Orally delivered small-molecule therapeutics are metabolized in the liver and intestine by phase I and phase II drug-metabolizing enzymes (DMEs), and transport proteins coordinate drug influx (phase 0) and drug/drug-metabolite efflux (phase III). Genes involved in drug metabolism and disposition are induced by xenobiotic-activated nuclear receptors (NRs), i.e. PXR (pregnane X receptor) and CAR (constitutive androstane receptor), and by the 1α, 25-dihydroxy vitamin D3-activated vitamin D receptor (VDR), due to transactivation of xenobiotic-response elements (XREs) present in phase 0-III genes. Additional NRs, like HNF4-α, FXR, LXR-α play important roles in drug metabolism in certain settings, such as in relation to cholesterol and bile acid metabolism. The phase I enzymes CYP3A4/A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, CYP1A2, CYP2C8, CYP2A6, CYP2J2, and CYP2E1 metabolize >90% of all prescription drugs, and phase II conjugation of hydrophilic functional groups (with/without phase I modification) facilitates drug clearance. The conjugation step is mediated by broad-specificity transferases like UGTs, SULTs, GSTs. This review delves into our current understanding of PXR/CAR/VDR-mediated regulation of DME and transporter expression, as well as effects of single nucleotide polymorphism (SNP) and epigenome (specified by promoter methylation, histone modification, microRNAs, long non coding RNAs) on the expression of PXR/CAR/VDR and phase 0-III mediators, and their impacts on variable drug response. Therapeutic agents that target epigenetic regulation and the molecular basis and consequences (overdosing, underdosing, or beneficial outcome) of drug-drug/drug-food/drug-herb interactions are also discussed. Precision medicine requires understanding of a drug's impact on DME and transporter activity and their NR-regulated expression in order to achieve optimal drug efficacy without adverse drug reactions. In future drug screening, new tools such as humanized mouse models and microfluidic organs-on-chips, which mimic the physiology of a multicellular environment, will likely replace the current cell-based workflow.
口服小分子治疗药物在肝脏和肠道中通过 I 期和 II 期药物代谢酶（DME）进行代谢，转运蛋白协调药物流入（0 期）和药物/药物代谢物流出（III 期）。参与药物代谢和处置的基因由异种生物激活的核受体（NRs）诱导，即 PXR（孕烷 X 受体）和 CAR（组成型雄烷受体），以及由 1α，25-二羟基维生素 D3 激活的维生素 D 受体（VDR）诱导，这是由于存在于 0-III 期基因中的异种生物反应元件（XREs）的转录激活所致。其他 NRs，如 HNF4-α、FXR、LXR-α 在某些情况下对药物代谢起着重要作用，如胆固醇和胆汁酸代谢。CYP3A4/A5、CYP2D6、CYP2B6、CYP2C9、CYP2C19、CYP1A2、CYP2C8、CYP2A6、CYP2J2 和 CYP2E1 等 I 期酶代谢超过 90% 的处方药，亲水官能团的 II 期共轭（有/无 I 期修饰）有助于药物清除。结合步骤由 UGTs、SULTs 和 GSTs 等广谱特异性转移酶介导。本综述深入探讨了我们目前对 PXR/CAR/VDR 介导的 DME 和转运体表达调控的理解，以及单核苷酸多态性（SNP）和表观基因组（启动子甲基化、组蛋白修饰、microRNA、长非编码 RNA）对 PXR/CAR/VDR 和 0-III 期介质表达的影响及其对不同药物反应的影响。此外，还讨论了针对表观遗传调控的治疗药物，以及药物-药物/药物-食物/药物-草药相互作用的分子基础和后果（用药过量、用药不足或有益结果）。精准医疗需要了解药物对 DME 和转运体活性的影响及其 NR 调控表达，以达到最佳药效，同时避免药物不良反应。在未来的药物筛选中，人源化小鼠模型和微流控芯片器官等模拟多细胞环境生理的新工具将有可能取代目前基于细胞的工作流程。
{"title":"Nuclear Receptors in Drug Metabolism, Drug Response and Drug Interactions.","authors":"Chandra Prakash, Baltazar Zuniga, Chung Seog Song, Shoulei Jiang, Jodie Cropper, Sulgi Park, Bandana Chatterjee","doi":"10.11131/2015/101178","DOIUrl":"10.11131/2015/101178","url":null,"abstract":"<p><p>Orally delivered small-molecule therapeutics are metabolized in the liver and intestine by phase I and phase II drug-metabolizing enzymes (DMEs), and transport proteins coordinate drug influx (phase 0) and drug/drug-metabolite efflux (phase III). Genes involved in drug metabolism and disposition are induced by xenobiotic-activated nuclear receptors (NRs), i.e. PXR (pregnane X receptor) and CAR (constitutive androstane receptor), and by the 1<i>α</i>, 25-dihydroxy vitamin D<sub>3</sub>-activated vitamin D receptor (VDR), due to transactivation of xenobiotic-response elements (XREs) present in phase 0-III genes. Additional NRs, like HNF4-<i>α</i>, FXR, LXR-<i>α</i> play important roles in drug metabolism in certain settings, such as in relation to cholesterol and bile acid metabolism. The phase I enzymes CYP3A4/A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, CYP1A2, CYP2C8, CYP2A6, CYP2J2, and CYP2E1 metabolize >90% of all prescription drugs, and phase II conjugation of hydrophilic functional groups (with/without phase I modification) facilitates drug clearance. The conjugation step is mediated by broad-specificity transferases like UGTs, SULTs, GSTs. This review delves into our current understanding of PXR/CAR/VDR-mediated regulation of DME and transporter expression, as well as effects of single nucleotide polymorphism (SNP) and epigenome (specified by promoter methylation, histone modification, microRNAs, long non coding RNAs) on the expression of PXR/CAR/VDR and phase 0-III mediators, and their impacts on variable drug response. Therapeutic agents that target epigenetic regulation and the molecular basis and consequences (overdosing, underdosing, or beneficial outcome) of drug-drug/drug-food/drug-herb interactions are also discussed. Precision medicine requires understanding of a drug's impact on DME and transporter activity and their NR-regulated expression in order to achieve optimal drug efficacy without adverse drug reactions. In future drug screening, new tools such as humanized mouse models and microfluidic organs-on-chips, which mimic the physiology of a multicellular environment, will likely replace the current cell-based workflow.</p>","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963026/pdf/nihms798073.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34331666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Napimoga, M. Galigniana, A. Figueira, S. Oñate, S. Castro-Obregón
1Laboratory of Immunology and Molecular Biology, Sao Leopoldo Mandic Institute and Research Center, Campinas/SP, Brazil 2Departamento de Quimica Biologica-IQUIBICEN, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and IBYME-CONICET, Buenos Aires, Argentina 3Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), P.O. Box 6192, Campinas-SP, Brazil 4School of Medicine, University of Concepcion, Chile 5Departamento de Neurodesarrollo y Fisiologia, Division de Neurociencias, Instituto de Fisiologia Celular, Universidad Nacional Autonoma de Mexico, Mexico
1Laboratory of Immunology和分子生物学,Sao清洁圣器曼迪奇研究所和研究中心,在巴西坎皮纳斯/ SP化学物质Biologica-IQUIBICEN 2Departamento法学院与自然科学系,布宜诺斯艾利斯大学和IBYME-CONICET,布宜诺斯艾利斯,阿根廷3Brazilian国家生物实验室(LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), po Box 6192 Campinas-SP巴西4School of Medicine, University of Concepcion,智利国立自治大学细胞生理学研究所神经发育和生理学系，神经科学部，墨西哥
{"title":"Nuclear Receptor Research: Contributions from Latin America","authors":"M. Napimoga, M. Galigniana, A. Figueira, S. Oñate, S. Castro-Obregón","doi":"10.11131/2014/101149","DOIUrl":"https://doi.org/10.11131/2014/101149","url":null,"abstract":"1Laboratory of Immunology and Molecular Biology, Sao Leopoldo Mandic Institute and Research Center, Campinas/SP, Brazil 2Departamento de Quimica Biologica-IQUIBICEN, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and IBYME-CONICET, Buenos Aires, Argentina 3Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), P.O. Box 6192, Campinas-SP, Brazil 4School of Medicine, University of Concepcion, Chile 5Departamento de Neurodesarrollo y Fisiologia, Division de Neurociencias, Instituto de Fisiologia Celular, Universidad Nacional Autonoma de Mexico, Mexico","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"63478587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
J. Toneatto, N. Charó, A. Naselli, Melina Muñoz-Bernart, A. Lombardi, G. Piwien-Pilipuk
It is well known that glucocorticoids and mineralocorticoids are part of the list of hormones that control adipogenesis as well as different aspects of the physiology of the adipose tissue. Their actions are mediated through their binding to the glucocorticoid and the mineralocorticoid receptors (GR and MR, respectively), in complex with heat shock proteins (Hsps) and high molecular weight immunophilins (IMMs). Albeit many aspects of the molecular mechanism of the corticosteroid receptors are not fully elucidated yet, it was not until recently that the first evidences of the functional importance of Hsps and IMMs in the process of adipocyte differentiation have been described. Hsp90 and the high molecular weight IMM FKBP51 modulate GR and MR activity at multiple levels, that is, hormone binding affinity, their subcellular distribution, and the transcriptional status, among other aspects of the NR function. Interestingly, it has recently been described that Hsp90 and FKBP51 also participate in the control of PPARγ`, a key transcription factor in the control of adipogenesis and the maintenance of the adipocyte phenotype. In addition, novel roles have been uncovered for FKBP51 in the organization of the nuclear architecture through its participation in the reorganization of the nuclear lamina and the control of the subnuclear distribution of GR. Thus, the aim of this review is to integrate and discuss the actual understanding of the role of corticosteroid receptors, their chaperones and cochaperones, in the process of adipocyte differentiation.
{"title":"Corticosteroid Receptors, Their Chaperones and Cochaperones: How Do They Modulate Adipogenesis?","authors":"J. Toneatto, N. Charó, A. Naselli, Melina Muñoz-Bernart, A. Lombardi, G. Piwien-Pilipuk","doi":"10.11131/2014/101092","DOIUrl":"https://doi.org/10.11131/2014/101092","url":null,"abstract":"It is well known that glucocorticoids and mineralocorticoids are part of the list of hormones that control adipogenesis as well as different aspects of the physiology of the adipose tissue. Their actions are mediated through their binding to the glucocorticoid and the mineralocorticoid receptors (GR and MR, respectively), in complex with heat shock proteins (Hsps) and high molecular weight immunophilins (IMMs). Albeit many aspects of the molecular mechanism of the corticosteroid receptors are not fully elucidated yet, it was not until recently that the first evidences of the functional importance of Hsps and IMMs in the process of adipocyte differentiation have been described. Hsp90 and the high molecular weight IMM FKBP51 modulate GR and MR activity at multiple levels, that is, hormone binding affinity, their subcellular distribution, and the transcriptional status, among other aspects of the NR function. Interestingly, it has recently been described that Hsp90 and FKBP51 also participate in the control of PPARγ`, a key transcription factor in the control of adipogenesis and the maintenance of the adipocyte phenotype. In addition, novel roles have been uncovered for FKBP51 in the organization of the nuclear architecture through its participation in the reorganization of the nuclear lamina and the control of the subnuclear distribution of GR. Thus, the aim of this review is to integrate and discuss the actual understanding of the role of corticosteroid receptors, their chaperones and cochaperones, in the process of adipocyte differentiation.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"63477933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Juliana Fattori, N. D. C. Indolfo, Jéssica L. O. Campos, N. B. Videira, A. Bridi, T. R. Doratioto, M. Assis, A. Figueira
Nuclear receptors (NRs) comprise a superfamily of proteins modulated by ligands that regulate the expression of target genes. These proteins share a multidomain structure harboring an N-terminal domain, a highly conserved DNA binding domain, and a ligand binding domain, which has ligand dependent activation function. They play key roles in development, metabolism, and physiology being closely related to diseases. Most of the knowledge about this superfamily emerges from investigations on new ligands and are mostly centered in the ligand binding domain. However, more investigation focusing on interactions between DNA and DNA binding domain is necessary to shed light on important roles of NRs' participation in transcriptional mechanisms and in specific genes network. Here, our goal is to discuss some nuances of NRs-DNA interaction, describing details of the most used techniques in this sort of study, such as gel shift (EMSA), DNA footprinting, reporter gene assay, ChIP-Seq, 3C, and fluorescence anisotropy. Additionally, we aim to provide tools, presenting advantages and disadvantages of these common methods, when choosing the most suitable one to study NRs-DNA interactions to answer specific questions.
{"title":"Investigation of Interactions between DNA and Nuclear Receptors: A Review of the Most Used Methods","authors":"Juliana Fattori, N. D. C. Indolfo, Jéssica L. O. Campos, N. B. Videira, A. Bridi, T. R. Doratioto, M. Assis, A. Figueira","doi":"10.11131/2014/101090","DOIUrl":"https://doi.org/10.11131/2014/101090","url":null,"abstract":"Nuclear receptors (NRs) comprise a superfamily of proteins modulated by ligands that regulate the expression of target genes. These proteins share a multidomain structure harboring an N-terminal domain, a highly conserved DNA binding domain, and a ligand binding domain, which has ligand dependent activation function. They play key roles in development, metabolism, and physiology being closely related to diseases. Most of the knowledge about this superfamily emerges from investigations on new ligands and are mostly centered in the ligand binding domain. However, more investigation focusing on interactions between DNA and DNA binding domain is necessary to shed light on important roles of NRs' participation in transcriptional mechanisms and in specific genes network. Here, our goal is to discuss some nuances of NRs-DNA interaction, describing details of the most used techniques in this sort of study, such as gel shift (EMSA), DNA footprinting, reporter gene assay, ChIP-Seq, 3C, and fluorescence anisotropy. Additionally, we aim to provide tools, presenting advantages and disadvantages of these common methods, when choosing the most suitable one to study NRs-DNA interactions to answer specific questions.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"63477920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. González-Arenas, Alejandro Cabrera-Wrooman, N. Díaz, Tania Karina González-García, I. Salido-Guadarrama, M. Rodríguez-Dorantes, I. Camacho-Arroyo
Intracellular progesterone receptor (PR) has been identified in human astrocytomas, the most common and aggressive primary brain tumors in humans. It has been reported that PR cell distribution affects their transcriptional activity and turnover. In this work we studied by immunofluorescence the effects of estradiol and progesterone on the subcellular localization of PR in a grade III human astrocytoma derived cell line (U373). We observed that total PR was mainly distributed in the cytoplasm without hormonal treatment. Estradiol (10 nM) increased PR presence in the cytoplasm of U373 cells, whereas progesterone (10 nM) and RU486 (PR antagonist, 1 µM) blocked this effect. To investigate the role of PR activity in the regulation of gene expression pattern of U373 cells, we evaluated by microarray analysis the profile of genes regulated by progesterone, RU486, or both steroids. We found different genes regulated by steroid treatments that encode for proteins involved in metabolism, transport, cell cycle, proliferation, metastasis, apoptosis, processing of nucleic acids and proteins, adhesion, pathogenesis, immune response, cytoskeleton, and membrane receptors. We determined that 30 genes were regulated by progesterone, 41 genes by RU486 alone, and 13 genes by the cotreatment of progesterone+RU486, suggesting that there are many genes regulated by intracellular PR or through other signaling pathways modulated by progesterone. All these data suggest that PR distribution and activity should modify astrocytomas growth.
{"title":"Progesterone Receptor Subcellular Localization and Gene Expression Profile in Human Astrocytoma Cells Are Modified by Progesterone","authors":"A. González-Arenas, Alejandro Cabrera-Wrooman, N. Díaz, Tania Karina González-García, I. Salido-Guadarrama, M. Rodríguez-Dorantes, I. Camacho-Arroyo","doi":"10.11131/2014/101098","DOIUrl":"https://doi.org/10.11131/2014/101098","url":null,"abstract":"Intracellular progesterone receptor (PR) has been identified in human astrocytomas, the most common and aggressive primary brain tumors in humans. It has been reported that PR cell distribution affects their transcriptional activity and turnover. In this work we studied by immunofluorescence the effects of estradiol and progesterone on the subcellular localization of PR in a grade III human astrocytoma derived cell line (U373). We observed that total PR was mainly distributed in the cytoplasm without hormonal treatment. Estradiol (10 nM) increased PR presence in the cytoplasm of U373 cells, whereas progesterone (10 nM) and RU486 (PR antagonist, 1 µM) blocked this effect. To investigate the role of PR activity in the regulation of gene expression pattern of U373 cells, we evaluated by microarray analysis the profile of genes regulated by progesterone, RU486, or both steroids. We found different genes regulated by steroid treatments that encode for proteins involved in metabolism, transport, cell cycle, proliferation, metastasis, apoptosis, processing of nucleic acids and proteins, adhesion, pathogenesis, immune response, cytoskeleton, and membrane receptors. We determined that 30 genes were regulated by progesterone, 41 genes by RU486 alone, and 13 genes by the cotreatment of progesterone+RU486, suggesting that there are many genes regulated by intracellular PR or through other signaling pathways modulated by progesterone. All these data suggest that PR distribution and activity should modify astrocytomas growth.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"63478545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Glucocorticoids (GCs) regulate numerous physiologic processes in order to maintain homeostasis. Most of their actions are mediated by an intracellular GC receptor (GR). The dysregulation of the GR function has been associated with different pathologies such as stress-related disorders and inflammatory and autoimmune diseases. The final outcome of GC actions is regulated at multiple levels and has been extensively reported. Nowadays, novel insights into the modulation of the GR activity arise from the study of the multiprotein chaperone/cochaperone machinery, the nuclear receptor cofactors (coactivators and corepressors), and chromatin regulation and their concomitant impact on GR-mediated gene transcription. Nevertheless, the complexity of GR-mediated gene regulation cannot be explained by a finite number of chaperones and cofactors. A further level in the regulation of GR activity is achieved by posttranslational modifications (PTMs) in response to external stimuli. PTMs can regulate protein stability, structure, function, activity, intracellular localization, and interaction with other proteins during cellular processes. Therefore, dynamic regulation of the molecular properties of these proteins by PTMs allows for further understanding the complexity of GR-dependent gene expression and its impact on GR-mediated pathophysiological processes.
{"title":"Modulation of the Glucocorticoid Receptor Activity by Post-Translational Modifications","authors":"A. Liberman, María Antunica-Noguerol, E. Arzt","doi":"10.11131/2014/101086","DOIUrl":"https://doi.org/10.11131/2014/101086","url":null,"abstract":"Glucocorticoids (GCs) regulate numerous physiologic processes in order to maintain homeostasis. Most of their actions are mediated by an intracellular GC receptor (GR). The dysregulation of the GR function has been associated with different pathologies such as stress-related disorders and inflammatory and autoimmune diseases. The final outcome of GC actions is regulated at multiple levels and has been extensively reported. Nowadays, novel insights into the modulation of the GR activity arise from the study of the multiprotein chaperone/cochaperone machinery, the nuclear receptor cofactors (coactivators and corepressors), and chromatin regulation and their concomitant impact on GR-mediated gene transcription. Nevertheless, the complexity of GR-mediated gene regulation cannot be explained by a finite number of chaperones and cofactors. A further level in the regulation of GR activity is achieved by posttranslational modifications (PTMs) in response to external stimuli. PTMs can regulate protein stability, structure, function, activity, intracellular localization, and interaction with other proteins during cellular processes. Therefore, dynamic regulation of the molecular properties of these proteins by PTMs allows for further understanding the complexity of GR-dependent gene expression and its impact on GR-mediated pathophysiological processes.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"63477857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gisela I. Mazaira, M. Lagadari, Alejandra G. Erlejman, M. Galigniana
In the absence of ligand, some members of nuclear receptor family such as corticosteroid receptors are primarily located in the cytoplasm, and they rapidly accumulate in the nucleus upon ligand-binding. Other members of the family such as the estrogen receptor are mostly nuclear. Regardless of their primary location, these oligomeric proteins undergo a dynamic nuclear-cytoplasmic shuttling, and their transport through the cytoplasmic compartment has always been assumed to occur in a stochastic manner by simple diffusion. Although heuristic, this oversimplified model has never been demonstrated. Moreover, it has always been assumed that the first step related to receptor activation is the dissociation of the Hsp90-based heterocomplex, a process referred to as `transformation.' Nonetheless, recent experimental evidence indicates that the chaperone machinery is required for the retrotransport of the receptor throughout the cytoplasm and facilitates its active passage through the nuclear pore. Therefore, transformation is actually a nuclear event. A group of Hsp90-binding cochaperones belonging to the immunophilin family plays a cardinal role not only in the mechanism for receptor movement, but also in nuclear events leading to interactions with nuclear sites of action and the regulation of transcriptional activity. In this article we analyze the importance of molecular chaperones and TPR-domain immunophilins in the molecular mechanism of action of steroid receptors.
{"title":"The Emerging Role of TPR-Domain Immunophilins in the Mechanism of Action of Steroid Receptors","authors":"Gisela I. Mazaira, M. Lagadari, Alejandra G. Erlejman, M. Galigniana","doi":"10.11131/2014/101094","DOIUrl":"https://doi.org/10.11131/2014/101094","url":null,"abstract":"In the absence of ligand, some members of nuclear receptor family such as corticosteroid receptors are primarily located in the cytoplasm, and they rapidly accumulate in the nucleus upon ligand-binding. Other members of the family such as the estrogen receptor are mostly nuclear. Regardless of their primary location, these oligomeric proteins undergo a dynamic nuclear-cytoplasmic shuttling, and their transport through the cytoplasmic compartment has always been assumed to occur in a stochastic manner by simple diffusion. Although heuristic, this oversimplified model has never been demonstrated. Moreover, it has always been assumed that the first step related to receptor activation is the dissociation of the Hsp90-based heterocomplex, a process referred to as `transformation.' Nonetheless, recent experimental evidence indicates that the chaperone machinery is required for the retrotransport of the receptor throughout the cytoplasm and facilitates its active passage through the nuclear pore. Therefore, transformation is actually a nuclear event. A group of Hsp90-binding cochaperones belonging to the immunophilin family plays a cardinal role not only in the mechanism for receptor movement, but also in nuclear events leading to interactions with nuclear sites of action and the regulation of transcriptional activity. In this article we analyze the importance of molecular chaperones and TPR-domain immunophilins in the molecular mechanism of action of steroid receptors.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"63478536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
T. S. Farnesi-de-Assunção, Vanessa Carregaro, Carlos Silva, Antonio José de Pinho, M. Napimoga
The PPAR-γ ligands, in special 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2), negatively regulate the cells of innate and adaptative immune system and present excellent results in different models of inflammatory diseases. These findings support the notion that PPAR-γ ligands may be used as therapeutic agents in different diseases. Although PPAR-γ is expressed in different cells and tissues including dendritic cells (DC), few studies have evaluated the effects of these ligands on DCs. Thus, in this study we evaluated the effect of 15d-PGJ2 on DC surface molecule expression, including MHC-II, CD80, and CD86. In addition, we quantified cytokine production in the presence of 15d-PGJ2 or rosiglitazone. Expression of the surface molecules was measured by flow cytometry and cytokines production was measured by ELISA in supernatant of BMDC cultures. The results suggest that 15d-PGJ2 reduced the expression of costimulatory molecules (CD80 and CD86), without altering MCH-class II expression. Furthermore the natural PPAR-γ agonist significantly reduced levels of proinflammatory cytokines (IL-12, IFN-γ, and TNF-α) and appears to also reduce IL-1β levels. Rosiglitazone reduced the expression of these cytokines albeit to a lesser extent. These data suggest the idea that 15d-PGJ2 could be a therapeutic strategy in diseases where DCs play a crucial role, due to its ability to reduce costimulatory molecules expression and modulate the inflammatory environment.
{"title":"The Modulatory Effect of 15d-PGJ2 in Dendritic Cells","authors":"T. S. Farnesi-de-Assunção, Vanessa Carregaro, Carlos Silva, Antonio José de Pinho, M. Napimoga","doi":"10.11131/2014/101083","DOIUrl":"https://doi.org/10.11131/2014/101083","url":null,"abstract":"The PPAR-γ ligands, in special 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2), negatively regulate the cells of innate and adaptative immune system and present excellent results in different models of inflammatory diseases. These findings support the notion that PPAR-γ ligands may be used as therapeutic agents in different diseases. Although PPAR-γ is expressed in different cells and tissues including dendritic cells (DC), few studies have evaluated the effects of these ligands on DCs. Thus, in this study we evaluated the effect of 15d-PGJ2 on DC surface molecule expression, including MHC-II, CD80, and CD86. In addition, we quantified cytokine production in the presence of 15d-PGJ2 or rosiglitazone. Expression of the surface molecules was measured by flow cytometry and cytokines production was measured by ELISA in supernatant of BMDC cultures. The results suggest that 15d-PGJ2 reduced the expression of costimulatory molecules (CD80 and CD86), without altering MCH-class II expression. Furthermore the natural PPAR-γ agonist significantly reduced levels of proinflammatory cytokines (IL-12, IFN-γ, and TNF-α) and appears to also reduce IL-1β levels. Rosiglitazone reduced the expression of these cytokines albeit to a lesser extent. These data suggest the idea that 15d-PGJ2 could be a therapeutic strategy in diseases where DCs play a crucial role, due to its ability to reduce costimulatory molecules expression and modulate the inflammatory environment.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"63477813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kelly Teske, Premchendar Nandhikonda, Jonathan W Bogart, Belaynesh Feleke, Preetpal Sidhu, Nina Yuan, Joshua Preston, Robin Goy, Lanlan Han, Nicholas R Silvaggi, Rakesh K Singh, Daniel D Bikle, James M Cook, Leggy A Arnold
Herein, we described the development of two virtual screens to identify new vitamin D receptor (VDR) antagonists among nuclear receptor (NR) ligands. Therefore, a database of 14330 nuclear receptor ligands and their NR affinities was assembled using the online available "Binding Database". Two different virtual screens were carried out in conjunction with a reported VDR crystal structure applying a stringent and less stringent pharmacophore model to filter docked NR ligand conformations. The pharmacophore models were based on the spatial orientation of the hydroxyl functionalities of VDR's natural ligands 1,25(OH2)D3 and 25(OH2)D3. The first virtual screen identified 32 NR ligands with a calculate free energy of VDR binding of more than -6.0 kJ/mol. All but nordihydroguaiaretic acid (NDGA) are VDR ligands, which inhibited the interaction between VDR and coactivator peptide SRC2-3 with an IC50 value of 15.8 µM. The second screen identified 162 NR ligands with a calculate free energy of VDR binding of more than -6.0 kJ/mol. More than half of these ligands were developed to bind VDR followed by ERα/β ligands (26%), TRα/β ligands (7%) and LxRα/β ligands (7%). The binding between VDR and ERα ligand H6036 as well as TRα/β ligand triiodothyronine and a homoserine analog thereof was confirmed by fluorescence polarization.
{"title":"IDENTIFICATION OF VDR ANTAGONISTS AMONG NUCLEAR RECEPTOR LIGANDS USING VIRTUAL SCREENING.","authors":"Kelly Teske, Premchendar Nandhikonda, Jonathan W Bogart, Belaynesh Feleke, Preetpal Sidhu, Nina Yuan, Joshua Preston, Robin Goy, Lanlan Han, Nicholas R Silvaggi, Rakesh K Singh, Daniel D Bikle, James M Cook, Leggy A Arnold","doi":"10.11131/2014/101076","DOIUrl":"https://doi.org/10.11131/2014/101076","url":null,"abstract":"<p><p>Herein, we described the development of two virtual screens to identify new vitamin D receptor (VDR) antagonists among nuclear receptor (NR) ligands. Therefore, a database of 14330 nuclear receptor ligands and their NR affinities was assembled using the online available \"Binding Database\". Two different virtual screens were carried out in conjunction with a reported VDR crystal structure applying a stringent and less stringent pharmacophore model to filter docked NR ligand conformations. The pharmacophore models were based on the spatial orientation of the hydroxyl functionalities of VDR's natural ligands 1,25(OH<sub>2</sub>)D<sub>3</sub> and 25(OH<sub>2</sub>)D<sub>3</sub>. The first virtual screen identified 32 NR ligands with a calculate free energy of VDR binding of more than -6.0 kJ/mol. All but nordihydroguaiaretic acid (NDGA) are VDR ligands, which inhibited the interaction between VDR and coactivator peptide SRC2-3 with an IC<sub>50</sub> value of 15.8 µM. The second screen identified 162 NR ligands with a calculate free energy of VDR binding of more than -6.0 kJ/mol. More than half of these ligands were developed to bind VDR followed by ERα/β ligands (26%), TRα/β ligands (7%) and LxRα/β ligands (7%). The binding between VDR and ERα ligand H6036 as well as TRα/β ligand triiodothyronine and a homoserine analog thereof was confirmed by fluorescence polarization.</p>","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240308/pdf/nihms591373.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32833055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
There are thousands of articles published each year covering various aspects of nuclear receptors. These publications appear in a plethora of journals, virtually buried among an overwhelming volume of unrelated articles. A group of prominent scientists active in the field of nuclear receptor research has concluded that gathering publications on this superfamily of receptors under one umbrella would provide an invaluable resource for a broad assemblage of scientists in the field. Thus, the idea for a new journal, Nuclear Receptor Research (NuRR), was born. I am pleased to share with researchers working in the field of nuclear receptors, basic scientists as well as clinicians, that NuRR is now a reality as an open access peerreviewed journal devoted to publishing high-quality, original research and review articles covering all aspects involving all members of the nuclear receptor superfamily. NuRR has an editorial board comprised of a group of renowned scientists in the field from the four corners of the globe. Board members are committed to make NuRR a vibrant forum showcasing global efforts in this everexpanding area of research. It is hoped that NuRR will encourage collaborative studies as well as foster interdisciplinary initiatives within the field. I invite you to consider NuRR (http://www.agialpress .com/ journals/nurr/) as a vehicle to share your novel research findings and vision for the future of nuclear receptor research with your colleagues around the world.
{"title":"Nuclear Receptor Research: A Vibrant Forum to Showcase Global Efforts and Act as A Catalyst for Interdisciplinary Initiatives","authors":"M. Badr","doi":"10.11131/2013/101033","DOIUrl":"https://doi.org/10.11131/2013/101033","url":null,"abstract":"There are thousands of articles published each year covering various aspects of nuclear receptors. These publications appear in a plethora of journals, virtually buried among an overwhelming volume of unrelated articles. A group of prominent scientists active in the field of nuclear receptor research has concluded that gathering publications on this superfamily of receptors under one umbrella would provide an invaluable resource for a broad assemblage of scientists in the field. Thus, the idea for a new journal, Nuclear Receptor Research (NuRR), was born. I am pleased to share with researchers working in the field of nuclear receptors, basic scientists as well as clinicians, that NuRR is now a reality as an open access peerreviewed journal devoted to publishing high-quality, original research and review articles covering all aspects involving all members of the nuclear receptor superfamily. NuRR has an editorial board comprised of a group of renowned scientists in the field from the four corners of the globe. Board members are committed to make NuRR a vibrant forum showcasing global efforts in this everexpanding area of research. It is hoped that NuRR will encourage collaborative studies as well as foster interdisciplinary initiatives within the field. I invite you to consider NuRR (http://www.agialpress .com/ journals/nurr/) as a vehicle to share your novel research findings and vision for the future of nuclear receptor research with your colleagues around the world.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"63477805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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