Molecular and Cellular Endocrinology最新文献

{"title":"Deciphering the allosteric control of androgen receptor DNA binding by its disordered N-terminal domain.","authors":"Laurens W H J Heling, Jolieke van der Veen, Adam Rofe, Eric West, Alba Jiménez-Panizo, Andrea Alegre-Martí, Vahid Sheikhhassani, Julian Ng, Thomas Schmidt, Eva Estébanez-Perpiñá, Iain J McEwan, Alireza Mashaghi","doi":"10.1016/j.mce.2025.112634","DOIUrl":"10.1016/j.mce.2025.112634","url":null,"abstract":"<p><p>The androgen receptor (AR) plays a pivotal role in male physiological development and is implicated in the pathogenesis of various diseases, including prostate cancer. Its N-terminal domain (NTD), characterized by intrinsic disorder, is essential for transcriptional activation. Despite its importance, the precise mechanisms by which the NTD regulates AR's DNA-binding activity remain incompletely understood. This research elucidates the allosteric control mediated by specific NTD subregions-the N-terminal region (NR) and the C-terminal region (CR)-over the DNA binding properties of a truncated AR construct comprising the DNA-binding and ligand-binding domains (ΔNTD-AR). Microscale Thermophoresis (MST) and single-molecule fluorescence imaging were employed to investigate these interactions. This study demonstrates that the NTD subregions exert differential modulatory effects on the kinetics and affinity of ΔNTD-AR binding to DNA. MST analyses indicated that CR reduces ΔNTD-AR DNA binding affinity concentration-dependently, whereas NR did not significantly alter affinity. Single-molecule investigations revealed NR accelerates dissociation, while CR markedly diminishes binding frequency and accelerates dissociation. Combined NR and CR exerted complex effects, synergistically reducing affinity at high concentrations and altering kinetics distinctively compared to individual subregions. Collectively, these results delineate distinct functional roles for the NR and CR subregions in allosterically modulating AR-DNA interactions. This detailed understanding of intrinsic AR regulation offers mechanistic insights into receptor function and highlights potential allosteric sites for therapeutic intervention.</p>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":" ","pages":"112634"},"PeriodicalIF":3.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812131","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 role of IGFBP7 in the immune regulation of PCOS-like symptoms based on spleen transcriptome and TCR β CDR3 repertoire analysis.","authors":"Li Chen, Linhu Hui, Yueping Shi, Anwei Wang, Yueheng Zhang, Xinsheng Yao, Jun Li","doi":"10.1016/j.mce.2025.112639","DOIUrl":"10.1016/j.mce.2025.112639","url":null,"abstract":"<p><p>Polycystic ovary syndrome (PCOS) is often linked with immune dysregulation and chronic inflammation, where immune responses play a significant role. Recent studies have identified IGFBP7 involvement in immune processes, suggesting its potential role in modulating immune function. However, the involvement of IGFBP7 in immune modulation within the context of PCOS remains underexplored. In this study, we utilized a Dehydroepiandrosterone (DHEA)-induced PCOS mouse model, including both wild-type and IGFBP7 knockout (KO) mice, to investigate the involvement of IGFBP7 in immune regulation related to PCOS. We performed spleen transcriptome sequencing and TCR β CDR3 repertoire sequencing to assess changes in immune gene expression and T cell receptor diversity. Our findings demonstrate that IGFBP7^-/- significantly mitigates PCOS-like symptoms, normalizing estrous cycles and improving ovarian morphology. Transcriptome analysis revealed a substantial downregulated genes in the spleen of IGFBP7^-/- mice, with enrichment in pathways associated with immune function. Additionally, in the DHEA-induced PCOS mouse model, TCR β CDR3 repertoire analysis indicated increased clonality and decreased diversity, alongside alterations in V and J gene usage in IGFBP7^-/- mice. These results highlight the critical role of IGFBP7 in immune regulation within the context of PCOS, offering new insights into the immune mechanisms underlying PCOS pathology.</p>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":" ","pages":"112639"},"PeriodicalIF":3.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804439","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 role of the mineralocorticoid receptor in skin.","authors":"Natalia Fossas De Mello, Wendy B Bollag","doi":"10.1016/j.mce.2025.112628","DOIUrl":"10.1016/j.mce.2025.112628","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":" ","pages":"112628"},"PeriodicalIF":3.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760555","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":"PACAP inhibits high fat-induced NLRP3 inflammasome-mediated pyroptosis in vascular endothelial cells by regulating the SIRT1/ROS pathway.","authors":"Jixiang Dong, Tianyu Ma, Yichen Qu, Runquan Ye, Jia Feng, Ge Bai, An Hong, Yi Ma","doi":"10.1016/j.mce.2025.112633","DOIUrl":"10.1016/j.mce.2025.112633","url":null,"abstract":"<p><p>High-fat diet (HFD)-induced obesity leads endothelial dysfunction and contributes to cardiovascular diseases. NLRP3-mediated pyroptosis plays a key role in endothelial injury induced by HFD. Pituitary adenylate cyclase activating polypeptide (PACAP), a neuropeptide belonging to the secretin family, has demonstrated diverse beneficial effects. However, its impact on a high-fat-induced pyroptosis remains unexplored. The purpose of this study is to evaluate the effect of PACAP in alleviating high-fat-induced pyroptosis of human umbilical vein endothelial cells (HUVECs) and to elucidate its potential mechanisms. The results show that palmitic acid (PA) induces HUVECs injury and pyroptosis, while PACAP alleviates PA-induced HUVECs injury and pyroptosis. In addition, PACAP also has a protective effect on vascular damage in the thoracic aorta of obese mice. We further found that PACAP reduced PA-induced intracellular Reactive Oxygen Species (ROS) in HUVECs, while also mitigating PA-induced HUVECs pyroptosis. Moreover, PACAP can inhibit PA-induced ROS and pyroptosis through activation of SIRT1, and the effects of PACAP are reversed by a SIRT1 inhibitor. In conclusion, our study demonstrates that PACAP can inhibit PA-induced oxidative stress and pyroptosis in HUVECs, and its action is closely related to the SIRT1 pathway.</p>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":" ","pages":"112633"},"PeriodicalIF":3.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144775790","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":"Sex-specific differences in the influence of maternal obesity on the oxidative and inflammatory status in the maternal-placental-fetal unit: new insights into the placental sphingolipid profile.","authors":"Marta Hita Hernández, Esther Dos Santos, Yoann Rodriguez, Véronique Ferchaud-Roucher, Delphine Rousseau-Ralliard, Anne Frambourg, Paul Berveiller, François Vialard, Anne Couturier-Tarrade, Marie-Noëlle Dieudonne","doi":"10.1016/j.mce.2025.112640","DOIUrl":"10.1016/j.mce.2025.112640","url":null,"abstract":"<p><p>Although maternal obesity influences placental and fetal development, the underlying molecular mechanisms have yet to be determined. Oxidative and inflammatory status at the fetal-placental unit appear to be involved in the early fetal metabolic programming. The objective of the present study is to reveal a potential role of sphingolipids in stablishing an oxidative and inflammatory status in the maternal-placental-fetal unit, as function of fetal sex. Term placenta and maternal and fetal plasma were collected from lean (BMI 18-25 kg/m²) and obese women (BMI 30-40 kg/m²) without gestational diabetes aged from 20 to 40 having undergone a cesarean section. Firstly, key markers of oxidative stress and inflammation were studied with immunoblotting and biochemical assays. Secondly, the maternal-placental-fetal unit's sphingolipid profile was determined by mass spectrometry. Lastly, the placental samples' transcriptome was analyzed by RNA sequencing. Obese mothers showed lower plasma levels of ceramide Cer 20:0 (p = 0.02). Surprisingly, placental ceramide content was not influenced by maternal obesity. Nevertheless, male placentas from obese women showed a higher sphingomyelin content and hypo-inflammation as showed by RNAseq. Both males and female placentas from obese women showed higher levels of oxidative stress as showed by the oxidative stress markers (protein carbonylation and lipid peroxidation). However, RNAseq revealed an upregulation of oxidative stress mechanisms only in female placentas. Whatever the newborn's sex, maternal obesity was associated with higher fetal plasma oxidative stress. In conclusion, our results revealed sex-specific features in the placental transcriptome, highlighted placental metabolic adaptations, and provided insights into the underlying molecular mechanisms of fetal programming.</p>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":" ","pages":"112640"},"PeriodicalIF":3.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804438","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":"4T1 breast cancer cells exposed to extracellular vesicles from MDA-MB-231 cells stimulated with Bisphenol A increase the growth of mammary tumors and metastasis in female Balb/cJ mice.","authors":"Pablo Torres-Alamilla, Rocio Castillo-Sanchez, Pedro Cortes-Reynosa, Maria Sanchez-Juarez, Rocio Gomez, Eduardo Perez Salazar","doi":"10.1016/j.mce.2025.112641","DOIUrl":"10.1016/j.mce.2025.112641","url":null,"abstract":"<p><p>Breast cancer is the most prevalent neoplasia in women worldwide. Triple negative breast cancer (TNBC) is a subtype characterized by the absence of estrogen receptor, progesterone receptor and HER2 expression. Bisphenol A (BPA) is a chemical used in the synthesis of polycarbonate plastics and epoxy resins and its intake is related with breast cancer progression. Extracellular vesicles (EVs) are vesicles released by cells that mediate intercellular communication. However, the role of BPA in the release of EVs mediating cancer progression in TNBC remains to be studied. We hypothesize that EVs from BPA-stimulated TNBC cells promote metastasis-related processes, tumor growth and enhanced metastasis in a breast cancer mouse model. This study aims to evaluate the functional role of EVs from BPA-stimulated TNBC cells in metastasis-related processes and breast cancer progression using \"in vitro\" 4T1 cells models and an \"in vivo\" breast cancer mouse model. Findings demonstrate that exposition of TNBC 4T1 cells to EVs from TNBC MDA-MB-231 cells stimulated with 1 μM BPA for 24 h (BPA-EVs) significantly increases migration, invasion and MMP-9 secretion, compared to 4T1 cells exposed to EVs from non-stimulated MDA-MB-231 cells (Ctrl-EVs). Furthermore, Balb/cJ mice inoculated in mammary fat pad with 4T1 cells exposed to BPA-EVs show mammary tumors with more weight and volume, and more metastatic nodules in lung and liver than Balb/cJ mice inoculated with 4T1 cells exposed to Ctrl-EVs. In conclusion, BPA-EVs represent a significant mediator of TNBC progression, which defining the EVs as a novel element through which BPA promotes breast cancer progression.</p>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":" ","pages":"112641"},"PeriodicalIF":3.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812130","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":"Mitochondrial dysfunction and defective quality control mechanisms in the kidney are not reversed by high-fat diet withdrawal in early obese mice.","authors":"Patrícia C Braga, Rui Vitorino, Rita Ferreira, Mariana Marques, Pedro F Oliveira, Anabela S Rodrigues, Marco G Alves","doi":"10.1016/j.mce.2025.112635","DOIUrl":"10.1016/j.mce.2025.112635","url":null,"abstract":"<p><p>High fat diet (HFD) induces glomerulopathy and proximal tubule injury. The precise pathophysiological mechanisms triggering obesity-related kidney impairment remain elusive, especially after dietary correction. Male C57BL6/J mice (n = 15) were divided in: control group (CTR) fed with standard chow; a group fed with HFD for 200 days (28-29 weeks); and a group fed with HFD for 60 days (8-9 weeks) and then with standard chow (HFDt)(∼21 weeks). Biometric data and whole-body metabolism were assessed. Expression of genes associated with mitochondrial dynamics, mitochondrial complexes and antioxidant defenses were analyzed. Kidney homogenates enriched in mitochondria were prepared and characterized by mass spectrometry-based proteomics. Kidney tissue of mice fed HFD exhibited reduced PGC-1α expression, an imbalance between fusion (increased MFN1 and decreased OPA1) and fission (decreased FIS1 and DRP1) processes. The activity of mitochondrial complex I (CI) was increased, while activity of complex II (CII) was decreased in the kidney after HFD and HFDt. Antioxidant defense Manganese Superoxide dismutase (MnSOD) was decreased in the kidney of HFD, while Glutathione reductase (GR) increased, with both activities being restored upon dietary reversion. Proteomic analysis showed alterations in proteins associated with glutathione and glycine metabolism, fatty acid oxidation (FAO), and peroxisomal function. HFD negatively impacted kidney glutathione related proteins (Gsta3 and Gsr); however dietary correction reverted this condition. Acsm3 protein was downregulated in kidney after HFD and upregulated after dietary correction. Some machinery is shared by mitochondria and peroxisomes, with their network being crucial particularly under stress conditions. A HFD impaired kidney FAO in peroxisomes, as evidenced by downregulation of Pecr after HFD and HFDt. Dietary correction after early-obesity mitigates the systemic metabolic dysfunction and can attenuate mitochondria dysfunction but is unable to completely restore mitochondria dynamics and bioenergetics. The results highlight the integrity of mitochondrial network as a main point for targeted therapeutic strategies aimed at preventing the progression of kidney disease.</p>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":" ","pages":"112635"},"PeriodicalIF":3.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799643","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":"Heterogeneity of Sox2-expressing cells in mouse pituitary and their roles in postnatal gonadotroph differentiation.","authors":"Kosara Smiljanic, Stephanie Constantin, Naseratun Nessa, Stanko S Stojilkovic","doi":"10.1016/j.mce.2025.112638","DOIUrl":"10.1016/j.mce.2025.112638","url":null,"abstract":"<p><p>Postnatal differentiation of gonadotrophs from Sox2-expressing stem cells is essential for maturation of the hypothalamic-pituitary-gonadal axis, puberty, and reproduction. Here, we examined the differentiation and maintenance of gonadotrophs in developing and adult mice. Gonadotrophs and Sox2-expressing cells were identified by immunostaining, and gonadotrophs were also visualized by specific expression of the fluorescent protein tdTomato during embryonic and postnatal differentiation. Sox2-expressing cells are localized in the anterior parenchyma, marginal zone, and posterior pituitary, regardless of mouse age. Gonadotrophs are localized in the anterior parenchyma separate from Sox2-expressing cells. During the juvenile and prepubertal periods, cells in transition from Sox2 expression to tdTomato expression, as well as numerous differentiated gonadotrophs, were also present in the marginal zone. The size and distribution of the newly differentiated gonadotrophs were consistent with their migration into the parenchyma and maturation into a secretory cell type. Specific knockout of PI4-kinase A in gonadotrophs slowed their postnatal differentiation in the marginal zone, causing a significant reduction in the size of the gonadotroph population. This was accompanied by a progressive loss of specific gene expression in the residual gonadotrophs, leading to an increase in the number of dedifferentiated cells expressing tdTomato. Thus, Sox2 expressing cells in the marginal zone serve as stem cells for postnatal gonadotrophs, and the differentiation and maintenance of these cells require phosphoinositides derived by PI4-kinase A.</p>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":" ","pages":"112638"},"PeriodicalIF":3.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799642","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":"2025-09-29","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":"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":"2025-09-27","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}