Journal of Steroid Biochemistry and Molecular Biology最新文献

{"title":"Association between serum 25-hydroxyvitamin D concentrations and urinary vitamin D metabolite concentrations measured by the NLucVDR assay","authors":"Takuya Kushioka ,&nbsp;Hiroki Mano ,&nbsp;Sayuri Matsuoka ,&nbsp;Miyu Nishikawa ,&nbsp;Kaori Yasuda ,&nbsp;Shinichi Ikushiro ,&nbsp;Toshiyuki Sakaki","doi":"10.1016/j.jsbmb.2025.106678","DOIUrl":"10.1016/j.jsbmb.2025.106678","url":null,"abstract":"<div><div>It is well known that vitamin D is essential for human health; however, many people suffer from vitamin D deficiency or insufficiency worldwide, including in Japan. Serum 25-hydroxyvitamin D (25(OH)D) concentrations are typically measured to evaluate vitamin D status. In a previous study, we demonstrated that the concentrations of vitamin D metabolites in urine, measured using the NLucVDR assay system composed of a split-type nanoluciferase and the ligand-binding domain (LBD) of the human vitamin D receptor, correlated with serum 25(OH)D concentrations measured using liquid chromatography-mass spectrometry (LC-MS) or electrochemiluminescence immunoassays (ECLIAs). However, the number of participants was limited to 23. In the present study, we investigated the relationship between urinary vitamin D metabolite concentrations measured using the NLucVDR assay and serum 25(OH)D concentrations measured using ECLIA in 292 healthy individuals aged 20–69 years. We observed a significant positive correlation between 25(OH)D concentrations and urinary vitamin D metabolite concentrations (r = 0.400, p &lt; 0.001). Furthermore, in a multiple regression model with serum 25(OH)D concentrations as the dependent variable and urinary vitamin D metabolite concentrations, sex, age, body mass index (BMI), and vitamin D intake as independent variables, urinary vitamin D metabolite concentrations showed a significant positive association with serum 25(OH)D concentrations regardless of sex, age, BMI, and vitamin D intake. Additionally, receiver operating characteristic (ROC) curve analysis was performed to evaluate whether this multiple regression model could predict vitamin D deficiency. The area under the curve (AUC) was 0.743 and 0.708 for women and men with vitamin D deficiency (serum 25(OH)D &lt; 20 ng/mL), respectively. Our results suggest that urinary vitamin D metabolite concentrations, measured by the NLucVDR assay, may be useful for the noninvasive predictive tool of vitamin D deficiency.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"247 ","pages":"Article 106678"},"PeriodicalIF":2.7,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing the causal effect of genetically predicted metabolites and metabolic pathways on vitiligo: Evidence from Mendelian randomization and animal experiments","authors":"Guanglu Li ,&nbsp;Baoquan Qu ,&nbsp;Tao Zheng ,&nbsp;Yi Cheng ,&nbsp;Ping Li ,&nbsp;Zunjing Liu ,&nbsp;Jingxia Zhao","doi":"10.1016/j.jsbmb.2025.106677","DOIUrl":"10.1016/j.jsbmb.2025.106677","url":null,"abstract":"<div><div>Vitiligo is a common chronic skin depigmentation disorder that seriously decreases the patients' overall quality of life. Human blood metabolites could contribute to unraveling the underlying biological mechanisms of vitiligo. We used GWAS summary statistics to assess the causal association between genetically predicted 1400 serum metabolites and vitiligo risk by Mendelian randomization (MR). Then, after constructing the mouse model of vitiligo, we did non-targeted metabolomics analysis on the mouse serum and validated MR's pathway enrichment results ulteriorly. In the initial phase, MR analysis revealed causative associations between 36 metabolites and vitiligo risk, including 8 metabolite ratios and 28 individual metabolites (19 known and 9 unknown metabolites). In the validation stage, 7 metabolites were successfully validated. Of the 28 individual metabolites, most are related to lipid metabolism. Genetically predicted higher 4-oxo-retinoic acid showed the strongest protective effect on vitiligo, while the most potent risk effect was the increase in quinate. The metabolites associated with vitiligo risk are mainly enriched in alpha-linolenic acid metabolism, linoleic acid metabolism, arginine biosynthesis and metabolism pathways, validated through the serum metabolomics of vitiligo mouse. By integrating genomics and metabolomics, this study provides new insights into the association between metabolites and vitiligo, highlighting the potential roles of specific metabolites in the pathogenesis of vitiligo. These metabolites associated with vitiligo could serve as new biomarkers, further research could help to reveal how these metabolites influence specific pathways in the development of vitiligo.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"247 ","pages":"Article 106677"},"PeriodicalIF":2.7,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute hyperglycemia induces podocyte apoptosis by monocyte TNF-α release, a process attenuated by vitamin D and GLP-1 receptor agonists","authors":"Rong M. Zhang ,&nbsp;Jisu Oh ,&nbsp;Burton M. Wice ,&nbsp;Adriana Dusso ,&nbsp;Carlos Bernal-Mizrachi","doi":"10.1016/j.jsbmb.2025.106676","DOIUrl":"10.1016/j.jsbmb.2025.106676","url":null,"abstract":"<div><div>Targeting optimal glycemic control based on hemoglobin A1c (A1c) values reduces but does not abolish the onset of diabetic kidney disease and its progression to chronic kidney disease (CKD). This suggests that factors other than the average glucose contribute to the residual risk. Vitamin D deficiency and frequent episodes of acute hyperglycemia (AH) are associated with the onset of albuminuria and CKD progression in diabetes. This study aimed to determine if moderate levels of AH harm podocytes directly or promote a pro-inflammatory monocyte/macrophage phenotype that leads to podocyte apoptosis, and whether vitamin D deficiency accelerates these processes. We found that AH (16.7 mM D- glucose) didn't induce podocyte apoptosis directly, but it did promote a pro-inflammatory response in human monocytes and macrophages, resulting in an increased TNF-α secretion causing podocyte apoptosis. The AH-induced monocyte TNF-α secretion was inversely correlated with healthy donors' serum 25(OH)D levels. AH induced monocyte TNF-α release by increasing oxidative and ER stress, which in turn increased ADAM17 (A Disintegrin And Metalloprotease 17) and iRhom2 (inactive Rhomboid protein 2) expression, both essential for TNF-α secretion. Additionally, monocyte activation of glucagon-like peptide-1 receptor (GLP-1R), using a GLP-1R agonist, downregulated ADAM17/iRhom2 expression, decreasing TNF-α release and reducing podocyte apoptosis. These results show that a normal vitamin D status may attenuate a mechanism by which AH contributes to podocyte apoptosis and CKD progression and might enhance a novel anti-inflammatory role of GLP-1 to prevent AH-driven CKD progression in diabetes.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"247 ","pages":"Article 106676"},"PeriodicalIF":2.7,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of DDB2 in type II diabetes mellitus induces dysregulated ubiquitination of KMT2A in lipid metabolism disorders","authors":"Lvqiu Li ,&nbsp;Maogeng Yang ,&nbsp;Longqiao Tan ,&nbsp;Yanhong Ni ,&nbsp;Yang Wu","doi":"10.1016/j.jsbmb.2025.106673","DOIUrl":"10.1016/j.jsbmb.2025.106673","url":null,"abstract":"<div><div>The disorders of glucose and lipid metabolism contribute to severe diseases, including cardiovascular disease, diabetes, and fatty liver. Here, we identified DNA damage-binding protein 2 (DDB2), an E3 ubiquitin ligase, as a pivotal regulator of lipid metabolism disorders in type II diabetes mellitus (T2DM). A mouse model of T2DM and primary mouse hepatocytes with steatosis were induced. DDB2 overexpression alone or in combination with lysine N-methyltransferase 2 A (KMT2A) overexpression vectors were delivered into db/db mice and <em>in vitro</em> hepatocytes. DDB2 was expressed poorly, while KMT2A was expressed highly in liver tissues and primary hepatocytes of db/db mice. DDB2 ameliorated glucose intolerance and insulin resistance, decreased liver/body weight ratio, downregulated expression of lipogenesis-associated proteins (SREBP1, FASN, and SCD1) and gluconeogenesis-related proteins (PEPCK and G6Pase) in liver tissues and cells, and decreased triglyceride and total cholesterol levels in steatotic hepatocytes. DDB2 reduced KMT2A expression through ubiquitination modification. Overexpression of KMT2A promoted insulin resistance, lipogenesis and lipid deposition, and glycogen accumulation in the presence of DDB2. Overall, our data demonstrate that DDB2 alleviates hepatic lipogenesis and lipid deposition via degradation of KMT2A, thereby repressing lipid metabolism disorders in T2DM.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"247 ","pages":"Article 106673"},"PeriodicalIF":2.7,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142973176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut microbiome-derived metabolites and their impact on gene regulatory networks in gestational diabetes","authors":"Sarvesh Sabarathinam ,&nbsp;Akash Jayaraman ,&nbsp;Ramesh Venkatachalapathy","doi":"10.1016/j.jsbmb.2025.106674","DOIUrl":"10.1016/j.jsbmb.2025.106674","url":null,"abstract":"<div><div>This study explored the therapeutic potential of gut microbiota metabolites in managing Gestational Diabetes Mellitus (GDM). Using network pharmacology, molecular docking, and dynamics simulations, we identified key targets and pathways involved in GDM. We screened 135 gut-derived metabolites, with 8 meeting drug-likeness and pharmacokinetic criteria. Analysis revealed significant overlap with GDM-related targets, including AKT1, IL6, TNF, and STAT3. Functional enrichment analysis highlighted the AGE-RAGE signaling and inflammatory pathways as crucial in GDM pathogenesis. Molecular docking and dynamics simulations showed strong binding affinities and stable interactions between two metabolites, luteolin and naringenin chalcone, and the target protein AKT1. These findings suggest that gut microbiota-derived metabolites, particularly luteolin and naringenin chalcone, may effectively modulate key pathways in GDM, offering promising avenues for novel treatment strategies.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"247 ","pages":"Article 106674"},"PeriodicalIF":2.7,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cyclocurcumin potently inhibits human aromatase as a potential therapeutic agent","authors":"Han Lu ,&nbsp;Jingyi Zheng ,&nbsp;Chunnan Hu ,&nbsp;Jiayi He ,&nbsp;Shaowei Wang ,&nbsp;Zhuoqi Chen ,&nbsp;Yiyan Wang ,&nbsp;Huitao Li ,&nbsp;Ren-shan Ge ,&nbsp;Yunbing Tang ,&nbsp;Yingfen Ying","doi":"10.1016/j.jsbmb.2024.106672","DOIUrl":"10.1016/j.jsbmb.2024.106672","url":null,"abstract":"<div><div>Curcuminoids, including curcumin and its derivatives, show potent inhibition of aromatase (CYP19A1), crucial for estradiol synthesis and breast cancer metastasis. Our study evaluated the efficacy and mechanism of 10 curcuminoids and their metabolites against human and rat CYP19A1 using placental microsomes, revealing species-specific IC₅₀ values. Cyclocurcumin (IC₅₀, 4.43 μM) and curcumin (IC₅₀, 3.49 μM) were the most effective inhibitors for human and rat CYP19A1, respectively. These compounds acted as mixed or competitive inhibitors, reducing estradiol production in human BeWo cells. Docking analysis showed that curcuminoids interact with CYP19A1 active site, forming a hydrogen bond with Met374. 3D-QSAR analysis highlighted the importance of hydrogen bonding in inhibition. A negative correlation was observed between the pKa values and IC₅₀ values for human CYP19A1. A positive correlation was observed between the lowest binding energy and IC₅₀ values for human CYP19A1. These findings underscore the potential of curcuminoids as therapeutic agents against breast cancer.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"247 ","pages":"Article 106672"},"PeriodicalIF":2.7,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142924009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive review of phthalate exposure: Health implications, biomarker detection and regulatory standards","authors":"Md. Mehedi Hasan ,&nbsp;Rahima Tanbin Tama ,&nbsp;Humayra Afroz Dona ,&nbsp;Naeema Salatia Hoque ,&nbsp;Md. Ashikur Rahaman ,&nbsp;Md. Ashraful Alam","doi":"10.1016/j.jsbmb.2024.106671","DOIUrl":"10.1016/j.jsbmb.2024.106671","url":null,"abstract":"<div><div>Phthalates are a wide family of chemicals that are used in many different industrial applications used in many different industrial applications, including the production of plastics, toys, food packaging particularly for kids, and medical equipment. Due to their various chemical and physical properties, phthalates may negatively impact humans, animals, and the environment. Thus the potential for phthalate exposure and harm to humans, animals, and the environment is high because its presence is alarming. Phthalates can be ingested, inhaled, absorbed topically, or via iatrogenic exposure in animals and humans. This article aimed to ascertain the modes of exposure, fate and detection techniques, and harmful effects of phthalates on humans, animals, and the environment. This review also shows that the intake of phthalate above the established daily limit from sources such as food, toys, and air causes serious harm, including impaired immune function, difficulties in pregnancy, loss of reproduction, and damage to the kidneys, lungs, heart, and brain in humans. Children and pregnant women are the most impacted groups and phthalates also negatively affect the environment and wildlife. A few methods to determine phthalate exposure, such as the LC and the HPLC-MS/MS methods, which employ human fluid or dust air as a biomarker, are also addressed here. Consequently, this comprehensive review aims to provide a detailed analysis of the existing evidence regarding explicit links between exposure to phthalates and subsequent health outcomes that may be directly related to this exposure. Additionally, we reviewed the developed and validated analytical methods and supplemented the literature with partial biomonitoring data on their metabolites.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"247 ","pages":"Article 106671"},"PeriodicalIF":2.7,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142924008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Segetalin B promotes bone formation in ovariectomized mice by activating PLD1/SIRT1 signaling to inhibit γ-secretase-mediated Notch1 overactivation","authors":"Huixian Du ,&nbsp;Furui Tang ,&nbsp;Haiping Ma ,&nbsp;Yipin Xiong ,&nbsp;Sijian Lin ,&nbsp;Zhen Yuan ,&nbsp;Jie Wu ,&nbsp;Binwu Xu ,&nbsp;Lei Xiao ,&nbsp;Xiaoyong Lan","doi":"10.1016/j.jsbmb.2024.106669","DOIUrl":"10.1016/j.jsbmb.2024.106669","url":null,"abstract":"<div><div>Segetalin B (SB) has shown promise in mitigating osteoporosis in ovariectomized (OVX) mice, though its underlying mechanisms remain unclear. This study investigates how SB promotes bone formation through Phospholipase D1 (PLD1) activation in OVX models. <em>In vitro</em>, bone marrow-derived mesenchymal stem cells (BMSCs) from OVX mice were cultured for osteogenic differentiation. The effects of SB, PLD1 inhibitor VU0359595, SIRT1 inhibitor EX527, and γ-secretase inhibitor LY-411575 were examined. <em>In vivo</em>, the impact of SB and LY-411575 on osteoporosis in OVX mice was evaluated. SB significantly increased PLD1 phosphorylation, enhancing osteogenic differentiation and SIRT1 activity. Blocking PLD1 with VU0359595 reversed these effects. Inhibiting SIRT1 with EX527 restored γ-secretase activity and Notch1 signaling but did not alter PLD1 activation. Notch1 overexpression weakened SB’s promotion of osteogenesis and activation of the Wnt/β-catenin pathway. <em>In vivo</em>, SB combined with LY-411575 showed stronger anti-bone loss effects compared to SB alone. These findings suggest that SB may directly activates PLD1, which enhances SIRT1 activity and suppresses Notch1 signaling overactivation via γ-secretase inhibition. This cascade promotes bone formation by upregulating Wnt/β-catenin signaling. Combining SB with LY-411575 may offer a novel therapeutic strategy for postmenopausal osteoporosis.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"247 ","pages":"Article 106669"},"PeriodicalIF":2.7,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Testosterone biosynthesis and spermatogenesis disruption by PM exposure: The hidden role of bitter taste transduction","authors":"Siwei Jiao ,&nbsp;Danyu Zhao ,&nbsp;Huilan Yi","doi":"10.1016/j.jsbmb.2024.106670","DOIUrl":"10.1016/j.jsbmb.2024.106670","url":null,"abstract":"<div><div>Male infertility, a major global reproductive health concern, has been linked to increased particulate air pollution and inflammatory response. Bitter taste transduction, involved in sensing bitterness, inflammation, and immune regulation, remains understudied in male reproductive damage. This research investigated how particulate matter (PM) impacts male reproductive health and the involvement of bitter taste transduction in reproductive toxicity. A PM exposure mouse model was established via aerosol inhalation of ovalbumin (OVA) following intraperitoneal injection of OVA. Results showed that PM exposure reduced sperm count, increased sperm malformation rate, decreased seminiferous epithelium height and tubular diameter, and caused disordered spermatogenic cell arrangement, along with decreased Johnsen scores, suggesting testicular structural damage and spermatogenesis disorders. Furthermore, PM exposure reduced serum testosterone levels and diminished the mRNA expression of genes involved in testosterone synthesis, transport, and spermatogenesis, including luteinizing hormone receptor (<em>LHR</em>), steroidogenic acute regulatory protein (<em>StAR</em>), cytochrome P450 side-chain cleavage enzyme (<em>P450scc</em>), 17-beta-hydroxysteroid dehydrogenase (<em>17β-HSD</em>), androgen-binding protein (<em>ABP</em>), and DEAD-box helicase 3 Y-linked (<em>Ddx3y</em>). Meanwhile, pro-inflammatory cytokine gene <em>TNF-α</em> and inflammatory genes <em>IL-4Rα</em>, <em>JAK1</em>, <em>JAK2</em>, <em>JAK3</em>, <em>STAT3</em>, and <em>STAT6</em> were significantly upregulated in testes of PM-exposed mice. This was accompanied by inhibited expression of Th1 cytokine gene <em>IFN-γ</em> and enhanced expression of Th2 cytokine genes <em>IL-4</em>, <em>IL-5</em>, and <em>IL-13</em>. Twenty-four out of thirty-five bitter taste receptor (T2R) genes, along with their downstream signaling molecules α-gustducin and transient receptor potential cation channel subfamily M member 5 (TRPM5) genes exhibited transcriptional repression in testes of PM-treated mice. The bitter compound baicalin alleviated PM-induced male reproductive damage accompanied with activating testis-specific T2R cluster (<em>T2R102</em>, <em>T2R109</em>, <em>T2R113</em>, <em>T2R117</em>, <em>T2R119</em>, <em>T2R124</em>, <em>T2R135</em>, <em>T2R136</em>), <em>α-gustducin</em> and <em>Trpm5</em>. In conclusion, PM inhalation affects testosterone biosynthesis and spermatogenesis, induces inflammatory response and immune imbalance, and causes testicular injury, all of which are associated with the inhibition of bitter taste transduction. The results indicate that bitter signaling molecules could serve as potential targets for preventing and managing infertility in men.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"247 ","pages":"Article 106670"},"PeriodicalIF":2.7,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143154565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ligand-independent homo-/hetero-dimerization events of ERα and ERβ occur in the cytoplasmic compartment: Evidences from receptor dynamics in live cells","authors":"Ayushi Chhabra,&nbsp;Anjali Tripathi,&nbsp;Sheeba Rizvi,&nbsp;Rakesh K. Tyagi","doi":"10.1016/j.jsbmb.2024.106668","DOIUrl":"10.1016/j.jsbmb.2024.106668","url":null,"abstract":"<div><div>Estrogen receptor α/β (ERα/β), are members of the steroid/nuclear receptor superfamily. They function as a ligand-inducible transcriptional regulator and are targets for the treatment of several endocrine diseases. Irrespective of the ligand binding status, ERα/β are primarily localized in the nucleus. However, when activated, they bind to specific DNA response elements as homo-/hetero-dimers to transactivate their target genes. Homo-/hetero-dimerization of ERα/β is crucial in ER-mediated regulation of gene expression and cellular responses. However, the cellular site that hosts the receptor homo-/hetero-dimerization, essential for its physiological function, is poorly explored. Here, using a comprehensive approach, we show that the initial intermolecular interaction between ERα/β monomers occurs in the cytoplasmic compartment of the cell in a ligand-independent manner. To explore the site of homo-/hetero-dimerization of ERα/β in living cells, we created GFP-ERα/β and mCherry-ERα constructs to perform co-receptor interaction studies through fluorescence microscopy and live-cell imaging. The study revealed that ERα/β monomers dimerize in the cytoplasmic compartment, facilitating the nuclear import of the complex. We also observed that ligand-independent homodimerization requires a functional nuclear localization signal in at least one of the ER monomers. Finally, it has also been shown that the ligand-binding domain of ERα plays a key role in ligand-independent homodimerization. Understanding the intricacies of ER homo-/hetero-dimerization events and their disease-associated dysregulation paves the way for potential therapeutic interventions.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"247 ","pages":"Article 106668"},"PeriodicalIF":2.7,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143154566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}