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Journal articles on the topic 'RORα'

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Published: 25 June 2021
Last updated: 1 February 2022

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1

Kang, Hong Soon, Martin Angers, Ju Youn Beak, Xiying Wu, Jeffrey M. Gimble, Taira Wada, Wen Xie, Jennifer B. Collins, Sherry F. Grissom, and Anton M. Jetten. "Gene expression profiling reveals a regulatory role for RORα and RORγ in phase I and phase II metabolism." Physiological Genomics 31, no. 2 (October 2007): 281–94. http://dx.doi.org/10.1152/physiolgenomics.00098.2007.

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Retinoid-related orphan receptors alpha (RORα) and gamma (RORγ) are both expressed in liver; however, their physiological functions in this tissue have not yet been clearly defined. The RORα1 and RORγ1 isoforms, but not RORα4, show an oscillatory pattern of expression during circadian rhythm. To obtain insight into the physiological functions of ROR receptors in liver, we analyzed the gene expression profiles of livers from WT, RORα-deficient staggerer (sg) mice ( RORα sg/sg), RORγ−/−, and RORα sg/sg RORγ−/− double knockout (DKO) mice by microarray analysis. DKO mice were generated to study functional redundancy between RORα and RORγ. These analyses demonstrated that RORα and RORγ affect the expression of a number of genes. RORα and RORγ are particularly important in the regulation of genes encoding several phase I and phase II metabolic enzymes, including several 3β-hydroxysteroid dehydrogenases, cytochrome P450 enzymes, and sulfotransferases. In addition, our results indicate that RORα and RORγ each affect the expression of a specific set of genes but also exhibit functional redundancy. Our study shows that RORα and RORγ receptors influence the regulation of several metabolic pathways, including those involved in the metabolism of steroids, bile acids, and xenobiotics, suggesting that RORs are important in the control of metabolic homeostasis.
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2

Park, Su, Il-Geun Park, Hyunkyung Kim, and Ji Lee. "N-Terminal Domain Mediated Regulation of RORα1 Inhibits Invasive Growth in Prostate Cancer." International Journal of Molecular Sciences 20, no. 7 (April 4, 2019): 1684. http://dx.doi.org/10.3390/ijms20071684.

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Four members of the retinoic acid-related orphan receptor α (RORα) family (RORα1, RORα2, RORα3 and RORα4) are transcription factors that regulate several processes including circadian rhythm, lipid metabolism, cerebellar development, immune function, and cancer. Only two isoforms, RORα1 and 4, are specifically co-expressed in the murine and human. In the present study, we identified a specific N-terminal domain (NTD) of RORα1 that potentiated the downregulation of target genes involved in tumor progression and proliferation, based on results from RORα-deficient mouse embryonic fibroblasts and prostate carcinoma tissues. The hyperactivation of proliferative target genes were observed in RORα-deficient embryonic fibroblasts, and reconstitution of RORα1 inhibited this activation by a NTD dependent manner. Downregulation of RORα1 and upregulation of Wnt/β-catenin target genes were correlated in prostate cancer patients. These findings revealed the control of invasive growth by NTD-mediated RORα1 signaling, suggesting advanced approaches for the development of therapeutic drugs.
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3

Jetten, Anton M. "Retinoid-Related Orphan Receptors (RORs): Critical Roles in Development, Immunity, Circadian Rhythm, and Cellular Metabolism." Nuclear Receptor Signaling 7, no. 1 (January 2009): nrs.07003. http://dx.doi.org/10.1621/nrs.07003.

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The last few years have witnessed a rapid increase in our knowledge of the retinoid-related orphan receptors RORα, -β, and -γ (NR1F1-3), their mechanism of action, physiological functions, and their potential role in several pathologies. The characterization of ROR-deficient mice and gene expression profiling in particular have provided great insights into the critical functions of RORs in the regulation of a variety of physiological processes. These studies revealed that RORa plays a critical role in the development of the cerebellum, that both RORα and RORβ are required for the maturation of photoreceptors in the retina, and that RORγ is essential for the development of several secondary lymphoid tissues, including lymph nodes. RORs have been further implicated in the regulation of various metabolic pathways, energy homeostasis, and thymopoiesis. Recent studies identified a critical role for RORγ in lineage specification of uncommitted CD4+T helper cells into Th17 cells. In addition, RORs regulate the expression of several components of the circadian clock and may play a role in integrating the circadian clock and the rhythmic pattern of expression of downstream (metabolic) genes. Study of ROR target genes has provided insights into the mechanisms by which RORs control these processes. Moreover, several reports have presented evidence for a potential role of RORs in several pathologies, including osteoporosis, several autoimmune diseases, asthma, cancer, and obesity, and raised the possibility that RORs may serve as potential targets for chemotherapeutic intervention. This prospect was strengthened by recent evidence showing that RORs can function as ligand-dependent transcription factors.
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4

Wada, Taira, Hong Soon Kang, Anton M. Jetten, and Wen Xie. "The Emerging Role of Nuclear Receptor RORα and Its Crosstalk with LXR in Xeno- and Endobiotic Gene Regulation." Experimental Biology and Medicine 233, no. 10 (October 2008): 1191–201. http://dx.doi.org/10.3181/0802-mr-50.

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Retinoid-related orphan receptors (RORs), including the α, β and γ isoforms (NR1F1–3), are orphan nuclear receptors that have been implicated in tissue development, immune responses, and circadian rhythm. Although RORα and RORγ have been shown to be expressed in the liver, the hepatic function of these two RORs remains unknown. We have recently shown that loss of RORα and/or RORγ can positively or negatively influence the expression of multiple Phase I and Phase II drug metabolizing enzymes and transporters in the liver. Among ROR responsive genes, we identified oxysterol 7α-hydroxylase (Cyp7b1), which plays a critical role in the homeostasis of cholesterol, as a RORα target gene. We showed that RORα is both necessary and sufficient for Cyp7b1 activation. Studies of mice deficient of RORα or liver X receptors (LXRs) revealed an interesting and potentially important functional crosstalk between RORα and LXR. The respective activation of LXR target genes and ROR target genes in RORα null mice and LXR null mice led to our hypothesis that these two receptors are mutually suppressive in vivo. LXRs have been shown to regulate a battery of metabolic genes. We conclude that RORs participate in the xeno- and endobiotic regulatory network by regulating gene expression directly or through crosstalk with LXR, which may have broad implications in metabolic homeostasis.
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5

CHAUVET, Caroline, Brigitte BOIS-JOYEUX, and Jean-Louis DANAN. "Retinoic acid receptor-related orphan receptor (ROR) α4 is the predominant isoform of the nuclear receptor RORα in the liver and is up-regulated by hypoxia in HepG2 human hepatoma cells." Biochemical Journal 364, no. 2 (June 1, 2002): 449–56. http://dx.doi.org/10.1042/bj20011558.

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The retinoic acid receptor-related orphan receptor α (RORα) is critically involved in many physiological functions in several organs. We find that the main RORα isoform in the mouse liver is the RORα4 isoform, in terms of both mRNA and protein levels, while the RORα1 isoform is less abundant. Because hypoxia is a major feature of liver physiology and pathology, we examined the effect of this stress on Rora gene expression and RORα transcriptional activity. HepG2 human hepatoma cells were cultured for 24h under normoxia (20% O2) or hypoxia (10, 2, and 0.1% O2) and the abundance of the Rora transcripts measured by Northern blot and semi-quantitative RT-PCR. Hypoxic HepG2 cells contained more Rora mRNA than controls. This was also observed in rat hepatocytes in primary culture. Cobalt chloride and desferrioxamine also increased the amount of Rora mRNA in HepG2 cells. It is likely that these treatments increase the amount of the RORα4 protein in HepG2 cells as evidenced by Western blotting in the case of desferrioxamine. Transient transfection experiments indicated that hypoxia, cobalt chloride, and desferrioxamine all stimulate RORα transcriptional activity in HepG2 cells. Hence, we believe that RORα participates in the control of gene transcription in hepatic cells and modulates gene expression in response to hypoxic stress.
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6

Koibuchi, Noriyuki, Ying Liu, Harumi Fukuda, Akira Takeshita, Paul M. Yen, and William W. Chin. "RORα Augments Thyroid Hormone Receptor-Mediated Transcriptional Activation*." Endocrinology 140, no. 3 (March 1, 1999): 1356–64. http://dx.doi.org/10.1210/endo.140.3.6562.

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Abstract This study is designed to clarify the role of an orphan nuclear hormone receptor, RORα, on thyroid hormone (TH) receptor (TR)-mediated transcription on a TH-response element (TRE). A transient transfection study using various TREs [i.e., F2 (chick lysozyme TRE), DR4 (direct repeat), and palindrome TRE] and TR and RORα1 was performed. When RORα1 and TR were cotransfected into CV1 cells, RORα1 enhanced the transactivation by liganded-TR on all TREs tested without an effect on basal repression by unliganded TR. By electrophoretic mobility shift assay, on the other hand, although RORα bound to all TREs tested as a monomer, no (or weak) TR and RORα1 heterodimer formation was observed on various TREs except when a putative ROR-response element was present. The transactivation by RORα1 on a ROR-response element, which does not contain a TRE, was not enhanced by TR. The effect of RORα1 on the TREs is unique, because, whereas other nuclear hormone receptors (such as vitamin D receptor) may competitively bind to TRE to exert dominant negative function, RORα1 augmented TR action. These results indicate that RORα1 may modify the effect of liganded TR on TH-responsive genes. Because TR and RORα are coexpressed in cerebellar Purkinje cells, and perinatal hypothyroid animals and RORα-disrupted animals show similar abnormalities of this cell type, cross-talk between these two receptors may play a critical role in Purkinje cell differentiation.
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7

Song, Hyerin, Jung Woong Chu, Su Chan Park, Hyuntae Im, Il-Geun Park, Hyunkyung Kim, and Ji Min Lee. "Isoform-Specific Lysine Methylation of RORα2 by SETD7 Is Required for Association of the TIP60 Coactivator Complex in Prostate Cancer Progression." International Journal of Molecular Sciences 21, no. 5 (February 27, 2020): 1622. http://dx.doi.org/10.3390/ijms21051622.

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The retinoid acid-related orphan receptor α (RORα), a member of the orphan nuclear receptor superfamily, functions as an unknown ligand-dependent transcription factor. RORα was shown to regulate a broad array of physiological processes such as Purkinje cell development in the cerebellum, circadian rhythm, lipid and bone metabolism, inhibition of inflammation, and anti-apoptosis. The human RORα gene encodes at least four distinct isoforms (RORα1, -2, -3, -4), which differ only in their N-terminal domain (NTD). Two isoforms, RORα2 and 3, are not expressed in mice, whereas RORα1 and 4 are expressed both in mice and humans. In the present study, we identified the specific NTD of RORα2 that enhances prostate tumor progression and proliferation via lysine methylation-mediated recruitment of coactivator complex pontin/Tip60. Upregulation of the RORα2 isoform in prostate cancers putatively promotes tumor formation and progression. Furthermore, binding between coactivator complex and RORα2 is increased by lysine methylation of RORα2 because methylation permits subsequent interaction with binding partners. This methylation-dependent activation is performed by SET domain containing 7 (SETD7) methyltransferase, inducing the oncogenic potential of RORα2. Thus, post-translational lysine methylation of RORα2 modulates oncogenic function of RORα2 in prostate cancer. Exploration of the post-translational modifications of RORα2 provides new avenues for the development of tumor-suppressive therapeutic agents through modulating the human isoform-specific tumorigenic role of RORα2.
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8

Qiu, Chun-Hong, Noriaki Shimokawa, Toshiharu Iwasaki, Ishwar S. Parhar, and Noriyuki Koibuchi. "Alteration of Cerebellar Neurotropin Messenger Ribonucleic Acids and the Lack of Thyroid Hormone Receptor Augmentation by staggerer-Type Retinoic Acid Receptor-Related Orphan Receptor-α Mutation." Endocrinology 148, no. 4 (April 1, 2007): 1745–53. http://dx.doi.org/10.1210/en.2006-1131.

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The mutant mouse staggerer (sg) harbors a deletion within the gene encoding the retinoic acid receptor-related orphan receptor-α (RORα). Homozygotes show aberrant cerebellar development. However, the mechanisms responsible for the cerebellar defect are still poorly understood. In the present study, the involvement of neurotropins (NTs), including nerve growth factor, brain-derived neurotropic factor, NT-3 and NT-4/5, and their receptors, which play a crucial role in brain development, on the cerebellar defects of sg mice was studied by semiquantitative RT-PCR and in situ hybridization histochemistry. An evident alteration of these mRNA levels was observed in both heterozygotes and homozygotes. Such difference was most evident in the internal granule cell layer. Because the changes in NT expression as well as morphological alterations in sg cerebellum are similar to those in hypothyroid animals, the effect of mutant RORα (RORsg) on transcriptional regulation through the thyroid hormone (TH) response element or the ROR response element (RORE) was then studied. RORsg neither activated the transcription through RORE nor suppressed RORα-induced transcription, indicating that it does not function as a dominant negative inhibitor. On the other hand, although wild-type RORα augmented TH receptor (TR)α1/β1-mediated transcription through various TH response elements, RORsg was not effective in augmenting TR action. These results suggest that the cerebellar defect of the sg mouse is partly caused by the altered expression of NTs and the lack of augmentation of TR-mediated transcription by RORα as well as the absence of RORα action through RORE.
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9

Doebelin, Christelle, Yuanjun He, Sean Campbell, Philippe Nuhant, Naresh Kumar, Marcel Koenig, Ruben Garcia-Ordonez, et al. "Discovery and Optimization of a Series of Sulfonamide Inverse Agonists for the Retinoic Acid Receptor-Related Orphan Receptor-α." Medicinal Chemistry 15, no. 6 (August 26, 2019): 676–84. http://dx.doi.org/10.2174/1573406415666190222124745.

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Background: Despite a massive industry endeavor to develop RORγ-modulators for autoimmune disorders, there has been no indication of efforts to target the close family member RORα for similar indications. This may be due to the misconception that RORα is redundant to RORγ, or the inherent difficulty in cultivating tractable starting points for RORα. RORα-selective modulators would be useful tools to interrogate the biology of this understudied orphan nuclear receptor. Objectives: he goal of this research effort was to identify and optimize synthetic ligands for RORα starting from the known LXR agonist T0901317. Methods: Fourty-five analogs of the sulfonamide lead (1) were synthesized and evaluated for their ability to suppress the transcriptional activity of RORα, RORγ, and LXRα in cell-based assays. Analogs were characterized by 1H-NMR, 13C-NMR, and LC-MS analysis. The pharmacokinetic profile of the most selective RORα inverse agonist was evaluated in rats with intraperitoneal (i.p.) and per oral (p.o.)dosing. Results: Structure-activity relationship studies led to potent dual RORα/RORγ inverse agonists as well as RORα-selective inverse agonists (20, 28). LXR activity could be reduced by removing the sulfonamide nitrogen substituent. Attempts to improve the potency of these selective leads by varying substitution patterns throughout the molecule proved challenging. Conclusion: The synthetic RORα-selective inverse agonists identified (20, 28) can be utilized as chemical tools to probe the function of RORα in vitro and in vivo.
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10

Gu, Feng, Yuming Liu, Yuan Liu, Shujie Cheng, Jihong Yang, Ming Kang, Wendu Duan, and Yan Liu. "Distinct functions and prognostic values of RORs in gastric cancer." Open Medicine 15, no. 1 (May 19, 2020): 424–34. http://dx.doi.org/10.1515/med-2020-0406.

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AbstractRetinoic acid receptor-related orphan receptors (RORs) are frequently abnormally expressed in several human malignancies, including gastric cancer (GC). RORs are involved in the development and progression of GC through Wnt signaling pathway receptors and other common receptors. However, the prognostic roles of individual RORs in patients with GC remain elusive. We accessed the prognostic roles of three RORs (RORα, RORβ, and RORγ) through “The Kaplan–Meier plotter” (KM plotter) database in patients with GC. For all patients with GC who were followed for 20 years, the low mRNA expression of all three RORs showed a significant correlation with better outcomes. We further accessed the prognostic value of individual RORs in different clinical pathological features including Lauren classification, clinical stages, pathological grades, HER2 status, and different treatments methods. The RORs demonstrated critical prognostic roles in GC. Expressions of RORs were higher in GC tissues when compared with normal gastric tissues. Moreover, knockdown of RORs significantly inhibited cell proliferation and migration, suggesting an oncogenic role of RORs in human GC. These findings suggest potential roles of RORs as biomarkers for GC prognosis and as oncogenes in GC.
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11

Brożyna, Anna A., Tae-Kang Kim, Marzena Zabłocka, Wojciech Jóźwicki, Junming Yue, Robert C. Tuckey, Anton M. Jetten, and Andrzej T. Slominski. "Association among Vitamin D, Retinoic Acid-Related Orphan Receptors, and Vitamin D Hydroxyderivatives in Ovarian Cancer." Nutrients 12, no. 11 (November 19, 2020): 3541. http://dx.doi.org/10.3390/nu12113541.

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Vitamin D and its derivatives, acting via the vitamin D receptor (VDR) and retinoic acid-related orphan receptors γ and α (RORγ and RORα), show anticancer properties. Since pathological conditions are characterized by disturbances in the expression of these receptors, in this study, we investigated their expression in ovarian cancers (OCs), as well as explored the phenotypic effects of vitamin D hydroxyderivatives and RORγ/α agonists on OC cells. The VDR and RORγ showed both a nuclear and a cytoplasmic location, and their expression levels were found to be reduced in the primary and metastatic OCs in comparison to normal ovarian epithelium, as well as correlated to the tumor grade. This reduction in VDR and RORγ expression correlated with a shorter overall disease-free survival. VDR, RORγ, and RORα were also detected in SKOV-3 and OVCAR-3 cell lines with increased expression in the latter line. 20-Hydroxy-lumisterol3 (20(OH)L3) and synthetic RORα/RORγ agonist SR1078 inhibited proliferation only in the OVCAR-3 line, while 20-hydroxyvitamin-D3 (20(OH)D3) only inhibited SKOV-3 cell proliferation. 1,25(OH)2D3, 20(OH)L3, and SR1078, but not 20(OH)D3, inhibited spheroid formation in SKOV-3 cells. In summary, decreases in VDR, RORγ, and RORα expression correlated with an unfavorable outcome for OC, and compounds targeting these receptors had a context-dependent anti-tumor activity in vitro. We conclude that VDR and RORγ expression can be used in the diagnosis and prognosis of OC and suggest their ligands as potential candidates for OC therapy.
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Raspè, Eric, Gisèle Mautino, Caroline Duval, Coralie Fontaine, Hélène Duez, Olivier Barbier, Didier Monte, Jamila Fruchart, Jean-Charles Fruchart, and Bart Staels. "Transcriptional Regulation of HumanRev-erbαGene Expression by the Orphan Nuclear Receptor Retinoic Acid-related Orphan Receptor α." Journal of Biological Chemistry 277, no. 51 (October 10, 2002): 49275–81. http://dx.doi.org/10.1074/jbc.m206215200.

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The Rev-erb and retinoic acid-related orphan receptors (ROR) are two related families of orphan nuclear receptors that recognize similar response elements but have opposite effects on transcription. Recently, theRev-erbαgene promoter has been characterized and shown to harbor a functional Rev-erbα-binding site known as Rev-DR2, responsible for negative feedback down-regulation of promoter activity by Rev-erbα itself. The present study aimed to investigate whetherRev-erbαgene expression is regulated by RORα. Gel shift analysis demonstrated thatin vitrotranslated hRORα1 protein binds to the Rev-DR2 site, both as monomer and dimer. Chromatin immunoprecipitation assays demonstrated that binding of RORα to this site also occurredin vivoin human hepatoma HepG2 cells. The Rev-DR2 site was further shown to be functional as it conferred hRORα1 responsiveness to a heterologous promoter and to the natural humanRev-erbαgene promoter in these cells. Mutation of this site in the context of the naturalRev-erbαgene promoter abolished its activation by RORα, indicating that this site plays a key role in hRORα1 action. Finally, adenoviral overexpression of hRORα1 in HepG2 cells led to enhanced hRev-erbα mRNA accumulation, further confirming the physiological importance of RORα1 in the regulation of Rev-erbα expression.
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13

Willson, Timothy M. "RORα." Structure 10, no. 12 (December 2002): 1605–6. http://dx.doi.org/10.1016/s0969-2126(02)00916-4.

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14

CHAUVET, Caroline, Brigitte BOIS-JOYEUX, Edurne BERRA, Jacques POUYSSEGUR, and Jean-Louis DANAN. "The gene encoding human retinoic acid-receptor-related orphan receptor α is a target for hypoxia-inducible factor 1." Biochemical Journal 384, no. 1 (November 9, 2004): 79–85. http://dx.doi.org/10.1042/bj20040709.

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Retinoic acid-receptor-related orphan receptor (ROR) α is a nuclear receptor involved in many pathophysiological processes such as cerebellar ataxia, inflammation, atherosclerosis and angiogenesis. In the present study we first demonstrate that hypoxia increases the amount of Rora transcripts in a wide panel of cell lines derived from diverse tissues. In addition, we identified a functional promoter sequence upstream of the first exon of the human Rora gene, spanning −487 and −45 from the translation initiation site of RORα1. When cloned in a luciferase reporter vector, this sequence allowed the efficient transcription of the luciferase gene in several cell lines. Interestingly, the activity of the Rora promoter was enhanced by hypoxia in HepG2 human hepatoma cells, and this effect was dependent on an HRE (hypoxia response element) spanning from −229 to −225. Using electrophoretic-mobility-shift assays, we showed that HIF-1 (hypoxia-inducible factor 1), which plays a key role in the transcriptional response to hypoxia, bound to this HRE. Overexpression of HIF-1α increased the activity of the Rora promoter through the HRE. Overexpression of a dominant-negative form of HIF-1α producing transcriptionally inactive HIF-1α/HIF-1β dimers abolished hypoxic activation of the Rora promoter. This indicated that HIF-1 is involved in the response of RORα to hypoxia. Taken together, our data reveal Rora as a new HIF-1 target gene. This illustrates, at the molecular level, the existence of cross-talk between signalling pathways mediated by HIF-1 and those mediated by nuclear receptors.
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Matysiak-Scholze, Uta, and Michael Nehls. "The Structural Integrity of RORα Isoforms Is Mutated instaggererMice: Cerebellar Coexpression of RORα1 and RORα4." Genomics 43, no. 1 (July 1997): 78–84. http://dx.doi.org/10.1006/geno.1997.4757.

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16

Istrate, Monica A., Timothy P. Spicer, Yan Wang, Jerrold A. Bernard, Leah M. Helvering, Wayne P. Bocchinfuso, Timothy I. Richardson, et al. "Development of an HTS-Compatible Assay for Discovery of RORα Modulators Using AlphaScreen® Technology." Journal of Biomolecular Screening 16, no. 2 (February 2011): 183–91. http://dx.doi.org/10.1177/1087057110389040.

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The retinoid acid receptor–related orphan receptors (RORs) represent important targets for the treatment of metabolic and immune disorders. Here the authors describe the application of AlphaScreen® technology to develop a high-throughput screening (HTS)–compatible assay to facilitate the discovery of RORα modulators. Using the ligand binding domain (LBD) of RORα and a peptide derived from the NR1 box of the nuclear receptor coactivator PGC-1α, a 384-well format assay was developed exhibiting high sensitivity, requiring only low nanomolar concentration of reagents. Recently, it was shown that oxysterols such as 7α-hydroxycholesterol (7α-OHC) function as modulators of the RORs. In this assay, 7α-OHC produced a concentration-response curve with an EC50 of 162 nM, a Z′ factor of 0.6, and a signal-to-background (S/B) ratio of 4.2, demonstrating that the assay is HTS compatible. Validation of the assay was afforded by screening against the Sigma LOPAC1280™ library in a 384-well format. In summary, the results presented here demonstrate that this assay can be used to screen large chemical libraries to discover novel modulators of RORα.
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Kang, Hong Soon, Kyoko Okamoto, Yukimasa Takeda, Ju Youn Beak, Kevin Gerrish, Carl D. Bortner, Laura M. DeGraff, Taira Wada, Wen Xie, and Anton M. Jetten. "Transcriptional profiling reveals a role for RORα in regulating gene expression in obesity-associated inflammation and hepatic steatosis." Physiological Genomics 43, no. 13 (July 2011): 818–28. http://dx.doi.org/10.1152/physiolgenomics.00206.2010.

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Retinoid-related orphan receptor (ROR)α4 is the major RORα isoform expressed in adipose tissues and liver. In this study we demonstrate that RORα-deficient staggerer mice (RORαsg/sg) fed with a high-fat diet (HFD) exhibited reduced adiposity and hepatic triglyceride levels compared with wild-type (WT) littermates and were resistant to the development of hepatic steatosis, adipose-associated inflammation, and insulin resistance. Gene expression profiling showed that many genes involved in triglyceride synthesis and storage, including Cidec, Cidea, and Mogat1, were expressed at much lower levels in liver of RORαsg/sg mice. In contrast, overexpression of RORα in mouse hepatoma Hepa1–6 cells significantly increased the expression of genes that were repressed in RORαsg/sg liver, including Sult1b1, Adfp, Cidea, and ApoA4. ChIP and promoter analysis suggested that several of these genes were regulated directly by RORα. In addition to reduced lipid accumulation, inflammation was greatly diminished in white adipose tissue (WAT) of RORαsg/sg mice fed with an HFD. The infiltration of macrophages and the expression of many immune response and proinflammatory genes, including those encoding various chemo/cytokines, Toll-like receptors, and TNF signaling proteins, were significantly reduced in RORαsg/sg WAT. Moreover, RORαsg/sg mice fed with an HFD were protected from the development of insulin resistance. RORαsg/sg mice consumed more oxygen and produced more carbon dioxide, suggesting increased energy expenditure in this genotype. Our study indicates that RORα plays a critical role in the regulation of several aspects of metabolic syndrome. Therefore, RORα may provide a novel therapeutic target in the management of obesity and associated metabolic diseases.
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18

Beak, Ju Youn, Hong Soon Kang, Wei Huang, Page H. Myers, Dawn E. Bowles, Anton M. Jetten, and Brian C. Jensen. "The nuclear receptor RORα protects against angiotensin II-induced cardiac hypertrophy and heart failure." American Journal of Physiology-Heart and Circulatory Physiology 316, no. 1 (January 1, 2019): H186—H200. http://dx.doi.org/10.1152/ajpheart.00531.2018.

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The nuclear receptor retinoic acid-related orphan receptor-α (RORα) regulates numerous critical biological processes, including central nervous system development, lymphocyte differentiation, and lipid metabolism. RORα has been recently identified in the heart, but very little is known about its role in cardiac physiology. We sought to determine whether RORα regulates myocardial hypertrophy and cardiomyocyte survival in the context of angiotensin II (ANG II) stimulation. For in vivo characterization of the function of RORα in the context of pathological cardiac hypertrophy and heart failure, we used the “staggerer” (RORαsg/sg) mouse, which harbors a germline mutation encoding a truncated and globally nonfunctional RORα. RORαsg/sg and wild-type littermate mice were infused with ANG II or vehicle for 14 days. For in vitro experiments, we overexpressed or silenced RORα in neonatal rat ventricular myocytes (NRVMs) and human cardiac fibroblasts exposed to ANG II. RORαsg/sg mice developed exaggerated myocardial hypertrophy and contractile dysfunction after ANG II treatment. In vitro gain- and loss-of-function experiments were consistent with the discovery that RORα inhibits ANG II-induced pathological hypertrophy and cardiomyocyte death in vivo. RORα directly repressed IL-6 transcription. Loss of RORα function led to enhanced IL-6 expression, proinflammatory STAT3 activation (phopho-STAT3 Tyr705), and decreased mitochondrial number and function, oxidative stress, hypertrophy, and death of cardiomyocytes upon ANG II exposure. RORα was less abundant in failing compared with nonfailing human heart tissue. In conclusion, RORα protects against ANG II-mediated pathological hypertrophy and heart failure by suppressing the IL-6-STAT3 pathway and enhancing mitochondrial function. NEW & NOTEWORTHY Mice lacking retinoic acid-related orphan receptor-α (RORα) develop exaggerated cardiac hypertrophy after angiotensin II infusion. Loss of RORα leads to enhanced IL-6 expression and NF-κB nuclear translocation. RORα maintains mitochondrial function and reduces oxidative stress after angiotensin II. The abundance of RORα is reduced in failing mouse and human hearts.
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19

Brożyna, Anna A., Wojciech Jóźwicki, Cezary Skobowiat, Anton Jetten, and Andrzej T. Slominski. "RORα and RORγ expression inversely correlates with human melanoma progression." Oncotarget 7, no. 39 (August 11, 2016): 63261–82. http://dx.doi.org/10.18632/oncotarget.11211.

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20

Sun, Ye, Chi-Hsiu Liu, John Paul SanGiovanni, Lucy P. Evans, Katherine T. Tian, Bing Zhang, Andreas Stahl, et al. "Nuclear receptor RORα regulates pathologic retinal angiogenesis by modulating SOCS3-dependent inflammation." Proceedings of the National Academy of Sciences 112, no. 33 (August 4, 2015): 10401–6. http://dx.doi.org/10.1073/pnas.1504387112.

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Pathologic ocular angiogenesis is a leading cause of blindness, influenced by both dysregulated lipid metabolism and inflammation. Retinoic-acid-receptor–related orphan receptor alpha (RORα) is a lipid-sensing nuclear receptor with diverse biologic function including regulation of lipid metabolism and inflammation; however, its role in pathologic retinal angiogenesis remains poorly understood. Using a mouse model of oxygen-induced proliferative retinopathy, we showed that RORα expression was significantly increased and genetic deficiency of RORα substantially suppressed pathologic retinal neovascularization. Loss of RORα led to decreased levels of proinflammatory cytokines and increased levels of antiinflammatory cytokines in retinopathy. RORα directly suppressed the gene transcription of suppressors of cytokine signaling 3 (SOCS3), a critical negative regulator of inflammation. Inhibition of SOCS3 abolished the antiinflammatory and vasoprotective effects of RORα deficiency in vitro and in vivo. Moreover, treatment with a RORα inverse agonist SR1001 effectively protected against pathologic neovascularization in both oxygen-induced retinopathy and another angiogenic model of very-low–density lipoprotein receptor (Vldlr)-deficient (Vldlr−/−) mice with spontaneous subretinal neovascularization, whereas a RORα agonist worsened oxygen-induced retinopathy. Our data demonstrate that RORα is a novel regulator of pathologic retinal neovascularization, and RORα inhibition may represent a new way to treat ocular neovascularization.
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Okada, Kosuke, Takeki Fujimura, Takeshi Kikuchi, Makoto Aino, Yosuke Kamiya, Ario Izawa, Yuki Iwamura, et al. "Effect of interleukin (IL)-35 on IL-17 expression and production by human CD4+ T cells." PeerJ 5 (February 15, 2017): e2999. http://dx.doi.org/10.7717/peerj.2999.

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Background Interleukin (IL)-17 produced by mainly T helper 17 (Th17) cells may play an important destructive role in chronic periodontitis (CP). Thus, anti-inflammatory cytokines, such as IL-35, might have a beneficial effect in periodontitis by inhibiting differentiation of Th17 cells. Th17 differentiation is regulated by the retinoic acid receptor-related orphan receptor (ROR) α (encoded by RORA) and RORγt (encoded by RORC). However, the role of IL-35 in periodontitis is not clear and the effect of IL-35 on the function of Th17 cells is still incompletely understood. Therefore, we investigated the effects of IL-35 on Th17 cells. Methods Peripheral blood mononuclear cells (PBMCs) were sampled from three healthy volunteers and three CP patients and were analyzed by flow cytometry for T cell population. Th17 cells differentiated by a cytokine cocktail (recombinant transforming growth factor-β, rIL-6, rIL-1β, anti-interferon (IFN)-γ, anti-IL-2 and anti-IL-4) from PBMCs were cultured with or without rIL-35. IL17A (which usually refers to IL-17), RORA and RORCmRNA expression was analyzed by quantitative polymerase chain reaction, and IL-17A production was determined by enzyme-linked immunosorbent assay. Results The proportion of IL-17A+CD4+ slightly increased in CP patients compared with healthy controls, however, there were no significant differences in the percentage of IL-17A+CD4+ as well as IFN-γ+CD4+ and Foxp3+CD4+ T cells between healthy controls and CP patients. IL17A, RORA and RORC mRNA expression was significantly increased in Th17 cells induced by the cytokine cocktail, and the induction was significantly inhibited by addition of rIL-35 (1 ng/mL). IL-17A production in Th17 cells was significantly inhibited by rIL-35 addition (1 ng/mL). Discussion The present study suggests that IL-35 could directly suppress IL-17 expression via RORα and RORγt inhibition and might play an important role in inflammatory diseases such as periodontitis.
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Kang, Jun, Haoling Chen, Fuping Zhang, Tong Yan, Wenguo Fan, Liulin Jiang, Hongwen He, and Fang Huang. "RORα Regulates Odontoblastic Differentiation and Mediates the Pro-Odontogenic Effect of Melatonin on Dental Papilla Cells." Molecules 26, no. 4 (February 19, 2021): 1098. http://dx.doi.org/10.3390/molecules26041098.

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Dental papilla cells (DPCs), precursors of odontoblasts, are considered promising seed cells for tissue engineering. Emerging evidence suggests that melatonin promotes odontoblastic differentiation of DPCs and affects tooth development, although the precise mechanisms remain unknown. Retinoid acid receptor-related orphan receptor α (RORα) is a nuclear receptor for melatonin that plays a critical role in cell differentiation and embryonic development. This study aimed to explore the role of RORα in odontoblastic differentiation and determine whether melatonin exerts its pro-odontogenic effect via RORα. Herein, we observed that RORα was expressed in DPCs and was significantly increased during odontoblastic differentiation in vitro and in vivo. The overexpression of RORα upregulated the expression of odontogenic markers, alkaline phosphatase (ALP) activity and mineralized nodules formation (p < 0.05). In contrast, odontoblastic differentiation of DPCs was suppressed by RORα knockdown. Moreover, we found that melatonin elevated the expression of odontogenic markers, which was accompanied by the upregulation of RORα (p < 0.001). Utilising small interfering RNA, we further demonstrated that RORα inhibition attenuated melatonin-induced odontogenic gene expression, ALP activity and matrix mineralisation (p < 0.01). Collectively, these results provide the first evidence that RORα can promote odontoblastic differentiation of DPCs and mediate the pro-odontogenic effect of melatonin.
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Kadiri, Sarah, Chloé Monnier, Munkhzul Ganbold, Tatiana Ledent, Jacqueline Capeau, and Bénédicte Antoine. "The nuclear retinoid-related orphan receptor-α regulates adipose tissue glyceroneogenesis in addition to hepatic gluconeogenesis." American Journal of Physiology-Endocrinology and Metabolism 309, no. 2 (July 15, 2015): E105—E114. http://dx.doi.org/10.1152/ajpendo.00518.2014.

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Circadian rhythms have an essential role in feeding behavior and metabolism. RORα is a nuclear receptor involved in the interface of the circadian system and metabolism. The adipocyte glyceroneogenesis pathway derives free fatty acids (FFA) liberated by lipolysis to reesterification into triglycerides, thus regulating FFA homeostasis and fat mass. Glyceroneogenesis shares with hepatic gluconeogenesis the key enzyme phospho enolpyruvate carboxykinase c (PEPCKc), whose gene is a RORα target in the liver. RORα-deficient mice (staggerer, RORsg/sg ) have been shown to exhibit a lean phenotype and fasting hypoglycemia for unsolved reasons. In the present study, we investigated whether adipocyte glyceroneogenesis might also be a target pathway of RORα, and we further evaluated the role of RORα in hepatocyte gluconeogenesis. In vivo investigations comparing RORsg/sg mice with their wild-type (WT) littermates under fasting conditions demonstrated that, in the absence of RORα, the release of FFA into the bloodstream was altered and the rise in glycemia in response to pyruvate reduced. The functional analysis of each pathway, performed in adipose tissue or liver explants, confirmed the impairment of adipocyte glyceroneogenesis and liver gluconeogenesis in the RORsg/sg mice; these reductions of FFA reesterification or glucose production were associated with decreases in PEPCKc mRNA and protein levels. Treatment of explants with RORα agonist or antagonist enhanced or inhibited these pathways, respectively, in tissues isolated from WT but not RORsg/sg mice. Our results indicated that both adipocyte glyceroneogenesis and hepatocyte gluconeogenesis were regulated by RORα. This study demonstrates the physiological function of RORα in regulating both glucose and FFA homeostasis.
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Matsuoka, Hiroshi, Miyu Katayama, Ami Ohishi, Kaoruko Miya, Riki Tokunaga, Sou Kobayashi, Yuya Nishimoto, Kazutake Hirooka, Akiho Shima, and Akihiro Michihara. "Orphan Nuclear Receptor RORα Regulates Enzymatic Metabolism of Cerebral 24S-Hydroxycholesterol through CYP39A1 Intronic Response Element Activation." International Journal of Molecular Sciences 21, no. 9 (May 7, 2020): 3309. http://dx.doi.org/10.3390/ijms21093309.

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Oxysterols, important regulators of cholesterol homeostasis in the brain, are affected by neurodegenerative diseases. Early-onset Alzheimer’s disease is associated with higher levels of circulating brain-derived 24S-hydroxycholesterol (24S-OHC). Conversion of cholesterol to 24S-OHC is mediated by cholesterol 24S-hydroxylase in the brain, which is the major pathway for oxysterol elimination, followed by oxidation through hepatic first-pass metabolism by CYP39A1. Abnormal CYP39A1 expression results in accumulation of 24S-OHC, influencing neurodegenerative disease-related deterioration; thus, it is important to understand the normal elimination of 24S-OHC and the system regulating CYP39A1, a selective hepatic metabolic enzyme of 24S-OHC. We examined the role of transcriptional regulation by retinoic acid receptor-related orphan receptor α (RORα), a nuclear receptor that responds to oxysterol ligands. In humans, the promoter and first intronic regions of CYP39A1 contain two putative RORα response elements (ROREs). RORα binding and responses of these ROREs were assessed using electrophoretic mobility shift, chromatin immunoprecipitation, and luciferase reporter assays. CYP39A1 was upregulated by RORα overexpression in HEK293 cells, while RORα knockdown by siRNA significantly downregulated CYP39A1 expression in human hepatoma cells. Additionally, CYP39A1 was induced by RORα agonist treatment, suggesting that CYP39A1 expression is activated by RORα nuclear receptors. This may provide a way to increase CYP39A1 activity using RORα agonists, and help halt 24S-OHC accumulation in neurodegenerative illnesses.
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Stapleton, Cliona M., Maisa Jaradat, Darlene Dixon, Hong Soon Kang, Seong-Chul Kim, Grace Liao, Michelle A. Carey, Joey Cristiano, Michael P. Moorman, and Anton M. Jetten. "Enhanced susceptibility of staggerer (RORαsg/sg) mice to lipopolysaccharide-induced lung inflammation." American Journal of Physiology-Lung Cellular and Molecular Physiology 289, no. 1 (July 2005): L144—L152. http://dx.doi.org/10.1152/ajplung.00348.2004.

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The retinoid-related orphan receptor α (RORα), a member of the ROR subfamily of nuclear receptors, has been implicated in the control of a number of physiological processes, including the regulation of several immune functions. To study the potential role of RORα in the regulation of innate immune responses in vivo, we analyzed the induction of airway inflammation in response to lipopolysaccharide (LPS) challenge in wild-type and staggerer (RORαsg/sg) mice, a natural mutant strain lacking RORα expression. Examination of hematoxylin and eosin-stained lung sections showed that RORαsg/sg mice displayed a higher degree of LPS-induced inflammation than wild-type mice. Bronchoalveolar lavage (BAL) was performed at 3, 16, and 24 h after LPS exposure to monitor the increase in inflammatory cells and the level of several cytokines/chemokines. The increased susceptibility of RORαsg/sg mice to LPS-induced airway inflammation correlated with a higher number of total cells and neutrophils in BAL fluids from LPS-treated RORαsg/sg mice compared with those from LPS-treated wild-type mice. In addition, IL-1β, IL-6, and macrophage inflammatory protein-2 were appreciably more elevated in BAL fluids from LPS-treated RORαsg/sg mice compared with those from LPS-treated wild-type mice. The enhanced susceptibility of RORαsg/sg mice appeared not to be due to a repression of IκBα expression. Our observations indicate that RORαsg/sg mice are more susceptible to LPS-induced airway inflammation and are in agreement with the hypothesis that RORα functions as a negative regulator of LPS-induced inflammatory responses.
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Lee, In Kyu, Hyerin Song, Hyerim Kim, Ik Soo Kim, Na Ly Tran, Sang-Heon Kim, Seung Ja Oh, and Ji Min Lee. "RORα Regulates Cholesterol Metabolism of CD8+ T Cells for Anticancer Immunity." Cancers 12, no. 7 (June 29, 2020): 1733. http://dx.doi.org/10.3390/cancers12071733.

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Retinoic acid-related orphan receptor α (RORα) functions as a transcription factor for various biological processes, including circadian rhythm, inflammation, cancer, and lipid metabolism. Here, we demonstrate that RORα is crucial for maintaining cholesterol homeostasis in CD8+ T cells by attenuating NF-κB transcriptional activity. Cholesterol sulfate, the established natural agonist of RORα, exhibits cellular cytotoxicity on, and increased effector responses in, CD8+ T cells. Transcript analysis reveals that the suppression of RORα leads to the upregulation of NF-κB target genes in T cells. Chromatin immunoprecipitation analysis was used to determine the corecruitment of RORα and histone deacetylase (HDAC) on NF-κB target promoters and the subsequent dismissal of coactivators for transcriptional repression. We demonstrate that RORα/HDAC-mediated attenuation of NF-κB signaling controls the balance of cholesterol metabolism in CD8+ T cells, and that therapeutic strategies targeting this epigenetic regulation could be beneficial to the treatment of solid tumors including colon cancers.
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Oh, Se Kyu, Dongha Kim, Kyeongkyu Kim, Kyungjin Boo, Young Suk Yu, Ik Soo Kim, Yoon Jeon, et al. "RORα is crucial for attenuated inflammatory response to maintain intestinal homeostasis." Proceedings of the National Academy of Sciences 116, no. 42 (September 30, 2019): 21140–49. http://dx.doi.org/10.1073/pnas.1907595116.

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Retinoic acid-related orphan receptor α (RORα) functions as a transcription factor for various biological processes, including circadian rhythm, cancer, and metabolism. Here, we generate intestinal epithelial cell (IEC)-specific RORα-deficient (RORαΔIEC) mice and find that RORα is crucial for maintaining intestinal homeostasis by attenuating nuclear factor κB (NF-κB) transcriptional activity. RORαΔIEC mice exhibit excessive intestinal inflammation and highly activated inflammatory responses in the dextran sulfate sodium (DSS) mouse colitis model. Transcriptome analysis reveals that deletion of RORα leads to up-regulation of NF-κB target genes in IECs. Chromatin immunoprecipitation analysis reveals corecruitment of RORα and histone deacetylase 3 (HDAC3) on NF-κB target promoters and subsequent dismissal of CREB binding protein (CBP) and bromodomain-containing protein 4 (BRD4) for transcriptional repression. Together, we demonstrate that RORα/HDAC3-mediated attenuation of NF-κB signaling controls the balance of inflammatory responses, and therapeutic strategies targeting this epigenetic regulation could be beneficial to the treatment of chronic inflammatory diseases, including inflammatory bowel disease (IBD).
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Dempsey, Laurie A. "RORα in Treg cells." Nature Immunology 19, no. 6 (April 18, 2018): 510. http://dx.doi.org/10.1038/s41590-018-0099-x.

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Lechtken, Adriane. "RORα - ein potentiellesTargetgegen Übergewicht?" Pharmazie in unserer Zeit 37, no. 5 (September 2008): 353–54. http://dx.doi.org/10.1002/pauz.200890068.

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Hu, Hao, and Masahiko Negishi. "RORα phosphorylation by casein kinase 1α as glucose signal to regulate estrogen sulfation in human liver cells." Biochemical Journal 477, no. 18 (September 28, 2020): 3583–98. http://dx.doi.org/10.1042/bcj20200427.

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Estrogen sulfotransferase (SULT1E1) metabolically inactivates estrogen and SULT1E1 expression is tightly regulated by multiple nuclear receptors. Human fetal, but not adult, livers express appreciable amounts of SULT1E1 protein, which is mimicked in human hepatoma-derived HepG2 cells cultured in high glucose (450 mg/dl) medium. Here, we have investigated this glucose signal that leads to phosphorylation of nuclear receptor RORα (NR1F1) at Ser100 and the transcription mechanism by which phosphorylated RORα transduces this signal to nuclear receptor HNF4α, activating the SULT1E1 promoter. The promoter is repressed by non-phosphorylated RORα which binds a distal enhancer (−943/−922 bp) and interacts with and represses HNF4α-mediated transcription. In response to high glucose, RORα becomes phosphorylated at Ser100 and reverses its repression of HNF4α promoter activation. Moreover, the casein kinase CK1α, which is identified in an enhancer-bound nuclear protein complex, phosphorylates Ser100 in in vitro kinase assays. During these dynamic processes, both RORα and HNF4α remain on the enhancer. Thus, RORα utilizes phosphorylation to integrate HNF4α and transduces the glucose signal to regulate the SULT1E1 gene in HepG2 cells and this phosphorylation-mediated mechanism may also regulate SULT1E1 expressions in the human liver.
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Hardeland, Ruediger. "Melatonin and retinoid orphan receptors: Demand for new interpretations after their exclusion as nuclear melatonin receptors." Melatonin Research 1, no. 1 (December 3, 2018): 78–93. http://dx.doi.org/10.32794/mr11250005.

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The demonstrated incapability of the retinoic acid receptor-related orphan receptor-α (RORα) to bind melatonin inevitably requires consequences for interpreting numerous reports on actions of this protein as far as it was believed to be a nuclear melatonin receptor. While the synthetic compound CGP 52608 is, in fact, a ligand of RORα, effects obtained with this molecule can no longer be attributed to melatonin. Moreover, the sometimes assumed interplay between melatonin membrane receptors and RORα as nuclear receptors has to be dropped. Conclusions on melatonin’s actions via RORα that were based on a lack of demonstrable involvement of membrane receptors appear to have been precocious. Nevertheless, findings on melatonin uptake into the nucleus may still be taken as a hint for nuclear melatonin receptors, but this would require thorough characterization. Although RORα does not bind melatonin, it is interrelated to the latter in regulatory terms by involvement of cellular circadian oscillators. A mode of action seems to be the upregulation of sirtuin-1 by melatonin, deacetylation of poly ADP ribose polymerase-γ coactivator-1α (PGC-1α) by sirtuin-1, and facilitation of RORα binding to its response element by deacetylated PGC-1α, a route that had been shown to exist in circadian oscillators, thereby enhancing their amplitude.
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Mühlbauer, Eckhard, Ivonne Bazwinsky-Wutschke, Sabine Wolgast, Karin Labucay, and Elmar Peschke. "Differential and day-time dependent expression of nuclear receptors RORα, RORβ, RORγ and RXRα in the rodent pancreas and islet." Molecular and Cellular Endocrinology 365, no. 2 (January 2013): 129–38. http://dx.doi.org/10.1016/j.mce.2012.10.001.

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Xiao, Lei, Jing Wang, Jiao Li, Xiongwei Chen, Pengfei Xu, Suozhu Sun, Dacheng He, Yusheng Cong, and Yonggong Zhai. "RORα inhibits adipocyte-conditioned medium-induced colorectal cancer cell proliferation and migration and chick embryo chorioallantoic membrane angiopoiesis." American Journal of Physiology-Cell Physiology 308, no. 5 (March 1, 2015): C385—C396. http://dx.doi.org/10.1152/ajpcell.00091.2014.

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Lipid metabolic disturbances are related to many diseases, such as obesity, diabetes, and certain cancers. Notably, lipid metabolic disturbances have been reported to be a risk factor for colorectal cancer. Nuclear receptors act as ligand-dependent transcription regulators and play key roles in the regulation of body lipid metabolism and the development of many cancers. Retinoic acid receptor-related orphan receptor α (RORα) is a nuclear receptor and can regulate several lipid metabolism genes in certain cancers. Herein, we demonstrate that the conditioned medium from adipocytes has a proproliferative and promigratory effect on colorectal cancer cells and enhances angiogenesis in chicken embryonic chorioallantoic membranes. In addition, the conditioned medium leads to a decrease in the expression of RORα and its target genes. Meanwhile, RORα and its target gene expressions are lower in human colorectal tumor tissue compared with control colorectal tissue. Activation of RORα inhibits the effect of conditioned medium on the proliferation and migration of colorectal cancer cells as well as the angiogenesis in chicken embryonic allantoic membranes. In colorectal cancer cells, the putative ligand of RORα, cholesterol sulfate (CS), prevents cell cycle progression at the G1/S boundary and concurrently modulates the expression of cell cycle-regulatory genes in colorectal cancer cell. CS inhibits angiogenesis in chicken embryonic chorioallantoic membranes and concurrently decreases the mRNA expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α as well as the secretion of VEGF. In addition, lipogenic gene expression is higher in human colorectal tumor tissue compared with control colorectal tissue. CS inhibits the expression of lipogenic genes in colorectal cancer cells. These results suggest that RORα could represent a direct link between local lipid metabolism of colorectal tissue and colorectal cancer. Therefore, the reduction of the expression of RORα could represent a potential warning sign of colorectal cancer.
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Onishi, Yoshiaki. "HSG cells, a model in the submandibular clock." Bioscience Reports 31, no. 1 (October 4, 2010): 57–62. http://dx.doi.org/10.1042/bsr20100007.

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Circadian rhythm of vital processes is essential to health, and various tissues show unique peripheral rhythms. HSG is the human submandibular gland cell line that has been used for analysing the effects of steroids and growth factors. In the present study, we analysed the transcriptional regulation of the BMAL1 gene, a critical component of the mammalian clock system to investigate the possibility of using HSG cells as a model system of the submandibular clock. The BMAL1 gene was expressed with circadian oscillation after stimulation with dexamethasone, and its regulatory region contained two recognition motifs for ROR (retinoic acid-receptor-related orphan receptor) and ROREs [RORα (ROR α-subunit)-binding elements] in hypomethylated CpG islands with an open chromatin structure. REV-ERBα was expressed with circadian oscillation, and knockdown experiments suggested that REV-ERBα is involved in circadian transcription of the BMAL1 gene in HSG cells. These results are similar to those in NIH 3T3 cells, a standard model for the circadian system, whereas RORα required for REV-ERBα antagonism was expressed very little in HSG cells. These findings show that in the salivary gland cell line HSG there is a rhythm in the core oscillator components BMAL1 and REV-ERBα, indicating that circadian-based transcriptional regulation can be modelled in this peripheral cell type.
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Moraitis, Anna N., Vincent Giguère, and Catherine C. Thompson. "Novel Mechanism of Nuclear Receptor Corepressor Interaction Dictated by Activation Function 2 Helix Determinants." Molecular and Cellular Biology 22, no. 19 (October 1, 2002): 6831–41. http://dx.doi.org/10.1128/mcb.22.19.6831-6841.2002.

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ABSTRACT Transcriptional regulation by nuclear receptors is controlled by the concerted action of coactivator and corepressor proteins. The product of the thyroid hormone-regulated mammalian gene hairless (Hr) was recently shown to function as a thyroid hormone receptor corepressor. Here we report that Hr acts as a potent repressor of transcriptional activation by RORα, an orphan nuclear receptor essential for cerebellar development. In contrast to other corepressor-nuclear receptor interactions, Hr binding to RORα is mediated by two LXXLL-containing motifs, a mechanism associated with coactivator interaction. Mutagenesis of conserved amino acids in the ligand binding domain indicates that RORα activity is ligand-dependent, suggesting that corepressor activity is maintained in the presence of ligand. Despite similar recognition helices shared with coactivators, Hr does not compete for the same molecular determinants at the surface of the RORα ligand binding domain, indicating that Hr-mediated repression is not simply through displacement of coactivators. Remarkably, the specificity of Hr corepressor action can be transferred to a retinoic acid receptor by exchanging the activation function 2 (AF-2) helix. Repression of the chimeric receptor is observed in the presence of retinoic acid, demonstrating that in this context, Hr is indeed a ligand-oblivious nuclear receptor corepressor. These results suggest a novel molecular mechanism for corepressor action and demonstrate that the AF-2 helix can play a dynamic role in controlling corepressor as well as coactivator interactions. The interaction of Hr with RORα provides direct evidence for the convergence of thyroid hormone and RORα-mediated pathways in cerebellar development.
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Helleboid, Stéphane, Christian Haug, Kai Lamottke, Yijun Zhou, Jianbing Wei, Sébastien Daix, Linda Cambula, Géraldine Rigou, Dean W. Hum, and Robert Walczak. "The Identification of Naturally Occurring Neoruscogenin as a Bioavailable, Potent, and High-Affinity Agonist of the Nuclear Receptor RORα (NR1F1)." Journal of Biomolecular Screening 19, no. 3 (July 29, 2013): 399–406. http://dx.doi.org/10.1177/1087057113497095.

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Plants represent a tremendous structural diversity of natural compounds that bind to many different human disease targets and are potentially useful as starting points for medicinal chemistry programs. This resource is, however, still underexploited due to technical difficulties with the identification of minute quantities of active ingredients in complex mixtures of structurally diverse compounds upon raw phytomass extraction. In this work, we describe the successful identification of a novel class of potent RAR-related orphan receptor alpha (RORα or nuclear receptor NR1F1) agonists from a library of 12,000 plant extract fractions by using an optimized, robust high-throughput cell-free screening method, as well as an innovative hit compound identification procedure through further extract deconvolution and subsequent structural elucidation of the active natural compound(s). In particular, we demonstrate that neoruscogenin, a member of the steroidal sapogenin family, is a potent and high-affinity RORα agonist, as shown by its activity in RORα reporter assays and from its effect on RORα target gene expression in vitro and in vivo. Neoruscogenin represents a universal pharmacological tool for RORα research due to its specific selectivity profile versus other nuclear receptors, its excellent microsomal stability, good bioavailability, and significant peripheral exposure in mouse.
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Abulmeaty, Mahmoud Mustafa Ali, Ali Madi Almajwal, Khalid S. Alnumair, Suhail Razak, Mai Mohammed Hasan, Amal Fawzy, Abdullah Ibrahim Farraj, Manal Abudawood, and Ghadeer S. Aljuraiban. "Effect of Long-Term Continuous Light Exposure and Western Diet on Adropin Expression, Lipid Metabolism, and Energy Homeostasis in Rats." Biology 10, no. 5 (May 7, 2021): 413. http://dx.doi.org/10.3390/biology10050413.

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Long-term continuous light exposure (CL) and western diet (WD) effects on Adropin expression, RORα, and Rev-erb-α nuclear receptors and energy homeostasis were studied in rats. Thirty-two male Wistar rats (250–290 g) were enrolled for 3 months in the following groups (n = 8/group): (a) Normal control group (NC), (b) CL group, (c) WD group, and (d) CL + WD group. Then, indirect calorimetry and food intake (FI) were measured. Finally, Adropin, hormone-sensitive lipase (HSL), adipocyte triglyceride lipase (ATGL), and free fatty acids (FFA) were measured. Additionally, the histopathology and gene expression of Enho, RORα, and Rev-erb-α genes were done. The CL alone elevated the Adropin plasma level and gene expression, increased RORα expression, and decreased the Rev-erb-α nuclear receptor expression mainly in the liver and kidney. Besides, CL increased the total energy expenditure (TEE) and decreased the respiratory quotient. WD alone or in combination with the CL reversed gene expression of Enho, RORα, and Rev-erb-α. Combined CL and WD increased the TEE, reduced the food intake, increased the ATGL, and reduced the Adropin level in addition to widespread degenerative changes in the liver, spleen, and renal tissues. The deleterious effects of CL and WD on energy homeostasis may include Adropin with the involvement of the RORα and Rev-erb-α nuclear receptors.
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Doulazmi, Mohamed, Florence Frédéric, Francesca Capone, Michael Becker-André, Nicole Delhaye-Bouchaud, and Jean Mariani. "A comparative study of Purkinje cells in two RORα gene mutant mice: staggerer and RORα−/−." Developmental Brain Research 127, no. 2 (April 2001): 165–74. http://dx.doi.org/10.1016/s0165-3806(01)00131-6.

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Wang, Yongjun, Naresh Kumar, Philippe Nuhant, Michael D. Cameron, Monica A. Istrate, William R. Roush, Patrick R. Griffin, and Thomas P. Burris. "Identification of SR1078, a Synthetic Agonist for the Orphan Nuclear Receptors RORα and RORγ." ACS Chemical Biology 5, no. 11 (August 30, 2010): 1029–34. http://dx.doi.org/10.1021/cb100223d.

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Yang, Xuexian O., Bhanu P. Pappu, Roza Nurieva, Askar Akimzhanov, Hong Soon Kang, Yeonseok Chung, Li Ma, et al. "T Helper 17 Lineage Differentiation Is Programmed by Orphan Nuclear Receptors RORα and RORγ." Immunity 28, no. 1 (January 2008): 29–39. http://dx.doi.org/10.1016/j.immuni.2007.11.016.

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Du, Linyong, Xiao Yang, Lu Yang, Xinyan Wang, Anying Zhang, and Hong Zhou. "Molecular evidence for the involvement of RORα and RORγ in immune response in teleost." Fish & Shellfish Immunology 33, no. 2 (August 2012): 418–26. http://dx.doi.org/10.1016/j.fsi.2012.05.033.

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Dang, Yanqi, Shuang Ling, Jing Ma, Rongzhen Ni, and Jin-Wen Xu. "Bavachalcone Enhances RORαExpression, Controls Bmal1 Circadian Transcription, and Depresses Cellular Senescence in Human Endothelial Cells." Evidence-Based Complementary and Alternative Medicine 2015 (2015): 1–11. http://dx.doi.org/10.1155/2015/920431.

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The circadian clock regulates many aspects of (patho)physiology in the central nervous system and in the peripheral tissues. RAR-related orphan receptorα(RORα), an orphan nuclear receptor, is involved in circadian rhythm regulation, including regulation of cardiovascular function. Bavachalcone, a prenylchalcone, is a major bioactive chalcone isolated fromPsoralea corylifolia. This natural ingredient activated RORα1 luciferase reporter activity on drug screening. In addition, bavachalcone induced RORα1 expression in mRNA and protein levels in a dose-dependent manner and enhanced the circadian amplitude of Bmal1 mRNA expression after serum shock. Moreover, bavachalcone suppressed senescence in human endothelial cells and mRNA expression ofp16ink4a(a marker of replicative senescence) and IL-1α(a proinflammatory cytokine of the senescence-associated secretory phenotype). These inhibitory effects were partially reversed by the RORαinhibitor VPR-66. Our results demonstrate that bavachalcone, as a natural medicine ingredient, has a pharmacological function in regulating RORα1.
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Duez, Hélène, Christian Duhem, Saara Laitinen, Prashant S. Patole, Mouaadh Abdelkarim, Brigitte Bois-Joyeux, Jean-Louis Danan, and Bart Staels. "Inhibition of adipocyte differentiation by RORα." FEBS Letters 583, no. 12 (May 18, 2009): 2031–36. http://dx.doi.org/10.1016/j.febslet.2009.05.019.

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Ruan, Qingguo, Vasumathi Kameswaran, Yan Zhang, Shijun Zheng, Jing Sun, Junmei Wang, Jennifer DeVirgiliis, Hsiou-Chi Liou, Amer A. Beg, and Youhai H. Chen. "The Th17 immune response is controlled by the Rel–RORγ–RORγT transcriptional axis." Journal of Experimental Medicine 208, no. 11 (October 17, 2011): 2321–33. http://dx.doi.org/10.1084/jem.20110462.

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The Th17 cells use the retinoid-related orphan receptor-γ (Rorg or Rorc) to specify their differentiation and lineage-specific function. However, how Rorg is switched on during Th17 differentiation is unknown. We report here that c-Rel and RelA/p65 transcription factors drive Th17 differentiation by binding to and activating two distinct Rorg promoters that control RORγT and RORγ expression, respectively. Similar to RORγT, RORγ is selectively expressed in Th17 cells and is effective in specifying the Th17 phenotype. T cells deficient in c-Rel or RelA are significantly compromised in Th17 differentiation, and c-Rel–deficient mice are defective in Th17 responses. Thus, Th17 immunity is controlled by a Rel–RORγ–RORγT axis, and strategies targeting Rel/NF-κB can be effective for controlling Th17 cell–mediated diseases.
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45

Karvonen, Hanna, Wilhelmiina Niininen, Astrid Murumägi, and Daniela Ungureanu. "Targeting ROR1 identifies new treatment strategies in hematological cancers." Biochemical Society Transactions 45, no. 2 (April 13, 2017): 457–64. http://dx.doi.org/10.1042/bst20160272.

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Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a member of the ROR receptor family consisting of two closely related type I transmembrane proteins ROR1 and ROR2. Owing to mutations in their canonical motifs required for proper kinase activity, RORs are classified as pseudokinases lacking detectable catalytic activity. ROR1 stands out for its selective and high expression in numerous blood and solid malignancies compared with a minimal expression in healthy adult tissues, suggesting high potential for this molecule as a drug target for cancer therapy. Current understanding attributes a survival role for ROR1 in cancer cells; however, its oncogenic function is cancer-type-specific and involves various signaling pathways. High interest in ROR1-targeted therapies resulted in the development of ROR1 monoclonal antibodies such as cirmtuzumab, currently in a phase I clinical trial for chronic lymphocytic leukemia. Despite these advances in translational studies, the molecular mechanism employed by ROR1 in different cancers is not yet fully understood; therefore, more insights into the oncogenic role of ROR1 signaling are crucial in order to optimize the use of targeted drugs. Recent studies provided evidence that targeting ROR1 simultaneously with inhibition of B-cell receptor (BCR) signaling is more effective in killing ROR1-positive leukemia cells, suggesting a synergistic correlation between co-targeting ROR1 and BCR pathways. Although this synergy has been previously reported for B-cell acute lymphoblastic leukemia, the molecular mechanism appears rather different. These results provide more insights into ROR1–BCR combinatorial treatment strategies in hematological malignancies, which could benefit in tailoring more effective targeted therapies in other ROR1-positive cancers.
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Im, Dong-Soon. "Maresin-1 resolution with RORα and LGR6." Progress in Lipid Research 78 (April 2020): 101034. http://dx.doi.org/10.1016/j.plipres.2020.101034.

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Atkins, G. Brandon, Xiao Hu, Matthew G. Guenther, Christophe Rachez, Leonard P. Freedman, and Mitchell A. Lazar. "Coactivators for the Orphan Nuclear Receptor RORα." Molecular Endocrinology 13, no. 9 (September 1, 1999): 1550–57. http://dx.doi.org/10.1210/mend.13.9.0343.

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Nejati Moharrami, Neda, Erlend Bjørkøy Tande, Liv Ryan, Terje Espevik, and Victor Boyartchuk. "RORα controls inflammatory state of human macrophages." PLOS ONE 13, no. 11 (November 28, 2018): e0207374. http://dx.doi.org/10.1371/journal.pone.0207374.

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Hwang, Eun Ju, Ji Min Lee, Jiyeong Jeong, Joo Hyeon Park, Young Yang, Jong-Seok Lim, Jung Hwa Kim, Sung Hee Baek, and Keun Il Kim. "SUMOylation of RORα potentiates transcriptional activation function." Biochemical and Biophysical Research Communications 378, no. 3 (January 2009): 513–17. http://dx.doi.org/10.1016/j.bbrc.2008.11.072.

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Lau, Patrick, Zewen K. Tuong, Shu-Ching Wang, Rebecca L. Fitzsimmons, Joel M. Goode, Gethin P. Thomas, Gary J. Cowin, et al. "Rorα deficiency and decreased adiposity are associated with induction of thermogenic gene expression in subcutaneous white adipose and brown adipose tissue." American Journal of Physiology-Endocrinology and Metabolism 308, no. 2 (January 15, 2015): E159—E171. http://dx.doi.org/10.1152/ajpendo.00056.2014.

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The Rar-related orphan receptor-α (Rorα) is a nuclear receptor that regulates adiposity and is a potential regulator of energy homeostasis. We have demonstrated that the Rorα-deficient staggerer ( sg/sg) mice display a lean and obesity-resistant phenotype. Adaptive Ucp1-dependent thermogenesis in beige/brite and brown adipose tissue serves as a mechanism to increase energy expenditure and resist obesity. DEXA and MRI analysis demonstrated significantly decreased total fat mass and fat/lean mass tissue ratio in male chow-fed sg/sg mice relative to wt mice. In addition, we observed increased Ucp1 expression in brown adipose and subcutaneous white adipose tissue but not in visceral adipose tissue from Rorα-deficient mice. Moreover, this was associated with significant increases in the expression of the mRNAs encoding the thermogenic genes (i.e., markers of brown and beige adipose) Pparα, Errα, Dio2, Acot11/Bfit, Cpt1β, and Cidea in the subcutaneous adipose in the sg/sg relative to WT mice. These changes in thermogenic gene expression involved the significantly increased expression of the (cell-fate controlling) histone-lysine N-methyltransferase 1 (Ehmt1), which stabilizes the Prdm16 transcriptional complex. Moreover, primary brown adipocytes from sg/sg mice displayed a higher metabolic rate, and further analysis was consistent with increased uncoupling. Finally, core body temperature analysis and infrared thermography demonstrated that the sg/sg mice maintained greater thermal control and cold tolerance relative to the WT littermates. We suggest that enhanced Ucp1 and thermogenic gene expression/activity may be an important contributor to the lean, obesity-resistant phenotype in Rorα-deficient mice.
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