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Pengguo Chen, Jie Li, Yan Huo, Jin Lu, Lili Wan, Quanjun Yang, Jinlu Huang, Run Gan, Cheng Guo
Liver fibrosis is a wound-healing response characterized with the accumulation of extracellular matrix (ECM). And hepatic stellate cells (HSCs) are the principal cell source of ECM. NR4A2 (Nurr1) is a member of orphan nuclear receptor NR4A family and acts as transcription factor. It participates in regulating cell differentiation, proliferation and apoptosis. We previously demonstrated that NR4A2 expression in fibrotic liver reduced significantly compared with normal liver and NR4A2 knockout in HSCs promoted ECM production...
2016: Scientific Reports
Arnaldo Parra-Damas, Meng Chen, Lilian Enriquez-Barreto, Laura Ortega, Sara Acosta, Judith Camats Perna, M Neus Fullana, José Aguilera, José Rodríguez-Alvarez, Carlos A Saura
BACKGROUND: Associative memory impairment is an early clinical feature of dementia patients, but the molecular and cellular mechanisms underlying these deficits are largely unknown. In this study, we investigated the functional regulation of the cyclic adenosine monophosphate response element binding protein (CREB)-regulated transcription coactivator 1 (CRTC1) by associative learning in physiological and neurodegenerative conditions. METHODS: We evaluated the activation of CRTC1 in the hippocampus of control mice and mice lacking the Alzheimer's disease-linked presenilin genes (presenilin conditional double knockout [PS cDKO]) after one-trial contextual fear conditioning by using biochemical, immunohistochemical, and gene expression analyses...
July 11, 2016: Biological Psychiatry
Yue Jiang, Ruiwei Jiang, Xi Cheng, Qun Zhang, Yali Hu, Hui Zhang, Yun Cao, Mei Zhang, Junxia Wang, Lijun Ding, Zhenyu Diao, Haixiang Sun, Guijun Yan
STUDY QUESTION: How do NR4A receptors drive decidualization of human endometrial stromal cells (hESCs)? SUMMARY ANSWER: NR4A receptors modulate endometrial decidualization by transcriptional activation of FOXO1A, and in adenomyosis patients, the reduced expression of NR4A receptors in the eutopic endometrium may represent a novel mechanism to explain impaired decidualization and subfertility. WHAT IS KNOWN ALREADY: A close relationship between impaired decidualization and subfertility has been established...
September 2016: Molecular Human Reproduction
Mohammad Jodeiri Farshbaf, Mahboobeh Forouzanfar, Kamran Ghaedi, Abbas Kiani-Esfahani, Maryam Peymani, Alireza Shoaraye Nejati, Tayebeh Izadi, Khadijeh Karbalaie, Maryam Noorbakhshnia, Soheila Rahgozar, Hossein Baharvand, Mohammad Hossein Nasr-Esfahani
Parkinson's disease (PD) can degenerate dopaminergic (DA) neurons in midbrain, substantia-nigra pars compacta. Alleviation of its symptoms and protection of normal neurons against degeneration are the main aspects of researches to establish novel therapeutic strategies. PPARγ as a member of PPARs have shown neuroprotection in a number of neurodegenerative disorders such as Alzheimer's disease and PD. Nuclear receptor related 1 protein (Nurr1) is, respectively, member of NR4A family and has received great attentions as potential target for development, maintenance, and survival of DA neurons...
September 2016: Molecular and Cellular Biochemistry
Merrick S Reynolds, Chad R Hancock, Jason D Ray, Kyle B Kener, Carrie Draney, Kevin Garland, Jeremy Hardman, Benjamin T Bikman, Jeffery S Tessem
β-Cell insulin secretion is dependent on proper mitochondrial function. Various studies have clearly shown that the Nr4a family of orphan nuclear receptors is essential for fuel utilization and mitochondrial function in liver, muscle, and adipose. Previously, we have demonstrated that overexpression of Nr4a1 or Nr4a3 is sufficient to induce proliferation of pancreatic β-cells. In this study, we examined whether Nr4a expression impacts pancreatic β-cell mitochondrial function. Here, we show that β-cell mitochondrial respiration is dependent on the nuclear receptors Nr4a1 and Nr4a3...
July 1, 2016: American Journal of Physiology. Endocrinology and Metabolism
R Grace Walton, Xiaolin Zhu, Ling Tian, Elizabeth B Heywood, Jian Liu, Helliner S Hill, Jiarong Liu, Dennis Bruemmer, Qinglin Yang, Yuchang Fu, W Timothy Garvey
The NR4A orphan nuclear receptors function as early response genes to numerous stimuli. Our laboratory has previously demonstrated that overexpression of NR4A3 (NOR-1, MINOR) in 3T3-L1 adipocytes enhances insulin-stimulated glucose uptake. To assess the in vivo effect of NR4A3 on adipocytes, we generated transgenic mice with NR4A3 overexpression driven by the adipocyte fatty acid-binding protein (AP2) promoter (AP2-NR4A3 mice). We hypothesized that AP2-NR4A3 mice would display enhanced glucose tolerance and insulin sensitivity...
July 1, 2016: American Journal of Physiology. Endocrinology and Metabolism
Francesca Montarolo, Simona Perga, Serena Martire, Désirée Nicole Navone, Alberto Marchet, Daniela Leotta, Antonio Bertolotto
Parkinson's disease (PD) is a neurodegenerative pathology characterized by the degeneration of midbrain dopamine neurons, whose development and maintenance in brain is related to the transcription factor NR4A2 (also called Nurr1). Notably, NR4A2 is a neuroprotective agent with anti-inflammatory role in microglia and astrocytes. Furthermore, mutations in NR4A2 gene are associated to the familial form of PD, and its gene expression level is down-regulated in blood obtained from PD patients. NR4A2 belongs to the NR4A subfamily consisting of three members: NR4A1, NR4A2, and NR4A3...
October 2016: Neurotoxicity Research
Ian Mitchelle S de Vera, Pankaj K Giri, Paola Munoz-Tello, Richard Brust, Jakob Fuhrmann, Edna Matta-Camacho, Jinsai Shang, Sean Campbell, Henry D Wilson, Juan Granados, William J Gardner, Trevor P Creamer, Laura A Solt, Douglas J Kojetin
Nurr1/NR4A2 is an orphan nuclear receptor, and currently there are no known natural ligands that bind Nurr1. A recent metabolomics study identified unsaturated fatty acids, including arachidonic acid and docosahexaenoic acid (DHA), that interact with the ligand-binding domain (LBD) of a related orphan receptor, Nur77/NR4A1. However, the binding location and whether these ligands bind other NR4A receptors were not defined. Here, we show that unsaturated fatty acids also interact with the Nurr1 LBD, and solution NMR spectroscopy reveals the binding epitope of DHA at its putative ligand-binding pocket...
July 15, 2016: ACS Chemical Biology
Takashi Sekiya, Hiroko Nakatsukasa, Qianjin Lu, Akihiko Yoshimura
Regulatory T (Treg) cells are an essential cell subset for the maintenance of immune homeostasis. Treg cells are characterized by a distinct pattern of gene expression, including the upregulation of immune-suppressive genes and the silencing of inflammatory genes. The molecular mechanisms involved in the development and maintenance of Tregs have been extensively investigated. We have identified essential transcription factors NR4a and Smad2/3 in the development of thymic Tregs and induced Tregs, respectively...
June 2016: Microbes and Infection
Evan Delgado, Michelle M Boisen, Robin Laskey, Rui Chen, Chi Song, Jad Sallit, Zachary A Yochum, Courtney L Andersen, Matthew J Sikora, Jacob Wagner, Stephen Safe, Esther Elishaev, Adrian Lee, Robert P Edwards, Paul Haluska, George Tseng, Mark Schurdak, Steffi Oesterreich
OBJECTIVE: Nuclear receptors (NRs) play a vital role in the development and progression of several cancers including breast and prostate. Using TCGA data, we sought to identify critical nuclear receptors in high grade serous ovarian cancers (HGSOC) and to confirm these findings using in vitro approaches. METHODS: In silico analysis of TCGA data was performed to identify relevant NRs in HGSOC. Ovarian cancer cell lines were screened for NR expression and functional studies were performed to determine the significance of these NRs in ovarian cancers...
May 2016: Gynecologic Oncology
Ryan P Duren, Seth P Boudreaux, Orla M Conneely
Members of the NR4A subfamily of orphan nuclear receptors regulate cell fate decisions via both genomic and non-genomic mechanisms in a cell and tissue selective manner. NR4As play a key role in maintenance of hematopoietic stem cell homeostasis and are critical tumor suppressors of acute myeloid leukemia (AML). Expression of NR4As is broadly silenced in leukemia initiating cell enriched populations from human patients relative to normal hematopoietic stem/progenitor cells. Rescue of NR4A expression in human AML cells inhibits proliferation and reprograms AML gene signatures via transcriptional mechanisms that remain to be elucidated...
2016: PloS One
Xiu-Ming Li, Shen Zhang, Xiao-Shun He, Peng-Da Guo, Xing-Xing Lu, Jing-Ru Wang, Jian-Ming Li, Hua Wu
BACKGROUND: Nur77, a key member of the NR4A receptor subfamily, is involved in the regulation of inflammation and immunity. However, the in vivo regulatory roles of Nur77 in sepsis and the mechanisms involved remains largely elusive. In this study, we used Nur77-deficient (Nur77(-/-)) mice and investigated the function of Nur77 in sepsis. FINDINGS: Compared to wild-type (Nur77(+/+)) mice, Nur77(-/-) mice are more susceptible to LPS-induced sepsis and acute liver inflammation...
2016: Journal of Inflammation
Pengguo Chen, Jie Li, Yan Huo, Jin Lu, Lili Wan, Bin Li, Run Gan, Cheng Guo
Hepatic stellate cells (HSCs) play a crucial role in liver fibrosis, which is a pathological process characterized by extracellular matrix accumulation. NR4A2 is a nuclear receptor belonging to the NR4A subfamily and vital in regulating cell growth, metabolism, inflammation and other biological functions. However, its role in HSCs is unclear. We analyzed NR4A2 expression in fibrotic liver and stimulated HSCs compared with control group and studied the influence on cell proliferation, cell cycle, cell apoptosis and MAPK pathway after NR4A2 knockdown...
2015: PeerJ
Pierre Leblanc, Minho Moon, Woori Kim, Inhye Jeong, Chun-Hyung Kim, Kwang-Soo Kim
The nuclear receptor subfamily 4 (NR4A) is composed of 3 related proteins sharing a DNA binding domain (DBD) and a ligand-binding domain (LBD). The nuclear receptor related 1 protein (Nurr1 or NR4A2) plays a key role in the maintenance of the dopaminergic system. Dopamine dysfunctions associated with the Nurr1 gene include Parkinson's disease, schizophrenia and manic depression among others. Furthermore, recent evidence indicates that Nurr1 is also expressed in other brain areas such as the hippocampus and plays critical roles for learning and memory...
2015: Journal of Visualized Experiments: JoVE
Takashi Sekiya, Taisuke Kondo, Takashi Shichita, Rimpei Morita, Hiroshi Ichinose, Akihiko Yoshimura
Regulatory T (T reg) cells are central mediators of immune suppression. As such, T reg cells are characterized by a distinct pattern of gene expression, which includes up-regulation of immunosuppressive genes and silencing of inflammatory cytokine genes. Although an increasing number of transcription factors that regulate T reg cells have been identified, the mechanisms by which the T reg cell-specific transcriptional program is maintained and executed remain largely unknown. The Nr4a family of nuclear orphan receptors, which we recently identified as essential for the development of T reg cells, is highly expressed in mature T reg cells as well, suggesting that Nr4a factors play important roles even beyond T reg cell development...
September 21, 2015: Journal of Experimental Medicine
Daniel Crean, Eoin P Cummins, Bojlul Bahar, Helen Mohan, Jason P McMorrow, Evelyn P Murphy
Adenosine receptor-mediated regulation of monocyte/macrophage inflammatory responses is critical in the maintenance of tissue homeostasis. In this study, we reveal that adenosine potently modulates the expression of NR4A1, 2, and 3 orphan nuclear receptors in myeloid cells, and this modulation is primarily through the adenosine A2a receptor subtype. We demonstrate that A2a receptor activation of NR4A1-3 receptor synthesis is further enhanced in TLR4-stimulated monocytes. After TLR4 stimulation, NR4A receptor-depleted monocyte/macrophage cells display significantly altered expression of cell-surface markers and produce increased inflammatory cytokine and chemokine secretion rendering the cells an enhanced proinflammatory phenotype...
August 15, 2015: Journal of Immunology: Official Journal of the American Association of Immunologists
Evelyn P Murphy, Daniel Crean
Appropriate innate and adaptive immune responses are essential for protection and resolution against chemical, physical or biological insults. Immune cell polarization is fundamental in orchestrating distinct phases of inflammation, specifically acute phase responses followed by resolution and tissue repair. Dysregulation of immune cell and inflammatory responses is a hallmark of multiple diseases encompassing atherosclerosis, rheumatoid arthritis, psoriasis and metabolic syndromes. A master transcriptional mediator of diverse inflammatory signaling and immune cell function is NF-κB, and altered control of this key regulator can lead to an effective switch from acute to chronic inflammatory responses...
2015: Biomolecules
Weidong Zhang, Xudong Zhu, Yang Liu, Minhao Chen, Shixian Yan, Xingxing Mao, Zhongbing Liu, Weijie Wu, Chen Chen, Xinbao Xu, Youhua Wang
Nur77, together with Nurr1 and NOR-1, constitutes the NR4A subgroup of orphan nuclear receptors and plays critical roles in cell proliferation, differentiation, migration, and apoptosis. Among them, Nur77 is universally well known to contribute to neurite outgrowth. However, information regarding its regulation and possible function in the peripheral nervous system is still limited. In this study, we performed a sciatic nerve injury model in adult rats and detected an increased expression of Nur77 in the sciatic nerve, which was similar to the expression of Oct-6...
September 2015: Journal of Molecular Neuroscience: MN
F De Paoli, J Eeckhoute, C Copin, J Vanhoutte, C Duhem, B Derudas, J Dubois-Chevalier, S Colin, C Zawadzki, B Jude, S Haulon, P Lefebvre, B Staels, G Chinetti-Gbaguidi
BACKGROUND: Atherosclerosis is an inflammatory disease in which macrophages play a crucial role. Macrophages are present in different phenotypes, with at the extremes of the spectrum the classical M1 pro-inflammatory and the alternative M2 anti-inflammatory macrophages. The neuron-derived orphan receptor 1 (NOR1), together with Nur77 and Nurr1, are members of the NR4A orphan nuclear receptor family, expressed in human atherosclerotic lesion macrophages. However, the role of NOR1 in human macrophages has not been studied yet...
July 2015: Atherosclerosis
Stephen Safe, Un-Ho Jin, Benjamin Morpurgo, Ala Abudayyeh, Mandip Singh, Ronald B Tjalkens
The orphan nuclear receptors NR4A1, NR4A2 and NR4A3 are immediate early genes induced by multiple stressors, and the NR4A receptors play an important role in maintaining cellular homeostasis and disease. There is increasing evidence for the role of these receptors in metabolic, cardiovascular and neurological functions and also in inflammation and inflammatory diseases and in immune functions and cancer. Despite the similarities of NR4A1, NR4A2 and NR4A3 and their interactions with common cis-genomic elements, they exhibit unique activities and cell-/tissue-specific functions...
March 2016: Journal of Steroid Biochemistry and Molecular Biology
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