Pub Date : 2025-02-01DOI: 10.1016/j.steroids.2025.109563
Haniyeh Amini , Alireza Shirpoor , Roya Naderi
Myocardial apoptosis is a leading cause of damage in cardiac tissues of nandrolone (ND) treatment. However, its molecular mechanism is not fully understood. This study aims to investigate the effect of ND with or without N −acetylcysteine (NAC) treatment on oxidative damage and TLR4/NF-κB /NLRP3 signaling pathway in the heart of male rats. Eighteen male Wistar rats with a weight range of 220 ± 10 g were selected. They were divided into three groups (n = 6): control (C) group, ND group, NAC + ND group. After six weeks of treatment, the TUNEL staining indicated that ND increased the number of apoptotic cells in the hearts of male rats. The molecular analysis demonstrated that ND exposure resulted in increased protein levels of cytochrome c, c-Caspase-3/p-Caspase-3 ratio, p53, TLR4, NF-κB, NLRP3, and 8-OHdG with a concomitant up-regulation of LDH and CK-MB enzymes activity in the heart tissue compared to the C group. Our findings suggested that ND can cause damage to heart tissue via induction of DNA damage, apoptosis, and probably TLR4/NF-κB/NLRP3 signaling pathway plays a crucial role in this process. It also demonstrates that these negative effects of ND can be reduced by using NAC treatment as an antioxidant and anti-inflammatory agent.
{"title":"Nandrolone decanoate induces heart injury via oxidative damage and mitochondrial apoptotic pathway by regulation of TLR4/NF-κB/NLRP3 axis in male rats: The rescue effect of N-acetylcysteine","authors":"Haniyeh Amini , Alireza Shirpoor , Roya Naderi","doi":"10.1016/j.steroids.2025.109563","DOIUrl":"10.1016/j.steroids.2025.109563","url":null,"abstract":"<div><div>Myocardial apoptosis is a leading cause of damage in cardiac tissues of nandrolone (ND) treatment. However, its molecular mechanism is not fully understood. This study aims to investigate the effect of ND with or without N −acetylcysteine (NAC) treatment on oxidative damage and TLR4/NF-κB /NLRP3 signaling pathway in the heart of male rats. Eighteen male Wistar rats with a weight range of 220 ± 10 g were selected. They were divided into three groups (n = 6): control (C) group, ND group, NAC + ND group. After six weeks of treatment, the TUNEL staining indicated that ND increased the number of apoptotic cells in the hearts of male rats. The molecular analysis demonstrated that ND exposure resulted in increased protein levels of cytochrome <em>c</em>, c-Caspase-3/p-Caspase-3 ratio, p53, TLR4, NF-κB, NLRP3, and 8-OHdG with a concomitant up-regulation of LDH and CK-MB enzymes activity in the heart tissue compared to the C group. Our findings suggested that ND can cause damage to heart tissue via induction of DNA damage, apoptosis, and probably TLR4/NF-κB/NLRP3 signaling pathway plays a crucial role in this process. It also demonstrates that these negative effects of ND can be reduced by using NAC treatment as an antioxidant and anti-inflammatory agent.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"214 ","pages":"Article 109563"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080910","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 : 2025-02-01DOI: 10.1016/j.steroids.2024.109555
Nuo Chen , Yunqiang Wu , Huamao Wei , Shuai Zhi , Liwei Liu
Toad venom, a family of toxic yet pharmacologically valuable biotoxins, has long been utilized in traditional medicine and holds significant promise in modern drug development. Bufotalin, a prominent bufotoxin, has demonstrated potent cytotoxic properties through mechanisms such as apoptosis induction, cell cycle arrest, endoplasmic reticulum stress activation, and inhibition of metastasis by modulating key pathways including Akt, p53, and STAT3/EMT signaling—these multi-target mechanisms position bufotalin as a promising agent to combat multidrug resistance in cancer therapy. Additionally, advances in bufotalin synthesis, including chemical and biocatalytic methods, have streamlined production, with strategies such as C14α-hydroxylation and novel coupling techniques enhancing yield and reducing environmental impact. This review consolidates recent progress on bufotalin’s structure, activity, cytotoxic mechanisms, and synthetic methodologies, offering a foundation for further development as an innovative chemotherapy agent.
{"title":"The advancement of structure, bioactivity, mechanism, and synthesis of bufotalin","authors":"Nuo Chen , Yunqiang Wu , Huamao Wei , Shuai Zhi , Liwei Liu","doi":"10.1016/j.steroids.2024.109555","DOIUrl":"10.1016/j.steroids.2024.109555","url":null,"abstract":"<div><div>Toad venom, a family of toxic yet pharmacologically valuable biotoxins, has long been utilized in traditional medicine and holds significant promise in modern drug development. Bufotalin, a prominent bufotoxin, has demonstrated potent cytotoxic properties through mechanisms such as apoptosis induction, cell cycle arrest, endoplasmic reticulum stress activation, and inhibition of metastasis by modulating key pathways including Akt, p53, and STAT3/EMT signaling—these multi-target mechanisms position bufotalin as a promising agent to combat multidrug resistance in cancer therapy. Additionally, advances in bufotalin synthesis, including chemical and biocatalytic methods, have streamlined production, with strategies such as C14α-hydroxylation and novel coupling techniques enhancing yield and reducing environmental impact. This review consolidates recent progress on bufotalin’s structure, activity, cytotoxic mechanisms, and synthetic methodologies, offering a foundation for further development as an innovative chemotherapy agent.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"214 ","pages":"Article 109555"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872833","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 : 2025-02-01DOI: 10.1016/j.steroids.2024.109544
Menghuan Wu , Zhaoxiang Wang
Purpose
Relative fat mass (RFM) is a novel obesity assessment metric, and we aim to explore the relationship between RFM and testosterone deficiency in US adult males.
Methods
This study included data from adult males aged 20–59 years from the NHANES 2013–2014 and 2015–2016 cycles. RFM was calculated using a linear equation based on height and waist circumference (WC). Testosterone deficiency was defined as a total serum testosterone level of less than 300 ng/dL. Logistic regression, subgroup analysis, and smooth curve fitting were employed to explore the relationship between RFM and the risk of testosterone deficiency.
Results
This study included 3243 participants, with 771 diagnosed with testosterone deficiency. Testosterone-deficient individuals exhibited significantly higher RFM levels compared to those with normal testosterone levels (31.23 ± 0.23 vs. 27.16 ± 0.19, P < 0.001). After adjusting for confounding variables, a positive correlation emerged between RFM and testosterone deficiency (OR = 1.16, 95 %CI = 1.11–1.22, P < 0.001). Smooth curve fitting further supported this relationship. Subgroup analysis did not identify any special populations. Receiver operating curve (ROC) analysis results indicated that RFM showed greater effectiveness compared to body mass index (BMI) and WC.
Conclusions
Elevated RFM levels were found to be linked to the risk of testosterone deficiency. Further studies on RFM hold promise to evaluate and address testosterone deficiency.
{"title":"Relative fat mass (RFM) is linked to testosterone deficiency in adult males","authors":"Menghuan Wu , Zhaoxiang Wang","doi":"10.1016/j.steroids.2024.109544","DOIUrl":"10.1016/j.steroids.2024.109544","url":null,"abstract":"<div><h3>Purpose</h3><div>Relative fat mass (RFM) is a novel obesity assessment metric, and we aim to explore the relationship between RFM and testosterone deficiency in US adult males.</div></div><div><h3>Methods</h3><div>This study included data from adult males aged 20–59 years from the NHANES 2013–2014 and 2015–2016 cycles. RFM was calculated using a linear equation based on height and waist circumference (WC). Testosterone deficiency was defined as a total serum testosterone level of less than 300 ng/dL. Logistic regression, subgroup analysis, and smooth curve fitting were employed to explore the relationship between RFM and the risk of testosterone deficiency.</div></div><div><h3>Results</h3><div>This study included 3243 participants, with 771 diagnosed with testosterone deficiency. Testosterone-deficient individuals exhibited significantly higher RFM levels compared to those with normal testosterone levels (31.23 ± 0.23 vs. 27.16 ± 0.19, <strong><em>P</em></strong> < 0.001). After adjusting for confounding variables, a positive correlation emerged between RFM and testosterone deficiency (OR = 1.16, 95 %CI = 1.11–1.22, <strong><em>P</em></strong> < 0.001). Smooth curve fitting further supported this relationship. Subgroup analysis did not identify any special populations. Receiver operating curve (ROC) analysis results indicated that RFM showed greater effectiveness compared to body mass index (BMI) and WC.</div></div><div><h3>Conclusions</h3><div>Elevated RFM levels were found to be linked to the risk of testosterone deficiency. Further studies on RFM hold promise to evaluate and address testosterone deficiency.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"214 ","pages":"Article 109544"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142786804","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 : 2025-02-01DOI: 10.1016/j.steroids.2024.109556
Lucas D. Ferreira, Bruno A. Aguilar, João V.M. Bernal, Kelly Y. Melo, Maria E. Gerolim, Tallys E.V. Paixão, Danielle A. Tiburcio, Hugo C.D. Souza
Introduction
The use of anabolic steroids is widely adopted for aesthetic purposes and sports performance. In supraphysiological doses, they can impair various physiological systems. However, we know little about their effects on the heart, especially when combined with strength training. In this regard, we investigated the effects of nandrolone decanoate at supraphysiological doses, combined with strength training, on cardiac hemodynamic, morphological, and functional parameters using different approaches.
Methods
Male Wistar rats (N = 64, 18 weeks old) were divided into two groups (N = 32): vehicle-treated (VEH; peanut oil, 0.2 ml/kg) and nandrolone decanoate-treated (NAN, 5 mg/kg). Half of each group (N = 16) underwent strength training following a progressive load stair protocol three times per week for 12 weeks (T-VEH and T-NAN). All groups had their cardiac hemodynamic, morphological, and functional parameters recorded through two-dimensional echocardiography, while coronary perfusion pressure and left ventricular pressure (LVP) were measured using the Langendorff technique in isolated hearts.
Results
Both nandrolone decanoate-treated groups showed higher values of relative cardiac mass, interventricular septum thickness, and final diastolic and systolic diameters of the left ventricle compared to vehicle-treated groups (VEH and T-VEH). The NAN group exhibited reductions in coronary perfusion pressure, LVP, and maximum and minimum dP/dT compared to the VEH and T-VEH groups, while the T-NAN group showed reduced values for coronary perfusion pressure and LVP compared to the VEH group.
Conclusions
Nandrolone decanoate treatment at supraphysiological doses reduced left ventricular performance. In turn, strength training appeared to provide minimal attenuation of these impairments.
{"title":"Chronic treatment with nandrolone decanoate reduces left ventricular contractile response even when combined with strength training","authors":"Lucas D. Ferreira, Bruno A. Aguilar, João V.M. Bernal, Kelly Y. Melo, Maria E. Gerolim, Tallys E.V. Paixão, Danielle A. Tiburcio, Hugo C.D. Souza","doi":"10.1016/j.steroids.2024.109556","DOIUrl":"10.1016/j.steroids.2024.109556","url":null,"abstract":"<div><h3>Introduction</h3><div>The use of anabolic steroids is widely adopted for aesthetic purposes and sports performance. In supraphysiological doses, they can impair various physiological systems. However, we know little about their effects on the heart, especially when combined with strength training. In this regard, we investigated the effects of nandrolone decanoate at supraphysiological doses, combined with strength training, on cardiac hemodynamic, morphological, and functional parameters using different approaches.</div></div><div><h3>Methods</h3><div>Male Wistar rats (N = 64, 18 weeks old) were divided into two groups (N = 32): vehicle-treated (VEH; peanut oil, 0.2 ml/kg) and nandrolone decanoate-treated (NAN, 5 mg/kg). Half of each group (N = 16) underwent strength training following a progressive load stair protocol three times per week for 12 weeks (<em>T</em>-VEH and <em>T</em>-NAN). All groups had their cardiac hemodynamic, morphological, and functional parameters recorded through two-dimensional echocardiography, while coronary perfusion pressure and left ventricular pressure (LVP) were measured using the Langendorff technique in isolated hearts.</div></div><div><h3>Results</h3><div>Both nandrolone decanoate-treated groups showed higher values of relative cardiac mass, interventricular septum thickness, and final diastolic and systolic diameters of the left ventricle compared to vehicle-treated groups (VEH and <em>T</em>-VEH). The NAN group exhibited reductions in coronary perfusion pressure, LVP, and maximum and minimum dP/dT compared to the VEH and <em>T</em>-VEH groups, while the <em>T</em>-NAN group showed reduced values for coronary perfusion pressure and LVP compared to the VEH group.</div></div><div><h3>Conclusions</h3><div>Nandrolone decanoate treatment at supraphysiological doses reduced left ventricular performance. In turn, strength training appeared to provide minimal attenuation of these impairments.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"214 ","pages":"Article 109556"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907711","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 : 2025-02-01DOI: 10.1016/j.steroids.2024.109552
Ying Deng , Ning Yang , Jun Wang , Taotao Tu
This study investigates the causal relationships between hormone levels and growth and development of children, focusing specifically on height disparities in cases of dwarfism. Besides utilizing double-debiased machine learning approach, the study integrates three alternative causal inference methods: partialing-out lasso linear regression, cross-fit partialing-out lasso linear regression, and post-double selection LASSO. These machine learning techniques are pivotal in identifying causal effects within observational data. The findings reveal a positive correlation between luteinizing hormone (LH) levels and adolescent height, while follicle-stimulating hormone (FSH) and the LH/FSH ratio show inverse correlations. The study underscores the significant role of hormone levels, particularly LH, in determining height, offering valuable insights that could guide future interventions or treatments for children and adolescents with dwarfism.
{"title":"Understanding the role of hormones in pediatric growth: Insights from a double-debiased machine learning approach","authors":"Ying Deng , Ning Yang , Jun Wang , Taotao Tu","doi":"10.1016/j.steroids.2024.109552","DOIUrl":"10.1016/j.steroids.2024.109552","url":null,"abstract":"<div><div>This study investigates the causal relationships between hormone levels and growth and development of children, focusing specifically on height disparities in cases of dwarfism. Besides utilizing double-debiased machine learning approach, the study integrates three alternative causal inference methods: partialing-out lasso linear regression, cross-fit partialing-out lasso linear regression, and post-double selection LASSO. These machine learning techniques are pivotal in identifying causal effects within observational data. The findings reveal a positive correlation between luteinizing hormone (LH) levels and adolescent height, while follicle-stimulating hormone (FSH) and the LH/FSH ratio show inverse correlations. The study underscores the significant role of hormone levels, particularly LH, in determining height, offering valuable insights that could guide future interventions or treatments for children and adolescents with dwarfism.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"214 ","pages":"Article 109552"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142802310","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}
Physalis alkekengi L. is recognized as a significant source of various secondary metabolites, particularly C28 steroidal lactones known as withanolides and physalins, renowned for their therapeutic properties with a rich history in traditional medicine. In this study, we characterized the sequences of key downstream genes (PaFPPS, PaSQS, PaSQE, PaCAS, PaHYD1, and PaDWF5-1) involved in the biosynthesis of withanolides, marking the first characterization of these genes in P. alkekengi. Our findings revealed highly conserved amino acid sequences in P. alkekengi, with maximum similarity observed with Withania somnifera. Notably, essential domains crucial for enzyme function were preserved in P. alkekengi, indicating conserved enzyme activity. Comparative analysis of secondary structures, 3D topologies, and evolutionary studies supported ancestral homology. Investigations into the differential gene expression of these genes across seven tissues (young leaves, stems, roots, flowers, mature green fruit, breaker fruit, and red ripe fruit) highlighted higher expression levels in P. alkekengi leaves. These gene expression patterns were corroborated by phytochemical analyses using chromatographic techniques. High-Performance Liquid Chromatography (HPLC) confirmed the production of two key withanolides, withanolide A and withanone, in P. alkekengi, with maximum production observed in leaves and flowers. These findings suggest that P. alkekengi holds promise as an alternative to W. somnifera for large-scale industrial production of withanolides, particularly withanolide A. Using P. alkekengi eliminates the need to sacrifice the plant, which is typically required in traditional extraction methods from the roots of W. somnifera.
{"title":"Structural and functional characterization of genes and enzymes involved in withanolide biosynthesis in Physalis alkekengi L.","authors":"Swati Gupta , Bashir Akhlaq Akhoon , Deepak Sharma , Deepika Singh , Sanjana Kaul , Manoj Kumar Dhar","doi":"10.1016/j.steroids.2024.109557","DOIUrl":"10.1016/j.steroids.2024.109557","url":null,"abstract":"<div><div><em>Physalis alkekengi</em> L. is recognized as a significant source of various secondary metabolites, particularly C<sub>28</sub> steroidal lactones known as withanolides and physalins, renowned for their therapeutic properties with a rich history in traditional medicine. In this study, we characterized the sequences of key downstream genes (<em>PaFPPS, PaSQS, PaSQE, PaCAS, PaHYD1, and PaDWF5-1</em>) involved in the biosynthesis of withanolides, marking the first characterization of these genes in <em>P. alkekengi</em>. Our findings revealed highly conserved amino acid sequences in <em>P. alkekengi</em>, with maximum similarity observed with <em>Withania somnifera</em>. Notably, essential domains crucial for enzyme function were preserved in <em>P. alkekengi</em>, indicating conserved enzyme activity. Comparative analysis of secondary structures, 3D topologies, and evolutionary studies supported ancestral homology. Investigations into the differential gene expression of these genes across seven tissues (young leaves, stems, roots, flowers, mature green fruit, breaker fruit, and red ripe fruit) highlighted higher expression levels in <em>P. alkekengi</em> leaves. These gene expression patterns were corroborated by phytochemical analyses using chromatographic techniques. High-Performance Liquid Chromatography (HPLC) confirmed the production of two key withanolides, withanolide A and withanone, in <em>P. alkekengi</em>, with maximum production observed in leaves and flowers. These findings suggest that <em>P. alkekengi</em> holds promise as an alternative to <em>W. somnifera</em> for large-scale industrial production of withanolides, particularly withanolide A. Using <em>P. alkekengi</em> eliminates the need to sacrifice the plant, which is typically required in traditional extraction methods from the roots of <em>W. somnifera.</em></div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"214 ","pages":"Article 109557"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142898305","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 : 2025-02-01DOI: 10.1016/j.steroids.2024.109554
Kehinde S. Olaniyi , Stephanie E. Areloegbe , Mohd Z. ul haq Shah
Background
Besides ovarian dysfunction and infertility, individuals with polycystic ovarian syndrome (PCOS) also present a number of systemic disturbances including functional derangements in the adipose tissue which possibly aggravates the endocrinometabolic abnormality in PCOS. Epigenetic changes have been implicated in metabolic-related disorders including PCOS. However, its pathogenic involvement in adipose-ovarian dysfunction is unclear. Therefore, the present research was designed to investigate the impact of epigenetic regulator, particularly short chain fatty acids (SCFAs) on adipose-ovarian dysfunction in PCOS rat model.
Materials and Methods
Eight-weeks-old female Wistar rats were allotted into four groups of n = 5, namely control, sodium acetate (SACT), letrozole (LETZ), and LETZ + SACT. Letrozole (1 mg/kg; p.o.) was administered daily for 21 days to induce PCOS. Thereafter, the animals were treated daily with SACT (200 mg/kg; p.o.) for 6 weeks.
Results
Letrozole-induced PCOS rats were presented with androgen excess, insulin resistance/hyperinsulinemia, ovarian cystic follicles, increased levels of anti-Mullerian hormone, leptin, with a corresponding decrease in 17-β estradiol, and adiponectin. In addition, the LETZ group also showed dyslipidemia, decreased levels of adipose/ovarian sirtuin-1, adipose triglyceride, increased lipase activity as well as ovarian triglyceride, with corresponding increase in adipose/ovarian lipid peroxidation, caspase-6, TGF-β1, inflammatory response (TNF-α, NF-κB and MIF) and decreased GSH. Adipose/ovarian mitofusin 2 depletion was observed in LETZ group and this was accompanied by elevated HDAC2. Nevertheless, administration of acetate reversed these perturbations.
Conclusion
Overall, the present results suggest that acetate ameliorates adipose-ovarian metabolic and endocrine disruptions that accompany PCOS, and these beneficial effects of acetate are associated with reduction of HDAC2 levels and elevation of mitofusin 2/sirtuin-1.
{"title":"Acetate abates adipose-ovarian endocrinometabolic disturbance in experimentally induced polycystic ovarian syndrome","authors":"Kehinde S. Olaniyi , Stephanie E. Areloegbe , Mohd Z. ul haq Shah","doi":"10.1016/j.steroids.2024.109554","DOIUrl":"10.1016/j.steroids.2024.109554","url":null,"abstract":"<div><h3>Background</h3><div>Besides ovarian dysfunction and infertility, individuals with polycystic ovarian syndrome (PCOS) also present a number of systemic disturbances including functional derangements in the adipose tissue which possibly aggravates the endocrinometabolic abnormality in PCOS. Epigenetic changes have been implicated in metabolic-related disorders including PCOS. However, its pathogenic involvement in adipose-ovarian dysfunction is unclear. Therefore, the present research was designed to investigate the impact of epigenetic regulator, particularly short chain fatty acids (SCFAs) on adipose-ovarian dysfunction in PCOS rat model.</div></div><div><h3>Materials and Methods</h3><div>Eight-weeks-old female Wistar rats were allotted into four groups of n = 5, namely control, sodium acetate (SACT), letrozole (LETZ), and LETZ + SACT. Letrozole (1 mg/kg; <em>p.o.</em>) was administered daily for 21 days to induce PCOS. Thereafter, the animals were treated daily with SACT (200 mg/kg; <em>p.o.</em>) for 6 weeks.</div></div><div><h3>Results</h3><div>Letrozole-induced PCOS rats were presented with androgen excess, insulin resistance/hyperinsulinemia, ovarian cystic follicles, increased levels of anti-Mullerian hormone, leptin, with a corresponding decrease in 17-β estradiol, and adiponectin. In addition, the LETZ group also showed dyslipidemia, decreased levels of adipose/ovarian sirtuin-1, adipose triglyceride, increased lipase activity as well as ovarian triglyceride, with corresponding increase in adipose/ovarian lipid peroxidation, caspase-6, TGF-β1, inflammatory response (TNF-α, NF-κB and MIF) and decreased GSH. Adipose/ovarian mitofusin 2 depletion was observed in LETZ group and this was accompanied by elevated HDAC2. Nevertheless, administration of acetate reversed these perturbations.</div></div><div><h3>Conclusion</h3><div>Overall, the present results suggest that acetate ameliorates adipose-ovarian metabolic and endocrine disruptions that accompany PCOS, and these beneficial effects of acetate are associated with reduction of HDAC2 levels and elevation of mitofusin 2/sirtuin-1.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"214 ","pages":"Article 109554"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142872839","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}
Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine and metabolic disorder associated with insulin resistance (IR) and hyperandrogenism. IR plays a crucial role in the etiology of PCOS. An insulin-sensitizing agent like metformin is most commonly used as an off-label drug for the treatment of PCOS. PSTi8 (a pancreastatin inhibitor) is known as a promising therapeutic insulin-sensitizing agent for the treatment of IR in metabolic diseases. Thus, this study evaluates the insulin-sensitizing effects of PSTi8 compared to metformin on IR, hyperandrogenism, ovarian, and metabolic dysfunction in a PCOS model. To induce PCOS, rats were administered letrozole at a dose of 2 mg/kg via oral administration and fed a 60 % high-fat diet. Metformin and PSTi8 lowered serum insulin, testosterone, luteinizing hormone (LH) levels, and the LH/follicle-stimulating hormone ratio in the blood serum and improved steroidogenic gene expression in the PCOS ovaries. Both treatments increased the levels of sex hormone-binding globulin and estrogen hormone. Metformin and PSTi8 restore ovarian and uterine histomorphometry and improve the estrous cycle in PCOS rats. Metformin and PSTi8 treatments also improve blood glucose level and increase insulin sensitivity, inflammation, reactive oxygen species accumulation, lipid parameters, body weight, and fat mass in PCOS rats. This study revealed that PSTi8 is as helpful as metformin in decreasing hyperandrogenism by improving insulin sensitivity, free testosterone level and restoring disturbed reproductive and metabolic parameters in PCOS rats. PSTi8 has potential to serve as a therapeutic molecule for preventing IR induced by a western diet in PCOS.
{"title":"Pancreastatin inhibitor PSTi8 improves ovarian health in Letrozole-HFD induced PCOS rats by ameliorating metabolic and reproductive parameters","authors":"Shubhi Yadav , Shailesh Dadge , Richa Garg , Umesh K. Goand , Arun Agarwal , Divya Chauhan , Jiaur R. Gayen","doi":"10.1016/j.steroids.2024.109558","DOIUrl":"10.1016/j.steroids.2024.109558","url":null,"abstract":"<div><div>Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine and metabolic disorder associated with insulin resistance (IR) and hyperandrogenism. IR plays a crucial role in the etiology of PCOS. An insulin-sensitizing agent like metformin is most commonly used as an off-label drug for the treatment of PCOS. PSTi8 (a pancreastatin inhibitor) is known as a promising therapeutic insulin-sensitizing agent for the treatment of IR in metabolic diseases. Thus, this study evaluates the insulin-sensitizing effects of PSTi8 compared to metformin on IR, hyperandrogenism, ovarian, and metabolic dysfunction in a PCOS model. To induce PCOS, rats were administered letrozole at a dose of 2 mg/kg via oral administration and fed a 60 % high-fat diet. Metformin and PSTi8 lowered serum insulin, testosterone, luteinizing hormone (LH) levels, and the LH/follicle-stimulating hormone ratio in the blood serum and improved steroidogenic gene expression in the PCOS ovaries. Both treatments increased the levels of sex hormone-binding globulin and estrogen hormone. Metformin and PSTi8 restore ovarian and uterine histomorphometry and improve the estrous cycle in PCOS rats. Metformin and PSTi8 treatments also improve blood glucose level and increase insulin sensitivity, inflammation, reactive oxygen species accumulation, lipid parameters, body weight, and fat mass in PCOS rats. This study revealed that PSTi8 is as helpful as metformin in decreasing hyperandrogenism by improving insulin sensitivity, free testosterone level and restoring disturbed reproductive and metabolic parameters in PCOS rats. PSTi8 has potential to serve as a therapeutic molecule for preventing IR induced by a western diet in PCOS.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"214 ","pages":"Article 109558"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915687","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 : 2025-02-01DOI: 10.1016/j.steroids.2024.109541
Ying Chen , Xiaofang Luo , Yizhe Li , Linhong Liu , Zhen Liu , Yunyue Tan , Ying Chen
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":"10.1016/j.steroids.2024.109541","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"214 ","pages":"Article 109541"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","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}
S-equol, an isoflavone metabolite with high estrogenic activity, exhibits organ-protective effects via the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. While estrogen has cardioprotective effects against ischemia–reperfusion injury, whether S-equol shares this capability remains uncertain. This study aimed to assess the cardioprotective effects of S-equol on stunned myocardium using an isolated rat heart model and investigate the involvement of PI3K/Akt signaling pathway.
Methods
Male rat hearts were perfused using the Langendorff system and divided into four groups: 1) modified Krebs–Henseleit (KH) buffer containing 1 μmol/L S-equol (EQ); 2) KH buffer (Cont); 3) KH buffer supplemented with 1 μmol/L S-equol and 100 nmol/L wortmannin (a specific PI3K inhibitor) (EQW); or 4) KH buffer containing wortmannin (ContW). After stabilization, each group was perfused for 20 min before undergoing 7.5 min of no-flow ischemia, followed by 20 min reperfusion. The primary outcome was the maximum left ventricular derivative of pressure development (left ventricle [LV] dP/dt max) after 20 min of reperfusion. Myocardial Akt and glycogen synthase kinase-3 beta (GSK-3β) were assayed using western blotting.
Results
LV dP/dt max was greater in the EQ group than that in the Cont group after 15 and 20 min of reperfusion; however, this effect was attenuated in the presence of PI3K inhibitors. S-equol treatment increased Akt and suppressed GSK-3β expression in the EQ group compared to that in the Cont group. However, these effects were not observed in the presence of wortmannin.
Conclusion
S-equol exerts a protective effect against myocardial ischemia–reperfusion injury, possibly by activating PI3K/Akt signaling.
{"title":"Cardioprotective effects of S-equol, a soybean metabolite with estrogen activity, and role of the PI3K/Akt pathway in a male rat model of ischemic reperfusion","authors":"Mariko Yamada , Yosuke Nakadate , Keisuke Omiya , Takeshi Oguchi , Masako Abe , Takashi Matsukawa","doi":"10.1016/j.steroids.2024.109542","DOIUrl":"10.1016/j.steroids.2024.109542","url":null,"abstract":"<div><h3>Purpose</h3><div>S-equol, an isoflavone metabolite with high estrogenic activity, exhibits organ-protective effects via the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. While estrogen has cardioprotective effects against ischemia–reperfusion injury, whether S-equol shares this capability remains uncertain. This study aimed to assess the cardioprotective effects of S-equol on stunned myocardium using an isolated rat heart model and investigate the involvement of PI3K/Akt signaling pathway.</div></div><div><h3>Methods</h3><div>Male rat hearts were perfused using the Langendorff system and divided into four groups: 1) modified Krebs–Henseleit (KH) buffer containing 1 μmol/L S-equol (EQ); 2) KH buffer (Cont); 3) KH buffer supplemented with 1 μmol/L S-equol and 100 nmol/L wortmannin (a specific PI3K inhibitor) (EQW); or 4) KH buffer containing wortmannin (ContW). After stabilization, each group was perfused for 20 min before undergoing 7.5 min of no-flow ischemia, followed by 20 min reperfusion. The primary outcome was the maximum left ventricular derivative of pressure development (left ventricle [LV] dP/dt max)<!--> <!-->after 20 min of reperfusion. Myocardial Akt and glycogen synthase kinase-3 beta (GSK-3β) were assayed using western blotting.</div></div><div><h3>Results</h3><div>LV dP/dt max was greater in the EQ group than that in the Cont group after 15 and 20 min of reperfusion; however, this effect was attenuated in the presence of PI3K inhibitors. S-equol treatment increased Akt and suppressed GSK-3β expression in the EQ group compared to that in the Cont group. However, these effects were not observed in the presence of wortmannin.</div></div><div><h3>Conclusion</h3><div>S-equol exerts a protective effect against myocardial ischemia–reperfusion injury, possibly by activating PI3K/Akt signaling.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"213 ","pages":"Article 109542"},"PeriodicalIF":2.1,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142743700","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}
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