Endocrinology最新文献

{"title":"Berberine Protects Pancreatic β-Cells From IL-1β Damage Through Hormetic Mechanisms Via P53-Mediated Apoptosis Pathways.","authors":"Xinyu Yang, Shuntao Liang, Mingyue Huang, Shijun Yue, Dechun Jiang, Dan Yan","doi":"10.1210/endocr/bqaf105","DOIUrl":"10.1210/endocr/bqaf105","url":null,"abstract":"<p><p>Damage to pancreatic β-cells serves as a critical pathological basis in the progression of diabetes. Berberine (BBR), an isoquinoline alkaloid, potentially protects pancreatic β-cells, exerting hypoglycemic effects. However, the dose-response relationship and the specific protective mechanism are still unclear. Hormesis is a self-protective response triggered by mild stimuli and has been reported to determine the extent to which phytochemicals can combat diabetes. In this study, we found that BBR exhibited a typical hormetic effect in IL-1β-induced damage to pancreatic β-cells, where low doses of BBR protect cells while high doses aggravate the damage. A model-based approach was used to describe dose-response relationships, as well as to detect and estimate hormetic effects. In addition, the regulatory effect of BBR in preventing apoptosis in pancreatic β-cells was confirmed, and an appropriate dose of BBR stabilized the mitochondrial membrane potential and prevented DNA damage. Moreover, the results showed that the hormetic effect of BBR was closely related to p53 and apoptosis pathways. To further investigate the role of the p53-mediated apoptosis pathways, our study interfered with the p53 pathway, resulting in the attenuation of the hormetic effect of BBR. These results introduce the concept of hormesis to study the biphasic effects of berberine on damaged pancreatic β-cells, while also exploring the relationship between the hormetic mechanism of BBR and the p53-mediated apoptosis pathway. These findings provide clues to explore the potential application of BBR in treating diabetes.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247058","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":"NEDD4 Promotes Sertoli Cell Proliferation and Adult Leydig Cell Differentiation in the Murine Testis.","authors":"Simon Peter Windley, Yasmine Neirijnck, Diana Vidovic, Quenten Schwarz, Sharad Kumar, Serge Nef, Dagmar Wilhelm","doi":"10.1210/endocr/bqaf115","DOIUrl":"10.1210/endocr/bqaf115","url":null,"abstract":"<p><p>Successful testis development relies on the coordinated differentiation and assembly of various cell types to establish both endocrine and reproductive functions. The ubiquitin ligase NEDD4 has emerged as a key player in murine testis development, with this enzyme being implicated in gonadal sex determination and spermatogonial stem cell differentiation. Here, we report hitherto uncharacterized roles of NEDD4 in postnatal testis development. Utilizing Nr5a1- and Amh-Cre drivers to conditionally ablate Nedd4 in testicular somatic cells, we show that NEDD4 promotes Sertoli cell proliferation through the modulation of the PI3K-AKT signaling pathway. This ubiquitin ligase also ensures proper differentiation of adult Leydig cells and may contribute to murine steroidogenesis. Furthermore, NEDD4 is essential for adrenal gland differentiation, as its loss results in adrenal dysgenesis. These findings highlight NEDD4 as a crucial factor in testis development, emphasizing the importance of ubiquitination and post-translational modifications in reproductive biology.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12280327/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144552690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Canine Adrenomedullary and Pheochromocytoma Organoids: A Novel In Vitro Model.","authors":"Marit F van den Berg, Elpetra P M Timmermans-Sprang, Fleur C Viets, Lucas van den Berg, Fatima Danawar, Monique E van Wolferen, Hans S Kooistra, Guy C M Grinwis, Wilhelmina H A de Jong, Martijn van Faassen, Sara Galac","doi":"10.1210/endocr/bqaf114","DOIUrl":"10.1210/endocr/bqaf114","url":null,"abstract":"<p><strong>Context: </strong>Given the lack of effective medical treatment for pheochromocytomas (PCCs), a reliable in vitro model is needed to explore new therapies. Organoids are three-dimensional (3D) self-renewing structures that exhibit key features of their tissue of origin, providing valuable platforms for disease modeling and drug screening.</p><p><strong>Objective: </strong>This study aimed to establish and characterize organoid cultures of canine normal adrenal medullas and PCCs.</p><p><strong>Methods: </strong>Normal adrenal medullas from healthy dogs and tumor tissue from client-owned dogs with PCC were used to develop organoids. Primary cell suspensions were cultured in a 3D matrix, and organoids were established under optimized conditions. Organoids were characterized using histology, immunohistochemistry, immunofluorescence, qPCR, and metanephrine analysis by LC-MS/MS.</p><p><strong>Results: </strong>Five adrenomedullary organoid lines were successfully established, demonstrating sustained growth. Organoid cultures were also derived from 9 PCCs, although expansion was limited after passages 1 to 2. Both adrenomedullary and PCC organoids expressed differentiation markers (chromogranin A, synaptophysin, phenylethanolamine N-methyltransferase) and stem/progenitor markers (nestin, SOX10). Organoids retained key functional traits, as indicated by metanephrine levels in culture supernatants, which initially mirrored primary tumor patterns. A decline in both differentiation marker expression and metanephrine levels was observed over time, possibly due to organoid dedifferentiation or selective loss of differentiated chromaffin cells.</p><p><strong>Conclusion: </strong>This study demonstrates the establishment of the first adrenomedullary and PCC organoid lines. While further optimization is needed, these organoids offer valuable potential as an in vitro model to investigate PCC pathophysiology and explore novel treatment strategies for this therapeutically challenging tumor.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12264429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144505212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AR PROTACs for PCOS: A Long-awaited Breakthrough?","authors":"Olga Astapova","doi":"10.1210/endocr/bqaf111","DOIUrl":"10.1210/endocr/bqaf111","url":null,"abstract":"","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511717","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":"Estradiol Promotes Habituation Learning via an Unidentified Target, Bypassing the Suppressive Effects of Established ERs.","authors":"Andrew Hsiao, Isabelle Darvaux-Hubert, Dominique Hicks, Emilie Joux, Sarah De Freitas, Emeline Dracos, Jeanne Lizé, Julien Perrichet, Dominique Baas, Owen Randlett","doi":"10.1210/endocr/bqaf110","DOIUrl":"10.1210/endocr/bqaf110","url":null,"abstract":"<p><p>Habituating to the constant stimuli in the environment is a critical learning process conserved across species. We use a larval zebrafish visual response to sudden darkness as a model for studying habituation learning, where zebrafish reduce their responses to repeated stimulations. In this paradigm, treatment with estradiol strongly increases learning rate, resulting in more strongly suppressed responses. We used mutant lines for the estrogen receptors (ERs)-esr1, esr2a, esr2b, gper1-in an attempt to identify the receptor(s) mediating these effects. These experiments failed to identify a necessary receptor (or combination of receptors). Surprisingly, esr1, esr2a, and gper1 mutants showed weak but consistent increases in habituation, indicating that these receptors suppress habituation learning. These experiments demonstrate that estradiol is a complex modulator of learning in our model, where the learning-promoting effects are mediated by an unidentified estradiol target, and the classical estrogen receptors act in competition to subtly suppress learning.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144505213","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":"Deficiency of Estrogen Receptor 2 Expression Enhances Disorganization of the Mouse Uterus With Age.","authors":"Tadaaki Nakajima, Reina Arakawa, Saki Nose, Norika Matsuda, Airi Tsuge, Mami Ishii, Tomohiro Ishikawa, Yurika Tsurugai, Shinichi Miyagawa, Taisen Iguchi, Tomomi Sato","doi":"10.1210/endocr/bqaf103","DOIUrl":"10.1210/endocr/bqaf103","url":null,"abstract":"<p><p>Constitutive stimulation of estrogen signaling in mice causes dilated uterine glands with activation of epithelial cell proliferation. In estrogen receptor β knockout (Esr2 KO) mice, cell proliferation in the uterine epithelium is permanently stimulated; therefore, we histologically analyzed the uterine structure in Esr2 KO mice with age. In the uterus of Esr2 KO mice, dilation of the uterine glands was accelerated and the collagen was accumulated in the stroma. The uterine glands were dilated with age even in wild-type (WT) mice; however, Esr2 KO accelerated the dilation of uterine glands quantitatively. The expression of FOXA2 transcription factor, which is essential for uterine glandular function, was diminished in dilated uterine glands of WT and Esr2 KO mice and decreased in the uterine glands of normal size in 12-month-old Esr2 KO mice. To investigate mechanisms of the collagen accumulation in the Esr2 KO uterus, we focused on collagen synthesis and degradation. In the uterine stroma of Esr2 KO mice, MMP8 expression in whole uteri and the number of MMP8-expressing macrophages were decreased. An analysis of the comprehensive gene expression suggested that increased expression of fibroblast growth factors and decreased expression of an aquaporin may be related to the dilation of uterine glands in Esr2 KO mice, and reduced infiltration or differentiation into the macrophages with MMP8 expression may be involved with the collagen accumulation in Esr2 KO mice with age. Taken together, the absence of ESR2 constitutively disrupts estrogen signaling and promotes aging in the uterus via stimulation of epithelial cell proliferation and a decrease of MMP8-expressing macrophages.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208040","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":"ATF4 Deletion in Brown Adipocytes Attenuates Diet-Induced Insulin Resistance in Male Mice Independently of Weight Gain.","authors":"Alex Marti, Sarah H Bjorkman, Luis Miguel García-Peña, Eric T Weatherford, Jayashree Jena, Renata O Pereira","doi":"10.1210/endocr/bqaf101","DOIUrl":"10.1210/endocr/bqaf101","url":null,"abstract":"<p><p>Expression of the activating transcription factor 4 (ATF4) in thermogenic adipocytes is required to maintain core body temperature and systemic metabolic homeostasis in models of mitochondrial stress. We have recently shown that ATF4 is required for thermoregulation in response to cold stress in mice, establishing a role for ATF4 in regulating brown adipose tissue (BAT) function during physiological stress. In the present study, we investigated the role of ATF4 in thermogenic adipocytes in regulating glucose metabolism and energy homeostasis during diet-induced obesity (DIO). To this end, we generated mice with selective Atf4 deletion in BAT (ATF4 BKO). After 12 weeks of high-fat-feeding, ATF4 BKO mice had similar weight gain and total fat mass relative to wild-type mice. Accordingly, no changes in food intake, locomotor activity, or energy expenditure were detected between genotypes. Nonetheless, diet-induced glucose intolerance and insulin resistance were attenuated in ATF4 BKO mice, which correlated with reduced markers of inflammation and increased levels of glucose transporters in BAT. Taken together, our results indicate that Atf4 deficiency in BAT during DIO improves glucose homeostasis and insulin sensitivity in mice without affecting energy homeostasis. Mechanistically, our data suggest ATF4 deletion leads to repressed inflammation in BAT of obese mice, while likely increasing glucose uptake and utilization, thereby contributing to overall improvement in glucose homeostasis.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208039","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":"Overexpression of PTHrP in β Cells Reveals Key Effects on Endoplasmic Reticulum Stress.","authors":"Ibiagbani M Max-Harry, Nida Ajmal, Palwasha Khan, Landen E Davis, Waleed J Hashmi, Noriko Kantake, Kathryn L Corbin, Thomas J Rosol, Craig S Nunemaker","doi":"10.1210/endocr/bqaf086","DOIUrl":"10.1210/endocr/bqaf086","url":null,"abstract":"<p><p>Administration of parathyroid hormone-related protein (PTHrP) has been shown to increase insulin content and secretion in mice. PTHrP also increases β-cell mass and proliferation. However, the mechanisms for these effects are unknown, and investigations have yet to examine PTHrP in the transcriptome. In this study, we transiently transfected a mouse β-cell line (MIN6) with either full-length PTHrP or DSred vector. Insulin content and glucose-stimulated insulin secretion were measured, and RNA from the cells after incubating in 20 mM glucose was collected. The results showed that PTHrP overexpression increased insulin content and the ratio of insulin secretion between low and high glucose (stimulation index). RNA sequencing showed that PTHrP overexpression downregulated many genes associated with responses to endoplasmic reticulum (ER) stress such as Hspa40, Dnajc3, and Xbp1. Among enriched Kyoto Encyclopedia of Genes and Genomes pathways, the ER stress gene pathway was the most strongly downregulated by far, and the most upregulated pathway was for biosynthesis of amino acids required for protein synthesis. These pathways suggest increased rates of protein biosynthesis. Quantitative polymerase chain reaction supported RNA-sequencing results for several ER stress genes (Xbp1, Bax, Bip). MIN6 cells transfected with PTHrP also had lower proinsulin-to-insulin ratio, indicating that PTHrP enhanced insulin processing in the ER. Our working hypothesis is that PTHrP augments insulin production and ER efficiency, which is consistent with observations of increased insulin content, decreased proinsulin-to-insulin ratio and reduced ER stress markers in MIN6 cells. In conclusion, our findings suggest a previously unknown role for PTHrP in β-cell endoplasmic reticulum, which may have therapeutic implications for enhancing insulin production.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968265","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":"Neuromedin U Deficiency Disrupts Daily Testosterone Fluctuation and Reduces Wheel-Running Activity in Rats.","authors":"Mai Otsuka, Yu Takeuchi, Maho Moriyama, Sakura Egoshi, Yuki Goto, Tingting Gu, Atsushi P Kimura, Shogo Haraguchi, Taishi Yoshii, Sakae Takeuchi, Makoto Matsuyama, George E Bentley, Sayaka Aizawa","doi":"10.1210/endocr/bqaf102","DOIUrl":"10.1210/endocr/bqaf102","url":null,"abstract":"<p><p>The objective of this study was to elucidate the role of endogenous Neuromedin U (NMU) in rats by performing NMU knockout (KO). Male, but not female NMU KO rats exhibited decreased wheel-running activity vs wildtype (WT), although overall home cage activity was not affected. Plasma testosterone in WT rats varied significantly over the course of a day, with a peak at ZT1 and a nadir at ZT18, whereas in NMU KO rats testosterone remained stable throughout the day. Chronic administration of testosterone restored wheel-running activity in NMU KO rats to the same level as in WT rats, suggesting that the decrease in wheel-running activity in NMU KO rats is due to the disruption of the diurnal change of testosterone. Accordingly, expression of the luteinizing hormone beta subunit (Lhb) mRNA in the pars distalis of anterior pituitary was significantly lower in NMU KO rats; immunostaining revealed that the size of luteinizing hormone (LH)-expressing cells was also relatively small in those animals. In the brain of male WT rats, Nmu was highly expressed in the pars tuberalis, and the NMU receptor Nmur2 was highly expressed in the ependymal cell layer of the third ventricle. This study reveals a novel function of NMU and indicates that endogenous NMU in rats plays a role in the regulation of motivated activity via regulation of testosterone.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12204324/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mini-ghrelins: Functional Characterization of N-terminal Peptides Derived From Ghrelin Proteolysis in Male Samples.","authors":"Gimena Fernandez, Antonela Fittipaldi, Daniela Lufrano, Emilio R Mustafá, Daniel Castrogiovanni, Franco Barrile, Pablo N De Francesco, María J Tolosa, Silvia S Rodriguez, Tyler Lalonde, Leonard G Luyt, Sebastián Trejo, Jesica Raingo, Mario Perello","doi":"10.1210/endocr/bqaf104","DOIUrl":"10.1210/endocr/bqaf104","url":null,"abstract":"<p><p>Some evidence suggests that ghrelin in plasma undergoes proteolytic processing, leading to the generation of shorter peptides containing the bioactive N-terminal end of this peptide hormone. However, the chemical nature and bioactivity of these shorter versions of ghrelin (termed mini-ghrelins) remain to be clearly defined. Mini-ghrelins generated in plasma were analyzed using mass spectrometry. The binding to and action on the GH secretagogue receptor (GHSR) of mini-ghrelins were assessed in vitro in a heterologous expression system using fluorescent imaging and electrophysiology, as well as in vivo in male mice through binding studies, immunohistochemistry, and behavioral assessments. We present the first characterization of peptides derived from ghrelin proteolysis in human, rat, and mouse plasma. We found that the shortest mini-ghrelin in humans and rats is ghrelin(1-11). In vitro, ghrelin(1-11) binds to GHSR, activates it with similar potency to ghrelin, and inhibits further ghrelin binding. In mice, ghrelin(1-11) binds to GHSR in orexigenic neurons of the arcuate nucleus but does not induce detectable changes in food intake or in the levels of the neuronal activation marker c-Fos in the hypothalamus. Instead, it prevents binding of fluorescent ghrelin and blocks its orexigenic effects. Ghrelin(1-14), the shortest mini-ghrelin detected in mice, exhibits similar properties to ghrelin(1-11) both in vitro and in vivo. We propose that ghrelin proteolysis in plasma-and the resulting generation of mini-ghrelins-is not merely a mechanism to reduce plasma ghrelin concentration but also a process that diminishes ghrelin's action by blocking its effects.</p>","PeriodicalId":11819,"journal":{"name":"Endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215229","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}