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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (15 January 2021) | Viewed by 21769

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Special Issue Editor

Dr. Amit V. Pandey

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Guest Editor

Pediatric Endocrinology, Diabetology and Metabolism, University Children’s Hospital Bern And Department of Biomedical Research, University of Bern, Freiburgstrasse 15, 3010 Bern, Switzerland
Interests: steroid metabolism; steroidogenesis; pregnenolone; cytochrome P450; P450 oxidoreductase; CYP17A1; CYP19A1; androgens; estrogens
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Special Issue Information

Dear Colleagues,

Steroid hormones are necessary for life, from salt balance by mineralocorticoids, sugar balance by glucocorticoids, to the growth, reproductive, and sexual functions of sex steroids.

Steroid hormones are synthesized from cholesterol, starting from conversion, to pregnenolone, which is then converted to many different metabolites in a series of metabolic reactions.

Defects in the steroid metabolism cause a wide range of disorders, including the most common endocrine disorder in women, polycystic ovary syndrome. Therefore, control of steroid hormones production and signalling is an attractive target for the treatment of many metabolic disorders, including hormonal dependent cancers (targeting CYP17A1 and the androgen receptor in prostate cancer, and aromatase in breast cancer).

This Special Issue will focus on the molecular biology and biochemistry of steroid hormones in health and disease, and potential topics of interest may include, but are not limited, to the following:

Molecular, cellular, and structural biology of steroid hormone production, regulation, and signalling in humans.
Genetics and pathology of metabolic disorders caused by the changes in steroid metabolism, including the study of human mutations causing disordered steroidogenesis.
Novel genes and mechanisms regulating steroid biosynthesis.
Targeting of steroid hormone production, regulation, and signalling in metabolic disorders, including hormone-dependent cancers, by drugs and protein therapeutics.

Through this Special Issue, we aim to provide the latest work on the topic of steroid metabolism in human health and disease by experts in the field to a broad range of readership.

Dr. Amit V. Pandey
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

Steroid biosynthesis
Steroidogenesis
Androgen
Estrogen
Hormone-dependent cancers
Metabolic disorders
Steroid metabolizing enzymes

Published Papers (6 papers)

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Research

14 pages, 1828 KiB

Open AccessArticle

Profiling of Steroid Metabolic Pathways in Human Plasma by GC-MS/MS Combined with Microwave-Assisted Derivatization for Diagnosis of Gastric Disorders

by Wonwoong Lee, Hyunjung Lee, You Lee Kim, Yong Chan Lee, Bong Chul Chung and Jongki Hong

Int. J. Mol. Sci. 2021, 22(4), 1872; https://doi.org/10.3390/ijms22041872 - 13 Feb 2021

Cited by 7 | Viewed by 3085

Abstract

Steroid hormones are associated in depth to cellular signaling, inflammatory immune responses, and reproductive functions, and their metabolism alterations incur various diseases. In particular, quantitative profiling of steroids in plasma of patients with gastric cancer can provide a vast information to understand development of gastric cancer, since both sex hormones and glucocorticoids might be correlated with the pathological mechanisms of gastric cancer. Here, we developed a gas chromatography-tandem mass spectrometry-dynamic multiple reaction monitoring (GC-MS/MS-dMRM) method combined with solid-phase extraction (SPE) and microwave-assisted derivatization (MAD) to determine 20 endogenous steroids in human plasma. In this study, MAD conditions were optimized with respect to irradiation power and time. The SPE enabled effective cleanup and extraction for profiling of steroid hormones in human plasma samples. The MAD could improve laborious and time-consuming derivatization procedure, since dielectric heating using microwave directly increase molecular energy of reactants by penetrating through medium. Furthermore, dMRM method provided more sensitive determination of 20 steroids, compared to traditional MRM detection. The limits of quantification of steroids were below 1.125 ng/mL and determination coefficients of calibration curves were higher than 0.9925. Overall precision and accuracy results were below 19.93% and within ±17.04%, respectively. The developed method provided sufficient detection sensitivities and reliable quantification results. The established method was successfully applied to profile steroid metabolism pathways in plasma of patients with chronic superficial gastritis (CSG), intestinal metaplasia (IM), and gastric cancer. Statistical significances of steroid plasma levels between gastric disorder groups were investigated. In conclusion, this method provided comprehensive profiling of 20 steroids in human plasma samples and will be helpful to discover potential biomarkers for the development of gastric cancer and to further understand metabolic syndrome. Full article

(This article belongs to the Special Issue Steroid Metabolism in Human Health and Disease)

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18 pages, 2426 KiB

Open AccessArticle

Finding New Molecular Targets of Familiar Natural Products Using In Silico Target Prediction

by Fabian Mayr, Gabriele Möller, Ulrike Garscha, Jana Fischer, Patricia Rodríguez Castaño, Silvia G. Inderbinen, Veronika Temml, Birgit Waltenberger, Stefan Schwaiger, Rolf W. Hartmann, Christian Gege, Stefan Martens, Alex Odermatt, Amit V. Pandey, Oliver Werz, Jerzy Adamski, Hermann Stuppner and Daniela Schuster

Int. J. Mol. Sci. 2020, 21(19), 7102; https://doi.org/10.3390/ijms21197102 - 26 Sep 2020

Cited by 13 | Viewed by 5108

Abstract

Natural products comprise a rich reservoir for innovative drug leads and are a constant source of bioactive compounds. To find pharmacological targets for new or already known natural products using modern computer-aided methods is a current endeavor in drug discovery. Nature’s treasures, however, could be used more effectively. Yet, reliable pipelines for the large-scale target prediction of natural products are still rare. We developed an in silico workflow consisting of four independent, stand-alone target prediction tools and evaluated its performance on dihydrochalcones (DHCs)—a well-known class of natural products. Thereby, we revealed four previously unreported protein targets for DHCs, namely 5-lipoxygenase, cyclooxygenase-1, 17β-hydroxysteroid dehydrogenase 3, and aldo-keto reductase 1C3. Moreover, we provide a thorough strategy on how to perform computational target predictions and guidance on using the respective tools. Full article

(This article belongs to the Special Issue Steroid Metabolism in Human Health and Disease)

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14 pages, 1857 KiB

Open AccessArticle

Characterization of Two Novel Variants of the Steroidogenic Acute Regulatory Protein Identified in a Girl with Classic Lipoid Congenital Adrenal Hyperplasia

by Efstathios Katharopoulos, Natascia Di Iorgi, Paula Fernandez-Alvarez, Amit V. Pandey, Michael Groessl, Shraddha Dubey, Núria Camats, Flavia Napoli, Giuseppa Patti, Marilea Lezzi, Mohamad Maghnie and Christa E. Flück

Int. J. Mol. Sci. 2020, 21(17), 6185; https://doi.org/10.3390/ijms21176185 - 27 Aug 2020

Cited by 4 | Viewed by 2792

Abstract

Congenital adrenal hyperplasia (CAH) consists of several autosomal recessive disorders that inhibit steroid biosynthesis. We describe a case report diagnosed with adrenal insufficiency due to low adrenal steroids and adrenocorticotropic hormone excess due to lack of cortisol negative feedback signaling to the pituary gland. Genetic work up revealed two missense variants, p.Thr204Arg and p.Leu260Arg in the STAR gene, inherited by both parents (non-consanguineous). The StAR protein supports CYP11A1 enzyme to cleave the side chain of cholesterol and synthesize pregnenolone which is metabolized to all steroid hormones. We used bioinformatics to predict the impact of the variants on StAR activity and then we performed functional tests to characterize the two novel variants. In a cell system we tested the ability of variants to support cholesterol conversion to pregnenolone and measured their mRNA and protein expression. For both variants, we observed loss of StAR function, reduced protein expression and categorized them as pathogenic variants according to guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. These results fit the phenotype of the girl during diagnosis. This study characterizes two novel variants and expands the list of missense variants that cause CAH. Full article

(This article belongs to the Special Issue Steroid Metabolism in Human Health and Disease)

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11 pages, 1507 KiB

Open AccessCommunication

In Silico Structural and Biochemical Functional Analysis of a Novel CYP21A2 Pathogenic Variant

by Michal Cohen, Emanuele Pignatti, Monica Dines, Adi Mory, Nina Ekhilevitch, Rachel Kolodny, Christa E. Flück and Dov Tiosano

Int. J. Mol. Sci. 2020, 21(16), 5857; https://doi.org/10.3390/ijms21165857 - 14 Aug 2020

Cited by 2 | Viewed by 2332

Abstract

Classical congenital adrenal hyperplasia (CAH) caused by pathogenic variants in the steroid 21-hydroxylase gene (CYP21A2) is a severe life-threatening condition. We present a detailed investigation of the molecular and functional characteristics of a novel pathogenic variant in this gene. The patient, 46 XX newborn, was diagnosed with classical salt wasting CAH in the neonatal period after initially presenting with ambiguous genitalia. Multiplex ligation-dependent probe analysis demonstrated a full deletion of the paternal CYP21A2 gene, and Sanger sequencing revealed a novel de novo CYP21A2 variant c.694–696del (E232del) in the other allele. This variant resulted in the deletion of a non-conserved single amino acid, and its functional relevance was initially undetermined. We used both in silico and in vitro methods to determine the mechanistic significance of this mutation. Computational analysis relied on the solved structure of the protein (Protein-data-bank ID 4Y8W), structure prediction of the mutated protein, evolutionary analysis, and manual inspection. We predicted impaired stability and functionality of the protein due to a rotatory disposition of amino acids in positions downstream of the deletion. In vitro biochemical evaluation of enzymatic activity supported these predictions, demonstrating reduced protein levels to 22% compared to the wild-type form and decreased hydroxylase activity to 1–4%. This case demonstrates the potential of combining in-silico analysis based on evolutionary information and structure prediction with biochemical studies. This approach can be used to investigate other genetic variants to understand their potential effects. Full article

(This article belongs to the Special Issue Steroid Metabolism in Human Health and Disease)

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14 pages, 1184 KiB

Open AccessArticle

Differential ESR1 Promoter Methylation in the Peripheral Blood—Findings from the Women 40+ Healthy Aging Study

by Elena S. Gardini, Gary G. Chen, Serena Fiacco, Laura Mernone, Jasmine Willi, Gustavo Turecki and Ulrike Ehlert

Int. J. Mol. Sci. 2020, 21(10), 3654; https://doi.org/10.3390/ijms21103654 - 21 May 2020

Cited by 6 | Viewed by 3016

Abstract

Background Estrogen receptor α (ERα) contributes to maintaining biological processes preserving health during aging. DNA methylation changes of ERα gene (ESR1) were established as playing a direct role in the regulation of ERα levels. In this study, we hypothesized decreased DNA methylation of ESR1 associated with postmenopause, lower estradiol (E2) levels, and increased age among healthy middle-aged and older women. Methods We assessed DNA methylation of ESR1 promoter region from dried blood spots (DBSs) and E2 from saliva samples in 130 healthy women aged 40–73 years. Results We found that postmenopause and lower E2 levels were associated with lower DNA methylation of a distal regulatory region, but not with DNA methylation of proximal promoters. Conclusion Our results indicate that decreased methylation of ESR1 cytosine-phosphate-guanine island (CpGI) shore may be associated with conditions of lower E2 in older healthy women. Full article

(This article belongs to the Special Issue Steroid Metabolism in Human Health and Disease)

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14 pages, 3815 KiB

Open AccessArticle

MicroRNA 322 Aggravates Dexamethasone-Induced Muscle Atrophy by Targeting IGF1R and INSR

by Hongwei Geng, Qinglong Song, Yunyun Cheng, Haoyang Li, Rui Yang, Songcai Liu and Linlin Hao

Int. J. Mol. Sci. 2020, 21(3), 1111; https://doi.org/10.3390/ijms21031111 - 07 Feb 2020

Cited by 16 | Viewed by 4342

Abstract

Dexamethasone (Dex) has been widely used as a potent anti-inflammatory, antishock, and immunosuppressive agent. However, high dose or long-term use of Dex is accompanied by side effects including skeletal muscle atrophy, whose underlying mechanisms remain incompletely understood. A number of microRNAs (miRNAs) have been shown to play key roles in skeletal muscle atrophy. Previous studies showed significantly increased miR-322 expression in Dex-treated C2C12 myotubes. In our study, the glucocorticoid receptor (GR) was required for Dex to increase miR-322 expression in C2C12 myotubes. miR-322 mimic or miR-322 inhibitor was used for regulating the expression of miR-322. Insulin-like growth factor 1 receptor (IGF1R) and insulin receptor (INSR) were identified as target genes of miR-322 using luciferase reporter assays and played key roles in Dex-induced muscle atrophy. miR-322 overexpression promoted atrophy in Dex-treated C2C12 myotubes and the gastrocnemius muscles of mice. Conversely, miR-322 inhibition showed the opposite effects. These data suggested that miR-322 contributes to Dex-induced muscle atrophy via targeting of IGF1R and INSR. Furthermore, miR-322 might be a potential target to counter Dex-induced muscle atrophy. miR-322 inhibition might also represent a therapeutic approach for Dex-induced muscle atrophy. Full article

(This article belongs to the Special Issue Steroid Metabolism in Human Health and Disease)

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