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Eric Gonzalez, Kevin M Johnson, Pradeep S Pallan, Thanh T N Phan, Wei Zhang, L I Lei, Zdzislaw Wawrzak, Francis K Yoshimoto, Martin Egli, F Peter Guengerich
Cytochrome P450 (P450) 17A1 catalyzes the oxidations of progesterone and pregnenolone and is the major source of androgens. The enzyme catalyzes both 17α-hydroxylation and a subsequent 17α, 20-lyase reaction, and several mechanisms have been proposed for the latter step. Zebrafish P450 17A2 catalyzes only the 17α-hydroxylations. We previously reported high similarity of the crystal structures of zebrafish P450 17A1 and 17A2 and human P450 17A1 (Pallan et al. (2015) J. Biol. Chem. 290, 3248- 3268). Five residues near the heme, which differed, were changed...
December 6, 2017: Journal of Biological Chemistry
Ye Young Shin, Jea Sic Jeong, Mee-Na Park, Jae-Eon Lee, Sung-Min An, Wan-Seob Cho, Seung Chul Kim, Beum-Soo An, Kyu-Sup Lee
Preeclampsia (PE) is a pregnancy‑specific hypertensive syndrome that results in substantial maternal and fetal morbidity and mortality. The exact cause of PE has not been completely elucidate, although abnormal formation of the placenta has been considered. The placenta connects the developing fetus to the uterine wall, producing a large quantity of steroid hormones to maintain pregnancy. Although steroid hormones, particularly progesterone (P4) and estrogen (E2), in the serum of women with PE have been studied, steroidogenesis in the placenta has not well been established...
November 27, 2017: Molecular Medicine Reports
Takashi Ando, Tsutomu Nishiyama, Itsuhiro Takizawa, Yoshimichi Miyashiro, Noboru Hara, Yoshihiko Tomita
BACKGROUND: Clarifying the mechanisms underlying prostate cancer (PC) progression and resistance to androgen deprivation therapy (ADT) is an urgent clinical issue. ADT influences steroidal metabolism in patients with PC and promotes the accumulation of carbon 21 steroids (C21s), such as progestin. Because the enzymes responsible for C21s metabolism are similar to those for androgen metabolism, PC cells may be able to metabolize C21s intracellularly. Therefore, there is a possibility that intracrine C21s are implicated in PC progression and resistance to ADT, and the influence of C21s on PC cells is yet to be elucidated...
December 1, 2017: Prostate
Ziling Luo, Tomislav Friščić, Rustam Z Khaliullin
Selective binding of steroid molecules is of paramount importance for designing drugs that can target the biological pathways of only individual steroids. From this perspective, it is remarkable that progesterone (PRO) and pregnenolone (PRE), two structurally similar steroids, demonstrate a dramatically different propensity to interact with aromatic molecules. It has been recently reported that, in solid-state cocrystallization, PRO forms cocrystals with a wide variety of aromatic systems whereas PRE cocrystallizes only with a few...
November 29, 2017: Physical Chemistry Chemical Physics: PCCP
Yanmin Huang, Erbin Kong, Junyan Zhan, Shuang Chen, Chunfang Gan, Zhiping Liu, Liping Pang, Jianguo Cui
Using estrone and pregnenolone as starting materials, some steroidal copper complexes were synthesized by the condensation of steroidal ketones with thiosemicarbazide or diazanyl pyridine and then complexation of steroidal thiosemicarbazones or steroidal diazanyl pyridines with Cu (II). The complexes were characterized by IR, NMR, and HRMS. The synthesized compounds were screened for their cytotoxicity against HeLa, Bel-7404, and 293T cell lines in vitro. The results show that all steroidal copper (II) complexes display obvious antiproliferative activity against the tested cancer cells...
2017: Bioinorganic Chemistry and Applications
Tianying Pan, Guolin He, Meng Chen, Chenyi Bao, Yan Chen, Guangyu Liu, Mi Zhou, Shuying Li, Wenming Xu, Xinghui Liu
Objective: In this study, we investigated the exact mechanism by which excessive CYP11A1 expression impairs the placentation process and whether this causes preeclampsia (PE) in an in vivo model. Setting and Design: In order to study CYP11A1 overexpression, BeWo cells were transfected with CYP11A1. Pregnenolone, progesterone, and testosterone levels were measured by enzyme linked immunosorbent assays, and levels of autophagy markers were quantified by western blotting and immunofluorescence...
October 27, 2017: Oncotarget
Kristin Hennig, Jean Philippe Antignac, Emmanuelle Bichon, Marie-Line Morvan, Isabelle Miran, Suzette Delaloge, Jean Feunteun, Bruno Le Bizec
Body mass index is a known breast cancer risk factor due to, among other mechanisms, adipose-derived hormones. We developed a method for steroid hormone profiling in adipose tissue to evaluate healthy tissue around the tumor and define new biomarkers for cancer development. A semi-automated sample preparation method based on gel permeation chromatography and subsequent derivatization with trimethylsilyl (TMS) is presented. Progestagens and androgens were determined by GC-EI-MS/MS (LOQ 0.5 to 10 ng/g lipids)...
November 16, 2017: Analytical and Bioanalytical Chemistry
George V Shpakovski, Svetlana G Spivak, Irina N Berdichevets, Olga G Babak, Svetlana V Kubrak, Alexander V Kilchevsky, Andrey V Aralov, Ivan Yu Slovokhotov, Dmitry G Shpakovski, Ekaterina N Baranova, Marat R Khaliluev, Elena K Shematorova
BACKGROUND: The initial stage of the biosynthesis of steroid hormones in animals occurs in the mitochondria of steroidogenic tissues, where cytochrome P450SCC (CYP11A1) encoded by the CYP11A1 gene catalyzes the conversion of cholesterol into pregnenolone - the general precursor of all the steroid hormones, starting with progesterone. This stage is missing in plants where mitochondrial cytochromes P450 (the mito CYP clan) have not been found. Generating transgenic plants with a mitochondrial type P450 from animals would offer an interesting option to verify whether plant mitochondria could serve as another site of P450 monooxygenase reaction for the steroid hormones biosynthesis...
November 14, 2017: BMC Plant Biology
Juilee Rege, Aya T Nanba, Richard J Auchus, Jianwei Ren, Hwei-Ming Peng, William E Rainey, Adina F Turcu
Background: Dehydroepiandrosterone sulfate (DHEAS) is the most abundant steroid in human circulation, and ACTH is considered the major regulator of its synthesis. Pregnenolone sulfate (PregS) and 5-Androstenediol-3-sulfate (AdiolS) have recently emerged as biomarkers of adrenal disorders. Objective: To define the relative human adrenal production of ∆5-steroid sulfates under basal and cosyntropin-stimulated conditions. Methods: Liquid chromatography-tandem mass spectrometry was used to quantify three unconjugated and four sulfated ∆5-steroids in: 1) paired adrenal vein (AV) and mixed venous serum samples (21 patients), and 2) cultured human adrenal cells, both before and after cosyntropin stimulation; 3) microdissected zona fasciculata (ZF) and zona reticularis (ZR) from 5 human adrenal glands; 4) reconstituted in vitro human 17α-hydroxylase/17,20-lyase (CYP17A1/ P450 17A1) system...
November 6, 2017: Journal of Clinical Endocrinology and Metabolism
M C Klymiuk, J Neunzig, R Bernhardt, A Sánchez-Guijo, M F Hartmann, S A Wudy, G Schuler
Sulfonated steroids are increasingly recognized as a circulating reservoir of precursors for the local production of active steroids in certain target tissues. As an alternative to sulfonation of unconjugated steroids by cytosolic sulfotransferases, their direct formation from sulfonated precursors has been described. However, productivity and physiological relevance of this sulfate pathway of steroidogenesis are still widely unclear. Applying the porcine testis as a model, conversion of pregnenolone sulfate (P5S, sulfate pathway) by CYP17A1 was assessed in comparison to the parallel conversions of pregnenolone (P5, Δ5-pathway) and progesterone (P4, Δ4-pathway)...
October 26, 2017: Journal of Steroid Biochemistry and Molecular Biology
Julie Islin, Cecilie Hurup Munkboel, Bjarne Styrishave
The aim of this study was to determine the steroidogenic endocrine disrupting effect of three widely used serotonin-noradrenaline reuptake inhibitors duloxetine, venlafaxine and tramadol, using two in vitro models, the H295R assay and a recombinant CYP17 enzyme assay. Steroid hormones were quantified using LC-MS/MS. Duloxetine showed endocrine disrupting effects at 5-20μM with CYP17 being the main target. Venlafaxine also affected the steroidogenesis, mainly by affecting the CYP17 lyase reaction, although at much higher concentrations i...
October 31, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Yuying Deng, Yifei Zhang, Shengxian Li, Wenzhong Zhou, Lei Ye, Lihua Wang, Tao Tao, Junjie Gu, Zuwei Yang, Dandan Zhao, Weiqiong Gu, Jie Hong, Guang Ning, Wei Liu, Weiqing Wang
The study explored differences in the steroidogenic pathway between obese and nonobese women with polycystic ovary syndrome (PCOS) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). 1044 women with PCOS (including 350 lean, 312 overweight and 382 obese) and 366 control women without PCOS (including 203 lean, 32 overweight and 131 obese) were enrolled. The differences in steroid hormones were amplified in lean PCOS versus lean controls compared with obese PCOS versus obese controls. Compared with obese PCOS, lean PCOS demonstrated increased dehydroepiandrosterone sulfate (P = 0...
October 26, 2017: Scientific Reports
Francis K Yoshimoto, Hadi D Arman, Wendell P Griffith, Fangzhi Yan, Daniel J Wherritt
7α-Hydroxypregnenolone is an endogenous neuroactive steroid that stimulates locomotor activity. A synthesis of 7α-hydroxypregnenolone from pregnenolone, which takes advantage of an orthogonal protecting group strategy, is described. In detail, the C7-position was oxidized with CrO3 and 3,5-dimethylpyrazole to yield a 7-keto steroid intermediate. The resulting 7-ketone was stereoselectively reduced to the 7α-hydroxy group with lithium tri-sec-butylborohydride. In contrast, reduction of the same 7-ketone intermediate with NaBH4 resulted in primarily the 7β-hydroxy epimer...
October 20, 2017: Steroids
Michelle A A Wynn, Alejandro Esteller-Vico, Erin L Legacki, Alan J Conley, Shavahn C Loux, Scott D Stanley, Thomas E Curry, Edward L Squires, Mats H Troedsson, Barry A Ball
During the latter half of gestation in mares, there is a complex milieu of pregnanes in peripheral blood. Progesterone concentrations are often assessed by immunoassay during late gestation as a measure of pregnancy well-being; however, interpretation of results is complicated by the numerous cross-reacting pregnanes present in high concentrations during late gestation. Further, many mares are supplemented with an exogenous progestin, altrenogest, which may also cross-react with existing assays and further confound interpretation...
October 7, 2017: Theriogenology
Radhakrishna Gattu, Prasanta Ray Bagdi, R Sidick Basha, Abu T Khan
A simple and an efficient one-pot three-component reaction of arylamines, aromatic aldehydes, and cyclic ketones was described for the synthesis of various fused quinoline, benzoquinoline, and naphthoquinoline derivatives by using camphorsulfonic acid as a catalyst. The exploitation of pregnenolone steroid for benzoquinolines and terephthalaldehyde for bis-benzoquinolines synthesis was achieved with 68-75% yields. The reactivity of arylamines and the mechanistic study for the formation of benzoquinoline was described precisely...
November 7, 2017: Journal of Organic Chemistry
Brittany L Mason, Erin Van Enkevort, Francesca Filbey, Christine E Marx, John Park, Alyson Nakamura, Prabha Sunderajan, E Sherwood Brown
PURPOSE/BACKGROUND: In animal models, levels of the neurosteroid pregnenolone increase after tetrahydrocannabinol (THC) administration and pregnenolone appears to attenuate the brain effects of THC. Given these interactions between pregnenolone and THC, we evaluated baseline neurosteroid levels in participants with a history of a cannabis use disorders (CUDs). METHODS/PROCEDURES: Bipolar depressed participants were enrolled in a randomized placebo-controlled clinical trial to evaluate the efficacy of add-on pregnenolone for depression and before receiving pregnenolone or placebo...
December 2017: Journal of Clinical Psychopharmacology
G Schuler, A Sánchez-Guijo, M F Hartmann, S A Wudy
Sulfonated steroids (s-St) have been usually regarded as inactive metabolites but are progressively considered as precursors for the intra-tissue formation of bioactive steroids. Moreover, independent effects without preceding removal of the sulfate group have been observed. We use the porcine testicular-epididymal compartment as a model to investigate the still largely unknown s-St physiology as the boar exhibits an intriguingly broad s-St spectrum predominantly originating from the testis. The application of LC-MS/MS in steroidomics enables the determination of unconjugated and intact sulfonated steroids with currently highest specificity and good sensitivity, allowing the concurrent measuring of numerous analytes in larger quantities of samples...
October 10, 2017: Journal of Steroid Biochemistry and Molecular Biology
Qianhong Zhu, Piotr J Mak, Robert C Tuckey, James R Kincaid
The rate-limiting step in the steroid synthesis pathway is catalyzed by CYP11A1 through three sequential reactions. The first two steps involve hydroxylations at positions 22 and 20, generating 20(R),22(R)-dihydroxycholesterol (20R,22R-DiOHCH), with the third stage leading to a C20-C22 bond cleavage, forming pregnenolone. This work provides detailed information about the active site structure of CYP11A1 in the resting state and substrate-bound ferric forms as well as the CO-ligated adducts. In addition, high-quality resonance Raman spectra are reported for the dioxygen complexes, providing new insight into the status of Fe-O-O fragments encountered during the enzymatic cycle...
October 31, 2017: Biochemistry
Sandra Rubil, Andrea Lesch, Naofumi Mukaida, Gerald Thiel
Stimulation of Ca(2+) permeable TRPM3 (transient receptor potential melastatin-3) channels with the steroid ligand pregnenolone sulfate activates stimulus-responsive transcription factors, including the transcription factor AP-1 (activator protein-1). As part of a search for AP-1-regulated target genes we analyzed the gene encoding interleukin-8 (IL-8) in HEK293 cells expressing TRPM3 channels. Here, we show that stimulation of TRPM3 channels activated transcription of an IL-8 promoter-controlled reporter gene that was embedded into the chromatin of the cells...
October 2, 2017: Cytokine
Catarina Canário, Samuel Silvestre, Amílcar Falcão, Gilberto Alves
BACKGROUND: Steroids play an important role in life because they can regulate a variety of biological processes and have been widely used in medicine namely as anti-inflammatory, anabolic, contraceptives and anticancer drugs. In recent years, there has been an increasing interest in the introduction of the oxime group in a large variety of molecules in order to increase their biological effects. This review highlights steroidal oximes with anticancer properties and their potential mechanisms of action, as well as data on their relative potencies reported in literature in the last few years...
October 3, 2017: Current Medicinal Chemistry
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