Molecular And Cellular Endocrinology[JOURNAL]
Sun
200 papers
The role of the mineralocorticoid receptor in skin.
Fossas De Mello N, Bollag WB
Mol Cell Endocrinol · 2025 Oct · PMID 40744405 · Publisher ↗
The mineralocorticoid receptor (MR) plays a pivotal role in skin homeostasis, inflammation, and repair, interacting closely with the glucocorticoid receptor (GR) to regulate various physiological and pathological process...
The mineralocorticoid receptor (MR) plays a pivotal role in skin homeostasis, inflammation, and repair, interacting closely with the glucocorticoid receptor (GR) to regulate various physiological and pathological processes. Dysregulation of MR signaling has been implicated in several skin disorders, including psoriasis, atopic dermatitis, and impaired wound healing. Furthermore, studies have shown that patients with primary hyperaldosteronism exhibit epidermal hyperplasia, impaired differentiation, increased immune cell infiltrates, and elevated pro-inflammatory cytokines due to MR overactivation. Pharmacological studies demonstrate that MR antagonists can mitigate glucocorticoid-induced skin barrier dysfunction, epidermal atrophy, and delayed wound healing. Additionally, skin sodium storage and water conservation mechanisms are emerging as key factors in systemic fluid balance and blood pressure regulation, with skin glycosaminoglycans (GAGs) thought to serve as sodium reservoirs. Mouse models of psoriasis further reveal how the disrupted skin barrier activates systemic protective mechanisms, including water retention processes in the skin that can lead to increased blood pressure; psoriasis in humans is also associated with hypertension. These findings and additional data are discussed in this review and underscore the dual role of cutaneous MR in both maintaining epidermal integrity and contributing to inflammatory skin disorders, and potentially hypertension, when dysregulated. Targeting MR signaling pathways may offer novel therapeutic strategies for skin diseases while enhancing our understanding of the skin's role in systemic homeostasis.
Liraglutide induces enhanced suppression of food intake in mice lacking the growth hormone secretagogue receptor.
Cassano DA, Aguggia J, Giovanini L … +7 more , Heredia F, De Francesco PN, Andreoli MF, Schöth HB, Habib AM, Fernandez G, Perello M
Mol Cell Endocrinol · 2025 Oct · PMID 40738311 · Publisher ↗
The glucagon-like peptide-1 receptor (GLP-1R) and the growth hormone secretagogue receptor (GHSR) exert opposing effects on food intake. GLP-1R activation produces potent appetite-suppressing effects, whereas GHSR activa...
The glucagon-like peptide-1 receptor (GLP-1R) and the growth hormone secretagogue receptor (GHSR) exert opposing effects on food intake. GLP-1R activation produces potent appetite-suppressing effects, whereas GHSR activation strongly stimulates food intake. Here, we tested the hypothesis that blocking GHSR could affect the anorectic and weight-reducing effects of liraglutide, a GLP-1R agonist widely used to treat diabetes and obesity. We first found that liraglutide induced a stronger reduction in food intake in ad libitum-fed GHSR-deficient mice compared to wild-type (WT) controls, regardless of sex. Liraglutide treatment also resulted in greater gastric content mass in ad libitum-fed GHSR-deficient mice than in WT mice. Interestingly, GLP-1R immunolabeling was elevated in the paraventricular nucleus of the hypothalamus (PVH) in GHSR-deficient mice, whereas the number of proopiomelanocortin (POMC) neurons and liraglutide-induced c-Fos activation-either in the entire arcuate nucleus or specifically within POMC neurons-remained unchanged compared to WT controls. Liraglutide-induced c-Fos expression in the lateral septum and PVH was reduced in GHSR-deficient mice. Conversely, pharmacological GHSR blockade using either JMV2959 or the endogenous antagonist/inverse agonist liver-expressed antimicrobial peptide 2 did not enhance liraglutide-induced food intake reduction. In conclusion, our findings reveal that genetic GHSR deficiency amplifies liraglutide's anorectic effects and provide new insight into the neurobiological mechanisms underlying this interaction. These results suggest that dual modulation of the GHSR and GLP-1R systems may represent a promising strategy for obesity treatment, though careful selection of GHSR-targeting agents and therapeutic protocols will be essential to optimize clinical outcomes.
RUNX3 drives HTR-8/SVneo cell ferroptosis and spontaneous abortion: involvement of the suppression of GDF15 transcriptional activity.
Cheng L, Zhang J, Xiang Y … +1 more , Tan L
Mol Cell Endocrinol · 2025 Oct · PMID 40712695 · Publisher ↗
Spontaneous abortion (SA) refers to the loss of a pregnancy without external intervention. The runt-related transcription factor 3 (RUNX3) is associated with gestational disorders in view of previous studies. However, RU...
Spontaneous abortion (SA) refers to the loss of a pregnancy without external intervention. The runt-related transcription factor 3 (RUNX3) is associated with gestational disorders in view of previous studies. However, RUNX3 has not been reported in SA. RUNX3 is significantly upregulated in the placental villi of abortion patients based on the GSE123719 microarray data. Herein, we further validated and found that the expression of RUNX3 in placental villi of SA women was higher than those of induced abortion (IA) women. In vitro, we constructed human RUNX3 overexpression or interference adenovirus vectors to modulate RUNX3 expression in trophoblast cells. Our findings revealed that RUNX3 overexpression accelerated trophoblast cell ferroptosis, while RUNX3 knockdown alleviated erastin-induced ferroptosis. Subsequently, the dual luciferase reporter assay was performed to confirm that RUNX3 bound to the GDF15 promoter to transcriptionally repress GDF15 transcriptional activity. Importantly, GDF15 attenuated the pro-ferroptosis effects of RUNX3 on HTR-8/SVneo cells. In vivo, mouse RUNX3 interference adenovirus vectors were used to silence RUNX3 in mice. The results presented that the reduction of RUNX3 inhibited embryo adsorption rate in SA mice, involving ferroptosis and the interaction between RUNX3 and GDF15. Taken together, this study established that RUNX3 advanced SA progression by enhancing trophoblast ferroptosis via transcriptionally repressing GDF15. These findings may provide novel therapeutic strategies for SA management.
Breaking immune evasion in breast cancer by targeting COX-2/PGE2 pathway.
Zheng X, Wang J, OuYang Y … +10 more , Yao K, Zheng J, Zeng L, Wang J, Chen H, Du H, Fu D, Shi L, Zhao A, Yin Q
Mol Cell Endocrinol · 2025 Oct · PMID 40712694 · Publisher ↗
The cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway plays a pivotal role in breast cancer (BC) progression by promoting immune suppression, tumor growth, and metastasis. PGE2 mediates these effects through EP re...
The cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway plays a pivotal role in breast cancer (BC) progression by promoting immune suppression, tumor growth, and metastasis. PGE2 mediates these effects through EP receptors (EP1-EP4), suppressing anti-tumor immunity while fostering an immunosuppressive tumor microenvironment (TME). This includes the recruitment and activation of tumor-associated macrophages (TAMs), dendritic cells (DCs), cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), ultimately impairing cytotoxic T lymphocyte and natural killer (NK) cell function. Targeting the COX-2/PGE2 axis presents a promising strategy for BC treatment. Dual inhibition of EP2 and EP4 has demonstrated superior efficacy in reversing immune suppression compared to single-receptor blockade. Additionally, combining EP4 antagonists with immune checkpoint inhibitors (ICIs) such as anti-PD-1 and anti-CTLA-4 enhances T cell infiltration and tumoricidal activity, leading to improved therapeutic outcomes. Another emerging approach involves enhancing the activity of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the key enzyme responsible for PGE2 degradation, to counteract PGE2-driven immune evasion. PTGES1 inhibitors have shown great potential in overcoming the immunosuppressive TME in BC patients. Elevated TIL levels in TNBC and HER2-positive BC are associated with improved prognosis; however, COX-2 inhibitors such as celecoxib failed to enhance survival and carry potential cardiovascular risks, highlighting the need for TIL-stratified trials to refine immunotherapeutic strategies. This review highlights the immunosuppressive mechanisms of the COX-2/PGE2 pathway in BC and explores novel therapeutic strategies targeting this axis. Understanding the intricate crosstalk between PGE2 signaling and immune modulation may lead to the development of more effective BC treatments, particularly in combination with immunotherapies.
Transcriptomic profiling of hypothalamic development in female rats.
Hilz EN, Streifer M, Milewski TM … +1 more , Gore AC
Mol Cell Endocrinol · 2025 Oct · PMID 40692004 · Full text
The hypothalamic arcuate nucleus (ARC) and anteroventral periventricular nucleus (AVPV) are critical regulators of reproductive function, energy balance, stress, and neuromodulation. These regions undergo substantial cha...
The hypothalamic arcuate nucleus (ARC) and anteroventral periventricular nucleus (AVPV) are critical regulators of reproductive function, energy balance, stress, and neuromodulation. These regions undergo substantial changes in neural and glial populations over development that enable the acquisition of adult functions. Although previous studies have examined developmental changes in specific hypothalamic cell populations or gene families, to our knowledge, none has comprehensively compared unbiased/bulk transcriptional profiles across key developmental stages in both the ARC and AVPV. In this study, we used 3' targeted RNA sequencing to profile gene expression in the ARC and AVPV of female rats at infantile (P8), peripubertal (P30), and adult (P60) life stages. We conducted unbiased and a priori selected differential gene expression analyses, the latter genes selected for their roles in reproduction, metabolism, stress, and neuromodulation. We also measured serum hormones as an index of physiology. Developmental analyses revealed robust differential gene expression between the infantile and prepubertal periods in both the ARC and AVPV, with substantial transcriptional overlap between regions. Fewer and more region-specific transcriptional changes were observed during the transition to adulthood. Gene ontology (GO) analyses revealed coordinated developmental programming prior to puberty, including downregulation of developmental processes and upregulation of metabolic and regulatory pathways. In adulthood, the AVPV showed continued transcriptional remodeling, while the ARC remained comparatively stable. FSH emerged as the strongest hormonal correlate of a priori hypothalamic gene expression. These data provide a reference for understanding hypothalamic development and hormone-gene interactions across life stages in the female rat.
Palmitate-induced downregulation of lipocalin prostaglandin D synthase accompanies hepatic lipid accumulation in HepG2 cells.
Khairnar R, Islam MA, Shetty DK … +2 more , Dukhande VV, Kumar S
Mol Cell Endocrinol · 2025 Oct · PMID 40692003 · Full text
Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with multiple metabolic dysfunctions and poses a significant global health challenge. Our prior in vivo studies demonstrated that the absence...
Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with multiple metabolic dysfunctions and poses a significant global health challenge. Our prior in vivo studies demonstrated that the absence of lipocalin prostaglandin D2 synthase (L-PGDS) leads to the development of fatty liver disease, and L-PGDS expression significantly decreased when C57BL/6 mice were kept on a high-fat diet. Briefly, L-PGDS belongs to the arachidonic acid pathway and enzymatically isomerizes prostaglandin H2 to prostaglandin D2, which imparts pharmacological effects via two receptors called DP1 and DP2. L-PGDS is an essential key player in fatty liver disease, but its mechanistic regulation still remains unknown. Therefore, we aimed to study the mechanistic regulation of L-PGDS using a palmitate-induced cellular MASLD model. We successfully recapitulated the MASLD phenotype in HepG2 cells with palmitate treatment. Our results showed significant lipid accumulation and increased lipidassociated protein and gene expression, along with palmitate concentration-dependent L-PGDS downregulation. To study the L-PGDS downregulation, we employed MG132, chloroquine, and cycloheximide to assess proteasomal degradation, autophagy, and translational activity, respectively. Our gene and protein expression data suggested the possible reason for L-PGDS downregulation via inhibiting transcription and subsequently translation. Additionally, our autophagy results also showed a role in LPGDS downregulation. In summary, it can be concluded that palmitate treatment downregulated L-PGDS, possibly involving transcription-translation and/or autophagy pathways. However, further studies are needed to delineate the precise molecular mechanism and apply this knowledge to MASLD pathogenesis and treatment.
Association between BRAFV600E mutation and gene expression of CLDN1, TIMP1, and KRT19 in papillary thyroid cancer.
Ross-Orozco A, Gastelum-Quiroz AR, Alvarez-Arrazola M … +5 more , Luque-Ortega F, Martínez-Camberos A, Morales-Hernandez K, Lopez-Herrera Y Cairo F, García-Magallanes N
Mol Cell Endocrinol · 2025 Sep · PMID 40669608 · Publisher ↗
The molecular mechanisms driving Papillary Thyroid Cancer (PTC) progression remain incompletely understood, although mutations in BRAF, are believed to affect the expression of key markers involved in PTC development. Th...
The molecular mechanisms driving Papillary Thyroid Cancer (PTC) progression remain incompletely understood, although mutations in BRAF, are believed to affect the expression of key markers involved in PTC development. This study aimed to investigate the BRAFV600E mutation and its association with the expression of CLDN1, TIMP1, and KRT19 in PTC. A total of 93 thyroid samples were retrospectively analyzed: 42 cytologically diagnosed as PTC (Bethesda VI/V), 4 suspicious for malignancy (Bethesda V), and 47 as nodular hyperplasia (Bethesda II). The presence of the BRAFV600E mutation and the expression levels of CLDN1, TIMP1, and KRT19 were determined using qPCR. BRAFV600E genotypes included 70.2 % TT (wild-type), 17 % TA (heterozygous), and 12.8 % AA (mutant homozygous), with a mutated allele frequency of 0.210. The TA genotype was exclusive to the cancer group and significantly increased malignancy risk (OR 3.667; 95 % CI 2.473-5.437; p < 0.001). Patients harboring the mutated A allele were significantly younger (p = 0.029) and exhibited higher expression of all three genes. Using Youden-derived cutoffs from ROC analysis, TIMP1 overexpression (cutoff 1.148) was most strongly associated with BRAFV600E (OR 4.34; 95 % CI 1.82-10.33; p < 0.001). The BRAFV600E mutation and TIMP1 overexpression are strongly associated with malignant thyroid nodules, suggesting a role in the molecular pathogenesis of PTC.
SP600125 decreases cAMP/PKA-dependent steroid production through ATF4/DDIT3 activation in MA-10 Leydig cells.
Basque A, Izichkis LS, Martin LJ
Mol Cell Endocrinol · 2025 Sep · PMID 40645321 · Publisher ↗
Leydig cells, located between seminiferous tubules within the testis, are the primary source of testosterone in males. In these cells, the luteinizing hormone (LH)/cAMP/protein kinase A (PKA) signaling pathway mainly reg...
Leydig cells, located between seminiferous tubules within the testis, are the primary source of testosterone in males. In these cells, the luteinizing hormone (LH)/cAMP/protein kinase A (PKA) signaling pathway mainly regulates androgen biosynthesis. We have previously reported that the connexin43 (Gja) promoter can be activated in mouse MA-10 Leydig cells as a result of a cooperation between the AP-1 transcription factors JUN and FOS. The mitogen-activated protein kinases (MAPK) signaling pathway, through the JUN N-terminal kinase (JNK), can phosphorylate members of the AP-1 family of transcription factors, modulating their activities. Hence, MA-10 Leydig cells were treated for 4 h with the JNK inhibitor SP600125 (pyrazolanthrone) at 25 μM, in the absence or presence of the activator of adenylate cyclase forskolin (FSK) at 10 μM, followed by RNA extractions and 3'Tag RNA-Seq analysis of the transcriptome. Interestingly, SP600125 decreases cAMP/PKA dependent expression of genes related to cholesterol and steroid biosynthetic/metabolic processes, resulting in decreased cAMP/PKA dependent progesterone production in MA-10 cells. Moreover, SP600125 increases the expression of genes involved in the endoplasmic reticulum stress response related to ATF4, resulting in activation of DDIT3 and apoptosis as indicated with cleaved caspase 3. Overall, our results suggest that SP600125 increases the ATF4/DDIT3-dependent endoplasmic reticulum stress response independently of MAPK9 (JNK2) inhibition, and inhibits LH/cAMP/PKA-dependent androgen synthesis in Leydig cells.
Timing of glucose intake drives distinct hepatic outcomes: Divergent glucose and lipid metabolism.
Zhang X, Ma C, Chang S … +2 more , Li X, Wang Q
Mol Cell Endocrinol · 2025 Sep · PMID 40639685 · Publisher ↗
OBJECTIVE: Excessive sugar intake is strongly associated with insulin resistance and type 2 diabetes (T2D), yet the metabolic consequences of nutrient timing-specifically glucose consumption during fasting versus feeding...
OBJECTIVE: Excessive sugar intake is strongly associated with insulin resistance and type 2 diabetes (T2D), yet the metabolic consequences of nutrient timing-specifically glucose consumption during fasting versus feeding-remain poorly understood. METHODS: C57BL/6 mice were subjected to an every-other-day fasting (EODF) regimen and randomly divided into three groups: control (tap water only), food-glucose (FG; glucose water during feeding), and starvation-glucose (SG; glucose water during fasting). After 22 weeks, metabolic phenotypes, hepatic lipid profiles, insulin signaling markers, and hepatic transcriptomes were analyzed. RESULTS: Glucose intake during fasting (SG) induced marked hepatic insulin resistance, as evidenced by reduced phosphorylation of Akt and FoxO1. In contrast, glucose intake during feeding (FG) promoted hepatic triglyceride accumulation, upregulated lipogenic genes (e.g., Acaca, Fasn), and increased expression of SREBP-1c and PPARγ. Transcriptomic and pathway enrichment analyses revealed distinct activation patterns of insulin signaling and lipid metabolism between FG and SG groups. CONCLUSIONS: Nutrient timing critically influences hepatic metabolic responses: glucose intake during feeding promotes lipogenesis, whereas intake during fasting triggers insulin resistance. These findings underscore the importance of chrononutritional strategies in preventing T2D and suggest that personalized dietary timing may offer therapeutic benefits.
Estrogen upregulates nucleophosmin 1 expression in mouse uterus through MYC induction.
Lee G, Suh Y, Kim B … +7 more , Kim J, Lee J, Park S, Lee OH, Hong K, Lee MR, Choi Y
Mol Cell Endocrinol · 2025 Sep · PMID 40618949 · Publisher ↗
The uterus undergoes transcriptional changes regulated by estrogen and progesterone throughout the menstrual cycle. Although the estrogen-regulated transcriptome has been extensively studied, the implications of gene exp...
The uterus undergoes transcriptional changes regulated by estrogen and progesterone throughout the menstrual cycle. Although the estrogen-regulated transcriptome has been extensively studied, the implications of gene expression alterations are not fully elucidated. Our analysis of publicly available RNA-seq and ChIP-seq data revealed that estrogen upregulates genes involved in ribosome biogenesis and MYC pathway. Specifically, we observed increased expression of nucleophosmin 1 (NPM1), a key regulator of ribosome biogenesis with MYC-binding sites in its promoter, in estrogen-stimulated endometrial epithelium. Utilizing an estrogen receptor (ER) antagonist, we demonstrated that estrogen's upregulation of Npm1 and Myc in the uterus is dependent on ER activation. Further, estrogen treatment of isolated endometrial epithelium from the uterus confirmed an increase in Myc and Npm1 expression. The application of Myc siRNA attenuated the estrogen-induced Npm1 expression in the isolated epithelium. These findings suggest that estrogen-enhanced MYC expression, mediated by ER, may play a crucial role in Npm1 expression in the uterus. This, in turn, contributes to ribosome biogenesis, underscoring its significance in endometrial proliferation and thickening. Therefore, our findings offer significant insights into NPM1 role in normal endometrial physiology, highlighting the connection between estrogen-mediated transcriptional regulation and ribosome biogenesis in the uterus.
Maternal thyroid hormones affect zebrafish embryo development.
da Silva Rodrigues M, Marques de Souza B, Rosa IF … +2 more , Doretto LB, Nóbrega RH
Mol Cell Endocrinol · 2025 Sep · PMID 40618948 · Publisher ↗
Thyroid hormones (THs), including thyroxine (T4) and triiodothyronine (T3), regulate vertebrate development, influencing critical processes during embryogenesis and larval stages. However, their maternal transfer and dev...
Thyroid hormones (THs), including thyroxine (T4) and triiodothyronine (T3), regulate vertebrate development, influencing critical processes during embryogenesis and larval stages. However, their maternal transfer and developmental roles in fish remain poorly understood. This study investigates maternal THs' impact on zebrafish development, focusing on the somatotropic axis, a key regulator of growth and metabolism. Female zebrafish were fed diets with 12.5 or 25 μg T4/g body weight/day for five days, while controls received vehicle-only food. Plasma TH levels were measured, and females were bred with untreated males. Embryos and larvae were assessed from 0 to 144 h post-fertilization for survival, heartbeat, morphology, T3 content, and gene expression. Elevated maternal T4 increased embryonic T3, causing growth retardation, edema, spinal deformities, tachycardia, and mortality. Gene expression analysis revealed dysregulation of TH axis components and somatotropic genes, highlighting the maternal THs' critical role in developmental trajectories and normal growth.
Exploring thyroid development and function: A systems biology search for new chemical disruptor targets.
Zenzeluk J, Oliveira JM, Sater AC … +4 more , Bargi-Souza P, Romano MA, Serrano-Nascimento C, Romano RM
Mol Cell Endocrinol · 2025 Sep · PMID 40615107 · Publisher ↗
Indiscriminate exposure to chemical substances has emerged as a critical global health concern. Human exposure to emerging contaminants, including pharmaceutical residues, pesticides, food additives, and chemicals employ...
Indiscriminate exposure to chemical substances has emerged as a critical global health concern. Human exposure to emerging contaminants, including pharmaceutical residues, pesticides, food additives, and chemicals employed in packaging and bottle production, is associated with an increased incidence of diseases, including thyroid disorders. Several chemicals potentially dysregulate thyroid embryonic development and the adult hypothalamic‒pituitary‒thyroid (HPT) axis. In this study, we applied systems biology approaches to identify biological processes associated with the most highly upregulated and downregulated genes in human thyroid transcriptome data from both the embryonic and adult stages. As a result, new gene/protein‒chemical interactions linked to recognized toxicities in the thyroid gland and the HPT axis were identified. This analysis identified 195 distinct chemical substances that may interact with these highly expressed proteins and exhibit thyroid toxicity. Our findings underscore the developmental period as a critical window of vulnerability to chemical exposure, with potential adverse effects on thyroid development and programming. Finally, our data suggest new targets for emerging chemicals in the thyroids of adult individuals, potentially compromising thyroid function.
Ghrelin treatment and exercise improve sperm quality in rats fed an obesogenic diet:A potential link to LEAP2.
Luque EM, Carlini VP, Guantay P … +8 more , Machuca D, Torres P, Ramírez N, Cantarelli V, Ponzio M, Castrogiovanni D, Perelló M, Martini AC
Mol Cell Endocrinol · 2025 Sep · PMID 40581206 · Publisher ↗
This study aimed to evaluate whether ghrelin, with or without exercise, can reverse the alterations caused by an obesogenic diet on sperm quality, metabolism, and endocrine profile with emphasis on LEAP2 levels. Fifty fi...
This study aimed to evaluate whether ghrelin, with or without exercise, can reverse the alterations caused by an obesogenic diet on sperm quality, metabolism, and endocrine profile with emphasis on LEAP2 levels. Fifty five male Wistar rats were randomly assigned, from weaning to postnatal day (pnd) 103, to five groups (n = 11/group): CD (standard chow + water); ObD (chow enriched with 30 % pork fat + water with 5 % fructose); ObD + ghrelin (obesogenic diet + 6 nmol/animal/day of ghrelin from pnd 85); ObD + Exc (obesogenic diet + standardized exercise in a running wheel, 15 min/day, 3 days/week); and ObD + ghrelin + Exc. Body weight gain was accelerated in ObD, but ghrelin and/or Exc slowed it down. At pnd 103, all treatment groups were significantly lighter than the ObD group. Metabolic parameters were impaired in ObD animals, with exercise markedly improving them, reducing cholesterol and triglyceride levels close to control values, while ghrelin exerted a modest effect, partially reducing triglycerides and the triglyceride/HDL index but leaving values still dysregulated. Sperm concentration and motility were significantly reduced in the ObD vs. CD; ghrelin and/or Exc completely reversed these detrimental effects. Plasma LEAP2 was significantly higher in the animals receiving the obesogenic diet, and, LEAP2 correlated inversely with sperm concentration, explaining 22 % of its variation. No synergistic effects were found between ghrelin and Exc. We demonstrated for the first time the potential of ghrelin to reverse sperm quality alterations secondary to obesity. Furthermore, ghrelin exhibited weight gain-slowing effects comparable to those of Exc. We also found an association between LEAP2 and sperm concentration, which warrants further investigation.
Enteroendocrine cell differentiation: Implications for human disease.
Saint-Denis E, Frintu B, Goldsmith M … +2 more , Ramos GP, Zeve D
Mol Cell Endocrinol · 2025 Sep · PMID 40581205 · Full text
Enteroendocrine cells are the most abundant hormone producing cells in humans. Though they make up less than 1 % of the gastrointestinal epithelium, these cells have a large physiological impact through the secretion of...
Enteroendocrine cells are the most abundant hormone producing cells in humans. Though they make up less than 1 % of the gastrointestinal epithelium, these cells have a large physiological impact through the secretion of hormones that act both locally and systemically to regulate intestinal function and whole-body metabolism, among other functions. The differentiation of enteroendocrine cells from intestinal stem cells is complex, involving not only lineage, but hormonal specification. This review highlights the specific signaling pathways and transcription factors that regulate enteroendocrine cell differentiation and hormone production, integrating newer findings into our growing understanding of this process. Further, it also describes how enteroendocrine cells and their differentiation are involved and altered in human health and disease: specifically aging, inflammatory bowel disease, obesity, and diabetes mellitus. Finally, we focus on how enteroendocrine cells can be targeted to produce insulin, a growing field with significant implications. Understanding what drives enteroendocrine differentiation, both molecularly and physiologically, will provide important insights into how these cells can serve as future therapeutic targets.
Gremlin 1 regulates granulosa cell apoptosis through the TGF-β/SMAD signaling pathway during bovine follicular atresia.
Xu Y, Liu M, Yang T … +9 more , Zhao B, Li Y, Wang J, Wang Y, Lin P, Chen H, Wang A, Jin Y, Tang K
Mol Cell Endocrinol · 2025 Sep · PMID 40578788 · Publisher ↗
Gremlin 1 is a highly conserved secretory glycoprotein of the DAN family that plays significant roles in human and mouse follicular development and ovulation through both BMP-dependent and BMP-independent pathways. Howev...
Gremlin 1 is a highly conserved secretory glycoprotein of the DAN family that plays significant roles in human and mouse follicular development and ovulation through both BMP-dependent and BMP-independent pathways. However, its function and mechanisms in bovine follicular development and atresia remain unclear. This study investigated its specific molecular mechanism during follicular development in bovines. Gremlin 1 protein is expressed in ovarian follicles at various developmental stages, with both its mRNA and protein levels increasing in correlation with the progression of follicular atresia. Following Si-RNA mediated knockdown of Gremlin 1 expression, a reduction in apoptosis and an enhancement in proliferative activity were observed in granulosa cells (GCs). In contrast, recombinant human Gremlin 1 (Rh-Gremlin 1) protein significantly induced apoptosis of GCs and inhibited cell proliferation. Previous studies have shown that Gremlin 1 can mediate apoptosis in a variety of cells through the TGF-β/SMAD signaling pathway. In our study, we observed that Gremlin 1 was associated with the phosphorylation levels of SMAD-2/3, and treatment with the TGF-β signaling pathway inhibitor SB431542 partially reversed Gremlin 1-induced apoptosis of GCs. Moreover, SB431542 significantly restored the proliferative viability and cell cycle progression of GCs. The results showed that Gremlin 1 was involved in follicular atresia-related processes by regulating the apoptosis and proliferation of GCs, and partially mediated this process through the TGF-β/SMAD signaling pathway. This provides a new avenue for further exploration of its role in follicular development.
Mdivi-1 promotes steroidogenesis in granulosa cells by inhibiting mitochondrial fission.
He Y, Li X, Kuai D … +4 more , Zhang H, Wang Y, Wang K, Tian W
Mol Cell Endocrinol · 2025 Sep · PMID 40571086 · Publisher ↗
Targeted metabolomics and ELISAs shown that Mdivi-1 treatment increased the levels of steroid hormones (progesterone and estradiol) in the supernatants of KGN cell culture medium. The purpose of this study was to explore...
Targeted metabolomics and ELISAs shown that Mdivi-1 treatment increased the levels of steroid hormones (progesterone and estradiol) in the supernatants of KGN cell culture medium. The purpose of this study was to explore the mechanism of Mdivi-1 promoting steroid hormone synthesis in granulosa cells (GCs). In vitro experiments revealed that Mdivi-1 did not affect the total protein expression of Drp1 in KGN cells or human luteinized GCs but increased Drp1 Ser637 phosphorylation, reduced Drp1 Ser616 phosphorylation, inhibited Drp1 mitochondrial translocation, and upregulated mitochondrial fusion proteins, promoting mitochondrial fusion. In terms of energy production, Mdivi-1 increased the expression of mitochondrial complexes I and V and the ATP concentration in GCs, increasing the energy supply for steroidogenesis. Mdivi-1 exposure significantly increased the expression and mitochondrial localization of StAR and CYP11A1 in the steroid production pathway of GCs. Further in vivo experiments demonstrated that, compared with the controls, Mdivi-1 treatment significantly increased the levels of Drp1 Ser637, StAR and CYP11A1 in ovarian tissue and the serum levels of progesterone and estradiol. Taken together, these findings suggest that Mdivi-1 induces mitochondrial fusion by increasing Drp1 phosphorylation at Ser637 and weakening the interaction between Drp1 and mitochondria. Moreover, mitochondrial fusion increases the cellular bioenergetics and the expression of StAR and CYP11A1 as well as their mitochondrial localization, thereby enhancing the activity of steroidogenesis in GCs.
CYR61 and CTGF mediate the stimulatory effect of amphiregulin on COX-2 expression in human granulosa-lutein cells.
Fu B, Guo M, Jia Y … +4 more , Han X, Bi B, Fang L, Cheng JC
Mol Cell Endocrinol · 2025 Sep · PMID 40506006 · Publisher ↗
Amphiregulin (AREG), an epidermal growth factor (EGF)-like ligand, is the predominant epidermal growth factor receptor (EGFR) ligand in human follicular fluid and mediates the effects of luteinizing hormone (LH) on ovari...
Amphiregulin (AREG), an epidermal growth factor (EGF)-like ligand, is the predominant epidermal growth factor receptor (EGFR) ligand in human follicular fluid and mediates the effects of luteinizing hormone (LH) on ovarian function. In this study, we investigated whether AREG regulates the expression of cysteine-rich angiogenic inducer 61 (CYR61) and connective tissue growth factor (CTGF), two key matricellular proteins involved in ovarian function, and whether they mediate AREG-induced cyclooxygenase-2 (COX-2) expression. Using the human granulosa cell tumor-derived KGN cell line and primary human granulosa-lutein (hGL) cells, we demonstrated that AREG treatment upregulated CYR61 and CTGF protein levels in an EGFR-dependent manner. Mechanistic analysis revealed that AREG-induced expression of CYR61 and CTGF was mediated through the ERK1/2, AKT, CREB, and YAP signaling pathways. Inhibition of these pathways using specific inhibitors or small interfering RNA blocked AREG-induced CYR61 and CTGF expression, indicating their essential roles in this process. Moreover, knockdown of CYR61 and CTGF attenuated AREG-induced COX-2 expression, establishing their role as key mediators of AREG signaling in human granulosa cells. Finally, our results showed that LH treatment induced the expression of CYR61 and CTGF, and this induction was attenuated by EGFR inhibition. Moreover, knockdown of CYR61 and CTGF reduced LH-induced COX-2 expression. These findings provide novel insights into the molecular mechanisms by which AREG regulates ovarian function and highlight potential targets for reproductive health research.
Corrigendum to "Angiotensin II type 2 receptor mediates high fat diet-induced cardiomyocyte hypertrophy and hypercholesterolemia" [Mol. Cell. Endocrinol. (2019), 498, 110576 (doi: 10.1016/j.mce.2019.110576)].
Lima VM, Lino CA, Senger N … +7 more , de Oliveira Silva T, Fonseca RIB, Bader M, Santos RAS, Júnior JD, Barreto-Chaves MLM, Diniz GP
Mol Cell Endocrinol · 2025 Sep · PMID 40500665 · Publisher ↗
Abstract loading — click title to view on PubMed.
Sarcospan, a candidate gene of fat distribution, may affect lipid storage in adipocytes.
Dinter KA, Aurich S, Müller L … +7 more , Ghosh A, Noé F, Wolfrum C, Blüher M, Hoffmann A, Kovacs P, Keller M
Mol Cell Endocrinol · 2025 Sep · PMID 40490051 · Publisher ↗
BACKGROUND AND AIMS: Genetic and epigenetic variations in the Sarcospan (SSPN) gene are associated with parameters of fat distribution (body mass index, waist-to-hip ratio), glucose homeostasis and adipocyte size in huma...
BACKGROUND AND AIMS: Genetic and epigenetic variations in the Sarcospan (SSPN) gene are associated with parameters of fat distribution (body mass index, waist-to-hip ratio), glucose homeostasis and adipocyte size in human potentially by affecting adipogenesis. This study aims at clarifying the impact of SSPN on adipogenesis, particularly focusing on its promoter methylation. MATERIALS AND METHODS: Immortalized murine epididymal preadipocytes were transfected with fluorescence-marked plasmids coding for DNMT3a, CRISPR/dCas9-Suntag and vectors carrying guide RNAs complementary to the transcription start site region and differentiated to mature adipocytes. We performed siRNA-mediated Sspn knockdown in epididymal preadipocytes, measured target DNA methylation using pyrosequencing and quantified transcriptional changes of Sspn and adipogenic genes by qPCR. Additionally, we correlated SSPN mRNA values and clinical characteristics from a large human adipose tissue biobank (Leipzig Obesity Biobank). RESULTS: Epigenetic editing of the Sspn regulatory region in preadipocytes resulted in a significant increase (up to 35 %) in DNA promoter methylation throughout adipocyte differentiation but showed only minor effects on Sspn expression and fat storage. Though siRNA knockdown could also not contribute to understand the role of Sspn in a 2D adipogenesis model, large-scale correlation analyses still indicate the gene to be a key player in fat distribution and glucose homeostasis. CONCLUSIONS: Although the epigenetic downregulation of Sspn showed only marginal effects on adipogenesis, associations of SSPN expression in human adipose tissue with parameters of fat distribution and glucose homeostasis make it a promising candidate for further studies addressing metabolic processes in adipose tissue.
Inhibition of the RIPK4 enhances suppression of human melanoma growth through vitamin D signaling.
Olajossy B, Slominski AT, Wolnicka-Glubisz A
Mol Cell Endocrinol · 2025 Sep · PMID 40490050 · Full text
Downregulation of Receptor-Interacting Protein Kinase 4 (RIPK4) inhibits NF-κB and Wnt/β-catenin signaling in melanoma and xenograft growth in mice. The active form of vitamin D3 (1,25-D3), in addition to regulating calc...
Downregulation of Receptor-Interacting Protein Kinase 4 (RIPK4) inhibits NF-κB and Wnt/β-catenin signaling in melanoma and xenograft growth in mice. The active form of vitamin D3 (1,25-D3), in addition to regulating calcium and phosphate metabolism in humans through the vitamin D receptor (VDR), can inhibit the NF-κB signaling pathway and can affect the proliferation and differentiation of normal and malignant cells, including melanoma. An hyperactive NF-κB pathway maintains the malignant behavior of melanoma, which can be influenced by both RIPK4 and activated VDR. As their interactions affecting the response to 1,25-D3 in melanoma have not been studied, we tested whether downregulation of RIPK4 affects the sensitivity of melanoma cells to 1,25-D3. Our results have shown that both siRIPK4 and CRISPR/Cas9-mediated RIPK4 knockout increase VDR expression in melanoma cells. Furthermore, a decrease in CYP24A1 expression and an increase in 1,25 D3-induced VDR levels were observed in cells with RIPK4 downregulation. Treatment with 1,25- D3 of RIPK4.KO cells, compared to their wild-type counterparts, significantly reduced proliferation in 2D and 3D culture (MTT or ATP assay) and decreased p-p65 and cyclin D1 levels in melanoma cells. These results indicate that RIPK4 knockout may enhance the therapeutic efficacy of 1,25-D3 against melanoma, which encourages further studies on targeting RIPK4 signaling for anti-melanoma effects in preclinical models.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe