Journal of Steroid Biochemistry and Molecular Biology最新文献

{"title":"GPER1 activation by estrogenic compounds in the inflammatory profile of breast cancer cells","authors":"Segovia-Mendoza Mariana ,&nbsp;Reyes-Plata Brenda ,&nbsp;Prado-Garcia Heriberto ,&nbsp;Lemini Cristina ,&nbsp;Barrera David ,&nbsp;Ángeles-López Guadalupe","doi":"10.1016/j.jsbmb.2024.106639","DOIUrl":"10.1016/j.jsbmb.2024.106639","url":null,"abstract":"<div><div>Breast cancer (BC) is the most frequent female neoplasm worldwide. Its establishment and development have been related to inflammatory cytokine expression. Steroid hormones such as estradiol (E₂) can regulate proinflammatory cytokine secretion through interaction with its nuclear receptors. However, little is known regarding the activation of its membrane estrogen receptor (GPER1) and the inflammatory cytokine environment in BC. We have studied the synthesis and biological effects of molecules analogs to E₂ for hormone replacement therapy (HRT), such as pentolame. Nevertheless, its interaction with GPER1 and the modulation of inflammatory cytokines in different BC types has been barely studied and deserves deeper investigation. In this research, the role of GPER1 in the proliferation and modulation of inflammatory cytokines involved in carcinogenesis and metastatic processes in different BC cell lines was assessed by binding to various compounds. To achieve this goal, the presence of GPER1 was identified in different BC cell lines. Subsequently, cell proliferation after exposure to E₂, pentolame and GPER1 agonist, G1, was subsequently determined alone or in combination with the GPER1 antagonist, G15. Finally, the pro-inflammatory cytokine secretion derived from the supernatants of BC cells exposed to the previous treatments was also assessed. Interestingly, GPER1 activation or inhibition has significant effects on the cytokine regulation associated with invasion in BC. Notably, pentolame did not induce cell proliferation or increase the proinflammatory cytokine expression compared to E₂ in BC cell lines. In addition, pentolame did not induce the presence of the cell adhesion molecule PECAM-1. In contrast, E2 treatment weakly induced the expression of PECAM-1 in MCF-7 and HCC1937 cells, and G1 treatment showed this effect only in MCF-7 cells. The results suggest that GPER1 might be a significant inflammatory modulator with angiogenic-related effects in BC cells. In addition, pentolame might represent an HRT alternative in patients with BC predisposition.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"245 ","pages":"Article 106639"},"PeriodicalIF":2.7,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142689423","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":"Effects of parabens on human and rat placental 3β-hydroxysteroid dehydrogenase isoforms: Structure activity relationship and docking analysis","authors":"Jie Xiang ,&nbsp;Mingzhu Zhong ,&nbsp;Qian Zhang ,&nbsp;Yang Zhu ,&nbsp;Peipei Pan ,&nbsp;Huitao Li ,&nbsp;Qianjin Fei ,&nbsp;Rongying Ou ,&nbsp;Ren-shan Ge ,&nbsp;Weibing Zhang","doi":"10.1016/j.jsbmb.2024.106638","DOIUrl":"10.1016/j.jsbmb.2024.106638","url":null,"abstract":"<div><div>Parabens are widely used as preservatives in personal care products and are linked to potential disruptions in placental steroidogenesis. However, their exact impact remains unclear. This study aimed to explore the inhibition, mechanisms, structure-activity relationships (SAR) of parabens on human placental 3β-hydroxysteroid dehydrogenase type 1 (h3β-HSD1) and its rat counterpart, r3β-HSD4.3β-HSD activity was assayed in placental microsomes using pregnenolone as substrate and HPLC-MS/MS to measure progesterone and the effects of parabens on 3β-HSD was evaluated and SAR was performed. The research identified their inhibition against h3β-HSD1, with nonylparaben showing the highest potency (IC₅₀, 4.17 µM), followed by phenylparaben, heptylparaben, hexylparaben, benzylparaben, butylparaben, propylparaben, and ethylparaben. The inhibition was characterized as mixed/noncompetitive. Additionally, these parabens inhibited progesterone secretion in human JAr cells at ≤100 µM. Similar trends were observed for r3β-HSD4. Docking simulations indicated that parabens interact with NAD⁺ and steroid-binding sites of both enzymes. A negative correlation between LogP, molecular weight, volume, and alcohol chain carbon with IC₅₀ values highlighted the role of carbon chain length in determining inhibitory efficacy. The inhibitory potency of parabens on 3β-HSD is significantly influenced by their structural attributes, particularly the length of their carbon chains and LogP values.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"245 ","pages":"Article 106638"},"PeriodicalIF":2.7,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142683458","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":"The role of estrogen receptors in intracellular estrogen signaling pathways, an overview","authors":"Zichang Gui ,&nbsp;Wei Shi ,&nbsp;Fangting Zhou ,&nbsp;Yongqing Yan ,&nbsp;Yuntian Li ,&nbsp;Yang Xu","doi":"10.1016/j.jsbmb.2024.106632","DOIUrl":"10.1016/j.jsbmb.2024.106632","url":null,"abstract":"<div><div>To date five members of estrogen receptors (ESRs) have been reported. They are grouped into two classes, the nuclear estrogen receptors are members of the nuclear receptor family which found at nuclear, cytoplasm and plasma membrane, and the membrane estrogen receptors, such as G protein-coupled estrogen receptor 1, ESR-X and Gq-coupled membrane estrogen receptor. The structure and function of estrogen receptors, and interaction between ESR and coregulators were reviewed. In canonical pathway ESRs can translocate to the nucleus, bind to the target gene promotor with or without estrogen responsive element and regulate transcription, mediating the genomic effects of estrogen. Coactivators and corepressors are recruited to activate or inhibit transcription by activated ESRs. Many coactivators and corepressors are recruited to activate or inhibit ESR mediated gene transcription via different mechanisms. ESRs also indirectly bind to the promoter via interaction with other transcription factors, tethering the transcription factors. ESRs can be phosphorylated by several kinases such as p38, extracellular-signal-regulated kinase, and activated protein kinase B, and which activates transcription without ligand binding. Non-genomic estrogen action can be manifested by the increases of cytoplasmic NO and Ca²⁺ through the activation of membrane ESRs. In female, ESRs signaling is crucial for folliculogenesis, oocyte growth, ovulation, oviduct and uterus. In male, ESRs signaling modulates libido, erectile function, leydig cell steroidogenesis, sertoli cell’s function, and epididymal fluid homeostatsis, supporting spermatogenesis and sperm maturation. The abnormal ESRs signaling is believed to be closely related to reproductive diseases and cancer.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"245 ","pages":"Article 106632"},"PeriodicalIF":2.7,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142649028","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":"Oxysterols in tumor immune microenvironment (TIME)","authors":"Yuanxin Liu ,&nbsp;Jie Qin ,&nbsp;Xiaorui Li ,&nbsp;Guangzhen Wu","doi":"10.1016/j.jsbmb.2024.106634","DOIUrl":"10.1016/j.jsbmb.2024.106634","url":null,"abstract":"<div><div>Oxysterols are compounds generated through oxidative reactions involving cholesterol and other steroid molecules. They play a crucial role in the tumor immune microenvironment by interacting with molecules such as the cell membrane receptor EBI2 and nuclear receptors like LXR and PXR. This interaction regulates immune cell signaling pathways, affecting proliferation, apoptosis, migration, and invasion in tumor-related processes. Activating these receptors alters the function and behavior of immune cells—such as macrophages, T cells, and dendritic cells—within the tumor microenvironment, thus promoting or inhibiting tumor development. Certain oxidized steroids can increase both the number and activation of infiltrating T cells, synergizing with anti-PD-1 to enhance anti-tumor efficacy. An in-depth study of the biological mechanisms of oxidized sterols will not only enhance our understanding of the complexity of the tumor immune microenvironment but may also reveal new therapeutic targets, providing innovative strategies for tumor immunotherapy.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"245 ","pages":"Article 106634"},"PeriodicalIF":2.7,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648886","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":"The validation of an LC-MS/MS method for the quantification of vitamin D metabolites in human milk and their biological variability in Gambian women","authors":"Kerry S. Jones ,&nbsp;Sarah R. Meadows ,&nbsp;Georgia Billing ,&nbsp;Albert Koulman ,&nbsp;Ann Prentice","doi":"10.1016/j.jsbmb.2024.106633","DOIUrl":"10.1016/j.jsbmb.2024.106633","url":null,"abstract":"<div><div>Vitamin D is required for healthy growth and development, but data on human milk vitamin D content is limited. We describe a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the analysis of vitamin D metabolites in human milk, and its application in samples collected on two consecutive days from women in rural Gambia. Vitamin D compounds were extracted from 1 mL of milk by liquid-liquid extraction and derivatised with 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) prior to analysis by LC-MS/MS. The limit of quantification was 0.05 nmol/L for vitamin D₂, 0.025 nmol/L for vitamin D₃ and 0.1 nmol/L for 25(OH)D₂ and 25(OH)D₃. Within- and between-day imprecision was &lt;12 % for all analytes except vitamin D₂ (14 %).</div><div>From all data combined, geometric mean (-/+ 1 SD) vitamin D₃ concentration was 0.94 (0.43, 1.80) nmol/L and for 25(OH)D₃ 0.32 (0.23, 0.42) nmol/L. The within-person (intra-individual) coefficient of variation (%CV) was 32 % and 12 % for vitamin D₃ and 25(OH)D₃, respectively. Between-person (inter-individual) %CVs were 89 % and 34 % for vitamin D₃ and 25(OH)D₃, respectively. There was no significant association between vitamin D metabolite concentrations and milk fat (creamatocrit). Mean vitamin D content of human milk as ARA averaged 42 IU/L with 25(OH)D₃ responsible for around two-thirds of the biological activity. In conclusion, this work describes a reliable LC-MS/MS method for quantification of vitamin D and 25(OH)D in low volumes of human milk providing a platform for future work. This study contributes to current understanding of variability of milk vitamin D content.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"245 ","pages":"Article 106633"},"PeriodicalIF":2.7,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640276","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":"Interactions of sphingomyelin with biologically crucial side chain-hydroxylated cholesterol derivatives","authors":"Patrycja Dynarowicz-Latka ,&nbsp;Anna Chachaj-Brekiesz ,&nbsp;Anita Wnętrzak ,&nbsp;Jan Kobierski ,&nbsp;Andżelika Półtorak ,&nbsp;Dawid Lupa ,&nbsp;Ewelina W. Lipiec","doi":"10.1016/j.jsbmb.2024.106635","DOIUrl":"10.1016/j.jsbmb.2024.106635","url":null,"abstract":"<div><div>Oxysterols are interesting molecules due to their dual nature, reflecting beneficial and harmful effects on the body. An issue that still needs to be solved is how slight modification of their structure owing to the location of the additional polar group in the molecules affects their biological activity. With this in mind, we selected three side chain-hydroxylated oxysterols namely: 20(<em>S</em>)-hydroxycholesterol (20(<em>S</em>)-OH), 24(<em>S</em>)-hydroxycholesterol (24(<em>S</em>)-OH), and 27-hydroxycholesterol (27-OH), and examined their behavior in mixtures with the bioactive sphingolipid – sphingomyelin (SM). Our research was based on the Langmuir monolayer technique supplemented with molecular dynamics (MD) and microscopic observation of the films texture (Brewster angle microscopy, BAM, and atomic force microscopy, AFM). Additionally, since 20(<em>S</em>)-hydroxycholesterol has not been studied so far, we thoroughly characterized this oxysterol in one-component monolayers. Our studies showed differences in the interactions of the studied oxysterols and sphingomyelin. Namely, it was found that 20(<em>S</em>)-OH binds to SM, unlike 24(<em>S</em>)-OH and 27-OH, which both weakly interact with SM. This distinct behavior was interpreted within the molecular dynamics as being due to weak intermolecular interactions between 20(<em>S</em>)-OH molecules, which allowed easy incorporation of SM into the 20(<em>S</em>)-OH monolayer. In contrast, the strong oxysterol-oxysterol interactions occurring in monolayers with 24(<em>S</em>)-OH or 27-OH make this process more difficult. This may be important in the process of bone formation/resorption. Other aspects derived from our study are: <em>(i)</em> the tendency of oxysterols to incorporate into lipid rafts (leading to their modification in structure and function), as well as <em>(ii)</em> the formation of multilayer structures, in which oxysterols are arranged in the characteristic forms of “strings of beads”, which may facilitate their transport across the membrane.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"245 ","pages":"Article 106635"},"PeriodicalIF":2.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640273","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":"Steroid receptors in hormone dependent or sensitive cancers: The field of play now and looking forward","authors":"Donita Africander,&nbsp;Theresa Hickey","doi":"10.1016/j.jsbmb.2024.106637","DOIUrl":"10.1016/j.jsbmb.2024.106637","url":null,"abstract":"","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"245 ","pages":"Article 106637"},"PeriodicalIF":2.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142632204","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":"A study of the role of androgen receptor and androgen receptor variant 7 in TNBC patients and the effect of their targeting by Enzalutamide and EPI-001 in MDA-MB-231","authors":"Belal M. Ali ,&nbsp;Hanan S. El-Abhar ,&nbsp;Ghada Mohamed ,&nbsp;Hanan R. Nassar ,&nbsp;Nelly Aliedin ,&nbsp;Marwa Sharaky ,&nbsp;Samia A. Shouman ,&nbsp;Marwa Kamel","doi":"10.1016/j.jsbmb.2024.106636","DOIUrl":"10.1016/j.jsbmb.2024.106636","url":null,"abstract":"<div><div>The lack of targeted therapy for triple-negative breast cancer (TNBC) is among the mainsprings of its poor prognosis. This study aimed to elucidate the role of the androgen receptor (AR) and its splice variant 7 (ARv7) in TNBC patients. Further, the molecular impact of their blockers, Enzalutamide and EPI-001, on the TNBC cell line MDA-MB-231 was investigated. Thereby, immunohistochemical expression of AR/ARv7 was assessed for TNBC Egyptian patients. Moreover, bioinformatics analysis of AR/ARv7 RNA status was carried out on TNBC patients from The Cancer Genome Atlas Breast Carcinoma project (TCGA-BRCA). Data from both groups was correlated with patients’ clinicopathological features. Besides, scratch wound healing assay and ELISA were employed to assess the effect of AR/ARv7 blockers on several metastasis markers in MDA-MB-231 cell line. In the Egyptian-TNBC patients, AR expression was associated with worse 7-year DFS (40.6 ± 18.6 %). In addition, ARv7 showed cytoplasmic and nuclear patterns, and both cytoplasmic and nuclear ARv7⁺ patients demonstrated a worse 7-year DFS (22.7 ± 17.7 % and 20 ± 17.9 %) and overall survival (63.6 ± 14.5 % and 40 ± 21.8 %). Importantly, 80 % of the nuclear ARv7⁺ patients developed distant metastasis. The data of the TCGA-TNBC patients showed a tendency for poor outcomes in the high ARv7-expressing patients. Molecularly, in MDA-MB-231, both inhibitors modulated metastasis and epithelial to mesenchymal transition (EMT) markers ROCK1, ROCK2, c-Myc, E-cadherin and N-cadherin, with EPI-001 downregulating NF-ĸB level as well. We concluded that ARv7 indicated poor prognosis in the studied cohorts and that blocking of AR/ARv7 abated metastasis and key regulators of EMT in MDA-MB-231, at least in part by targeting ROCK/NF-ĸB/c-Myc axis.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"245 ","pages":"Article 106636"},"PeriodicalIF":2.7,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142632190","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":"Panax notoginseng saponins improves lipid metabolism and prevents atherosclerosis in mice with steroid-resistant lupus nephritis via the SIRT1/PPARγ signaling pathway","authors":"Zheng Xu ,&nbsp;Jie Huang ,&nbsp;Kaishun Shi ,&nbsp;Ying Lu","doi":"10.1016/j.jsbmb.2024.106631","DOIUrl":"10.1016/j.jsbmb.2024.106631","url":null,"abstract":"<div><div>Steroids serve as the primary medication for treating lupus nephritis (LN), however, steroid-resistance (SR) occurs sporadically in clinical practice, significantly affecting the therapeutic effect and long-term prognosis of patients. Our previous study found that panax notoginseng saponins (PNS) could partially reverse SR in LN. To further explore the role of PNS in reversing SR and reducing cardiovascular complications in LN, we conducted this study. Lupus mice were induced into SR while simultaneously receiving PNS. SIRT1-siRNA, SIRT1-siRNA NC, normal and lupus mice were used as control groups. Urine protein levels were measured at week 0, 4 and 8. Lipid metabolism-related biomarkers and renal function were assessed. The apoptosis rate of abdominal aortic endothelial cells was detected using flow-cytometry. The expression levels of PPARγ and SIRT1 were measured using RT-PCR and Western Blotting. Immunohistochemistry was performed to examine ACAT1 and VCAM-1 expressions. The results showed that compared to the SR lupus mice, the lupus mice treated with low/high dose PNS presented lower levels of urinary protein, serum creatinine, and blood lipids, a lower apoptosis rate of abdominal aortic endothelial cells, and decreased levels of ACAT1 and VCAM-1 PI in liver tissue, while the high-dose PNS exhibited more evidently. The PPARγ expression in SIRT1-siRNA group, as well as in low-dose and high-dose PNS groups was higher than that in the lupus and SR lupus group. In contrast, the expression of SIRT1 showed the opposite trend. Therefore, we conclude that PNS has the efficacy of reversing SR and ameliorating dyslipidemia in LN by modulating the SIRT1/PPARγ signaling pathway.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"245 ","pages":"Article 106631"},"PeriodicalIF":2.7,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142632203","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":"Calcitriol prevents SARS-CoV spike-induced inflammation in human trophoblasts through downregulating ACE2 and TMPRSS2 expression","authors":"Rafael Vargas-Castro ,&nbsp;Janice García-Quiroz ,&nbsp;Andrea Olmos-Ortiz ,&nbsp;Euclides Avila ,&nbsp;Fernando Larrea ,&nbsp;Lorenza Díaz","doi":"10.1016/j.jsbmb.2024.106625","DOIUrl":"10.1016/j.jsbmb.2024.106625","url":null,"abstract":"<div><div>SARS-CoV-2, the causative virus of COVID-19, increases the risk of pregnancy complications including hypertensive disorders and placental inflammation. The spike glycoprotein mediates viral cell entry by interacting with the angiotensin-converting enzyme (ACE)2 in conjunction with the transmembrane serine protease 2 (TMPRSS2). ACE1, ACE2 and renin are components of the renin-angiotensin system (RAS), which regulates blood pressure. As the placenta expresses all these proteins, it is a target for SARS-CoV-2 and a source of blood pressure modulators. Noteworthy, an ACE1/ACE2 ratio imbalance can lead to RAS dysregulation and a bad prognosis in COVID-19 patients. Calcitriol, the most active vitamin D metabolite, negatively regulates RAS, reduces inflammation, and enhances antiviral immunity, thereby protecting against COVID-19 severity. However, contrasting information exists on the regulatory role of calcitriol upon RAS components and SARS-CoV-2 receptors; while the impact of calcitriol on spike-induced inflammation in placental cells has not been explored. Thus, we studied the effects of calcitriol on these parameters using the trophoblast cell line HTR-8/SVneo and primary syncytiotrophoblasts. By RT-qPCR, ELISA, and immunocytochemistry, we found that the spike enhanced proinflammatory cytokines expression and secretion, while calcitriol significantly downregulated this effect. Calcitriol also diminished <em>ACE1, ACE2, TMPRSS2</em>, and renin gene expression, as well as <em>ACE1/ACE2</em> mRNA ratio.</div></div><div><h3>Conclusions</h3><div>In the human placenta, calcitriol reduced the gene expression of main RAS components and <em>TMPRSS2</em>, resulting in the inhibition of spike-induced inflammation. This outcome suggest that vitamin D participates in restricting SARS-CoV-2 placental infection by rendering trophoblasts less permissive to infection while helping to regulate maternal blood pressure and decreasing inflammation.</div></div>","PeriodicalId":51106,"journal":{"name":"Journal of Steroid Biochemistry and Molecular Biology","volume":"245 ","pages":"Article 106625"},"PeriodicalIF":2.7,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142632206","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}