Pub Date : 2025-09-16DOI: 10.1016/j.mce.2025.112660
Xiaoyu Liu , Guoyan Xu , Yunlu Xu , Yuling Xu
Background
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.
Methods
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.
Results
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.
Conclusions
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.
{"title":"Ox-LDL-stimulated macrophage-derived exosomes regulate adipose tissue remodeling and promote the progression of atherosclerosis","authors":"Xiaoyu Liu , Guoyan Xu , Yunlu Xu , 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<sup>−/−</sup> 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<sup>−/−</sup> 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}
Pub Date : 2025-09-16DOI: 10.1016/j.mce.2025.112659
Cigdem Aydin Acar , Suray Pehlivanoglu
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.
{"title":"Three-dimensional (3D) pancreatic β-cell models reveal insulin-secretion enhancing potential of green synthesized silver nanoparticles","authors":"Cigdem Aydin Acar , 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 IC<sub>50</sub> 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}
Pub Date : 2025-09-13DOI: 10.1016/j.mce.2025.112657
Daniel M. Gallagher , Md Zahidul Islam Khan , Steven Patterson , Finbarr P.M. O'Harte , Nigel Irwin
Objective
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.
Methods
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.
Results
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.
Conclusions
Acylation creates stable spexin analogues with similar bioactivity as native spexin, including promotion of beta-cell proliferation and partial protection against apoptosis.
{"title":"Impact of novel amino acid substituted and acylated spexin analogues on pancreatic beta-cell function, appetite and glucose homeostasis","authors":"Daniel M. Gallagher , Md Zahidul Islam Khan , Steven Patterson , Finbarr P.M. O'Harte , 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 Asp<sup>1</sup> for Asn<sup>1</sup> substituted spexin analogue, D<sup>1</sup>Spx, alongside two related fatty acid derivatised analogues, (γGlu-Pal)-D<sup>1</sup>Spx and (K<sup>11</sup>γGlu-Pal)-D<sup>1</sup>Spx, 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, D<sup>1</sup>Spx 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<sup>−8</sup> and 10<sup>−6</sup> M) promoted beta-cell proliferation, whilst native spexin and (γGlu-Pal)-D<sup>1</sup>Spx 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 D<sup>1</sup>Spx. When administered together with glucose, (γGlu-Pal)-D<sup>1</sup>Spx 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}
<div><div>Over the past few decades, a significant change globally in sugar intake has coincided with a rising incidence of male infertility, which is now a major public health concern. Diets rich in fructose have been implicated in both male infertility and increased susceptibility to metabolic disorders, such as obesity, diabetes, and related heart problems. While fructose is known to be present in seminal fluid and crucial for sperm motility, the precise role of fructose in testicular function remains largely unknown.</div><div>GLUT5 is an exclusive fructose transporter essential for dietary fructose uptake in the intestine. It is also expressed mainly in germ and Leydig cells. We recently revealed that disrupting the <em>Glut5</em> gene in male mice impairs spermatogenesis and steroidogenesis. However, its specific role within Leydig cells remains unexplored. Therefore, we investigated its role by inhibiting GLUT5 in a murine Leydig cell line (mLTC-1) using a specific inhibitor of GLUT5, MSNBA, combined with a multi-omics approach.</div><div>Exposing mLTC-1 cells to MSNBA reduced the intracellular fructose content, limited cell proliferation, and enhanced progesterone and androgens production (Δ4-androstenedione and testosterone). The latter was associated with the upregulation of two genes and proteins involved in steroidogenesis, such as <em>Hsd3b</em> and steroidogenic acute regulatory protein (<em>StAR</em>). GLUT5 inhibition in mLTC-1 cells also modified lipid and carbohydrate metabolism. Lipidomic analysis showed decreased cholesterol esters and a shift in the ratio of polyunsaturated fatty acids (PUFAs) to monounsaturated fatty acids (MUFAs). These lipid changes correlated with alterations in the expression of mRNA-encoding enzymes involved in lipogenesis, such as ELOVL6. Metabolomics analysis showed a reduction in most glycolysis metabolites, except for pyruvate and lactate. However, pyruvate could conserve its level by a production through an amino acid pathway using the higher branched-chain amino acid content. Nevertheless, the activity of mitochondria measured by seahorse was not altered. The transcriptomic analysis performed by BRB-seq approach revealed an upregulation of several androgen-sensitive genes, such as <em>Akap5, Slc39a9,</em> an androgen receptor or lactate dehydrogenase A (<em>Ldha</em>), which produces lactate, and downregulation of several genes associated with the insulin pathway such as <em>Tsc2 or</em> the hexokinase <em>Hkdc1</em>.</div><div>In conclusion, GLUT5 supported fructose intake in the murine Leydig cell line mLTC-1, leading to a reduction in cell proliferation. The consequences of inhibition of GLUT5 led to an increase in fatty acids cell content, a perturbation in glycolysis and amino-acid metabolism but an enhanced androgen production. Since androgens regulate spermatogenesis, hyperandrogenism induced by a lower fructose content in Leydig cells may be a primary cause leading to the disruption of spe
{"title":"Inhibiting the fructose transporter GLUT5 boosts testosterone production in a murine mLTC-1 leydig cell line","authors":"Aikaterini Kallianioti , Guillaume Bourdon , Claire Chevaleyre , Christine Péchoux , Christelle Ramé , Jérôme Bourgeais , Olivier Hérault , Nancy Geoffre , Thomas Darde , Ingrid Plotton , Véronique Douard , Joëlle Dupont , Pascal Froment","doi":"10.1016/j.mce.2025.112658","DOIUrl":"10.1016/j.mce.2025.112658","url":null,"abstract":"<div><div>Over the past few decades, a significant change globally in sugar intake has coincided with a rising incidence of male infertility, which is now a major public health concern. Diets rich in fructose have been implicated in both male infertility and increased susceptibility to metabolic disorders, such as obesity, diabetes, and related heart problems. While fructose is known to be present in seminal fluid and crucial for sperm motility, the precise role of fructose in testicular function remains largely unknown.</div><div>GLUT5 is an exclusive fructose transporter essential for dietary fructose uptake in the intestine. It is also expressed mainly in germ and Leydig cells. We recently revealed that disrupting the <em>Glut5</em> gene in male mice impairs spermatogenesis and steroidogenesis. However, its specific role within Leydig cells remains unexplored. Therefore, we investigated its role by inhibiting GLUT5 in a murine Leydig cell line (mLTC-1) using a specific inhibitor of GLUT5, MSNBA, combined with a multi-omics approach.</div><div>Exposing mLTC-1 cells to MSNBA reduced the intracellular fructose content, limited cell proliferation, and enhanced progesterone and androgens production (Δ4-androstenedione and testosterone). The latter was associated with the upregulation of two genes and proteins involved in steroidogenesis, such as <em>Hsd3b</em> and steroidogenic acute regulatory protein (<em>StAR</em>). GLUT5 inhibition in mLTC-1 cells also modified lipid and carbohydrate metabolism. Lipidomic analysis showed decreased cholesterol esters and a shift in the ratio of polyunsaturated fatty acids (PUFAs) to monounsaturated fatty acids (MUFAs). These lipid changes correlated with alterations in the expression of mRNA-encoding enzymes involved in lipogenesis, such as ELOVL6. Metabolomics analysis showed a reduction in most glycolysis metabolites, except for pyruvate and lactate. However, pyruvate could conserve its level by a production through an amino acid pathway using the higher branched-chain amino acid content. Nevertheless, the activity of mitochondria measured by seahorse was not altered. The transcriptomic analysis performed by BRB-seq approach revealed an upregulation of several androgen-sensitive genes, such as <em>Akap5, Slc39a9,</em> an androgen receptor or lactate dehydrogenase A (<em>Ldha</em>), which produces lactate, and downregulation of several genes associated with the insulin pathway such as <em>Tsc2 or</em> the hexokinase <em>Hkdc1</em>.</div><div>In conclusion, GLUT5 supported fructose intake in the murine Leydig cell line mLTC-1, leading to a reduction in cell proliferation. The consequences of inhibition of GLUT5 led to an increase in fatty acids cell content, a perturbation in glycolysis and amino-acid metabolism but an enhanced androgen production. Since androgens regulate spermatogenesis, hyperandrogenism induced by a lower fructose content in Leydig cells may be a primary cause leading to the disruption of spe","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"610 ","pages":"Article 112658"},"PeriodicalIF":3.6,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145065021","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}
Pub Date : 2025-09-11DOI: 10.1016/j.mce.2025.112656
Pengtao Chen , Jinpeng Ruan , Fanzheng Xue , Xuejuan Dai , Chen Tang , Mingyue Chen , Nengming Xiao , Zhijian Cai , Chunyan Yang , Chengyong He , Wei Wang , Zhenghong Zuo
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates various biological processes, including xenobiotic metabolism, immune response, and reproduction. Although previous studies have shown that AHR plays a role in ovarian follicle development, the precise role of oocyte-expressed AHR in female reproduction remains unclear. In this study, oocyte-specific Ahr knockout (cKO) mice generated by crossing the Ahrflox/flox (Ahrfl/fl) and Gdf9-cre transgenic mouse strains were used to answer this open question. The cKO female mice exhibited a disrupted estrous cyclicity and subfertility. Histological analyses demonstrated that oocyte AHR loss reduces the number of primary follicles while increasing the number of secondary follicles and corpus lutea in mouse ovary. Hormonal analysis revealed decreased serum estradiol and follicle-stimulating hormone, indicating a disruption of the hypothalamic-pituitary-gonadal axis in cKO mice. TUNEL and Western blotting results demonstrate that deletion of oocyte AHR also results in increased apoptosis in ovarian granulosa cells (GCs), downregulated expression of Gdf9 and Bmp15 in oocytes, and disrupted bidirectional oocyte-GC communication. In conclusion, our findings reveal that the aryl hydrocarbon receptor plays a role beyond sensing environmental chemicals and endogenous compounds and underscore a critical role of oocyte-expressed Ahr in maintain follicle development, ovarian function, and female reproductive health.
{"title":"Oocyte-specific Ahr deletion disrupts folliculogenesis and female fertility in mice","authors":"Pengtao Chen , Jinpeng Ruan , Fanzheng Xue , Xuejuan Dai , Chen Tang , Mingyue Chen , Nengming Xiao , Zhijian Cai , Chunyan Yang , Chengyong He , Wei Wang , Zhenghong Zuo","doi":"10.1016/j.mce.2025.112656","DOIUrl":"10.1016/j.mce.2025.112656","url":null,"abstract":"<div><div>The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates various biological processes, including xenobiotic metabolism, immune response, and reproduction. Although previous studies have shown that AHR plays a role in ovarian follicle development, the precise role of oocyte-expressed AHR in female reproduction remains unclear. In this study, oocyte-specific <em>Ahr</em> knockout (cKO) mice generated by crossing the <em>Ahr</em> <sup><em>flox/flox</em></sup> (<em>Ahr</em> <sup><em>fl/fl</em></sup>) and <em>Gdf9-cre</em> transgenic mouse strains were used to answer this open question. The cKO female mice exhibited a disrupted estrous cyclicity and subfertility. Histological analyses demonstrated that oocyte AHR loss reduces the number of primary follicles while increasing the number of secondary follicles and corpus lutea in mouse ovary. Hormonal analysis revealed decreased serum estradiol and follicle-stimulating hormone, indicating a disruption of the hypothalamic-pituitary-gonadal axis in cKO mice. TUNEL and Western blotting results demonstrate that deletion of oocyte AHR also results in increased apoptosis in ovarian granulosa cells (GCs), downregulated expression of <em>Gdf9</em> and <em>Bmp15</em> in oocytes<em>,</em> and disrupted bidirectional oocyte-GC communication. In conclusion, our findings reveal that the aryl hydrocarbon receptor plays a role beyond sensing environmental chemicals and endogenous compounds and underscore a critical role of oocyte-expressed Ahr in maintain follicle development, ovarian function, and female reproductive health.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"609 ","pages":"Article 112656"},"PeriodicalIF":3.6,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058593","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}
Pub Date : 2025-09-04DOI: 10.1016/j.mce.2025.112655
John Dou , Soundara Viveka Thangaraj , Yiran Zhou , Vasantha Padmanabhan , Kelly Bakulski
Steroid hormones are integral to pregnancy and fetal development, regulating processes such as metabolism, inflammation, and immune responses. Excessive prenatal steroid exposure, through lifestyle choices or environmental chemicals, can lead to metabolic dysfunctions in offspring. The research focuses on how exposure to testosterone (T) and bisphenol A (BPA) affects the liver's DNA methylome, a key component of the epigenome influencing long-term health. Using Suffolk sheep, the study involved two cohorts: one exposed to prenatal-T and the other to prenatal-BPA. Whole genome bisulfite sequencing was employed to map DNA methylation across over 22 million CpG sites. Regions with p-value<10−4 and a magnitude of difference of at least 5 % methylation between groups were considered differentially methylated. Results demonstrated substantial differential methylation in the liver tissues due to both treatments, with prenatal-T causing unique epigenetic modifications distinct from those induced by prenatal-BPA. Specifically, prenatal-T treatment resulted in 53 differentially methylated regions (DMRs), of which 31 were located in gene regions, including exons. Prenatal-BPA exposure led to 32 DMRs, with 22 associated with gene regions. These modifications were associated with genes governing lipid and glucose metabolism, potentially underlying the observed metabolic disruptions such as insulin resistance and dyslipidemia. Pathway analysis revealed that genes differentially methylated due to prenatal-T were involved in cellular organization, while those affected by prenatal-BPA were enriched in signal regulation pathways. The findings underscore how prenatal exposure to steroid excess and steroid-mimics influence epigenetic landscapes, contributing to metabolic disease programming.
{"title":"Developmental programming: Differing impact of prenatal testosterone and prenatal bisphenol-A -treatment on hepatic methylome in female sheep","authors":"John Dou , Soundara Viveka Thangaraj , Yiran Zhou , Vasantha Padmanabhan , Kelly Bakulski","doi":"10.1016/j.mce.2025.112655","DOIUrl":"10.1016/j.mce.2025.112655","url":null,"abstract":"<div><div>Steroid hormones are integral to pregnancy and fetal development, regulating processes such as metabolism, inflammation, and immune responses. Excessive prenatal steroid exposure, through lifestyle choices or environmental chemicals, can lead to metabolic dysfunctions in offspring. The research focuses on how exposure to testosterone (T) and bisphenol A (BPA) affects the liver's DNA methylome, a key component of the epigenome influencing long-term health. Using Suffolk sheep, the study involved two cohorts: one exposed to prenatal-T and the other to prenatal-BPA. Whole genome bisulfite sequencing was employed to map DNA methylation across over 22 million CpG sites. Regions with p-value<10<sup>−4</sup> and a magnitude of difference of at least 5 % methylation between groups were considered differentially methylated. Results demonstrated substantial differential methylation in the liver tissues due to both treatments, with prenatal-T causing unique epigenetic modifications distinct from those induced by prenatal-BPA. Specifically, prenatal-T treatment resulted in 53 differentially methylated regions (DMRs), of which 31 were located in gene regions, including exons. Prenatal-BPA exposure led to 32 DMRs, with 22 associated with gene regions. These modifications were associated with genes governing lipid and glucose metabolism, potentially underlying the observed metabolic disruptions such as insulin resistance and dyslipidemia. Pathway analysis revealed that genes differentially methylated due to prenatal-T were involved in cellular organization, while those affected by prenatal-BPA were enriched in signal regulation pathways. The findings underscore how prenatal exposure to steroid excess and steroid-mimics influence epigenetic landscapes, contributing to metabolic disease programming.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"609 ","pages":"Article 112655"},"PeriodicalIF":3.6,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008373","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}
Pub Date : 2025-09-01DOI: 10.1016/j.mce.2025.112644
Lingjuan Wang, Sijin OuYang, Bin Li, Na Kong
RNA-binding proteins (RBPs) are critical regulators of post-transcriptional gene expression and RNA processing during mammalian oocyte development. SERPINE1 mRNA-binding protein 1 (SERBP1), a conserved RNA-binding protein (RBP), exhibits prominent expression in the female reproductive system and throughout oogenesis. Conditional deletion of Serbp1 using oocyte-specific Zp3/Gdf9-Cre drivers resulted in arrested oocyte growth, female infertility, and failure of blastocyst formation from two-cell embryos. Phenotypic analysis revealed spindle assembly defects, impaired asymmetric division, and compromised meiotic competence in oocytes. Notably, Serbp1 ablation also induced granulosa cell apoptosis and elevated Erk1/2 phosphorylation levels, indicating dysregulation of somatic microenvironment. Furthermore, conditional knockout mice exhibited prolonged diestrus cycles. Collectively, these findings demonstrate that SERBP1 coordinates essential RNA-regulatory functions for oocyte developmental competence through both cell-autonomous mechanisms and somatic-germline crosstalk.
{"title":"RNA binding protein SERBP1 is indispensable for oocyte development and maturation in mice.","authors":"Lingjuan Wang, Sijin OuYang, Bin Li, Na Kong","doi":"10.1016/j.mce.2025.112644","DOIUrl":"https://doi.org/10.1016/j.mce.2025.112644","url":null,"abstract":"<p><p>RNA-binding proteins (RBPs) are critical regulators of post-transcriptional gene expression and RNA processing during mammalian oocyte development. SERPINE1 mRNA-binding protein 1 (SERBP1), a conserved RNA-binding protein (RBP), exhibits prominent expression in the female reproductive system and throughout oogenesis. Conditional deletion of Serbp1 using oocyte-specific Zp3/Gdf9-Cre drivers resulted in arrested oocyte growth, female infertility, and failure of blastocyst formation from two-cell embryos. Phenotypic analysis revealed spindle assembly defects, impaired asymmetric division, and compromised meiotic competence in oocytes. Notably, Serbp1 ablation also induced granulosa cell apoptosis and elevated Erk1/2 phosphorylation levels, indicating dysregulation of somatic microenvironment. Furthermore, conditional knockout mice exhibited prolonged diestrus cycles. Collectively, these findings demonstrate that SERBP1 coordinates essential RNA-regulatory functions for oocyte developmental competence through both cell-autonomous mechanisms and somatic-germline crosstalk.</p>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":" ","pages":"112644"},"PeriodicalIF":3.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992903","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}
Pub Date : 2025-08-28DOI: 10.1016/j.mce.2025.112645
Haojie Li , Yaoting Xu , Xinyi Jiang , Jie Ren , Yulian Wang , Xiangzheng Zhang , Mengmeng Gao , Longsheng Zhang , Yue Wang , Zongze Li , Suwei Wang , Tianye Wang , Mengyi Wang , Chenghao Situ , Xuejiang Guo , Hui Zhu
Protein phosphorylation is an important post-translational modification that plays a critical regulatory role in meiosis. HASPIN, a kinase highly conserved from yeast to mammals, is required for male fertility. In this study, we found that the intrinsically disordered N-terminal domain of HASPIN is also required for this function. Mice with deletion of N-terminal amino acids (aa) 1-243 of HASPIN exhibited reduced testicular size, sperm count, and fertility. Using immunoprecipitation-mass spectrometry and phosphoproteomics analysis, we found that HASPIN could interact with AURKA and regulate its phosphorylation at T279 via its N-terminus. Taken together, our results suggest that the N-terminus of HASPIN regulates AURKA kinase activity to affect male fertility.
{"title":"The N-terminal region of HASPIN regulates phosphorylation of AURKA and meiotic progression in spermatocytes","authors":"Haojie Li , Yaoting Xu , Xinyi Jiang , Jie Ren , Yulian Wang , Xiangzheng Zhang , Mengmeng Gao , Longsheng Zhang , Yue Wang , Zongze Li , Suwei Wang , Tianye Wang , Mengyi Wang , Chenghao Situ , Xuejiang Guo , Hui Zhu","doi":"10.1016/j.mce.2025.112645","DOIUrl":"10.1016/j.mce.2025.112645","url":null,"abstract":"<div><div>Protein phosphorylation is an important post-translational modification that plays a critical regulatory role in meiosis. HASPIN, a kinase highly conserved from yeast to mammals, is required for male fertility. In this study, we found that the intrinsically disordered N-terminal domain of HASPIN is also required for this function. Mice with deletion of N-terminal amino acids (aa) 1-243 of HASPIN exhibited reduced testicular size, sperm count, and fertility. Using immunoprecipitation-mass spectrometry and phosphoproteomics analysis, we found that HASPIN could interact with AURKA and regulate its phosphorylation at T279 via its N-terminus. Taken together, our results suggest that the N-terminus of HASPIN regulates AURKA kinase activity to affect male fertility.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"609 ","pages":"Article 112645"},"PeriodicalIF":3.6,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144926158","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}
Pub Date : 2025-08-20DOI: 10.1016/j.mce.2025.112643
Michelle Berenice Vega Joubert , María Eugenia Oliva , Paola Ingaramo , María Eugenia D'Alessandro
Metabolic dysfunction-associated steatotic liver disease (MASLD) is recognized as the hepatic manifestation of Metabolic Syndrome. The aim of this work was to evaluate the effects of chia seed, rich in α-linolenic acid, on glucose tolerance, enzyme activities and transcription factors involved in gluconeogenesis, and key molecules in insulin signaling in sucrose-rich diet (SRD) fed rats. Male Wistar rats were fed a reference diet (RD) for 6 months or a SRD for 3 months. Then, the latter group was randomly divided into two subgroups. One subgroup continued receiving SRD for up to 6 months and the other was fed with a SRD where chia seed was incorporated as a source of dietary fat for the next 3 months (SRD + CHIA). The results showed that chia seed improved glucose tolerance, reversed the increase in PEPCK, FBPase, and Glucose-6-Pase, and reduced the Glucose-6-Pase/GK ratio. Additionally, chia seed improved tAMPK and pAMPK protein levels, while maintaining GLUT-2 protein levels similar to those in the RD group. Under insulin stimulation, p-AKT protein levels were higher in the SRD + CHIA group than in the unstimulated group. IRS-1 and PGC-1α protein expression levels were similar among the three experimental groups. Liver FOXO-1 mRNA expression was decreased in the SRD + CHIA group. Finally, chia seed increased the n-3/n-6 ratio in hepatic membrane phospholipids. The present study demonstrated that chia seed modulate multiple mechanisms that enhance glucose metabolism and insulin signaling in SRD fed rats. These effects are mediated, at least in part, by the enrichment of n-3 PUFAs in liver tissue.
{"title":"α-Linolenic acid rich-chia seed improves glucose tolerance, modulates gluconeogenic pathway and hepatic insulin signaling in an experimental model of metabolic syndrome","authors":"Michelle Berenice Vega Joubert , María Eugenia Oliva , Paola Ingaramo , María Eugenia D'Alessandro","doi":"10.1016/j.mce.2025.112643","DOIUrl":"10.1016/j.mce.2025.112643","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is recognized as the hepatic manifestation of Metabolic Syndrome. The aim of this work was to evaluate the effects of chia seed, rich in α-linolenic acid, on glucose tolerance, enzyme activities and transcription factors involved in gluconeogenesis, and key molecules in insulin signaling in sucrose-rich diet (SRD) fed rats. Male Wistar rats were fed a reference diet (RD) for 6 months or a SRD for 3 months. Then, the latter group was randomly divided into two subgroups. One subgroup continued receiving SRD for up to 6 months and the other was fed with a SRD where chia seed was incorporated as a source of dietary fat for the next 3 months (SRD + CHIA). The results showed that chia seed improved glucose tolerance, reversed the increase in PEPCK, FBPase, and Glucose-6-Pase, and reduced the Glucose-6-Pase/GK ratio. Additionally, chia seed improved tAMPK and pAMPK protein levels, while maintaining GLUT-2 protein levels similar to those in the RD group. Under insulin stimulation, p-AKT protein levels were higher in the SRD + CHIA group than in the unstimulated group. IRS-1 and PGC-1α protein expression levels were similar among the three experimental groups. Liver FOXO-1 mRNA expression was decreased in the SRD + CHIA group. Finally, chia seed increased the n-3/n-6 ratio in hepatic membrane phospholipids. The present study demonstrated that chia seed modulate multiple mechanisms that enhance glucose metabolism and insulin signaling in SRD fed rats. These effects are mediated, at least in part, by the enrichment of n-3 PUFAs in liver tissue.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"609 ","pages":"Article 112643"},"PeriodicalIF":3.6,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144907880","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}
Identifying the mechanisms and molecular factors that enhance beta-cell mass is crucial for developing strategies to combat diabetes, as beta-cell mass declines with disease progression. Recent research has indicated an increase in beta-cell proliferation and a significant islet expansion around the weaning period in mice. This study aims to identify transcripts associated with changes in the islets around weaning—a physiological stage previously unexplored in islets. A ribonucleic acid (RNA) sequencing analysis of the transcriptome was performed at four key time points: the end of lactation, when beta-cell proliferation increases; the day of weaning, when the hormonal and metabolic environment transitions from lactation to the non-lactating stage; the third day post-weaning, when islet area peaks, as observed in our prior studies; and in age-matched female control mice. The results revealed dynamic transcriptomic changes. The messenger ribonucleic acid (mRNA) expression levels of genes regulated by prolactin, including its receptor, signaling inhibitor Cish, tryptophan hydroxylase, and osteoprotegerin, increased during lactation and subsequently declined. Plasma prolactin concentrations rose during lactation, but plasma osteoprotegerin levels remained stable across groups. Notably, no changes were observed in known prolactin-regulated cyclins that positively influence the cell cycle, such as Ccna2, Ccnb1, and Ccnb2. However, a decrease in the expression of Cdkn1a, a negative regulator of the cell cycle, was noted. Surprisingly, microscopy analysis indicated increased apoptosis markers in islet peripheral cells that were negative for insulin immunostaining. This study is the first to identify transcriptomic and cellular changes around weaning, offering new insights into islet mass plasticity.
{"title":"Transcriptomic modifications in maternal pancreatic islets during the period around weaning in mice","authors":"Xadeni Burgos-Gamez , Paulina Morales-Castillo , Alain Hernández-Vázquez , Karina Pastén-Hidalgo , Francisco García-Vázquez , Cristina Fernandez-Mejia","doi":"10.1016/j.mce.2025.112642","DOIUrl":"10.1016/j.mce.2025.112642","url":null,"abstract":"<div><div>Identifying the mechanisms and molecular factors that enhance beta-cell mass is crucial for developing strategies to combat diabetes, as beta-cell mass declines with disease progression. Recent research has indicated an increase in beta-cell proliferation and a significant islet expansion around the weaning period in mice. This study aims to identify transcripts associated with changes in the islets around weaning—a physiological stage previously unexplored in islets. A ribonucleic acid (RNA) sequencing analysis of the transcriptome was performed at four key time points: the end of lactation, when beta-cell proliferation increases; the day of weaning, when the hormonal and metabolic environment transitions from lactation to the non-lactating stage; the third day post-weaning, when islet area peaks, as observed in our prior studies; and in age-matched female control mice. The results revealed dynamic transcriptomic changes. The messenger ribonucleic acid (mRNA) expression levels of genes regulated by prolactin, including its receptor, signaling inhibitor <em>Cish</em>, tryptophan hydroxylase, and osteoprotegerin, increased during lactation and subsequently declined. Plasma prolactin concentrations rose during lactation, but plasma osteoprotegerin levels remained stable across groups. Notably, no changes were observed in known prolactin-regulated cyclins that positively influence the cell cycle, such as <em>Ccna2</em>, <em>Ccnb1</em>, and <em>Ccnb2</em>. However, a decrease in the expression of <em>Cdkn1a</em>, a negative regulator of the cell cycle, was noted. Surprisingly, microscopy analysis indicated increased apoptosis markers in islet peripheral cells that were negative for insulin immunostaining. This study is the first to identify transcriptomic and cellular changes around weaning, offering new insights into islet mass plasticity.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"609 ","pages":"Article 112642"},"PeriodicalIF":3.6,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855800","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}
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