Molecular and Cellular Endocrinology最新文献

{"title":"Relation of mitochondrial DNA copy number and variants with the clinical characteristics of polycystic ovary syndrome","authors":"","doi":"10.1016/j.mce.2024.112386","DOIUrl":"10.1016/j.mce.2024.112386","url":null,"abstract":"<div><div>Mounting evidences suggests mitochondrial dysfunction as a novel contributor in the pathogenesis of PCOS. Herein, we analyzed mtDNA copy number, a biomarker of mitochondrial function in women with PCOS and non-PCOS participants and study its correlation with their clinical characteristics. In this study, we further analyzed association of 383 mtDNA variants, as reported previously by us, with characteristic traits of PCOS and perform structural analysis of mutated protein. Our results indicate relative mitochondrial DNA <strong>(</strong>mtDNA) copy number to be significantly reduced in women with PCOS compared to non-PCOS group and significantly inversely related to waist to hip ratio (WHR), triglycerides and positively related to high density lipoprotein-cholesterol (HDL-C). After adjustment of the age in the PCOS group, significantly negative correlation of mtDNA copy number with WHR was observed. Unsupervised hierarchical clustering analysis revealed rare, low heteroplasmic mtDNA variants such as 12556G, 1488T, 9200G, 9670G, 3308G, 14480G, 15914T and 5426G to be strongly associated with PCOS related traits. Among these variants, variant 12256G in <em>ND5</em> gene affected both the flexibility and overall stability of the protein structure. This study is first to reveal significant correlation of mtDNA copy number with WHR in women with PCOS indicating link between mitochondrial dysfunction with central obesity in PCOS. we also first time showed association of rare mtDNA variants with characteristics traits of PCOS highlighting the clinical significance of rare mtDNA variants, which may cumulatively act as early predictors of risk of PCOS and its related comorbidities which may help in the management of PCOS.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470053","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 impact of mineralocorticoid and glucocorticoid receptor interaction on corticosteroid transcriptional outcomes","authors":"","doi":"10.1016/j.mce.2024.112389","DOIUrl":"10.1016/j.mce.2024.112389","url":null,"abstract":"<div><div>The mineralocorticoid and glucocorticoid receptors (MR and GR, respectively) are members of the steroid receptor subfamily of nuclear receptors. Their main function is to act as ligand-activated transcription factors, transducing the effects of corticosteroid hormones (aldosterone and glucocorticoids) by modulating gene expression. Corticosteroid signaling is essential for homeostasis and adaptation to different forms of stress. GR responds to glucocorticoids by regulating genes involved in development, metabolism, immunomodulation and brain function. MR is best known for mediating the effects of aldosterone, a key hormone controlling electrolyte and water homeostasis. In addition to aldosterone, MR binds glucocorticoids (cortisol and corticosterone) with equally high affinity. This ligand promiscuity has important repercussions to understand MR function, as well as glucocorticoid signaling. MR and GR share significant sequence and structural similarities, regulate overlapping sets of genes and are able to interact forming heteromeric complexes. However, the precise role of these heteromers in regulating corticosteroid-regulated transcriptional outcomes remains an open question. In this review, we examine the evidence supporting MR-GR heteromerization, the molecular determinants of complex formation and their possible role in differential regulation of transcription in different cellular contexts and ligand availability.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470041","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":"Bone action of the phytoestrogen genistein under hypoestrogenism and obesity","authors":"","doi":"10.1016/j.mce.2024.112388","DOIUrl":"10.1016/j.mce.2024.112388","url":null,"abstract":"<div><div>Osteoporosis and obesity are prevalent diseases in menopause. The phytoestrogen genistein (Gen) is an antioxidant/anti-inflammatory agent proposed as natural therapy to counteract syndromes associated to menopause. In this work we evaluated the bone effect of Gen in a stress environment induced by hypoestrogenism and obesity. Bilaterally ovariectomized female Wistar rats were fed with high-fat diet (obese), or standard diet (non-obese). Osteoblasts (OB) primary cultures from femoral shafts, and retroperitoneal explants of white adipose tissue (WAT) <em>in vitro</em> exposed to Gen were employed as experimental systems. In obese rats, bone oxidative stress revealed by enhancement on H₂O₂ release, and significant reduction in OB nitric oxide (NO) production, cell growth, alkaline phosphatase activity (ALP), matrix mineralization and collagen deposition was detected. In OB-WAT co-cultures, Gen treatment inhibited H₂O₂ secretion, and prompted OB differentiation. A direct action of Gen on WAT was demonstrated. The phytoestrogen inhibited H₂O₂ and TBARS production, and diminished the secretion of the inflammatory adipokine leptin, through a mechanism of action mediated by estrogen receptor (ER) involvement, and MAPK and PI3K signal transduction pathways participation. A directional interaction from WAT to bone was evidenced by the incubation OB with conditioned medium obtained from WAT exposed to Gen (Gen-CM). The presence of Gen-CM improved OB growth, and reduced H₂O₂ production. The antioxidative effect of Gen on obese bone cells was partially dependent on its ability to reduce leptin secretion by WAT. Altogether, the results suggest that, under obesity, Gen may improve bone metabolism through a direct action on WAT.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470043","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":"Small molecule modulation of insulin receptor-insulin like growth factor-1 receptor heterodimers in human endothelial cells","authors":"","doi":"10.1016/j.mce.2024.112387","DOIUrl":"10.1016/j.mce.2024.112387","url":null,"abstract":"<div><h3>Objectives</h3><div>The insulin receptor (IR) and insulin like growth factor-1 receptor (IGF-1R) are heterodimers consisting of two extracellular α-subunits and two transmembrane β -subunits. Insulin αβ and insulin like growth factor-1 αβ hemi-receptors can heterodimerize to form hybrids composed of one IR αβ and one IGF-1R αβ. The function of hybrids in the endothelium is unclear. We sought insight by developing a small molecule capable of reducing hybrid formation in endothelial cells.</div></div><div><h3>Methods</h3><div>We performed a high-throughput small molecule screening, based on a homology model of the apo hybrid structure. Endothelial cells were studied using western blotting and qPCR to determine the effects of small molecules that reduced hybrid formation.</div></div><div><h3>Results</h3><div>Our studies unveil a first-in-class quinoline-containing heterocyclic small molecule that reduces hybrids by &gt;50% in human umbilical vein endothelial cells (HUVECs) with no effects on IR or IGF-1R. This small molecule reduced expression of the negative regulatory p85α subunit of phosphatidylinositol 3-kinase, increased basal phosphorylation of the downstream target Akt and enhanced insulin/insulin-like growth factor-1 and shear stress-induced serine phosphorylation of Akt. In primary saphenous vein endothelial cells (SVEC) from patients with type 2 diabetes mellitus undergoing coronary artery bypass (CABG) surgery, hybrid receptor expression was greater than in patients without type 2 diabetes mellitus. The small molecule significantly reduced hybrid expression in SVEC from patients with type 2 diabetes mellitus.</div></div><div><h3>Conclusions</h3><div>We identified a small molecule that decreases the formation of IR: IGF-1R hybrid receptors in human endothelial cells, without significant impact on the overall expression of IR or IGF-1R. In HUVECs, reduction of IR: IGF-1R hybrid receptors leads to an increase in insulin-induced serine phosphorylation of the critical downstream signalling kinase, Akt. The underpinning mechanism appears, at least in part to involve the attenuation of the inhibitory effect of IR: IGF-1R hybrid receptors on PI3-kinase signalling.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470039","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":"Identifying prognostic hub genes and key pathways in pediatric adrenocortical tumors through RNA sequencing and Co-expression analysis","authors":"","doi":"10.1016/j.mce.2024.112383","DOIUrl":"10.1016/j.mce.2024.112383","url":null,"abstract":"<div><div>Pediatric adrenocortical tumors (ACTs), rare conditions with uncertain prognoses, have high incidence in southern and southeastern Brazil. Pediatric ACTs are highly heterogeneous, so establishing prognostic markers for these tumors is challenging. We have conducted transcriptomic analysis on 14 pediatric ACT samples and compared cases with favorable and unfavorable clinical outcomes to identify prognostically significant genes. This comparison showed 1257 differentially expressed genes in favorable and unfavorable cases. Among these genes, 15 out of 60 hub genes were significantly associated with five-year event-free survival (EFS), and 10 had significant diagnostic value for predicting ACT outcomes in an independent microarray dataset of pediatric adrenocortical carcinomas (GSE76019). Overexpression of <em>N4BP2</em>, <em>HSPB6</em>, <em>JUN</em>, <em>APBB1IP</em>, <em>STK17B</em>, <em>CSNK1D</em>, and <em>KDM3A</em> was associated with poorer EFS, whereas lower expression of <em>ISCU</em>, <em>PTPR</em>, <em>PRKAB2</em>, <em>CD48</em>, <em>PRF1</em>, <em>ITGAL</em>, <em>KLK15</em>, and <em>HIST1H3J</em> was associated with worse outcomes. Collectively, these findings underscore the prognostic significance of these hub genes and suggest that they play a potential role in pediatric ACT progression and are useful predictors of clinical outcomes.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470052","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 impact of acyl-CoA:cholesterol transferase (ACAT) inhibitors on biophysical membrane properties depends on membrane lipid composition","authors":"","doi":"10.1016/j.mce.2024.112385","DOIUrl":"10.1016/j.mce.2024.112385","url":null,"abstract":"<div><div>Acyl-coenzyme A: cholesterol acyltransferases are enzymes which are involved in the homeostasis of cholesterol. Impaired enzyme activity is associated with the occurrence of various diseases like Alzheimer's disease, atherosclerosis, and cancers. At present, mitotane is the only inhibitor of this class of enzymes in clinical use for the treatment of adrenocortical carcinoma but associated with common and severe adverse effects. The therapeutic effect of mitotane depends on its interaction with cellular membranes. The search for less toxic but equally effective compounds is hampered by an incomplete understanding of these biophysical properties. In the present study, the interaction of the three ACAT inhibitors nevanimibe, Sandoz 58-035, and AZD 3988 with membranes has been investigated using lipid model membranes in conjunction with biophysical experimental (NMR, ESR, fluorescence) and theoretical (MD simulations) approaches. The data show, that the drugs (i) incorporate into lipid membranes, (ii) differently influence the structure of lipid membranes; (iii) affect membrane structure depending on the lipid composition; and (iv) do not cause hemolysis of red blood cells. The results are discussed with regard to the use of the drugs, in particular to better understand their efficacy and possible side effects.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470040","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":"NLRP3 blockade by MCC950 suppressed osteoclastogenesis via NF-κB/c-Fos/NFATc1 signal pathway and alleviated bone loss in diabetes mellitus","authors":"","doi":"10.1016/j.mce.2024.112382","DOIUrl":"10.1016/j.mce.2024.112382","url":null,"abstract":"<div><div>Obesity and type 2 diabetes mellitus (T2DM) are linked to osteoporosis development, with obesity being a significant risk factor for T2DM. T2DM patients with obesity exhibit a higher fracture rate and often have a poor prognosis post-fracture. To address the urgent need for understanding the mechanisms of diabetic osteoporosis (DOP), research is ongoing to explore how obesity and T2DM impact bone metabolism. The NLRP3 inflammasome has been implicated in the pathogenesis of osteoporosis, and MCC950, an NLRP3 inflammasome inhibitor, has shown promise in various diseases but its role in osteoporosis remains unexplored. In this study, BMMs and BMSCs were isolated and cultured to investigate the effects of MCC950 on bone metabolism, and DOP model was used to evaluate the efficacy of MCC950 <em>in vivo</em>. The study demonstrated that MCC950 treatment inhibited osteoclast differentiation, reduced bone resorption capacity in BMMs without suppression for osteoblast differentiation from BMSCs. Additionally, MCC950 suppressed the activation of the NF-κB signaling pathway and downregulated key factors associated with osteoclast differentiation. Additionally, MCC950 alleviated bone loss in DOP mouse. These findings suggest that MCC950, by targeting the NLRP3 inflammasome, may have a protective role in preventing osteoporosis induced by T2DM with obesity. The study highlights the potential therapeutic implications of MCC950 in managing diabetic osteoporosis and calls for further research to explore its clinical application in high-risk patient populations.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350238","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":"Development and primary characterization of a human thyroid organoid in vitro model for thyroid metabolism investigation","authors":"","doi":"10.1016/j.mce.2024.112377","DOIUrl":"10.1016/j.mce.2024.112377","url":null,"abstract":"<div><div>A 3D thyroid model was developed to address the limitations of 2D cultures and study the effects of compounds like 3-MNT on dehalogenase 1 (IYD) and metabolic activity. Morphology was assessed by TEM, and the expression of tissue-specific genes (<em>TPO</em>, <em>TSHR</em>, <em>PAX8</em>, <em>TTF-1</em>, <em>NIS</em>, <em>IYD</em>, <em>TG</em>) and metabolic features were analyzed using qRT-PCR, immunofluorescence, western blotting, ELISA, and LC-MS/MS, with and without TSH stimulus and 3-MNT treatment. Confocal and TEM analyses confirmed a follicle-like 3D structure. Expression of <em>TPO</em>, <em>NIS</em>, <em>TG</em>, <em>TSH</em>, and <em>PAX</em> markers was significantly higher (p &lt; 0.05) in 3D versus 2D cultures, and ELISA showed increased TG protein production. 3-MNT treatment inhibited IYD activity, indicated by increased MIT and DIT in the media, and significantly altered (p &lt; 0.05) <em>NIS</em>, <em>TG</em>, <em>IYD</em>, <em>TSHR</em>, and <em>TPO</em> expression. These findings suggest 3D thyroid cultures closely replicate tissue traits and functionality, providing a valuable tool for thyroid research.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350237","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":"TIGAR relieves PCOS by inhibiting granulosa cell apoptosis and oxidative stress through activating Nrf2","authors":"","doi":"10.1016/j.mce.2024.112381","DOIUrl":"10.1016/j.mce.2024.112381","url":null,"abstract":"<div><div>This study aimed to elucidate the role of TP53-induced glycolysis and apoptosis regulator (TIGAR) in polycystic ovary syndrome (PCOS). A rat model PCOS was constructed by subcutaneous injection with dehydroepiandrosterone (DHEA). Follicular atresia and reduced granular cells (GCs) in ovaries suggested successful modeling. The low expression of TIGAR was observed in ovarian tissue of PCOS rat. To explore the role of TIGAR in PCOS, lentivirus carrying the <em>TIGAR</em> were used to up-regulate TIGAR expression. TIGAR overexpression reduced the DHEA-induced increase of ovarian weight, the levels of estradiol (E2), and the ratio of luteinizing hormone/follicle-stimulating hormone (LH/FSH) in the serum, as well as improved the morphology of the follicle, especially increased the thickness of the GC layer, which attributed to the inhibition of apoptosis by TIGAR. In addition, high expression of TIGAR inhibited oxidative stress in ovaries of PCOS rat, as evidenced by decreased level of malondialdehyde (MDA), and reactive oxygen species (ROS), and enhanced activity of glutathione peroxidase (GPX) and superoxide dismutase (SOD). Mechanically, Nrf2/OH-1 signal pathway was activated by TIGAR. The effect of TIGAR on PCOS were verified in the primary rat GCs treated with dihydrotestosterone, but also the rescue experiment was performed. Downregulation of Nrf2 reversed the effects of TIGAR, indicating that TIGAR suppressed oxidative stress and GC apoptosis by activating Nrf2/OH-1 pathway in PCOS. Finally, non-targeted metabolomics revealed that TIGAR might affect the energy metabolic pathway, thereby altering the metabolic profile of primary rat GCs. This study provided new insights into the prevention and treatment of PCOS.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350239","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":"LDT409 (pan-PPAR partial agonist) mitigates metabolic dysfunction-associated steatotic liver disease in high-fructose-fed mice","authors":"","doi":"10.1016/j.mce.2024.112380","DOIUrl":"10.1016/j.mce.2024.112380","url":null,"abstract":"<div><h3>Aim</h3><div>This study sought to evaluate the effects of LDT409, a pan-PPAR partial agonist obtained from the main industrial waste from cashew nut processing, on hepatic remodeling, highlighting energy metabolism and endoplasmic reticulum (ER) stress in high-fructose-fed mice.</div></div><div><h3>Methods</h3><div>Male C57BL/6 mice received a control diet (C) or a high-fructose diet (HFRU) for ten weeks. Then, a five-week treatment started: C, C-LDT409, HFRU, and HFRU-LDT409. The LDT409 (40 mg/kg of body weight) was mixed with the diets.</div></div><div><h3>Results</h3><div>The HFRU diet caused insulin resistance and endoplasmic reticulum (ER) stress. High <em>Pparg</em> and decreased <em>Ppara</em> expression increased steatosis and pro-fibrogenic gene expression in livers of HFRU-fed mice. Suppressed lipogenic factors, orchestrated by PPAR-gamma, and mitigated ER stress concomitant with the increase in beta-oxidation driven by PPAR-alpha mediated the LDT409 beneficial effects.</div></div><div><h3>Conclusions</h3><div>LDT409 may represent a potential low-cost approach to treat metabolic dysfunction-associated steatotic liver disease, which does not currently have a specific treatment.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350241","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}