Journal of Steroid Biochemistry and Molecular Biology最新文献

This study explored the therapeutic potential of gut microbiota metabolites in managing Gestational Diabetes Mellitus (GDM). Using network pharmacology, molecular docking, and dynamics simulations, we identified key targets and pathways involved in GDM. We screened 135 gut-derived metabolites, with 8 meeting drug-likeness and pharmacokinetic criteria. Analysis revealed significant overlap with GDM-related targets, including AKT1, IL6, TNF, and STAT3. Functional enrichment analysis highlighted the AGE-RAGE signaling and inflammatory pathways as crucial in GDM pathogenesis. Molecular docking and dynamics simulations showed strong binding affinities and stable interactions between two metabolites, luteolin and naringenin chalcone, and the target protein AKT1. These findings suggest that gut microbiota-derived metabolites, particularly luteolin and naringenin chalcone, may effectively modulate key pathways in GDM, offering promising avenues for novel treatment strategies.

Curcuminoids, including curcumin and its derivatives, show potent inhibition of aromatase (CYP19A1), crucial for estradiol synthesis and breast cancer metastasis. Our study evaluated the efficacy and mechanism of 10 curcuminoids and their metabolites against human and rat CYP19A1 using placental microsomes, revealing species-specific IC₅₀ values. Cyclocurcumin (IC₅₀, 4.43 μM) and curcumin (IC₅₀, 3.49 μM) were the most effective inhibitors for human and rat CYP19A1, respectively. These compounds acted as mixed or competitive inhibitors, reducing estradiol production in human BeWo cells. Docking analysis showed that curcuminoids interact with CYP19A1 active site, forming a hydrogen bond with Met374. 3D-QSAR analysis highlighted the importance of hydrogen bonding in inhibition. A negative correlation was observed between the pKa values and IC₅₀ values for human CYP19A1. A positive correlation was observed between the lowest binding energy and IC₅₀ values for human CYP19A1. These findings underscore the potential of curcuminoids as therapeutic agents against breast cancer.

Phthalates are a wide family of chemicals that are used in many different industrial applications used in many different industrial applications, including the production of plastics, toys, food packaging particularly for kids, and medical equipment. Due to their various chemical and physical properties, phthalates may negatively impact humans, animals, and the environment. Thus the potential for phthalate exposure and harm to humans, animals, and the environment is high because its presence is alarming. Phthalates can be ingested, inhaled, absorbed topically, or via iatrogenic exposure in animals and humans. This article aimed to ascertain the modes of exposure, fate and detection techniques, and harmful effects of phthalates on humans, animals, and the environment. This review also shows that the intake of phthalate above the established daily limit from sources such as food, toys, and air causes serious harm, including impaired immune function, difficulties in pregnancy, loss of reproduction, and damage to the kidneys, lungs, heart, and brain in humans. Children and pregnant women are the most impacted groups and phthalates also negatively affect the environment and wildlife. A few methods to determine phthalate exposure, such as the LC and the HPLC-MS/MS methods, which employ human fluid or dust air as a biomarker, are also addressed here. Consequently, this comprehensive review aims to provide a detailed analysis of the existing evidence regarding explicit links between exposure to phthalates and subsequent health outcomes that may be directly related to this exposure. Additionally, we reviewed the developed and validated analytical methods and supplemented the literature with partial biomonitoring data on their metabolites.

Segetalin B (SB) has shown promise in mitigating osteoporosis in ovariectomized (OVX) mice, though its underlying mechanisms remain unclear. This study investigates how SB promotes bone formation through Phospholipase D1 (PLD1) activation in OVX models. In vitro, bone marrow-derived mesenchymal stem cells (BMSCs) from OVX mice were cultured for osteogenic differentiation. The effects of SB, PLD1 inhibitor VU0359595, SIRT1 inhibitor EX527, and γ-secretase inhibitor LY-411575 were examined. In vivo, the impact of SB and LY-411575 on osteoporosis in OVX mice was evaluated. SB significantly increased PLD1 phosphorylation, enhancing osteogenic differentiation and SIRT1 activity. Blocking PLD1 with VU0359595 reversed these effects. Inhibiting SIRT1 with EX527 restored γ-secretase activity and Notch1 signaling but did not alter PLD1 activation. Notch1 overexpression weakened SB's promotion of osteogenesis and activation of the Wnt/β-catenin pathway. In vivo, SB combined with LY-411575 showed stronger anti-bone loss effects compared to SB alone. These findings suggest that SB may directly activates PLD1, which enhances SIRT1 activity and suppresses Notch1 signaling overactivation via γ-secretase inhibition. This cascade promotes bone formation by upregulating Wnt/β-catenin signaling. Combining SB with LY-411575 may offer a novel therapeutic strategy for postmenopausal osteoporosis.

Programmed cell death (PCD) is a fundamental process in the development process of organisms, including apoptosis, autophagy, ferroptosis, and pyroptosis. In mammalian ovaries, 99 % of follicles undergo atresia, while only 1 % mature and ovulate, which limits the reproductive efficiency of mammals. The PCD process is closely related to the regulation of follicle development and atresia. Recently, an increasing number of studies have reported that autophagy, pyroptosis, and ferroptosis of PCD are involved in regulating granulosa cell apoptosis and follicular atresia. Granulosa cell apoptosis is a hallmark of follicular atresia. Therefore, an understanding of molecular mechanisms regulating PCD events is required for future advances in the diagnosis and management of various disorders of follicular atresia. This review summarizes recent work on apoptosis, autophagy, pyroptosis, and ferroptosis of PCD that affect granulosa cell survival and follicular atresia, and further elucidating the mechanisms of follicular atresia and providing new directions for improving the reproductive capacity of humans and animals.

Cushing syndrome represents a multitude of signs and symptoms associated with long-term and excessive exposure to glucocorticoids. Solitary cortisol-producing adenomas (CPAs) account for most cases of ACTH-independent Cushing syndrome (CS). Technological advances in next-generation sequencing have significantly increased our understanding about the genetic landscape of CPAs. However, the conventional approach utilizes fresh/frozen tissue samples, which are not routinely available for most clinical adrenal adenoma specimens. This coupled with the fact that CS is relatively rare reduces the accessibility to CPAs for research. In order to circumvent this issue, our group recently developed a sequencing strategy that allowed the use of formalin-fixed paraffin-embedded (FFPE) CPA samples for mutation analysis. Our streamlined approach includes the visualization and genomic DNA (gDNA) capture of the cortisol-producing regions in the tumor using immunohistochemistry (IHC)-guided techniques followed by targeted and/or whole-exome sequencing analysis. This approach has the advantage of using both prospective and retrospective CPA cohorts since FFPE pathologic specimens are routinely banked. This review discusses this advanced approach using IHC-guided gDNA capture of pathologic tissue followed by NGS as a preferred method for mutational analysis of CPAs.

Osteosarcoma (OS), an extremely aggressive form of bone tumor primarily affects young adults. Despite significant advancements in clinical trials, the ability of cancer cells to metastasize and resist apoptosis remains a major challenge. To address these issues, novel therapeutic interventions with high specificity for these processes are essential. Alpha-lipoic acid (ALA), an organosulfur compound derived from octanoic acid, possesses a range of pharmacological properties. This study hypothesizes that ALA would inhibit metastasis and induce cell apoptosis in OS. To evaluate the potential of ALA, its effects on the migration, metastasis, and cell cycle of MG-63 OS cells were assessed, along with its ability to trigger apoptosis. To these aims, MG-63 cells were exposed to varying concentrations of ALA, and cell viability was measured using the alamarBlue assay. The impact of ALA on cell cycle progression, apoptosis, migration, and metastasis was analyzed through flow cytometry, scratch assay, and gelatin zymography. After validating the expression of MMP2, MMP9, VEGF, VEGFR, BAX, BCL-2, and P53 by the GEO database, the expression levels of these genes were examined through quantitative PCR (qPCR). Eventually, molecular docking was employed to simulate the interactions between ALA and matrix metalloproteinase (MMPs). The results demonstrated that ALA significantly inhibited cell migration, induced cell cycle arrest, and promoted apoptosis by upregulating P53 and BAX expression while downregulating BCL-2 levels. Furthermore, ALA was found to suppress the activity and expression of MMP2 and MMP9 and reduce the expression of angiogenesis markers. Notably, ALA interacted directly with the active site of MMP2 and MMP9. These findings suggest that ALA has the potential to be a promising agent with anti-cancer effects on MG-63 cells, warranting further preclinical investigations.

Polystyrene (PS) microplastics are pervasive environmental pollutants that are harmful to aquatic organisms upon degradation. The synthetic androgen 17α-methyltestosterone (MT) is an environmental endocrine-disrupting chemical. This study aimed to systematically evaluate the combined histological and molecular effects of MT and PS exposure on the liver and brain tissues of Danio rerio with focus on lipid metabolism and neural function disruption. Female D. rerio were exposed to 50ng/L MT and 0.5mg/L PS (5 μm in diameter) for 21 d. Histological observations, real-time quantitative PCR (qPCR), and RNA-sequencing (RNA-seq) analysis were employed to assess the effects of PS and MT. These results indicated that MT and PS co-exposure caused fatty degeneration of liver cells and a significant upregulation of lipid synthesis-related genes (ACSS1, CEL, FASN, and GK5). In brain tissue, the observed effects included reduced marginal layer neuron counts, cytoplasmic loosening of central layer neurons, disordered gray matter layer cells, and vascular congestion. RNA-seq analysis further revealed significant enrichment of differentially expressed genes in the "glycine, serine, and threonine metabolism" and "neuroactive ligand-receptor interaction" signaling pathways. Thus, MT and PS co-exposure induced lipid metabolism disorders in D. rerio and influence neural signaling by altering the "neuroactive ligand-receptor interaction" pathway. These findings highlight the complex risks posed by environmental pollutants to aquatic life and provide critical insights for environmental protection and aquatic health research.

Background: This study investigates the protective effects and potential mechanisms of 1,25-(OH)₂D₃ against high-altitude pulmonary edema (HAPE).

Methods: Hypoxia-induced rats were administered 1,25-(OH)₂D₃ for 24, 48, and 72 hours, and we observed lung tissue injury and pulmonary edema. Immunohistochemistry (IHC) and Western blot analyses were employed to analyze the expression of markers associated with ferroptosis and ferritinophagy in rat lungs. Metabolomics analysis was conducted to investigate changes in serum lipid metabolites. We validated the mechanism of action of 1,25-(OH)₂D₃ in type II alveolar epithelial cells induced by hypoxia.

Results: Our results demonstrated that hypoxic exposure significantly altered sodium-water transport in the lungs, leading to edema formation. The degree of pulmonary edema was most pronounced at 48 hours of hypoxi. Treatment with 1,25-(OH)₂D₃ improved lung function and reduced the degree of pulmonary edema in hypoxic rats. Hypoxia-induced increases in 4-HNE and MDA levels in the lungs, along with iron accumulation, were observed. Hypoxia also resulted in elevated levels of NCOA4, LC3Ⅱ, and FTH1 proteins in the lungs. Furthermore, treatment with 1,25-(OH)₂D₃ significantly inhibited ferroptosis and ferritinophagy in the lungs after hypoxia. The levels of lipid metabolites, such as L-Aspartic acid and L-Fucose, were significantly elevated in the serum of hypoxic rats. After 1,25-(OH)₂D₃ treatment, these levels exhibited a significant reduction.

Conclusion: In hypoxic type II alveolar epithelial cells, 1,25-(OH)₂D₃ improved hypoxia-induced sodium-water transport, ferroptosis, and ferritinophagy, which were reversed by the autophagy agonist Rapamycin.By modulating ferroptosis and ferritinophagy, 1,25-(OH)₂D₃ mitigated the deleterious effects of hypoxia on pulmonary function.

We aimed to estimate the prevalence of vitamin D deficiency in Mongolian men aged from 15 to 49 years at the National level as part of the Fifth National Nutrition Survey in 2016. This was a cross-sectional survey, conducted between September and November in 21 aimags of 4 economic regions of the country, and also in Ulaanbaatar. Given the regional differences in lifestyle and nutritional status, the target populations were stratified into 5 strata based on their economic region and in Ulaanbaatar, with equal samples drawn from each stratum using a cluster-randomized sampling design. A representative sample of 30 clusters [villages] was randomly selected using Probability Proportional to Size [PPS] methodology in each of the 4 regions and in Ulaanbaatar for a total of 150 cluster units. The selection of survey participants differed for the three sampling regions. Household eligibility was based on having a child 0-59 months of age, living in the household which was randomly selected from each cluster for a total of 450 households in each region. Households with a child 0-59 months of age were selected from household lists available at the kheseg or bagh level. All men 15-49 years of age who resided in the selected households were also eligible to participate in the survey. Serum concentration of 25-hydroxyvitamin D [25(OH)D] were measured using an enzyme-linked fluorescence assay in 377 men aged 15-49 years. The overall mean serum level of 25(OH)D concentration was 22.26 ± 0.48 ng/mL (95 % CI 21.31-23.21). The mean serum 25(OH)D concentrations were 19.65 ± 0.32 ng/mL (95 % CI19.01-19.82), and 33.68 ± 0.49 ng/mL (95 % CI 32.72-34.64) in vitamin D deficient, and in vitamin D sufficient subjects, respectively. The prevalence of vitamin D deficiency was 83.5 % with no significant difference in the prevalence of vitamin D deficiency by age group, economic region, area, location, education, and wealth index quintile. The prevalence of men in this study who were overweight or obese was 48.8 % and 14.6 % respectively. Although no significant difference was found between vitamin D deficiency and obesity, vitamin D deficiency was higher among men aged 30-39 and 40-49 years old by age specific analyses. The men did not take vitamin D supplements, and there is currently no vitamin D food fortification in Mongolia. The findings of this survey showed that vitamin D deficiency in men is a public health problem in Mongolia. In conclusion, vitamin D deficiency are common in Mongolian men, which indicates the need for vitamin D screening and treatment, as well as for an increased use of vitamin D supplements and for implementing vitamin D food fortification programs.