Journal of Steroid Biochemistry and Molecular Biology最新文献

Introduction: Human milk oligosaccharides (HMOs) arise from tightly regulated glycosylation pathways and exert pleiotropic effects on infant immune, microbial, and neurodevelopmental trajectories. Vitamin D influences gene transcription and cellular metabolism, yet its potential role in mammary glycosylation remains unexplored. We examined whether maternal vitamin D status during lactation is associated with HMO composition and whether effects vary by maternal secretor phenotype.

Methods: We performed a post hoc analysis of two clinical studies: the NICHD vitamin D lactation randomized controlled trial (2005-2012) and the Lactation Immune Trial pilot (n = 88). Serum 25-hydroxyvitamin D [25(OH)D, vitamin D status] and 19 HMOs concentrations were measured at 1 and 4 months postpartum. Secretor status was defined by presence of 2'-fucosyllactose. Statistical analyses were conducted using SAS 9.4 with p < 0.05.

Results: The cohort comprised 41% White, 7% Black, and 52% Hispanic women. Black and Hispanic mothers exhibited lower 25(OH)D concentrations than White mothers (p < 0.001), and Hispanic mothers were more likely to be secretors (p = 0.006). In secretors, higher 25(OH)D was significantly associated with increased fucosylated and complex HMOs, including lacto-N-fucopentaose II, lacto-N-hexaose, and fucosyl-disialyl-lacto-N-hexaose I at 1 month, with sustained association for the latter at 4 months. In non-secretors, higher 25(OH)D was associated with lower 6'-sialyllactose at 4 months. Distinct HMO patterns were observed by secretor phenotype.

Conclusion: Vitamin D status is associated with differential HMO profiles during early lactation, supporting a potential role for vitamin D-mediated regulation of mammary glycosylation that is modified by secretor status.

We investigate how oxidation of cholesterol at the C7 position alters sterol hydration and interfacial organization by combining Langmuir monolayer experiments with all-atom molecular dynamics simulations employing the OPC water model. While cholesterol forms tightly packed and weakly hydrated monolayers, 7-ketocholesterol exhibits increased molecular area, enhanced compressibility, and pronounced orientational disorder. These differences originate from altered hydration: the hydroxyl group of 7-ketocholesterol at C3 position retains cholesterol-like hydration, whereas the additional carbonyl group at C7 introduces a pressure-dependent hydration site that becomes increasingly exposed upon monolayer expansion. Consequently, 7-ketocholesterol monolayers accommodate more interfacial water, display deeper water penetration, and form an extensive network of water-mediated sterol-sterol bridges. Energetic analysis reveals that van der Waals cohesion remains comparable to cholesterol, whereas electrostatic interactions are significantly less unfavorable due to effective hydration and screening of polar groups. These hydration-driven effects, captured only with an accurate interfacial water description, provide a molecular basis for the altered mechanical properties and biological behavior of 7-ketocholesterol-rich membranes.

This study investigated the role of vitamin D (VD) in disuse skeletal muscle atrophy, with a particular focus on muscle type-specific differences. Male C57BL/6 J mice were fed either a standard or VD-deficient diet and subjected to hindlimb immobilization to induce disuse atrophy. The expression of vitamin D receptor (VDR) was analyzed across several skeletal muscles, and muscle fiber atrophy and mitochondrial function were evaluated. In addition, cultured C2C12 myotubes were used to assess the direct effects of VD on oxidative stress-induced mitochondrial dysfunction. VDR expression was markedly higher in the soleus (SOL) muscle than in other muscles at both mRNA and protein levels. VD deficiency selectively exacerbated immobilization-induced atrophy solely in the SOL muscle, characterized by a significant reduction in muscle fiber cross-sectional area and downregulation of mitochondria-related genes (Pgc1α, Cox1, Cox5b, Cytb, Sdha). Consistently, mitochondrial function, which was assessed based on succinate dehydrogenase activity, further decreased in the VD-deficient SOL muscle. In contrast, the gastrocnemius (GC) and tibialis anterior (TA) muscles showed no significant VD-dependent changes. In C2C12 myotubes, active VD [1,25(OH)₂VD₃] attenuated hydrogen peroxide-induced reductions in mitochondrial gene expression and mitochondrial DNA content, suggesting a direct protective role of VD in muscle cells. Taken together, these findings demonstrate that VD deficiency aggravates disuse muscle atrophy through impaired mitochondrial function, particularly in muscles with high VDR expression, such as the SOL. The study highlights muscle type-specific vulnerability to VD deficiency and suggests that VD supplementation can protect certain muscles from disuse-induced atrophy.

Halogenated phenolic disinfectants (HDs) are widely used in industrial and personal care products. However, whether these HDs inhibit human and rat 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) activity to interfere with glucocorticoid metabolism remains unclear. Michaelis-Menten kinetics showed high 11β-HSD2 activity (human placenta: Km, 46.0 nM, Vmax, 48.21pmol/mg/min; rat kidney: Km, 50.01 nM, Vmax, 70.6pmol/mg/min). Screening at 100 µM revealed significant inhibition by most HDs (residual activity <50%), except triclocarban and trichloroacetone. Dose-response assays identified hexachlorophene as the most potent inhibitor (human IC₅₀, 3.83 µM; rat IC₅₀, 1.48 µM). The binding affinities of hexachlorophene and dichlorophene were assessed using Surface Plasmon Resonance, showing KDs of 10.60 and 48.50 μM, respectively. Enzyme kinetics and Lineweaver-Burk plots demonstrated mixed inhibition by HDs, suggesting dual interference with substrate binding and NAD⁺ binding. In human BeWo trophoblast cells, HDs differentially suppressed cortisone formation, with dichlorophene, bromochlorophene, and fenticlor showing inhibition even at 1 µM. Molecular docking revealed HDs binding to NAD⁺ and cortisol binding sites in human 11β-HSD2, with hexachlorophene forming hydrogen bonds with catalytic residues (Ser219, Tyr232). Structure-activity relationship (SAR) and 3D-QSAR analyses highlighted inverse correlations between inhibitory potency and LogP/molecular volume (r = 0.9214 for pharmacophore). ADMET (absorption, distribution, metabolism, elimination, and toxicity) profiling indicated poor solubility, high plasma protein binding, and potential hepatotoxicity. Network toxicology analysis for hypertensive disorders of pregnancy (including gestational hypertension and preeclampsia), now supported by cellular bioassay data, implicates this dysregulated pathway in the potential pathogenesis of HD-induced disorders. These findings elucidate HDs as potent, species-conserved 11β-HSD2 inhibitors with mixed mechanisms, underscoring their endocrine-disrupting potential and structure-dependent bioactivity.

Liver fibrosis is closely linked to metabolic dysfunction and hormonal regulation, with sex differences influencing disease progression. This study combined untargeted liver metabolomic profiling with ovariectomy and orchiectomy mouse models to investigate the roles of estrogen and testosterone in liver injury caused by carbon tetrachloride (CCl₄). Estrogen deficiency aggravated fibrotic injury and liver dysfunction in female mice, whereas testosterone deficiency exerted relatively modest effects in males. Estrogen supplementation significantly attenuated fibrosis in estrogen-deficient females, while testosterone supplementation produced limited and context-dependent responses. Metabolomic profiling revealed hormone-specific metabolic remodeling: estrogen predominantly influenced tryptophan, glycerophospholipid, and nicotinate metabolism, whereas testosterone was associated with alterations in purine, taurine/hypotaurine, and cysteine-methionine pathways. Notably, glycerophospholipid metabolism emerged as a shared but oppositely regulated pathway between estrogen and testosterone exposure. These findings support the established protective role of estrogen and highlight sex-dependent differences in hormone-associated metabolic remodeling during liver fibrosis.

7-Ketocholesterol (7-KC), a highly cytotoxic oxysterol generated during cholesterol oxidation, accumulates in obesity-associated dyslipidemia and plays a significant role in sustaining chronic low-grade inflammation, oxidative stress, and apoptosis. These pathogenic processes contribute to the development and progression of major obesity-related complications, including insulin resistance, cardiovascular disease, and non-alcoholic fatty liver disease. Existing pharmacological interventions offer limited efficacy in counteracting 7-KC induced cellular toxicity, highlighting the need for safe and sustainable nutrition-based strategies. This review examines emerging evidence supporting the role of Bifidobacterium species in modulating cholesterol metabolism, bile acid signaling, gut barrier integrity, and adipose tissue inflammation, all of which are central to oxysterol-mediated metabolic disruption. In addition, the synergistic effects of probiotics and dietary antioxidants in reducing oxidative stress, restoring gut microbial balance, and improving metabolic homeostasis are discussed. Finally, translational insights into functional foods, Synbiotic formulations, and precision nutrition approaches are presented as promising avenues to attenuate 7-KC toxicity and reduce the burden of obesity and its associated comorbidities.

Androgens are a class of steroid hormones that play essential roles in somatic development, reproductive physiology, and anabolic processes in both males and females. Beyond their physiological importance, androgens are implicated in the pathogenesis of several diseases and contribute to the progression of hormone-sensitive malignancies such as prostate, breast, lung, and ovarian cancers. The metabolic conversion of androgens is primarily catalyzed by two major enzyme classes: cytochrome P450 monooxygenases and NAD(P)H-dependent hydroxysteroid dehydrogenases (HSDHs). While endogenous androgen biosynthesis occurs predominantly in the testes, ovaries, adrenal glands, and placenta, emerging evidence suggests that host-associated microbial communities, including those residing in the urinary tract, may also contribute to local androgen metabolism. In our previous work, we identified the desG gene from the urinary tract isolate Propionimicrobium lymphophilum strain API-1, which encodes a novel NADPH-dependent 17β-HSDH. This enzyme catalyzes the bidirectional conversion between androstenedione (AD) and testosterone (T), suggesting a microbial route for androgen production within the urinary tract. In the present study, we expand on these findings by conducting detailed kinetic and substrate-specificity analyses of this enzyme, alongside bioconversion assays using a broad panel of steroid substrates. These results shed light on the steroid-transforming potential of urinary bacteria. IMPORTANCE: This work represents an important advance in the understanding of androgen metabolism by urinary tract bacteria through the characterization of an NADPH-dependent 17β-HSDH encoded by the desG gene. By elucidating kinetic properties, substrate specificity, and bioconversion capabilities of recombinant DesG, this research provides valuable insights into steroid hormone regulation.