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Bisphenol A (BPA) is a well-known environmental endocrine disruptor that has detrimental effects on reproduction. This study aimed to investigate whether BPA exposure could disrupt the function of cumulus cells and influence oocyte maturation and development. Porcine oocytes at the germinal vesicle stage were exposed to BPA for 44 h. The results revealed that BPA exposure led to dysfunction in cumulus cells by inhibiting meiotic division, inducing endoplasmic reticulum stress, and disrupting steroid synthesis. Furthermore, BPA exposure significantly increased reactive oxygen species and caused abnormal distribution of mitochondria in the oocytes. Notably, matured oocytes in the MII stage from the BPA-exposed groups showed significantly reduced development to the blastocyst stage, along with increased autophagy and apoptosis. These findings suggest that cumulus-oocyte complexes are sensitive to BPA exposure during the germinal vesicle stage, and the toxic effects of BPA on cumulus cells can severely inhibit oocyte and parthenogenetic embryos development. [Display omitted] [ABSTRACT FROM AUTHOR]

Congenital adrenal hyperplasia (CAH) manifests as an autosomal recessive disorder characterized by defects in the enzymes responsible for steroid synthesis. This work aims to perform metabolic profiling of patients with CAH, screen key differential metabolites compared to the control group, and discover the associated metabolic pathways implicated in CAH. Serum samples obtained from 32 pediatric male patients with CAH and 31 healthy control group candidates were subjected to analysis using non-targeted metabolomics strategy using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). A total of 278 differential metabolites were identified and annotated in KEGG. Operating characteristic curves (ROC) measurement exhibited 9 metabolites exhibiting high efficacy in differential diagnosis, as evidenced by an area under ROC curve (AUC) exceeding 0.85. Pathway analysis uncovered notable disruptions in steroid hormone biosynthesis (p <0.0001), purine metabolism and irregularities in lipid metabolism and amino acid metabolism, including tyrosine and alanine, in CAH patients. These findings demonstrate that metabolic pathways of purine, amino acid and lipid metabolism, apart from steroid hormone biosynthesis, may be disrupted and associated with CAH. This study helps provide insight into the metabolic profile of CAH patients and offers a new perspective for monitoring and administering follow-up care to CAH patients. [ABSTRACT FROM AUTHOR]

The redclaw crayfish is sexually dimorphic, with males preferring females in terms of growth rate and size. Currently, the molecular mechanism of sexual dimorphism is not well understood in crustaceans, and studies on the joint analysis of the gonadal metabolome and transcriptome of male and female individuals of redclaw crayfish are limited. In this study, we found that there were differences in relevant metabolites and metabolic pathways between intersex and normal individuals, including metabolites such as testosterone glucuronide, cortisol, pregnenolone sulfate, and estrone glucuronide, as well as steroid hormone synthesis pathways, lipid metabolism pathways, amino acid metabolism, and other metabolic pathways. The joint analysis of metabolome and transcriptome identified differential genes such as cyp3a40 , cyp18a1 , hsd17b12b , and cyp19a , and co-enriched pathways such as insulin signaling pathway, TGF-β signaling pathway, and FoxO signaling pathway, indicating that they may play a significant role in sex differentiation of redclaw crayfish. Our results provide a reference for the molecular mechanism of gonadal development between male and female individuals of redclaw crayfish. [ABSTRACT FROM AUTHOR]

Summary: Triterpene skeletons, catalyzing by 2,3‐oxidosqualene cyclases (OSCs), are essential for synthesis of steroids and triterpenoids. In japonica rice cultivars Zhonghua11, a total of 12 OsOSCs have been found. While the catalytic functions of OsOSC1, 3, 4, 9, and 10 remain unclear, the functions of the other OsOSCs have been well studied.In this study, we conducted a comprehensive analysis of 12 OSC genes within genus Oryza with the aid of 63 genomes from cultivated and wild rice. We found that OSC genes are relatively conserved within genus Oryza with a few exceptions. Collinearity analysis further suggested that, throughout the evolutionary history of genus Oryza, the OSC genes have not undergone significant rearrangements or losses.Further functional analysis of 5 uncharacterized OSCs revealed that OsOSC10 was a friedelin synthase, which affected the development of rice grains. Additionally, the reconstructed ancestral sequences of Oryza OSC3 and Oryza OSC9 had lupeol synthase and poaceatapetol synthase activity, respectively.The discovery of friedelin synthase in rice unlocks a new catalytic path and biological function of OsOSC10. The pan‐genome analysis of OSCs within genus Oryza gives insights into the evolutionary trajectory and products diversity of Oryza OSCs. [ABSTRACT FROM AUTHOR]

Premature ovarian insufficiency (POI) has recently been reported to be linked with epigenetic changes. Previous studies have focused on the regulation of individual genes associated with ovarian function through single‐gene epigenetic variations; however, there is a deficiency in the comprehensive comprehension of the epigenetic profile for POI. Therefore, we conducted a multi‐omics study integrating methylation, hydroxymethylation and transcriptome sequencing analyses in cumulus cells from women with POI and their matched controls. Our data revealed significant global increases in methylation and hydroxymethylation levels in POI patients. We observed a predominance of hypermethylated and hyperhydroxymethylated regions across the genome, with methylation in gene bodies negatively correlating with gene expression, especially in promoter regions. Subsequent experimental validation was performed to confirm the involvement of candidate genes (EGR1, EGR2 and DLX5) in ovarian steroid hormone synthesis. Interestingly, our findings indicate that these epigenetic modifications are associated with genes implicated in POI, ovarian function and the epigenetic age clock. This comprehensive epigenetic profile underscores the potential for identifying novel biomarkers and therapeutic targets for POI by unravelling the complex interplay between DNA epigenetics and ovarian function. [ABSTRACT FROM AUTHOR]

Background Objectives Results and Discussion Conclusions Gonadotropins are glycoprotein hormones fundamental in the endocrine regulation of reproduction. They act on structurally similar members of G protein‐coupled receptors (GPCRs) expressed exclusively in the gonads and support gametogenesis, sex steroid synthesis, and pregnancy. While it is a common opinion that the gonadotropin receptors act as a single molecule entity (monomer), increasing evidence underlines the formation of molecular complexes involving multiple receptors.To review current knowledge of membrane receptor‐receptor interactions in reproduction.Homo/heteromers of gonadotropin receptors may act as allosteric modulators, act as biased agonist and/or cooperate in sustaining intracellular signals fundamental to support reproduction. Technical limitations lead to in vitro data that require to be confirmed in vivo to figure out the physiological impact of gonadotropin receptor assemblies.Gonadotropin receptor homo/heteromers provide a new field of research that deserves attention for possible clinical and therapeutic implications in physiology and pathophysiology. [ABSTRACT FROM AUTHOR]

A preparation method for steroid‐based difluoroboron complexes has been developed using lumiestrone as a steroid example. Previously inaccessible lumiestrone‐based difluoroboron complexes annulated at positions 16 and 17 of the D ring have been prepared. Such difluoroboron complexes may have large synthetic potential for heterofunctionalization of steroids at the D ring. An application of a borylation mixture Ac2O‐BF3⋅OEt2 significantly simplify the preparation of steroid "dimers" bearing two estrone moieties connected at positions 2 and 2′ via a linker. Crystal structures of key representatives have been determined by X‐ray diffraction. [ABSTRACT FROM AUTHOR]

Prostate cancer is common in men and continues to pose a significant medical challenge. The primary feature of prostate cancer is hormone sensitivity. Prostate cancer cells become dependent on testicular androgen for survival. Steroidogenesis involves the synthesis of steroid hormones such as androgens from cholesterol. Tumor cells increase fatty acid production with androgens. Synthesized fatty acids contribute to membrane formation and support oncogenic signaling. Hormone-dependent tumors require cholesterol for proliferation. Cancer cells have higher intracellular cholesterol levels than non-tumor cells. STARD3, a member of the START protein family, is a transmembrane protein that facilitates cholesterol transport and resides in late endosomes. STARD3 stimulates steroidogenesis by inducing the motion of lysosomal cholesterol into mitochondria. High mitochondrial cholesterol levels can prevent apoptotic cell death in different cancer types, thereby triggering tumor progression. This review discusses recent studies on the relationship between cholesterol levels and prostate cancer risk, as well as the properties and activity of STARD3. To the best of our knowledge, this study is the first to comprehensively summarize the role and therapeutic potential of STARD3 in prostate cancer. Keywords:Cancer, lipid, prostate, STARD3: [ABSTRACT FROM AUTHOR]

Biotransformation is a reliable method for steroid development, with fungi serving as practical tools in this process. Fungal biocatalysts are known for their regio- and stereo-specificity, making them superior to chemical synthesis methods for steroid biotransformation. This work reported the biotransformation of dehydroepiandrosterone 1 with Penicillium olsonii MRC500780. A 5-day biotransformation study with the relevant microorganism resulted in 5 different products. Structure determinations using spectroscopic methods revealed that biotransformation of 1 by Penicillium olsonii MRC500780 afforded 5 metabolites as androst-4-ene-3,17-dione 2, 15α-hydroxyandrost-4-ene-3,17-dione 3, 3β,7β-dihydroxyandrost-5-en-17-one 4, 3β,7α-dihydroxyandrost-5-en-17-one 5, and 15α,17β-dihydroxyandrost-4-en-3-one 6. This fungus primarily isomerized the starting material in terms of the double bond and the hydroxyl group at 3β oxidised, then hydroxylated it at the C-15α position and reduced it at the C-17 position; also, hydroxylations at the C-7α position and C-7β position were observed. [ABSTRACT FROM AUTHOR]

【Objective】22 (R)-hydroxycholesterol is an important precursor of veratrol alkaloid biosynthesis. The function of cholesterol C-22 hydroxylase in Veratrum nigrum was verified by heteroexpression, and the yeast chassis was constructed to produce 22 (R)- hydroxycholesterol, which lays a foundation for deciphering the biosynthetic pathway of veratrol alkaloid.【Method】Based on the transcriptome data of V. nigrum, three full-length CYP90B subfamily gene sequences were cloned from the root of V. nigrum, the yeast Y33 expression vector was constructed and transferred into the cholesterol yeast chassis for functional verification. The yeast fermentaed products in shake flask were detected by high performance liquid chromatography and liquid chromatography-mass spectrometry. The enzyme VnCYP90B27-1 with cholesterol C-22 hydroxylase catalytic function was screened. VnCYP90B27-1 was integrated into the yeast chromosome by multi- fragment assembly, homologous recombination and lithium acetate conversion to construct a yeast chassis for 22 (R)-hydroxycholesterol. 【Result】RT-qPCR showed that the expressions of the three candidate genes in the roots and leaves was consistent with the trend of transcriptome expression. The expression of VnCYP90B27-1 in the roots was significantly higher than that in the leaves. The results of phylogenetic tree showed that VnCYP90B27-1 had high homology with VcCYP90B27 of Veratrum californicum and VnCYP90B27 of V. nigrum, and belonged to CYP90B subfamily. In addition, the results of heterologous expression in the yeast showed that VnCYP90B27-1 had the function of cholesterol C-22 hydroxylase, and successfully achieved the heterologous synthesis of 22 (R)-hydroxycholesterol in S. cerevisiae, with the yield of (5.37±0.37) mg / L in shake flask.【Conclusion】The function of 22 (R)-hydroxycholesterol synthesis gene VnCYP90B27-1 from V. nigrum is successfully cloned and verified. The 22 (R)-hydroxycholesterol yeast chassis is constructed. It is proved that the catalytic activity of VnCYP90B27-1 in S. cerevisiae is higher than that of VcCYP90B27 from V. californicum, which provides genetic resources for heterologous synthesis of steroid alkaloids. [ABSTRACT FROM AUTHOR]

Androstenedione (AD) is a vital intermediate in the synthesis of steroid drugs, making its efficient production critical in the steroid drug industry. Acetyl-CoA acetyltransferase (FadA5), a thiolase enzyme, plays an important role in the metabolic process of degrading phytosterol side chains in Mycolicibacterium to produce AD. This work is the first systematic analysis of the role of FadA5 in the transformation of phytosterols by Mycolicibacterium to produce AD. The relationship between redox potential and AD production was examined using resting cells, and it was confirmed that FadA5 is a key enzyme for AD production. Mutating the 87th cysteine of FadA5 to alanine reduced its redox effect, enhancing the substrate tolerance and biotransformation capacity of the strain. Co-expressing Vitreoscilla hemoglobin (VHb) and propionyl-CoA metabolized the transcription activator (PrpR), decreased intracellular reactive oxygen species levels, and improved cell viability. The AD yield of MSP-fA5C87A-VP/ΔfA5 was 2.541 g/L, an increase of 16.83% over the control strain. Using a repeated batch fermentation process, the production efficiency of the MSP-fA5C87A-VP/ΔfA5 strain was 0.658 g/L/d, which was 1.82 times higher than that of the control strain. These findings provide a theoretical basis for understanding and regulating steroid side-chain catabolism in Mycolicibacterium and offer support for the rational modification of industrial strains for steroidal drug precursor production. [ABSTRACT FROM AUTHOR]

Background: The human adrenal gland is composed of the cortex and the medulla, which contain different function cells. The aim of this study was to build a 3D culture system for human adrenal glands. Methods: Human fetal adrenal tissues were digested into a cell suspension culture and processed in three-phase 3D cultures. Results: Apparent spheroids could be seen from the 4th day on. After 21 days of 3D culture, steroid synthesis cells were evident via CYP17A1+ immunohistochemical staining and flow cytometry analysis. Electron microscopy analysis showed that these cells were present in lipid droplets in the cytoplasm. Meanwhile, TH+ cells represented catecholamine-producing cells, and these cells exhibited electron density particle gathering in the cytoplasm. Dehydroepiandrosterone and epinephrine syntheses were further confirmed via enzyme-linked immunosorbent assay. Conclusions: We established a 3D culture system for human adrenal glands by using a sequential processing medium to facilitate cortical-medullary cell development. [ABSTRACT FROM AUTHOR]

Background/Objective: A dysregulated metabolism has been studied as a key aspect of the COVID-19 pathophysiology, but its longitudinal progression in severe cases remains unclear. In this study, we aimed to investigate metabolic dysregulation over time in patients with severe COVID-19 requiring mechanical ventilation (MV). Methods: In this single-center, prospective, observational study, we obtained 236 serum samples from 118 adult patients on MV in an ICU. The metabolite measurements were performed using capillary electrophoresis Fourier transform mass spectrometry, and we categorized the sampling time points into three time zones to align them with the disease progression: time zone 1 (T1) (the hyperacute phase, days 1–3 post-MV initiation), T2 (the acute phase, days 4–14), and T3 (the chronic phase, days 15–30). Using volcano plots and enrichment pathway analyses, we identified the differential metabolites (DMs) and enriched pathways (EPs) between the survivors and non-survivors for each time zone. The DMs and EPs were further grouped into early-stage, late-stage, and consistent groups based on the time zones in which they were detected. Results: With the 566 annotated metabolites, we identified 38 DMs and 17 EPs as the early-stage group, which indicated enhanced energy production in glucose, amino acid, and fatty acid metabolisms in non-survivors. As the late-stage group, 84 DMs and 10 EPs showed upregulated sphingolipid, taurine, and tryptophan–kynurenine metabolisms with downregulated steroid hormone synthesis in non-survivors. Three DMs and 23 EPs in the consistent group showed more pronounced dysregulation in the dopamine and arachidonic acid metabolisms across all three time zones in non-survivors. Conclusions: This study elucidated the temporal differences in metabolic dysregulation between survivors and non-survivors of severe COVID-19, offering insights into its longitudinal progression and disease mechanisms. [ABSTRACT FROM AUTHOR]

Steroidal–nitroxide hybrid molecules and non-radical controls were synthesised in good yields using simple carbodiimide coupling. An unexpected product arose from reactions between the nitroxide moiety and the solvent THF. Methoxyamine derivatives of the nitroxide drug hybrids were produced using Fenton chemistry without side reactions occurring on the steroid. The hybrid compounds bind to the glucocorticoid receptor and are relevant for the study of radical biological chemistry and redox-related disease processes. [ABSTRACT FROM AUTHOR]

The development of ovarian follicles in poultry is a key factor affecting the performance of egg production. Ovarian follicle development is regulated via the Wnt/β-catenin signaling pathway, and β-catenin, encoded by CTNNB1, is a core component of this pathway. In this study, using ovary GCs from laying hens, we investigated the regulatory role of CTNNB1 in steroid synthesis. We found that CTNNB1 significantly regulates the expression of StAR and CYP11A1 (key genes related to progesterone synthesis) and the secretion of progesterone (P4). Furthermore, simultaneous overexpression of CTNNB1 and SF1 resulted in significantly higher levels of CYP11A1 and secretion of P4 than in cells overexpressing CTNNB1 or SF1 alone. We also found that in GCs overexpressing SF1, levels of CYP11A1 and secreted P4 were significantly greater than in controls. Silencing of CYP11A1 resulted in the inhibition of P4 secretion while overexpression of SF1 in CYP11A1-silenced cells restored P4 secretion to normal levels. Together, these results indicate that synergistic cooperation between the β-catenin and SF1 regulates progesterone synthesis in laying hen ovarian hierarchical granulosa cells to promote CYP11A1 expression. [ABSTRACT FROM AUTHOR]

Heat stress (HS) has become a common stressor, owing to the increasing frequency of extreme high-temperature weather triggered by global warming, which has seriously affected the reproductive capacity of important livestock such as sheep. However, little is known about whether HS reduces sperm motility by inducing circadian rhythm disorders in rumen microorganisms and metabolites in sheep. In this study, the year-round reproduction of two-year-old Hu rams was selected, and the samples were collected in May and July 2022 at average environmental temperatures between 18.71 °C and 33.58 °C, respectively. The experiment revealed that the mean temperature-humidity index was 86.34 in July, indicating that Hu rams suffered from HS. Our research revealed that HS significantly decreased sperm motility in Hu rams. Microbiome analysis further revealed that HS reshaped the composition and circadian rhythm of rumen microorganisms, leading to the circadian disruption of microorganisms that drive cortisol and testosterone synthesis. Serum indicators further confirmed that HS significantly increased the concentrations of cortisol during the daytime and decreased the testosterone concentration at the highest body temperature. Untargeted metabolomics analysis revealed that the circadian rhythm of rumen fluid metabolites in the HS group was enriched by the cortisol and steroid synthesis pathways. Moreover, HS downregulated metabolites, such as kaempferol and L-tryptophan in rumen fluid and seminal plasma, which are associated with promotion of spermatogenesis and sperm motility; furthermore, these metabolites were found to be strongly positively correlated with Veillonellaceae_UCG_001. Overall, this study revealed the relationship between the HS-induced circadian rhythm disruption of rumen microorganisms and metabolites and sperm motility decline. Our findings provide a new perspective for further interventions in enhancing sheep sperm motility with regard to the circadian time scale. [ABSTRACT FROM AUTHOR]

Phylloporia pulla, a macrofungal species in the Hymenochaetales, Basidiomycota, is known to enhance the nutritional and bioactive properties of rice through co-fermentation; however, its own secondary metabolites are not well understood. In this study, an integrative analysis of transcriptome and metabolome data revealed that the accumulation of steroids, steroid derivatives, and triterpenoids in P. pulla peaks during the mid-growth stage, while the genes associated with these metabolites show higher expression levels from the early to mid-growth stages. Weighted gene co-expression network analysis identified several modules containing candidate genes involved in the synthesis of steroids, steroid derivatives, and triterpenoids. Specifically, six key hub genes were identified, along with their connectivity to other related genes, as potential catalysts in converting the precursor lanosterol to celastrol. This study enhances our understanding of the secondary metabolites of P. pulla and is essential for the selective utilization of these bioactive compounds. [ABSTRACT FROM AUTHOR]

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Seasonal reproduction is an adaptive strategy that benefits the survival and growth of offspring. However, the regulatory mechanisms affecting spermatogenesis in male seasonal breeders are not well understood. We examined the actions of testosterone on seasonal spermatogenesis of Plateau Pika (Ochotona curzoniae), a typical long-day breeder living on the Qinghai–Tibetan Plateau. The annual dynamics of germ cell development and steroid hormone synthesis were confirmed and were consistent with testicular morphology. Furthermore, a testosterone regulation experiment showed that elevated testosterone stimulated proliferation of spermatogonia and regeneration of advanced spermatogenic cells in reproductively dormant pika, while testosterone suppression induced cell apoptosis both in reproductively active and dormant pikas. Transcriptomic analyses indicated that testosterone-regulated genes related to spermatogonial fate determination by binding to androgen receptors and inducing the production of retinoic acid, which was responsible for the initiation of spermatogonial differentiation. We show that testosterone orchestrates downstream signaling pathways to balance spermatogonial self-renewal and development. These findings provide a new perspective on seasonal regulation of mammalian spermatogenesis. [ABSTRACT FROM AUTHOR]

Litter size is a key indicator of production performance in livestock. However, its genetic basis in goats remains poorly understood. In this work, a genome‐wide selection sweep analysis (GWSA) on 100 published goat genomes with different litter rates was performed for the first time to identify candidate genes related to kidding rate. This analysis was combined with the public RNA‐sequencing data of ovary tissues (follicular phase) from high‐ and low‐yielding goats. A total of 2278 genes were identified by GWSA. Most of these genes were enriched in signaling pathways related to ovarian follicle development and hormone secretion. Moreover, 208 differentially expressed genes between groups were obtained from the ovaries of goats with different litter sizes. These genes were substantially enriched in the cholesterol and steroid synthesis signaling pathways. Meanwhile, the weighted gene co‐expression network was used to perform modular analysis of differentially expressed genes. The results showed that seven modules were reconstructed, of which one module showed a very strong correlation with litter size (r = −0.51 and p‐value <0.001). There were 51 genes in this module, and 39 hub genes were screened by Pearson's correlation coefficient between core genes > 0.4, correlation coefficient between module members > 0.80 and intra‐module connectivity ≥5. Finally, based on the results of GWSA and hub gene Venn analysis, seven key genes (ACSS2, HECW2, KDR, LHCGR, NAMPT, PTGFR and TFPI) were found to be associated with steroid synthesis and follicle growth development. This work contributes to understanding of the genetic basis of goat litter size and provides theoretical support for goat molecular breeding. [ABSTRACT FROM AUTHOR]

Background: Ovarian granulosa cells (GCs) play crucial roles in follicular growth and development. Their normal function is influenced by various factors, including oxidative stress, which is a significant factor. Afamin protein is a vitamin E-specific binding protein that acts as a vitamin E carrier in follicular fluid. Although the mechanism of the protective effect of afamin on human ovarian GCs is still unclear, there is evidence it has an antioxidant effect in neuronal cells. Methods: In this study, we investigated the protective effects of afamin proteins on testosterone propionate (TP)-induced ovarian GCs using a human ovarian tumor granulosa cell line (KGN). Results: The results showed that afamin reduced TP-induced oxidative stress in KGN cells by decreasing the levels of oxidative damage markers, enhancing the activity of antioxidant enzymes, and exerting a protective effect on GCs. Supplementation with afamin repaired mitochondrial dysfunction by improving mitochondrial membrane potential damage and ATP levels. It counteracted TP-induced apoptosis by decreasing the activity of Caspase-3 and upregulating the expression of the anti-apoptotic gene (BCL-2) while downregulating the expression of the pro-apoptotic gene BCL-2-associated X protein (BAX). In addition, afamin regulated the expression of genes related to ovarian steroid hormone synthesis, ameliorating the endocrine dysfunction observed in TP-induced KGN cells. Conclusion: Therefore, Afamin proteins may serve as important complementary factors that protect GCs from other types of damage, such as oxidative stress, and may help improve ovarian follicle quality and female reproductive function. [ABSTRACT FROM AUTHOR]

Nature offers a variety of structurally unique, sulfated endobiotics including sulfated glycosaminoglycans, sulfated tyrosine peptides, sulfated steroids/bile acids/catecholamines. Sulfated molecules display a large number of biological activities including antithrombotic, antimicrobial, anticancer, anti‐inflammatory, and others, which arise from modulation of intracellular signaling and enhanced in vivo retention of certain hormones. These characteristics position sulfated molecules very favorably as drug‐like agents. However, few have reached the clinic. Major hurdles exist in realizing sulfated molecules as drugs. This state‐of‐the‐art has been transformed through recent works on the development of sulfate masking technologies for both alkyl (sulfated carbohydrates, sulfated steroids) and aryl (sTyr‐bearing peptides/proteins, sulfated flavonoids) sulfates. This review compiles the literature on different strategies implemented for different types of sulfate groups. Starting from early efforts in protection of sulfate groups to the design of newer SuFEx, trichloroethyl, and gem‐dimethyl‐based protection technologies, this review presents the evolution and application of concepts in realizing highly diverse, sulfated molecules as candidate drugs and/or prodrugs. Overall, the newer strategies for sulfate masking and demasking are likely to greatly enhance the design and development of sulfated molecules as non‐toxic drugs of the future. [ABSTRACT FROM AUTHOR]

Background: Testicular macrophages (TM) have long been recognized for their role in immune response within the testicular environment. However, their involvement in steroid hormone synthesis, particularly testosterone, has not been fully elucidated. This study aims to explore the capability of TM to synthesize and secrete testosterone de novo and to investigate the regulatory mechanisms involved. Results: Transcriptomic analysis revealed significant expression of Cyp11a1, Cyp17a1, Hsd3b1, and Hsd17b3 in TM, which are key enzymes in the testosterone synthesis pathway. qPCR analysis and immunofluorescence validation confirmed the autonomous capability of TM to synthesize testosterone. Ablation of TM in mice resulted in decreased physiological testosterone levels, underscoring the significance of TM in maintaining testicular testosterone levels. Additionally, the study also demonstrated that Cebpb regulates the expression of these crucial genes, thereby modulating testosterone synthesis. Conclusions: This research establishes that TM possess the autonomous capacity to synthesize and secrete testosterone, contributing significantly to testicular testosterone levels. The transcription factor Cebpb plays a crucial role in this process by regulating the expression of key genes involved in testosterone synthesis. [ABSTRACT FROM AUTHOR]

Background: Blotched snakehead (Channa maculata) displays significant sexual dimorphism, with males exhibiting faster growth rates and larger body sizes compared to females. The cultivation of the all-male population of snakeheads holds substantial economic and ecological value. Nonetheless, the intricate processes governing the development of bipotential gonads into either testis or ovary in C. maculata remain inadequately elucidated. Therefore, it is necessary to determine the critical time window of sex differentiation in C. maculata, providing a theoretical basis for sex control in production practices. Methods: The body length and weight of male and female C. maculata were measured at different developmental stages to reveal when sexual dimorphism in growth initially appears. Histological observations and spatiotemporal comparative transcriptome analyses were performed on ovaries and testes across various developmental stages to determine the crucial time windows for sex differentiation in each sex and the sex-related genes. Additionally, qPCR and MG2C were utilized to validate and locate sex-related genes, and levels of E2 and T were quantified to understand sex steroid synthesis. Results: Sexual dimorphism in growth became evident starting from 90 dpf. Histological observations revealed that morphological sex differentiation in females and males occurred between 20 and 25 dpf or earlier and 30–35 dpf or earlier, respectively, corresponding to the appearance of the ovarian cavity or efferent duct anlage. Transcriptome analyses revealed divergent gene expression patterns in testes and ovaries after 30 dpf. The periods of 40–60 dpf and 60–90 dpf marked the initiation of molecular sex differentiation in females and males, respectively. Male-biased genes (Sox11a, Dmrt1, Amh, Amhr2, Gsdf, Ar, Cyp17a2) likely play crucial roles in male sex differentiation and spermatogenesis, while female-biased genes (Foxl2, Cyp19a1a, Bmp15, Figla, Er) could be pivotal in ovarian differentiation and development. Numerous biological pathways linked to sex differentiation and gametogenesis were also identified. Additionally, E2 and T exhibited sexual dimorphism during sex differentiation and gonadal development. Based on these results, it is hypothesized that in C. maculata, the potential male sex differentiation pathway, Sox11a–Dmrt1–Sox9b, activates downstream sex-related genes (Amh, Amhr2, Gsdf, Ar, Cyp17a2) for testicular development, while the antagonistic pathway, Foxl2/Cyp19a1a, activates downstream sex-related genes (Bmp15, Figla, Er) for ovarian development. Conclusions: This study provides a comprehensive overview of gonadal dynamic changes during sex differentiation and gametogenesis in C. maculata, establishing a scientific foundation for sex control in this species. Plain language summary: Blotched snakehead (Channa maculata) exhibits significant sexual dimorphism, as males display faster growth rates and larger body sizes compared to females. The cultivation of the all-male population of snakeheads holds substantial economic and ecological value. However, the mechanisms underlying sex determination and differentiation in C. maculata remain insufficiently elucidated. In this study, sexual dimorphism in growth became evident starting from 90 dpf through the measurement of body length and weight of male and female C. maculata at different developmental stages. Histological observations indicated that morphological sex differentiation in females and males occurred at 20–25 dpf or earlier and 30–35 dpf or earlier, respectively, corresponding to the appearance of the ovarian cavity or efferent duct anlage. Transcriptome analyses revealed divergent gene expression patterns in male and female gonads after 30 dpf, suggesting that the period preceding 30 dpf might be the critical time window for sex control in C. maculata. The periods of 40–60 dpf and 60–90 dpf marked the initiation of molecular sex differentiation in females and males, respectively. Male-biased genes (Sox11a, Dmrt1, Amh, Amhr2, Gsdf, Ar, Cyp17a2) likely play crucial roles in testicular differentiation and spermatogenesis, while female-biased genes (Foxl2, Cyp19a1a, Bmp15, Figla, Er) could be pivotal in ovarian differentiation and oogenesis. Additionally, numerous biological pathways linked to sex differentiation and gametogenesis were identified. Moreover, sexual dimorphism was observed in the levels of E2 and T during gonadal differentiation and development. Based on these findings, it is hypothesized that in C. maculata, the potential male sex differentiation pathway, Sox11a–Dmrt1–Sox9b, activates downstream sex-related genes (Amh, Amhr2, Gsdf, Ar, Cyp17a2) for testicular development, while the antagonistic pathway, Foxl2/Cyp19a1a, activates downstream sex-related genes (Bmp15, Figla, Er) for ovarian development. This study provides a comprehensive overview of gonadal dynamic changes during sex differentiation and gametogenesis in C. maculata, thereby establishing a scientific foundation for sex control in this species. Highlights: Sexual dimorphism in growth became apparent starting from 90 dpf. The morphological differentiation of ovary and testis occurred at 20–25 dpf or earlier and 30–35 dpf or earlier, respectively, and the period preceding 30 dpf may be the critical time for sex control in C. maculata. Male-biased genes (Sox11a, Dmrt1, Amh, Amhr2, Gsdf, Ar, Cyp17a2) likely play crucial roles in testicular differentiation and spermatogenesis, whereas female-biased genes (Foxl2, Cyp19a1a, Bmp15, Figla, Er) could be pivotal in ovarian differentiation and oogenesis. The fate of undifferentiated primordial gonads in C. maculata may be determined by the antagonistic action of the Sox11a–Dmrt1–Sox9b and Foxl2/Cyp19a1a pathways. [ABSTRACT FROM AUTHOR]

17α-Methyltestosterone (MT) is a widely used androgen for all-male fish production in aquaculture. However, the molecular mechanism underlying MT-induced masculinization remains unclear. In this study, we aim to identify the key gene responsible for MT-induced masculinization using the Nile tilapia (Oreochromis niloticus) amhy, dmrt1, and gsdf mutants, which exhibit male-to-female sex reversal. Nile tilapia fry from these three mutant lines were treated with 50 μg/g MT from 5 to 30 days after hatching (dah). The results showed that amhy and gsdf mutants, but not dmrt1 mutants, were masculinized by the MT treatment. Gonadal transcriptome analysis revealed that genes involved in steroidogenesis and germ cell development in MT-treated dmrt1 mutants exhibited a similar expression pattern to that of the wild type (WT) XX. In addition, the dmrt1 mutants cannot be masculinized by co-treatment with MT and the aromatase inhibitor fadrozole. The MT treatment completely blocked early steroidogenic enzyme (Star2, Cyp17a2, and Cyp19a1a) expression independent of amhy, gsdf, and dmrt1. A luciferase analysis showed that MT directly suppressed basal and Sf-1-activated cyp19a1a promoter activity through ara and arb in cultured HEK293 cells. Furthermore, MT treatment inhibited germ cell proliferation in amhy and gsdf mutants but not in dmrt1 mutants. Consistently, dmrt1 expression was induced in MT-treated WT XX, -amhy, and -gsdf mutants. Taken together, these results suggest that dmrt1 is indispensable for MT-induced masculinization in Nile tilapia and that MT functions by inhibiting early steroid synthesis and activating dmrt1 to promote testis development. [ABSTRACT FROM AUTHOR]

This article presents a comprehensive overview of recent discoveries and advancements in the field of steroid chemistry, highlighting the isolation and characterization of various steroidal compounds from natural sources. This paper discusses a wide range of steroids, including pregnane steroids, steroidal alkaloids, ketosteroids, and novel triterpenoids, derived from marine organisms, fungi, and plants. Significant findings include the isolation of bioactive compounds such as the cytotoxic erectsterates from microorganisms, soft corals, the unusual tetracyclic steroid penicillitone from a fungal culture, and innovative steroidal derivatives with potential anti-inflammatory and anticancer activities. The synthesis of steroids from microorganisms as a tool for pharmaceutical development is also explored, showcasing the role of microbial biotransformation in generating steroidal drugs. Additionally, this paper emphasizes the ecological and medicinal relevance of these compounds, which are often used in traditional medicine and have potential therapeutic applications in treating diseases like cancer and microbial infections. This article serves as a vital resource for researchers interested in the chemical diversity of steroids and their applications in drug discovery and development. [ABSTRACT FROM AUTHOR]

The first-line treatment for Cushing's disease is transsphenoidal adenomectomy, which can be curative in a significant number of patients. The second-line options in cases of failed primary pituitary surgery include repeat surgery, medical therapy, and radiation. The role for medical therapy has expanded in the last decade, and options include pituitary-targeting drugs, steroid synthesis inhibitors, and glucocorticoid receptor antagonists. Bilateral adrenalectomy is a more aggressive approach, which may be necessary in cases of persistent hypercortisolism despite surgery, medical treatment, or radiation or when rapid normalization of cortisol is needed. We review the available treatment options for Cushing's disease, focusing on the second-line treatment options to consider after failed primary pituitary surgery. [ABSTRACT FROM AUTHOR]

The triazole antifungals posaconazole and itraconazole can cause pseudohyperaldosteronism with hypertension and hypokalemia, edema, and gynecomastia by inhibiting steroid synthesis and metabolism. Mechanisms underlying pseudohyperaldosteronism include inhibition of adrenal 11β-hydroxylase cytochrome-P450 (CYP) 11B1 and 17α-hydroxylase (CYP17A1) as well as peripherally expressed 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). To enhance specificity for fungal CYP51, tetrazoles have been developed. This study employed H295R adrenocortical cells and enzyme activity assays to assess the potential risk of oteseconazole and two other tetrazoles, VT-1598 and quilseconazole, to inhibit adrenal steroidogenesis or 11β-HSD2. Steroidomic footprint analyses of H295R cell supernatants using untargeted liquid-chromatography-high-resolution mass-spectrometry (LC-HRMS) indicated overall patterns common to oteseconazole, quilseconazole and itraconazole, as well as similarities between VT-1598 and isavuconazole. Additionally, more specific features of the steroid signatures were observed. Targeted quantification of nine adrenal steroids in supernatants from treated H295R cells revealed an overall inhibition of adrenal steroidogenesis by the three tetrazoles, itraconazole and isavuconazole, providing an explanation for their similar steroidomic pattern. Applying recombinant enzymes indicated that this effect is not due to direct inhibition of steroidogenic enzymes because no or only weak inhibition could be observed. Moreover, oteseconazole and the two other tetrazoles did not inhibit 11β-HSD2, suggesting that they do not pose a risk of pseudohyperaldosteronism. Furthermore, oteseconazole did not alter steroid concentrations in a recent clinical study. Nevertheless, follow-up studies should assess the mechanism underlying the observed overall steroidogenesis inhibition by tetrazoles, itraconazole and isavuconazole, and whether concentrations achievable in a subgroup of susceptible patients might cause adrenal insufficiency and hyperplasia. [ABSTRACT FROM AUTHOR]

Summary: Sterols have long been associated with diverse fields, such as cancer treatment, drug development, and plant growth; however, their underlying mechanisms and functions remain enigmatic. Here, we unveil a critical role played by a GmNF‐YC9‐mediated CCAAT‐box transcription complex in modulating the steroid metabolism pathway within soybeans. Specifically, this complex directly activates squalene monooxygenase (GmSQE1), which is a rate‐limiting enzyme in steroid synthesis. Our findings demonstrate that overexpression of either GmNF‐YC9 or GmSQE1 significantly enhances soybean stress tolerance, while the inhibition of SQE weakens this tolerance. Field experiments conducted over two seasons further reveal increased yields per plant in both GmNF‐YC9 and GmSQE1 overexpressing plants under drought stress conditions. This enhanced stress tolerance is attributed to the reduction of abiotic stress‐induced cell oxidative damage. Transcriptome and metabolome analyses shed light on the upregulation of multiple sterol compounds, including fucosterol and soyasaponin II, in GmNF‐YC9 and GmSQE1 overexpressing soybean plants under stress conditions. Intriguingly, the application of soybean steroids, including fucosterol and soyasaponin II, significantly improves drought tolerance in soybean, wheat, foxtail millet, and maize. These findings underscore the pivotal role of soybean steroids in countering oxidative stress in plants and offer a new research strategy for enhancing crop stress tolerance and quality from gene regulation to chemical intervention. [ABSTRACT FROM AUTHOR]

Microplastics (MPs) have emerged as a major environmental issue. They have been found to cause significant reproductive toxicity and lower testosterone levels in adult males, though the exact mechanisms remain unclear. In this study, C57bl/6 mice were orally exposed to saline or varying doses (0.25, 0.5, and 1 mg/day) of 5 μm polystyrene MPs (PS-MPs) for 4 weeks, and TM3 mouse Leydig cells were treated with different concentrations of PS-MPs. Our results found that exposure to PS-MPs significantly reduced testosterone levels and impaired the synthesis function of testicular steroids. In vitro, PS-MPs reduced steroid synthesis in Leydig cells. Treatment with PS-MPs significantly increased the apoptosis rate and BAX/BCL2 ratio in Leydig cells. Additionally, GSH-px and SOD activities decreased, while MDA levels increased, along with a rise in mitochondrial ROS. In conclusion, chronic PS-MP exposure reduced testosterone levels in mice through mitochondrial oxidative stress and BAX/BCL2-mediated apoptosis. This study offers new insights into the health risks posed by MPs. [ABSTRACT FROM AUTHOR]

Background: Ulcerative colitis (UC) is a common chronic disease associated with inflammation and oxidative stress. This study aimed to construct a long noncoding RNA (lncRNA)-microRNA (miRNA)-messenger RNA (mRNA) network based on bioinformatics analysis and to explore oxidative stress-related genes underlying the pathogenesis of UC. Methods: The GSE75214 , GSE48959 , and GSE114603 datasets were downloaded from the Gene Expression Omnibus database. Following differentially expressed (DE) analysis, the regulatory relationships among these DERNAs were identified through miRDB, miRTarBase, and TargetScan; then, the lncRNA-miRNA-mRNA network was established. The Molecular Signatures Database (MSigDB) was used to search oxidative stress-related genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed for functional annotation and enrichment analyses. Based on the drug gene interaction database DGIdb, drugs that interact with oxidative stress-associated genes were explored. A dextran sulfate sodium (DSS)-induced UC mouse model was used for experimental validation. Results: A total of 30 DE-lncRNAs, 3 DE-miRNAs, and 19 DE-mRNAs were used to construct a lncRNA-miRNA-mRNA network. By comparing these 19 DE-mRNAs with oxidative stress-related genes in MSigDB, three oxidative stress-related genes (CAV1, SLC7A11, and SLC7A5) were found in the 19 DEM sets, which were all negatively associated with miR-194. GO and KEGG analyses showed that CAV1, SLC7A11, and SLC7A5 were associated with immune inflammation and steroid hormone synthesis. In animal experiments, the results showed that dexamethasone, a well-known glucocorticoid drug, could significantly decrease the expression of CAV1, SLC7A11, and SLC7A5 as well as improve UC histology, restore antioxidant activities, inhibit inflammation, and decrease myeloperoxidase activity. Conclusion: SLC7A5 was identified as a representative gene associated with glucocorticoid therapy resistance and thus may be a new therapeutic target for the treatment of UC in the clinic. [ABSTRACT FROM AUTHOR]

Monitoring the maturation of fish gonads requires an understanding of the locations of reproductive hormone formation both under the influence of environmental factors and under normal conditions. A crucial role in the biosynthesis of active steroid hormones is played by 3β-hydroxysteroid dehydrogenase (3β-HSD). The male and female Oreochromis niloticus gonads at different stages of the annual sexual cycle were analyzed for 3β-HSD using histochemical techniques to pinpoint the locations of steroid synthesis. In females, a specific cell type in the thecal layer, interstitial cells, and ovarian wall epithelial cells exhibited 3β-HSD activity. In males, only Leydig cells (interstitial cells) and lobule boundary cells exhibited 3β-HSD activity. During the stages of sexual maturation and spawning, the Leydig cells' steroidogenic activity increased. Additionally, during the maturing and spawning stages, 3β-HSD exhibited a strong reaction that increased in intensity and the apparent quantity of cells exhibiting a reaction. However, after spawning, the reaction decreased. Furthermore, during the oogenesis process, which is the development of the previtellogenic oocytes to the ripe oocytes, 3β-HSD activity was elevated in the various phases of ovarian maturation. In conclusion, it can be stated that the cells producing steroid hormones in the male and female gonads of O. niloticus have been sufficiently identified, and their steroid hormoneproducing capacity has been demonstrated. Naturally, more research is necessary to apply this finding to the development of fish gonads during the reproduction in aquaculture settings or under situations where this teleost species is concerned to environmental treatments. [ABSTRACT FROM AUTHOR]

Per- and polyfluoroalkyl substances (PFAS) are a group of synthetic chemicals that are resistant to biodegradation and are environmentally persistent. PFAS are found in many consumer products and are a major source of water and soil contamination. This study investigated the effects of an environmentally relevant PFAS mixture (perfluorooctanoic acid [PFOA], perfluorooctanesulfonic acid [PFOS], perfluorohexanesulfonic acid [PFHxS]) on the transcriptome and function of human granulosa cells (hGCs). Primary hGCs were harvested from follicular aspirates of healthy, reproductive-age women who were undergoing oocyte retrieval for in vitro fertilization. Liquid Chromatography with tandem mass spectrometry (LC/MS-MS) was performed to identify PFAS compounds in pure follicular fluid. Cells were cultured with vehicle control or a PFAS mixture (2 nM PFHxS, 7 nM PFOA, 10 nM PFOS) for 96 h. Analyses of cell proliferation/apoptosis, steroidogenesis, and gene expression were measured via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays/immunofluorescence, ELISA/western blotting, and RNA sequencing/bioinformatics, respectively. PFOA, PFOS, and PFHxS were detected in 100% of follicle fluid samples. Increased cell proliferation was observed in hGCs treated with the PFAS mixture with no impacts on cellular apoptosis. The PFAS mixture also altered steroid hormone synthesis, increasing both follicle-stimulating hormone-stimulated and basal progesterone secretion and concomitant upregulation of STAR protein. RNA sequencing revealed inherent differences in transcriptomic profiles in hGCs after PFAS exposure. This study demonstrates functional and transcriptomic changes in hGCs after exposure to a PFAS mixture, improving our knowledge about the impacts of PFAS exposures and female reproductive health. These findings suggest that PFAS compounds can disrupt normal granulosa cell function with possible long-term consequences on overall reproductive health. [ABSTRACT FROM AUTHOR]

Dexamethasone is widely used in pregnant women at risk of preterm birth to reduce the occurrence of neonatal respiratory distress syndrome and subsequently reduce neonatal mortality. Studies have suggested that dexamethasone has developmental toxicity, but there is a notable absence of systematic investigations about its characteristics. In this study, we examined the effects of prenatal dexamethasone exposure (PDE) on mother/fetal mice at different doses (0.2, 0.4, or 0.8 mg/kg b.i.d), stages (gestational day 14–15 or 16–17) and courses (single- or double-course) based on the clinical practice. Results showed that PDE increased intrauterine growth retardation rate, and disordered the serum glucose, lipid and cholesterol metabolic phenotypes, and sex hormone level of mother/fetal mice. PDE was further discovered to interfere with the development of fetal lung, hippocampus and bone, inhibits steroid synthesis in adrenal and testis, and promotes steroid synthesis in the ovary and lipid synthesis in the liver, with significant effects observed at high dose, early stage and double course. The order of severity might be: ovary > lung > hippocampus/bone > others. Correlation analysis revealed that the decreased serum corticosterone and insulin-like growth factor 1 (IGF1) levels were closely related to PDE-induced low birth weight and abnormal multi-organ development in offspring. In conclusion, this study systematically confirmed PDE-induced multi-organ developmental toxicity, elucidated its characteristics, and proposed the potential "glucocorticoid (GC)-IGF1" axis programming mechanism. This research provided an experimental foundation for a comprehensive understanding of the effect and characteristics of dexamethasone on fetal multi-organ development, thereby guiding the application of "precision medicine" during pregnancy. [ABSTRACT FROM AUTHOR]

Triphenyl phosphate (TPhP), a chemical commonly found in human placenta and breast milk, has been shown to disturb the endocrine system. Our previous study confirmed that TPhP could accumulate in the placenta and interference with placental lipid metabolism and steroid hormone synthesis, as well as induce endoplasmic reticulum (ER) stress through PPARγ in human placental trophoblast JEG‐3 cells. However, the molecular mechanism underlying this disruption remains unknown. Our study aimed to identify the role of the PPARγ/CD36 pathway in TPhP‐induced steroid hormone disruption. We found that TPhP increased lipid accumulation, total cholesterol, low‐ and high‐density protein cholesterol, progesterone, estradiol, glucocorticoid, and aldosterone levels, and genes related to steroid hormones synthesis, including 3βHSD1, 17βHSD1, CYP11A, CYP19, and CYP21. These effects were largely blocked by co‐exposure with either a PPARγ antagonist GW9662 or knockdown of CD36 using siRNA (siCD36). Furthermore, an ER stress inhibitor 4‐PBA attenuated the effect of TPhP on progesterone and glucocorticoid levels, and siCD36 reduced ER stress‐related protein levels induced by TPhP, including BiP, PERK, and CHOP. These findings suggest that ER stress may also play a role in the disruption of steroid hormone synthesis by TPhP. As our study has shed light on the PPARγ/CD36 pathway's involvement in the disturbance of steroid hormone biosynthesis by TPhP in the JEG‐3 cells, further investigations of the potential impacts on the placental function and following birth outcome are warranted. [ABSTRACT FROM AUTHOR]

Background: The gonadotropins lutropin and follitropin stimulate steroid synthesis in the gonads during gonadal maturation by promoting oogenesis and spermatogenesis. Endocrine disruptors such as lindane (γHCH) can alter the reproductive stage so and could alter puberty by interfering with lutropin and follitropin signaling. γHCH was classified by World Health Organization as "moderately restricted", and in 2009 it is production and agricultural use was prohibited, under the Stockholm Convention, however, its use as a pharmaceutical treatment against lice and scabies is still allowed (and mainly, for use by the health sector). This study aimed to examine the effects of single-dose exposure to γHCH in young mice (Mus musculus) on lutropin and follitropin concentration, and to correlate gonadal maturity status and phenotypic characteristics. Methods: Young γHCH-treated mice (16 females and 16 males) received a single dose of 25, 10, 5, or 0 µg/ml γHCH per gram of body weight, ocular route. Once secondary sexual characteristics were observed, the gonads were dissected and examined using histological techniques and the ovarian follicles were classified as dependent and independent of gonadotropins; the testicles were classified as inactive, early and late spermatogenesis; and the blood was processed with the lutropin and follitropin ELISA kit. Results: The results indicate significant differences in the concentration of lutropin and follitropin between males and females (Fisher p < 0.05). The lutropin and follitropin levels showed a tendency to decrease in females, whereas, in males they tended to increase as the dose of γHCH increased. In females, it was observed that at the follitropin and lutropin decreased 42.3% and 83.7%, respectively at dose of 25 µg/ml; while in males, follitropin increased 51.9% at the dose of 25 µg/ml, and at the dose of 10 µg/ml lutropin increased by 242.5%. Contrary to that, gonadal maturity increased in females and decreased in males with increasing γHCH dose, disagreeing with the idea that gonadotropins coincide with the onset of puberty and gonadal maturity. Conclusions: The results allow us to infer that exposure to γHCH could promote non-monotonic responses; however, this does not seem to alter puberty in the doses and conditions of the present experiment. [ABSTRACT FROM AUTHOR]

Ammonia nitrogen is one of the major pollutants in aquaculture. However, the mechanism of ammonia stress on ovarian development and follicular atresia is unknown. In this study, goldfish (Carassius auratus) were exposed to different ammonia concentrations, including 0 (control, C) and 50 mg/L (high, H) for 48 hr at 21 ± 0.5°C. Histology of the ovarian tissue sections revealed that the high ammonia concentrations inhibited the maturation of oocytes, and induced broken and wrinkled radiation bands, follicular membranes, and the accumulation of rod-shaped yolk particles. From the transcriptome data, a total of 1,405 differentially expressed genes (DEGs) were detected between H and C groups. Most DEGs were highly enriched in low-density lipoprotein particle-mediated signaling, oxidative stress-induced premature senescence, and ovarian steroidogenesis pathway. Furthermore, a total of 19 genes were selected and determined by quantitative real-time polymerase chain reaction (qRT-PCR). The changes in oxidative stress and antioxidant activity indicated the excessive accumulation of reactive oxygen species (ROS) in ovarian tissue. The ovarian apoptosis was induced in the H group. The downregulation of genes involved in the ovarian steroidogenesis pathway indicated that ammonia nitrogen stress prevented the synthesis of sexual hormones. These results suggest that high-concentration ammonia stress induces ovarian damage in goldfish, affecting its antioxidant function, leading to excessive ROS accumulation, ovarian apoptosis, and hindered steroid synthesis, adversely affecting reproductive performance. [ABSTRACT FROM AUTHOR]

The endoplasmic reticulum (ER) is the largest membranous network serving as a region for protein, lipid and steroid synthesis, transport and storage. Detailed information about ER-cisternae, ER-tubules and rough endoplasmic reticulum (rER) is scarce in human blood cells. This study describes a series of giant inclusions and Auer bodies in promyeloblasts in six patients with acute promyelocytic leukemia (APL), by light microscopy, transmission electron microscopy (TEM) and cytochemical stains. TEM revealed that giant inclusions and pro-Auer bodies were associated with rER and surrounded by tubular structures composed of degenerated or redundant membrane in promyeloblasts, which corresponded with elements of the ER system. This paper reveals that in the promyeloblasts of APL, ER is the source of and transforms progressively into giant inclusions and Auer bodies. [ABSTRACT FROM AUTHOR]

For many years, research in the field of steroid synthesis has aimed to understand the regulation of the rate-limiting step of steroid synthesis, i.e. the transport of cholesterol from the outer to the inner mitochondrial membrane, and identify the protein involved in the conversion of cholesterol into pregnenolone. The extraordinary work by B Clark, J Wells, S R King, and D M Stocco eventually identified this protein and named it steroidogenic acute regulatory protein (StAR). The group's finding was also one of the milestones in understanding the mechanism of nonvesicular lipid transport between organelles. A notable feature of StAR is its high degree of phosphorylation. In fact, StAR phosphorylation in the acute phase is required for full steroid biosynthesis. As a contribution to this subject, our work has led to the characterization of StAR as a substrate of kinases and phosphatases and as an integral part of a mitochondrion-associated multiprotein complex, essential for StAR function and cholesterol binding and mitochondrial transport to yield maximum steroid production. Results allow us to postulate the existence of a specific cellular microenvironment where StAR protein synthesis and activation, along with steroid synthesis and secretion, are performed in a compartmentalized manner, at the site of hormone receptor stimulation, and involving the compartmentalized formation of the steroid molecule-synthesizing complex. [ABSTRACT FROM AUTHOR]

Background: The male reproductive system consists of the testes, epididymis, accessorygonads, and genital ducts. The physiological integrity of the testicles is essential forsuccessful sperm production, but the testes are susceptible to a variety of exogenous andendogenous toxins, which can lead to structural damage to tissues and spermabnormalities. Spermatogenesis is always in a homeostatic process and is sensitive to changes intheexternal environment. Huperzia serrata flavonoids (HSF) have a variety of pharmacological effects, including the treatment of bruises, strains, etc. HSF can improve the reproductivefunction of male mice, so the purpose of this experiment is to explore whether huperzineflavonoids are involved in and regulate the male reproductive process. Methods: Ourexperimental animals were ICR mice, and samples were collected after 28 days of HSFtreatment, and verified by a series of experimental methods such as immunofluorescence, immunohistochemistry, HE staining, protein hybridization, and screening of relatedgenes. Results: RNA sequencing results showed that HSF up-regulated genes related to spermdevelopment and differentiation in testes and promoted spermatogenesis. HSF is effectiveinpromoting steroid hormone synthesis by modulating STAR, CYP11A1, and CYP17A1. Conclusion: Thus, HSF can regulate testicular gene expression, stabilize the gut microbiome, alter serum metabolites, and regulate steroid homeostasis. [ABSTRACT FROM AUTHOR]

The Chinese tree shrew (Tupaia belangeri chinensis) has emerged as a promising model for investigating adrenal steroid synthesis, but it is unclear whether the same cells produce steroid hormones and whether their production is regulated in the same way as in humans. Here, we comprehensively mapped the cell types and pathways of steroid metabolism in the adrenal gland of Chinese tree shrews using single-cell RNA sequencing, spatial transcriptome analysis, mass spectrometry, and immunohistochemistry. We compared the transcriptomes of various adrenal cell types across tree shrews, humans, macaques, and mice. Results showed that tree shrew adrenal glands expressed many of the same key enzymes for steroid synthesis as humans, including CYP11B2, CYP11B1, CYB5A, and CHGA. Biochemical analysis confirmed the production of aldosterone, cortisol, and dehydroepiandrosterone but not dehydroepiandrosterone sulfate in the tree shrew adrenal glands. Furthermore, genes in adrenal cell types in tree shrews were correlated with genetic risk factors for polycystic ovary syndrome, primary aldosteronism, hypertension, and related disorders in humans based on genome-wide association studies. Overall, this study suggests that the adrenal glands of Chinese tree shrews may consist of closely related cell populations with functional similarity to those of the human adrenal gland. [ABSTRACT FROM AUTHOR]

Ovarian follicle development is an important physiological activity for females and makes great significance in maintaining female health and reproduction performance. The development of ovarian follicle is mainly affected by the granulosa cells (GCs), whose growth is regulated by a variety of factors. Here, we identified a novel circular RNA (circRNA) derived from the Ribosomal protein S19 (RPS19) gene, named circRPS19, which is differentially expressed during chicken ovarian follicle development. Further explorations identified that circRPS19 promotes GCs proliferation and steroid hormone synthesis. Furthermore, circRPS19 was found to target and regulate miR-218-5p through a competitive manner with endogenous RNA (ceRNA). Functionals investigation revealed that miR-218-5p attenuates GCs proliferation and steroidogenesis, which is opposite to that of circRPS19. In addition, we also confirmed that circRPS19 upregulates the expression of Inhibin beta B subunit (INHBB) by binding with miR-218-5p to facilitate GCs proliferation and steroidogenesis. Overall, this study revealed that circRPS19 regulates GCs development by releasing the repression of miR-218-5p on INHBB, which suggests a novel mechanism in respect to circRNA and miRNA regulation in ovarian follicle development. • A novel circRNA circRPS19 is differentially expressed during ovarian follicle development. • CircRPS19 promotes chicken GCs proliferation and steroid hormone synthesis. • CircRPS19 control GCs development via upregulating INHBB by antagonizing miR-218-5p. [ABSTRACT FROM AUTHOR]

The integral role of the hypothalamic-pituitary-gonadal axis in reproductive processes makes it a prime therapeutic target. By inhibiting sex steroid synthesis, gonadotropin-releasing hormone (GnRH) analogues are used in the management of cancers, benign neoplasms, infertility and gender dysphoria. However, the wide application of these therapeutics raises concerns regarding the unintended effects upon the cardiovascular system. In males with prostate cancer, GnRH analogues when used as an androgen deprivation therapy appear to increase the risk of cardiovascular disease, which is the leading cause of death in this population. Therefore, due to the utilisation of GnRH analogues across the lifespan and gender spectrum, this relationship merits discussion. Existing data suggest an association between GnRH analogues and major adverse cardiovascular events in males. Conversely, females receiving GnRH analogues for breast cancer treatment appear to be at an increased risk of developing hypertension. In this narrative review, we describe the uses of GnRH analogues in adults, adolescents and children. We discuss whether sex plays a role in the cardiovascular effects of GnRH analogues and explore the significance of sex hormone receptors in the vasculature. We also consider confounding factors such as malignancy, advanced age and infertility. [ABSTRACT FROM AUTHOR]

[Display omitted] • Dysfunction of steroid hormone synthesis mediated by retinol metabolism was the main cause of low fertility of sows. • Retinoic acid synthesis was dominated by ALDH1A1, and required the assistance of ALDH1A2 in ovarian granulosa cells. • ALDH1A1 enhanced the proliferation of ovarian granulosa cells by activating PI3K-Akt-hedgehog signaling pathways. • ALDH1A1 regulated the expression of transcription factor MESP2, which targeted the transcription of STAR and CYP11A1 through directly binding to their promoter regions. Ovarian steroidogenesis not only affects the embryonic development and pregnancy outcome, but also associates with many diseases in mammals and women. Exploring the nutrients and mechanisms influencing ovarian steroidogenesis is critical to maintaining the optimal reproductive performance, as well as guaranteeing body health. This research aimed to explore the effect of retinol metabolism on ovarian steroidogenesis and the underlying mechanisms. Comparative transcriptomic analysis of ovaries from normal and low reproductive performance sows were performed to identify the main causes leading to low fertility. The metabolites regulating steroid hormones synthesis were investigated in ovarian granulosa cells. Gene interference, overexpression, dual-luciferase reporter assays, chromatin immunoprecipitation and transcriptome analysis were further conducted to explore the underlying mechanisms of Aldh1a1 mediating ovarian steroidogenesis. Transcriptome analysis of ovaries from normal and low reproductive performance sows showed the significant differences in both retinol metabolism and steroid hormones synthesis, indicating retinol metabolism probably influenced steroid hormones synthesis. The related metabolite retinoic acid was furtherly proven a highly active and potent substance strengthening estrogen and progesterone synthesis in ovarian granulosa cells. For the first time, we revealed that retinoic acid synthesis in porcine and human ovarian granulosa cells was dominated by Aldh1a1 , and required the assistance of Aldh1a2. Importantly, we demonstrated that Aldh1a1 enhanced the proliferation of ovarian granulosa cells by activating PI3K-Akt-hedgehog signaling pathways. In addition, Aldh1a1 regulated the expression of transcription factor MESP2, which targeted the transcription of Star and Cyp11a1 through binding to corresponding promoter regions. Our data identified Aldh1a1 modulates ovarian steroidogenesis through enhancing granulosa cell proliferation and MESP2/STAR/CYP11A1 pathway. These findings provide valuable clues for improving ovarian health in mammals. [ABSTRACT FROM AUTHOR]

Glucose metabolism in granulosa cells (GCs) is essential for follicle development and oocyte maturation. Porcine follicular fluid exosomes promote the proliferation of porcine GCs and the synthesis of steroid hormones. However, their role in regulating glucose uptake in GCs is unclear. The objective of this study was to elucidate the effects of porcine follicular fluid exosomes on glucose uptake in porcine GCs and the intrinsic mechanisms involved. First, transcriptome sequencing revealed that glucose metabolism-related pathways were altered in GCs treated with follicular fluid exosomes. Next, in vitro culture experiments showed that glucose uptake was increased and the IRS1/AKT signaling pathway was activated in GCs after treatment with follicular fluid exosomes. Finally, miRNA sequencing of follicular fluid exosomes revealed that miR-21-5p was the most abundant miRNA. Subsequent investigations indicated that miR-21-5p promoted glucose uptake in GCs by targeting BTG2 , which activated the IRS1/AKT signaling pathway. In conclusion, the findings of this study indicate that porcine follicular fluid exosomes promote glucose uptake in porcine GCs by delivering miR-21-5p, which inhibits the expression of BTG2 , activating the IRS1/AKT signaling pathway. • Follicular fluid exosomes promoted glucose uptake in granulosa cells. • Overexpression of miR-21-5p promoted glucose uptake in granulosa cells. • The follicular fluid exosomes carried miR-21-5p targets BTG2 , activating the IRS1/AKT signaling pathway. [ABSTRACT FROM AUTHOR]

C19 steroids and C22 steroids are vital intermediates for the synthesis of steroid drugs. Compared with C19 steroids, C22 steroids are more suitable for synthesizing progesterone and adrenocortical hormones, albeit less developed. 9,22-dihydroxy-23,24-bisnorchol-4-ene-3-one(9-OHBA), due to its substituents at positions C-9 and C-22, is a beneficial and innovative steroid derivative for synthesizing corticosteroids. We focused on the C22 pathway in Mycobacterium fortuitum ATCC 35855, aiming to develop a productive strain that produces 9-OHBA. We used a mutant strain, MFΔkstD, that knocked out kstds from Mycobacterium fortuitum ATCC 35855 named MFKD in this study as the original strain. Hsd4A and FadA5 are key enzymes in controlling the C19 metabolic pathway of steroids in Mycobacterium fortuitum ATCC 35855. After knocking out hsd4A, MFKDΔhsd4A accumulated 81.47% 9-OHBA compared with 4.13% 9-OHBA in the strain MFKD. The double mutant MFKDΔhsd4AΔfadA5 further improved the selectivity of 9-OHBA to 95.13%, and 9α-hydroxy-4-androstenedione (9-OHAD) decreased to 0.90% from 4.19%. In the end, we obtained 6.81 g/L 9-OHBA from 10 g/L phytosterols with a molar yield of 80.33%, which showed the best performance compared with formerly reported strains. [ABSTRACT FROM AUTHOR]

An effective method for the synthesis of heterocyclic steroids with the [1,2,5]oxadiazolo[3,4-b]pyrazine and [1,2,5]thiadiazolo[3,4-b]-pyrazine fragments was developed. The structure of the products was confirmed by X-ray structural analysis. The resulting compounds showed high antiproliferative activity against breast (MCF7) and prostate (22Rv1) cancer cells, which was not inferior to that of cisplatin and abiraterone acetate. [ABSTRACT FROM AUTHOR]

The potential effects of poly- and perfluoroalkyl substances (PFAS) are a recently emergent human and environmental health concern. There is a consistent link between PFAS exposure and cancer, but the mechanisms are poorly understood. Although epidemiological evidence supporting PFAS exposure and cancer in general is conflicting, there is relatively strong evidence linking PFAS and testicular germ cell tumors (TGCTs). However, no mechanistic studies have been performed to date concerning PFAS and TGCTs. In this report, the effects of the legacy PFAS perfluorooctanesulfonic acid (PFOS) and the newer "clean energy" PFAS lithium bis(trifluoromethylsulfonyl)imide (LiTFSi, called HQ-115), on the tumorigenicity of TGCTs in mice, TGCT cell survival, and metabolite production, as well as gene regulation were investigated. In vitro, the proliferation and survival of both chemo-sensitive and -resistant TGCT cells were minimally affected by a wide range of PFOS and HQ-115 concentrations. However, both chemicals promoted the growth of TGCT cells in mouse xenografts at doses consistent with human exposure but induced minimal acute toxicity, as assessed by total body, kidney, and testis weight. PFOS, but not HQ-115, increased liver weight. Transcriptomic alterations of PFOS-exposed normal mouse testes were dominated by cancer-related pathways and gene expression alterations associated with the H3K27me3 polycomb pathway and DNA methylation, epigenetic pathways that were previously showed to be critical for the survival of TGCT cells after cisplatin-based chemotherapy. Similar patterns of PFOS-mediated gene expression occurred in PFOS-exposed cells in vitro. Metabolomic studies revealed that PFOS also altered metabolites associated with steroid biosynthesis and fatty acid metabolism in TGCT cells, consistent with the proposed ability of PFAS to mimic fatty acid-based ligands controlling lipid metabolism and the proposed role of PFAS as endocrine disrupters. Our data, is the first cell and animal based study on PFAS in TGCTs, support a pro-tumorigenic effect of PFAS on TGCT biology and suggests epigenetic, metabolic, and endocrine disruption as potential mechanisms of action that are consistent with the non-mutagenic nature of the PFAS class. [ABSTRACT FROM AUTHOR]

The occupational chemical 4-Vinylcyclohexene diepoxide (VCD) is a reproductively toxic environmental pollutant that causes follicular failure, leading to premature ovarian insufficiency (POI), which significantly impacts a woman's physical health and fertility. Investigating VCD's pathogenic mechanisms can offer insights for the prevention of ovarian impairment and the treatment of POI. This study established a mouse model of POI through intraperitoneal injection of VCD into female C57BL/6 mice for 15 days. The results were then compared with those of the control group, including a comparison of phenotypic characteristics and transcriptome differences, at two time points: day 15 and day 30. Through a comprehensive analysis of differentially expressed genes (DEGs), key genes were identified and validated some using RT-PCR. The results revealed significant impacts on sex hormone levels, follicle number, and the estrous cycle in VCD-induced POI mice on both day 15 and day 30. The DEGs and enrichment results obtained on day 15 were not as significant as those obtained on day 30. The results of this study provide a preliminary indication that steroid hormone synthesis, DNA damage repair, and impaired oocyte mitosis are pivotal in VCD- mediated ovarian dysfunction. This dysfunction may have been caused by VCD damage to the primordial follicular pool, impairing follicular development and aggravating ovarian damage over time, making it gradually difficult for the ovaries to perform their normal functions. [ABSTRACT FROM AUTHOR]

Elucidation of the thermotolerance mechanism of erythritol-producing Yarrowia lipolytica is of great significance to breed robust industrial strains and reduce cost. This study aimed to breed thermotolerant Y. lipolytica and investigate the mechanism underlying the thermotolerant phenotype. Yarrowia lipolytica HT34, Yarrowia lipolytica HT36, and Yarrowia lipolytica HT385 that were capable of growing at 34 °C, 36 °C, and 38.5 °C, respectively, were obtained within 150 days (352 generations) by adaptive laboratory evolution (ALE) integrated with 60Co-γ radiation and ultraviolet ray radiation. Comparative genomics analysis showed that genes involved in signal transduction, transcription, and translation regulation were mutated during adaptive evolution. Further, we demonstrated that thermal stress increased the expression of genes related to DNA replication and repair, ceramide and steroid synthesis, and the degradation of branched amino acid (BCAA) and free fatty acid (FFA), while inhibiting the expression of genes involved in glycolysis and the citrate cycle. Erythritol production in thermotolerant strains was remarkably inhibited, which might result from the differential expression of genes involved in erythritol metabolism. Exogenous addition of BCAA and soybean oil promoted the growth of HT385, highlighting the importance of BCAA and FFA in thermal stress response. Additionally, overexpression of 11 out of the 18 upregulated genes individually enabled Yarrowia lipolytica CA20 to grow at 34 °C, of which genes A000121, A003183, and A005690 had a better effect. Collectively, this study provides novel insights into the adaptation mechanism of Y. lipolytica to thermal stress, which will be conducive to the construction of thermotolerant erythritol-producing strains. Key points: • ALE combined with mutagenesis is efficient for breeding thermotolerant Y. lipolytica • Genes encoding global regulators are mutated during thermal adaptive evolution • Ceramide and BCAA are critical molecules for cells to tolerate thermal stress [ABSTRACT FROM AUTHOR]