Steroid Research Articles

Deciphering the Transcriptional Metabolic Profile of Adipose-Derived Stem Cells During Osteogenic Differentiation and Epigenetic Drug Treatment.

Adipose-derived mesenchymal stem cells (ASCs) are commonly employed in clinical treatment for various diseases due to their ability to differentiate into multi-lineage and anti-inflammatory/immunomodulatory properties. Preclinical studies support their use for bone regeneration, healing, and the improvement of functional outcomes. However, a deeper understanding of the molecular mechanisms underlying ASC biology is crucial to identifying key regulatory pathways that influence differentiation and enhance regenerative potential. In this study, we employed the NanoString nCounter technology, an advanced multiplexed digital counting method of RNA molecules, to comprehensively characterize differentially expressed transcripts involved in metabolic pathways at distinct time points in osteogenically differentiating ASCs treated with or without the pan-DNMT inhibitor RG108. In silico annotation and gene ontology analysis highlighted the activation of ethanol oxidation, ROS regulation, retinoic acid metabolism, and steroid hormone metabolism, as well as in the metabolism of lipids, amino acids, and nucleotides, and pinpointed potential new osteogenic drivers like AOX1 and ADH1A. RG108-treated cells, in addition to the upregulation of the osteogenesis-related markers RUNX2 and ALPL, showed statistically significant alterations in genes implicated in transcriptional control (MYCN, MYB, TP63, and IRF1), ethanol oxidation (ADH1C, ADH4, ADH6, and ADH7), and glucose metabolism (SLC2A3). These findings highlight the complex interplay of the metabolic, structural, and signaling pathways that orchestrate osteogenic differentiation. Furthermore, this study underscores the potential of epigenetic drugs like RG108 to enhance ASC properties, paving the way for more effective and personalized cell-based therapies for bone regeneration.

HBM4EU E-waste study - An untargeted metabolomics approach to characterize metabolic changes during E-waste recycling.

E-waste contains hazardous chemicals that may be a direct health risk for workers involved in recycling. We conducted an untargeted metabolomics analysis of urine samples collected from male e-waste processing workers to explore metabolic changes associated with chemical exposures in e-waste recycling in Belgium, Finland, Latvia, Luxembourg, the Netherlands, Poland, and Portugal. Questionnaire data and urine samples were obtained from workers involved in the processing of e-waste (sorting, dismantling, shredding, pre-processing, metal, and non-metal processing), as well as from controls with no known occupational exposure. Pre- and post-shift urine samples were collected and analysed using ultrahigh-performance liquid chromatography-mass spectrometry (UPLC-MS). A total of 32 endogenous urinary metabolites were annotated with a Variable Importance in Projection (VIP) above 2, indicating that e-waste recycling is mainly associated with changes in steroid hormone and neurotransmitter metabolism, energy metabolism, bile acid biosynthesis, and inflammation. The highest VIP was observed for dopamine-o-quinone, which is linked to Parkinson's disease. These and other changes in metabolism in workers employed in the processing of e-waste need further verification in targeted studies.

Integrated transcriptome and metabolome analysis of liver reveals unsynchronized growth mechanisms in blunt-snout bream (Megalobrama amblycephala)

BackgroundMegalobrama amblycephala presents unsynchronized growth, which affects its productivity and profitability. The liver is essential for substance exchange and energy metabolism, significantly influencing the growth of fish.ResultsTo investigate the differential metabolites and genes governing growth, and understand the mechanism underlying their unsynchronized growth, we conducted comprehensive transcriptomic and metabolomic analyses of liver from fast-growing (FG) and slow-growing (SG) M. amblycephala individuals. A total of 2,097 differentially expressed genes (DEGs) were identified between FG and SG, with 830 genes exhibiting significantly higher expression level in FG. KEGG and GO enrichment analysis indicated that the DEGs with higher expression level were significantly correlated with insulin signaling pathway, steroid hormone and lipid metabolism related pathway (PPAR signaling pathway and fatty acid degradation). In the metabolomic analysis, 224 differentially expressed metabolites (DEMs) were detected, of which 128 were significantly more abundant in FG. These more abundant DEMs were prominently enriched in pathways associated with cell proliferation and energy metabolism (Oxidative phosphorylation, mTOR signaling pathway and FoxO signaling pathway). In addition, DEGs and DEMs in adenosine diphosphate (ATP) hydrolysis activity and associate with fatty acid metabolism, glucose metabolism, and amino acid metabolism pathways were both found in the transcriptomic and metabolomic integrated data. These findings suggest that the large amounts of energy generated by fatty acid, glucose metabolism and other energy metabolism pathway promote the rapid growth of FG.ConclusionsThis research is the first to integrate metabolomic and transcriptomic analyses of liver to identify key genes, metabolites, and pathways to uncover the molecular and metabolic mechanisms of unsynchronized growth in M. amblycephala. The identified metabolic and genes can be potential targets for selective breeding programs to improve growth performance in aquaculture.

Identification of immune characteristics between different subtypes in kidney renal clear cell carcinoma based on lysosome-related genes to assist immunotherapy.

Previous studies have revealed the essential role of lysosomes in human diseases, including cancer. However, there is a lack of in-depth systematic research on its function in kidney renal clear cell carcinoma (KIRC). In this project, we collected the public dataset of KIRC and selected lysosomal genes tightly linked with survival. Cluster analysis uncovered that these genes possess good classification ability and can divide KIRC patients into multiple subtypes with different survival rates. Enrichment analyses revealed that the main biological processes associated with differentially expressed genes (DEGs) in the two representative subpopulations with the largest survival differences (cluster1 and cluster2) were steroid metabolic process, neutrophil extracellular trap formation, and tyrosine metabolism. The immune-related analysis demonstrated notable differences in immune cell infiltration levels between cluster1 and cluster2 subpopulations of KIRC. More specifically, Tfh and TIL were highly infiltrated in the cluster1, and Type II IFN response, mast cells, and basophils were highly infiltrated in the cluster2. The immunotherapy-related analysis demonstrated that cluster1 may be more sensitive to immunotherapy and more likely to benefit from immunotherapy due to its higher immune checkpoint expression, ESTIMATE score, immune score, and higher immunophenoscore (IPS). In addition, gene mutations occurred in the two subtypes, exhibiting similar mutation patterns between the two subtypes. Finally, based on the cMAP database, we identified some small molecules that may target DEGs between the two subtypes, such as epibatidine, mepyramine, and reboxetine. In conclusion, our investigation unearthed that different subtypes of KIRC patients exhibited different survival outcomes and sensitivity to the immune microenvironment, as well as different responses to immunotherapy. These findings may be beneficial for further mechanistic exploration and therapeutic research of KIRC in the future.

Perfluorooctanoate and nano-titanium dioxide modulate male gonadal function in the mussel Mytilus coruscus.

Perfluorooctanoic acid (PFOA) and nano-titanium dioxide (nano-TiO₂) are widely used in industrial applications such as manufacturing and textiles, and can be released into the environment, causing toxicity to marine organisms. To study the effects of these pollutants on the gonadal development, we exposed the males of Mytilus coruscus to varying PFOA concentrations (2 and 200 μg/L) alone or combined with nano-TiO2 (0.1 mg/L, size: 25 nm) for 14 days. Co-exposure to PFOA and nano-TiO₂ resulted in a short-term (7 days) decrease in the gonadosomatic index (GSI), which recovered to baseline levels. In contrast, long-term (14 days) exposure induced changes in the testes, including increased protein content, decreased lipid content, reductions in spermatic area and sperm count, and elevated apoptotic cell levels. Furthermore, key genes essential for gonadal maturation were significantly upregulated after long-term exposure. PFOA and nano-TiO2 can disrupt the gonadal function in the male mussels by interfering with Wnt family signaling pathways, modulation of steroid and lipid metabolism and induction of apoptosis. Therefore, PFOA and nanoparticle pollutants may pose a significant risk to the reproductive capacity of mussels' populations from polluted coastal environments.

The impacts of 2,4-D herbicide DMA® 4 IVM on reproductive health and gene expression along the hypothalamic-pituitary-gonad-liver [HPGL] axis in the fathead minnow (Pimephales promelas).

Aquatic herbicides are commonly used to control a variety of non-native plants. One common active ingredient used in commercial herbicide formulations globally is 2,4-dichlorophenoxyacetic acid (2,4-D). Though 2,4-D is used in aquatic ecosystems, no studies have investigated cellular, biochemical, and transcriptional effects or mechanisms of 2,4-D exposure on fathead minnows (Pimephales promelas) throughout juvenile development. Herein, we aim to evaluate the impacts of chronic ecologically relevant 2,4-D exposure on reproductive systems of fathead minnow. Juvenile fathead minnows were exposed to ecologically relevant concentrations of 2,4-D in DMA4 herbicide under laboratory conditions in a flow through system. Male plasma testosterone concentrations, testicular and ovarian histology, and differential gene expression along the HPGL axis in three tissue types (brain, liver, and gonad) were assessed after a chronic 120 day exposure period. We observed significantly decreased plasma testosterone concentration in male fish exposed to environmentally relevant concentrations (0.50, 2.00, and 4.00 mg/L) of 2,4-D. We observed a significant increase in ovarian severity grading and oocyte atresia in female fish exposed to 4.00 mg/L. Of differential expression analysis in fish exposed to 2.00 mg/L 2,4-D in DMA4, we identified significantly decreased expression of the steroid hormone receptors ESR1, ESR2b, and AR in males. Expression of male steroidogenic genes 3βHSD and 11βHSD2 along with expression of genes regulating steroid metabolism, SULT1st2 and CBR1l were increased. Altogether, these data suggest that 2,4-D could act as an endocrine disrupting chemical that alters expression of primary genes regulating hormone receptors, steroidogenesis, and steroid metabolism along the hypothalamic-pituitary-gonad-liver (HPGL) axis. The use of 2,4-D herbicides for weed control in aquatic ecosystems could present risks to the reproductive health of non-target aquatic species.

GWAS-Significant Loci and Uterine Fibroids Risk: Analysis of Associations, Gene-Gene and Gene-Environmental Interactions.

Uterine fibroids (UF) is the most common benign tumour of the female reproductive system. We investigated the joint contribution of genome-wide association studies (GWAS)-significant loci and environment-associated risk factors to the UF risk, along with epistatic interactions between single nucleotide polymorphisms (SNPs). DNA samples from 737 hospitalised patients with UF and 451 controls were genotyped using probe-based PCR for seven common GWAS SNPs: rs117245733 LINC00598, rs547025 SIRT3, rs2456181 ZNF346, rs7907606 STN1, SLK, rs58415480 SYNE1, rs7986407 FOXO1, and rs72709458 TERT. We observed an association between rs547025 SIRT3 and the decreased risk of UF in overall group (effect allele C, odds ratio (OR) = 0.61, 95% confidence interval (CI) = 0.43-0.866, p = 0.005). SNP rs547025 exhibits protective effects against UF exclusively in patients with normal fruit and vegetable intake (OR = 0.39, 95% CI = 0.21-0.75, p = 0.002), no history of spontaneous abortions (OR = 0.48, 95% CI = 0.33-0.70, p = 0.0001), no pelvic inflammatory diseases (PID) in anamnesis (OR = 0.55, 95% CI = 0.38-0.80, p = 0.0016), and in smokers (OR = 0.20, 95% CI = 0.06-0.65, p = 0.006). In addition, rs7907606 STN1, SLK was associated with the risk of UF in patients without a history of pelvic inflammatory diseases (PID) (OR = 1.34, 95% CI = 1.03-1.74, p = 0.028). SNPs rs547025 SIRT3 and rs7907606 STN1, SLK, displayed the strongest mono-effects (0.71% and 0.52% contribution to UF entropy) and were characterized by the most pronounced gene-gene (G×G) effects when interacting with each other (0.60% contribution to entropy). The interaction Medical abortion×rs547025 SIRT3 served as the base for all the best gene-environment (G×E) models. Medical abortions have the most pronounced mono-effect (1.15% contribution to the entropy of UF), exceeding the mono-effects of SNPs involved in the most significant G×E-models (0.01%-0.49% contribution to entropy) and spontaneous abortions (0.48% of UF entropy) and exceeding the effects of G×E interactions (0.05-0.46% of UF entropy). Bioinformatics analysis showed that GWAS SNPs are involved in the molecular mechanisms of UF mainly through the regulation of vasculogenesis, cell proliferation, apoptosis, DNA damage, inflammation, hypoxia, steroid hormone metabolism, cell signaling, organ formation.

Metabolomics with gut microbiota analysis of podophyllotoxin-mediated cardiotoxicity in mice based on the toxicological evidence chain (TEC) concept.

Podophyllotoxin (PPT) is a lignan isolated from the traditional Chinese medicine Dysosma Versipellis, with significant anti-tumor activity. However, its cardiotoxicity restricts its clinical application. This study aims to investigate the cardiotoxicity of PPT in mice and its underlying mechanisms based on the concept of toxicological evidence chain (TEC). In this study, alterations in body weight, behavior, and the levels of myocardial enzymes and histopathology in mice were observed. Additionally, microbiome and metabolome were integrated to identify potential microorganisms, metabolic markers and major pathways with correlation analysis. The results indicated that PPT induced pathological changes in mice, including weight loss, diarrhea, alopecia and dehydration accompanied by increased levels of serum myocardial enzymes. The results of microbiome showed that PPT altered the gut microbiota composition, changing the abundance of microbial community. The results of metabolome studies indicated total of 55 differential metabolites were involved in glycine, serine, and threonine metabolism, alanine, glutamate, and aspartate metabolism, purine, pyrimidine metabolism, and steroid hormone metabolism. Integrating the results of microbiome and metabolome, it was concluded that PPT remodeled the gut microbiota composition, which in turn modified the gut microbiota metabolism, affecting amino acid metabolisms, nucleotide metabolism, and steroid hormone metabolism in the heart, potentially leading to energy metabolism disorders, apoptosis, and oxidative stress, ultimately inducing cardiotoxicity.

Cloning, expression, and purification of recombinant AKR1D1 for therapeutic applications.

AKR1D1, a key enzyme in the aldo-keto reductase superfamily, plays a dual role in both steroid metabolism and bile acid synthesis by catalyzing the NADPH-dependent reduction of carbon-carbon double bonds, specifically converting 3-ketosteroid hormones into 5β-steroids. Positioned at the critical intersection of steroid hormone and bile acid metabolism, AKR1D1 has the potential to profoundly influence metabolic homeostasis and drug metabolism. Despite its importance, the enzyme's therapeutic implications and role in drug metabolism remain underexplored. This study presents an optimized methodology for the cloning, expression, and purification of AKR1D1 using an Escherichia coli expression system. We identified optimal conditions for ligation and precise DNA sequencing, emphasizing the need for lower DNA concentrations and higher purity. Protein expression was evaluated in E. coli strains BL21 and Rosetta, with the highest yields achieved under extended incubation at 25 °C with controlled IPTG concentrations. Using freshly transformed cells was essential for maintaining consistent protein expression. The enzyme's activity was confirmed using a spectrofluorometric assay, demonstrating efficient reduction of testosterone to 5β-DHT. This optimized methodology facilitates the production of AKR1D1 with high specific activity, establishing a valuable platform for future research. It enables a deeper investigation into AKR1D1's contributions to drug metabolism and its therapeutic potential.

Effects of Diazinon in endocrine disruption: molecular docking and dynamics simulation on hormonal receptors in the context of the extensive use

Diazinon (DZN) was extensively utilized as an organophosphorus pesticide in developing countries. DZN has the ability to generate distinct metabolites, namely diazinon-oxon (DZNO) and 2-isopropyl-6-methyl-4-hydroxypyrimidine (IMHP), as well as non-specific metabolites diethylthiophosphate (DETP) and diethylphosphate (DEP). The aim of this study was to use computational methods to identify possible ways in which DZN and its main metabolites interact with estrogen, progesterone and estrogen-related receptors. This was done by in silico molecular docking. Molecular docking and dynamics simulation were conducted to comprehend the molecular interaction between diazinon and its metabolites (DZNO and DETP) with the human receptors. Chronic sublethal exposure to this insecticide is known to cause harmful effects on the metabolism of sex hormones and the functioning of the nervous system. This substance is believed to be an endocrine-disrupting agent and is known to produce aberrant patterns of development, shrinkage of the gonads, and issues with neurodevelopment. The metabolites produced during the metabolism of diazinon can bind to estrogen and progesterone receptors, specifically human progesterone receptor (hPR), estrogen-related receptor alpha (ERRα), estrogen-related receptor gamma (ERRγ) estrogen receptor alpha (Erα) and estrogen receptor beta (Erβ). This binding has the potential to interfere with estrogen and progesterone signaling in humans. These compounds provide a possible danger of interfering with estrogen and progesterone signaling in humans.

Development and application of a predictive model for survival and drug therapy based on COVID-19-related lncRNAs in non-small cell lung cancer.

Numerous studies have substantiated the pivotal role of long non-coding RNAs (lncRNAs) in the progression of non-small cell lung cancer (NSCLC) and the prognosis of afflicted patients. Notably, individuals with NSCLC may exhibit heightened vulnerability to the novel coronavirus disease (COVID-19), resulting in a more unfavorable prognosis subsequent to infection. Nevertheless, the impact of COVID-19-related lncRNAs on NSCLC remains unexplored. The aim of our study was to develop an innovative model that leverages COVID-19-related lncRNAs to optimize the prognosis of NSCLC patients. Pertinent genes and patient data were procured from reputable databases, including TCGA, Finngen, and RGD. Through co-expression analysis, we identified lncRNAs associated with COVID-19. Subsequently, we employed univariate, LASSO, and multivariate COX regression techniques to construct a risk model based on these COVID-19-related lncRNAs. The validity of the risk model was assessed using KM analysis, PCA, and ROC. Furthermore, functional enrichment analysis was conducted to elucidate the functional pathways linked to the identified lncRNAs. Lastly, we performed TME analysis and predicted the drug sensitivity of the model. Based on risk scores, patients were categorized into high- and low-risk subgroups, revealing distinct clinicopathological factors, immune pathways, and chemotherapy sensitivity between the subgroups. Four COVID-19-related lncRNAs (AL161431.1, AC079949.1, AC123595.1, and AC108136.1) were identified as potential candidates for constructing prognostic prediction models for NSCLC. We also observed a positive correlation between risk score and MDSC, exclusion, and CAF. Additionally, two immune pathways associated with high-risk and low-risk subgroups were identified. Our findings further support the association between COVID-19 infection and neuroactive ligand-receptor interaction, as well as steroid metabolism in NSCLC. Moreover, we identified several highly sensitive chemotherapy drugs for NSCLC treatment. The developed model holds significant value in predicting the prognosis of NSCLC patients and guiding treatment decisions.

Steroid metabolism and hormonal dynamics in normal and malignant ovaries.

The ovaries are key steroid hormone production sites in post-pubertal females. However, current research on steroidogenic enzymes, endogenous hormone concentrations and their effects on healthy ovarian function and malignant development is limited. Here, we discuss the importance of steroid enzymes in normal and malignant ovaries, alongside hormone concentrations, receptor expression and action. Key enzymes include STS, 3β-HSD2, HSD17B1, ARK1C3, and aromatase, which influence ovarian steroidal action. Both androgen and oestrogen action, via their facilitating enzyme, drives ovarian follicle activation, development and maturation in healthy ovarian tissue. In ovarian cancer, some data suggest STS and oestrogen receptor α may be linked to aggressive forms, while various oestrogen-responsive factors may be involved in ovarian cancer metastasis. In contrast, androgen receptor expression and action vary across ovarian cancer subtypes. For future studies investigating steroidogenesis and steroidal activity in ovarian cancer, it is necessary to differentiate between disease subtypes for a comprehensive understanding.

Characterization of an Activated Metabolic Transcriptional Program in Hepatoblastoma Tumor Cells Using scRNA-seq.

Hepatoblastoma is the most common primary liver malignancy in children, with metabolic reprogramming playing a critical role in its progression due to the liver's intrinsic metabolic functions. Enhanced glycolysis, glutaminolysis, and fatty acid synthesis have been implicated in hepatoblastoma cell proliferation and survival. In this study, we screened for altered overexpression of metabolic enzymes in hepatoblastoma tumors at tissue and single-cell levels, establishing and validating a hepatoblastoma tumor expression metabolic score using machine learning. Starting from the Mammalian Metabolic Enzyme Database, bulk RNA sequencing data from GSE104766 and GSE131329 datasets were analyzed using supervised methods to compare tumors versus adjacent liver tissue. Differential expression analysis identified 287 significantly regulated enzymes, 59 of which were overexpressed in tumors. Functional enrichment in the KEGG metabolic database highlighted a network enriched in amino acid metabolism, as well as carbohydrate, steroid, one-carbon, purine, and glycosaminoglycan metabolism pathways. A metabolic score based on these enzymes was validated in an independent cohort (GSE131329) and applied to single-cell transcriptomic data (GSE180665), predicting tumor cell status with an AUC of 0.98 (sensitivity 0.93, specificity 0.94). Elasticnet model tuning on individual marker expression revealed top tumor predictive markers, including FKBP10, ATP1A2, NT5DC2, UGT3A2, PYCR1, CKB, GPX7, DNMT3B, GSTP1, and OXCT1. These findings indicate that an activated metabolic transcriptional program, potentially influencing epigenetic functions, is observed in hepatoblastoma tumors and confirmed at the single-cell level.

Epidemiological investigation of sex hormones and their metabolism-related gene single nucleotide polymorphisms in patients with benign prostatic hyperplasia complicated with late-onset hypogonadism: a retrospective cohort study.

Benign prostatic hyperplasia (BPH) is a common disease in middle-aged and elderly men, and its etiology is not completely clear. Late-onset hypogonadism (LOH) is a relatively common disease in the aging process of men. BPH is often accompanied by varying degrees of LOH, and the pathogenesis and progression of the two diseases are related. Sex hormone metabolism-related genes affect sex hormone metabolism, to determine androgen, estrogen, androgen/estrogen ratio, and their single nucleotide polymorphisms (SNPs) are common in the population. The relationship between BPH combined with LOH (LOH-BPH) and SNPs in genes related to sex hormone metabolism is still unclear. In this study, the authors hope to clarify the relationship between them through epidemiological investigation. To investigate the association between LOH-BPH and SNPs of sex hormone metabolism-related genes. A total of 821 middle-aged and elderly men from 1 January 2017 to 31 December 2022, were retrospectively analyzed. According to the diagnosis of LOH-BPH, the patients were divided into LOH-BPH group and non-LOH-BPH group, and the related parameters of the two groups were compared. The parameters included age, total testosterone (tT), estradiol (E2), testosterone/estradiol ratio (T/E), dihydrotestosterone (DHT), sex hormone-binding globulin (SHBG), parameters associated with metabolic syndrome, parameters related to BPH, the International Index of Erectile Function 5 (IIEF-5) and erectile dysfunction (ED), and SNPs of genes related to sex hormone metabolism. Sixty-eight participants were excluded from this study, and 753 eventually completed the study. ED accounted for 48.21%, LOH-BPH accounted for 41.30%, and non-LOH-BPH accounted for 58.70%. tT decreased with age and was negatively correlated with age (r=-0.68, P<0.0001). E2 increased with age and was positively correlated with age (r=0.61, P=0.032). T/E decreased with age and was negatively correlated with age (r=-0.71, P<0.0001). After adjusting for age, LOH-BPH is significantly correlated with tT (r=-0.754, OR=0.071, 95% CI: 0.0048-0.105, P<0.0001), E2 (r=0.765, OR=3.855, 95% CI: 1.828-5.833, P<0.0001), T/E (r=-0.751, OR=0.000, 95% CI: 0.000-0.000, P<0.0001) and ED (r=0.973, OR=5.02, 95% CI: 4.898-6.578, P=0.001). At the same time, the AA genotype of rs1843090 (r=-0.613, OR=0.052, 95% CI: 0.006-0.44, P=0.007), the CC genotype of rs2279357 (r=0.636, OR=20.963, 95% CI: 2.268-93.793, P=0.004), the GG genotype of rs743572 (r=0.681, OR=7.642, 95% CI: 5.005-11.668, P<0.0001), the AA genotype of rs712221 (r=-0.012, OR=0.468, 95% CI: 0.220-0.881, P=0.018), and the TT genotype of rs700518 (r=0.699, OR=26.04, 95% CI: 16.142-42.008, P<0.0001) were significantly associated with LOH-BPH. The morbidity of LOH-BPH can be associated with SNPs of genes related to sex hormone metabolism.

Short-term exposure of enrofloxacin inhibits synthesis of central estradiol through secretoneurin a/aromatase B (cyp19a1b) pathway in crucian carp.

It has been reported that enrofloxacin (ENR) disrupts metabolic pathway of steroid in female crucian carp, promoting testosterone (T) synthesis through stimulating expression of luteinizing hormone (LH) and inhibiting conversion of T to estradiol (E2) through repressing aromatase A expression. To further learn effect of ENR on steroid metabolism in fish, this work investigated effect of ENR on central E2 synthesis and the involved mechanisms in female crucian carp through evaluating contents of T and E2 in blood and brain, expression of secretogranin 2a (scg2a), gonadotrophin 2 β (gth 2β, namely LH) and aromatase B (cyp19a1b) genes in brain, and activation of PI3K/Akt pathway in brain of ENR exposed female crucian carp. Results revealed that ENR promoted steroid metabolism in brain of female crucian carp, stimulated synthesis of T synthesis but inhibited conversion of T to E2 through promoting expression of scg2a and gth 2β but repressing expression of cyp19a1b, PI3K/Akt signaling pathway participated in regulating the biological process.

Steroid Profiles and Precursor-to-Product Ratios Are Altered in Pregnant Women with Preeclampsia.

Steroid hormone imbalance is associated with the pathogenesis of preeclampsia. However, affected enzymes of steroid metabolism and gene and protein expression in serum and placenta have not been elucidated yet. We aimed to investigate steroid hormone profiles and precursor-to-product ratios in preeclamptic women compared to women with healthy pregnancy (controls) to identify potentially affected steroid hormones and their metabolizing enzymes. Also, we aimed to investigate whether the mRNA expression of these enzymes is different between the study groups and whether levels of serum mRNA expression reflect postnatal placental protein expression. Serum levels of 14 steroid hormones were measured at eight time points throughout pregnancy in nine preeclamptic women and 36 controls. Serum mRNA expression of selected steroid-metabolizing enzymes was assessed, and their protein expression was analyzed in additional nine preeclamptic women. Mean levels of sex steroid and corticosteroid hormones were significantly altered in preeclamptic women. Precursor-to-product ratios of 5α-reductase, aromatase and 11β-hydroxysteroid dehydrogenase 1 were significantly increased, those of steroid 17α-hydroxylase, 17β-hydroxysteroid-dehydrogenase, steroid 11β-hydroxylase and 11β-hydroxysteroid dehydrogenase 2 were significantly decreased. Serum mRNA expression and placenta protein expression were comparable between the groups. Results contribute to understanding the heterogeneity of preeclampsia and can thus promote future research in personalized medicine.

Synthesis of novel estradiol bisselenocyanate with unique 2-selenocyano-17-selenocyanoesteryl structure and evaluation of antitumor activity.

Cancer is one of the most significant diseases that afflict human beings. The pursuit of high efficacy and low-toxicity anticancer drugs has always been a paramount research objective for scientists. In the present study, we incorporated two selenocyano pharmacophores into the 2-site and 17-branch chain of the steroid nucleus in various manners, utilizing estradiol as the fundamental framework. Consequently, several estradiol bisselenocyanate compounds with a 2-selenocyano-17-selenocyanoester structure were synthesized. When compared to the positive control steroidal anti-tumor drug 2-methoxyestradiol, certain derivatives exhibited superior inhibitory activity against tumor cells in vitro, surpassing their monoselenocyanate precursors. The representative compound 4b induced programmed apoptosis in HeLa cells in a concentration-dependent manner during apoptosis and cell cycle experiments, while causing G2 phase arrest predominantly in the cell cycle. Moreover, compound 4b exhibited significant inhibitory effects on cell migration and demonstrated remarkable inhibitory activity against HeLa xenograft tumors in zebrafish models. These findings suggest that these compounds hold potential as promising candidates for anti-tumor drugs and warrant further investigation.

The gut-microbiota-brain axis: Focus on gut steroids.

There are over 1000 varieties of steroids that have been reported in nature, including the endogenous sex steroid hormones (i.e., progesterone, testosterone, and 17β-estradiol) and corticosteroids which are mainly synthesized by gonads and adrenals, respectively. In addition, an extra-glandular steroidogenesis has been also reported in the brain and in the gastrointestinal tract (GIT). The reason why intestinal steroidogenesis and consequently gut steroids draw our attention is for the communication and interaction with the gut microbiota, which functions like a virtual endocrine organ, and it is also involved in the steroid production. Moreover, both GIT and gut microbiota communicate through neural, endocrine, and humoral ways with the brain, in the so-called gut-microbiota-brain axis. On this basis, in this review, we will discuss several aspects such as (1) intestinal steroidogenesis and its possible regulation, (2) the potential role of gut steroids in physiopathological conditions, and (3) the role of microbiome in steroidogenesis and steroid metabolism. Overall, this review highlights new points of view considering steroid molecules as potential therapeutic approach for gastrointestinal disorders and brain comorbidities.

Effects of High-Dose Vitamin D3 Supplementation on Pig Performance, Vitamin D Content in Meat, and Muscle Transcriptome in Pigs.

Vitamin D is known for its role in calcium homeostasis, bone health, and immune function. Recent research has explored its effects on muscle functionality and meat quality in pigs. This study examined high-dose vitamin D3 supplementation in pigs, focusing on growth, blood and tissue vitamin D3 levels, and muscle transcriptome changes. Thirty pigs were divided into three groups, given different amounts of oral supplementation: control, 5000 IU/kg and 10,000 IU/kg vitamin D3. Biochemical and haematological blood parameters, vitamin D content in blood and muscle, and kidney calcium content were evaluated. RNA-seq and qPCR analysed muscle transcriptome changes, while gene set enrichment analysis (GSEA) identified gene expression enrichments. Results showed that 5000 IU/kg vitamin D3 supplementation altered blood parameters like platelet anisocytosis and glucose levels but did not affect body weight, weight gain, or feed intake. Kidney calcium content increased with supplementation. The muscle (longissimus dorsi) vitamin D content increased, suggesting the potential for biofortified pork, although still not optimal as a dietary vitamin D source. Transcriptome analysis revealed minimal gene expression changes, with only the interferon-gamma receptor 2 (IFNGR2) gene differentially expressed at the highest dose. GSEA indicated enrichment in ATP metabolic processes and electron transport chain genes in the 5000 IU/kg group, and immune system, cholesterol, steroid, and fatty acid metabolism genes in the 10,000 IU/kg group. Despite literature suggesting a role for vitamin D in muscle gene expression and growth improvement, this study found its effects limited.

Comparative ultrastructural and transcriptomic profile analysis of skin tissues from indigenous, improved meat, and dairy goat breeds

BackgroundHigh-quality goatskins are valuable byproducts usually produced by indigenous goat breeds with poorer production performance in Asia and Africa. However, the genetic and molecular mechanisms underpinning goatskin’s biomechanical properties (e.g., tensile strength) remain elusive. Mechanistic exploration of these traits could greatly aid the genetic improvement and genetic resource conservation of native breeds in these regions. To fulfill this purpose, we collected skin tissues from three goat breeds: Huai goat (HG), a Chinese native variety producing high-quality goatskins; Yudong meat goat (YDMG), a crossbreed of HG and Boer goat; Henan dairy goat (HNDG), a dairy goat breed.ResultsScanning electronic microscopy analysis of skin tissues found that the collagen fiber diameters, collagen fibril diameters, and crimps significantly differed among the three goat breeds; however, collagen fibril diameters are similar in HG and HNDG. A sum of 230, 775, and 86 differentially expressed genes (DEGs) were identified from YDMG versus HNDG, HG versus HNDG, and YDMG versus HG, respectively. Functional enrichment analysis suggested that signaling pathways involved in fatty acid, retinol, steroid metabolisms, and GO items related to the physical properties of the skin (e.g., collagen-containing extracellular matrix) are significantly overrepresented in DEGs identified from meat versus dairy goats. Furthermore, 106 DEGs (e.g., COL1A1, COL1A2, and SPARC) showed specific expression patterns in HG and YDMG versus HNDG. Items about biophysical features of skin (e.g., extracellular matrix organization and ECM proteoglycans) are markedly enriched. Protein-protein interaction analysis suggested that two growth factors (IGF1 and PDGFD) are latent collagen and other ECM protein expression modulators.ConclusionUltrastructural analysis of goat skin tissues suggested that collagen fibril diameter is not a major factor affecting goatskin quality. Transcriptomic profiles unveiled core genes and associated biological processes potentially involved in regulating goatskin quality. These discoveries shined new light on deeper understanding the mechanisms of hide-related traits in goat and other livestock.