Nuclear Receptor Research最新文献

{"title":"Lipids and NMR: More Than Mere Acquaintances","authors":"Cecilia Castro, J. Griffin","doi":"10.32527/2020/101452","DOIUrl":"https://doi.org/10.32527/2020/101452","url":null,"abstract":"Recognising the paramount importance of lipids in cell physiology and function, there is an analytical need to measure the composition of lipids within the cell and how different lipid species interact. In this review, we will explore the role NMR spectroscopy can have in this. We will show how the technique can be used to measure lipid concentrations, but we will also provide evidences of its importance to characterise lipid interactions with other molecules, such as proteins, and to measure lipoproteins, the transporters of triglycerides and cholesterol, discussing advantages and limitations. Furthermore, we will highlight its potential for quality control analysis, particularly in food science and industry, if further development of benchtop instruments continues. Complementary to liquid chromatography mass spectrometry, which is able to measure numerous lipids in a complex mixture, NMR is an invaluable tool for fulfilling this need of better characterising lipids.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45195085","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}

{"title":"Carboxylesterases: Pharmacological Inhibition Regulated Expression and Transcriptional Involvement of Nuclear Receptors and other Transcription Factors","authors":"Yuanjun Shen, Zhanquan Shi, B. Yan","doi":"10.32527/2019/101435","DOIUrl":"https://doi.org/10.32527/2019/101435","url":null,"abstract":"Carboxylesterases (CESs, E.C.3.1.1.1) constitute a large class of enzymes that determine the therapeutic efficacy and toxicity of ester/amide drugs. Without exceptions, all mammalian species studied express multiple forms of carboxylesterases. Two human carboxylesterases, CES1 and CES2, are major contributors to hydrolytic biotransformation. Recent studies have identified therapeutic agents that potently inhibit carboxylesterases-based catalysis. Some of them are reversible whereas others irreversible. The adrenergic antagonist carvedilol, for example, reversibly inhibits CES2 but this carboxylesterase is irreversibly inhibited by orlistat, a popular anti-obesity medicine. Kinetically, the inhibition occurs competitively, non-competitively or in combination, depending on a carboxylesterase. For example, the calcium channel blocker diltiazem competitively inhibits CES1 but non-competitively inhibits CES2. In addition to inhibited catalysis, several therapeutic agents or disease mediators have been shown to regulate the expression of carboxylesterases. For example, the antiepileptic drug phenobarbital induces both human and rodent carboxylesterases, whereas the antibiotic rifampicin induces human carboxylesterases only. Conversely, the proinflammatory cytokine interleukin-6 (IL-6) suppresses the expression of carboxylesterases across species, but depending on the concentrations of glucose in the culture medium. Transactivation, transrepression and altered mRNA stability contribute to the regulated expression. Several nuclear receptors are established to support the regulation including constitutive androstane receptor, glucocorticoid receptor and pregnane X receptor. In addition, non-ligand transcription factors are also involved in the regulation and exemplified by differentiated embryo chondrocyte-1, nuclear factor (erythroid-derived 2)-like 2 and tumor protein p53. These transcription factors coordinate the regulated expression of carboxylesterases, constituting a regulatory network for the hydrolytic biotransformation.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42038167","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}

{"title":"Intrinsic Disorder in Nuclear Receptor Amino Termini: From Investigational Challenge to Therapeutic Opportunity","authors":"R. Shamilov, B. Aneskievich","doi":"10.32527/2019/101417","DOIUrl":"https://doi.org/10.32527/2019/101417","url":null,"abstract":"Epidermal keratinocytes form an effective renewable barrier to surface assaults and \u0000desiccation of underlying tissues through a tightly controlled program of regeneration and \u0000terminal differentiation which is significantly impacted by the activity of several members of the \u0000nuclear receptor (NR) superfamily. As such, there is significant interest in physiological and \u0000pharmacological control of select NRs. NRs are usually considered quintessential examples of \u0000constrained structure-function relationships among protein families because of amino acid \u0000identity and sequence subserving physical requirements inherent to a relatively centrally-located \u0000DNA-binding domain and carboxyl-terminal ligand-recognition domain which together lead to \u0000agonist-activated gene expression. Nevertheless, across the superfamily the amino terminus of \u0000many NR is an often-critical contributor in degree of receptor-dependent transcriptional activity \u0000despite little in apparent sequence similarity that might be instructive in understanding this \u0000ability. By looking beyond shared strict amino acid sequence identity, a number of \u0000investigations are revealing the “unstructured\"-function consequences of this disparity. \u0000Significant correlations between in silico and in vitro biophysical assessments are highlighting \u0000the shared trait of the unstructured nature or intrinsic disorder (ID) of NR amino termini and \u0000related functional consequences. Rather than the limited protein sequence variation-on-a-theme \u0000seen for zinc fingers (DNA binding) or a hydrophobic pocket (ligand binding), these \u0000amino-termini show sequence order diversity but often strikingly shared amino acid composition \u0000profiles not supporting a one-sequence–one-structure conformation. In this review, we look to \u0000integrate amino-termini ID reported in the literature, or predicted here, for select keratinocyte-expressed \u0000NR. As evidenced by success in drug targeting the amino-terminus of the androgen \u0000receptor, increased appreciation of amino-termini structure - or unstructure - might provide \u0000better understanding of NR function in general and possible future investigations on \u0000pharmacologic control over keratinocyte regeneration and/or differentiation.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43478806","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}

{"title":"Ligand-Induced Allosteric Effects Governing SR Signaling","authors":"C. Okafor, J. K. Colucci, E. Ortlund","doi":"10.32527/2019/101382","DOIUrl":"https://doi.org/10.32527/2019/101382","url":null,"abstract":"Steroid receptors (SRs) are a class of ligand-regulated transcription factors that regulate gene expression in response to the binding of steroid hormones. Ligand binding drives conformational changes within the SR ligand binding domain that alters the receptors' affinity for coregulator proteins that in turn modulate chromatin state and either promote or block the recruitment of transcriptional machinery to a gene. Structural characterizations of SRs have provided insight into how these conformational rearrangements modulate receptor function, including signaling between the ligand binding pocket and the site of coregulator binding. Here, we review some of the proposed structural mechanisms put forward to explain the ability of ligands to modulate SR function. We also provide a discussion on computational methods that have contributed to the elucidation of SR allosteric regulation. Finally, we consider broader discussions of allostery within the SR family, such as receptor-induced reverse allostery and allosteric binding sites located outside of the canonical ligand interaction site.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47062327","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}

{"title":"The Role of Mineralocorticoid Receptor Signaling in Genitourinary Cancers","authors":"Y. Nagata, T. Goto, H. Miyamoto","doi":"10.32527/2019/101410","DOIUrl":"https://doi.org/10.32527/2019/101410","url":null,"abstract":"A steroid hormone receptor, mineralocorticoid receptor (MR), is well known to play a critical role in maintaining normal homeostasis in the body primarily via regulating ionic and water transports. Indeed, MR antagonists have been prescribed to the patients as diuretic drugs. Meanwhile, emerging evidence has indicated that MR signaling, with or without functional interplay with glucocorticoid receptor or androgen receptor, contributes to modulating the development and progression of several types of neoplasms including genitourinary malignancies. This review summarizes the available data suggesting the involvement of MR signaling in renal cell carcinoma, prostatic adenocarcinoma, urothelial carcinoma, and other malignancies, and highlights potential underlying molecular mechanisms.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42879194","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}

{"title":"Phase 0 of the Xenobiotic Response: Nuclear Receptors and Other Transcription Factors as a First Step in Protection from Xenobiotics.","authors":"William S Baldwin","doi":"10.32527/2019/101447","DOIUrl":"10.32527/2019/101447","url":null,"abstract":"<p><p>This mini-review examines the crucial importance of transcription factors as a first line of defense in the detoxication of xenobiotics. Key transcription factors that recognize xenobiotics or xenobiotic-induced stress such as reactive oxygen species (ROS), include AhR, PXR, CAR, MTF, Nrf2, NF-κB, and AP-1. These transcription factors constitute a significant portion of the pathways induced by toxicants as they regulate phase I-III detoxication enzymes and transporters as well as other protective proteins such as heat shock proteins, chaperones, and anti-oxidants. Because they are often the first line of defense and induce phase I-III metabolism, could these transcription factors be considered the phase 0 of xenobiotic response?</p>","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":"6 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6897393/pdf/nihms-1061035.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49683035","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}

{"title":"Functional Characterization of a Novel Variant of the Constitutive Androstane Receptor (CAR, NR1I3)","authors":"V. Prantner, Y. Cinnamon, Jenni Küblbeck, Ferdinand Molnár, P. Honkakoski","doi":"10.32527/2018/101386","DOIUrl":"https://doi.org/10.32527/2018/101386","url":null,"abstract":"The nuclear receptor constitutive androstane receptor (CAR; NR1I3) controls the inducible expression of many enzymes and transporters involved in drug metabolism and transport, energy metabolism and toxicity. Single nucleotide variants of CAR are quite rare and usually associated with changes in pharmacokinetics of therapeutic drugs. Recently, a non-synonymous variant (F243S in the wild-type CAR) has been linked to the Kleefstra syndrome (MIM 610253) affecting neurological development. We identified another, previously unknown CAR variant (I281T) in a patient suffering from Kleefstra-like symptoms. Detailed reporter gene assays and molecular modelling indicated that the I281T mutation decreases the ability of CAR to recruit co-activators, likely by interfering with the assembly of functional CAR/retinoid X receptor (RXR) heterodimers. Although the I281T variant does not seem to cause the features of the patient, the present study adds to our knowledge about CAR function.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47357120","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}

{"title":"Physiology and Pathophysiology of PPARs in the Eye","authors":"V. Castelli, M. d’Angelo, A. Antonosante, M. Catanesi, E. Benedetti, G. Desideri, A. Cimini","doi":"10.11131/2018/101370","DOIUrl":"https://doi.org/10.11131/2018/101370","url":null,"abstract":"Peroxisome proliferator-activated receptor (PPARs) are ligand-activated transcription factors that exert significant roles in the control of multiple physiological processes. The last decade has shown an increasing interest in the role played by the agonists of PPARs in anti-inflammatory, anti-angiogenic, anti-fibrotic effects and in modulating oxidative stress response in different organs. Since the pathologic mechanisms of the majority of the blinding diseases, such as diabetic retinopathy (DR), age-related macular degeneration (AMD), glaucoma and optic neuropathy (ON), often involve neo-angiogenesis, inflammation and oxidative stress-mediated cell death, evidences are accumulating on the potential benefits of PPAR modulation to prevent or ameliorate eye pathologies. In this review, we focused on the description of what is known about the role of PPARs in the ocular pathophysiological processes and on PPARs agonists as innovative adjuvants in the treatment of ocular diseases.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42280503","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}

{"title":"A Comprehensive Analysis and Prediction of Sub-Cellular Localization of Human Nuclear Receptors","authors":"Samatha Mathew, Keshav Thakur, Sudhir Kumar, A. Yende, Shashi Singh, A. K. Dash, R. Tyagi","doi":"10.11131/2018/101324","DOIUrl":"https://doi.org/10.11131/2018/101324","url":null,"abstract":"The Nuclear Receptor (NR) superfamily comprises of conserved ligand-modulated intracellular transcription factors which in the presence of their cognate ligands activate a plethora of signaling networks, thereby commencing their respective transcription functions. All NRs are nuclear when liganded or active. However, their localization may differ between nucleus and cytoplasm when unliganded or inactive. NRs control a majority of physiological processes in body ranging from metabolism to reproduction and development. Hitherto, in case of humans, 48 NRs have been identified which are localized either in cytosolic, nuclear or both compartments of the cell. Sub-cellular localization of proteins has great relevance in relation to their function. However, specific sub-cellular localization patterns of human NRs are clouded with ambiguity and are mostly ridden with controversy, with only a few of them being well-studied and established under specific physiological conditions. In the present study, we attempted to bridge the gap and attempted to draw conclusions in relation to sub-cellular localization of human NRs based on published experimental data and by in-silico prediction methods. This comprehensive analysis may not only be useful to draw conclusions on their control of physiological processes but may also open new avenues towards understanding of the molecular basis of NR-mediated diseases attributed to their mislocalization and malfunctioning.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43574545","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}

{"title":"Biphasic hCAR Inhibition-Activation by Two Aminoazo Liver Carcinogens","authors":"K. Bogen","doi":"10.11131/2018/101321","DOIUrl":"https://doi.org/10.11131/2018/101321","url":null,"abstract":"Detailed dose-response data recently archived by the National Center for Biotechnology Information (NCBI) identified 853 human CAR (hCAR) agonists by quantitative high-throughput screening (qHTS) assays applied to >9,000 chemicals tested at ≥14 concentrations using n = 3–48 replicates. By re-examining NCBI data on 746 agonists with replicate data sets each satisfying additional quality criteria, ∼95% had average values of agonist-specific Hill-model slopes estimated by NCBI that exceed 1 (i.e., exhibited an overall sublinear low-dose dose-response), and two unambiguously biphasic hCAR inhibitor-agonists were identified, 4-aminoazobenzene (n = 37) and ortho-aminoazotoluene (n = 3), both of which also cause rodent liver tumors. Although evidently rare among hCAR agonists, such biphasic responses add to evidence that nuclear receptors can exhibit complex patterns of low-dose response, consistent with previous observations and theoretical predictions for endpoints governed by ultrasensitive molecular switches. The pronounced biphasic hCAR response pattern observed for 4-aminoazobenzene is particularly noteworthy insofar as it was identified with statistical power that exceeds that of most if not all other receptor-mediated biphasic cellular responses to any single-chemical exposure reported to date.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46677671","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}