Pub Date : 2025-10-24DOI: 10.1016/j.steroids.2025.109705
Damião Sampaio de Sousa , Marcus Vinicius Ferreira da Silva , Aluísio Marques da Fonseca , Maria Mabelle Pereira Costa Paiva , Carminda Sandra Brito Salmito Vanderley , Gabrielle Silva Marinho
Alzheimer’s disease (AD) is the leading form of dementia in the world. It presents significant therapeutic challenges, especially in terms of the efficacy and safety of current cholinesterase inhibitors, such as AChE. To explore more effective therapeutic alternatives, this study investigated the potential of steroids derived from Spongia sp. as inhibitors of AChE and BuChE, utilizing in silico approaches. Six compounds (SP1-SP6) were subjected to pharmacokinetic property predictions (ADMET), metabolic stability evaluation, and molecular docking and molecular dynamics studies. The analyses indicated that compounds SP4-SP6 show greater polarity and metabolic stability in the hepatic microsomal system, while SP1-SP3 exhibit greater cell permeability and bioaccumulation potential. Among them, compound SP6 stood out for showing relevant interactions with active residues of BuChE, suggesting selectivity and structural compatibility with this enzyme. The results were reinforced by molecular dynamics simulations, which confirmed the stability of the SP6-BuChE complex, characterized by low structural deviations (RMSD), minimal residual fluctuations (RMSF), maintenance of hydrogen bonds, and a favorable binding free energy (MMGBSA). Thus, the steroids evaluated, especially SP6, have promising characteristics for modulating BuChE, with potential therapeutic application in AD. Additional experimental studies are needed to validate the efficacy and selectivity of these drugs. Additional experimental studies are needed to validate the efficacy and selectivity of these compounds in biological models.
{"title":"Selectivity, stability, and pharmacokinetic profiling of Spongia-derived steroids targeting AChE and BuChE for Alzheimer’s therapy","authors":"Damião Sampaio de Sousa , Marcus Vinicius Ferreira da Silva , Aluísio Marques da Fonseca , Maria Mabelle Pereira Costa Paiva , Carminda Sandra Brito Salmito Vanderley , Gabrielle Silva Marinho","doi":"10.1016/j.steroids.2025.109705","DOIUrl":"10.1016/j.steroids.2025.109705","url":null,"abstract":"<div><div>Alzheimer’s disease (AD) is the leading form of dementia in the world. It presents significant therapeutic challenges, especially in terms of the efficacy and safety of current cholinesterase inhibitors, such as AChE. To explore more effective therapeutic alternatives, this study investigated the potential of steroids derived from <em>Spongia</em> sp. as inhibitors of AChE and BuChE, utilizing in silico approaches. Six compounds (SP1-SP6) were subjected to pharmacokinetic property predictions (ADMET), metabolic stability evaluation, and molecular docking and molecular dynamics studies. The analyses indicated that compounds SP4-SP6 show greater polarity and metabolic stability in the hepatic microsomal system, while SP1-SP3 exhibit greater cell permeability and bioaccumulation potential. Among them, compound SP6 stood out for showing relevant interactions with active residues of BuChE, suggesting selectivity and structural compatibility with this enzyme. The results were reinforced by molecular dynamics simulations, which confirmed the stability of the SP6-BuChE complex, characterized by low structural deviations (RMSD), minimal residual fluctuations (RMSF), maintenance of hydrogen bonds, and a favorable binding free energy (MMGBSA). Thus, the steroids evaluated, especially SP6, have promising characteristics for modulating BuChE, with potential therapeutic application in AD. Additional experimental studies are needed to validate the efficacy and selectivity of these drugs. Additional experimental studies are needed to validate the efficacy and selectivity of these compounds in biological models.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"224 ","pages":"Article 109705"},"PeriodicalIF":2.3,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145418131","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 : 2025-10-23DOI: 10.1016/j.steroids.2025.109704
Ambreen Aziz , Atia-tul-Wahab , Ghulam Farooq , Nimra Naveed Shaikh , Sammer Yousuf , Humaira Zafar , Zaheer Ahmed , M. Iqbal Choudhary
The purpose of this study was to identify potential aromatase inhibitors, which might play a role in preventing breast cancer. The fungal-catalyzed microbial transformation of an anti-mineralocorticoid, canrenone (1), was catalyzed by Glomerella fusarioides, and Cunninghamella blakesleeana. Bioconversion of canrenone (1) with G. fusarioides provided a new polar metabolite 2, and two known metabolites 3 and 4, while C. blakesleana transformed compound 1 into two known polar metabolites 4, and 5. Modern spectroscopic techniques were employed to identify the structures of metabolites as 1-dehydro-11α-hydroxycanrenone (2), 1-dehydrocanrenone (3), 11α-hydroxycanrenone (4), and 11β-hydroxycanrenone (5). The SingleCrystal X-ray Diffraction (SCXRD) based structures of metabolites 2, and 3 are reported here for the first time. Canrenone (1) and the resulting metabolites 2–4 were evaluated for their human aromatase inhibitory activity. Compounds 1–4 showed the IC50 values of 0.288 ± 0.0392, 0.372 ± 0.002, 0.328 ± 0.0083, and 1.102 ± 0.099, µM comparable to the standard drug, exemestane (0.26 ± 0.011 µM). All transformed products were found non-cytotoxic to human fibroblast (BJ) cell line. Furthermore, the docking studies predicted the interaction of potential inhibitors with the active site residues of the enzyme via hydrogen bonding and other non-covalent interactions. Simulation studies predicted the formation of stable enzyme-inhibitor complexes with no or insignificant perturbation during the simulation time of 100 nsec. Hence, these inhibitors may serve as preliminary hits for drug discovery against ER+ breast cancer.
{"title":"Microbial catalyzed derivatization of canrenone with Glomerella fusarioides, and Cunninghamella blakesleeana, and evaluation of aromatase inhibitory activity of the resulting metabolites","authors":"Ambreen Aziz , Atia-tul-Wahab , Ghulam Farooq , Nimra Naveed Shaikh , Sammer Yousuf , Humaira Zafar , Zaheer Ahmed , M. Iqbal Choudhary","doi":"10.1016/j.steroids.2025.109704","DOIUrl":"10.1016/j.steroids.2025.109704","url":null,"abstract":"<div><div>The purpose of this study was to identify potential aromatase inhibitors, which might play a role in preventing breast cancer. The fungal-catalyzed microbial transformation of an anti-mineralocorticoid, canrenone (<strong>1</strong>), was catalyzed by <em>Glomerella fusarioides</em>, and <em>Cunninghamella blakesleeana</em>. Bioconversion of canrenone (<strong>1</strong>) with <em>G. fusarioides</em> provided a new polar metabolite <strong>2</strong>, and two known metabolites <strong>3</strong> and <strong>4</strong>, while <em>C. blakesleana</em> transformed compound <strong>1</strong> into two known polar metabolites <strong>4</strong>, and <strong>5</strong>. Modern spectroscopic techniques were employed to identify the structures of metabolites as 1-dehydro-11<em>α</em>-hydroxycanrenone (<strong>2</strong>), 1-dehydrocanrenone (<strong>3</strong>), 11<em>α</em>-hydroxycanrenone (<strong>4</strong>), and 11<em>β</em>-hydroxycanrenone (<strong>5</strong>). The SingleCrystal X-ray Diffraction (SCXRD) based structures of metabolites <strong>2</strong>, and <strong>3</strong> are reported here for the first time. Canrenone (<strong>1</strong>) and the resulting metabolites <strong>2</strong>–<strong>4</strong> were evaluated for their human aromatase inhibitory activity. Compounds <strong>1</strong>–<strong>4</strong> showed the IC<sub>50</sub> values of 0.288 ± 0.0392, 0.372 ± 0.002, 0.328 ± 0.0083, and 1.102 ± 0.099, µM comparable to the standard drug, exemestane (0.26 ± 0.011 µM). All transformed products were found non-cytotoxic to human fibroblast (BJ) cell line. Furthermore, the docking studies predicted the interaction of potential inhibitors with the active site residues of the enzyme <em>via</em> hydrogen bonding and other non-covalent interactions. Simulation studies predicted the formation of stable enzyme-inhibitor complexes with no or insignificant perturbation during the simulation time of 100 nsec. Hence, these inhibitors may serve as preliminary hits for drug discovery against ER+ breast cancer.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"225 ","pages":"Article 109704"},"PeriodicalIF":2.3,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145370468","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}
Parkinson’s disease (PD) ranks as the second most prevalent neurodegenerative disorder but is still devoid of neuroprotective treatment. Although approaches with disease modifying ability along with symptomatic relief has become an utmost necessity, the multifactorial nature of PD presents challenges for efficacy evaluation of potential test compound. This study attempts to address these issues by employing a rotenone induced PD model involving intranigral rotenone injection for evaluation of the neuroprotective efficacy of Daidzein (DZ) a soy isoflavone and a phytoestrogen. In this study, male Sprague Dawley rats after bilateral intranigral rotenone (12 μg) injection, were treated with DZ at a dose of 5, 10 and 20 mg/kg for 30 days. The neurobehavioral evaluation comprised of Rota-rod, Open field and Barnes maze test. The biochemical analysis constituting oxidative stress (Reduced glutathione, superoxide dismutase, catalase and lipid peroxidation), inflammation (TNF-α), mitochondrial alteration (complex I activity and biogenesis) was conducted on mid-brain tissue after 30 days of treatment. The Substantia nigra and striatum were subjected to immunohistochemical analysis (IHC) for TH positive neurons and Glial Fibrillary Acidic Protein. The analysis revealed significant improvement by daidzein in motor co-ordination and attenuation in cognitive deficits due to rotenone. The biochemical assessment exhibited significant decrement in oxidative stress as well as inflammation. DZ treatment also prevented complex I inhibition and promoted mitochondrial biogenesis eventually contributing to the neuroprotection apparent in IHC. Thus, the results strongly corroborate the neuroprotective potential of DZ against rotenone induced model of PD.
{"title":"Soy isoflavone Daidzein resembling the vertebrate steroid structure exhibits neuroprotection via mitochondrial biogenesis in rotenone induced Parkinson’s disease in preclinical model","authors":"Vaibhavi Peshattiwar , Suraj Muke , Aakruti Kaikini , Sneha Bagle , Vikas Dighe , Sadhana Sathaye","doi":"10.1016/j.steroids.2025.109703","DOIUrl":"10.1016/j.steroids.2025.109703","url":null,"abstract":"<div><div>Parkinson’s disease (PD) ranks as the second most prevalent neurodegenerative disorder but is still devoid of neuroprotective treatment. Although approaches with disease modifying ability along with symptomatic relief has become an utmost necessity, the multifactorial nature of PD presents challenges for efficacy evaluation of potential test compound. This study attempts to address these issues by employing a rotenone induced PD model involving intranigral rotenone injection for evaluation of the neuroprotective efficacy of Daidzein (DZ) a soy isoflavone and a phytoestrogen. In this study, male Sprague Dawley rats after bilateral intranigral rotenone (12 μg) injection, were treated with DZ at a dose of 5, 10 and 20 mg/kg for 30 days. The neurobehavioral evaluation comprised of Rota-rod, Open field and Barnes maze test. The biochemical analysis constituting oxidative stress (Reduced glutathione, superoxide dismutase, catalase and lipid peroxidation), inflammation (TNF-α), mitochondrial alteration (complex I activity and biogenesis) was conducted on mid-brain tissue after 30 days of treatment. The Substantia nigra and striatum were subjected to immunohistochemical analysis (IHC) for TH positive neurons and Glial Fibrillary Acidic Protein. The analysis revealed significant improvement by daidzein in motor co-ordination and attenuation in cognitive deficits due to rotenone. The biochemical assessment exhibited significant decrement in oxidative stress as well as inflammation. DZ treatment also prevented complex I inhibition and promoted mitochondrial biogenesis eventually contributing to the neuroprotection apparent in IHC. Thus, the results strongly corroborate the neuroprotective potential of DZ against rotenone induced model of PD.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"224 ","pages":"Article 109703"},"PeriodicalIF":2.3,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145337455","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 : 2025-10-17DOI: 10.1016/j.steroids.2025.109702
Camila Aparecida Pereira da Silva , Nara Juliana Santos Araújo , Maria do Socorro Costa , Ana Raquel Pereira da Silva , Cícera Laura Roque Paulo , José Bezerra de Araújo Neto , José Maria Barbosa Filho , Thiago Sampaio de Freitas , Juliete Bezerra Soares , Josefa Sayonara dos Santos , Maria Flaviana Bezerra Morais Braga , Henrique Douglas Melo Coutinho , Jacqueline Cosmo Andrade-Pinheiro
Bacterial biofilms are complex, organized structures that adhere to surfaces, protected by a self-produced extracellular matrix. This conformation makes it difficult to eradicate infections with conventional treatments. In view of this, natural compounds have emerged as promising therapeutic alternatives. This study evaluated the potential of betulinic acid, a pentacyclic triterpene, in inhibiting the formation and eradication of bacterial biofilms, as well as predicting its pharmacokinetic properties and toxicity by means of in silico analyses. Six bacterial strains were tested. The crystal violet test was used to evaluate the antibiofilm activity, with chlorhexidine and the antibiotics norfloxacin, ampicillin and gentamicin as controls. The results showed that betulinic acid had moderate to good activity in inhibiting biofilm formation and a variable response in eradication, depending on the strain. In silico analyses indicated favorable physicochemical and pharmacokinetic properties, with emphasis on good intestinal absorption, oral bioavailability and absence of inhibition of cytochrome P450 enzymes, although potential toxicity risks were identified. These findings suggest that betulinic acid is a promising candidate for the development of new therapeutic strategies to combat infections associated with biofilms.
{"title":"Potential of betulinic acid in the Antiformation and eradication of bacterial biofilms and pharmacokinetic and toxicological analysis","authors":"Camila Aparecida Pereira da Silva , Nara Juliana Santos Araújo , Maria do Socorro Costa , Ana Raquel Pereira da Silva , Cícera Laura Roque Paulo , José Bezerra de Araújo Neto , José Maria Barbosa Filho , Thiago Sampaio de Freitas , Juliete Bezerra Soares , Josefa Sayonara dos Santos , Maria Flaviana Bezerra Morais Braga , Henrique Douglas Melo Coutinho , Jacqueline Cosmo Andrade-Pinheiro","doi":"10.1016/j.steroids.2025.109702","DOIUrl":"10.1016/j.steroids.2025.109702","url":null,"abstract":"<div><div>Bacterial biofilms are complex, organized structures that adhere to surfaces, protected by a self-produced extracellular matrix. This conformation makes it difficult to eradicate infections with conventional treatments. In view of this, natural compounds have emerged as promising therapeutic alternatives. This study evaluated the potential of betulinic acid, a pentacyclic triterpene, in inhibiting the formation and eradication of bacterial biofilms, as well as predicting its pharmacokinetic properties and toxicity by means of in silico analyses. Six bacterial strains were tested. The crystal violet test was used to evaluate the antibiofilm activity, with chlorhexidine and the antibiotics norfloxacin, ampicillin and gentamicin as controls. The results showed that betulinic acid had moderate to good activity in inhibiting biofilm formation and a variable response in eradication, depending on the strain. In silico analyses indicated favorable physicochemical and pharmacokinetic properties, with emphasis on good intestinal absorption, oral bioavailability and absence of inhibition of cytochrome P450 enzymes, although potential toxicity risks were identified. These findings suggest that betulinic acid is a promising candidate for the development of new therapeutic strategies to combat infections associated with biofilms.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"224 ","pages":"Article 109702"},"PeriodicalIF":2.3,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145329857","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 : 2025-10-17DOI: 10.1016/j.steroids.2025.109701
Jana Benešová , Martin Hill , Daniela Dlouhá , Kateřina Roberts , Jana Ullmann , Peter Koliba , Marta Velíková , Šárka Kaňková
Nausea and vomiting in pregnancy (NVP) affect approximately 70 % of women worldwide. It is thought to have an adaptive function in the first trimester, when it protects the mother and the fetus against potential dangers from the diet. Proximate causes of NVP include hormonal changes during pregnancy. This longitudinal prospective study examined associations between various endogenous steroids and NVP. In the first and third trimester, pregnant women (N = 179) completed the Index of Nausea, Vomiting, and Retching questionnaire (92.1 % of women reported at least some symptoms of NVP in the first trimester and 37.4 % in the third trimester) and we analyzed their blood serum concentrations of 91 endogenous steroids. In the first trimester, NVP intensity was significantly positively associated with progesterone metabolites from the C21 5α/β-reduced steroid group (e.g., allopregnanolone sulfate) and with conjugated 5α-androstane-3α,17β-diol and conjugated 5α-androstane-3β,17β-diol. In the third trimester, we found significant negative associations between NVP and progesterone, conjugated testosterone, 7-oxo-DHEA, 5-androstene-3β,16α,17β-triol sulfate, some C21 Δ5 steroids (e.g., pregnenolone sulfate, 17-hydroxypregnenolone sulfate), and C21 5α/β-reduced steroids (such as allopregnanolone sulfate and conjugated pregnanolone). Our findings suggest that sulfated 3α-hydroxy-5α-steroids may contribute to NVP in early pregnancy by affecting brainstem regions involved in the vomiting reflex. In late pregnancy, higher levels of immunomodulatory androstanes and progesterone may reduce NVP severity via immune regulation and smooth muscle relaxation.
{"title":"Exploring the relationship between endogenous steroids and nausea and vomiting in pregnancy: A longitudinal prospective study","authors":"Jana Benešová , Martin Hill , Daniela Dlouhá , Kateřina Roberts , Jana Ullmann , Peter Koliba , Marta Velíková , Šárka Kaňková","doi":"10.1016/j.steroids.2025.109701","DOIUrl":"10.1016/j.steroids.2025.109701","url":null,"abstract":"<div><div>Nausea and vomiting in pregnancy (NVP) affect approximately 70 % of women worldwide. It is thought to have an adaptive function in the first trimester, when it protects the mother and the fetus against potential dangers from the diet. Proximate causes of NVP include hormonal changes during pregnancy. This longitudinal prospective study examined associations between various endogenous steroids and NVP. In the first and third trimester, pregnant women (N = 179) completed the Index of Nausea, Vomiting, and Retching questionnaire (92.1 % of women reported at least some symptoms of NVP in the first trimester and 37.4 % in the third trimester) and we analyzed their blood serum concentrations of 91 endogenous steroids. In the first trimester, NVP intensity was significantly positively associated with progesterone metabolites from the C21 5α/β-reduced steroid group (e.g., allopregnanolone sulfate) and with conjugated 5α-androstane-3α,17β-diol and conjugated 5α-androstane-3β,17β-diol. In the third trimester, we found significant negative associations between NVP and progesterone, conjugated testosterone, 7-oxo-DHEA, 5-androstene-3β,16α,17β-triol sulfate, some C21 Δ<sup>5</sup> steroids (e.g., pregnenolone sulfate, 17-hydroxypregnenolone sulfate), and C21 5α/β-reduced steroids (such as allopregnanolone sulfate and conjugated pregnanolone). Our findings suggest that sulfated 3α-hydroxy-5α-steroids may contribute to NVP in early pregnancy by affecting brainstem regions involved in the vomiting reflex. In late pregnancy, higher levels of immunomodulatory androstanes and progesterone may reduce NVP severity via immune regulation and smooth muscle relaxation.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"225 ","pages":"Article 109701"},"PeriodicalIF":2.3,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145329918","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}
Solanum viarum is a valuable medicinal plant native to India and widely distributed throughout Asia. It serves as a commercially viable raw source for the steroidal drug industry, being the richest natural source of an important steroidal alkaloid- solasodine. Enhancement of solasodine content in in vitro plant cultures is always a keen interest for tissue culturists for the research and development in pharmaceutical industries. In the present study, a multiple linear regression (MLR) model was employed to investigate the synergistic effects of key nutrient components in the growth medium (Mg, Ca, Fe, N, and sucrose) for optimized growth and solasodine production in in vitro plant cultures of S. viarum. All the cultures were harvested after 35, 45, and 55 days of the culture cycle. The three models were designed to predict growth index, solasodine content, and solasodine yield in the plant cultures. The designed model was further evaluated by performing a validation experiment using ten different experimental setups, which showed a greater similarity between the predicted and experimental datasets. The results of the model-based experimental set showed that 1.4 mM Mg, 2.9 mM Ca, 1.9 µM Fe, 41.9 mM Nitrogen, and 4 % (w/v) sucrose resulted in achieving maximum solasodine yield (108.82 mg/g DW) in the plant culture of S. viarum after 54 days of harvest. The proposed MLR model offers a robust and reliable approach for predicting the optimal concentrations of micro- and macronutrients to maximize growth and solasodine accumulation in in vitro cultures of Solanum viarum. This study establishes a strategic framework that can be leveraged to enhance biomass production and secondary metabolite yield, contributing significantly to the large-scale cultivation and pharmaceutical exploitation of this valuable medicinal plant.
龙葵（Solanum viarum）是一种原产于印度的珍贵药用植物，在亚洲广泛分布。它作为一种商业上可行的甾体药物工业原料来源，是一种重要的甾体生物碱- solasodine的最丰富的天然来源。提高植物离体培养物中solasodine的含量一直是制药行业组织培养研究和开发的热点。本研究采用多元线性回归（MLR）模型，研究了生长培养基中关键营养成分（Mg、Ca、Fe、N和蔗糖）对紫葡萄（S. viarum）体外培养物生长和产茄碱的协同效应。在培养周期的35、45和55 天后收获所有的培养物。这三个模型被设计用来预测植物生长指数、茄碱含量和茄碱产量。通过使用10种不同的实验设置进行验证实验，进一步评估设计的模型，结果表明预测数据集与实验数据集之间具有更大的相似性。基于模型的实验结果表明，收获54 d后，1.4 mM Mg、2.9 mM Ca、1.9 µM Fe、41.9 mM Nitrogen和4 % （w/v）蔗糖的植株培养可获得最大的solasodine产量（108.82 Mg /g DW）。所提出的MLR模型提供了一种稳健可靠的方法来预测微量营养素和宏量营养素的最佳浓度，以最大限度地提高龙葵体外培养物的生长和茄碱积累。本研究建立了一个战略框架，可用于提高生物质产量和次生代谢物产量，为这种珍贵药用植物的大规模种植和药用开发做出重大贡献。
{"title":"Nutrient manipulation regulates growth and steroidal alkaloid production in plant cultures of Solanum viarum Dunal","authors":"Archana Prasad , Preeti Patel , Abhishek Niranjan , Gauri Saxena , Debasis Chakrabarty","doi":"10.1016/j.steroids.2025.109700","DOIUrl":"10.1016/j.steroids.2025.109700","url":null,"abstract":"<div><div><em>Solanum viarum</em> is a valuable medicinal plant native to India and widely distributed throughout Asia. It serves as a commercially viable raw source for the steroidal drug industry, being the richest natural source of an important steroidal alkaloid- solasodine. Enhancement of solasodine content in <em>in vitro</em> plant cultures is always a keen interest for tissue culturists for the research and development in pharmaceutical industries. In the present study, a multiple linear regression (MLR) model was employed to investigate the synergistic effects of key nutrient components in the growth medium (Mg, Ca, Fe, N, and sucrose) for optimized growth and solasodine production in <em>in vitro</em> plant cultures of <em>S. viarum</em>. All the cultures were harvested after 35, 45, and 55 days of the culture cycle. The three models were designed to predict growth index, solasodine content, and solasodine yield in the plant cultures. The designed model was further evaluated by performing a validation experiment using ten different experimental setups, which showed a greater similarity between the predicted and experimental datasets. The results of the model-based experimental set showed that 1.4 mM Mg, 2.9 mM Ca, 1.9 µM Fe, 41.9 mM Nitrogen, and 4 % (w/v) sucrose resulted in achieving maximum solasodine yield (108.82 mg/g DW) in the plant culture of <em>S. viarum</em> after 54 days of harvest<em>.</em> The proposed MLR model offers a robust and reliable approach for predicting the optimal concentrations of micro- and macronutrients to maximize growth and solasodine accumulation in <em>in vitro</em> cultures of <em>Solanum viarum</em>. This study establishes a strategic framework that can be leveraged to enhance biomass production and secondary metabolite yield, contributing significantly to the large-scale cultivation and pharmaceutical exploitation of this valuable medicinal plant.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"224 ","pages":"Article 109700"},"PeriodicalIF":2.3,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145313632","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 : 2025-10-04DOI: 10.1016/j.steroids.2025.109693
Anna Xie , Libo Wang , Yu Zhang, Sunzhengyuan Zhang, Jinlong Cao, Chenglong Wang, Hongjin Wu, Weiwei Dai
Glucocorticoid-induced osteoporosis (GIOP) is a leading cause of secondary osteoporosis (OP). β-Ecdysone (βEcd), a naturally occurring estrogen analog, was evaluated for its ability to mitigate the effects of glucocorticoids (GCs) on osteocytes, the crucial cells in bone remodeling. In GIOP mouse model induced by dexamethasone (Dex), micro-CT, biomechanical testing, silver nitrate staining, and hematoxylin-eosin (HE) staining were employed, demonstrating that βEcd effectively attenuated Dex-induced decreases in bone mass and strength, and alleviated Dex induced reduction in osteocyte dendrite and viability. Network pharmacology analysis predicted that the therapeutic efficacy of βEcd against GIOP is mediated through the crucial targets such as protein kinase B (Akt1), with significant enrichment in pathways including apoptosis and phosphoinositide 3-kinase (PI3K)-Akt signaling. In vitro, the osteocyte-like MLO-Y4 cells were treated with 10 μM Dex for 48 h in the presence or absence of βEcd or the PI3K inhibitor LY294002 (LY). Crystal violet staining and connexin43 (CX43) immunofluorescence (IF) staining were employed, and western blot was used to assess the levels of Akt1, phospho (p)-Akt, CX43, p-CX43, and apoptosis-related factors. Hoechst staining and annexin V/PI apoptosis assays were also used to evaluate apoptosis. The results demonstrated that βEcd counteracted Dex-induced apoptosis by modulating Akt1 and CX43 expression in MLO-Y4 cells, while inhibition of Akt activity reversed these effects, suggesting that βEcd targets the Akt1 gene. The findings indicate that βEcd protects osteocytes from GC-induced apoptosis through Akt-mediated regulation of CX43, highlighting its potential as a therapeutic approach for the prevention and treatment of GIOP.
{"title":"Beta-Ecdysone protects osteocytes from excess glucocorticoids via Akt1-mediated regulation of Connexin43","authors":"Anna Xie , Libo Wang , Yu Zhang, Sunzhengyuan Zhang, Jinlong Cao, Chenglong Wang, Hongjin Wu, Weiwei Dai","doi":"10.1016/j.steroids.2025.109693","DOIUrl":"10.1016/j.steroids.2025.109693","url":null,"abstract":"<div><div>Glucocorticoid-induced osteoporosis (GIOP) is a leading cause of secondary osteoporosis (OP). β-Ecdysone (βEcd), a naturally occurring estrogen analog, was evaluated for its ability to mitigate the effects of glucocorticoids (GCs) on osteocytes, the crucial cells in bone remodeling. In GIOP mouse model induced by dexamethasone (Dex), micro-CT, biomechanical testing, silver nitrate staining, and hematoxylin-eosin (HE) staining were employed, demonstrating that βEcd effectively attenuated Dex-induced decreases in bone mass and strength, and alleviated Dex induced reduction in osteocyte dendrite and viability. Network pharmacology analysis predicted that the therapeutic efficacy of βEcd against GIOP is mediated through the crucial targets such as protein kinase B (Akt1), with significant enrichment in pathways including apoptosis and phosphoinositide 3-kinase (PI3K)-Akt signaling. In vitro, the osteocyte-like MLO-Y4 cells were treated with 10 μM Dex for 48 h in the presence or absence of βEcd or the PI3K inhibitor LY294002 (LY). Crystal violet staining and connexin43 (CX43) immunofluorescence (IF) staining were employed, and western blot was used to assess the levels of Akt1, phospho (p)-Akt, CX43, p-CX43, and apoptosis-related factors. Hoechst staining and annexin V/PI apoptosis assays were also used to evaluate apoptosis. The results demonstrated that βEcd counteracted Dex-induced apoptosis by modulating Akt1 and CX43 expression in MLO-Y4 cells, while inhibition of Akt activity reversed these effects, suggesting that βEcd targets the Akt1 gene. The findings indicate that βEcd protects osteocytes from GC-induced apoptosis through Akt-mediated regulation of CX43, highlighting its potential as a therapeutic approach for the prevention and treatment of GIOP.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"224 ","pages":"Article 109693"},"PeriodicalIF":2.3,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145239818","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) represents a complex endocrine disorder with profound detrimental effects on women's reproductive and metabolic health, yet the absence of specific pharmacotherapeutic interventions has resulted in a significant therapeutic gap. To elucidate the metabolic alterations in PCOS, we conducted a comprehensive targeted metabolomics analysis of plasma samples from healthy control mice and PCOS model mice, examining a panel of 197 metabolites spanning diverse metabolic classes. Our analysis revealed substantial metabolic differences between the groups, with organic acids, amino acids, and fatty acids emerging as the most abundant metabolite classes in both cohorts. Among the 197 metabolites analyzed, 86 demonstrated a Variable Importance in Projection (VIP) score > 1, with univariate analysis confirming 76 distinct metabolites showing significant alterations. Notably, the PCOS group exhibited marked increases in metabolites such as tartaric acid and docosapentaenoic acid, while hippuric acid showed the most pronounced reduction. Pathway enrichment analysis identified significant perturbations in key metabolic pathways, including amino acid metabolism, fatty acid oxidation, and the urea cycle in PCOS mice. The exogenous administration of hippuric acid led to a significant amelioration of ovarian pathology in PCOS mice, highlighting its promising therapeutic potential. These findings provide crucial insights into the altered metabolic landscape of PCOS, identifying potential biomarkers and therapeutic targets, with particular emphasis on the promising therapeutic role of hippuric acid in mitigating PCOS pathology, thereby offering a valuable avenue for further investigation and clinical translation.
{"title":"Targeted metabolomics in PCOS mice identifies hippuric acid as a therapeutic metabolite.","authors":"Hui Lan, Bin Meng, Jianbo Li, Chenjin Duan, Shuangqing Liu, Pengxiang Qu, Hongyu Qin","doi":"10.1016/j.steroids.2025.109665","DOIUrl":"10.1016/j.steroids.2025.109665","url":null,"abstract":"<p><p>Polycystic ovary syndrome (PCOS) represents a complex endocrine disorder with profound detrimental effects on women's reproductive and metabolic health, yet the absence of specific pharmacotherapeutic interventions has resulted in a significant therapeutic gap. To elucidate the metabolic alterations in PCOS, we conducted a comprehensive targeted metabolomics analysis of plasma samples from healthy control mice and PCOS model mice, examining a panel of 197 metabolites spanning diverse metabolic classes. Our analysis revealed substantial metabolic differences between the groups, with organic acids, amino acids, and fatty acids emerging as the most abundant metabolite classes in both cohorts. Among the 197 metabolites analyzed, 86 demonstrated a Variable Importance in Projection (VIP) score > 1, with univariate analysis confirming 76 distinct metabolites showing significant alterations. Notably, the PCOS group exhibited marked increases in metabolites such as tartaric acid and docosapentaenoic acid, while hippuric acid showed the most pronounced reduction. Pathway enrichment analysis identified significant perturbations in key metabolic pathways, including amino acid metabolism, fatty acid oxidation, and the urea cycle in PCOS mice. The exogenous administration of hippuric acid led to a significant amelioration of ovarian pathology in PCOS mice, highlighting its promising therapeutic potential. These findings provide crucial insights into the altered metabolic landscape of PCOS, identifying potential biomarkers and therapeutic targets, with particular emphasis on the promising therapeutic role of hippuric acid in mitigating PCOS pathology, thereby offering a valuable avenue for further investigation and clinical translation.</p>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":" ","pages":"109665"},"PeriodicalIF":2.3,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144800317","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}
Breast cancer is the most common cancer in women, with triple-negative breast cancer (TNBC) accounting for approximately 20% of cases. TNBC lacks estrogen receptors (ER), progesterone receptors (PR), and epidermal growth factor receptor 2 (HER2) expression, which makes targeted therapies ineffective. The luminal androgen receptor (LAR) subtype of TNBC expresses androgen receptor (AR), highlighting the need for treatment strategies that target androgen signaling. Recently, the role of 11-oxygenated androgens, in addition to conventional androgens such as testosterone and dihydrotestosterone, in androgen-related diseases in women has gained increased attention.
In this study, we investigated the involvement of 11-oxygenated androgens in LAR TNBC and explored the anti-androgenic effects of Kobochromone A (KC-A), a natural compound derived from Carex kobomugi. KC-A inhibits the androgen-synthesizing enzyme dehydrogenase/reductase short-chain dehydrogenase/reductase family member 11 (DHRS11) and suppresses AR expression. Using the AR-positive TNBC cell line MDA-MB-453, we demonstrated that 11-oxygenated androgens activate androgen signaling and promote cell proliferation. KC-A significantly inhibited androgen signaling by reducing nuclear AR localization and decreasing transmembrane protease, serine 2, and c-Myc expression. Furthermore, KC-A synergistically enhanced antiproliferative effects of the AKT inhibitor capivasertib (Cap), promoted apoptosis, and further suppressed AR expression. The primary therapeutic mechanisms of KC-A were identified as its dual actions: inhibition of DHRS11 and suppression of AR expression. These findings suggest that KC-A, either alone or in combination with AKT inhibitors, may offer a promising therapeutic strategy for LAR TNBC by targeting androgen signaling. Further studies are needed to confirm the efficacy and safety of KC-A in clinical applications.
乳腺癌是女性中最常见的癌症，三阴性乳腺癌（TNBC）约占病例的20%。TNBC缺乏雌激素受体（ER）、孕激素受体（PR）和表皮生长因子受体2 （HER2）的表达，这使得靶向治疗无效。TNBC的腔内雄激素受体（LAR）亚型表达雄激素受体（AR），强调了针对雄激素信号传导的治疗策略的必要性。最近，除了睾酮和双氢睾酮等传统雄激素外，11-氧合雄激素在女性雄激素相关疾病中的作用越来越受到关注。在这项研究中，我们研究了11-氧合雄激素在LAR TNBC中的作用，并探讨了Kobochromone A （KC-A）的抗雄激素作用。KC-A抑制雄激素合成酶脱氢酶/还原酶短链脱氢酶/还原酶家族成员11 (DHRS11)，抑制AR表达。利用ar阳性的TNBC细胞系MDA-MB-453，我们证明了11-氧合雄激素激活雄激素信号并促进细胞增殖。KC-A通过降低核AR定位和降低跨膜蛋白酶、丝氨酸2和c-Myc的表达，显著抑制雄激素信号传导。此外，KC-A协同增强AKT抑制剂capivasertib （Cap）的抗增殖作用，促进细胞凋亡，进一步抑制AR表达。KC-A的主要治疗机制被确定为其双重作用：抑制DHRS11和抑制AR表达。这些发现表明，KC-A单独或与AKT抑制剂联合，可能通过靶向雄激素信号通路，为LAR TNBC提供一种有希望的治疗策略。KC-A在临床应用中的有效性和安全性有待进一步研究证实。
{"title":"Kobochromone A, a polyphenol in Carex kobomugi, suppresses androgen signaling induced by 11-oxygenated androgens and enhances the efficacy of AKT inhibitors in triple-negative breast cancer cells","authors":"Masatoshi Tanio , Yuri Miyamoto , Tomofumi Saka , Yudai Kudo , Riri Hayashi , Shinya Kawano , Yuta Yoshino , Naohito Abe , Eiji Yamaguchi , Yuki Arai , Hirohito Kashiwagi , Masayoshi Oyama , Akichika Itoh , Akira Ikari , Satoshi Endo","doi":"10.1016/j.steroids.2025.109692","DOIUrl":"10.1016/j.steroids.2025.109692","url":null,"abstract":"<div><div>Breast cancer is the most common cancer in women, with triple-negative breast cancer (TNBC) accounting for approximately 20% of cases. TNBC lacks estrogen receptors (ER), progesterone receptors (PR), and epidermal growth factor receptor 2 (HER2) expression, which makes targeted therapies ineffective. The luminal androgen receptor (LAR) subtype of TNBC expresses androgen receptor (AR), highlighting the need for treatment strategies that target androgen signaling. Recently, the role of 11-oxygenated androgens, in addition to conventional androgens such as testosterone and dihydrotestosterone, in androgen-related diseases in women has gained increased attention.</div><div>In this study, we investigated the involvement of 11-oxygenated androgens in LAR TNBC and explored the anti-androgenic effects of Kobochromone A (KC-A), a natural compound derived from <em>Carex kobomugi</em>. KC-A inhibits the androgen-synthesizing enzyme dehydrogenase/reductase short-chain dehydrogenase/reductase family member 11 (DHRS11) and suppresses AR expression. Using the AR-positive TNBC cell line MDA-MB-453, we demonstrated that 11-oxygenated androgens activate androgen signaling and promote cell proliferation. KC-A significantly inhibited androgen signaling by reducing nuclear AR localization and decreasing transmembrane protease, serine 2, and c-Myc expression. Furthermore, KC-A synergistically enhanced antiproliferative effects of the AKT inhibitor capivasertib (Cap), promoted apoptosis, and further suppressed AR expression. The primary therapeutic mechanisms of KC-A were identified as its dual actions: inhibition of DHRS11 and suppression of AR expression. These findings suggest that KC-A, either alone or in combination with AKT inhibitors, may offer a promising therapeutic strategy for LAR TNBC by targeting androgen signaling. Further studies are needed to confirm the efficacy and safety of KC-A in clinical applications.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"223 ","pages":"Article 109692"},"PeriodicalIF":2.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182200","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 : 2025-09-24DOI: 10.1016/j.steroids.2025.109691
Sarvesh Sabarathinam , Nila Ganamurali
Obesity-associated Dyslipidemia and inflammation are aggravated by the accumulation of toxic oxysterols, particularly 7-ketocholesterol (7-KC), which amplifies oxidative stress and metabolic dysfunction. The steroidal scaffold is a central determinant of whether such molecules exert protective or pathogenic effects. This review highlights the dichotomy between 7-KC, a cytotoxic oxysterol, and Guggulsterone, a Phytosteroids with therapeutic potential. Guggulsterone retains the tetracyclic steroid backbone, enabling it to mimic endogenous sterols while functioning as a farnesoid X receptor (FXR) antagonist. By relieving FXR-mediated suppression of CYP7A1, Guggulsterone enhances bile acid synthesis, promotes cholesterol clearance, and improves lipid profiles. Additionally, its structural features confer anti-inflammatory activity via NF-κB inhibition, contrasting with the pro-oxidant nature of 7-KC. The concept of steroid scaffold mimicry underscores the potential of Phytosteroids as blueprints for drug design, offering a path toward innovative therapies for obesity-linked metabolic disorders.
{"title":"Steroidal scaffold dichotomy: pathogenic role of 7-ketocholesterol versus protective FXR-antagonistic actions of guggulsterone in metabolic regulation","authors":"Sarvesh Sabarathinam , Nila Ganamurali","doi":"10.1016/j.steroids.2025.109691","DOIUrl":"10.1016/j.steroids.2025.109691","url":null,"abstract":"<div><div>Obesity-associated Dyslipidemia and inflammation are aggravated by the accumulation of toxic oxysterols, particularly 7-ketocholesterol (7-KC), which amplifies oxidative stress and metabolic dysfunction. The steroidal scaffold is a central determinant of whether such molecules exert protective or pathogenic effects. This review highlights the dichotomy between 7-KC, a cytotoxic oxysterol, and Guggulsterone, a Phytosteroids with therapeutic potential. Guggulsterone retains the tetracyclic steroid backbone, enabling it to mimic endogenous sterols while functioning as a farnesoid X receptor (FXR) antagonist. By relieving FXR-mediated suppression of CYP7A1, Guggulsterone enhances bile acid synthesis, promotes cholesterol clearance, and improves lipid profiles. Additionally, its structural features confer anti-inflammatory activity via NF-κB inhibition, contrasting with the pro-oxidant nature of 7-KC. The concept of steroid scaffold mimicry underscores the potential of Phytosteroids as blueprints for drug design, offering a path toward innovative therapies for obesity-linked metabolic disorders.</div></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":"223 ","pages":"Article 109691"},"PeriodicalIF":2.3,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145157805","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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