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Steroids exist universally and play critical roles in various biological processes. Identifying potential targets of steroids is of great significance in studying their physiological and biochemical activities, the side effects and for drug repurposing. Herein, aiming at more precise steroids targets prediction, a steroids-specific target library integrating 3325 PDB or homology modeling structures categorized into 196 proteins was built by considering chemical similarity from DrugBank and biological processes from KEGG. The main properties of this library include: (1) It was manually prepared and checked to eliminate mistakes. (2) The library enriched the possible steroids targets and could decrease the false positives of structure-based target screening for steroids. (3) The ranking by protein name instead of PDB ID could make the screening more efficiency and precise. (4) Protein flexibility was taken into account partially by the different active conformations through the structural redundancy of each category of protein, which leads to more accurate prediction. The case studies of glycocholic acid and 24-epibrassinolide proved its powerful predictive accuracy. In summary, our strategy to build the steroids-specific protein library for steroids target prediction is a promising approach and it provides a novel idea for the target prediction of small molecules.
Illicit use of performance-enhancing steroids has proliferated among a wide range of professional and amateur athletes. This problem has attracted broad public attention and has led the United States Congress to draft legislation that proposes frequent testing of athletes. However, current testing protocols are inadequate as athletes can evade detection by using novel steroids that are unknown to authorities. We have developed a strategy that overcomes this limitation by virtue of its ability to detect "designer steroids" without prior knowledge of their existence.
In search of antiparasitic agents, we here identify arylmethylamino steroids as potent compounds and characterize more than 60 derivatives. The lead compound 1o is fast acting and highly active against intraerythrocytic stages of chloroquine-sensitive and resistant Plasmodium falciparum parasites (IC50 1-5 nM) as well as against gametocytes. In P. berghei-infected mice, oral administration of 1o drastically reduces parasitaemia and cures the animals. Furthermore, 1o efficiently blocks parasite transmission from mice to mosquitoes. The steroid compounds show low cytotoxicity in mammalian cells and do not induce acute toxicity symptoms in mice. Moreover, 1o has a remarkable activity against the blood-feeding trematode parasite Schistosoma mansoni. The steroid and the hydroxyarylmethylamino moieties are essential for antimalarial activity supporting a chelate-based quinone methide mechanism involving metal or haem bioactivation. This study identifies chemical scaffolds that are rapidly internalized into blood-feeding parasites.
One new sterol, crassarosterol A (1), and four new steroidal glycosides, crassarosterosides A-D (2-5) were isolated from the Formosan soft coral Sinularia crassa. The absolute configuration of 1 was determined using the Mosher's method. The absolute configurations for the sugar moieties of 2-5 were determined by HPLC analysis on the o-tolylthiocarbamates derived from the liberated sugar after acid hydrolysis. Compounds 2 and 4 could significantly inhibit the expression of pro-inflammatory iNOS protein at 10 µM. In contrast, 1-3 were found to stimulate the expression of COX-2 protein at this concentration. Steroids 1 and 4 also showed cytotoxicity toward the selected human liver cancer cells.
Bioassay-guided fractionation of an EtOH extract of Monascus purpureus-fermented rice led to the isolation of two new steroids (22S, 23R, 24S)-20β,23α,25α-trihydroxy-16,22-epoxy-4,6,8(14)-trienergosta-3-one (1), the first example of a steroid possessing both a conjugated triene ketone system and a fused 4H-furan ring side chain within one molecule, and (22E, 24R)-3β,5α-dihydroxyergosta-23-methyl-7,22-dien-6-one (2), as well as two known compounds (22E, 24R)-3β,5α-dihydroxyergosta-7,22-dien-6-one (3) and (22E, 24R)-6β-methoxy-ergosta-7,22-diene-3β,5α-diol (4). Their structures were assigned by detailed interpretation of HRESIMS, 1D and 2D NMR spectroscopic data. The absolute stereochemistry of 1 was determined by single-crystal X-ray crystallography while the absolute stereochemistry of 2 was established by CD. Compounds 1-4 showed cytotoxic activity against the lung adenocarcinoma (A549) with IC(50) values of 0.08, 0.94, 12.6 and 13.5 μM, respectively. In addition, compounds 1 and 2 exhibited moderate activities against human ovarian cancer (A2780), with IC(50) values of 2.8 and 5.1 μM.
Transient hypothalamic-pituitary-adrenal axis dysfunction occurs in critically ill foals with sepsis and neonatal maladjustment syndrome (NMS). Cortisol is the most commonly measured steroid. However, a complex interaction of various steroid compounds might play a role in pathophysiology of this disorder.
Pregnant women with asthma are frequently exposed to synthetic glucocorticoids and glucocorticoids are known to reduce fetal growth. The fetus is normally protected from the harmful effects of maternally derived glucocorticoids by the placental enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2). Whether 11beta-HSD2 inactivates the synthetic glucocorticoids used for asthma treatment during pregnancy (budesonide, beclomethasone dipropionate and fluticasone propionate) remains unknown. To investigate the relationship between steroid use during pregnancy and fetal growth and development, pregnant women with (n=119) and without asthma (n=84) were followed throughout pregnancy. Data on asthma medication use, neonatal size at birth, placental weight and cord blood cortisol and estriol were collected. Placental tissue samples were collected from non-asthmatic women (n=8) for metabolism studies. Placental 11beta-HSD2 activity was determined using beclomethasone dipropionate, budesonide, fluticasone propionate, prednisolone, dexamethasone and betamethasone as steroid substrates. Steroids and their oxidised metabolites were examined using thin layer chromatography and densitometry. Placental 11beta-HSD2 metabolised beclomethasone, prednisolone, dexamethasone and betamethasone, but not budesonide or fluticasone. No association between the use of inhaled steroids for asthma treatment during pregnancy and alterations in neonatal size, placental weight, gestational age at delivery, or umbilical vein estriol concentrations was demonstrated compared to non-asthmatic women. In conclusion, the use of inhaled steroids for asthma treatment does not affect fetal growth, despite differences in placental metabolism by 11beta-HSD2.
In previous studies on the secondary metabolites of the Taiwanese octocoral Isis hippuris, specimens have always been collected at Green Island. In the course of our studies on bioactive compounds from marine organisms, the acetone-solubles of the Taiwanese octocoral I. hippuris collected at Orchid Island have led to the isolation of five new polyoxygenated steroids: hipposterone M-O (1-3), hipposterol G (4) and hippuristeroketal A (5). The structures of these compounds were determined on the basis of their spectroscopic and physical data. The anti-HCMV (human cytomegalovirus) activity of 1-5 and their cytotoxicity against selected cell lines were evaluated. Compound 2 exhibited inhibitory activity against HCMV, with an EC(50) value of 6.0 μg/mL.
Women are more than three times as likely as men to experience migraine headaches and temporomandibular joint pain, and painful episodes are often linked to the menstrual cycle. To understand how hormone levels may influence head and face pain, we assessed expression of pain-associated neuropeptides and estrogen receptor alpha (ERalpha) during the natural estrous cycle in mice. Gene expression was analyzed in the trigeminal ganglia of cycling female mice at proestrus, estrus and diestrus using RT-PCR. Peptide/protein expression in trigeminal neurons was analyzed using immunohistochemistry. ERalpha mRNA was present at all stages and highest at estrus. ERalpha protein was present in the cytoplasm of medium-sized and small trigeminal neurons. ERalpha immunoreactive neurons were most common at diestrus. CGRP and ANP mRNAs did not change across the estrous cycle, while expression of galanin and NPY mRNAs were strongly linked to the estrous cycle. Galanin mRNA levels peaked at proestrus, when expression was 8.7-fold higher than the diestrus levels. Galanin immunoreactivity also peaked at proestrus. At proestrus, 7.5% of trigeminal neurons contained galanin, while at estrus, 6.2% of trigeminal neurons contained galanin, and at diestrus, 4.9% of trigeminal neurons contained galanin. NPY mRNA peaked at estrus, when levels were 4.7-fold higher than at diestrus. Our findings suggest that estrogen receptors in trigeminal neurons modulate nociceptive responses through effects on galanin and NPY. Variations in neuropeptide content in trigeminal neurons across the natural estrous cycle may contribute to increases in painful episodes at particular phases of the menstrual cycle.
A new cytotoxic 19-oxygenated steroid, nebrosteroid Q(1) and two new cytotoxic 19-norergosterols, nebrosteroids R and S (2 and 3) were isolated from the soft coral Nephthea chabrolii collected at San-Hsian-Tai. The structures of nebrosteroids Q-S (1-3) were elucidated by spectral analysis, and their cytotoxicity against selected cancer cells as well as antiviral activity against human cytomegalovirus (HCMV) were measured in vitro.
In this study, we demonstrated the presence of the enzymatic complex able to perform aromatization (estrogen synthesis) in both, the microsomal and mitochondrial fractions of gills and gonads from Mytilus trossulus. Based on in vitro experiments, we highlighted the importance of temperature as the limiting factor of aromatisation efficiency (AE) in mussels. After testing range of temperatures (4-23 °C), the highest AE was found during incubation at 8 °C and pH 7.6 (41.66 pmol/h/mg protein in gills and 58.37 pmol/h/mg protein in gonads). The results were confirmed during field studies where the most efficient aromatisation occurred in bivalves collected in spring while the least effective in those collected in winter. During in vitro studies, AE turned out to be more intensive in female gonads than in male gonads. The process was also more intensive in mitochondrial fraction than in microsomal one (62.97 pmol/h/mg protein in male gills and 73.94 pmol/h/mg protein in female gonads). Enzymatic complex (aromatase-like enzyme) catalysing aromatisation in mussels was found to be insensitive to inhibitory effect of selective inhibitors of mammalian aromatase such as letrozole and anastrazole, suggesting its different structure from vertebrate aromatase. Further in vivo studies using 13C-labeled steroids at 8 °C temperature window confirmed that bivalves are able to uptake testosterone and androstenedione from the ambient environment and metabolise them to estrone and 17β-estradiol thus confirming endogenous estrogen' synthesis.
Steroid hormones and their respective nuclear receptors are essential mediators in numerous physiologic and pathophysiologic processes, ranging from regulation of metabolism, immune function, and reproductive processes to the development of hormone-dependent cancers such as those of the breast and prostate. Because steroids must enter cells before activating nuclear receptors, understanding the mechanisms by which cellular uptake occurs is critical, yet a clear understanding of these mechanisms has been elusive. It is generally assumed that diffusion-driven uptake is similar across various steroids whereas an elevated cellular concentration is thought to reflect active uptake, but these assumptions have not been directly tested. Here we show that intact cells rapidly accumulate free steroids to markedly elevated concentrations. This effect varies widely depending on steroid structure; more lipophilic steroids reach more elevated concentrations. Strong preferences exist for 3β-OH, Δ5-steroids vs. 3-keto, Δ4-structural features and for progestogens vs. androgens. Surprisingly, steroid-structure-specific preferences do not require cell viability, implying a passive mechanism, and occur across cells derived from multiple tissue types. Physiologic relevance is suggested by structure-specific preferences in human prostate tissue compared with serum. On the other hand, the presence of serum proteins in vitro blocks much, but not all, of the passive accumulation, while still permitting a substantial amount of active accumulation for certain steroids. Our findings suggest that both passive and active uptake mechanisms make important contributions to the cellular steroid uptake process. The role of passive, lipophilicity-driven accumulation has previously been largely unappreciated, and its existence provides important context to studies on steroid transport and action both in vitro and in vivo.
Glucose is a major energy source for growth. At birth, neonates must change their energy source from maternal supply to its own glucose production. The mechanism of this transition has not been clearly elucidated. To evaluate the possible roles of steroids in this transition, here we examine the defects associated with energy production of a mouse line that cannot synthesize steroids de novo due to the disruption of its Cyp11a1 (cytochrome P450 family 11 subfamily A member 1) gene. The Cyp11a1 null embryos had insufficient blood insulin and failed to store glycogen in the liver since embryonic day 16.5. Their blood glucose dropped soon after maternal deprivation, and the expression of hepatic gluconeogenic and glycogenic genes were reduced. Insulin was synthesized in the mutant fetal pancreas but failed to be secreted. Maternal glucocorticoid supply rescued the amounts of blood glucose, insulin, and liver glycogen in the fetus but did not restore expression of genes for glycogen synthesis, indicating the requirement of de novo glucocorticoid synthesis for glycogen storage. Thus, our investigation of Cyp11a1 null embryos reveals that the energy homeostasis is established before birth, and fetal steroids are required for the regulation of glycogen synthesis, hepatic gluconeogenesis, and insulin secretion at the fetal stage.
Short interfering RNA (siRNA) has broad applications in biology and medicine, and holds tremendous potential to become a new class of therapeutics for many diseases. As a highly anionic macrobiomolecule, its cytosolic delivery, however, has been a major roadblock in translation. Here, we report the development of small, bifunctional chemical tags capable of transporting siRNA directly into the cytosol. The bifunctional tags consist of a siRNA-binding moiety that interacts with siRNA non-covalently, and a steroid domain that readily fuses with the mammalian cell membrane. In contrast to the conventional covalently conjugated siRNA-steroid that enters cells largely via endocytosis which substantially limits siRNA bioavailability, the non-covalently tagged siRNA is cell membrane-permeant, avoiding the endocytic pathway. This new methodology enables effective RNA interference (RNAi) without the need of cationic transfection or endosomolytic agents, opening a new avenue for intracellular delivery of native biologics.
Sex steroids (SS) typically rise during pregnancy and decline after birth, but no consistent reference values exist for these hormonal courses. We aimed to establish an overview of SS secretion patterns during the peripartum and to better understand how SS contribute to maternal and fetal pathologies.
Sex steroids, derived mainly from gonads, can shape microbiota composition; however, the impact of gonadectomy and sex on steroid production in the gut (i.e., gut steroids), and its interaction with microbiota composition, needs to be clarified. In this study, steroid environment and gut steroidogenesis were analysed by liquid chromatography tandem mass spectrometry and expression analyses. Gut microbiota composition as branched- and short-chain fatty acids were determined by 16S rRNA gene sequence analysis and gas chromatography flame ionisation detection, respectively. Here, we first demonstrated that levels of pregnenolone (PREG), progesterone (PROG), and isoallopregnanolone (ISOALLO) were higher in the female rat colon, whereas the level of testosterone (T) was higher in males. Sexual dimorphism on gut steroidogenesis is also reported after gonadectomy. Sex, and more significantly, gonadectomy, affects microbiota composition. We noted that a number of taxa and inferred metabolic pathways were associated with gut steroids, such as positive associations between Blautia with T, dihydroprogesterone (DHP), and allopregnanolone (ALLO), whereas negative associations were noted between Roseburia and T, ALLO, PREG, ISOALLO, DHP, and PROG. In conclusion, this study highlights the novel sex-specific association between microbiota and gut steroids with possible relevance for the gut-brain axis.
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