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https://www.readbyqxmd.com/read/27889530/identification-of-proximal-biomarkers-of-pkc-agonism-and-evaluation-of-their-role-in-hiv-reactivation
#1
Sai Vikram Vemula, Jill W Maxwell, Alexey Nefedov, Bang-Lin Wan, Justin Steve, William Newhard, Rosa I Sanchez, David Tellers, Richard J Barnard, Wade Blair, Daria Hazuda, Andrea L Webber, Bonnie J Howell
DESIGN: The HIV latent CD4(+) T cell reservoir is broadly recognized as a barrier to HIV cure. Induction of HIV expression using protein kinase C (PKC) agonists is one approach under investigation for reactivation of latently infected CD4(+) T cells (Beans et al., 2013; Abreu et al., 2014; Jiang et al., 2014; Jiang and Dandekar, 2015). We proposed that an increased understanding of the molecular mechanisms of action of PKC agonists was necessary to inform on biological signaling and pharmacodynamic biomarkers...
November 23, 2016: Antiviral Research
https://www.readbyqxmd.com/read/27876882/nr4a1-knockdown-suppresses-seizure-activity-by-regulating-surface-expression-of-nr2b
#2
Yanke Zhang, Guojun Chen, Baobing Gao, Yunlin Li, Shuli Liang, Xiaofei Wang, Xuefeng Wang, Binglin Zhu
Nuclear receptor subfamily 4 group A member 1 (NR4A1), a downstream target of CREB that is a key regulator of epileptogenesis, has been implicated in a variety of biological processes and was previously identified as a seizure-associated molecule. However, the relationship between NR4A1 and epileptogenesis remains unclear. Here, we showed that NR4A1 protein was predominantly expressed in neurons and up-regulated in patients with epilepsy as well as pilocarpine-induced mouse epileptic models. NR4A1 knockdown by lentivirus transfection (lenti-shNR4A1) alleviated seizure severity and prolonged onset latency in mouse models...
November 23, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27873103/differential-regulation-of-angiogenic-cellular-processes-and-claudin-5-by-histamine-and-vegf-via-pi3k-signaling-transcription-factor-snai2-and-interleukin-8
#3
Johanna P Laakkonen, Jari P Lappalainen, Thomas L Theelen, Pyry I Toivanen, Tiina Nieminen, Suvi Jauhiainen, Minna U Kaikkonen, Judith C Sluimer, Seppo Ylä-Herttuala
AIMS: Histamine and vascular endothelial growth factor A (VEGF) are central regulators in vascular pathologies. Their gene regulation leading to vascular remodeling has remained obscure. In this study, EC regulation mechanisms of histamine and VEGF were compared by RNA sequencing of primary endothelial cells (ECs), functional in vitro assays and in vivo permeability mice model. METHODS AND RESULTS: By RNA sequencing, similar transcriptional alterations of genes involved in activation of primary ECs, cell proliferation and adhesion were observed between histamine and VEGF...
November 21, 2016: Angiogenesis
https://www.readbyqxmd.com/read/27864345/pax3-foxo1a-expression-in-rhabdomyosarcoma-is-driven-by-the-targetable-nuclear-receptor-nr4a1
#4
Alexandra Lacey, Aline Rodrigues Hoffman, Stephen Safe
Alveolar rhabdomyosarcoma (ARMS) is a devastating pediatric disease driven by expression of the oncogenic fusion gene PAX3-FOXO1A. In this study, we report overexpression of the nuclear receptor NR4A1 is rhabdomyosarcomas which is sufficient to drive high expression of PAX3-FOXO1A there. RNAi-mediated silencing of NR4A1 decreased expression of PAX3-FOXO1A and its downstream effector genes. Similarly, cell treatment with the NR4A1 small molecule antagonists 1,1-bis(3-indolyl)-1-(p-hydroxy or p-carbomethoxyphenyl)methane (C-DIM) decreased PAX3-FOXO1A...
November 18, 2016: Cancer Research
https://www.readbyqxmd.com/read/27856455/map3k8-modulates-monocyte-state-and-atherogenesis-in-apoe-mice
#5
Carlos Sanz-Garcia, Ángela Sánchez, Constanza Contreras-Jurado, Carmela Cales, Cristina Barranquero, Marta Muñóz, Ramón Merino, Paula Escudero, Maria-Jesús Sanz, Jesús Osada, Ana Aranda, Susana Alemany
OBJECTIVE: Map3k8 (Cot/Tpl2) activates the MKK1/2-ERK1/2, MAPK pathway downstream from interleukin-1R, tumor necrosis factor-αR, NOD-2R, adiponectinR, and Toll-like receptors. Map3k8 plays a key role in innate and adaptive immunity and influences inflammatory processes by modulating the functions of different cell types. However, its role in atherogenesis remains unknown. In this study, we analyzed the role of this kinase in this pathology. APPROACH AND RESULTS: We show here that Map3k8 deficiency results in smaller numbers of Ly6C(high)CD11c(low) and Ly6C(low)CD11c(high) monocytes in ApoE(-)(/-) mice fed a high-fat diet (HFD)...
November 17, 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/27814941/deleting-an-nr4a1-super-enhancer-subdomain-ablates-ly6c-low-monocytes-while-preserving-macrophage-gene-function
#6
Graham D Thomas, Richard N Hanna, Neelakatan T Vasudevan, Anouk A Hamers, Casey E Romanoski, Sara McArdle, Kevin D Ross, Amy Blatchley, Deborah Yoakum, Bruce A Hamilton, Zbigniew Mikulski, Mukesh K Jain, Christopher K Glass, Catherine C Hedrick
Mononuclear phagocytes are a heterogeneous family that occupy all tissues and assume numerous roles to support tissue function and systemic homeostasis. Our ability to dissect the roles of individual subsets is limited by a lack of technologies that ablate gene function within specific mononuclear phagocyte sub-populations. Using Nr4a1-dependent Ly6C(low) monocytes, we present a proof-of-principle approach that addresses these limitations. Combining ChIP-seq and molecular approaches we identified a single, conserved, sub-domain within the Nr4a1 enhancer that was essential for Ly6C(low) monocyte development...
November 15, 2016: Immunity
https://www.readbyqxmd.com/read/27814740/spatio-temporal-profile-phenotypic-diversity-and-fate-of-recruited-monocytes-into-the-post-ischemic-brain
#7
Lidia Garcia-Bonilla, Giuseppe Faraco, Jamie Moore, Michelle Murphy, Gianfranco Racchumi, Jayashree Srinivasan, David Brea, Costantino Iadecola, Josef Anrather
BACKGROUND: A key feature of the inflammatory response after cerebral ischemia is the brain infiltration of blood monocytes. There are two main monocyte subsets in the mouse blood: CCR2(+)Ly6C(hi) "inflammatory" monocytes involved in acute inflammation, and CX3CR1(+)Ly6C(lo) "patrolling" monocytes, which may play a role in repair processes. We hypothesized that CCR2(+)Ly6C(hi) inflammatory monocytes are recruited in the early phase after ischemia and transdifferentiate into CX3CR1(+)Ly6C(lo) "repair" macrophages in the brain...
November 4, 2016: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/27811009/penfluridol-represses-integrin-expression-in-breast-cancer-through-induction-of-reactive-oxygen-species-and-downregulation-of-sp-transcription-factors
#8
Erik Hedrick, Xi Li, Stephen Safe
It was recently demonstrated the penfluridol inhibited breast tumor growth and metastasis and this was associated with downregulation of α6- and β4-integrins. In this study, we observed the penfluridol induced reactive oxygen species (ROS) and this was the primary mechanism of action. Penfluridol-mediated growth inhibition, induction of apoptosis, and inhibition breast cancer cell migration was attenuated after cotreatment with glutathione (GSH). Penfluridol also downregulated Sp transcription factors Sp1, Sp3 and Sp4 through epigenetic downregulation of cMyc and cMyc-regulated microRNAs (miR-27a and miR-20a/miR-17) and induction of the miR-regulated Sp transcriptional repressors ZBTB10 and ZBTB4...
November 3, 2016: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/27807832/transcriptome-and-proteome-analyses-of-tnfaip8-knockdown-cancer-cells-reveal-new-insights-into-molecular-determinants-of-cell-survival-and-tumor-progression
#9
Timothy F Day, Rajshree R Mewani, Joshua Starr, Xin Li, Debyani Chakravarty, Habtom Ressom, Xiaojun Zou, Ofer Eidelman, Harvey B Pollard, Meera Srivastava, Usha N Kasid
Tumor necrosis factor-α-inducible protein 8 (TNFAIP8) is the first discovered oncogenic and an anti-apoptotic member of a conserved TNFAIP8 or TIPE family of proteins. TNFAIP8 mRNA is induced by NF-kB, and overexpression of TNFAIP8 has been correlated with poor prognosis in many cancers. Downregulation of TNFAIP8 expression has been associated with decreased pulmonary colonization of human tumor cells, and enhanced sensitivities of tumor xenografts to radiation and docetaxel. Here we have investigated the effects of depletion of TNFAIP8 on the mRNA, microRNA and protein expression profiles in prostate and breast cancers and melanoma...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27778276/transcriptional-modulation-of-regulatory-t-cell-development-by-novel-regulators-nr4as
#10
Hee Yeon Won, Eun Sook Hwang
Regulatory T (Treg) cells with high expression of both CD25 and Foxp3 are developed in the thymus and also peripheral tissues. Treg cells suppress the activation and functions of effector T cells raised against specific antigens and are crucial for maintaining immune homeostasis. Treg cell development is associated with the induction of and epigenetic alterations of forkhead transcription factor Foxp3. Foxp3 expression is increased by the activation of several transcription factors including nuclear factor-kappa B (NF-κB), nuclear factor of activated T cells (NFAT), and Smad3 in response to various signals such as TGFβ, retinoic acid, and rapamycin...
October 25, 2016: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/27670690/dna-methylation-is-not-involved-in-specific-down-regulation-of-hsd3b2-nr4a1-and-rarb-genes-in-androgen-secreting-cells-of-human-adrenal-cortex
#11
María Sonia Baquedano, Natalia Perez Garrido, Javier Goñi, Nora Saraco, Paula Aliberti, Esperanza Berensztein, Marco A Rivarola, Alicia Belgorosky
We hypothesized that DNA methylation is involved in human adrenal functional zonation. mRNAs expression and methylation pattern of RARB, NR4A1 and HSD3B2 genes in human adrenal tissues (HAT) and in pediatric virilizing adrenocortical tumors (VAT) were analyzed. For analysis of the results samples were divided into 3 age groups according to FeZ involution, pre and post-adrenarche ages. In all HAT, similar RARB mRNA was found including microdissected zona reticularis (ZR) and zona fasciculata, but HSD3B2 and NR4A1 mRNAs were lower in ZR (p < 0...
September 23, 2016: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/27644246/%C3%AE-aminobutyric-acid-inhibits-the-proliferation-and-increases-oxaliplatin-sensitivity-in-human-colon-cancer-cells
#12
Lihua Song, Aiying Du, Ying Xiong, Jing Jiang, Yao Zhang, Zhaofeng Tian, Hongli Yan
γ-Aminobutyric acid (GABA) is a natural non-protein amino acid, which broadly exists in many plant parts and is widely used as an ingredient in the food industry. In mammals, it is widely distributed in central nervous system and non-neural tissues. In addition to a primary inhibitory neurotransmitter in the central nervous system, endogenous GABA content has been found to be elevated in neoplastic tissues in colon cancer. However, the effect of extraneous GABA on colon cancer has rarely been reported. In this study, we found the inhibitory effects of GABA on the proliferation of colon cancer cells (CCCs)...
September 19, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/27617863/abc-transporters-and-nr4a1-identify-a-quiescent-subset-of-tissue-resident-memory-t-cells
#13
Chandra Sekhar Boddupalli, Shiny Nair, Simon M Gray, Heba N Nowyhed, Rakesh Verma, Joanna A Gibson, Clara Abraham, Deepak Narayan, Juan Vasquez, Catherine C Hedrick, Richard A Flavell, Kavita M Dhodapkar, Susan M Kaech, Madhav V Dhodapkar
Immune surveillance in tissues is mediated by a long-lived subset of tissue-resident memory T cells (Trm cells). A putative subset of tissue-resident long-lived stem cells is characterized by the ability to efflux Hoechst dyes and is referred to as side population (SP) cells. Here, we have characterized a subset of SP T cells (Tsp cells) that exhibit a quiescent (G0) phenotype in humans and mice. Human Trm cells in the gut and BM were enriched in Tsp cells that were predominantly in the G0 stage of the cell cycle...
October 3, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27600773/nr4a1-dependent-ly6c-low-monocytes-contribute-to-reducing-joint-inflammation-in-arthritic-mice-through-treg-cells
#14
Alexandre Brunet, Manon LeBel, Benoit Egarnes, Carine Paquet-Bouchard, Anne-Julie Lessard, Jacques P Brown, Jean Gosselin
Monocytes are central to the physiopathology of arthritis, but their roles in progression and resolution of the disease remain to be clarified. Using NR4A1(-/-) mice, which lack patrolling lymphocyte antigen 6C (Ly6C(low) ) monocytes, we found that inflammatory Ly6C(high) monocytes contribute to rapid development of arthritis in a serum transfer-induced arthritis (STIA) model. Our experiments suggest that patrolling monocytes do not promote the initiation and progression of arthritis in mice, as severity of symptoms was amplified in NR4A1(-/-) mice...
September 7, 2016: European Journal of Immunology
https://www.readbyqxmd.com/read/27587263/crtc1-function-during-memory-encoding-is-disrupted-in-neurodegeneration
#15
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
https://www.readbyqxmd.com/read/27517611/cognition-and-synaptic-plasticity-related-changes-in-aged-rats-supplemented-with-8-and-10-carbon-medium-chain-triglycerides
#16
Dongmei Wang, Ellen S Mitchell
Brain glucose hypometabolism is a common feature of Alzheimer's disease (AD). Previous studies have shown that cognition is improved by providing AD patients with an alternate energy source: ketones derived from either ketogenic diet or supplementation with medium chain triglycerides (MCT). Recently, data on the neuroprotective capacity of MCT-derived medium chain fatty acids (MCFA) suggest 8-carbon and 10-carbon MCFA may have cognition-enhancing properties which are not related to ketone production. We investigated the effect of 8 week treatment with MCT8, MCT10 or sunflower oil supplementation (5% by weight of chow diet) in 21 month old Wistar rats...
2016: PloS One
https://www.readbyqxmd.com/read/27515096/decreased-expression-of-nr4a-nuclear-receptors-in-adenomyosis-impairs-endometrial-decidualization
#17
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
https://www.readbyqxmd.com/read/27430727/the-autism-related-gene-snrpn-regulates-cortical-and-spine-development-via-controlling-nuclear-receptor-nr4a1
#18
Huiping Li, Pingping Zhao, Qiong Xu, Shifang Shan, Chunchun Hu, Zilong Qiu, Xiu Xu
The small nuclear ribonucleoprotein polypeptide N (SNRPN) gene, encoding the RNA-associated SmN protein, duplications or deletions of which are strongly associated with neurodevelopmental disabilities. SNRPN-coding protein is highly expressed in the brain. However, the role of SNRPN protein in neural development remains largely unknown. Here we showed that the expression of SNRPN increased markedly during postnatal brain development. Overexpression or knockdown of SNRPN in cortical neurons impaired neurite outgrowth, neuron migration, and the distribution of dendritic spines...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27322146/inhibition-of-dna-methyltransferase-1-increases-nuclear-receptor-subfamily-4-group-a-member-1-expression-and-decreases-blood-glucose-in-type-2-diabetes
#19
Yng-Tay Chen, Jiunn-Wang Liao, Ya-Ching Tsai, Fuu-Jen Tsai
Our previous genome-wide association studies showed that DNA methyltransferase 1 (DNMT1) is associated with increased susceptibility to type 2 diabetes (T2D) in Han Chinese individuals. Here, we aimed to further evaluate the role of DNMT1 in T2D. We performed a genome-wide DNA methylation array and found that the nuclear receptor subfamily 4 group A member 1 (NR4A1) promoter was hypermethylated in patients with T2D and in a mouse model of T2D. Moreover, DNA hypermethylation of the NR4A1 promoter reduced NR4A1 mRNA expression...
June 14, 2016: Oncotarget
https://www.readbyqxmd.com/read/27221116/%C3%AE-cell-deletion-of-nr4a1-and-nr4a3-nuclear-receptors-impedes-mitochondrial-respiration-and-insulin-secretion
#20
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
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