Molecular and Cellular Endocrinology最新文献

{"title":"Periostin-positive stellate cells associated with perineural invasion in pancreatic adenocarcinoma","authors":"Carlos Alberto de Carvalho Fraga ,&nbsp;Catarina Rosa e Silva Santos ,&nbsp;Kayo Felipe Barbosa Lima ,&nbsp;Gustavo Henrique Brasil Rodrigues ,&nbsp;Caio Cesar Fernandes Nobre Porto ,&nbsp;Maria Nathália de Menezes ,&nbsp;Gabriel Victor Lucena da Silva ,&nbsp;Adriana Simizo ,&nbsp;Ana Kelly da Silva Fernandes Duarte ,&nbsp;Jussara Almeida de Oliveira Baggio ,&nbsp;Amanda Karine Barros Ferreira Rodrigues ,&nbsp;Karol Fireman de Farias ,&nbsp;Elaine Virginia Martins de Souza Figueiredo ,&nbsp;Carolinne de Sales Marques ,&nbsp;Pedro Luiz Serrano Uson Junior ,&nbsp;Paulo Vidal Campregher ,&nbsp;Helder I. Nakaya","doi":"10.1016/j.mce.2025.112678","DOIUrl":"10.1016/j.mce.2025.112678","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"611 ","pages":"Article 112678"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145313208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The importance of CTGF regulation by FSH, IGF1, and estradiol in bovine granulosa cells","authors":"Leonardo Guedes de Andrade ,&nbsp;Valério Marques Portela ,&nbsp;Karine de Vargas Aires ,&nbsp;Natalia Jakuc ,&nbsp;Ana Paula da Silva ,&nbsp;Alfredo Quites Antoniazzi ,&nbsp;Paulo Bayard Dias Gonçalves ,&nbsp;Gustavo Zamberlam","doi":"10.1016/j.mce.2025.112688","DOIUrl":"10.1016/j.mce.2025.112688","url":null,"abstract":"<div><div>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) <em>CYP19A1</em> transcription level. The connective tissue growth factor (CTGF) has emerged as a potential novel and important player in the modulation of <em>CYP19A1</em> 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 <em>CTGF</em> mRNA levels are downregulated by insulin-like growth factor 1 (IGF1) and E2, two critical regulators of follicle dominance establishment <em>in vivo</em>. In turn, CTGF suppresses <em>CYP19A1</em> 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 <em>NR5A2</em>, a critical transcription factor of <em>CYP19A1.</em> Overall, our study indicates that <em>CTGF</em> downregulation in GC may represent a critical step for enabling the increased <em>CYP19A1</em> transcriptional activity of the dominant follicle in cattle.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"611 ","pages":"Article 112688"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"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","authors":"Justin D. Fletcher ,&nbsp;Hailey L. Maurer ,&nbsp;Mark A. Eschenfelder ,&nbsp;Benjamin R. Smith ,&nbsp;Sama Nayakanti ,&nbsp;Jennifer Guergues ,&nbsp;Tiara Wolf ,&nbsp;Stanley M. Stevens Jr. ,&nbsp;Brant R. Burkhardt","doi":"10.1016/j.mce.2025.112675","DOIUrl":"10.1016/j.mce.2025.112675","url":null,"abstract":"<div><div>We aimed to identify and isolate the metabolically active compounds from <em>Cornus officinalis</em> (<em>C. officinalis</em>) that underlie the biological effects previously observed in our in vitro and in vivo studies. Our prior findings demonstrated that <em>C. officinalis</em> 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 <em>C. officinalis</em>, 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 <em>C. officinalis</em> 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 <em>C. officinalis</em> that stimulates partial activation of the Keap1/Nrf2 pathway.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"611 ","pages":"Article 112675"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145195922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Raman spectroscopic characterization of liver steatosis and fibrosis in a 2D and 3D in vitro thyroxine-treated hypothyroid cellular model","authors":"S. Maurotti ,&nbsp;B. Scopacasa ,&nbsp;F. Scionti ,&nbsp;R. Pujia ,&nbsp;M. Frosina ,&nbsp;A. Mirarchi ,&nbsp;N. Geirola ,&nbsp;R. Mare ,&nbsp;T. Montalcini ,&nbsp;P. Candeloro ,&nbsp;L. Tirinato ,&nbsp;A. Pujia","doi":"10.1016/j.mce.2025.112679","DOIUrl":"10.1016/j.mce.2025.112679","url":null,"abstract":"<div><div>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.</div><div>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. <em>In vitro</em> 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.</div><div>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 <em>in-vitro</em> systems, further validation in intact tissue and <em>in vivo</em> 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.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"611 ","pages":"Article 112679"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bisphenol S chronic exposure impairs pancreatic function and induces obesity in male mice independently of high-fat diet intake","authors":"Ana Paula de Paula Alves ,&nbsp;Emanuelle Barreto-Reis ,&nbsp;Beatriz Gouvêa de Luca ,&nbsp;Thaís de Souza Carvalho ,&nbsp;Giovanna Palermo de Andrade ,&nbsp;Vinicius Sepúlveda-Fragoso ,&nbsp;Beatriz Alexandre-Santos ,&nbsp;Ana Beatriz Proença Souza ,&nbsp;Ana Lívia Ladislau de Souza Vieira ,&nbsp;Milena Barcza Stockler-Pinto ,&nbsp;Eliete Dalla Corte Frantz ,&nbsp;Clarice Machado-Santos ,&nbsp;Denise Pires de Carvalho ,&nbsp;Leandro Miranda-Alves ,&nbsp;D'Angelo Carlo Magliano","doi":"10.1016/j.mce.2025.112689","DOIUrl":"10.1016/j.mce.2025.112689","url":null,"abstract":"<div><div>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, <em>Pparγ</em> mRNA level, GRP78, ERO1 and ATF4 protein expression, epididymal adipocyte size, and insulin, glucose, and cholesterol levels. HF and HFB groups also showed increased <em>Grp7</em>8 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.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"611 ","pages":"Article 112689"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145321936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IGF2BP2/ISG15/c-Myc axis promotes the excessive proliferation of granulosa cells in polycystic ovary syndrome","authors":"Lijuan Han,&nbsp;Hui Miao,&nbsp;Na Li,&nbsp;Congxiu Miao","doi":"10.1016/j.mce.2025.112666","DOIUrl":"10.1016/j.mce.2025.112666","url":null,"abstract":"<div><h3>Objective</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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 <em>in vivo</em>. 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.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"611 ","pages":"Article 112666"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145176859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “The impact of mineralocorticoid and glucocorticoid receptor interaction on corticosteroid transcriptional outcomes” [Molecul. Cell. Endocrinol. 594 (2024) 112389]","authors":"Diego Alvarez de la Rosa ,&nbsp;Zuleima Ramos-Hernández ,&nbsp;Julián Weller-Pérez ,&nbsp;Thomas A. Johnson ,&nbsp;Gordon L. Hager","doi":"10.1016/j.mce.2025.112690","DOIUrl":"10.1016/j.mce.2025.112690","url":null,"abstract":"","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"611 ","pages":"Article 112690"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145391459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polycystic ovary syndrome: Long-term effects on fertility and uterine lesions","authors":"Gisela Soledad Bracho ,&nbsp;María Virginia Acosta ,&nbsp;Inri Iñiguez ,&nbsp;Gabriela Anahí Altamirano ,&nbsp;Laura Kass ,&nbsp;Verónica Lis Bosquiazzo","doi":"10.1016/j.mce.2025.112681","DOIUrl":"10.1016/j.mce.2025.112681","url":null,"abstract":"<div><div>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 (s<em>teroid sulfatase</em>, <em>5α-reductase type I)</em> 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.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"611 ","pages":"Article 112681"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Perinatal exposure to BPA leads to pronounced prostatic morphophysiological disorders in a rodent model of induced hyperplasia","authors":"Stella Bicalho-Silva ,&nbsp;Vitor Grigio ,&nbsp;Thalles Fernando Rocha Ruiz ,&nbsp;Marília de Freitas Calmon ,&nbsp;Paula Rahal ,&nbsp;Sebastião Roberto Taboga ,&nbsp;Fernanda Cristina Alcântara dos Santos ,&nbsp;Patrícia Simone Leite Vilamaior","doi":"10.1016/j.mce.2025.112664","DOIUrl":"10.1016/j.mce.2025.112664","url":null,"abstract":"<div><div>Bisphenol A (BPA) is a ubiquitous endocrine disruptor potentially harmful to male reproductive health. We aimed to investigate the impacts of perinatal exposure to a historically relevant and realistic dose of BPA on the ventral prostate under normal conditions and with prostatic hyperplasia in Mongolian gerbils (<em>Meriones unguiculatus</em>). Females were exposed to BPA (50 μg/kg/day) during gestation and lactation. The F1 male offspring were maintained until adulthood and subsequently treated with testosterone to induce prostatic hyperplasia. Morphological, molecular, and hormonal parameters were assessed on the ventral prostate. Testosterone-supplemented gerbils showed increased epithelium height and smooth muscle layer thickness. In the context of hyperplasia, perinatal exposure to BPA led to the onset of severe histopathologies (e.g., prostatic intraepithelial neoplasia, adenocarcinoma, and microacini), associated with increased cell proliferation. Perinatal BPA-exposed gerbils with prostatic hyperplasia showed increased pro-inflammatory markers (e.g., IL-6, COX-2, and F4/80), followed by a reduction in IL-10 protein levels. Regarding the steroid receptors, gerbils from this group presented a decrease in AR, followed by an increase in epithelial ERα expression. Molecularly, ERβ protein levels were higher in the prostate of perinatally exposed to BPA or testosterone-supplemented gerbils. Moreover, serum testosterone and estradiol levels increased after testosterone supplementation, whereas the T/E2 ratio increased in gerbils exposed to both treatments. Overall, the current study presents novel and comprehensive data on the life-long morphophysiological disorders caused by perinatal exposure to BPA on the ventral prostate of gerbils, highlighting the pronounced impacts observed in the context of hyperplasia.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"610 ","pages":"Article 112664"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145150096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adenosine A2AR agonist blocks mesenteric lymphatic epithelium, adipose tissue and Treg cells links of metabolic dysfunction-associated steatotic liver disease mice","authors":"Tzu-Hao Li ,&nbsp;Hsiao-Yun Yeh ,&nbsp;Shang-Wei Lin ,&nbsp;Yu-Shin Huang ,&nbsp;Zhen-Wei Zhuo ,&nbsp;Chia-Chen Ma ,&nbsp;Tsui-Ling Hsu ,&nbsp;Wei-Kai Wu ,&nbsp;Hung-Cheng Tsai ,&nbsp;Hsiao-Chin Shen ,&nbsp;Chien-Wei Su ,&nbsp;Ying-Ying Yang ,&nbsp;Han-Chieh Lin ,&nbsp;Ming-Chih Hou","doi":"10.1016/j.mce.2025.112667","DOIUrl":"10.1016/j.mce.2025.112667","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"610 ","pages":"Article 112667"},"PeriodicalIF":3.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145192154","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}