Molecular And Cellular Endocrinology[JOURNAL]
Sun
200 papers
Bisphenol S chronic exposure impairs pancreatic function and induces obesity in male mice independently of high-fat diet intake.
Alves APP, Barreto-Reis E, Gouvêa de Luca B … +12 more , Carvalho TS, de Andrade GP, Sepúlveda-Fragoso V, Alexandre-Santos B, Proença Souza AB, de Souza Vieira ALL, Stockler-Pinto MB, Frantz EDC, Machado-Santos C, Pires de Carvalho D, Miranda-Alves L, Magliano DC
Mol Cell Endocrinol · 2026 Jan · PMID 41110818 · Publisher ↗
Obesity is a chronic inflammatory disease linked to several comorbidities. Bisphenol S (BPS), a BPA substitute, is an endocrine disruptor that may impact pancreas and white adipose tissue (WAT) morphology and metabolism....
Obesity is a chronic inflammatory disease linked to several comorbidities. Bisphenol S (BPS), a BPA substitute, is an endocrine disruptor that may impact pancreas and white adipose tissue (WAT) morphology and metabolism. This study investigated the obesogenic effects of BPS, alone or with a high-fat diet (HF), on pancreas and epididymal WAT (eWAT) morphology. Male C57BL/6 mice (n = 12) were divided into four groups: standard chow (SC), standard chow + BPS (SCB), HF diet (HF), and HF diet + BPS (HFB). BPS exposure (25 μg/kg/day) occurred via drinking water for 12 weeks. Body mass, pancreas and eWAT weights, plasma parameters, insulin resistance, morphometry, stereology, eWAT mRNA levels and protein expression of ER stress markers were analyzed. All interventions increased body and tissue masses, pancreatic α-cells and β-cells, Pparγ mRNA level, GRP78, ERO1 and ATF4 protein expression, epididymal adipocyte size, and insulin, glucose, and cholesterol levels. HF and HFB groups also showed increased Grp78 mRNA level, p-eIF2α and CHOP expression, pancreatic islet diameter, inflammatory infiltrate, and triacylglycerol levels. BPS combined with HF diet worsened insulin resistance. These findings suggest that BPS has obesogenic activity, affecting metabolism and remodeling pancreatic islets and eWAT, even at low doses, independently of a HF diet.
Raman spectroscopic characterization of liver steatosis and fibrosis in a 2D and 3D in vitro thyroxine-treated hypothyroid cellular model.
Maurotti S, Scopacasa B, Scionti F … +9 more , Pujia R, Frosina M, Mirarchi A, Geirola N, Mare R, Montalcini T, Candeloro P, Tirinato L, Pujia A
Mol Cell Endocrinol · 2026 Jan · PMID 41109556 · Publisher ↗
Primary hypothyroidism has been associated with metabolic dysfunction-associated steatotic liver disease and, potentially, increased liver fibrosis risk. Although T4-analog drug is one of the standard treatments, its mol...
Primary hypothyroidism has been associated with metabolic dysfunction-associated steatotic liver disease and, potentially, increased liver fibrosis risk. Although T4-analog drug is one of the standard treatments, its molecular effects on the liver are not fully understood. To elucidate drug-induced hepatic metabolic changes, chronic human 2D and 3D hypothyroid models were developed. The effects of T4 were assessed by Raman spectroscopy and complementary biological techniques to observe lipid and fibrotic changes. In vitro chronic hypothyroidism caused lipid droplet (LDs) accumulation in liver cells which was unaffected by T4 therapy. Notably, TSH and T4 influenced TG fatty acid saturation in different ways: T4-exposed cells accumulated monounsaturated fatty acids at the expense of saturated fatty acids. In the case of liver fibrosis, TSH treatment activated hepatic stellate cells as evidenced by increased collagen secretion and decreased LD content, regardless of T4 co-treatment. Data confirmed that TSH induced pro-inflammatory changes leading to higher inflammasome levels in a 3D liver model. These findings indicate the detrimental effects of elevated TSH levels, and it is worth noting that T4 administration does not reverse the excess of hepatic lipid overload but has the ability to alter its lipid composition. Furthermore, T4 administration did not reverse TSH-induced hepatic fibrogenesis in the hypothyroid cell models. Because micro-Raman spectroscopy is currently restricted to 2D/3D in-vitro systems, further validation in intact tissue and in vivo is warranted. In conclusion, our results highlight the importance of further research into the molecular pathways associated with chronic liver injury in patients with chronic hypothyroidism.
The importance of CTGF regulation by FSH, IGF1, and estradiol in bovine granulosa cells.
de Andrade LG, Portela VM, Aires KV … +5 more , Jakuc N, da Silva AP, Antoniazzi AQ, Gonçalves PBD, Zamberlam G
Mol Cell Endocrinol · 2026 Jan · PMID 41109555 · Publisher ↗
During the ovarian follicle growth of monovulatory species, the dominant follicle is characterized by a greater capacity for estradiol (E2) production mainly due to an increased granulosa cell (GC) CYP19A1 transcription...
During the ovarian follicle growth of monovulatory species, the dominant follicle is characterized by a greater capacity for estradiol (E2) production mainly due to an increased granulosa cell (GC) CYP19A1 transcription level. The connective tissue growth factor (CTGF) has emerged as a potential novel and important player in the modulation of CYP19A1 expression in this cell type. To gain insight into how CTGF is regulated in GC and to better understand its role during GC differentiation into a more estrogenic phenotype, we have performed in the present study a series of experiments employing bovine GC cultures. We demonstrate herein that CTGF mRNA levels are downregulated by insulin-like growth factor 1 (IGF1) and E2, two critical regulators of follicle dominance establishment in vivo. In turn, CTGF suppresses CYP19A1 mRNA levels in bovine GC both in the presence or absence of FSH or IGF1, through a mechanism that seems to involve altering the phosphorylation pattern of AKT and the modulation of NR5A2, a critical transcription factor of CYP19A1. Overall, our study indicates that CTGF downregulation in GC may represent a critical step for enabling the increased CYP19A1 transcriptional activity of the dominant follicle in cattle.
Periostin-positive stellate cells associated with perineural invasion in pancreatic adenocarcinoma.
de Carvalho Fraga CA, Santos CRES, Lima KFB … +14 more , Rodrigues GHB, Porto CCFN, de Menezes MN, da Silva GVL, Simizo A, da Silva Fernandes Duarte AK, de Oliveira Baggio JA, Rodrigues AKBF, de Farias KF, de Souza Figueiredo EVM, de Sales Marques C, Uson Junior PLS, Campregher PV, Nakaya HI
Mol Cell Endocrinol · 2026 Jan · PMID 41106801 · Publisher ↗
Perineural invasion (PNI) is a hallmark of pancreatic ductal adenocarcinoma (PDAC) associated with poor prognosis. Despite its clinical significance, the specific cellular and molecular mechanisms driving PNI in PDAC rem...
Perineural invasion (PNI) is a hallmark of pancreatic ductal adenocarcinoma (PDAC) associated with poor prognosis. Despite its clinical significance, the specific cellular and molecular mechanisms driving PNI in PDAC remain poorly defined. In this study, we analyzed transcriptomic data from approximately 60,000 single cells across 24 PDAC biopsy specimens to characterize the cellular composition and signaling networks associated with PNI. We found that pancreatic stellate cells (PSCs) expressing high levels of Periostin (POSTN), collagens, and metalloproteinases are enriched in PNI-positive samples, suggesting an active role in extracellular matrix remodeling and tumor invasion. Spatial transcriptomics revealed that these POSTN + PSCs are located adjacent to tumor cells in invasive regions but are more distant in non-invasive samples. Invasive tumors show a coordinated expression pattern involving ANXA1 in tumor cells, SPP1 and PLAU in PSCs, and their receptors in myeloid cells, supporting a signaling axis that promotes perineural invasion. This spatial arrangement indicates that POSTN + PSCs are not merely bystanders but active participants in driving tumor infiltration and perineural dissemination. Together, these findings reveal coordinated multicellular programs that underlie tumor invasion and spread in PDAC, offering new insights into its aggressive biology.
Polycystic ovary syndrome: Long-term effects on fertility and uterine lesions.
Bracho GS, Acosta MV, Iñiguez I … +3 more , Altamirano GA, Kass L, Bosquiazzo VL
Mol Cell Endocrinol · 2026 Jan · PMID 41101377 · Publisher ↗
Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. In this study, we aimed to investigate the long-term effects of PCOS. We assessed fertility at 3 months of age and uterine his...
Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. In this study, we aimed to investigate the long-term effects of PCOS. We assessed fertility at 3 months of age and uterine histomorphology along with endocrine status at 6 and 24 months of age in an experimental model. PCOS was induced in female Wistar rats from 21 to 40 days of age by subcutaneous injection of dehydroepiandrosterone (6 mg/100 g bw). After treatment, rats were separated into groups and euthanized on gestational day 18 (GD18), 6 months and 24 months of age. Fertility test was performed on GD18 and no changes were observed in the PCOS rats. At 6 months of age, PCOS rats showed uterine lesions associated with a higher serum 17-β estradiol (E2)/progesterone (P4) ratio. At 24 months of age, PCOS rats had a higher incidence of luminal hyperplasia and a greater number of glands with metaplasia and conglomerates of glands. This was associated with increased serum E2/P4 ratio, uterine steroidogenic enzymes (steroid sulfatase, 5α-reductase type I) and estrogen receptor alpha expression. In addition, an increased infiltration of eosinophils in the uterus was observed, suggesting an estrogenic effect. These results show that PCOS induced early in life alters the uterine endocrine status in the long term, suggesting increased uterine exposure and sensitivity to estrogens. Taken together, these findings may explain the increased incidence/multiplicity of uterine lesions observed in the PCOS group.
Interrelationship between alcohol consumption, overnutrition, and pharmacotherapy for liver steatosis: Considerations and proposals.
Valenzuela R, Farías C, Muñoz Y … +2 more , Zúñiga-Hernández J, Videla LA
Mol Cell Endocrinol · 2026 Jan · PMID 41076005 · Publisher ↗
Alcoholism and overnutrition both contribute to the development of hepatic steatosis in humans. In alcoholic liver disease, steatosis is driven by (i) alcohol oxidation via alcohol dehydrogenase (ADH), which increases th...
Alcoholism and overnutrition both contribute to the development of hepatic steatosis in humans. In alcoholic liver disease, steatosis is driven by (i) alcohol oxidation via alcohol dehydrogenase (ADH), which increases the NADH/NAD ratio, and (ii) induction of cytochrome P450 2E1 (CYP2E1), which elevates oxidative stress. Both pathways generate toxic acetaldehyde. Overnutrition is characterized by excessive energy intake, high consumption of refined carbohydrates and saturated fatty acids (FAs), and low intake of dietary fiber, fruits, vegetables, and n-3 polyunsaturated fatty acids (n-3 PUFAs). The increased NADH/NAD ratio inhibits the Krebs cycle and FA β-oxidation, redirecting acetyl-CoA toward de novo lipogenesis. This process is mainly regulated by insulin-mediated activation of sterol regulatory element-binding protein-1c (SREBP-1c) and suppression of peroxisome proliferator-activated receptor-α (PPAR-α) related to n-3 PUFA depletion, which further impairs FA β-oxidation and upregulates citrate carrier expression, promoting lipogenesis. Chronic exposure to either alcohol or overnutrition independently promotes steatosis; however, co-exposure significantly exacerbates the condition, as shown in emerging preclinical studies. In humans, the relationship remains complex and inconsistent. Several anti-steatotic agents have been explored, including n-3 PUFAs, vitamins (E, C, D), polyphenols (curcumin, resveratrol, anthocyanins), anti-craving medications (disulfiram, naltrexone, nalmefene, acamprosate), and appetite suppressants (e.g., topiramate), as well as combination therapies such as naltrexone with bupropion. Despite the range of available interventions, inconsistent outcomes in past clinical trials hinder the establishment of standardized protocols. This underscores the urgent need to investigate synergistic effects of combined risk factors to better guide therapeutic strategies for hepatic steatosis prevention and reversal, and inform the health professionals on these aspects.
Aerobic exercise attenuates intramyocellular lipid accumulation by upregulating vitamin D receptor.
Wang K, Zhang JH, Cui XN … +6 more , Niu YJ, Liu JJ, Lu SQ, Liu XM, Zhu Z, Cao ZB
Mol Cell Endocrinol · 2026 Jan · PMID 41076004 · Publisher ↗
Vitamin D deficiency is a global public health problem associated with intramyocellular lipid (IMCL) accumulation, leading to insulin resistance. Aerobic exercise improves lipid metabolism, insulin sensitivity, and vitam...
Vitamin D deficiency is a global public health problem associated with intramyocellular lipid (IMCL) accumulation, leading to insulin resistance. Aerobic exercise improves lipid metabolism, insulin sensitivity, and vitamin D levels. However, the mechanism by which aerobic exercise regulates IMCL remains unclear. C57BL/6J male mice were randomly divided into four groups: control (CON), vitamin D-deficient (VDD), control exercise, and vitamin D-deficient exercise (VDDE). Moreover, we generated skeletal muscle-specific vitamin D receptor (VDR)-knockout (mVDR) mice and classified them into four groups: VDR control (FC); mVDR; exercise and VDR control; and exercise and mVDR (emVDR). All exercise mice underwent a 12-week aerobic exercise program on a treadmill at speeds progressively increasing from 10 to 17 m/min. The VDD group mice exhibited decreased VDR expression, lipolysis factors (ATGL and Hormone-sensitive lipase (HSL)), and fatty acid oxidation (SIRT1 and PGC1α), and increased expression of lipid synthesis factors (DGAT1 and FATP1) compared with the CON group. Conversely, the VDDE group mice showed a significant increase in VDR, ATGL, HSL, SIRT1 and PGC1α expression, alongside a decrease in DGAT1, DGAT2, FATP1 and CD36 expression compared with the VDD group. Moreover, mVDR mice exhibited impaired lipid metabolism (FATP1, CD36, SREBP1C, DGAT1, DGAT2 and ATGL) and fatty acid oxidation (SIRT1 and PGC1α) compared with the FC group mice. However, emVDR mice did not show improved lipid metabolism or fatty acid oxidation related factors compared with mVDR mice. Therefore, aerobic exercise attenuates IMCL accumulation may by upregulating VDR associated with restored SIRT1/PGC1α signaling mediated lipid metabolism in skeletal muscle.
NMR and proteomic analysis of Cornus officinalis extract reveals abundance of 5-hydroxymethylfurfural and induced expression of Nrf2 and superoxide dismutase-2 in 1.1B4 human pancreatic β-cells and murine islets.
Fletcher JD, Maurer HL, Eschenfelder MA … +6 more , Smith BR, Nayakanti S, Guergues J, Wolf T, Stevens SM, Burkhardt BR
Mol Cell Endocrinol · 2026 Jan · PMID 41033431 · Full text
We aimed to identify and isolate the metabolically active compounds from Cornus officinalis (C. officinalis) that underlie the biological effects previously observed in our in vitro and in vivo studies. Our prior finding...
We aimed to identify and isolate the metabolically active compounds from Cornus officinalis (C. officinalis) that underlie the biological effects previously observed in our in vitro and in vivo studies. Our prior findings demonstrated that C. officinalis promoted activation of the Keap1/Nrf2 pathway in a pancreatic β-cell line and delayed the onset of type 1 diabetes (T1D) in non-obese diabetic (NOD) mice. To characterize the metabolically active compounds within C. officinalis, the concentrated extract was fractionated by column chromatography, and evaluated for their effect on β-cell metabolic activity and expression of Nrf2 targets such as heme oxygenase-1 (HO1) and superoxide dismutase 2 (SOD2). Highly concentrated compounds of interest within metabolically active fractions were isolated using high performance liquid chromatography (HPLC). Elucidation of a highly abundant compound within C. officinalis extract was identified by mass spectrometry and nuclear magnetic resonance (NMR) as 5-hydroxymethylfurfural (5-HMF) which was demonstrated by immunoblotting to significantly increase SOD2 expression. Quantitative proteomics was performed on 5-HMF treated murine non-obese diabetic (NOD) islets and revealed increased expression of Nrf2 and downstream targets such as SOD2, GSTA3, GSTA4 and GCLC. Our findings suggest that 5-HMF is a highly abundant and metabolically active compound within C. officinalis that stimulates partial activation of the Keap1/Nrf2 pathway.
Adenosine A2AR agonist blocks mesenteric lymphatic epithelium, adipose tissue and Treg cells links of metabolic dysfunction-associated steatotic liver disease mice.
Li TH, Yeh HY, Lin SW … +11 more , Huang YS, Zhuo ZW, Ma CC, Hsu TL, Wu WK, Tsai HC, Shen HC, Su CW, Yang YY, Lin HC, Hou MC
Mol Cell Endocrinol · 2025 Dec · PMID 41022170 · Publisher ↗
Recent studies in diet-induced obese mice indicate crosstalk among mesentery, spleen, serum, and liver metabolites. Observations include decreased expression of the adenosine A2A receptor (A2AR), mesenteric lymphatic hyp...
Recent studies in diet-induced obese mice indicate crosstalk among mesentery, spleen, serum, and liver metabolites. Observations include decreased expression of the adenosine A2A receptor (A2AR), mesenteric lymphatic hyperpermeability, and reduced Treg cell populations in splenic and adipose tissues in metabolic dysfunction-associated steatotic liver disease (MASLD). This study aims to investigate the mechanisms and effects of a four-week treatment with the A2AR agonist CGS21680 in mice on a high-fat, high-sucrose diet-induced MASLD. In MASLD mice, reduced levels of mesenteric A2AR and the lymphatic epithelial marker LYVE1 (lymphatic vessel endothelial hyaluronan receptor 1) are associated with decreased Treg and M2 phenotype markers, alongside increased permeability markers/permeability of mesenteric lymphatic epithelium. Furthermore, elevated levels of pro-inflammatory cytokines IL-6 and TNFα were observed in serum and tissue homogenates, correlating with reduced splenic Treg cell populations and increased inflammation and fibrosis in mesenteric and hepatic tissues. Chronic treatment with CGS21680 significantly reversed these pathological changes. Additionally, co-incubation of splenic Treg cells with CGS21680 mitigated apoptosis, cellular injury, and leakage in SVEC monolayers, thereby preserving their integrity. This treatment also led to reduced cytokine release and promoted a shift towards an M2 phenotype in RAW 264.7 macrophages. Overall, the A2AR agonist CGS21680 shows promise as a therapeutic agent to inhibit both adipose tissue inflammation and hepatic inflammation/fibrosis by disrupting pathogenic links between adipose tissue, mesenteric lymphatics, and splenic Treg cells in MASLD mice.
Endometrial cells and extracellular vesicles response to high body energy reserves in bovine: Insights into miRNA and mRNA regulation before embryo arrival.
Fontoura Saldanha S, Marins Bastos N, Germano Ferst J … +7 more , Silva Goulart R, Perecin Nociti R, Chiaratti MR, Camargo Dos Santos A, Vieira Meirelles F, Perecin F, Coelho da Silveira J
Mol Cell Endocrinol · 2025 Dec · PMID 41015228 · Publisher ↗
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 c...
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.
OXTR overexpression induces polycystic ovary syndrome-like phenotype via prolactin/p-STAT3 signaling in mice.
Wang S, Bao X, Liu Z … +6 more , San M, Zhang L, Liu Y, Yang M, Zheng Y, Li D
Mol Cell Endocrinol · 2025 Dec · PMID 41015227 · Publisher ↗
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 ro...
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 (Oxtr) recapitulates cardinal PCOS features, including hyperandrogenism, oligo-ovulation, and polycystic ovarian changes. Oxtr 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 Oxtr 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 Oxtr ovaries - absent in WT controls at pregnancy - upregulated folliculogenesis genes (Lhcgr, Pgr, Leptin, Cyp17a1) while impairing ovulation. Therapeutic intervention with bromocriptine normalized prolactin and progesterone levels, partially restoring ovarian function. Notably, Oxtr 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.
IGF2BP2/ISG15/c-Myc axis promotes the excessive proliferation of granulosa cells in polycystic ovary syndrome.
Han L, Miao H, Li N … +1 more , Miao C
Mol Cell Endocrinol · 2026 Jan · PMID 41005645 · Publisher ↗
OBJECTIVE: 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. METHODS: Dehydroepiandrosterone (DHEA) was used...
OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Perinatal exposure to BPA leads to pronounced prostatic morphophysiological disorders in a rodent model of induced hyperplasia.
Bicalho-Silva S, Grigio V, Ruiz TFR … +5 more , de Freitas Calmon M, Rahal P, Taboga SR, Dos Santos FCA, Vilamaior PSL
Mol Cell Endocrinol · 2025 Dec · PMID 40998086 · Publisher ↗
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...
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 (Meriones unguiculatus). 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.
Notch signaling modulates Fgf23 expression through crosstalk with hypoxia and PTH pathways in osteogenic cells.
Tamamura Y, Terai K, Yamaguchi A
Mol Cell Endocrinol · 2025 Dec · PMID 40992566 · Publisher ↗
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...
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 in vivo. Here, we investigated the underlying mechanisms using osteogenic cell lines UMR-106 and IDG-SW3 cells. NICD overexpression increased Fgf23 levels in both cell types. Manipulating RBPJ-κ activity, either a dominant-negative or constitutively active form, revealed that Notch-mediated Fgf23 expression is dependent on RBPJ-κ. Treatment with iron chelator Desferrioxamine (DFO) upregulated Fgf23 expression, which was abolished by dominant-negative RBPJ-κ overexpression. This effect was partially attenuated by short hairpin RNA (shRNA) targeting hypoxia-inducible factor (HIF)-2α, but not HIF-1α. DFO treatment also increased expression of Notch1 protein, but not Notch2 and Nocth3, in parallel with upregulation of the Notch target mRNAs, Hes1 and Hey1. In addition, DFO elevated the expression of γ-secretase subunits, whereas a γ-secretase inhibitor suppressed DFO-induced increases in Notch1 and Fgf23 levels, suggesting that increased γ-secretase expression promotes Notch processing. Moreover, Notch signaling exerted an additive stimulatory effect on parathyroid hormone (PTH)-induced Fgf23 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. 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.
Advanced maternal age induced altered FoxO1 activation and cellular senescence in early placenta development in rats.
Leonardi ML, Ranieri A, Gatti CR … +3 more , Capobianco E, Jawerbaum A, Higa R
Mol Cell Endocrinol · 2025 Dec · PMID 40976335 · Publisher ↗
INTRODUCTION: 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 aime...
INTRODUCTION: 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. METHODS: 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. RESULTS: 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 Cdkn1a (P21) and Cdkn2a (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. CONCLUSION: 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.
Nrf2/Bach1 axis regulates redox homeostasis and energy metabolism to optimize Sertoli cell-mediated efferocytosis.
Wu D, Zhang K, Tan J … +3 more , Khan FA, Huang C, Sun F
Mol Cell Endocrinol · 2025 Dec · PMID 40975426 · Publisher ↗
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 res...
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.
Three-dimensional (3D) pancreatic β-cell models reveal insulin-secretion enhancing potential of green synthesized silver nanoparticles.
Acar CA, Pehlivanoglu S
Mol Cell Endocrinol · 2025 Nov · PMID 40967299 · Publisher ↗
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 poten...
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 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.
Ox-LDL-stimulated macrophage-derived exosomes regulate adipose tissue remodeling and promote the progression of atherosclerosis.
Liu X, Xu G, Xu Y … +1 more , Xu Y
Mol Cell Endocrinol · 2025 Nov · PMID 40967298 · Publisher ↗
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...
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.
Impact of novel amino acid substituted and acylated spexin analogues on pancreatic beta-cell function, appetite and glucose homeostasis.
Gallagher DM, Khan MZI, Patterson S … +2 more , O'Harte FPM, Irwin N
Mol Cell Endocrinol · 2025 Nov · PMID 40953657 · Publisher ↗
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 chall...
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 Asp for Asn substituted spexin analogue, DSpx, alongside two related fatty acid derivatised analogues, (γGlu-Pal)-DSpx and (KγGlu-Pal)-DSpx, 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, DSpx 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 and 10 M) promoted beta-cell proliferation, whilst native spexin and (γGlu-Pal)-DSpx 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 DSpx. When administered together with glucose, (γGlu-Pal)-DSpx 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.
Inhibiting the fructose transporter GLUT5 boosts testosterone production in a murine mLTC-1 leydig cell line.
Kallianioti A, Bourdon G, Chevaleyre C … +10 more , Péchoux C, Ramé C, Bourgeais J, Hérault O, Geoffre N, Darde T, Plotton I, Douard V, Dupont J, Froment P
Mol Cell Endocrinol · 2025 Dec · PMID 40947002 · Publisher ↗
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...
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. 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 Glut5 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. 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 Hsd3b and steroidogenic acute regulatory protein (StAR). 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 Akap5, Slc39a9, an androgen receptor or lactate dehydrogenase A (Ldha), which produces lactate, and downregulation of several genes associated with the insulin pathway such as Tsc2 or the hexokinase Hkdc1. 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 sperm production and quality, as well as sexual behavior, as described in the GLUT5 KO mouse model.
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