Journal of molecular endocrinology最新文献

{"title":"Antioxidant, Bioenergetic, and Metabolic Effects of Novel Mitochondria-Targeted Estrogens.","authors":"Geovanni Alberto Ruiz-Romero, Johanna Bernáldez-Sarabia, Magdiel Orozco-Valdivia, Jessica Yazbel Romero-Rico, Pablo Garrido, Gonzalo Isaí Flores-Acosta, Alfredo Martínez, Carolina Álvarez-Delgado","doi":"10.1530/JME-25-0081","DOIUrl":"https://doi.org/10.1530/JME-25-0081","url":null,"abstract":"<p><p>Estrogens are steroid hormones that regulate antioxidant and mitochondrial bioenergetic metabolism in addition to activating nuclear genomic pathways. Concentrating these effects within the mitochondria is a novel strategy for ameliorating mitochondrial dysfunction, which is characteristic of cancer, metabolic, and neurodegenerative diseases. The use of synthetic mitochondria-targeted estrogens containing a triphenylphosphonium group may provide a basis for improving mitochondrial function in these conditions. Here, we evaluate the effects of two compounds, one derived from 17β-estradiol (mitoE2) and the other from 17α-ethinylestradiol (mitoEE2) on cell viability in MCF-7 and CCD-1112Sk cells. We further examine their influence on the activities of superoxide dismutase (MnSOD), citrate synthase (CS), cytochrome c oxidase (COX), and ATP synthase, as well as in the glycolytic reserve and cellular respiration. In both cellular models, cell viability assays indicated that MitoE2 was well tolerated below 500 nM, while MitoEE2 allowed treatments up to 100 nM for up to 24 hours. We found that the molecules act differently on enzymatic targets. Exposure of MCF-7 cells to mitoE2 resulted in reduced MnSOD activity. Pretreatment with MitoE2 or MitoEE2 restored the viability of MCF-7 cells exposed to H2O2-induced oxidative damage to levels comparable to untreated controls. Additionally, MitoEE2 increased the activities of CS and COX. Both mitochondria-targeted estrogens increased glycolytic reserve and mitochondrial respiration, as determined by extracellular flux assays. Overall, these findings suggest that the antioxidant and bioenergetic effects observed encourage further investigation into their potential as therapeutic strategies for conditions linked to mitochondrial dysfunction.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145258320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MicroRNA-411-5p alleviates hepatic insulin resistance via suppressing transcription factor Sp2 in MASLD mice.","authors":"Chunli Song, Jinglin Shao, Qingquan Xiong, Yao Men, Hezhongrong Nie","doi":"10.1530/JME-24-0156","DOIUrl":"https://doi.org/10.1530/JME-24-0156","url":null,"abstract":"<p><p>Insulin resistance is often characterized as the factor that contributes to the emergence of metabolic diseases. Hepatic microRNAs (miRNAs) played critical roles in the development of metabolic-associated steatotic liver disease (MASLD) and insulin resistance. To investigate the effects of hepatic miR-411-5p in regulating insulin resistance, the present study utilized primary mouse hepatocytes and mice with MASLD. Suppression of miR-411-5p decreased hepatocyte glycogen production and phosphorylation of AKT, but miR-411-5p mimic improved insulin sensitivity. Mechanistically, 3'-UTR of transcription factor Sp2 was one of binding sites of miR-411-5p. Treatment of miR-411-5p mimic suppressed the Sp2 mRNA and protein levels, enhancing the insulin signaling activity in the primary mouse hepatocytes. Hepatocyte-specific overexpression of Sp2 induced hepatic lipid accumulation and activation of related metabolic pathways. On the contrast, inhibition of miR-411-5p reversely upregulated the expression of Sp2, and exaggerated the insulin resistance in primary hepatocytes and mouse model. Similarly, miR-411-5p mimic decreased obesity-induced hyperinsulinemia, glucose intolerance, insulin intolerance, and pyruvate intolerance. Furthermore, the parameters of MASLD, including lipid deposits, inflammation and fibrosis, were improved after miR-411-5p replenishment, but co-administration with adeno-associated virus (AAV)-Sp2 abolished these benefits in obese mouse model. Taken together, these findings demonstrated that Sp2-dependent miR-411-5p action regulates insulin resistance and MASLD, which provides therapeutic approach toward resolving insulin resistance.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145258354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intronic IGF1R Variant Causing Aberrant Splicing, Short Stature and Neurological Impairments.","authors":"Liya Kerem, Jonathan Rips, Adam Zaretsky, Itay Grundwag, Ehud Cohen, Shira Yanovsky-Dagan, Tamar Harel","doi":"10.1530/JME-25-0002","DOIUrl":"https://doi.org/10.1530/JME-25-0002","url":null,"abstract":"","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ERRATUM: Effect of insulin-like growth factor binding protein-1 on integrin signalling and the induction of apoptosis in human breast cancer cells.","authors":"C M Perks, P V Newcomb, M R Norman, J M Holly","doi":"10.1530/JME-22-0141e","DOIUrl":"10.1530/JME-22-0141e","url":null,"abstract":"","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":"75 3","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Contrasting roles for GLP-1R and GIPR in a model of diet-induced obesity.","authors":"Jie Gao, Shelby Cree, Seungmin Ham, Cameron Nowell, Alex Parker, Peishen Zhao, Lynda Whiting, Kyle W Sloop, Ricardo J Samms, Patrick M Sexton, Denise Wootten, Dana S Hutchinson","doi":"10.1530/JME-25-0053","DOIUrl":"10.1530/JME-25-0053","url":null,"abstract":"<p><p>The glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) are important incretin receptors that are therapeutic targets for the treatment of type 2 diabetes and obesity. This study extensively characterised the metabolic phenotype of mice with global deletion of either the GLP-1R or GIPR side by side under identical conditions. Age-matched male wild-type (WT) C57Bl6NTac, GLP-1RKO or GIPRKO mice were placed on a high-fat or chow diet for 12 weeks, and a range of in vivo (weight gain, food intake, glucose tolerance, insulin tolerance, and whole-body energy metabolism) and ex vivo (white adipocyte lipolysis, brown adipose tissue and liver mitochondrial function, adipocyte and islet size, and hepatic steatosis) parameters were measured. While both WT and GLP-1RKO mice gained weight similarly on a HFD, obese high-fat-fed GLP-1RKO mice had altered glucose and insulin tolerance, and exhibited hepatic steatosis, highlighting the physiological importance of the GLP-1R in the regulation of blood glucose and lipid homoeostasis. In contrast, GIPRKO mice were partially resistant to diet-induced obesity compared to the WT mice, which was associated with a small reduction in food intake and intact epididymal and subcutaneous white adipocyte β-adrenoceptor-mediated lipolysis. Similarly, WT mice treated with a GIPR antagonist prevented weight gain due to a reduction in food intake on a HFD. These findings provide further support that the GLP-1R is important for normal glycaemic control, whereas the GIPR may play a role in the regulation of body weight.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Capsaicin-activated autophagy protects BMSC function under oxidative stress: mechanisms and therapeutic implications.","authors":"Yurong Chen, Qian Peng, Dongmei Lan, Chao Yao, Xiang Chen, Yan Wang, Shengcai Qi","doi":"10.1530/JME-25-0063","DOIUrl":"10.1530/JME-25-0063","url":null,"abstract":"<p><p>Bone marrow stromal cells (BMSCs) play an important role in bone regeneration, but their functional activity is affected by oxidative stress, which is a key pathological feature of osteoporosis. The aim of this study was to investigate the effects of capsaicin on the proliferation and differentiation of BMSCs under oxidative stress. We assessed cell viability and osteogenic potential of capsaicin in promoting BMSC survival and enhancing osteogenic capacity under oxidative stress by cell counting kit-8 (CCK-8), reactive oxygen species fluorescence staining, alkaline phosphatase (ALP) staining, Alizarin Red S (ARS) staining, Western blot (WB), and real-time PCR (RT-PCR). Our results indicate that capsaicin improves cell viability, antioxidant capacity, and osteogenic differentiation in rat BMSCs treated with hydrogen peroxide (H2O2). In addition, immunohistochemistry (IHC) analysis revealed that the surface of BMSCs expressed the capsaicin receptor transient receptor potential vanilloid protein 1 (TRPV1). More importantly, capsaicin increased Ca2+ influx and autophagy and inhibited phosphorylation of the PI3K/AKT/mTOR signaling pathway. In conclusion, capsaicin protects BMSC function during oxidative stress, possibly through inducing TRPV1-mediated Ca2+ influx and PI3K/AKT/mTOR-activated autophagy. The results suggest the potential of capsaicin as a therapeutic agent for osteoporosis.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NR4A3 affects fibrotic activation of orbital fibroblasts and thyroid-associated ophthalmopathy through regulating NF-κB signaling.","authors":"Jinping Yi, Shenghua Liu, Shiyao Lu, Yao Tan, Wei Xiong","doi":"10.1530/JME-25-0068","DOIUrl":"https://doi.org/10.1530/JME-25-0068","url":null,"abstract":"<p><p>Orbital fibroblast proliferation and activation contribute to the development of thyroid-associated ophthalmopathy (TAO). In this study, nuclear receptor subfamily 4 group A member 3 (NR4A3) was predicted to play a role in TAO based on bioinformatics analysis. Validation of NR4A3 expression in human TAO orbital samples confirmed its elevated levels compared to normal controls. In vitro studies demonstrated that transforming growth factor beta 1 (TGF-β1)-induced NR4A3 expression in human TAO orbital fibroblasts (OFs) enhanced cell viability, DNA synthesis, and fibrotic marker expression. Conversely, NR4A3 knockdown inhibited these fibrotic responses, suggesting a pro-fibrotic role for NR4A3 in TAO. In vivo experiments further validated these findings, with NR4A3 knockdown in a TAO mouse model leading to reduced pathological injury and fibrosis in orbital tissues. Additionally, NR4A3 knockdown decreased the expression of fibrotic markers in the orbital tissues of TAO mice, corroborating the in vitro results. Finally, NR4A3 was shown to modulate the nuclear factor kappa B (NF-κB) pathway, which is activated in TAO. NR4A3 overexpression enhanced, while its knockdown suppressed, NF-κB activation in both human TAO OFs and orbital tissues from TAO mice. These findings suggest that NR4A3 promotes TAO progression through its pro-fibrotic effects and activation of NF-κB signaling, highlighting its potential as a therapeutic target for TAO. Collectively, NR4A3 plays a pivotal regulatory role in both fibroblast proliferation and the fibrotic response in TAO, acting through mechanisms involving the NF-κB signaling pathway. Its ability to enhance TGF-β1-induced changes and activate NF-κB underscores its potential as a key therapeutic target for addressing the complex pathophysiology of TAO.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single cell analysis of uterine artery endothelial cells reveals cytokine induced emergence of specific immunomodulatory subtypes: implications for preeclampsia.","authors":"Dahn Rl, B M Lett, Clemente L, Austin Jl, Yi Fx, D S Boeldt, Stanic Ak, Ong Im, Bird Im","doi":"10.1530/JME-24-0086","DOIUrl":"https://doi.org/10.1530/JME-24-0086","url":null,"abstract":"<p><p>While pregnancy is known to be an inflammatory condition, preeclampsia (PE) is associated with higher chemokines and pro-inflammatory cytokines, and higher Th1/Th2 and Th17/Treg ratios. Since the uteroplacental space can secrete cytokines, including TNF and IL1B, a common assumption is the proinflammatory immune cell profile of Th1 and Th17 cells dominating over Th2 and Treg cells begins in that space. To date, a possible role for endothelium in this initiation process has not been considered. Nonetheless, recent publications show that endothelium can become immunomodulatory on exposure to TNF and IL1B, and in systemic hypertension, endothelium has been shown to exist as multiple cell subtypes. We have recently shown that uterine artery endothelial cells from late-pregnant sheep (P-UAEC) treated with TNF alone secrete many of the chemokines and cytokines further elevated in PE subjects. Herein we show that P-UAEC also exist in multiple subtypes with distinct chemokine and cytokine secretory and immunomodulatory properties. The 5 subtypes are differentially regulated by TNF-alpha (TNF) and IL1-beta (IL1B) that may favor subtype specific binding and interaction with distinct classes of Th cells, and an altered ability to respond to Th secreted cytokines (such as IL17 and IL10). Thus, our data demonstrates the possibility that certain endothelial cell subtypes can be pushed to express immunomodulatory proteins by early exposure to increases in TNF or IL1B of immune cell, trophoblast and decidual origin. This in turn begs the question if such endothelial changes could contribute to subsequent immune disturbances seen at the time of clinical presentation.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aldosterone synthase inhibition: a novel bullet to fight cardiovascular-kidney-metabolic syndrome.","authors":"Jonatan Barrera-Chimal, Anand Vaidya, Frederic Jaisser","doi":"10.1530/JME-25-0047","DOIUrl":"10.1530/JME-25-0047","url":null,"abstract":"<p><p>Aldosterone is synthesized by the CYP11B2 enzyme, primarily in the zona glomerulosa of the adrenal gland. It exerts its classical effects on sodium and water balance in the renal distal nephron through binding to the mineralocorticoid receptor (MR). Excess aldosterone production or overactivation of the MR outside the distal nephron leads to cardiac, renal, and vascular injury by increasing oxidative stress and activating the inflammatory and fibrotic pathways. MR antagonists (MRAs) have proved effective at decreasing organ damage and the deleterious effects of excess aldosterone/MR activation. However, MRAs do not fully block the non-genomic effects of aldosterone, which may contribute to residual risks. CYP11B2 inhibition has emerged as an additional therapeutic approach to decreasing the deleterious genomic and non-genomic effects of aldosterone. The development of specific aldosterone synthase inhibitors (ASi) has proved challenging due to the considerable similarity between aldosterone synthase and 11β-hydroxylase, an enzyme encoded by the CYP11B1 gene that catalyzes cortisol synthesis. In this review, we summarize the latest developments on preclinical evidence and clinical trials for ASi and explore the potential clinical advantages of ASi.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of Parabacteroides distasonis colonization on host microbiome, metabolome, immunity, and diabetes onset.","authors":"Khyati Girdhar, Audrey Randall, Keiichiro Mine, Clarissa Howard, Alessandro Pezzella, Dogus Dogru, Lukas Rhodes, Brady James, Umesh K Gautam, Dagmar Šrůtková, Tomas Hudcovic, Juan J Aristizabal-Henao, Michael Kiebish, Emrah Altindis","doi":"10.1530/JME-25-0025","DOIUrl":"10.1530/JME-25-0025","url":null,"abstract":"<p><p>Type 1 diabetes (T1D) is caused by autoimmune destruction of pancreatic β-cells. The insulin B-chain 9-23 (insB9-23) peptide is a critical epitope in triggering T1D. In our previous study, we showed that Parabacteroides distasonis, a human gut commensal, contains an insB9-23 mimic in its hprt protein (residues 4-18). This mimic (hprt4-18) peptide activates insB9-23-specific T cells, and P. distasonis colonization enhanced diabetes in NOD mice. However, the impact of the P. distasonis colonization on inflammation, gut microbiome, intestinal immune cells, gut permeability, cytokine, and serum metabolome profiles remained unknown. Here, we investigated these effects using specific pathogen-free (SPF) and germ-free (GF) female NOD mice. P. distasonis colonization minimally impacted gut microbiome composition, altering only 28 ASVs. In P. distasonis-colonized mice, there was a reduction in T-helper, T-effector, and B-cell populations in the intraepithelial lymphocytes, indicating a potential decrease in immune activation. Furthermore, P. distasonis colonization did not alter serum metabolome and circulating cytokine profiles (except for a decrease in IL-15) and gut permeability gene expressions. P. distasonis colonization in GF NOD mice induced severe insulitis without affecting gut permeability. Interestingly, mice gavaged with heat-inactivated (HI) P. distasonis did not affect insulitis scores or immune cell composition. These findings support our hypothesis that P. distasonis functions as a gut commensal, exerting no effect on the gut microbiome, metabolome, gut permeability, intestinal immune cell composition, or nonspecific immune activation. Instead, P. distasonis appears to trigger an insB9-23-specific immune response, potentially accelerating T1D onset in NOD mice through molecular mimicry.</p>","PeriodicalId":16570,"journal":{"name":"Journal of molecular endocrinology","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12400532/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}