Molecular and Cellular Endocrinology最新文献

{"title":"Selenoprotein M protects cardiac endothelial cell integrity against high-glucose stress via enhancing Parkin-mediated mitophagy","authors":"Bin Zhao ,&nbsp;Wen-Liang Tan ,&nbsp;Bing-Bo Yu ,&nbsp;Jun Fan ,&nbsp;Chang Liu ,&nbsp;Jian Liu ,&nbsp;Zhen Liu","doi":"10.1016/j.mce.2024.112392","DOIUrl":"10.1016/j.mce.2024.112392","url":null,"abstract":"<div><div>Selenoprotein M (SELENOM) has emerged as a crucial factor in maintaining cellular redox homeostasis and mitigating oxidative damage. This study aims to investigate its protective role in cardiac endothelial cells under hyperglycemic stress, a condition commonly associated with diabetes mellitus and its cardiovascular complications. Diabetic mice model and human umbilical vein endothelial cells (HUVECs) were applied for <em>in vivo</em> and <em>in vitro</em> studies. Results reveal that hyperglycemia significantly downregulates <em>SELENOM</em> expression in both diabetic mouse hearts and primary cultured cardiac endothelial cells. Overexpression of <em>SELENOM</em> in HUVECs mitigated high-glucose-induced FITC-Dextran diffusion and the loss of transendothelial electrical resistance. Additionally, <em>SELENOM</em> overexpression decreased reactive oxygen species (ROS) levels, preserved tight junction protein expression, and maintained cellular structural integrity under hyperglycemic conditions. Furthermore, <em>SELENOM</em> overexpression attenuated high-glucose-induced mitochondrial apoptosis. High-glucose conditions decreased Parkin and increased p62 and Beclin1 expressions. <em>SELENOM</em> overexpression restored Parkin levels and promoted co-localization of LAMP1 and TOMM20. Knockdown of Parkin significantly attenuated these protective effects, suggesting the importance of Parkin in Selenoprotein M-mediated mitophagy. Collectively, these findings suggest that Selenoprotein M enhances Parkin-mediated mitophagy to protect endothelial cells from hyperglycemic stress, offering potential therapeutic insights for diabetic cardiovascular complications.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"595 ","pages":"Article 112392"},"PeriodicalIF":3.8,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504280","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":"HSF1/HSP25 system protects mitochondria function from heat stress and assists steroidogenesis in MA-10 Leydig cells","authors":"Shintaro Oka ,&nbsp;Ryosuke Takii ,&nbsp;Mitsuaki Fujimoto ,&nbsp;Akira Nakai ,&nbsp;Koji Shiraishi","doi":"10.1016/j.mce.2024.112391","DOIUrl":"10.1016/j.mce.2024.112391","url":null,"abstract":"<div><div>Heat shock response is characterized by the induction of heat shock proteins (HSPs) or molecular chaperones that maintain protein homeostasis. Heat shock transcription factor 1 (HSF1) plays a central role in heat shock response in mammalian cells. To investigate the impact of the heat shock response mechanism on steroidogenesis, we generated MA-10 mouse Leydig tumor cells deficient in HSF1 using CRISPR-Cas9 genome editing. Under heat stress conditions, the levels of StAR protein, but not its mRNA, decreased more in HSF1-knockout cells than in wild-type cells, confirming that HSF1 stabilizes StAR protein. Simultaneously, HSP110, HSP70, and HSP25 were markedly upregulated in a manner dependent on HSF1. Mitochondrial membrane potential (MMP) and ATP synthesis were decreased in HSF1-knockout cells under heat stress conditions, and mitochondrial fragmentation was enhanced. Furthermore, treatment with carbonyl cyanide 3-chlorophenylhydrazone (CCCP), a disruptor of MMP, reduced the levels of StAR protein to a greater extent in HSF1-knockout cells than in wild-type cells, which was associated with decreased MMP and ATP synthesis. Unexpectedly, HSP25 expression was markedly increased in wild-type cells following CCCP treatment. HSP25 knockdown reduces MMP under heat stress conditions and decreases StAR protein levels and progesterone synthesis. HSP25 overexpression in HSF1KO cells restored StAR protein levels. These results show that the HSF1/HSP25 pathway protects mitochondrial function and maintains StAR synthesis.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"595 ","pages":"Article 112391"},"PeriodicalIF":3.8,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504279","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":"Vasopressinergic sexual dimorphism: Sex chromosome complement and organizational hormonal effects","authors":"Florencia María Dadam ,&nbsp;Lihue Gonzalez ,&nbsp;Laura Vivas,&nbsp;Andrea Godino,&nbsp;Ximena E. Caeiro","doi":"10.1016/j.mce.2024.112390","DOIUrl":"10.1016/j.mce.2024.112390","url":null,"abstract":"<div><div>This study aimed to analyze the role of the sex chromosomes (SCC: XX/XY) and the interaction with organizational hormonal effects on Avp gene expression at the supraoptic (SON) and paraventricular nuclei (PVN) due to water deprivation, as well as on the vasopressinergic sexually dimorphic antidiuretic and pressor responses. For this purpose, we used gonadectomized (GDX) transgenic mice of the \"four core genotypes\" model, in which the effect of gonadal sex and SCC are dissociated.</div><div>A significant interaction between treatment and SCC on Avp gene expression at the SON was observed. Regardless of sex, XX mice showed higher basal expression than those with XY; however after water deprivation no changes in mRNA Avp expression were observed in the XX group, while an increase for XY was reported. At the PVN an interaction of SCC, organizational hormonal, and treatment factors was observed, revealing an increase in Avp gene expression in the XY-GDX male DEP group.</div><div>Although no SCC or organizational hormonal effects were observed on the demopressin-antidiuretic response and renal Avpr2 mRNA expression, an interplay of organizational hormonal and SCC factors in short and medium-term vasopressin-blood pressure regulation were reported. XX-GDX females showed a facilitated vasopressin-bradycardic baroreflex response when compared to the other genotypes. Furthermore, although vasopressin continuous infusion resulted initially in the expected increase in the percentage change in MAP in all genotypes, in XX-GDX male and female this increase was sustained until the 30-min infusion, while in XY-GDX male and in XY-GDX female mice a decrease in MAP was observed.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"594 ","pages":"Article 112390"},"PeriodicalIF":3.8,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470042","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":"High glucose elevates intracellular calcium level and induces ferroptosis in glomerular endothelial cells through the miR-223-3p/ITPR3 pathway","authors":"Dekai Wang ,&nbsp;Lihua Zhang ,&nbsp;Juanli Nan ,&nbsp;Shengbi Wan ,&nbsp;Jingmei Luo ,&nbsp;Xueqiong Li ,&nbsp;Wei Chen","doi":"10.1016/j.mce.2024.112384","DOIUrl":"10.1016/j.mce.2024.112384","url":null,"abstract":"<div><div>We investigated the link between ferroptosis and the miR-223-3p/inositol 1,4,5-trisphosphate receptor type 3 (ITPR3) pathway in diabetic kidney disease (DKD). Blood samples from DKD patients and healthy controls were analysed for iron ions, calcium ions, and lipid peroxidation. High-glucose-induced glomerular endothelial cells were used to simulate DKD. MiR-223-3p overexpression or silencing was achieved using adenoviruses, affecting ferroptosis regulators (glutathione peroxidase 4 [GPX4], cystine/glutamate transporter (xCT), and long-chain acyl-CoA synthetase 4 [ACSL4]) and ITPR3. DKD patients showed elevated levels of iron ions, calcium ions, and lipid peroxidation. High glucose downregulated miR-223-3p, reducing xCT and GPX4 expression and increasing ACSL4 expression. MiR-223-3p was confirmed to target ITPR3 through luciferase reporter assay. MiR-223-3p overexpression reversed high-glucose-induced effects on ferroptosis markers and ITPR3 expression. In summary, high glucose levels decreased miR-223-3p expression, leading to increased calcium ion levels and ferroptosis, potentially through ITPR3 modulation. These findings provide insights into the mechanisms underlying DKD and its potential therapeutic targets.</div></div>","PeriodicalId":18707,"journal":{"name":"Molecular and Cellular Endocrinology","volume":"594 ","pages":"Article 112384"},"PeriodicalIF":3.8,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470038","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":"Relation of mitochondrial DNA copy number and variants with the clinical characteristics of polycystic ovary syndrome","authors":"Samia Palat Tharayil ,&nbsp;Sayli Rasal ,&nbsp;Ulka Gawde ,&nbsp;Srabani Mukherjee ,&nbsp;Anushree Patil ,&nbsp;Beena Joshi ,&nbsp;Susan Idicula-Thomas ,&nbsp;Pallavi Shukla","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":"594 ","pages":"Article 112386"},"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":"Diego Alvarez de la Rosa ,&nbsp;Zuleima Ramos-Hernández ,&nbsp;Julián Weller-Pérez ,&nbsp;Thomas A. Johnson ,&nbsp;Gordon L. Hager","doi":"10.1016/j.mce.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":"594 ","pages":"Article 112389"},"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":"Sabrina B. Cepeda ,&nbsp;Pablo H. Cutini ,&nbsp;María I. Valle,&nbsp;Adrián E. Campelo,&nbsp;Virginia L. Massheimer ,&nbsp;Marisa J. Sandoval","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":"594 ","pages":"Article 112388"},"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":"Chloe G. Myers ,&nbsp;Hema Viswambharan ,&nbsp;Natalie J. Haywood ,&nbsp;Katherine Bridge ,&nbsp;Samuel Turvey ,&nbsp;Tom Armstrong ,&nbsp;Lydia Lunn ,&nbsp;Paul J. Meakin ,&nbsp;Karen E. Porter ,&nbsp;Eva M. Clavane ,&nbsp;David J. Beech ,&nbsp;Richard M. Cubbon ,&nbsp;Stephen B. Wheatcroft ,&nbsp;Martin J. McPhillie ,&nbsp;Tarik Issad ,&nbsp;Colin WG. Fishwick ,&nbsp;Mark T. Kearney ,&nbsp;Katie J. Simmons","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":"594 ","pages":"Article 112387"},"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":"Luciana Chain Veronez ,&nbsp;Alcides Euzebio Tavares Xavier ,&nbsp;Luiz Fernando Nagano ,&nbsp;Carolina Alves Pereira Correa ,&nbsp;Kleiton Silva Borges ,&nbsp;Paula Santos ,&nbsp;Mirella Baroni ,&nbsp;Rosane de Paula Silva Queiroz ,&nbsp;Sonir Roberto Rauber Antonini ,&nbsp;José Andres Yunes ,&nbsp;Silvia Regina Brandalise ,&nbsp;Carlos Augusto Fernandes Molina ,&nbsp;Emilia Modolo Pinto ,&nbsp;Elvis Terci Valera ,&nbsp;Luiz Gonzaga Tone ,&nbsp;Carlos Alberto Scrideli","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":"594 ","pages":"Article 112383"},"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":"Huong To ,&nbsp;Peter Reinholdt ,&nbsp;Mohammad Bashawat ,&nbsp;Meike Luck ,&nbsp;Line Lauritsen ,&nbsp;Vibeke Akkerman ,&nbsp;Matthias Kroiss ,&nbsp;Daniel Wüstner ,&nbsp;Jacob Kongsted ,&nbsp;Peter Müller ,&nbsp;Holger A. Scheidt","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":"594 ","pages":"Article 112385"},"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}