Polycystic Ovary Syndrome (PCOS) is an endocrine disorder syndrome among women in their reproductive years and is often linked to chronic inflammation. Pentraxin 3 (PTX3), a member of the pentraxin protein family, plays a key role in inflammation. In our study, we explored whether PTX3 influences granulosa cell function via its involvement in inflammation. Our analysis revealed elevated PTX3 concentrations in the follicular fluid and granulosa cells of patients with PCOS. Overexpression of PTX3 promoted apoptosis in the cultured murine granulosa cell line KK1 and inhibited the proliferation of these cells. Additionally, it suppressed the expression of luteinizing hormone receptor (LHR) and follicle-stimulating hormone receptor (FSHR), as well as those of key enzymes involved in steroid hormone synthesis, CYP19A1, and HSD3β, leading to reduced secretion of estradiol and progesterone. Moreover, both recombinant PTX3 protein and PTX3 secreted by granulosa cells (GCs) promoted the secretion of inflammatory cytokines IL-1β, IL-6, and TNF-α by M1 macrophages via the JAK pathway, which impaired the function of granulosa cells. This study may advance the understanding of cell-cell interactions in follicles and the inflammatory factors that contribute to PCOS pathophysiology.
{"title":"PTX3 impairs granulosa cell function by promoting the secretion of inflammatory cytokines in M1 macrophages via the JAK pathway.","authors":"Ying Chen, Xiaofang Luo, Yizhe Li, Linhong Liu, Zhen Liu, Yunyue Tan, Ying Chen","doi":"10.1016/j.steroids.2024.109541","DOIUrl":"https://doi.org/10.1016/j.steroids.2024.109541","url":null,"abstract":"<p><p>Polycystic Ovary Syndrome (PCOS) is an endocrine disorder syndrome among women in their reproductive years and is often linked to chronic inflammation. Pentraxin 3 (PTX3), a member of the pentraxin protein family, plays a key role in inflammation. In our study, we explored whether PTX3 influences granulosa cell function via its involvement in inflammation. Our analysis revealed elevated PTX3 concentrations in the follicular fluid and granulosa cells of patients with PCOS. Overexpression of PTX3 promoted apoptosis in the cultured murine granulosa cell line KK1 and inhibited the proliferation of these cells. Additionally, it suppressed the expression of luteinizing hormone receptor (LHR) and follicle-stimulating hormone receptor (FSHR), as well as those of key enzymes involved in steroid hormone synthesis, CYP19A1, and HSD3β, leading to reduced secretion of estradiol and progesterone. Moreover, both recombinant PTX3 protein and PTX3 secreted by granulosa cells (GCs) promoted the secretion of inflammatory cytokines IL-1β, IL-6, and TNF-α by M1 macrophages via the JAK pathway, which impaired the function of granulosa cells. This study may advance the understanding of cell-cell interactions in follicles and the inflammatory factors that contribute to PCOS pathophysiology.</p>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":" ","pages":"109541"},"PeriodicalIF":2.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-19DOI: 10.1016/j.steroids.2024.109540
Qiurong Zeng , Junlong Li , Yi Yang, Yifan He, Ying Song, Jinbo Hu, Yue Wang, Qifu Li, Shumin Yang, on behalf of the Chongqing Primary Aldosteronism Study CONPASS Group
Purpose
Compared with chemiluminescence immunoassay (CLIA), the quantification of the plasma aldosterone concentration (PAC) via liquid chromatography–tandem mass spectrometry (LC–MS/MS) yields lower values. The extent to which this difference is exacerbated by a reduced glomerular filtration rate (eGFR) is unclear. Therefore, this study aims to assess the impact of renal insufficiency on PAC as measured by CLIA using LC–MS/MS as the reference method.
Methods
In subjects with a normal or reduced estimated eGFR, the PAC was measured using both LC–MS/MS and two different CLIA kits (Mindray and Liaison).
Results
In total, 383 patients were included in our study. Among them, 71 subjects had eGFRs > 90 (Group one), 79 had eGFRs range from 60 to 89 (Group two), 108 had eGFR range from 30 to 59 (Group three), 51 had eGFRs range from 15 to 29 (Group four), and 74 had eGFRs < 15 (Group five) ml/min per 1.73 m2. In all the subjects, PAC as measured by CLIA [68.2 (37.1–122.1) pg/ml for Mindray, 109.0 (68.1–170.0) pg/ml for Liaison] were significantly higher than those measured by LC–MS/MS [47.2 (22.9–88.7) pg/ml]. PAC as measured by CLIA was positively correlated with PAC as measured by LC–MS/MS, but the correlation coefficient gradually decreased as eGFR decreased. Between the LC–MS/MS and Liaison CLIA kits, the difference in PAC values increased with reduced eGFR in groups one through five (76.8 %, 69.2 %, 113.2 %, 152.2 %, and 476.2 % for groups one through five, respectively). However, this difference increased only in Group five with the Mindray CLIA kit (46.4 %, 48.1 %, 45.7 %, 45.0 %, and 74.9 % for groups one through five, respectively).
Conclusion
CLIA progressively overestimated PAC as eGFR decreased, particularly with the Liaison method, indicating the need for caution when interpreting these measurements in patients with impaired renal function. In patients with impaired renal function, LC‒MS/MS measurements for PAC are preferable.
{"title":"Comparison of a chemiluminescence immunoassay with LC–MS/MS in the determination of the plasma aldosterone concentration in patients with impaired renal function","authors":"Qiurong Zeng , Junlong Li , Yi Yang, Yifan He, Ying Song, Jinbo Hu, Yue Wang, Qifu Li, Shumin Yang, on behalf of the Chongqing Primary Aldosteronism Study CONPASS Group","doi":"10.1016/j.steroids.2024.109540","DOIUrl":"10.1016/j.steroids.2024.109540","url":null,"abstract":"<div><h3>Purpose</h3><div>Compared with chemiluminescence immunoassay (CLIA), the quantification of the plasma aldosterone concentration (PAC) via liquid chromatography–tandem mass spectrometry (LC–MS/MS) yields lower values. The extent to which this difference is exacerbated by a reduced glomerular filtration rate (eGFR) is unclear. Therefore, this study aims to assess the impact of renal insufficiency on PAC as measured by CLIA using LC–MS/MS as the reference method.</div></div><div><h3>Methods</h3><div>In subjects with a normal or reduced estimated eGFR, the PAC was measured using both LC–MS/MS and two different CLIA kits (Mindray and Liaison).</div></div><div><h3>Results</h3><div>In total, 383 patients were included in our study. Among them, 71 subjects had eGFRs > 90 (Group one), 79 had eGFRs range from 60 to 89 (Group two), 108 had eGFR range from 30 to 59 (Group three), 51 had eGFRs range from 15 to 29 (Group four), and 74 had eGFRs < 15 (Group five) ml/min per 1.73 m<sup>2</sup>. In all the subjects, PAC as measured by CLIA [68.2 (37.1–122.1) pg/ml for Mindray, 109.0 (68.1–170.0) pg/ml for Liaison] were significantly higher than those measured by LC–MS/MS [47.2 (22.9–88.7) pg/ml]. PAC as measured by CLIA was positively correlated with PAC as measured by LC–MS/MS, but the correlation coefficient gradually decreased as eGFR decreased. Between the LC–MS/MS and Liaison CLIA kits, the difference in PAC values increased with reduced eGFR in groups one through five (76.8 %, 69.2 %, 113.2 %, 152.2 %, and 476.2 % for groups one through five, respectively). However, this difference increased only in Group five with the Mindray CLIA kit (46.4 %, 48.1 %, 45.7 %, 45.0 %, and 74.9 % for groups one through five, respectively).</div></div><div><h3>Conclusion</h3><div>CLIA progressively overestimated PAC as eGFR decreased, particularly with the Liaison method, indicating the need for caution when interpreting these measurements in patients with impaired renal function. In patients with impaired renal function, LC‒MS/MS measurements for PAC are preferable.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"213 ","pages":"Article 109540"},"PeriodicalIF":2.1,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142689009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-17DOI: 10.1016/j.steroids.2024.109537
Basel A. Abdel-Wahab , Ehab A.M. El-Shoura , Mohammed S. Habeeb , Nayef A. Aldabaan , Yasmine H. Ahmed , Dalia Zaafar
Background
Diabetes has been a long-known risk factor for male sexual dysfunction, which may be caused by persistent hyperglycemia, oxidative stress, and spermatogenesis inhibition. This study explored the potential of Semaglutide (Sem) to alleviate testicular dysfunction and spermatogenesis impairment in diabetic rats to understand the molecular mechanism of this protective effect.
Methodology
A controlled experiment was conducted where 28 adult male rats were divided into four groups: control, Semaglutide, diabetic, and diabetes + Sem. Diabetes was induced using a single STZ dose (50 mg/kg, i.p.). At the same time, Sem was administered as a daily subcutaneous dose (25 nmol/kg) for four weeks after the confirmed diagnosis of diabetes.
Several biochemical and histochemical analyses were performed in addition to mating behavior assessments. The estimation of spermatogenesis-related genes and proteins was conducted using PCR and western blotting techniques.
Results
revealed promising outcomes, wherein Sem treatment effectively mitigated diabetes-induced sexual and testicular dysfunction. Specifically, it regulated the disrupted redox balance, restored spermatogenesis gene and protein levels, modulated hormonal profiles, and mitigated testicular inflammation.
Conclusion
Sem protects against diabetes-induced testicular and sexual impairments by influencing several pathways and restoring spermatogenesis-related genes and proteins. Future studies may involve a potential investigation of Sem translational applications in clinical settings for treating male infertility associated with diabetes.
{"title":"Unraveling the impact of semaglutide in a diabetic rat model of testicular dysfunction: Insights into spermatogenesis pathways and miRNA-148a-5p","authors":"Basel A. Abdel-Wahab , Ehab A.M. El-Shoura , Mohammed S. Habeeb , Nayef A. Aldabaan , Yasmine H. Ahmed , Dalia Zaafar","doi":"10.1016/j.steroids.2024.109537","DOIUrl":"10.1016/j.steroids.2024.109537","url":null,"abstract":"<div><h3>Background</h3><div>Diabetes has been a long-known risk factor for male sexual dysfunction, which may be caused by persistent hyperglycemia, oxidative stress, and spermatogenesis inhibition. This study explored the potential of Semaglutide (Sem) to alleviate testicular dysfunction and spermatogenesis impairment in diabetic rats to understand the molecular mechanism of this protective effect.</div></div><div><h3>Methodology</h3><div>A controlled experiment was conducted where 28 adult male rats were divided into four groups: control, Semaglutide, diabetic, and diabetes + Sem. Diabetes was induced using a single STZ dose (50 mg/kg, i.p.). At the same time, Sem was administered as a daily subcutaneous dose (25 nmol/kg) for four weeks after the confirmed diagnosis of diabetes.</div><div>Several biochemical and histochemical analyses were performed in addition to mating behavior assessments. The estimation of spermatogenesis-related genes and proteins was conducted using PCR and western blotting techniques.</div></div><div><h3>Results</h3><div>revealed promising outcomes, wherein Sem treatment effectively mitigated diabetes-induced sexual and testicular dysfunction. Specifically, it regulated the disrupted redox balance, restored spermatogenesis gene and protein levels, modulated hormonal profiles, and mitigated testicular inflammation.</div></div><div><h3>Conclusion</h3><div>Sem protects against diabetes-induced testicular and sexual impairments by influencing several pathways and restoring spermatogenesis-related genes and proteins. Future studies may involve a potential investigation of Sem translational applications in clinical settings for treating male infertility associated with diabetes.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"213 ","pages":"Article 109537"},"PeriodicalIF":2.1,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142649180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-10DOI: 10.1016/j.steroids.2024.109528
Muhammed A. Saad , Alyasaa A. Rastanawi , Ayman E. El-Sahar , Alshaymaa A. Z. El-Bahy
Purpose
Polycystic ovary syndrome (PCOS) is an endocrine disorder with the highest prevalence among other disorders in sexually-active women. It is associated with broad-spectrum hormonal and metabolic disturbances with behavioural difficulties. Experimentally, letrozole administration causes similar findings. Ascorbic acid is powerful anti-oxidant; and its cellular levels decrease with “hyperglycemic and poor anti-oxidative” status, which is, a main hallmark of PCOS. Thus, ascorbic acid administration may prevent the induction of PCOS and its consequences.
Basic procedures: Forty female rats were divided into four groups (n = 10 in each): normal control (CTRL), ascorbic acid (ASC), letrozole (LTZ), and ascorbic acid + letrozole (ASC + LTZ) group. Behavioural tests (Y-maze spontaneous alteration, tail suspension test, forced swimming test) were performed. In serum, hormones (testosterone, estradiol, progesterone), glycemia (blood glucose, insulin and HOMA-IR) and oxidative stress (SOD activity, GSH) markers were measured. In hippocampus, inflammation and apoptosis indicators (p-JAK2, p-STAT5, p-ERK1/2, NF-κB, BAX, Bcl2, BAX/Bcl2 ratio) and neurotransmitters (DA, 5-HT, NE, BDNF) were determined. Lastly, ovary histopathological investigation was conducted to confirm PCOS induction.
Principal results: Letrozole induced PCOS with subsequent disturbances. Testosterone levels were augmented while estradiol and progesterone were declined. Fasting blood glucose, insulin, HOMA-IR and oxidative stress markers were elevated. The expression of p-JAK2, p-STAT5, p-ERK1/2, BAX and the levels of NF-κB were increased, but Bcl2 expression, monoamines and BDNF levels were lowered. Importantly, ASC restored the last mentioned parameters markedly. Major conclusions: Ascorbic acid mitigated the behavioural difficulties of PCOS possibly by switching-off JAK2/STAT5 and JAK2/ERK1/2 pathways in hippocampus along with its neurotransmission-improving, hormonal-normalizing, anti-hyperglycemic and anti-oxidative effects.
{"title":"Ascorbic acid Mitigates behavioural disturbances associated with letrozole-induced PCOS via switching-off JAK2/STAT5 and JAK2/ERK1/2 pathways in rat hippocampus","authors":"Muhammed A. Saad , Alyasaa A. Rastanawi , Ayman E. El-Sahar , Alshaymaa A. Z. El-Bahy","doi":"10.1016/j.steroids.2024.109528","DOIUrl":"10.1016/j.steroids.2024.109528","url":null,"abstract":"<div><h3>Purpose</h3><div>Polycystic ovary syndrome (PCOS) is an endocrine disorder with the highest prevalence among other disorders in sexually-active women. It is associated with broad-spectrum hormonal and metabolic disturbances with behavioural difficulties. Experimentally, letrozole administration causes similar findings. Ascorbic acid is powerful anti-oxidant; and its cellular levels decrease with “hyperglycemic and poor anti-oxidative” status, which is, a main hallmark of PCOS. Thus, ascorbic acid administration may prevent the induction of PCOS and its consequences.</div><div><strong>Basic procedures:</strong> Forty female rats were divided into four groups (n = 10 in each): normal control (CTRL), ascorbic acid (ASC), letrozole (LTZ), and ascorbic acid + letrozole (ASC + LTZ) group. Behavioural tests (Y-maze spontaneous alteration, tail suspension test, forced swimming test) were performed. In serum, hormones (testosterone, estradiol, progesterone), glycemia (blood glucose, insulin and HOMA-IR) and oxidative stress (SOD activity, GSH) markers were measured. In hippocampus, inflammation and apoptosis indicators (p-JAK2, p-STAT5, p-ERK1/2, NF-κB, BAX, Bcl2, BAX/Bcl2 ratio) and neurotransmitters (DA, 5-HT, NE, BDNF) were determined. Lastly, ovary histopathological investigation was conducted to confirm PCOS induction.</div><div><strong>Principal results:</strong> Letrozole induced PCOS with subsequent disturbances. Testosterone levels were augmented while estradiol and progesterone were declined. Fasting blood glucose, insulin, HOMA-IR and oxidative stress markers were elevated. The expression of p-JAK2, p-STAT5, p-ERK1/2, BAX and the levels of NF-κB were increased, but Bcl2 expression, monoamines and BDNF levels were lowered. Importantly, ASC restored the last mentioned parameters markedly. <strong>Major conclusions:</strong> Ascorbic acid mitigated the behavioural difficulties of PCOS possibly by switching-off JAK2/STAT5 and JAK2/ERK1/2 pathways in hippocampus along with its neurotransmission-improving, hormonal-normalizing, anti-hyperglycemic and anti-oxidative effects.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"213 ","pages":"Article 109528"},"PeriodicalIF":2.1,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142628494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-10DOI: 10.1016/j.steroids.2024.109529
Donald Poirier
The family of 17β-hydroxysteroid dehydrogenases (17β-HSDs) occupies a prominent place due to its number of isoforms, which carry out a bidirectional transformation (reduction of a steroid carbonyl to alcohol and oxidation of a steroid alcohol to ketone) depending on the nature of the cofactor present. Involved in the activation or inactivation of key estrogens and androgens, 17β-HSDs are therefore therapeutic targets whose selective inhibition would make it possible to be considered for the treatment of several diseases, such as breast cancer, prostate cancer, endometriosis, Alzheimer’s disease and osteoporosis. This review article is a continuation of those having reported the great diversity of inhibitors developed over the last years but focusses on inhibitors recently developed. Work to obtain more effective inhibitors that target the first known isoforms (types 1, 2, 3, 5 and 7) has continued, among others, but new inhibitors that target the isoforms more recently reported in the literature (types 10, 12, 13 and 14) are now being reported. Dual inhibitors of two enzymes (17β-HSD1 and steroid sulfatase) were also reported. These inhibitors were grouped according to the 17β-HSD type inhibited and their backbone (steroidal or non-steroidal) when necessary. They were also reported in chronological order and according to the research group.
{"title":"Recent advances in the development of 17beta-hydroxysteroid dehydrogenase inhibitors","authors":"Donald Poirier","doi":"10.1016/j.steroids.2024.109529","DOIUrl":"10.1016/j.steroids.2024.109529","url":null,"abstract":"<div><div>The family of 17β-hydroxysteroid dehydrogenases (17β-HSDs) occupies a prominent place due to its number of isoforms, which carry out a bidirectional transformation (reduction of a steroid carbonyl to alcohol and oxidation of a steroid alcohol to ketone) depending on the nature of the cofactor present. Involved in the activation or inactivation of key estrogens and androgens, 17β-HSDs are therefore therapeutic targets whose selective inhibition would make it possible to be considered for the treatment of several diseases, such as breast cancer, prostate cancer, endometriosis, Alzheimer’s disease and osteoporosis. This review article is a continuation of those having reported the great diversity of inhibitors developed over the last years but focusses on inhibitors recently developed. Work to obtain more effective inhibitors that target the first known isoforms (types 1, 2, 3, 5 and 7) has continued, among others, but new inhibitors that target the isoforms more recently reported in the literature (types 10, 12, 13 and 14) are now being reported. Dual inhibitors of two enzymes (17β-HSD1 and steroid sulfatase) were also reported. These inhibitors were grouped according to the 17β-HSD type inhibited and their backbone (steroidal or non-steroidal) when necessary. They were also reported in chronological order and according to the research group.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"213 ","pages":"Article 109529"},"PeriodicalIF":2.1,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142628496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Starting from 3-methoxyestra-1,3,5(10),16-tetraene-17-carbaldehydes of natural (13β) and epimeric (13α) series, a series of isomeric 3-hydroxy-17-hydroxymethylestra-1,3,5(10)-trienes, including those containing 16α,17α-annulated cyclopropane and cyclohexane ring D’, were prepared using the Corey-Chaykovsky and Diels-Alder reactions followed by reduction-demethylation with diisobutylaluminum hydride and hydrogenation. Target compounds showed antiproliferative effects on MCF-7 breast cancer cells to varying degrees superior to that on MCF-10A cells, in low micromolar concentrations. The ERα-mediated luciferase reporter gene assay demonstrated that obtained steroids without an additional carbocycle or with a cyclopropane 16α,17α-annulated carbocycle are effective ERα activators. In this test, steroids of the natural configuration showed high activity at both 10 nM and 100 nM concentrations, whereas 13α-steroids showed a strong dose-dependent effect, surpassing their natural counterparts at a concentration of 100 nM. The 13β-steroid bearing additional 16α,17α-cyclohexane ring had low activity in the test. A simple docking approach using AutoDock Vina was used as a test for a preliminary assessment of the estrogenicity of the compounds. The scope of its applicability and limitations were shown using examples of synthesized molecules.
{"title":"Synthesis of 13β- and 13α-epimers of 3-hydroxy-17-hydroxymethylestra-1,3,5(10)-triene and considerations on their hormonal and antiproliferative potency","authors":"Yu.V. Kuznetsov , M.O. Tserfas , A.M. Scherbakov , O.E. Andreeva , D.I. Salnikova , E.I. Bozhenko , I.V. Zavarzin , I.S. Levina","doi":"10.1016/j.steroids.2024.109527","DOIUrl":"10.1016/j.steroids.2024.109527","url":null,"abstract":"<div><div>Starting from 3-methoxyestra-1,3,5(10),16-tetraene-17-carbaldehydes of natural (13β) and epimeric (13α) series, a series of isomeric 3-hydroxy-17-hydroxymethylestra-1,3,5(10)-trienes, including those containing 16α,17α-annulated cyclopropane and cyclohexane ring D’, were prepared using the Corey-Chaykovsky and Diels-Alder reactions followed by reduction-demethylation with diisobutylaluminum hydride and hydrogenation. Target compounds showed antiproliferative effects on MCF-7 breast cancer cells to varying degrees superior to that on MCF-10A cells, in low micromolar concentrations. The <em>ER</em>α<em>-mediated luciferase reporter gene assay</em> demonstrated that obtained steroids without an additional carbocycle or with a cyclopropane 16α,17α-annulated carbocycle are effective <em>ER</em>α activators. In this test, steroids of the natural configuration showed high activity at both 10 nM and 100 nM concentrations, whereas 13α-steroids showed a strong dose-dependent effect, surpassing their natural counterparts at a concentration of 100 nM. The 13β-steroid bearing additional 16α,17α-cyclohexane ring had low activity in the test. A simple docking approach using AutoDock Vina was used as a test for a preliminary assessment of the estrogenicity of the compounds. The scope of its applicability and limitations were shown using examples of synthesized molecules.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"212 ","pages":"Article 109527"},"PeriodicalIF":2.1,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142565059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This study aimed to investigate the effects of testosterone replacement therapy on hemostasis and some procoagulant gene expression in mice. 42 mice were randomly divided into two groups of non-orchiectomized (non-ORX) and orchiectomized (ORX) with three subgroups (n = 7) each, were subcutaneously administered with sesame oil (control), 2 and 20 mg/kg/week testosterone enanthate. Orchiectomized mice were allowed to recover for one week before treatment. On the 7th week of treatment, blood samples were collected for coagulation parameters analysis and measurement of plasma testosterone levels. Moreover, quantitative real-time PCR analysis was performed on liver samples to assess the expression of factor IX, factor X, and prothrombin genes. The results showed that supraphysiological doses (20 mg/kg) of testosterone significantly increased plasma testosterone levels in all groups, while physiological doses (2 mg/kg) only increased testosterone levels in non-ORX animals. Although testosterone administration had no effect on prothrombin time (PT) and activated partial thromboplastin time (aPTT), supraphysiological doses reduced bleeding time and clotting time. Furthermore, platelet count increased in a dose-dependent manner with testosterone enanthate treatment. The expression of coagulation factors was also decreased with supraphysiological doses of testosterone. In conclusion, testosterone had significant effects on primary hemostasis and common coagulation pathway, including increased platelet number and aggregation, decreased clotting time, and altered gene expression of coagulation factors.
{"title":"Testosterone replacement has a beneficial effect on the hemostatic system by altered gene expression of coagulation factors","authors":"Jafar Vatandoost, Amirreza Yaghoubi-Nezhad, Amir Masoud Sadr, Madjid Momeni-Moghaddam, Toktam Hajjar","doi":"10.1016/j.steroids.2024.109525","DOIUrl":"10.1016/j.steroids.2024.109525","url":null,"abstract":"<div><div>This study aimed to investigate the effects of testosterone replacement therapy on hemostasis and some procoagulant gene expression in mice. 42 mice were randomly divided into two groups of non-orchiectomized (non-ORX) and orchiectomized (ORX) with three subgroups (n = 7) each, were subcutaneously administered with sesame oil (control), 2 and 20 mg/kg/week testosterone enanthate. Orchiectomized mice were allowed to recover for one week before treatment. On the 7th week of treatment, blood samples were collected for coagulation parameters analysis and measurement of plasma testosterone levels. Moreover, quantitative real-time PCR analysis was performed on liver samples to assess the expression of factor IX, factor X, and prothrombin genes. The results showed that supraphysiological doses (20 mg/kg) of testosterone significantly increased plasma testosterone levels in all groups, while physiological doses (2 mg/kg) only increased testosterone levels in non-ORX animals. Although testosterone administration had no effect on prothrombin time (PT) and activated partial thromboplastin time (aPTT), supraphysiological doses reduced bleeding time and clotting time. Furthermore, platelet count increased in a dose-dependent manner with testosterone enanthate treatment. The expression of coagulation factors was also decreased with supraphysiological doses of testosterone. In conclusion, testosterone had significant effects on primary hemostasis and common coagulation pathway, including increased platelet number and aggregation, decreased clotting time, and altered gene expression of coagulation factors.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"212 ","pages":"Article 109525"},"PeriodicalIF":2.1,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142565061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-30DOI: 10.1016/j.steroids.2024.109526
Shabir Ahmad Mir , Sameera Firdous , Mir Shahid Maqbool , Gulzar Hussain , Mohammad Yaqoob Bhat , Fayaz A. Malik , Syed Khalid Yousuf
{"title":"Sonogashira coupling-based synthesis and in vitro cytotoxic evaluation of C-2 alkynyl derivatives of withaferin A","authors":"Shabir Ahmad Mir , Sameera Firdous , Mir Shahid Maqbool , Gulzar Hussain , Mohammad Yaqoob Bhat , Fayaz A. Malik , Syed Khalid Yousuf","doi":"10.1016/j.steroids.2024.109526","DOIUrl":"10.1016/j.steroids.2024.109526","url":null,"abstract":"","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"212 ","pages":"Article 109526"},"PeriodicalIF":2.1,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142565057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-28DOI: 10.1016/j.steroids.2024.109523
Zain Ullah , Mehmet Öztürk
The growing demand for wild mushrooms as functional foods has increased due to their pharmacological significance. Sarcosphaera crassa is a deadly poisonous mushroom consumed by people living in northern and eastern Europe after being cooked adequately due to its significant properties. Herein, the baked Sarcosphaera crassa was studied for its ingredients. The cytotoxicity of hexane, acetone, and methanol extracts of baked Sarcosphaera crassa was investigated against MCF-7, HT-29, and HeLa cancer cell lines while toxicity against PDF fibroblast healthy cell lines using MTT assay. Acetone and methanol extracts of the baked mushroom exhibited significant cytotoxic activity. Further investigation of cytotoxic extracts afforded three new secondary metabolites, namely, (3β, 22E) ergosta-5, 22-dienyl 3-O-α-yl decanoate (Brassicasteryl decanoate) (1), bis (2- ethylpentadecyl) benzene-1,2-dicarboxylate (2), and (2S)-4-(aziridine-1-yl)-4-oxobutan-2-yl hexadecanoate (3), and six known compounds including ᴅ-sorbitol (4), 3β-ergosta-5,22-dien (5), two ergosterol-endoperoxides (6 and 7), nigerasterol A (8) and 5α,9α-epoksiergosta-7,22-dien, 3β,6α-diol (9). Among them, 2 exhibited effective cytotoxic activity against MCF-7 (IC50: 33.45 ± 2.9 μg/mL) and HT-29 (IC50: 45.53 ± 0.8 μg/mL) cancer cell lines. Compound 3 demonstrated high activity against HeLa (IC50: 30.45 ± 0.35 μg/mL) and MCF-7 (IC50: 33.55 ± 0.49 μg/mL) cancer cell lines, respectively. On the other hand, compound 1 demonstrated moderate cytotoxic activity against MCF-7 and HT-29 cancer cell lines. Besides, against PDF healthy cell lines, all extracts demonstrated lower toxicity. This discovery highlights the significance of Sarcosphaera crassa as a natural functional food reservoir.
{"title":"Assessment of anti-cancer evaluation of new metabolites isolated from baked Sarcosphaera crassa: An edible poisonous mushroom","authors":"Zain Ullah , Mehmet Öztürk","doi":"10.1016/j.steroids.2024.109523","DOIUrl":"10.1016/j.steroids.2024.109523","url":null,"abstract":"<div><div>The growing demand for wild mushrooms as functional foods has increased due to their pharmacological significance. <em>Sarcosphaera crassa</em> is a deadly poisonous mushroom consumed by people living in northern and eastern Europe after being cooked adequately due to its significant properties. Herein, the baked <em>Sarcosphaera crassa</em> was studied for its ingredients. The cytotoxicity of hexane, acetone, and methanol extracts of baked <em>Sarcosphaera crassa</em> was investigated against MCF-7, HT-29, and HeLa cancer cell lines while toxicity against PDF fibroblast healthy cell lines using MTT assay. Acetone and methanol extracts of the baked mushroom exhibited significant cytotoxic activity. Further investigation of cytotoxic extracts afforded three new secondary metabolites, namely, (3<em>β,</em> 22<em>E</em>) ergosta-5, 22-dienyl 3-<em>O</em>-<em>α</em>-yl decanoate (Brassicasteryl decanoate) (<strong>1</strong>), bis (2- ethylpentadecyl) benzene-1,2-dicarboxylate (<strong>2</strong>), and (2<em>S</em>)-4-(aziridine-1-yl)-4-oxobutan-2-yl hexadecanoate (<strong>3</strong>), and six known compounds including ᴅ-sorbitol (<strong>4</strong>), 3<em>β</em>-ergosta-5,22-dien (<strong>5</strong>), two ergosterol-endoperoxides (<strong>6</strong> and <strong>7</strong>), nigerasterol A (<strong>8</strong>) and 5<em>α</em>,9<em>α</em>-epoksiergosta-7,22-dien, 3<em>β</em>,6<em>α</em>-diol (<strong>9</strong>). Among them, <strong>2</strong> exhibited effective cytotoxic activity against MCF-7 (IC<sub>50</sub>: 33.45 ± 2.9 μg/mL) and HT-29 (IC<sub>50</sub>: 45.53 ± 0.8 μg/mL) cancer cell lines. Compound <strong>3</strong> demonstrated high activity against HeLa (IC<sub>50</sub>: 30.45 ± 0.35 μg/mL) and MCF-7 (IC<sub>50</sub>: 33.55 ± 0.49 μg/mL) cancer cell lines, respectively. On the other hand, compound <strong>1</strong> demonstrated moderate cytotoxic activity against MCF-7 and HT-29 cancer cell lines. Besides, against PDF healthy cell lines, all extracts demonstrated lower toxicity. This discovery highlights the significance of <em>Sarcosphaera crassa</em> as a natural functional food reservoir.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"212 ","pages":"Article 109523"},"PeriodicalIF":2.1,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-26DOI: 10.1016/j.steroids.2024.109524
Susana N Paul, Anna De Visser, Federica Motta, Caroline A Rivers, John R Pooley, Stafford L Lightman, Onno C Meijer
Mineralocorticoid (MR) and glucocorticoid receptors (GR) act as transcription factors and major mediators of glucocorticoid signalling, with pivotal roles in regulating the stress response and hormonal signalling, mood, cognition and memory. The MR and GR and share many target genes, have a high degree of homology in their DNA binding (DBD) and ligand binding domain (LBD) but differ considerably in the N-terminal domain (NTD). Using Proximity Ligation Assay (PLA) we quantitatively assessed MR-GR complex subcellular localisation and transcriptional regulation in murine neuroblastoma (N2A) cells stimulated by constant or pulsatile corticosterone (CORT) patterns. We observe that continuous receptor activation by CORT caused localisation at the periphery of the cell nucleus. Truncation of the receptor Ligand Binding Domain (LBD) led to a stronger localisation of MR-GR complexes at the periphery of the cell nuclei. This was also observed for GR immunofluorescence (IF), while in cells expressing only MR or GR the mRNA response to pulsatile hormone treatment was substantially attenuated. However, there was no clearcut correlation between the spatial distribution of MR-GR complexes and the mRNA levels of target genes. Overall, our findings suggest that longer presence in the cell nucleus favors more peripheral nuclear localisation.
矿质类固醇受体（MR）和糖皮质激素受体（GR）是糖皮质激素信号转导的转录因子和主要介质，在调节应激反应和激素信号、情绪、认知和记忆方面起着关键作用。MR 和 GR 共享许多靶基因，它们的 DNA 结合域（DBD）和配体结合域（LBD）具有高度的同源性，但在 N 端域（NTD）上存在很大差异。我们使用近接分析法（PLA）定量评估了受恒定或脉冲性皮质酮（CORT）模式刺激的小鼠神经母细胞瘤（N2A）细胞中 MR-GR 复合物的亚细胞定位和转录调控。我们观察到，CORT 对受体的持续激活导致受体定位于细胞核外围。截断受体配体结合域（LBD）会导致 MR-GR 复合物在细胞核外围更强的定位。在 GR 免疫荧光（IF）中也观察到了这种情况，而在只表达 MR 或 GR 的细胞中，mRNA 对脉冲激素处理的反应大大减弱。然而，MR-GR 复合物的空间分布与靶基因的 mRNA 水平之间没有明显的相关性。总之，我们的研究结果表明，在细胞核中存在更长的时间有利于更周边的核定位。
{"title":"Patterns of corticosterone exposure affect the subcellular localisation of mineralocorticoid and glucocorticoid receptor complexes and gene expression.","authors":"Susana N Paul, Anna De Visser, Federica Motta, Caroline A Rivers, John R Pooley, Stafford L Lightman, Onno C Meijer","doi":"10.1016/j.steroids.2024.109524","DOIUrl":"https://doi.org/10.1016/j.steroids.2024.109524","url":null,"abstract":"<p><p>Mineralocorticoid (MR) and glucocorticoid receptors (GR) act as transcription factors and major mediators of glucocorticoid signalling, with pivotal roles in regulating the stress response and hormonal signalling, mood, cognition and memory. The MR and GR and share many target genes, have a high degree of homology in their DNA binding (DBD) and ligand binding domain (LBD) but differ considerably in the N-terminal domain (NTD). Using Proximity Ligation Assay (PLA) we quantitatively assessed MR-GR complex subcellular localisation and transcriptional regulation in murine neuroblastoma (N2A) cells stimulated by constant or pulsatile corticosterone (CORT) patterns. We observe that continuous receptor activation by CORT caused localisation at the periphery of the cell nucleus. Truncation of the receptor Ligand Binding Domain (LBD) led to a stronger localisation of MR-GR complexes at the periphery of the cell nuclei. This was also observed for GR immunofluorescence (IF), while in cells expressing only MR or GR the mRNA response to pulsatile hormone treatment was substantially attenuated. However, there was no clearcut correlation between the spatial distribution of MR-GR complexes and the mRNA levels of target genes. Overall, our findings suggest that longer presence in the cell nucleus favors more peripheral nuclear localisation.</p>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":" ","pages":"109524"},"PeriodicalIF":2.1,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号