William S Baldwin, W Tyler Boswell, Gautam Ginjupalli, Elizabeth J Litoff
{"title":"Annotation of the Nuclear Receptors in an Estuarine Fish species, <i>Fundulus heteroclitus</i>.","authors":"William S Baldwin, W Tyler Boswell, Gautam Ginjupalli, Elizabeth J Litoff","doi":"10.11131/2017/101285","DOIUrl":"https://doi.org/10.11131/2017/101285","url":null,"abstract":"<p><p>The nuclear receptors (NRs) are ligand-dependent transcription factors that respond to various internal as well as external cues such as nutrients, pheromones, and steroid hormones that play crucial roles in regulation and maintenance of homeostasis and orchestrating the physiological and stress responses of an organism. We annotated the <i>Fundulus heteroclitus</i> (mummichog; Atlantic killifish) nuclear receptors. Mummichog are a non-migratory, estuarine fish with a limited home range often used in environmental research as a field model for studying ecological and evolutionary responses to variable environmental conditions such as salinity, oxygen, temperature, pH, and toxic compounds because of their hardiness. <i>F. heteroclitus</i> have at least 74 NRs spanning all seven gene subfamilies. <i>F. heteroclitus</i> is unique in that no RXRα member was found within the genome. Interestingly, some of the NRs are highly conserved between species, while others show a higher degree of divergence such as PXR, SF1, and ARα. Fundulus like other fish species show expansion of the RAR (NR1B), Rev-erb (NR1D), ROR (NR1F), COUPTF (NR2F), ERR (NR3B), RXR (NR2B), and to a lesser extent the NGF (NR4A), and NR3C steroid receptors (GR/AR). Of particular interest is the co-expansion of opposing NRs, Reverb-ROR, and RAR/RXR-COUPTF.</p>","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5552072/pdf/nihms884962.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35316257","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}
Brandon Praslicka, Jeremy S Harmson, Joohyun Kim, Vittobai Rashika Rangaraj, Aikseng Ooi, Chris R Gissendanner
{"title":"BINDING SITE ANALYSIS OF THE <i>CAENORHABDITIS ELEGANS</i> NR4A NUCLEAR RECEPTOR NHR-6 DURING DEVELOPMENT.","authors":"Brandon Praslicka, Jeremy S Harmson, Joohyun Kim, Vittobai Rashika Rangaraj, Aikseng Ooi, Chris R Gissendanner","doi":"10.11131/2017/101288","DOIUrl":"https://doi.org/10.11131/2017/101288","url":null,"abstract":"<p><p>Members of the NR4A subfamily of nuclear receptors make up a highly conserved, functionally diverse group of transcription factors implicated in a multitude of cellular processes such as proliferation, differentiation, apoptosis, metabolism and DNA repair. The gene <i>nhr-6,</i> which encodes the sole <i>C. elegans</i> NR4A nuclear receptor homolog, has a critical role in organogenesis and regulates the development of the spermatheca organ system. Our previous work revealed that <i>nhr-6</i> is required for spermatheca cell divisions in late L3 and early L4 and spermatheca cell differentiation during the mid L4 stage. Here, we utilized chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) to identify NHR-6 binding sites during both the late L3/early L4 and mid L4 developmental stages. Our results revealed 30,745 enriched binding sites for NHR-6, ~70% of which were within 3 kb upstream of a gene transcription start site. Binding sites for a cohort of candidate target genes with probable functions in spermatheca organogenesis were validated through qPCR. Reproductive and spermatheca phenotypes were also evaluated for these genes following a loss-of-function RNAi screen which revealed several genes with critical functions during spermatheca organogenesis. Our results uncovered a complex nuclear receptor regulatory network whereby NHR-6 regulates multiple cellular processes during spermatheca organogenesis.</p>","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5634515/pdf/nihms891763.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35446438","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":"Nuclear Receptor SHP: A Critical Regulator of miRNA and lncRNA Expression and Function.","authors":"Yongfeng Song, Shan Lu, Jiajun Zhao, Li Wang","doi":"10.11131/2017/101312","DOIUrl":"10.11131/2017/101312","url":null,"abstract":"<p><p>Small heterodimer partner (SHP, NR0B2) is identified as a unique orphan nuclear receptor that acts as a transcriptional repressor. SHP plays a crucial role in the control of various physiological processes and in several diseases by regulating the expression of disease-specific genes. Non-coding RNAs (ncRNAs), including long noncoding RNAs (lncRNAs) and microRNAs (miRNAs), are encoded of RNAs that are transcribed but not translated into proteins, which are involved in diverse developmental and cellular processes in eukaryotic organisms. Research during the past decade has identified factors participating in the regulation of ncRNAs biogenesis and function. In this review, we summarize recent findings demonstrating a critical role of SHP as a transcriptional regulator of ncRNAs expression and function.</p>","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103530/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36430111","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":"CONSERVED AND EXAPTED FUNCTIONS OF NUCLEAR RECEPTORS IN ANIMAL DEVELOPMENT.","authors":"Shari Bodofsky, Francine Koitz, Bruce Wightman","doi":"10.11131/2017/101305","DOIUrl":"10.11131/2017/101305","url":null,"abstract":"<p><p>The nuclear receptor gene family includes 18 members that are broadly conserved among multiple disparate animal phyla, indicating that they trace their evolutionary origins to the time at which animal life arose. Typical nuclear receptors contain two major domains: a DNA-binding domain and a C-terminal domain that may bind a lipophilic hormone. Many of these nuclear receptors play varied roles in animal development, including coordination of life cycle events and cellular differentiation. The well-studied genetic model systems of <i>Drosophila, C. elegans</i>, and mouse permit an evaluation of the extent to which nuclear receptor function in development is conserved or exapted (repurposed) over animal evolution. While there are some specific examples of conserved functions and pathways, there are many clear examples of exaptation. Overall, the evolutionary theme of exaptation appears to be favored over strict functional conservation. Despite strong conservation of DNA-binding domain sequences and activity, the nuclear receptors prove to be highly-flexible regulators of animal development.</p>","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761748/pdf/nihms906252.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35736804","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}
N. Castagnino, Massimo E. Maffei, L. Tortolina, G. Zoppoli, D. Piras, A. Nencioni, A. Ballestrero, F. Patrone, S. Parodi
{"title":"Transcription Factors Synergistically Activated at the Crossing of the Restriction Point between G1 and S Cell Cycle Phases. Pathologic Gate Opening during Multi-Hit Malignant Transformation","authors":"N. Castagnino, Massimo E. Maffei, L. Tortolina, G. Zoppoli, D. Piras, A. Nencioni, A. Ballestrero, F. Patrone, S. Parodi","doi":"10.11131/2016/101201","DOIUrl":"https://doi.org/10.11131/2016/101201","url":null,"abstract":"Transcription factors (TFs) represent key regulators of gene-expression patterns controlling cell behavior. TFs are active at nuclear – chromatin levels. TFs do not act in isolation; small sets of TFs cooperate toward the transcription of sets of mRNAs and consequently the translation of new proteins (the molecular phenotypes of a cell). Most TFs are activated through a cascade of biochemical reactions mediated by receptors expressed on the target cell surface. Nuclear Receptors (NRs) are transcription factors activated instead by small hydrophobic molecules capable of crossing the plasma membrane. The convergence of different pathways on TFs and their posttranslational modifications ensure that the external stimuli generate appropriate and integrated responses. The reconstruction of the molecular anatomy of these pathways through Molecular Interactions Maps (MIMs) can depict these intricate interactions. A mathematical modeling approach simulates/mimics their mechanism of action in normal and pathological conditions. We can simulate the effect of virtual hits in neoplastic transformation as mutations/alterations in these pathways. We can also simulate the effect of targeted inhibitors on these deregulated pathways. This strategy can help to guide an appropriate combination of targeted drugs in the treatment of a cancer patient, a major innovative perspective of incoming years.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"63479567","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":"On the Pharmacology of Farnesoid X Receptor Agonists: Give me an \"A\", Like in \"Acid\"","authors":"E. Hambruch, O. Kinzel, C. Kremoser","doi":"10.11131/2016/101207","DOIUrl":"https://doi.org/10.11131/2016/101207","url":null,"abstract":"The Farnesoid X Receptor (FXR) has recently moved into the spotlight through the release of clinical data using Obeticholic Acid, an FXR agonist, that demonstrated effectiveness of this bile acid-like drug in patients with Primary Biliary Cirrhosis and Non-alcoholic Steatohepatitis (NASH). FXR holds the promise to become an attractive drug target for various conditions, from Non-alcoholic Fatty Liver Disease (NAFLD), NASH, liver cirrhosis, portal hypertension and a variety of cholestatic disorders to intestinal diseases including inflammatory bowel disease and bile acid diarrhea. Despite the wide therapeutic potential, surprisingly little is known about the pharmacology, pharmacokinetics and tissue distribution properties of drugs targeting FXR. Are tissue specific FXR agonists preferable for different indications, or might one type of ligand fit all purposes? This review aims to summarize the sparse data which are available on this clinically and pharmacologically relevant topic and provides a mechanistic model for understanding tissue-specific effects in vivo.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"63479597","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":"Applying Computational Scoring Functions to Assess Biomolecular Interactions in Food Science: Applications to the Estrogen Receptors","authors":"F. Spyrakis, P. Cozzini, G. Kellogg","doi":"10.11131/2016/101202","DOIUrl":"https://doi.org/10.11131/2016/101202","url":null,"abstract":"During the last decade, computational methods, which were for the most part developed to study protein-ligand interactions and especially to discover, design and develop drugs by and for medicinal chemists, have been successfully applied in a variety of food science applications [1,2]. It is now clear, in fact, that drugs and nutritional molecules behave in the same way when binding to a macromolecular target or receptor, and that many of the approaches used so extensively in medicinal chemistry can be easily transferred to the fields of food science. For instance, nuclear receptors are common targets for a number of drug molecules and could be, in the same way, affected by the interaction with food or food-like molecules. \u0000Thus, key computational medicinal chemistry methods like molecular dynamics can be used to decipher protein flexibility and to obtain stable models for docking and scoring in food-related studies, and virtual screening is increasingly being applied to identify molecules with potential to act as endocrine disruptors, food mycotoxins, and new nutraceuticals [3,4,5]. All of these methods and simulations are based on protein-ligand interaction phenomena, and represent the basis for any subsequent modification of the targeted receptor's or enzyme's physiological activity. We describe here the energetics of binding of biological complexes, providing a survey of the most common and successful algorithms used in evaluating these energetics, and we report case studies in which computational techniques have been applied to food science issues. In particular, we explore a handful of studies involving the estrogen receptors for which we have a long-term interest.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"63479491","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}
Nicola Porta, A. Roncaglioni, M. Marzo, E. Benfenati
{"title":"QSAR Methods to Screen Endocrine Disruptors","authors":"Nicola Porta, A. Roncaglioni, M. Marzo, E. Benfenati","doi":"10.11131/2016/101203","DOIUrl":"https://doi.org/10.11131/2016/101203","url":null,"abstract":"The identification of endocrine disrupting chemicals (EDCs) is one of the important goals of environmental chemical hazard screening. We report on in silico methods addressing toxicological studies about EDCs with a special focus on the application of QSAR models for screening purpose. Since Estrogen-like (ER) activity has been extensively studied, the majority of the available models are based on ER-related endpoints. Some of these models are here reviewed and described. As example for their application, we screen an assembled dataset of candidate substitutes for some known EDCs belonging to the chemical classes of phthalates, bisphenols and parabens, selected considering their toxicological relevance and broad application, with the general aim of preliminary assessing their ED potential. The goal of the substitution processes is to advance inherently safer chemicals and products, consistent with the principles of green chemistry. Results suggest that the integration of a family of different models accounting for different endpoints can be a convenient way to describe ED as properly as possible and allow also both to increase the confidence of the predictions and to maximize the probability that most active compounds are correctly found.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"63479533","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":"Pregnane X Receptor and Cancer: Context-Specificity is Key.","authors":"S. Pondugula, P. Pávek, S. Mani","doi":"10.11131/2016/101198","DOIUrl":"https://doi.org/10.11131/2016/101198","url":null,"abstract":"Pregnane X receptor (PXR) is an adopted orphan nuclear receptor that is activated by a wide-range of endobiotics and xenobiotics, including chemotherapy drugs. PXR plays a major role in the metabolism and clearance of xenobiotics and endobiotics in liver and intestine via induction of drug-metabolizing enzymes and drug-transporting proteins. However, PXR is expressed in several cancer tissues and the accumulating evidence strongly points to the differential role of PXR in cancer growth and progression as well as in chemotherapy outcome. In cancer cells, besides regulating the gene expression of enzymes and proteins involved in drug metabolism and transport, PXR also regulates other genes involved in proliferation, metastasis, apoptosis, anti-apoptosis, inflammation, and oxidative stress. In this review, we focus on the differential role of PXR in a variety of cancers, including prostate, breast, ovarian, endometrial, and colon. We also discuss the future directions to further understand the differential role of PXR in cancer, and conclude with the need to identify novel selective PXR modulators to target PXR in PXR-expressing cancers.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.11131/2016/101198","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"63478266","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":"GW501516 Ameliorates A Fructose-Induced Inflammation Independent of AT1r Downregulation in Kidney","authors":"D. C. Magliano, I. Bringhenti, V. Souza-Mello","doi":"10.11131/2016/101206","DOIUrl":"https://doi.org/10.11131/2016/101206","url":null,"abstract":"AT1r high activation is linked to low-grade inflammation and oxidative stress, which yield impaired renal function. This study aimed to verify if GW501516 could improve damage in the kidney of mice with high activation of AT1r. Mice were fed a high-fructose diet (HFru) for eight weeks to induce an activation of the AT1r, whereas the control group received standard chow. The animals were randomly divided into four groups and the administration of GW501516 lasted three weeks. Morphological outcomes, urine and plasma determinations were assessed. Renin and ACE/AT1r axis protein and gene expression were evaluated as well as inflammatory cytokines and proteins. Also, the protein and gene expression of the antioxidant enzymes were verified. GW501516 improved systolic blood pressure and urinary parameters in HFru group. Although GW501516 had no effects either on ACE/AT1r axis or renin expression, it improved the inflammatory state, with increased IκB-α protein expression and decreased ERK and JNK phosphorylation. No differences were found in oxidative stress. We conclude that GW501516 acts downstream AT1r activation, improving inflammatory pathways in the kidney of HFru fed model. This is the first report demonstrating the anti-inflammatory actions of GW501516 upon kidney independently of AT1r downregulation in an HFru model.","PeriodicalId":30720,"journal":{"name":"Nuclear Receptor Research","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"63479553","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}