Journal of Steroid Biochemistry and Molecular Biology最新文献

Interleukin-2 (IL-2) receptor γ (IL2RG) is present in the Leydig cell lineage, but its functional role remains elusive. To investigate how IL2RG impacts Leydig cell development from stem cells and elucidate the underlying mechanisms, we used a rat model of ethane dimethanesulfonate (EDS)-induced cell depletion in Wild-type (WT) and Il2rg knockout (KO) mice. WT and KO male rats received intratesticular IL-2 injections (1 and 10 ng/testis) from day 7 to day 21 post-EDS. Stem Leydig cells around tubules and isolated progenitor Leydig cells were cultured with IL-2 (1 and 10 ng/mL) with/without STAT3 inhibitor. Hormone levels, cell counts, gene/protein expression, and signaling pathways were analyzed. The results revealed that IL-2 significantly reduced serum testosterone levels in WT rats but had no effects in KO rats, without altering luteinizing hormone and follicle-stimulating hormone levels. Furthermore, IL-2 lowered Leydig cell numbers and the labeling index of PCNA in CYP11A1⁺ Leydig cells at 10 ng/testis, and downregulated the expression of SCARB1, HSD3B1, CYP17A1, SRD5A1, and NR5A1, as well as their corresponding mRNA levels in WT rats with no effect observed in KO rats. IL-2 also inhibited the incorporation of 5-ethynyl-2'-deoxyuridine (EdU) into stem Leydig cells in WT rats and [³H] thymidine incorporation into progenitor Leydig cells, as well as their differentiation. Importantly, the effects of IL-2 were reversed by the STAT3 inhibitor. Signaling pathway analysis showed that IL-2 exerted effects via increasing JAK1, STAT5, and STAT3 phosphorylation. This study provides insights into the inhibitory effects of IL2RG on Leydig cell development and highlights the involvement of the JAK-STAT pathway, offering potential targets for further exploration in the context of Leydig cell biology and male reproductive health.

7-ketocholesterol (7KCh), a cytotoxic oxysterol enriched in atherosclerotic plaques, provokes macrophage dysfunction through oxiapoptophagy, a linked process of oxidative stress, apoptosis and autophagy culminating in pro-inflammatory M1 polarization. Targeting this process could mitigate oxysterol-driven vascular inflammation. In this study, murine IC-21 macrophages were induced with 7KCh and co-exposed to fenchone, a bicyclic monoterpene with known anti-inflammatory properties. Cellular oxidative stress, apoptosis and autophagy were assessed by spectrofluorometric and cytometric assays. Expression of key mediators (iNOS, COX2, HO1, Casp3, Bcl2, LC3B, PARP1, Arg1, KLF4 and PPARγ) was quantified by RT-qPCR and western blotting. Molecular docking was used to identify interactions of fenchone with KLF4 and PPARγ. The results showed that 7KCh significantly increased ROS and NO production, disrupted mitochondrial membrane potential and induced apoptosis and autophagy in macrophages. Fenchone co-treatment counteracted these effects, restoring redox balance and membrane integrity. Molecular analyses revealed downregulation of iNOS, COX2, Casp3 and PARP1, alongside upregulation of HO1, Arg1, KLF4 and PPARγ. Docking analysis confirmed strong binding of fenchone to KLF4 and PPARγ, suggesting transcriptional regulation of macrophage polarization via the KLF4-PPARγ-Arg1 axis. These findings suggest that fenchone mitigates 7KCh-induced oxiapoptophagy and reprograms macrophages toward an anti-inflammatory M2 phenotype through modulation of KLF4/PPARγ signalling, positioning fenchone as a potential immunomodulatory candidate for combating oxysterol-mediated vascular inflammation.

Steroids represent a large family of organic compounds that, as signaling molecules, play important role in variety of physiological processes as control of metabolic pathways, inflammation processes, immune response, and growth, development and reproduction. Modifying the steroid core has allowed the creation of novel synthetic derivatives, which can offer significant benefits in medicine for treating a wide range of pathological conditions. Quite a number of natural steroids have been identified as effective inhibitors of cholinesterases, pointing them out as potential therapeutic alternatives in the application in Alzheimer's disease (AD). Nevertheless, only a limited number of synthetic steroids have so far been studied as cholinesterase inhibitors, highlighting an opportunity for the development of new therapeutic agents derived from natural steroidal frameworks. In this study, we selected a set of structurally diverse steroid hormone derivatives and evaluated in vitro their inhibitory activity against human AChE and BChE. IC₅₀ values were estimated for several of the most active compounds, with pyridine-containing hydroxy derivative 8 exhibiting affinity toward BChE (IC₅₀ 2.76 µM), similar to that for clinically used cholinesterase inhibitors. In silico analyses suggest that hydrophobic interactions with key amino-acid residues predominantly govern the binding of these compounds within the enzyme's active site.

Anabolic androgenic steroids are synthetic derivatives of testosterone that mimic its actions in various tissues. Due to its strong anabolic activity, weak androgenic effects, and resistance to hepatic metabolism, oxandrolone is one of the most commonly used anabolic steroids among female athletes. This study aimed to evaluate the anabolic effects of oxandrolone and its toxicological profile in female rats subjected to a strength training protocol. A total of 24 female Wistar rats (60 days old) were randomly assigned to receive oxandrolone (1.77 mg/kg/day) or its vehicle (corn oil) (n = 12 per group) via daily gavage for 28 days. The exercise protocol consisted of six climbs on an inclined ladder, with two climbs per workload (50 %, 75 %, and 100 % of each animal's maximum load) performed three times per week. Investigators remained blinded throughout experimentation and data analysis. Oxandrolone did not significantly affect body weight gain, relative organ and muscle mass, or muscle strength. However, it altered mean corpuscular volume, eosinophil count, and urea levels. Additionally, liver TBARS levels increased, while no changes were observed in plasma lipid peroxidation, antioxidant enzyme activity, total non-protein thiol levels, or mitochondrial respiratory chain complex activity. Histopathological analysis revealed oxandrolone-induced damage to cardiac and skeletal muscle, along with structural alterations in the spleen and adrenal gland. Given its limited effect on muscle strength, along with histopathological changes and increased liver lipoperoxidation, these findings raise concerns about oxandrolone use in healthy individuals seeking aesthetic or athletic benefits.