Molecular and Cellular Endocrinology最新文献

{"title":"OXTR overexpression induces polycystic ovary syndrome-like phenotype via prolactin/p-STAT3 signaling in mice","authors":"Shuilian Wang ,&nbsp;Xinyue Bao ,&nbsp;Ziying Liu ,&nbsp;Mingjun San ,&nbsp;Lingyu Zhang ,&nbsp;Yanjun Liu ,&nbsp;Mingyan Yang ,&nbsp;Yaowu Zheng ,&nbsp;Dan Li","doi":"10.1016/j.mce.2025.112668","DOIUrl":"10.1016/j.mce.2025.112668","url":null,"abstract":"<div><div>Polycystic ovary syndrome (PCOS), a prevalent endocrine disorder, represents the most common cause of anovulatory infertility. While the oxytocin receptor (OXTR) is well-characterized in parturition and lactation, its role in follicular development remains undefined. In this study, we establish that global OXTR overexpression in female mice (⁺⁺<em>Oxtr</em>) recapitulates cardinal PCOS features, including hyperandrogenism, oligo-ovulation, and polycystic ovarian changes. ⁺⁺<em>Oxtr</em> females exhibited distinct ovarian pathology marked by follicular atresia, cystic changes, hemorrhage, and deficient corpus luteum formation. These morphological alterations coincided with profound endocrine dysregulation, featuring hyperprolactinemia, suppressed luteinizing hormone (LH) secretion, and progesterone (P) deficiency, contrasting with preserved fertility in ⁺⁺<em>Oxtr</em> males. Mechanistically, we identified an OXTR-prolactin (PRL)-p-STAT3 axis as central to PCOS pathogenesis. Corresponding to hyperprolactinemia, persistent activation of nuclear p-STAT3 (Tyr705) in ⁺⁺<em>Oxtr</em> ovaries - absent in WT controls at pregnancy - upregulated folliculogenesis genes (<em>Lhcgr</em>, <em>Pgr</em>, <em>Leptin</em>, <em>Cyp17a1</em>) while impairing ovulation. Therapeutic intervention with bromocriptine normalized prolactin and progesterone levels, partially restoring ovarian function. Notably, ⁺⁺<em>Oxtr</em> females developed metabolic dysfunction characterized by insulin resistance and gonadal adiposity despite maintaining lean phenotypes. Our findings position OXTR as a novel upstream regulator of PCOS pathogenesis with hyperprolactinemia, suggesting bromocriptine may have therapeutic value in hyperprolactinemic PCOS cases. These insights open new avenues for targeted PCOS interventions.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"610 ","pages":"Article 112668"},"PeriodicalIF":3.6,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endometrial cells and extracellular vesicles response to high body energy reserves in bovine: Insights into miRNA and mRNA regulation before embryo arrival","authors":"Schaienni Fontoura Saldanha ,&nbsp;Natália Marins Bastos ,&nbsp;Juliana Germano Ferst ,&nbsp;Rodrigo Silva Goulart ,&nbsp;Ricardo Perecin Nociti ,&nbsp;Marcos Roberto Chiaratti ,&nbsp;Angélica Camargo dos Santos ,&nbsp;Flávio Vieira Meirelles ,&nbsp;Felipe Perecin ,&nbsp;Juliano Coelho da Silveira","doi":"10.1016/j.mce.2025.112665","DOIUrl":"10.1016/j.mce.2025.112665","url":null,"abstract":"<div><div>Body energy reserves influence reproductive performance in cattle. Previous findings from our laboratory showed that cows with high body energy reserves (HBER) have lower ovulation and embryo recovery rates compared to cows with moderate reserves (MBER). To investigate whether these reproductive differences are associated with changes in the uterine environment, Nelore cows from the same herd were assigned to MBER or HBER groups through nutritional management. Following estrous synchronization and artificial insemination, animals were slaughtered ∼120 h after ovulation induction. Samples from the uterotubal junction (UTJ) and anterior uterine horn (ANT) were collected. Extracellular vesicles (EVs) were isolated from uterine fluid by flushing, and endometrial tissue was sampled for molecular analysis. Nanoparticle tracking analysis revealed no differences in EV concentration or size between groups. However, when comparing MBER and HBER groups, miRNA profiling identified 8 and 9 differentially expressed miRNAs between MBER and HBER in EVs from the UTJ and ANT, respectively, and 2 differentially expressed miRNAs in endometrial cells from the UTJ, suggesting potential differences in molecular profiles. Transcriptomic analysis of endometrial cells revealed 430 and 35 differentially expressed genes (DEGs) in the UTJ and ANT, respectively, between MBER and HBER groups. The higher number of DEGs in the UTJ may suggest a greater molecular response, which is reflected by more extensive pathway enrichment compared to the ANT. miRNA–mRNA integration, performed by intersecting predicted miRNA targets with the differentially expressed mRNAs from our RNA-seq data, suggests that differentially expressed genes may be regulated by miRNAs altered between groups, indicating miRNA-mediated effects of metabolic condition on the uterine transcriptome. These findings suggest that high body energy reserves are associated with enrichment of immune and metabolism related pathways in the uterine environment, especially in the UTJ, which may reflect a pro-inflammatory, metabolically altered state potentially impairing early embryo development and maternal-embryonic communication.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"610 ","pages":"Article 112665"},"PeriodicalIF":3.6,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IGF2BP2/ISG15/c-Myc axis promotes the excessive proliferation of granulosa cells in polycystic ovary syndrome.","authors":"Lijuan Han, Hui Miao, Na Li, Congxiu Miao","doi":"10.1016/j.mce.2025.112666","DOIUrl":"https://doi.org/10.1016/j.mce.2025.112666","url":null,"abstract":"<p><strong>Objective: </strong>Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder. This study aimed to investigate the role of IGF2BP2 in the pathogenesis of PCOS.</p><p><strong>Methods: </strong>Dehydroepiandrosterone (DHEA) was used to establish mouse PCOS model. Histological analysis was conducted using HE staining and immunohistochemistry. Gene expression was detected using RT-qPCR and Western blot. Mitochondrial respiration was detected using OCR assay. Glycolysis was detected using ECAR assay. Cell viability was detected using CCK-8 assay. Cell proliferation was detected using colony formation and EdU assays.</p><p><strong>Results: </strong>IGF2BP2 expression was upregulated in PCOS. However, overexpressed IGF2BP2 promoted mitochondrial respiration and glycolysis as well as the proliferation of human ovarian granulosa cells (KGN). IGF2BP2 knockdown inhibited mitochondrial respiration, glycolysis, and proliferation of KGN, leading to improved endocrine and reproductive function in vivo. Mechanically, IGF2BP2-mediated m6A modification promoted the upregulation of ISG15. ISG15 drove the ISGylation and upregulation of c-Myc, which transcriptionally activated IGF2BP2. Additionally, overexpressed ISG15 reversed the effects of IGF2BP2 knockdown and promoted the proliferation of KGN.</p><p><strong>Conclusion: </strong>In summary, IGF2BP2-mediated m6A modification and upregulation of ISG15 contributes to excessive proliferation of GCs via mediating ISGylation of c-Myc. Moreover, IGF2BP2/ISG15/c-Myc axis forms a positive feedback loop to promote the progression of PCOS. These findings may provide novel therapeutic strategies for PCOS treatment.</p>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":" ","pages":"112666"},"PeriodicalIF":3.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145176859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Perinatal exposure to BPA leads to pronounced prostatic morphophysiological disorders in a rodent model of induced hyperplasia","authors":"Stella Bicalho-Silva ,&nbsp;Vitor Grigio ,&nbsp;Thalles Fernando Rocha Ruiz ,&nbsp;Marília de Freitas Calmon ,&nbsp;Paula Rahal ,&nbsp;Sebastião Roberto Taboga ,&nbsp;Fernanda Cristina Alcântara dos Santos ,&nbsp;Patrícia Simone Leite Vilamaior","doi":"10.1016/j.mce.2025.112664","DOIUrl":"10.1016/j.mce.2025.112664","url":null,"abstract":"<div><div>Bisphenol A (BPA) is a ubiquitous endocrine disruptor potentially harmful to male reproductive health. We aimed to investigate the impacts of perinatal exposure to a historically relevant and realistic dose of BPA on the ventral prostate under normal conditions and with prostatic hyperplasia in Mongolian gerbils (<em>Meriones unguiculatus</em>). Females were exposed to BPA (50 μg/kg/day) during gestation and lactation. The F1 male offspring were maintained until adulthood and subsequently treated with testosterone to induce prostatic hyperplasia. Morphological, molecular, and hormonal parameters were assessed on the ventral prostate. Testosterone-supplemented gerbils showed increased epithelium height and smooth muscle layer thickness. In the context of hyperplasia, perinatal exposure to BPA led to the onset of severe histopathologies (e.g., prostatic intraepithelial neoplasia, adenocarcinoma, and microacini), associated with increased cell proliferation. Perinatal BPA-exposed gerbils with prostatic hyperplasia showed increased pro-inflammatory markers (e.g., IL-6, COX-2, and F4/80), followed by a reduction in IL-10 protein levels. Regarding the steroid receptors, gerbils from this group presented a decrease in AR, followed by an increase in epithelial ERα expression. Molecularly, ERβ protein levels were higher in the prostate of perinatally exposed to BPA or testosterone-supplemented gerbils. Moreover, serum testosterone and estradiol levels increased after testosterone supplementation, whereas the T/E2 ratio increased in gerbils exposed to both treatments. Overall, the current study presents novel and comprehensive data on the life-long morphophysiological disorders caused by perinatal exposure to BPA on the ventral prostate of gerbils, highlighting the pronounced impacts observed in the context of hyperplasia.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"610 ","pages":"Article 112664"},"PeriodicalIF":3.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145150096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Notch signaling modulates Fgf23 expression through crosstalk with hypoxia and PTH pathways in osteogenic cells","authors":"Yoshihiro Tamamura ,&nbsp;Kenta Terai ,&nbsp;Akira Yamaguchi","doi":"10.1016/j.mce.2025.112663","DOIUrl":"10.1016/j.mce.2025.112663","url":null,"abstract":"<div><div>Fibroblast growth factor 23 (Fgf23) is produced by bone and functions primarily as a phosphaturia hormone. We previously reported that overexpression of the Notch intracellular domain (NICD) in osteogenic cells enhances Fgf23 expression in association with osteomalacia <em>in vivo</em>. Here, we investigated the underlying mechanisms using osteogenic cell lines UMR-106 and IDG-SW3 cells. NICD overexpression increased <em>Fgf23</em> levels in both cell types. Manipulating RBPJ-κ activity, either a dominant-negative or constitutively active form, revealed that Notch-mediated <em>Fgf23</em> expression is dependent on RBPJ-κ. Treatment with iron chelator Desferrioxamine (DFO) upregulated <em>Fgf23</em> expression, which was abolished by dominant-negative RBPJ-κ overexpression. This effect was partially attenuated by short hairpin RNA (shRNA) targeting hypoxia-inducible factor (<em>HIF</em>)-2α, but not <em>HIF-1</em>α. DFO treatment also increased expression of Notch1 protein, but not Notch2 and Nocth3, in parallel with upregulation of the Notch target mRNAs, <em>Hes1</em> and <em>Hey1</em>. In addition, DFO elevated the expression of γ<strong><em>-</em></strong>secretase subunits, whereas a γ<strong>-</strong>secretase inhibitor suppressed DFO-induced increases in Notch1 and Fgf23 levels, suggesting that increased γ<strong><em>-</em></strong>secretase expression promotes Notch processing. Moreover, Notch signaling exerted an additive stimulatory effect on parathyroid hormone (PTH)-induced <em>Fgf23</em> expression, at least in part through interaction with the protein kinase A (PKA) pathway. Co-immunoprecipitation assays revealed a physical interaction between NICD and CREB period Collectively, these findings demonstrate that Notch signaling regulates Fgf23 expression through crosstalk with hypoxic and PTH pathways, providing novel insights into Fgf23 regulation and identifying potential therapeutic targets for Fgf23-related disorders.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"610 ","pages":"Article 112663"},"PeriodicalIF":3.6,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advanced maternal age induced altered FoxO1 activation and cellular senescence in early placenta development in rats","authors":"María Laura Leonardi ,&nbsp;Alejandro Ranieri ,&nbsp;Cintia Romina Gatti ,&nbsp;Evangelina Capobianco ,&nbsp;Alicia Jawerbaum ,&nbsp;Romina Higa","doi":"10.1016/j.mce.2025.112662","DOIUrl":"10.1016/j.mce.2025.112662","url":null,"abstract":"<div><h3>Introduction</h3><div>Advanced maternal age (AMA) is associated with increased risks of adverse pregnancy outcomes partly due to placental dysfunction; however, the underlying mechanisms remain poorly understood. This study aimed to investigate early placental development in AMA pregnancies, focusing on FoxO1 activation and its role in cellular senescence and oxidative stress.</div></div><div><h3>Methods</h3><div>Three-month-old (Control) and 10-month-old (AMA) Wistar rats were mated with young males. On day 12 of pregnancy, FOXO1 activity and the expression of its target genes, oxidative status and morphometry were evaluated in the decidua and developing placenta.</div></div><div><h3>Results</h3><div>AMA rats exhibited a reduced number of implantation sites, fewer viable embryos, and decreased embryonic crown-rump length, indicating restricted growth. Markers of oxidative stress were increased in the decidua. At the molecular level, FOXO1 phosphorylation was reduced in the decidua, suggesting increased FOXO1 activation, whereas in the developing placenta, FOXO1 phosphorylation was elevated, indicating its inactivation. SGK1, a kinase that regulates FOXO1 phosphorylation, showed decreased phosphorylation in the decidua of AMA rats. Moreover, the senescence markers <em>Cdkn1a</em> (P21) and <em>Cdkn2a</em> (P16), known FOXO1 target genes, were upregulated in the decidua and downregulated in the developing placenta. These changes were associated with impaired cell proliferation in the decidua and a reduced syncitiotrophoblast layer in the developing placenta.</div></div><div><h3>Conclusion</h3><div>These findings highlight the differential regulation of FOXO1 in the decidua and placenta during AMA pregnancies. Increased FOXO1 activity in the decidua, likely driven by oxidative stress, and reduced SGK1 phosphorylation, may impair decidual function and contribute to altered placenta development with reduced FOXO1 activity.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"610 ","pages":"Article 112662"},"PeriodicalIF":3.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145113819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nrf2/Bach1 axis regulates redox homeostasis and energy metabolism to optimize Sertoli cell-mediated efferocytosis","authors":"Di Wu ,&nbsp;Kejia Zhang ,&nbsp;Jiachen Tan ,&nbsp;Faheem Ahmed Khan ,&nbsp;Chunjie Huang ,&nbsp;Fei Sun","doi":"10.1016/j.mce.2025.112661","DOIUrl":"10.1016/j.mce.2025.112661","url":null,"abstract":"<div><div>Efferocytosis is energy-consuming, and continuous efferocytosis imposes metabolic burdens on the phagocytes. Sertoli cells (SCs) are specialized phagocytes in the testis for efferocytosis of non-viable germ cells and residual bodies. What remains elusive is how SCs integrate metabolic adaptations in response to efferocytosis. Here, we identify the Nrf2/Bach1 axis as an important molecular machinery of SC-mediated efferocytosis. Nrf2 activation during efferocytosis stabilizes Bach1 expression. Nrf2 activation or Bach1 overexpression promotes SC-mediated efferocytosis, while the opposite phenotype is incurred by Nrf2 inactivation or Bach1 deficiency, with oxidative stress being a contributing factor. Beyond experiencing attenuated glucose uptake and ATP production, Bach1-deficient SCs exhibit a reduced NAD⁺/NADH ratio, and restraining NAD⁺ consumption by inhibiting serine biosynthesis rescues their impaired efferocytosis. We further observe an up-regulation of anti-ferroptotic genes in SCs upon Bach1 deficiency and demonstrate a protective role of ferroptosis in this scenario. We thus propose that redox homeostasis and energy metabolism lie at the nexus of the Nrf2/Bach1 axis in the regulation of SC-mediated efferocytosis. Our study explores the regulatory role of the Nrf2/Bach1 axis in SC-mediated efferocytosis, which will lead to a better appreciation of SCs in male reproductive health.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"610 ","pages":"Article 112661"},"PeriodicalIF":3.6,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ox-LDL-stimulated macrophage-derived exosomes regulate adipose tissue remodeling and promote the progression of atherosclerosis","authors":"Xiaoyu Liu ,&nbsp;Guoyan Xu ,&nbsp;Yunlu Xu ,&nbsp;Yuling Xu","doi":"10.1016/j.mce.2025.112660","DOIUrl":"10.1016/j.mce.2025.112660","url":null,"abstract":"<div><h3>Background</h3><div>Atherosclerosis (AS) is a chronic vascular disease, and perivascular adipose tissue dysfunction is an important cause of the arterial plaque formation involved. However, the underlying mechanism has not been fully elucidated. The aim of this study was to investigate the mechanism of oxidized low-density lipoprotein (ox-LDL) stimulation of macrophage-derived exosomes in the development of AS.</div></div><div><h3>Methods</h3><div>We isolated exosomes from ox-LDL-treated macrophages and injected them into Western diet-fed ApoE^−/− mice. We assessed AS, lipid metabolism, and endothelial function by histology, ELISA, qPCR, and western blotting, and examined BMP7 and OPA1 regulation in brown fat and vascular endothelium.</div></div><div><h3>Results</h3><div>Macrophage-derived exosomes were extracted, and their size was determined by transmission electron microscopy. Additionally, CD9, CD63, and TSG101 protein expression within these macrophages was determined. Compared with the control group, the exosomes group showed increased expression of AP2 and PPAR and decreased expression of UCP-1, PGC-1α, and BMP7. Furthermore, when BMP7 was knocked down, the expression of the lipid metabolites FASN, SCD1, HSL, and ATGL as well as of OPA1 decreased. In an ApoE^−/− mouse model, compared to the control group, increased arterial plaques and plaque lesion formation were observed in the exosome group, along with elevated expression of the lipid metrics TC, TG, LDL-C, and HDL-C and significant increases in the expression of the proinflammatory factors VCAM1, ICAM1, MCP-1, and IL-6. Consequently the progression of AS was aggravated in this group.</div></div><div><h3>Conclusions</h3><div>This study demonstrated that ox-LDL stimulated exosome secretion from macrophages, accelerating the AS process. It also showed that, mechanistically, BMP7 regulates the expression of OPA1 and affects the normal lipid metabolism, thereby accelerating AS.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"609 ","pages":"Article 112660"},"PeriodicalIF":3.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Three-dimensional (3D) pancreatic β-cell models reveal insulin-secretion enhancing potential of green synthesized silver nanoparticles","authors":"Cigdem Aydin Acar ,&nbsp;Suray Pehlivanoglu","doi":"10.1016/j.mce.2025.112659","DOIUrl":"10.1016/j.mce.2025.112659","url":null,"abstract":"<div><div>This study synthesized silver nanoparticles using cherry stem aqueous extract (Cs-AgNPs) and evaluated their physicochemical properties, cytotoxic effects on pancreatic β-cell lines, antioxidant activity, and their potential to enhance insulin secretion in 3D pancreatic β-cell models. Cs-AgNPs were synthesized via a reaction between cherry stem extract and silver nitrate, confirmed through color change and UV–Vis spectrophotometry. Characterization using EDS, TEM, and XRD revealed spherical nanoparticles with a crystalline structure, sizes ranging from 10.93 to 31.18 nm, and an average size of 26.67 nm. Biological assessments showed dose-dependent cytotoxic effects on pancreatic β-cell lines, with reduced viability observed at ≥2 μg/mL for INS-1 cells and ≥5 μg/mL for RINm5F cells. Antioxidant activity was confirmed through ABTS assay, with an IC₅₀ value of 78.81 μg/mL. Functional studies on 3D pancreatic β-cell spheroids revealed a significant 1.6-fold increase in insulin secretion in RINm5F cells (p = 0.0166) and a modest 1.2-fold increase in INS-1 cells. The results highlight the antioxidant properties and insulin secretion enhancement potential of Cs-AgNPs, suggesting their promise for diabetes-related applications. Further research is recommended to explore their therapeutic benefits and expand their biomedical utility.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"609 ","pages":"Article 112659"},"PeriodicalIF":3.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of novel amino acid substituted and acylated spexin analogues on pancreatic beta-cell function, appetite and glucose homeostasis","authors":"Daniel M. Gallagher ,&nbsp;Md Zahidul Islam Khan ,&nbsp;Steven Patterson ,&nbsp;Finbarr P.M. O'Harte ,&nbsp;Nigel Irwin","doi":"10.1016/j.mce.2025.112657","DOIUrl":"10.1016/j.mce.2025.112657","url":null,"abstract":"<div><h3>Objective</h3><div>The neuropeptide spexin is recognised as a satiety-inducing hormone, but overall effects on metabolism are less characterised. Rapid enzymatic metabolism means elucidating biological effects of spexin is challenging, because the bioactive profile is short.</div></div><div><h3>Methods</h3><div>Therefore, in the present study, an Asp¹ for Asn¹ substituted spexin analogue, D¹Spx, alongside two related fatty acid derivatised analogues, (γGlu-Pal)-D¹Spx and (K¹¹γGlu-Pal)-D¹Spx, were synthesised and effects on pancreatic beta-cell secretory function and health investigated together with impact on appetite and glucose homeostasis in mice.</div></div><div><h3>Results</h3><div>Spexin immunoreactivity was initially confirmed in BRIN-BD11 beta-cells. Interestingly, like native spexin, D¹Spx was liable to plasma enzyme degradation, but the fatty acid derivatised molecules remained intact. None of the peptides augmented insulin secretion from BRIN-BD11 cells. Moreover, the spexin peptides inhibited alanine‐induced insulin secretion, with native spexin having no effect on intracellular calcium. However, all spexin peptides (10⁻⁸ and 10⁻⁶ M) promoted beta-cell proliferation, whilst native spexin and (γGlu-Pal)-D¹Spx protected against cytokine-induced beta-cell apoptosis. When administered intraperitoneally to mice, spexin peptides lacked effects on appetite regulation, even at elevated doses of 250 nmol/kg. Following conjoint injection with saline, none of the spexin peptides affected blood glucose levels barring a negligible increase by D¹Spx. When administered together with glucose, (γGlu-Pal)-D¹Spx slightly increased blood glucose at 30 min post-injection, but there was no overall difference between the spexin peptides when compared to glucose alone.</div></div><div><h3>Conclusions</h3><div>Acylation creates stable spexin analogues with similar bioactivity as native spexin, including promotion of beta-cell proliferation and partial protection against apoptosis.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"609 ","pages":"Article 112657"},"PeriodicalIF":3.6,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145070028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}