Steroids最新文献

Anabolic-androgenic steroids (AAS) abuse is linked to some abnormalities in several tissues including the kidney. However, the precise molecular mediators involved in AAS-induced kidney disorder remain elusive. The main objective of the present study was to investigate the effect of Nandrolone decanoate on kidney injury alone or in combination with moderate exercise and its related mechanisms. Thirty-two male Wistar rats were subdivided randomly into four groups. control (Con), Nandrolone (10 mg/kg) (N), Exercise (Exe), Nandrolone + Exercise (N+Exe).

Results

After 6 weeks, nandrolone treatment led to a significant increase in functional parameters such as serum cystatin c, urea, creatinine, albuminuria and Albumin/ creatinine ratio indicating kidney dysfunction. Moreover, nandrolone treatment increased vacuolization, focal inflammation, hemorragia, cast formation fibrosis in the renal tissue of rats. miRNA-146a increased in kidney tissue after nandrolone exposure by using RT-PCR which may be considered ideal theranomiRNA candidates for diagnosis and treatment.

Western blotting indicated that IRAK1, TRAF6, TNF-α, NF-κB, iNOS and TGF-β protein expressions were considerably elevated in the kidneys of nandrolone treated rats. Moderate exercise could alleviate the renal dysfunction, histological abnormalities and aforementioned proteins. Our findings suggested that nandrolone consumption can cause damage to kidney tissue probably through miRNA-146a targeting IRAK1 and TRAF6 via activation of the NF-κB and TGF-β pathway. These results provide future lines of research in the identification of theranoMiRNAs related to nandrolone treatment, which can be ameliorated by moderate exercise.

The androgen receptor (AR) is a type I nuclear receptor and master transcription factor responsible for development and maintenance of male secondary sex characteristics. Aberrant AR activity is associated with numerous diseases, including prostate cancer, androgen insensitivity syndrome, spinal and bulbar muscular atrophy, and androgenic alopecia. Recent studies have shown that AR adopts numerous conformations that can modulate its ability to bind and transcribe its target DNA substrates, a feature that can be hijacked in the context of cancer. Here, we summarize a series of structural observations describing how this elusive shape-shifter binds to multiple partners, including self-interactions, DNA, and steroid and non-steroidal ligands. We present evidence that AR’s pervasive structural plasticity confers an ability to broadly bind and transcribe numerous ligands in the normal and disease state, and explain the structural basis for adaptive resistance mutations to antiandrogen treatment. These evolutionary features are integral to receptor function, and are commonly lost in androgen insensitivity syndrome, or reinforced in cancer.

Estrogen-related receptor gamma (ERRγ) is a member of the ERR orphan nuclear receptor family which possesses three subtypes, α, β, and γ. ERRγ is reportedly predominantly expressed in metabolically active tissues and cells, which promotes positive and negative effects in different tissues. ERRγ overexpression in the liver, pancreas, and thyroid cells is related to liver cancer, oxidative stress, reactive oxygen species (ROS) regulation, and carcinoma. Reduced ERRγ expression in the brain, immune cells, tumor cells, and energy metabolism causes neurological dysfunction, gastric cancer, and obesity. ERRγ is a constitutive receptor; however, its transcriptional activity also depends on co-regulators, agonists, and antagonists, which, when after forming a complex, can play a role in targeting and treating diseases. Moreover, ERRγ has proven crucial in regulating cellular and metabolic activity. However, many functions mediated via ERRγ remain unknown and require further exploration. Hence, considering the importance of ERRγ, this review focuses on the critical findings and interactions between ERRγ and co-regulators, agonists, and antagonists alongside its relationship with downstream and upstream signaling pathways and diseases. This review highlights new findings and provides a path to understanding the current ideas and future studies on ERRγ-mediated cellular activity.

Double-headed warheads focusing on the pharmacological aspects as well as membrane permeability can contribute a lot to medicinal chemistry. Over the past few decades, a lot of research has been conducted on steroid-heterocycle conjugates as possible therapeutic agents against a variety of disorders. In the second half of the 20th century, successful research was conducted on cholesterol-based heterocyclic moieties. Keeping in view the biological significance of various triazoles, research on fusion with cholesterol has emerged. This review has been designed to explore the chemistry of cholesterol-based triazoles for the duration from 2010 to 2023 and their significance in medicinal chemistry.

Several studies have indicated that 1α,25-hydroxyvitamin D [1α,25(OH)₂D₃] inhibits the proliferation and metastasis of cancer cells through suppressing epithelial-mesenchymal transition. However, its influence on the translocation of β-catenin remains unclear. In the present study, ovarian cancer stem-like cells (CSCs), including side population (SP) and CD44⁺/CD117⁺, were isolated from mouse ovarian surface epithelial (MOSE) cells with malignant transformation. The findings revealed that 1α,25(OH)₂D₃ obviously reduced the sphere-forming ability, as well as Notch1 and Klf levels. Moreover, the limiting dilution assay demonstrated that 1α,25(OH)₂D₃ effectively hindered the tumorigenesis of ovarian CSCs in vitro. Notably, treatment with 1α,25(OH)₂D₃ led to a substantial increase in the cell population of CD44⁺/CD117⁺ forming one tumor from ≤ 100 to 445 in orthotopic transplanted model, indicating a pronounced suppression of stemness of ovarian CSCs. Additionally, 1α,25(OH)₂D₃ robustly promoted the translocation of β-catenin from the nuclear to the cytoplasm through directly binding to VDR, which resulted in decreased levels of c-Myc and CyclinD1 within late MOSE cells. Taken together, these results strongly supported the role of 1α,25(OH)₂D₃ in inhibiting stem-like properties in ovarian cancer cells by restraining nuclear translocation of β-catenin, thereby offering a promising target for cancer therapeutics.

The therapeutic role of dehydroepiandrosterone (DHEA) supplementation among infertile women with diminished ovarian reserve (DOR) is still unclear. Objective evaluation of different ovarian reserve tests (ORTs) such as serum anti-Mullerian hormone (AMH), serum follicle stimulating hormone (FSH), and antral follicle count (AFC) in women with diminished ovarian reserve is required. This is a cross-sectional study performed in Mosul city, Iraq, with 122 infertile women who had been diagnosed with DOR. The enrolled women’s age ranged from 18 to 45 years old (mean age of 29.46 ± 2.64 years). The ages of the enrolled women ranged from 18 to 45 years (mean age of 29.46 ± 2.64 years). To assess the influence of DHEA supplements (25 mg, three times/day for 12 weeks) across different age groups, the women were initially divided into three groups (18 to 27 years old, 28 to 37 years old, and ≥ 38 years old). Significant differences were noticed in AMH, FSH, level and AFC before and after DHEA supplementation. (AMH: 0.64 ± 0.82 vs. 1.98 ± 1.32, AFC: 2.86 ± 0.64 vs. 5.82 ± 2.42, and FSH: 12.44 ± 3.85 vs. 8.12 ± 4.64), statistically obvious significant differences regarding the results of AMH (p < 0.001), AFC (p < 0.001), and FSH (p < 0.001). DHEA supplementations improved the ovarian reserve of the enrolled women, which was more evident in younger women (<38 years old) than older women (≥38 years old). The AMH serum levels and AFC value can be considered the best, most reliable and significant OR parameters. However, large randomized multicenter studies are required to confirm the available results and data.

Cholesteryl esters (CE) are sterols comprising various fatty acyl chains attached to a cholesterol hydroxyl moiety. CEs are often considered plasma biomarkers of liver function; however, their absolute concentrations in the plasma of Japanese preadolescents have not been well explored. This study aimed to determine the plasma CE levels in Japanese preadolescents of different sexes, ages, and body weights living in Hokkaido, Japan using targeted liquid chromatography/tandem mass spectrometry. The analysis was performed on the non-fasting plasma of preadolescents aged 9–12 years (n = 339 healthy volunteers; 178 boys and 161 girls) from Sapporo, Hokkaido, Japan. The analysis results showed that the total CE levels in boys and girls were 871 ± 153 and 862 ± 96 pmol/μL, respectively. CE 18:2 (41 ± 2.9 %) was found to be the most abundant species followed by CE 18:1 (16 ± 1.5 %) and CE 16:0 (13 ± 1.1 %). The ω-3 fatty acid-containing CEs such as CE 18:3 and CE 20:5 were significantly lower in girls than in boys. Despite the different ages, CEs were tightly regulated in the plasma of children’s, and the total CEs ranged between 844 and 906 pmol/μL in boys and 824 and 875 pmol/μL in girls. The participants were further classified into three groups based on their body mass index underweight (n = 237), normal weight (n = 94), and overweight (n = 8). Most of the quantified CEs were accumulated in the overweight group. Interestingly, CE 18:3 was significantly upregulated in the overweight group compared to that in the normal range, and the area under the receiver operating characteristic curve was 0.73, suggesting that it could be a possible marker for obesity. This study marks the initial investigation of absolute CE levels in the plasma of children and can help elucidate the relationship between CEs and childhood obesity.

The most prevalent reason for female infertility is polycystic ovarian syndrome (PCOS) exhibiting two of three phenotypes including biochemical or clinical hyperandrogenism, anovulation and polycystic ovaries. Insulin resistance and obesity are common in PCOS-afflicted women. Androgens are thought to be the primary cause of PCOS causing symptoms including anovulation, follicles that resemble cysts, higher levels of the luteinizing hormone (LH), increased adiposity, and insulin resistance. However, due to the heterogeneity of PCOS, it is challenging to establish a single model that accurately mimics all the reproductive and metabolic phenotypes seen in PCOS patients. In this review, we aimed to investigate rodent models of PCOS and related phenotypes with or without direct hormonal treatments and to determine the underlying mechanisms to comprehend PCOS better. We summarized rodent models of PCOS that includes direct and indirect hormone intervention and discussed the aetiology of PCOS and related phenotypes produced in rodent models. We presented combined insights on multiple rodent models of PCOS and compared their reproductive and/or metabolic phenotypes. Our review indicates that there are various models for studying PCOS and one should select a model most suitable for their purpose. This review will be helpful for consideration of rodent models for PCOS which are not conventionally used to determine mechanisms at the molecular/cellular levels encouraging development of novel treatments and control methods for PCOS.

Androgen receptor (AR) and its ligand androgens are important for development and physiology of various tissues. AR and its ligands also play critical role in the development of various diseases, making it a valuable therapeutic target. AR ligands, both agonists and antagonists, are being widely used to treat pathological conditions, including prostate cancer and hypogonadism. Despite AR being studied widely over the last five decades, the last decade has seen striking advances in the knowledge on AR and discoveries that have the potential to translate to the clinic. This review provides an overview of the advances in AR biology, AR molecular mechanisms of action, and next generation molecules that are currently in development. Several of the areas described in the review are just unraveling and the next decade will bring more clarity on these developments that will put AR at the forefront of both basic biology and drug development.

Gastric cancer (GC)-diabetes co-morbidity is nowadays growing into a rising concern. However, no separate treatment procedures have been outlined for such patients. Phytochemicals and their derivatives can therefore be used as therapeutics as they have greater effectiveness, reduced toxicity, and a reduced likelihood of developing multi-drug resistance in cancer treatments. The present study intended to assess the therapeutic efficacy of Shatavarin-IV – a major steroidal saponin from the roots of Asparagus racemosus, in human gastric adenocarcinoma cell line under hyperglycemic conditions and explore its mechanism of action in controlling GC progression. For the present study, AGS cells were incubated in high glucose-containing media and the effects of Shatavarin-IV therein have been evaluated. Cell proliferation, confocal microscopic imaging, flow-cytometric analysis for cell cycle and apoptosis, immunoblotting, zymography, reverse zymography, wound-healing, colony formation, and invasion assays were performed. Shatavarin-IV has a prominent effect on AGS cell proliferation; with IC50 of 2.463 µ M under hyperglycemic conditions. Shatavarin-IV induces cell cycle arrest at the G0/G1 phase, thereby preventing hyperglycemia-induced excessive cell proliferation that later on leads to apoptotic cell death at 36 h of incubation. Shatavarin-IV further inhibits the migratory and invasive potential of AGS cells by altering the expression patterns of different EMT markers. It also inhibits MMP-9 while promoting TIMP-1 activity and expression; thereby regulating ECM turnover. This is the first report demonstrating the therapeutic efficacy of Shatavarin-IV against AGS cells grown in hyperglycemic conditions, implicating new insights into the treatment paradigm of patients with GC-diabetes co-morbidity.