo, Adriana S Veleiro, Pablo H Di Chenna
A new methodology to obtain C-25 and C-26 steroidal acids starting from pregnenolone is described. Construction of the side chain was achieved by applying the Mukaiyama aldol reaction with a non-hydrolytic work-up to isolate the trapped silyl enol ether with higher yields. Using this methodology we synthesized three new steroidal acids as potential ligands of DAF-12, Liver X and Glucocorticoid nuclear receptors and studied their activity in reporter gene assays. Our results show that replacement of the 21-CH3 by a 20-keto group in the side chains of the cholestane scaffold of DAF-12 or Liver X receptors ligands causes the loss of the activity...
March 11, 2017: Steroids
https://www.readbyqxmd.com/read/28295471/long-term-feeding-of-hydroalcoholic-extract-powder-of-lepidium-meyenii-maca-enhances-the-steroidogenic-ability-of-leydig-cells-to-alleviate-its-decline-with-ageing-in-male-rats
#12
K Yoshida, Y Ohta, N Kawate, M Takahashi, T Inaba, S Hatoya, H Morii, K Takahashi, M Ito, H Tamada
This study examined whether feeding hydroalcoholic extract of Lepidium meyenii (maca) to 8-week-old (sexually maturing) or 18-week-old (mature) male rats for more than a half year affects serum testosterone concentration and testosterone production by Leydig cells cultured with hCG, 22R-hydroxycholesterol or pregnenolone. Testosterone concentration was determined in the serum samples obtained before and 6, 12, 18 and 24 weeks after the feeding, and it was significantly increased only at the 6 weeks in the group fed with the maca extract to maturing rats when it was compared with controls...
March 10, 2017: Andrologia
https://www.readbyqxmd.com/read/28274746/transcription-factors-sf1-and-cjun-cooperate-to-activate-the-fdx1-promoter-in-ma-10-leydig-cells
#13
Pauline Roumaud, Arlette Rwigemera, Luc J Martin
The Ferredoxin 1 (FDX1) protein supports steroid biosynthesis in steroidogenic cells through electron transfer to the rate-limiting steroidogenic enzyme, CYP11A1. The latter catalyzes the conversion of cholesterol to pregnenolone through side chain cleavage inside the mitochondria. Thus far, only several transcription factors have been implicated in the regulation of mouse Fdx1 promoter activity in Leydig cells. These include the nuclear receptor SF1 and SP1. Since two conserved regulatory elements for AP1 transcription factors have been located at -764 and -617bp of the Fdx1 promoter, we hypothesized that cJUN may cooperate with other partners to regulate Fdx1 in Leydig cells...
March 6, 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28254952/effects-of-microrna-34a-on-the-pharmacokinetics-of-cytochrome-p450-probe-drugs-in-mice
#14
Joseph L Jilek, Ye Tian, Ai-Ming Yu
MicroRNAs (miRNAs or miRs), including miR-34a, have been shown to regulate nuclear receptor, drug-metabolizing enzyme, and transporter gene expression in various cell model systems. However, to what degree miRNAs affect pharmacokinetics (PK) at the systemic level remains unknown. In addition, miR-34a replacement therapy represents a new cancer treatment strategy, although it is unknown whether miR-34a therapeutic agents could elicit any drug-drug interactions. To address this question, we refined a practical single-mouse PK approach and investigated the effects of a bioengineered miR-34a agent on the PK of several cytochrome P450 probe drugs (midazolam, dextromethorphan, phenacetin, diclofenac, and chlorzoxazone) administered as a cocktail...
May 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28237809/pregnenolone-16%C3%AE-carbonitrile-ameliorates-concanavalin-a-induced-liver-injury-in-mice-independent-of-the-nuclear-receptor-pxr-activation
#15
Susumu Kodama, Takuto Shimura, Hideaki Kuribayashi, Taiki Abe, Kouichi Yoshinari
The pregnane X receptor (PXR) is well-known as a key regulator of drug/xenobiotic clearance. Upon activation by ligand, PXR transcriptionally upregulates the expression of drug-metabolizing enzymes and drug transporters. Recent studies have revealed that PXR also plays a role in regulating immune/inflammatory responses. Specific PXR activators, including synthetic ligands and phytochemicals, have been shown to ameliorate chemically induced colitis in mice. In this study, we investigated an anti-inflammatory effect of pregnenolone 16α-carbonitrile (PCN), a prototypical activator for rodent PXR, in concanavalin A (Con A)-induced liver injury, a model of immune-mediated liver injury, using wild-type and Pxr(-/-) mice...
April 5, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28220044/pregnenolone-blocks-cannabinoid-induced-acute-psychotic-like-states-in-mice
#16
A Busquets-Garcia, E Soria-Gómez, B Redon, Y Mackenbach, M Vallée, F Chaouloff, M Varilh, G Ferreira, P-V Piazza, G Marsicano
Cannabis-induced acute psychotic-like states (CIAPS) represent a growing health issue, but their underlying neurobiological mechanisms are poorly understood. The use of antipsychotics and benzodiazepines against CIAPS is limited by side effects and/or by their ability to tackle only certain aspects of psychosis. Thus, safer wide-spectrum treatments are currently needed. Although the blockade of cannabinoid type-1 receptor (CB1) had been suggested as a therapeutical means against CIAPS, the use of orthosteric CB1 receptor full antagonists is strongly limited by undesired side effects and low efficacy...
February 21, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28213302/disrupting-effects-of-azocyclotin-to-the-hypothalamo-pituitary-gonadal-axis-and-reproduction-of-xenopus-laevis
#17
Shuying Li, Meng Li, Wenjun Gui, Qiangwei Wang, Guonian Zhu
Over the past few decades, the hazards associated with the extensive use of organictin compounds have become an issue of extreme concern, while at present the effects of these substances on amphibians remain poorly understood. In the present study, we chose azocyclotin, one of common use acaricides in China. We focused on sexual development and steroidogenesis disrupting effects of azocyclotin in the Xenopus laevis. Tadpoles were exposed to azocyclotin (0.05 and 0.5μg/L) for long-term (4 months) study. Results showed that exposure to azocyclotin caused developmental toxicity, including decreased survival, body weight, body length, gonadosomatic index, hepatosomatic index and female phenotype...
April 2017: Aquatic Toxicology
https://www.readbyqxmd.com/read/28205173/measurement-of-mitochondrial-cholesterol-import-using-a-mitochondria-targeted-cyp11a1-fusion-construct
#18
Barry E Kennedy, Mark Charman, Barbara Karten
All animal membranes require cholesterol as an essential regulator of biophysical properties and function, but the levels of cholesterol vary widely among different subcellular compartments. Mitochondria, and in particular the inner mitochondrial membrane, have the lowest levels of cholesterol in the cell. Nevertheless, mitochondria need cholesterol for membrane maintenance and biogenesis, as well as oxysterol, steroid, and hepatic bile acid production. Alterations in mitochondrial cholesterol have been associated with a range of pathological conditions, including cancer, hepatosteatosis, cardiac ischemia, Alzheimer's, and Niemann-Pick Type C Disease...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28202325/synthesis-and-biological-evaluation-of-heterocyclic-analogues-of-pregnenolone-as-novel-anti-osteoporotic-agents
#19
Saransh Wales Maurya, Kapil Dev, Krishna Bhan Singh, Reena Rai, Ibadur Rahman Siddiqui, Divya Singh, Rakesh Maurya
The structural modifications of pregnenolone have been described via the introduction of heterocyclic moieties at C-17 position by limiting the acyl group. Novel heterocyclic analogues of pregnenolone have been synthesized by using Friedlander and Claisen-Schmidt reactions, and the synthesized compounds were evaluated for their osteogenic activity. Among the synthesized derivatives, four compounds showed significantly increased ALP activity. Among all four active compounds, the novel compound 3a has shown significant bone matrix mineralization and mRNA expressions of osteogenic marker genes, BMP2, RUNX-2 and OCN at 1pM concentration...
February 4, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28129443/anxiolytic-effects-of-hippocampal-neurosteroids-in-normal-and-neuropathic-rats-with-spared-nerve-injury
#20
Meng Zhang, Jia Liu, Meng-Meng Zhou, Honghai Wu, Yanning Hou, Yun-Feng Li, Yuxin Yin, Lemin Zheng, Jie Cai, Fei-Fei Liao, Feng-Yu Liu, Ming Yi, You Wan
Neurosteroids are synthesized in the nervous system from cholesterol or steroidal precursors imported from peripheral sources. These compounds are important allosteric modulators of GABAA receptors, which play a vital role in modulating hippocampal functions. Chronic pain is accompanied by increased neurosteroid production in the spinal cord and thalamus. We hypothesize that hippocampal neurosteroids participate in pain or pain-associated emotions, which we tested with high-performance liquid chromatography/tandem mass spectrometry and pharmacological behavioral tests...
January 27, 2017: Journal of Neurochemistry
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