Parkinsons disease (PD), primarily caused by selective degeneration of midbrain dopamine (mDA) neurons, is the most prevalent movement disorder, affecting 1-2% of the global population over the age of 65. Currently available pharmacological treatments are largely symptomatic and lose their efficacy over time with accompanying severe side effects such as dyskinesia. Thus, there is an unmet clinical need to develop mechanism-based and/or disease-modifying treatments. Based on the unique dual role of the nuclear orphan receptor Nurr1 for development and maintenance of mDA neurons and their protection from inflammation-induced death, we hypothesize that Nurr1 can be a molecular target for neuroprotective therapeutic development for PD. Here we show successful identification of Nurr1 agonists sharing an identical chemical scaffold, 4-amino-7-chloroquinoline, suggesting a critical structure-activity relationship. In particular, we found that two antimalarial drugs, amodiaquine and chloroquine ...
The orphan nuclear receptor Nurr1 is ascribed high potential as molecular target for Parkinsons Disease and Alzheimers Disease treatment1,2 but small molecule Nurr1 ligands and mechanistic understanding of Nurr1 modulation are scarce.. Inspired by a PDB-deposited X-ray structure of Nurr1 in complex with the arachidonic acid metabolite prostaglandin A13, we hypothesized non-steroidal anti-inflammatory drugs (NSAIDs) as Nurr1 ligands. Screening of a structurally diverse collection of NSAIDs indeed discovered several Nurr1 modulators most of which, interestingly, exhibited inverse agonism on Nurr1. Together with the previously reported Nurr1 agonist amodiaquine4, these molecules add up to a set of initial tool compounds, i.e. parecoxib, oxaprozin, amodiaquine and chloroquine, to decipher the molecular function of Nurr1.. Using this initial tool, we probed the response of the Nurr1 ligand binding domain to modulation by ligands. We observed an ability of Nurr1 agonists to stimulate homo- and ...
Nurr1 is an orphan member of the nuclear receptor superfamily; these orphan receptors are a group for which a ligand has yet to be identified. Nurr1 has been shown to regulate the expression of a small number of genes as a monomeric, constitutively active receptor. These Nurr1 regulated genes are primarily associated with dopamine cell maturation and survival. However, previous reports have shown an increased expression of Nurr1 in the synovium of patients with rheumatoid arthritis (RA) suggesting a pro-inflammatory role for Nurr1 in RA. In this study we investigate the potential pro-inflammatory role of Nurr1 by monitoring Nurr1 dependent gene expression in an immortalised synoviocyte cell line, K4IM. We overexpressed the wild type and a dominant negative form of the orphan nuclear receptor Nurr1, in a model synoviocyte cell line. Using the Affymetrix HG-U133 Genechips we demonstrate the effects on the transcriptome by the receptor. Further evidence of gene expression change was demonstrated using
Nurr1, an orphan nuclear receptor, plays an essential role in the generation and maintenance of dopaminergic neurons in the brain. Rare mutations in Nurr1 are associated with familial Parkinsons disease, but the underlying basis for this relationship has not been established. Here, we demonstrate that Nurr1 unexpectedly functions to inhibit expression of pro-inflammatory neurotoxic mediators in both microglia and astrocytes. Reduced Nurr1 expression results in exaggerated inflammatory responses in microglia that are further amplified by astrocytes, leading to the production of factors that cause death of tyrosine hydroxylase-expressing neurons. Nurr1 exerts anti-inflammatory effects by docking to NF-kappaB-p65 on target inflammatory gene promoters in a signal-dependent manner. Subsequently, Nurr1 recruits the CoREST corepressor complex, resulting in clearance of NF-kappaB-p65 and transcriptional repression. These studies suggest that Nurr1 protects against loss of dopaminergic neurons in ...
PubMedID: 27474396 | Iterative use of nuclear receptor Nr5a2 regulates multiple stages of liver and pancreas development. | Developmental biology | 10/1/2016
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A major consequence of Parkinsons disease (PD) involves the loss of dopaminergic neurons in the substantia nigra (SN) and a subsequent loss of dopamine (DA) in the striatum. We have shown that glial cell line-derived neurotrophic factor (GDNF) shows robust restorative and protective effects for DA neurons in rats, non-human primates and possibly in humans. Despite GDNFs therapeutic potential, its clinical value has been questioned due to its limited diffusion to target areas from its large size and chemical structure. Several comparatively smaller peptides are thought to be generated from the prosequence. A five amino-acid peptide, dopamine neuron stimulating peptide-5 (DNSP-5), has been proposed to demonstrate biological activity relevant to neurodegenerative disease. We tested the in vitro effects of DNSP-5 in primary dopaminergic neurons dissected from the ventral mesencephalon of E14 Sprague Dawley rat fetuses. Cells were treated with several doses (0.03, 0.1, 1.0, 10.0 ng/mL) of GDNF, ...
Acts as a negative regulator of G1 to S cell cycle phase progression by inhibiting cyclin-dependent kinases. Inhibitory effects are additive with GADD45 proteins but occurs also in the absence of GADD45 proteins. Acts as a repressor of the orphan nuclear receptor NR4A1 by inhibiting AB domain-mediated transcriptional activity. May be involved in the hormone-mediated regulation of NR4A1 transcriptional activity. May play a role in mitochondrial protein synthesis ...
Idiopathic inflammatory myopathy is a group of disorders characterized by inflammation of the muscles used for movement (skeletal muscles). Idiopathic inflammatory myopathy usually appears in adults between ages 40 and 60 or in children between ages 5 and 15, though it can occur at any age.The primary symptom of idiopathic inflammatory myopathy is muscle weakness, which develops gradually over a period of weeks to months or even years. Other symptoms include joint pain and general tiredness (fatigue).There are several forms of idiopathic inflammatory myopathy, including polymyositis, dermatomyositis, and sporadic inclusion body myositis.Polymyositis and dermatomyositis involve weakness of the muscles closest to the center of the body (proximal muscles), such as the muscles of the hips and thighs, upper arms, and neck. People with these forms of idiopathic inflammatory myopathy may find it difficult to climb stairs, get up from a seated position, or lift items above their head. In some cases, ...
The effects of retinoids on adrenal aldosterone synthase gene (CYP11B2) expression and aldosterone secretion are still unknown. We therefore examined the effects of nuclear retinoid X receptor (RXR) pan-agonist PA024 on CYP11B2 expression, aldosterone secretion and blood pressure, to elucidate its potential as a novel anti-hypertensive drug. We demonstrated that PA024 significantly suppressed angiotensin II (Ang II)-induced CYP11B2 mRNA expression, promoter activity and aldosterone secretion in human adrenocortical H295R cells. Human CYP11B2 promoter functional analyses using its deletion and point mutants indicated that the suppression of CYP11B2 promoter activity by PA024 was in the region from -1521 (full length) to -106 including the NBRE-1 and the Ad5 elements, and the Ad5 element may be mainly involved in the PA024-mediated suppression. PA024 also significantly suppressed the Ang II-induced mRNA expression of transcription factors NURR1 and NGFIB that bind to and activate the Ad5 element. ...
J:151918 Jiang H, Xiang M, Subtype specification of GABAergic amacrine cells by the orphan nuclear receptor Nr4a2/Nurr1. J Neurosci. 2009 Aug 19;29(33):10449-59 ...
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dalam ketegasanmu terselit kelembutan..dalam kesungguhanmu terselit seribu duka penderitaan..jerit perihmu menuju puncak kegemilangan..kau..syaukah istimewa..dipagari sinar nur islami..
TY - JOUR. T1 - Caspase-dependent and -independent cell death pathways in primary cultures of mesencephalic dopaminergic neurons after neurotoxin treatment. AU - Han, Baek S.. AU - Hong, Hyun Seung. AU - Choi, Won Seok. AU - Markelonis, George J.. AU - Oh, Tae H.. AU - Oh, Young Jun. PY - 2003/6/15. Y1 - 2003/6/15. N2 - Although the cause of neuronal death in Parkinsons disease (PD) is mainly unknown, growing evidence suggests that both apoptotic and non-apoptotic death may occur in PD. Using primary cultures of mesencephalic dopaminergic neurons and the MN9D dopaminergic neuronal cell line, we attempted to evaluate specifically the existence of the mitochondrial apoptotic pathway, focusing on the mitochondrial release of cytochrome c to the activation of the caspases after 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenylpyridinium (MPP+) treatment. Both immunofluorescent labeling and immunoblot analysis indicated mitochondrial release of cytochrome c into the cytosol after 6-OHDA or MPP+ ...
In the present study, we describe our findings that provide valuable insight on the role of nuclear receptor Nur77 in macrophages in atherosclerosis. Nur77 modulates macrophage M1/M2 polarization as concluded from the comparison of the expression pattern of phenotype-specific markers in macrophages from WT and Nur77−/− mice. Furthermore, we show that thioglycollate-mediated cell migration is markedly increased in Nur77−/− mice, and, in line with those observations, that bone marrow-specific deficiency of Nur77 dramatically enhances atherosclerosis in Ldlr−/− mice, which involves increased expression of SDF-1α (Online Figure V).. Macrophages play a critical role in initiation, progression, and stability of atherosclerotic lesions and during development of atherosclerotic lesions these cells are subjected to changing microenvironmental signals. In response to such signals, macrophages can polarize toward the proinflammatory M1 or the nonclassically activated M2 phenotype, yet these ...
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Distal arthrogryposis (DA) constitutes a frequent but heterogeneous subgroup among multiple congenital contractures (MCC). Despite its frequency only a limited number of genes have been associated with rare but well characterized types of DA, implicating almost exclusively genes of the contractile apparatus. Our aim was to identify new genes associated with DA. We therefore performed a SNP array based homozygosity mapping approach in two consanguineous African families presenting with an unclassified DA phenotype. We further screened potential candidate genes in 18 familial or sporadic cases with DA that did not show mutations in known genes associated with DA. Combined multipoint linkage analysis of the two families revealed an overlapping locus at 2q37 of 5.7 Mb with a LOD score Zmax = 5.1 at = 0.0 and harboring 77 annotated genes. We excluded pathogenic mutations in the genes encoding the gamma (CHRNG) and delta (CHRND) subunits of the acetylcholine receptor at the neuromuscular junction ...
Marian Blanca Ramírez from the CSIC in Spain has been studying the effects of LRRK2, a protein associated with Parkinsons disease, on cell motility. A Travelling Fellowship from Journal of Cell Science allowed her to spend time in Prof Maddy Parsons lab at Kings College London, learning new cell migration assays and analysing fibroblasts cultured from individuals with Parkinsons. Read more on her story here. Where could your research take you? The deadline to apply for the current round of Travelling Fellowships is 23rd Feburary 2018. Apply now!. ...
As part of our mission, Dup15q Alliance seeks to unite families, researchers, and professionals; and promote research, awareness, and understanding of chromosome 15q11.2-13.1 duplication syndrome and related disorders. Dup15q Alliance formally endorses and funds research and collaborates with researchers interested in research on chromosome 15q duplications by disseminating research information and promoting opportunities for Dup15q Alliance families to participate in research studies.. ...
This gene encodes a member of the steroid-thyroid hormone-retinoid receptor superfamily. Expression is induced by phytohemagglutinin in human lymphocytes and by serum stimulation of arrested fibroblasts. The encoded protein acts as a nuclear transcription factor. Translocation of the protein from the nucleus to mitochondria induces apoptosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2011 ...
Complete information for NR1D1 gene (Protein Coding), Nuclear Receptor Subfamily 1 Group D Member 1, including: function, proteins, disorders, pathways, orthologs, and expression. GeneCards - The Human Gene Compendium
Complete information for NR4A1 gene (Protein Coding), Nuclear Receptor Subfamily 4 Group A Member 1, including: function, proteins, disorders, pathways, orthologs, and expression. GeneCards - The Human Gene Compendium
Nr3c1 - Nr3c1 (untagged) - Mouse nuclear receptor subfamily 3, group C, member 1 (Nr3c1), (10ug) available for purchase from OriGene - Your Gene Company.
Homo sapiens nuclear receptor subfamily 1, group I, member 2 (NR1I2), transcript variant 3, mRNA. (H00008856-R03) - Products - Abnova
cdna: chromosome:VEGA66:4:133553376:133556536:1 gene:OTTMUSG00000011155 gene_biotype:protein_coding transcript_biotype:protein_coding gene_symbol:Nr0b2 description:nuclear receptor subfamily 0, group B, member 2 ...
The recurrent missense variant in Nuclear Receptor Subfamily 2 Group E Member 3 (NR2E3), c.166G>A, p.(Gly56Arg) or G56R, underlies 1%-2% of cases with ...
GCNF antibody (nuclear receptor subfamily 6, group A, member 1) for IHC-P. Anti-GCNF pAb (GTX70915) is tested in Human samples. 100% Ab-Assurance.
I think if you ever wanted to know what gene expression exactly is, look no further than nuclear receptors. You have receptors around your DNA nucleus in your cells that bind different things, this basically causes activation of your DNA to produce difference proteins ( polypeptides is a better word ) , thus expressing different genes ...
Medical and Surgical NursingGastro-intestinal DisorderPrepared: Mark Fredderick Abejo RN, MAN MEDICAL AND SURGICAL NUR…
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The initial strategies for generation of DA neurons from hESCs were based on previous experience with mouse ESCs, which commonly used the developmental cues known at the time (Kawasaki et al., 2000; Kim et al., 2002). Several of these early differentiation protocols did indeed produce a relatively high number of cells expressing tyrosine hydroxylase (TH, the rate-limiting enzyme in dopamine synthesis and most commonly used marker for DA neurons), yet the midbrain properties of these neurons were not clear and their in vivo performance after grafting in standard animal models of PD was modest. A breakthrough in optimization of the differentiation protocols came when our understanding of how midbrain DA neurons are formed during normal development radically changed. In 2007 and 2008, two ground-breaking studies were published, both reporting that midbrain DA neurons were not derived from neuroepithelial cells (like all other neurons) but were in fact derived from floor-plate cells expressing ...
This gene encodes a member of the nuclear receptor superfamily, and is a key regulator of xenobiotic and endobiotic metabolism. The protein binds to DNA as a monomer or a heterodimer with the retinoid X receptor and regulates the transcription of target genes involved in drug metabolism and bilirubin clearance, such as cytochrome P450 family members. Unlike most nuclear receptors, this transcriptional regulator is constitutively active in the absence of ligand but is regulated by both agonists and inverse agonists. Ligand binding results in translocation of this protein to the nucleus, where it activates or represses target gene transcription. These ligands include bilirubin, a variety of foreign compounds, steroid hormones, and prescription drugs. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008 ...
Subplate cells in the mouse are generally defined as cells located in the subplate layer between the white matter and layer 6a. They are some of the earliest born and maturing cells of the cerebral cortex. The postnatal subplate layer in mouse contains neurons with expression of the presynaptic protein complexin 3 (Cplx3), connective tissue growth factor (CTGF), the orphan nuclear receptor Nr4a2 (Nurr1), and the G-protein-coupled lysophosphatidic acid receptor 1 (Lpar1/Edg2). All 4 of these molecular markers show layer 6b-restricted expression at young postnatal ages, with CTGF expression being the most widespread in the young postnatal subplate. However, all 4 markers overlap in their expression pattern to varying degrees. Here we demonstrate with bromodeoxyuridine birthdating that cells labeled with any 1 of these molecular subplate markers are indeed generated at E11.5 or E12.5 in the mouse. Furthermore, we demonstrate a correlation between gene expression and cell birthdates. Lpar1-GFP cells are
STEMdiff™ Forebrain Neuron Differentiation Kit generates forebrain-type neural precursors from ESC- and iPSC-derived neural progenitor cells
Expert-reviewed interactive pathway providing a current overview Nuclear Receptor Signaling and links to products from Cell Signaling Technology.
Everson Lecture: Dr. Joyce Repa - University of Texas Southwestern Medical Center - Orphan Nuclear Receptors: From Gene to Function
Androgen Receptor (Dihydrotestosterone Receptor or Nuclear Receptor Subfamily 3 Group C Member 4 or DHTR or NR3C4 or AR) - Drugs in Development, 2021 provides in depth analysis on Androgen Receptor (Dihydrotestosterone Receptor or Nuclear Receptor Subfamily 3 Group C Member 4 or DHTR or NR3C4 or AR) targeted pipeline therapeutics. The report provides comprehensive information complete with Analysis by Indications, Stage of Development, Mechanism of Action (MoA), Route of Administration (RoA) and Molecule Type. The report also covers the descriptive pharmacological action of the therapeutics, its complete research and development history and latest news and press releases. Additionally, the report provides an overview of key players involved in Androgen Receptor (Dihydrotestosterone Receptor or Nuclear Receptor Subfamily 3 Group C Member 4 or DHTR or NR3C4 or AR) targeted therapeutics development and features dormant and discontinued projects. The report analyses the pipeline products across ...
Nurr1, a transcription factor belonging to the nuclear receptor family, is essential for the generation of midbrain dopamine (DA) cellsduring embryonic development and it continues to be expressed in adult DA neurons. However, the mechanism by which Nurr1 promotes dopamine cell differentiation has remained unknown. In this study, I have used a neuronal progenitor cell line (NT2/D1), which retains some stem cell characteristics and is capable only of terminal differentiation into neurons, to analyze the function of Nurr1 in dopamine cell development. The results demonstrated that Nurr1 can induce cell cycle arrest and the cells differentiated with distinct neuronal morphology after all-trans retinoic acid treatment. It was also indicated that up-regulation of some dopaminergic neuron markers (e.g. TH, DAT and D2DR) while down-regulation of CyclinD1-Cdk6 activity marks the key events in the early stages of dopaminergic neuron differentiation. Furthermore, Pin1, a highly conserved isomerase, which ...
Dopaminergic (DA) neurons display two functionally distinct modes of electrical activity: low- and high-frequency firing. We suggest a new minimal computational model that unites data on these firing modes obtained under different experimental conditions. The model reproduces the separation of maximal frequencies under NMDA synaptic stimulation vs. other treatments. In accord to recent experimental data, NMDA stimulation restricted to the soma effectively evokes high-frequency oscillations in the model. We have also reproduced low- and high-frequency oscillations under blockade of the SK current. Thus, the new model suggests a way that overcomes all major limitations of the switching dominance mechanism for controlling the frequency of the DA neuron. We explain recent experimental facts and make further predictions. ...
Rabbit Anti-NR0B2 Polyclonal Antibody,Nuclear receptor subfamily 0 group B member 2; Orphan nuclear receptor SHP; Small heterodimer partner,The protein encoded by NR0B2 (Nuclear Receptor Subfamily 0 Group B Member 2) is an unusual orphan receptor that contains a putative ligand-binding domain but lacks a conventional DNA-binding domain. NR0B2 product is a member of the nuclear hormone receptor family, a group of transcription factors regulated by small hydrophobic hormones, a subset of which do not have known ligands and are referred to as orphan nuclear receptors. The protein has been shown to interact with retinoid and thyroid hormone receptors, inhibiting their ligand-dependent transcriptional activation.
Supplementary MaterialsSupplemental figure 1 Legend 12276_2019_343_MOESM1_ESM. manifestation resulted in the downregulation of Ki-67 appearance mediated with the inhibited appearance of Nurr1, and FoxM1 overexpression marketed IEC-6 cell proliferation after H/R damage through activating Nurr1 appearance. Furthermore, FoxM1 directly promoted the transcription of Nurr1 by binding the promoter of Nurr1 directly. Further investigation demonstrated low appearance degrees of FoxM1, Nurr1, and Ki-67 in the intestinal epithelium of sufferers with intestinal ischemic damage. FoxM1 serves as a crucial regulator of intestinal regeneration after I/R damage by directly marketing the transcription of Nurr1. The FoxM1/Nurr1 signaling pathway represents a appealing therapeutic focus on for intestinal I/R damage and related scientific diseases. strong course=kwd-title Subject conditions: Injury, RNAi Launch Intestinal ischemia/reperfusion (I/R) damage is definitely a common pathophysiological process in many ...
In this study, we identified a novel class of CRAC channel blockers using high-throughput chemical library screen and asked how inhibition of Ca2+ signaling during TCR stimulation influenced differentiation and effector functions of T cells in vitro and in vivo. Using a combination of NFAT translocation as readout and a cell line harboring amplified CRAC currents, we identified a novel class of immunomodulators, compound 5, and its analogs. A more potent analog of the lead compound, compound 5D, blocked CRAC currents generated by WT Orai1 and a constitutively active mutant of Orai1 without affecting Orai1 and STIM1 translocation, indicating that the blocking mechanism directly involves the pore-forming subunit, Orai1. Further studies of CRAC current inhibition showed block by extracellular, but not intracellular, application of compound 5D, suggesting that the binding site is accessible only from the extracellular face of Orai1. Comprehensive mutational analysis of all the residues with possible ...
The anticancer drug 6-mercaptopurine (6-MP) inhibits purine synthesis and acts as an antiproliferative agent by interfering with protein, RNA and DNA activity and promoting apoptosis. modifies human being leukemic Capital t cells rate of metabolism with potential antiproliferative results. purine activity [1C6, 10]which can be important for lymphocyte expansion because these cells rely even more on path than on the repair path [5, 16, 17]. 6-MP may inhibit biosynthesis of ATP PX-866 and GTP PX-866 [18] also. In addition, latest proof shows that 6-MP prevents the phosphatidylinositol 3 kinase (PI3E) / mammalian focus on of rapamycin (mTOR) signaling path [8], recommending that these medicines might get in the way with metabolic checkpoints and effect metabolic reprogramming in regular Capital t cells and tumor [19]. In range with its feasible part in cell metabolic reprogramming, 6-MP manages the activity of people of the orphan nuclear receptor NR4A family members, which functions as crucial ...
Nuclear receptor subfamily 1 group D member 2, BD73, V-erbA-related protein 1-related (EAR-1r), Hs.37288, HZF2, Rev-erb alpha-related receptor (RVR), Rev-erb-beta ...
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Three members have been identified in humans nerve Growth factor IB (Nur77, or NR4A1), nuclear receptor related 1 protein (Nurr1, or NR4A2), and neuron-derived orphan receptor 1 (Nor-1, or NR4A3 ...
[ATTACH] This junkie is about to begin a three-day, neo-African, sometimes-terrifying, ritualistic trip. Can it help her get clean? PART I Its been 56 hours since Grace Bergeres last shot of...
Keegan McAuliffe MCB 432: Computing in Molecular Biology The following is my final presentation for MCB 432: detailing the process our group undertook to deter…