Pub Date : 2023-12-13DOI: 10.1016/j.steroids.2023.109351
Yaowen Liu , Tianqing Nie , Jinjun Hou , Huali Long , Zijia Zhang , Min Lei , Yechun Xu , Wanying Wu
During the coronavirus reproduction process, 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro) are accountable for the fragmentation of two polyprotein precursors (pp1a/pp1ab) into substructural proteins. These two proteins are vital for the replication and transcription of the viral genome. Therefore, 3CLpro is a key protein and target for the design of coronavirus inhibitors. In previous studies, we found that betulinic acid has an inhibitory effect on 3CLpro, with 51.5 % inhibition of 3CLpro at 20 µM. Then, series of betulinic acid derivatives were designed, synthesized, and evaluated for their inhibition activities. The results showed that BA02 and BA05 showed significant inhibitory activity on 3CLpro with inhibitory rates of 78.1 % and 82.5 % at 20 µM, respectively. Further evaluation of these two compounds shows that their IC50 values are 7.22 ± 0.14 μM and 6.40 ± 0.14 μM, respectively.
{"title":"Design, synthesis and biological evaluation of betulinic acid derivatives as potential inhibitors of 3CL-protease of SARS-CoV-2","authors":"Yaowen Liu , Tianqing Nie , Jinjun Hou , Huali Long , Zijia Zhang , Min Lei , Yechun Xu , Wanying Wu","doi":"10.1016/j.steroids.2023.109351","DOIUrl":"https://doi.org/10.1016/j.steroids.2023.109351","url":null,"abstract":"<div><p>During the coronavirus reproduction process, 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro) are accountable for the fragmentation of two polyprotein precursors (pp1a/pp1ab) into substructural proteins. These two proteins are vital for the replication and transcription of the viral genome. Therefore, 3CLpro is a key protein and target for the design of coronavirus inhibitors. In previous studies, we found that betulinic acid has an inhibitory effect on 3CLpro, with 51.5 % inhibition of 3CLpro at 20 µM. Then, series of betulinic acid derivatives were designed, synthesized, and evaluated for their inhibition activities. The results showed that <strong>BA02</strong> and <strong>BA05</strong> showed significant inhibitory activity on 3CLpro with inhibitory rates of 78.1 % and 82.5 % at 20 µM, respectively. Further evaluation of these two compounds shows that their IC<sub>50</sub> values are 7.22 ± 0.14 μM and 6.40 ± 0.14 μM, respectively.</p></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2023-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138656408","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 : 2023-12-12DOI: 10.1016/j.steroids.2023.109350
Mária Janubová, Ingrid Žitňanová
Vitamin D is neccessary for regulation of calcium and phosphorus metabolism in bones, affects imunity, the cardiovascular system, muscles, skin, epithelium, extracellular matrix, the central nervous system, and plays a role in prevention of aging-associated diseases. Vitamin D receptor is expressed in almost all types of cells and its activation leads to modulation of different signaling pathways. In this review, we have analysed the current knowledge of 1,25-dihydroxyvitamin D3 or 25-hydroxyvitamin D3 effects on metabolism of cells important for the function of the cardiovascular system (endothelial cells, vascular smooth muscle cells, cardiac cells and pericytes), tissue healing (fibroblasts), epithelium (various types of epithelial cells) and the central nervous system (neurons, astrocytes and microglia). The goal of this review was to compare the effects of vitamin D on the above mentioned cells in in vitro conditions and to summarize what is known in this field of research.
维生素 D 是调节骨骼中钙磷代谢的必需物质,影响免疫系统、心血管系统、肌肉、皮肤、上皮细胞、细胞外基质和中枢神经系统,并在预防衰老相关疾病方面发挥作用。维生素 D 受体几乎在所有类型的细胞中都有表达,它的激活会导致不同信号通路的调节。在这篇综述中,我们分析了 1,25-二羟维生素 D3 或 25- 羟维生素 D3 对心血管系统(内皮细胞、血管平滑肌细胞、心肌细胞和周细胞)、组织愈合(成纤维细胞)、上皮细胞(各种类型的上皮细胞)和中枢神经系统(神经元、星形胶质细胞和小胶质细胞)等重要功能细胞的新陈代谢的影响。本综述旨在比较维生素 D 在体外条件下对上述细胞的影响,并总结这一研究领域的已知情况。
{"title":"The effects of vitamin D on different types of cells","authors":"Mária Janubová, Ingrid Žitňanová","doi":"10.1016/j.steroids.2023.109350","DOIUrl":"10.1016/j.steroids.2023.109350","url":null,"abstract":"<div><p>Vitamin D is neccessary for regulation of calcium and phosphorus metabolism in bones, affects imunity, the cardiovascular system, muscles, skin, epithelium, extracellular matrix, the central nervous system, and plays a<!--> <span>role in prevention of aging-associated diseases. Vitamin D receptor is expressed in almost all types of cells and its activation leads to modulation of different signaling pathways. In this review, we have analysed the current knowledge of 1,25-dihydroxyvitamin D</span><sub>3</sub> or 25-hydroxyvitamin D<sub>3</sub> effects on metabolism of cells important for the function of the cardiovascular system (endothelial cells, vascular smooth muscle cells, cardiac cells and pericytes), tissue healing (fibroblasts), epithelium (various types of epithelial cells) and the central nervous system (neurons, astrocytes and microglia). The goal of this review was to compare the effects of vitamin D on the above mentioned cells in <em>in vitro</em> conditions and to summarize what is known in this field of research.</p></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2023-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138810149","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 : 2023-12-09DOI: 10.1016/j.steroids.2023.109349
Xingru Guo , Tianshu Dai , Shihao Wei , Ziming Ma , Hongxi Zhao , Xingang Dan
RFRP-3 is a functional ortholog of avian GnIH and regulates reproductive activities in the gonads of animals. However, the role of RFRP-3 in the function of ovarian granulosa cells in mice remains unclear. First, we detected the expression of the RFRP-3 receptor (GPR147) in the ovarian granulosa cells of mice. Second, the effect of RFRP-3 treatment on estradiol and progesterone secretions from granulosa cells was tested by ELISA. Meanwhile, the expression of genes and proteins regulating steroid hormone synthesis was respectively examined by qPCR and western blot. Furthermore, the effect of RFRP-3 treatment on the apoptosis of granulosa cells was analyzed. The results revealed that the GPR147 protein (a RFRP-3 receptor) was expressed in the ovarian granulosa cells of mice. Low and medium doses RFRP-3 treatment significantly reduced progesterone secretion in the granulosa cells (P < 0.05), while RFRP-3 suppressed p450scc, 3β-HSD, StAR, and FSHR expression in a non-dose-dependent manner. Moreover, RFRP-3 treatment might induce the apoptosis of granulosa cells. Additionally, low doses RFRP-3 significantly reduced p-ERK1/2 protein expression (P < 0.05) in the ovarian granulosa cells. We here, for the first time, confirmed that GPR147 was expressed in the ovarian granulosa cells of mice. Our findings suggested that and RFRP-3 regulates the granulosa cell function through the ERK signaling pathway, which will lay the foundation for uncovering molecular mechanisms by which RFRP-3 regulates follicle development in future.
{"title":"Rfamide-related peptide-3(RFRP-3) receptor gene is expressed in mouse ovarian granulosa cells: Potential role of RFRP-3 in steroidogenesis and apoptosis","authors":"Xingru Guo , Tianshu Dai , Shihao Wei , Ziming Ma , Hongxi Zhao , Xingang Dan","doi":"10.1016/j.steroids.2023.109349","DOIUrl":"10.1016/j.steroids.2023.109349","url":null,"abstract":"<div><p>RFRP-3 is a functional ortholog of avian GnIH and regulates reproductive activities in the gonads of animals. However, the role of RFRP-3 in the function of ovarian granulosa cells in mice remains unclear. First, we detected the expression of the RFRP-3 receptor (GPR147) in the ovarian granulosa cells of mice. Second, the effect of RFRP-3 treatment on estradiol and progesterone secretions from granulosa cells was tested by ELISA. Meanwhile, the expression of genes and proteins regulating steroid hormone synthesis was respectively examined by qPCR and western blot. Furthermore, the effect of RFRP-3 treatment on the apoptosis of granulosa cells was analyzed. The results revealed that the GPR147 protein (a RFRP-3 receptor) was expressed in the ovarian granulosa cells of mice. Low and medium doses RFRP-3 treatment significantly reduced progesterone secretion in the granulosa cells (<em>P</em> < 0.05), while RFRP-3 suppressed p450scc, 3β-HSD, StAR, and FSHR expression in a non-dose-dependent manner. Moreover, RFRP-3 treatment might induce the apoptosis of granulosa cells. Additionally, low doses RFRP-3 significantly reduced p-ERK1/2 protein expression (<em>P</em> < 0.05) in the ovarian granulosa cells. We here, for the first time, confirmed that GPR147 was expressed in the ovarian granulosa cells of mice. Our findings suggested that and RFRP-3 regulates the granulosa cell function through the ERK signaling pathway, which will lay the foundation for uncovering molecular mechanisms by which RFRP-3 regulates follicle development in future.</p></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2023-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138610240","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 : 2023-12-02DOI: 10.1016/j.steroids.2023.109348
Brian J. Harvey
The COVID-19 pandemic has been a global health crisis of unprecedented magnitude. In the battle against the SARS-CoV-2 coronavirus, dexamethasone, a widely used corticosteroid with potent anti-inflammatory properties, has emerged as a promising therapy in the fight against severe COVID-19.
Dexamethasone is a synthetic glucocorticoid that exerts its therapeutic effects by suppressing the immune system and reducing inflammation. In the context of COVID-19, the severe form of the disease is often characterized by a hyperactive immune response, known as a cytokine storm. Dexamethasone anti-inflammatory properties make it a potent tool in modulating this exaggerated immune response.
Lung inflammation may lead to excessive fluid accumulation in the airways which can reduce gas exchange and mucociliary clearance. Pulmonary oedema and flooding of the airways are hallmarks of severe COVID-19 lung disease. The volume of airway surface liquid is determined by a delicate balance of salt and water secretion and absorption across the airway epithelium. In addition to its anti-inflammatory actions, dexamethasone modulates the activity of ion channels which regulate electrolyte and water transport across the airway epithelium. The observations of dexamethasone activation of sodium ion absorption via ENaC Na+ channels and inhibition of chloride ion secretion via CFTR Cl− channels to decrease airway surface liquid volume indicate a novel therapeutic action of the glucocorticoid to reverse airway flooding.
This brief review delves into the early non-genomic and late genomic signaling mechanisms of dexamethasone regulation of ion channels and airway surface liquid dynamics, shedding light on the molecular mechanisms underpinning the action of the glucocorticoid in managing COVID-19.
{"title":"Molecular mechanisms of dexamethasone actions in COVID-19: Ion channels and airway surface liquid dynamics","authors":"Brian J. Harvey","doi":"10.1016/j.steroids.2023.109348","DOIUrl":"10.1016/j.steroids.2023.109348","url":null,"abstract":"<div><p>The COVID-19 pandemic has been a global health crisis of unprecedented magnitude. In the battle against the SARS-CoV-2 coronavirus, dexamethasone, a widely used corticosteroid with potent anti-inflammatory properties, has emerged as a promising therapy in the fight against severe COVID-19.</p><p>Dexamethasone is a synthetic glucocorticoid that exerts its therapeutic effects by suppressing the immune system and reducing inflammation. In the context of COVID-19, the severe form of the disease is often characterized by a hyperactive immune response, known as a cytokine storm. Dexamethasone anti-inflammatory properties make it a potent tool in modulating this exaggerated immune response.</p><p>Lung inflammation may lead to excessive fluid accumulation in the airways which can reduce gas exchange and mucociliary clearance. Pulmonary oedema and flooding of the airways are hallmarks of severe COVID-19 lung disease. The volume of airway surface liquid is determined by a delicate balance of salt and water secretion and absorption across the airway epithelium. In addition to its anti-inflammatory actions, dexamethasone modulates the activity of ion channels which regulate electrolyte and water transport across the airway epithelium. The observations of dexamethasone activation of sodium ion absorption via ENaC Na<sup>+</sup> channels and inhibition of chloride ion secretion via CFTR Cl<sup>−</sup> channels to decrease airway surface liquid volume indicate a novel therapeutic action of the glucocorticoid to reverse airway flooding.</p><p>This brief review delves into the early non-genomic and late genomic signaling mechanisms of dexamethasone regulation of ion channels and airway surface liquid dynamics, shedding light on the molecular mechanisms underpinning the action of the glucocorticoid in managing COVID-19.</p></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2023-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0039128X23001769/pdfft?md5=5f7cd7b98eca68f78db28af47e23f638&pid=1-s2.0-S0039128X23001769-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138483069","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}
Pub Date : 2023-11-18DOI: 10.1016/j.steroids.2023.109345
Aerab Abdul Karim , Atia-tul-Wahab , Ambreen Aziz , Nimra Naveed Shaikh , M. Iqbal Choudhary
The present study describes the microbial transformation of anabolic drugs, metenolone acetate (1), and epiandrosterone (6). Three new metabolites, 6β,17β-dihydroxy-1-methyl-3-oxo-5α-androst-1-en (2), 5α,15α-dihydroxy-1-methyl-3-oxo-1-en-17-yl acetate (3), 15β-hydroxy-1-methyl-3-oxo-5α-androst-1,4-dien-17-yl acetate (4), and a known metabolite, 17β-hydroxy-1-methyl-4-androstadiene-3-one (5) were obtained by biotransformation of metenolone acetate (1) via Trametes hirsuta mushroom. Metabolites 7, and 8 were obtained from the incubation of epiandrosterone (6) with Cunninghamella blakesleeana. While bioconversion of compound 6 with Aspergillus alliaceus yielded seven known metabolites 9–15. Modern spectroscopic techniques were employed for the structure elucidation of biotransformed products. All compounds were evaluated for their aromatase inhibitory activity. Among them, new metabolite 3 exhibited a significant human placental aromatase activity with an IC50 = 19.602 ± 0.47 µM, as compared to standard anti-cancer drug exemestane (IC50 = 0.232 ± 0.031 µM), whereas, metabolite 5 (IC50 = 0.0049 ± 0.0032 µM) exhibited a very potent activity. While substrate 6, and metabolites 2, 7, and 9 were found inactive. Aromatase plays a key role in the biosynthesis of estrogen hormone, responsible for cancer cell proliferation. Its inhibition is therefore targeted for the treatment of ER + breast cancer. Further structural modifications (lead optimization) of compound 3 can lead to more potent aromatase inhibition for possible treatment of ER + breast cancer.
{"title":"Biotransformation of metenolone acetate and epiandrosterone by fungi and evaluation of resulting metabolites for aromatase inhibition","authors":"Aerab Abdul Karim , Atia-tul-Wahab , Ambreen Aziz , Nimra Naveed Shaikh , M. Iqbal Choudhary","doi":"10.1016/j.steroids.2023.109345","DOIUrl":"10.1016/j.steroids.2023.109345","url":null,"abstract":"<div><p>The present study describes the microbial transformation of anabolic drugs, metenolone acetate (<strong>1</strong>), and epiandrosterone (<strong>6</strong>). Three new metabolites, 6<em>β,17β</em>-dihydroxy-1-methyl-3-oxo-5<em>α</em>-androst-1-en (<strong>2</strong>), 5<em>α</em>,15<em>α</em>-dihydroxy-1-methyl-3-oxo-1-en-17-yl acetate (<strong>3</strong>), 15<em>β</em>-hydroxy-1-methyl-3-oxo-5<em>α</em>-androst-1,4-dien-17-yl acetate (<strong>4</strong>), and a known metabolite, 17<em>β</em>-hydroxy-1-methyl-4-androstadiene-3-one (<strong>5</strong>) were obtained by biotransformation of metenolone acetate (<strong>1</strong>) <em>via Trametes hirsuta</em> mushroom. Metabolites <strong>7</strong>, and <strong>8</strong> were obtained from the incubation of epiandrosterone (<strong>6</strong>) with <em>Cunninghamella blakesleeana</em>. While bioconversion of compound <strong>6</strong> with <em>Aspergillus alliaceus</em> yielded seven known metabolites <strong>9</strong>–<strong>15</strong>. Modern spectroscopic techniques were employed for the structure elucidation of biotransformed products. All compounds were evaluated for their aromatase inhibitory activity. Among them, new metabolite <strong>3</strong> exhibited a significant human placental aromatase activity with an IC<sub>50</sub> = 19.602 ± 0.47 µM, as compared to standard anti-cancer drug exemestane (IC<sub>50</sub> = 0.232 ± 0.031 µM), whereas, metabolite <strong>5</strong> (IC<sub>50 =</sub> 0.0049 ± 0.0032 µM) exhibited a very potent activity. While substrate <strong>6</strong>, and metabolites <strong>2</strong>, <strong>7</strong>, and <strong>9</strong> were found inactive. Aromatase plays a key role in the biosynthesis of estrogen hormone, responsible for cancer cell proliferation. Its inhibition is therefore targeted for the treatment of ER + breast cancer. Further structural modifications (lead optimization) of compound <strong>3</strong> can lead to more potent aromatase inhibition for possible treatment of ER + breast cancer.</p></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2023-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138177317","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 : 2023-11-17DOI: 10.1016/j.steroids.2023.109344
Stephanie B. Proaño , Christiana K. Miller , Amanda A. Krentzel , David M. Dorris , John Meitzen
The striatal brain regions encompassing the nucleus accumbens core (NAcc), shell (NAcs) and caudate-putamen (CPu) regulate cognitive functions including motivated behaviors, habit, learning, and sensorimotor action, among others. Sex steroid hormone sensitivity and sex differences have been documented in all of these functions in both normative and pathological contexts, including anxiety, depression and addiction. The neurotransmitter glutamate has been implicated in regulating these behaviors as well as striatal physiology, and there are likewise documented sex differences in glutamate action upon the striatal output neurons, the medium spiny neurons (MSNs). Here we review the available data regarding the role of steroid sex hormones such as 17β-estradiol (estradiol), progesterone, and testosterone in rapidly modulating MSN glutamatergic synapse properties, presented in the context of the estrous cycle as appropriate. Estradiol action upon glutamatergic synapse properties in female NAcc MSNs is most comprehensively discussed. In the female NAcc, MSNs exhibit development period-specific sex differences and estrous cycle variations in glutamatergic synapse properties as shown by multiple analyses, including that of miniature excitatory postsynaptic currents (mEPSCs). Estrous cycle-differences in NAcc MSN mEPSCs can be mimicked by acute exposure to estradiol or an ERα agonist. The available evidence, or lack thereof, is also discussed concerning estrogen action upon MSN glutamatergic synapse in the other striatal regions as well as the underexplored roles of progesterone and testosterone. We conclude that there is strong evidence regarding estradiol action upon glutamatergic synapse function in female NAcs MSNs and call for more research regarding other hormones and striatal regions.
{"title":"Sex steroid hormones, the estrous cycle, and rapid modulation of glutamatergic synapse properties in the striatal brain regions with a focus on 17β-estradiol and the nucleus accumbens","authors":"Stephanie B. Proaño , Christiana K. Miller , Amanda A. Krentzel , David M. Dorris , John Meitzen","doi":"10.1016/j.steroids.2023.109344","DOIUrl":"https://doi.org/10.1016/j.steroids.2023.109344","url":null,"abstract":"<div><p>The striatal brain regions encompassing the nucleus accumbens core (NAcc), shell (NAcs) and caudate-putamen (CPu) regulate cognitive functions including motivated behaviors, habit, learning, and sensorimotor action, among others. Sex steroid hormone sensitivity and sex differences have been documented in all of these functions in both normative and pathological contexts, including anxiety, depression and addiction. The neurotransmitter glutamate has been implicated in regulating these behaviors as well as striatal physiology, and there are likewise documented sex differences in glutamate action upon the striatal output neurons, the medium spiny neurons (MSNs). Here we review the available data regarding the role of steroid sex hormones such as 17β-estradiol (estradiol), progesterone, and testosterone in rapidly modulating MSN glutamatergic synapse properties, presented in the context of the estrous cycle as appropriate. Estradiol action upon glutamatergic synapse properties in female NAcc MSNs is most comprehensively discussed. In the female NAcc, MSNs exhibit development period-specific sex differences and estrous cycle variations in glutamatergic synapse properties as shown by multiple analyses, including that of miniature excitatory postsynaptic currents (mEPSCs). Estrous cycle-differences in NAcc MSN mEPSCs can be mimicked by acute exposure to estradiol or an ERα agonist. The available evidence, or lack thereof, is also discussed concerning estrogen action upon MSN glutamatergic synapse in the other striatal regions as well as the underexplored roles of progesterone and testosterone. We conclude that there is strong evidence regarding estradiol action upon glutamatergic synapse function in female NAcs MSNs and call for more research regarding other hormones and striatal regions.</p></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2023-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136717977","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}
{"title":"Uphill running preferred over downhill running for recovery from glucocorticoid-induced muscle atrophy","authors":"Masanobu Murao , Tetsuo Imano , Yoshinobu Sato , Masaaki Nakajima","doi":"10.1016/j.steroids.2023.109337","DOIUrl":"10.1016/j.steroids.2023.109337","url":null,"abstract":"","PeriodicalId":21997,"journal":{"name":"Steroids","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2023-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136399256","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 : 2023-11-10DOI: 10.1016/j.steroids.2023.109335
Jingyuan Wang , Ye Feng , Brian Liu , Wen Xie
Sulfation and desulfation of steroids are opposing processes that regulate the activation, metabolism, excretion, and storage of steroids, which account for steroid homeostasis. Steroid sulfation and desulfation are catalyzed by cytosolic sulfotransferase and steroid sulfatase, respectively. By modifying and regulating steroids, cytosolic sulfotransferase (SULT) and steroid sulfatase (STS) are also involved in the pathophysiology of steroid-related diseases, such as hormonal dysregulation, metabolic disease, and cancer. The estrogen sulfotransferase (EST, or SULT1E1) is a typical member of the steroid SULTs. This review is aimed to summarize the roles of SULT1E1 and STS in steroid homeostasis and steroid-related diseases.
{"title":"Estrogen sulfotransferase and sulfatase in steroid homeostasis, metabolic disease, and cancer","authors":"Jingyuan Wang , Ye Feng , Brian Liu , Wen Xie","doi":"10.1016/j.steroids.2023.109335","DOIUrl":"10.1016/j.steroids.2023.109335","url":null,"abstract":"<div><p>Sulfation<span><span> and desulfation of steroids are opposing processes that regulate the activation, metabolism, excretion, and storage of steroids, which account for steroid homeostasis. Steroid sulfation and desulfation are catalyzed by cytosolic </span>sulfotransferase<span> and steroid sulfatase<span>, respectively. By modifying and regulating steroids, cytosolic sulfotransferase (SULT) and steroid sulfatase (STS) are also involved in the pathophysiology of steroid-related diseases, such as hormonal dysregulation, metabolic disease, and cancer. The estrogen sulfotransferase (EST, or SULT1E1) is a typical member of the steroid SULTs. This review is aimed to summarize the roles of SULT1E1 and STS in steroid homeostasis and steroid-related diseases.</span></span></span></p></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2023-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89719594","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 : 2023-11-09DOI: 10.1016/j.steroids.2023.109334
Martiniano Bello
Estrogen receptors (ERs) are nuclear factors that exist as two subtypes: ERα and ERβ. Among the different selective ERβ agonist ligands, the widely used ERβ-selective agonist DPN (diarylpropionitrile) is highlighted. Recent experimental and thermodynamic information between R-DPN and S-DPN enantiomers with ERβ is important for evaluating further the ability of MD simulations combined with end-point methods to reproduce experimental binding affinity and generate structural insight not provided through crystallographic data. In this research, starting from crystallographic data and experimental binding affinities, we explored the structural and thermodynamic basis of the molecular recognition of ERβ with DPN and derivatives through triplicate MD simulations combined with end-point methods. Conformational analysis showed some regions with the highest mobility linked to ligand association that, at the time, impacted the total protein fluctuation. Binding free energy (ΔG) analysis revealed that the Molecular Mechanics Generalized-Born Surface Area (MMGBSA) approach was able to reproduce the experimental tendency with a strong correlation (R = 0.778), whereas per-residue decomposition analysis revealed that all the systems interacted strongly with eight residues (L298, E305, L339, M340, L343, F356, H475, and L476). The comparison between theoretical studies using the MMGBSA approach with experimental results provides new insights for drug designing of new DPN derivatives.
{"title":"Evaluation of structural and thermodynamic insight of ERβ with DPN and derivatives through MMGBSA/MMPBSA methods","authors":"Martiniano Bello","doi":"10.1016/j.steroids.2023.109334","DOIUrl":"10.1016/j.steroids.2023.109334","url":null,"abstract":"<div><p>Estrogen receptors (ERs) are nuclear factors that exist as two subtypes: ERα and ERβ. Among the different selective ERβ agonist ligands, the widely used ERβ-selective agonist DPN (diarylpropionitrile) is highlighted. Recent experimental and thermodynamic information between R-DPN and S-DPN enantiomers with ERβ is important for evaluating further the ability of MD simulations combined with end-point methods to reproduce experimental binding affinity and generate structural insight not provided through crystallographic data. In this research, starting from crystallographic data and experimental binding affinities, we explored the structural and thermodynamic basis of the molecular recognition of ERβ with DPN and derivatives through triplicate MD simulations combined with end-point methods. Conformational analysis showed some regions with the highest mobility linked to ligand association that, at the time, impacted the total protein fluctuation. Binding free energy (ΔG) analysis revealed that the Molecular Mechanics Generalized-Born Surface Area (MMGBSA) approach was able to reproduce the experimental tendency with a strong correlation (<em>R</em> = 0.778), whereas per-residue decomposition analysis revealed that all the systems interacted strongly with eight residues (L298, E305, L339, M340, L343, F356, H475, and L476). The comparison between theoretical studies using the MMGBSA approach with experimental results provides new insights for drug designing of new DPN derivatives.</p></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2023-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72210775","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 : 2023-11-07DOI: 10.1016/j.steroids.2023.109332
Olexander M. Semenenko , Victoria V. Lipson , Alina O. Sadchenko , Olga V. Vashchenko , Natalia A. Kasian , Liliia V. Sviechnikova , Longin M. Lisetski , Mykola L. Babak , Volodymyr M. Vakula , Oleksandr V. Borysov , Yuliia V. Holota , Sergey O. Zozulya , Petro O. Borysko , Olexander V. Mazepa
An efficient protocol for the synthesis of novel methotrexate-betulonic acid hybrids with a (tert-butoxycarbonylamino)-3,6-dioxa-8-octanamine (Boc-DOOA) linkage has been developed. Reaction of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-betulonamide with methotrexate resulted in a mixture of isomeric conjugates which were separated by column chromatography. Their structures and composition have been fully established by 1H NMR, 13C spectra, FAB mass spectrometry and elemental analysis. The identity of conjugates was confirmed by LC-MS data. Membranotropic properties of the new hybrids were assessed on the basis of their interactions with artificial lipid membranes by differential scanning calorimetry (DSC) method. The ability of the conjugates to penetrate Caco-2 cells is inferior to methotrexate. Probably, this is due to the increasing lipophilicity, the affinity of these hybrid molecules for the lipid bilayer increases, which is confirmed by experiments with artificial membranes.
{"title":"Synthesis of methotrexate-betulonic acid hybrids and evaluation of their effect on artificial and Caco-2 cell membranes","authors":"Olexander M. Semenenko , Victoria V. Lipson , Alina O. Sadchenko , Olga V. Vashchenko , Natalia A. Kasian , Liliia V. Sviechnikova , Longin M. Lisetski , Mykola L. Babak , Volodymyr M. Vakula , Oleksandr V. Borysov , Yuliia V. Holota , Sergey O. Zozulya , Petro O. Borysko , Olexander V. Mazepa","doi":"10.1016/j.steroids.2023.109332","DOIUrl":"10.1016/j.steroids.2023.109332","url":null,"abstract":"<div><p>An efficient protocol for the synthesis of novel methotrexate-betulonic acid hybrids with a (<em>tert</em>-butoxycarbonylamino)-3,6-dioxa-8-octanamine (<em>Boc</em>-DOOA) linkage has been developed. Reaction of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-betulonamide with methotrexate resulted in a mixture of isomeric conjugates which were separated by column chromatography. Their structures and composition have been fully established by <sup>1</sup>H NMR, <sup>13</sup>C spectra, FAB mass spectrometry and elemental analysis. The identity of conjugates was confirmed by LC-MS data. Membranotropic properties of the new hybrids were assessed on the basis of their interactions with artificial lipid membranes by differential scanning calorimetry (DSC) method. The ability of the conjugates to penetrate Caco-2 cells is inferior to methotrexate. Probably, this is due to the increasing lipophilicity, the affinity of these hybrid molecules for the lipid bilayer increases, which is confirmed by experiments with artificial membranes.</p></div>","PeriodicalId":21997,"journal":{"name":"Steroids","volume":null,"pages":null},"PeriodicalIF":2.7,"publicationDate":"2023-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71522652","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}