Stigmasterol alleviates central precocious puberty by targeting the IGF-1/PI3K/Akt/mTOR signaling pathway and modulating the Kisspeptin/GnRH axis.

Dendrobium officinale polysaccharide ameliorates polycystic ovary syndrome by modulating the MAPK/ERK signaling pathway

Polycystic ovary syndrome (PCOS) is one of the most common endocrine and metabolic disorders affecting women of reproductive age. Dendrobium officinale polysaccharides (DOP) have shown multiple pharmacological activities, but their therapeutic effects and underlying mechanisms in PCOS remain incompletely understood. A dehydroepiandrosterone (DHEA)-induced mouse model of PCOS was established to evaluate the effects of DOP. Estrous cyclicity, ovarian histopathology, serum hormone levels, RT-qPCR, and Western blot analyses were performed to assess reproductive function, endocrine changes, and MAPK/ERK-related signaling. DOP treatment restored estrous cyclicity, improved ovarian morphology, and partially normalized serum luteinizing hormone, follicle-stimulating hormone, and testosterone levels. In addition, DOP reduced ERK1/2 phosphorylation and downregulated the expression of CYP17A1 and CYP19A1. DOP ameliorated reproductive and endocrine abnormalities in a DHEA-induced mouse model of PCOS. The findings suggest that modulation of MAPK/ERK signaling may contribute to the biological effects of DOP, although further mechanistic studies are required to establish causal relationships.

Dynamic Profiles of Serum Kisspeptin and DLK1 During GnRH Stimulation in Central Precocious Puberty and Premature Thelarche.

BACKGROUND The neuropeptides kisspeptin and Delta-like 1 homolog (DLK1) regulate pubertal timing by activating and inhibiting the hypothalamic-pituitary-gonadal (HPG) axis, respectively. Given these opposing regulatory roles, quantifying serum kisspeptin and DLK1 levels during gonadotropin-releasing hormone (GnRH) stimulation may serve as novel biomarkers for distinguishing between central precocious puberty (CPP) and premature thelarche (PT) in girls. METHODS A cross-sectional study was conducted on girls presenting with breast development before eight years of age. Participants were stratified into CPP or PT cohorts based on peak luteinizing hormone (LH) levels following GnRH stimulation (CPP: peak LH ≥ 7 IU/L; PT: peak LH < 7 IU/L). Serum samples were analyzed for kisspeptin and DLK1 at baseline, as well as at 60- and 120-minute post-stimulation. RESULTS The study included 40 girls (20 CPP, 20 PT) with comparable baseline characteristics, except for significantly advanced bone age in the CPP group (P < 0.05). Although baseline serum kisspeptin and DLK1 levels showed no significant intergroup differences, their dynamic responses to GnRH stimulation were distinct. At 60 minutes post-stimulation, the percentage change in serum kisspeptin was significantly lower in the CPP group compared to the PT group (median -35.74% vs. 17.66%; P=0.042). Conversely, the percentage change in DLK1 was significantly elevated in CPP patients (78.38% vs. 19.22%; P<0.001). At 120 minutes, the difference in DLK1 percentage change remained significant (P<0.001), whereas kisspeptin levels showed no significant difference (P=0.499). A positive correlation was observed between kisspeptin and DLK1 levels at both baseline and 60 minutes. CONCLUSION Our findings indicate that the dynamic profiles of kisspeptin and DLK1 reflect distinct neuroendocrine mechanisms distinguishing CPP from PT. These findings underscore the complexity of neuroendocrine regulation of puberty involving kisspeptin and DLK1; however, given the considerable overlap between CPP and PT patients observed in this study, their diagnostic potential as standalone or adjunctive clinical tools remains uncertain and would require validation in larger, independent cohorts.

Pentadecanoic Acid as a Potential Endogenous mTOR Modulator for Age-Related Female Infertility: Mechanistic Insights, Molecular Docking Evidence, and Therapeutic Perspectives.

Kaempferol Counteracts Obesity and Impairs Adipogenesis by Suppressing PI3K/AKT/GSK3β-Mediated Mitotic Clonal Expansion and Attenuating Adipose Tissue Fibrosis.

Kaempferol, a widely present dietary flavonoid in numerous fruits and vegetables, possesses antiobesity potential with unclearly defined mechanisms. This study investigated how kaempferol regulates adipogenesis in 3T3-L1 preadipocytes and exerts antiobesity effects in high-fat diet (HFD)-induced obese mice. Kaempferol inhibited preadipocyte differentiation at the early mitotic clonal expansion (MCE) stage by S-phase (18 h) and G2/M-phase (24 h) cell cycle arrest. Mechanistically, this action was mediated through inhibition of the PI3K/AKT/GSK3β pathway. Application of the AKT activator SC79 confirmed that kaempferol suppresses AKT phosphorylation to inhibit terminal adipogenesis. In vivo, kaempferol significantly alleviated HFD-induced body weight gain, adiposity, dyslipidemia, and insulin resistance. Transcriptomic and histological analyses revealed that kaempferol reversed obesity-associated upregulation of cell cycle and metabolic pathways in white adipose tissue and alleviated adipose tissue fibrosis. These findings underscore the potential of kaempferol as a promising functional food ingredient for preventing obesity and related metabolic diseases.

An N-Salicyloyl Tryptamine Derivative (Compound 18) Improves Spermatogenic Impairment in Obese Mice via Regulating Insulin Resistance and Enhancing Sertoli Cell Glycolysis.

OBJECTIVE This study aimed to investigate the therapeutic potential of compound 18, an N-salicyloyl tryptamine derivative with established anti-neuroinflammatory and neuroprotective properties, in ameliorating male reproductive dysfunction induced by high-fat diet (HFD) in obese mice and to elucidate the underlying mechanisms. METHODS Male mice were fed a HFD to induce obesity and subsequently treated with compound 18 at doses of 25 or 50 mg/kg. Systemic metabolic parameters including body weight, blood glucose, insulin, and lipid profiles were measured. Histopathological assessments were conducted on liver, adipose tissue, testes, and epididymis. Molecular analyses were performed to evaluate the expression of markers related to proliferation (PCNA), apoptosis (BAX and Bcl-2), components of the insulin signaling pathway (IGF1, IGF1R), and key glycolytic enzymes (HK2, PKM2, LDHA). RESULTS Administration of compound 18 led to significant and dose-dependent improvements in systemic metabolism, characterized by reductions in body weight, blood glucose, insulin levels, and lipid parameters. The compound also attenuated hepatic steatosis and adipocyte hypertrophy, while notably restoring testicular and epididymal tissue architecture. At the molecular level, compound 18 up-regulated the proliferative marker PCNA, modulated apoptosis-related proteins (down-regulating Bax and up-regulating Bcl-2), enhanced insulin sensitivity-as indicated by increased IGF1R and decreased IGF1 expression-and augmented glycolytic capacity in Sertoli cells through elevated expression of HK2, PKM2, and LDHA. CONCLUSION These results demonstrate that compound 18 effectively alleviates HFD-induced spermatogenic dysfunction concomitantly with ameliorating testicular insulin resistance and promoting glycolytic flux in Sertoli cells.

GSK3α-mediated regulation of the RNA demethylase fat mass and obesity-associated protein (FTO) during murine spermatogenesis.

Idiopathic male infertility is a rising global concern characterised by ejaculatory defects, absence or low sperm count with abnormal morphology, and poor sperm motility. Deciphering the aetiology of male infertility requires a fundamental understanding of multiple spermatogenic events, including sperm maturation. Glycogen synthase kinase 3 paralog-α (GSK3α) plays a critical role in sperm maturation, specifically during epididymal motility, capacitation and hyperactivation. Methylation modulates mRNA transport, stability, turnover, and translational efficiency to meet cellular requirements. The mRNA demethylase, fat mass and obesity-associated protein (FTO), is a target for phosphorylation by GSK3α, suggesting the potential role of this enzyme in male fertility. This study focuses on the high-affinity spatiotemporal interaction between FTO and GSK3α to delineate the post-transcriptional modifications in the murine testis. Expression of Gsk3a and Fto increases temporally starting with day 18-20 postpartum testis, coinciding with meiosis I and gradually peaks by day 25-34 with the formation of spermatids and completion of spermatogenesis. Co-immunoprecipitation of GSK3α and GSK3β with FTO using respective antibodies and super-resolution microscopy shows a preferential interaction of GSK3α with FTO. Moreover, Gsk3a knockout mice showed significantly low m6A levels in testis, presumably due to enhanced FTO activity. In silico protein-protein docking and molecular dynamics analysis demonstrated an energetically favourable, consensus phosphorylation motif-dependent high-affinity interaction between FTO and GSK3α, further validating our observation. A specific missense mutation (Cys326 > Ser) permitted an additional GSK3-phosphorylation site in FTO, leading to teratozoospermia in a patient. Collectively, this study affirms GSK3α as a spatiotemporal regulator of FTO function inside the mammalian testis.